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Boicean A, Ichim C, Sasu SM, Todor SB. Key Insights into Gut Alterations in Metabolic Syndrome. J Clin Med 2025; 14:2678. [PMID: 40283508 PMCID: PMC12028006 DOI: 10.3390/jcm14082678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2025] [Revised: 04/08/2025] [Accepted: 04/11/2025] [Indexed: 04/29/2025] Open
Abstract
Over time, extensive research has underscored the pivotal role of gut microbiota in the onset and progression of various diseases, with a particular focus on fecal microbiota transplantation (FMT) as a potential therapeutic approach. The practice of transferring fecal matter from a healthy donor to a patient provides valuable insights into how alterations in gut microbiota can impact disease development and how rectifying dysbiosis may offer therapeutic benefits. Re-establishing a balanced symbiotic relationship in the gastrointestinal tract has shown positive results in managing both intestinal and systemic conditions. Currently, one of the most pressing global health issues is metabolic syndrome-a cluster of conditions that includes insulin resistance, lipid imbalances, central obesity and hypertension. In this context, FMT has emerged as a promising strategy for addressing key components of metabolic syndrome, such as improving insulin sensitivity, body weight and lipid profiles. However, further well-structured studies are needed to refine treatment protocols and establish the long-term safety and efficacy of this intervention.
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Affiliation(s)
| | - Cristian Ichim
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania; (A.B.); (S.B.T.)
| | - Sabina-Maria Sasu
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania; (A.B.); (S.B.T.)
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2
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Wychowaniec JK, Bektas EI, Vernengo AJ, Muerner M, Airoldi M, Tipay PS, Sapudom J, Teo J, Eglin D, D'Este M. Effect of molecular weight of tyramine-modified hyaluronan on polarization state of THP-1 and peripheral blood mononuclear cells-derived macrophages. BIOMATERIALS ADVANCES 2025; 169:214166. [PMID: 39823943 DOI: 10.1016/j.bioadv.2024.214166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 10/31/2024] [Accepted: 12/27/2024] [Indexed: 01/20/2025]
Abstract
The immunomodulatory properties of hyaluronan and its derivatives are key to their use in medicine and tissue engineering. In this work we evaluated the capability of soluble tyramine-modified hyaluronan (THA) synthesized from hyaluronan of two molecular weights (low Mw = 280 kDa and high Mw = 1640 kDa) for polarization of THP-1 and peripheral blood mononuclear cells (PBMCs)-derived macrophages (MΦs). We demonstrate the polarization effects of the supplemented THA by flow cytometry and bead-based multiplex immunoassay for the THP-1 derived MΦs and by semi-automated image analysis from confocal microscopy, immunofluorescent staining utilizing CD68 and CD206 surface markers, RT-qPCR gene expression analysis, as well as using the enzyme-linked immunosorbent assay (ELISA) for PBMCs-derived MΦs. Our data indicate that supplementation with LMW THA drives changes in THP-1 derived MΦs towards a pro-inflammatory M1-like phenotype, whereas supplementation with the HMW THA leads to a more mixed profile with some features of both M1 and M2 phenotypes, suggesting either a heterogeneous population or a transitional state. For cells directly sourced from human patients, PMBCs-derived MΦs, results exhibit a higher degree of variability, pointing out a differential regulation of factors including IL-10 and CD206 between the two cell sources. While human primary cells add to the clinical relevance, donor diversity introduces wider variability in the dataset, preventing drawing strong conclusions. Nevertheless, the MΦs profiles observed in THP-1 derived cells for treatments with LMW and HMW THA are generally consistent with what might be expected for the treatment with non-modified hyaluronans of respective molecular weights, confirming the known association holds true for the chemically tyramine-modified hyaluronan. We stipulate that these responses will provide basis for more accurate in vivo representation and translational immunomodulatory guidance for the use of THA-based biomaterials to a wider biomaterials and tissue engineering communities.
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Affiliation(s)
| | - Ezgi Irem Bektas
- AO Research Institute Davos, Clavadelerstrasse 8, Davos 7270, Switzerland
| | - Andrea J Vernengo
- AO Research Institute Davos, Clavadelerstrasse 8, Davos 7270, Switzerland
| | - Marcia Muerner
- AO Research Institute Davos, Clavadelerstrasse 8, Davos 7270, Switzerland; ETH Zürich, Rämistrasse 101, Zürich 8092, Switzerland
| | - Marielle Airoldi
- AO Research Institute Davos, Clavadelerstrasse 8, Davos 7270, Switzerland
| | | | - Jiranuwat Sapudom
- Laboratory for Immuno Bioengineering Research and Applications, Division of Engineering, New York University Abu Dhabi, Abu Dhabi 129188, United Arab Emirates
| | - Jeremy Teo
- Laboratory for Immuno Bioengineering Research and Applications, Division of Engineering, New York University Abu Dhabi, Abu Dhabi 129188, United Arab Emirates
| | - David Eglin
- Mines Saint-Étienne, Univ Jean Monnet, INSERM, U1059 Sainbiose, Saint-Étienne, France
| | - Matteo D'Este
- AO Research Institute Davos, Clavadelerstrasse 8, Davos 7270, Switzerland
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3
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Soma GI, Oda M, Tjhin VT, Kohchi C, Inagawa H. Oral and transdermal administration of lipopolysaccharide safely enhances self-healing ability through the macrophage network. Front Immunol 2025; 16:1563484. [PMID: 40230835 PMCID: PMC11994614 DOI: 10.3389/fimmu.2025.1563484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Accepted: 03/13/2025] [Indexed: 04/16/2025] Open
Abstract
Lipopolysaccharide (LPS), also known as an endotoxin, is derived from Gram-negative bacteria. The intravenous administration of LPS induces an inflammatory response and causes systemic inflammation, such as cytokine storm. Gram-negative bacteria that produce LPS are found in the environment and digestive tract. The mucous membrane, the primary barrier between the interior of the body and the external environment, is constantly exposed to LPS. Moreover, no toxicity is observed when administering LPS through the mucous membranes of the mouth or skin. The presence of LPS in the mucous membranes is necessary not only for maintaining health but also for inducing preventive and therapeutic effects against multiple diseases when administered orally or topically. LPS is an environmental substance that is useful when administered to mucous membranes. The general information emphasizes the role of LPS as an inflammatory substance that occurs when administered intravenously. Therefore, the valuable role of LPS is unknown. Thus, mucosal administration of LPS has received little attention, and the mechanism underlying the expression of its beneficial effects has not been fully elucidated. We proposed a comprehensive concept, the "macrophage network," which proposes a regulatory system in which the mucosa receives environmental information, membrane-bound cytokines are expressed in phagocytes (macrophages), and these macrophages migrate distally to exert effects, such as anti-inflammatory and tissue repair effects, on distal tissues through cell-to-cell communication (juxtacrine signaling) with tissue macrophages. This macrophage network is effective not only for preventing and treating diseases but also for increasing the efficacy of pharmaceuticals. This review aims to investigate the preventive and therapeutic effects of oral and transdermal administration of LPS on various diseases and present an introduction to the concept of the macrophage network and the latest findings.
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Affiliation(s)
- Gen-Ichiro Soma
- Control of Innate Immunity, Technology Research Association, Takamatsu, Kagawa, Japan
- Research Institute for Healthy Living, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan
| | - Masataka Oda
- Control of Innate Immunity, Technology Research Association, Takamatsu, Kagawa, Japan
| | - Vindy Tjendana Tjhin
- Control of Innate Immunity, Technology Research Association, Takamatsu, Kagawa, Japan
| | - Chie Kohchi
- Control of Innate Immunity, Technology Research Association, Takamatsu, Kagawa, Japan
| | - Hiroyuki Inagawa
- Control of Innate Immunity, Technology Research Association, Takamatsu, Kagawa, Japan
- Research Institute for Healthy Living, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan
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4
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Gamal NK, El-Naga RN, Ayoub IM, George MY. Neuromodulatory effect of troxerutin against doxorubicin and cyclophosphamide-induced cognitive impairment in rats: Potential crosstalk between gut-brain and NLRP3 inflammasome axes. Int Immunopharmacol 2025; 149:114216. [PMID: 39919456 DOI: 10.1016/j.intimp.2025.114216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 08/29/2024] [Accepted: 01/31/2025] [Indexed: 02/09/2025]
Abstract
"Chemobrain" refers to the cognitive impairment induced by chemotherapy. The doxorubicin and cyclophosphamide cocktail has been used for various cancers, especially breast cancer. However, both have been linked to chemobrain as well as gastrointestinal toxicity. Despite being distinct organs, the gut and the brain have a bidirectional connection between them known as the gut-brain axis. This research aimed to study the neuroprotective effect of troxerutin, a rutin derivative, in chemobrain induced by doxorubicin and cyclophosphamide via a potential impact on the gut-inflammasome-brain axis. Troxerutin was administered at 75, 150, and 300 mg/kg doses. Furthermore, behavioral, histological, and acetylcholinesterase assessments were performed. Accordingly, the highest dose of troxerutin was selected to investigate the potential underlying mechanisms. Troxerutin treatment reversed the chemotherapy-fecal metabolite alterations. Additionally, troxerutin demonstrated positive effects against deterioration of intestinal integrity, permeability, and microbial endotoxins translocation, as evidenced by its effect on tight junction proteins; ZO-1, and claudin-1 expression, and lipopolysaccharide serum levels. Consequently, troxerutin hindered lipopolysaccharide-induced oxidative damage, systemic inflammation, and neuroinflammation. Moreover, troxerutin demonstrated antioxidant effects via its impact on lipid peroxidation, catalase levels, and the Nrf2/HO-1 pathway. Furthermore, chemotherapy-induced inflammation was opposed by troxerutin via downregulation of NLRP3, caspase-1, and the downstream cytokines; IL-18 and IL-1β. Importantly, troxerutin did not abrogate the anticancer activity of doxorubicin and cyclophosphamide in human MCF7 cells. Collectively, our study suggested the potentiality of troxerutin as a therapeutic choice against chemobrain by inhibiting the gut-inflammasome-brain axis and hindering acetylcholinesterase, oxidative stress, and neuroinflammation.
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Affiliation(s)
- Nada K Gamal
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University 11566 Cairo, Egypt
| | - Reem N El-Naga
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University 11566 Cairo, Egypt
| | - Iriny M Ayoub
- Department of Pharmacognosy, Faculty of Pharmacy, Ain Shams University, Cairo 11566 Egypt
| | - Mina Y George
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University 11566 Cairo, Egypt.
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Junyi L, Yueyang W, Bin L, Xiaohong D, Wenhui C, Ning Z, Hong Z. Gut Microbiota Mediates Neuroinflammation in Alzheimer's Disease: Unraveling Key Factors and Mechanistic Insights. Mol Neurobiol 2025; 62:3746-3763. [PMID: 39317889 DOI: 10.1007/s12035-024-04513-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Accepted: 09/18/2024] [Indexed: 09/26/2024]
Abstract
The gut microbiota, the complex community of microorganisms that inhabit the gastrointestinal tract, has emerged as a key player in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease (AD). AD is characterized by progressive cognitive decline and neuronal loss, associated with the accumulation of amyloid-β plaques, neurofibrillary tangles, and neuroinflammation in the brain. Increasing evidence suggests that alterations in the composition and function of the gut microbiota, known as dysbiosis, may contribute to the development and progression of AD by modulating neuroinflammation, a chronic and maladaptive immune response in the central nervous system. This review aims to comprehensively analyze the current role of the gut microbiota in regulating neuroinflammation and glial cell function in AD. Its objective is to deepen our understanding of the pathogenesis of AD and to discuss the potential advantages and challenges of using gut microbiota modulation as a novel approach for the diagnosis, treatment, and prevention of AD.
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Affiliation(s)
- Liang Junyi
- Heilongjiang University of Traditional Chinese Medicine, Harbin, 150040, Heilongjiang Province, China
| | - Wang Yueyang
- Heilongjiang University of Traditional Chinese Medicine, Harbin, 150040, Heilongjiang Province, China
| | - Liu Bin
- Heilongjiang University of Traditional Chinese Medicine, Harbin, 150040, Heilongjiang Province, China.
| | - Dong Xiaohong
- Jiamusi College, Heilongjiang University of Traditional Chinese Medicine, Jiamusi, Heilongjiang Province, China
| | - Cai Wenhui
- Heilongjiang University of Traditional Chinese Medicine, Harbin, 150040, Heilongjiang Province, China
| | - Zhang Ning
- Heilongjiang University of Traditional Chinese Medicine, Harbin, 150040, Heilongjiang Province, China
| | - Zhang Hong
- Heilongjiang Jiamusi Central Hospital, Jiamusi, Heilongjiang Province, China
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6
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Baishan A, Aikebaier A, Dilimulati D, Nueraihemaiti N, Paerhati Y, Hailati S, Maihemuti N, Zhou W. Bioinformatics Analysis of the Anti-Inflammatory Mechanism and Potential Therapeutic Efficacy of Kezimuke granules in Treating Urinary Tract Infections by Inhibiting NLRP3 Inflammasome Activation. Int J Mol Sci 2025; 26:1764. [PMID: 40004227 PMCID: PMC11854959 DOI: 10.3390/ijms26041764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Revised: 02/09/2025] [Accepted: 02/15/2025] [Indexed: 02/27/2025] Open
Abstract
Kezimuke granules (KZMK), derived from traditional Kazakh folk medicine, exhibit a variety of pharmacological properties. Long-term clinical studies have demonstrated their efficacy in clearing heat, detoxifying, promoting qi circulation, and alleviating gonorrhea. However, their specific pharmacological effects on urinary tract infections remain unclear. This study employed UHPLC-MS/MS technology to identify the blood components of KZMK and integrated network pharmacology with bioinformatics analysis for molecular docking validation. The anti-inflammatory activity of KZMK was further evaluated using a rat model of LPS-induced cystitis. A total of 17 components in KZMK were identified as capable of entering the bloodstream. Predictive analysis revealed that its primary targets include Caspase-1, NLRP3, STAT1, TLR4, and TNF, with the NLRP3 inflammasome signaling pathway emerging as the key mechanism. In vivo studies showed that KZMK effectively reduced the white blood cell (WBC) count and bladder index in urine sediments of rats with cystitis. Additionally, KZMK alleviated bladder congestion, edema, and histopathological changes in the animals. Treatment with KZMK led to decreased levels of IL-18 and IL-1β cytokines. KZMK significantly inhibited the expression of NLRP3, GSDMD, and Caspase-1 in LPS-induced cystitis, further confirming its anti-inflammatory effects. These findings indicate that KZMK provides protection against LPS-induced cystitis, primarily by inhibiting the activation of the NLRP3 inflammasome. Collectively, the results suggest that KZMK holds promise as a potential therapeutic option for urinary tract infections.
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Affiliation(s)
- Alhar Baishan
- Department of Pharmacology, School of Pharmacy, Xinjiang Medical University, Urumqi 830017, China; (A.B.); (A.A.); (D.D.); (N.N.); (Y.P.); (S.H.); (N.M.)
- Xinjiang Key Laboratory of Natural Medicines Active Components and Drug Release Technology, Urumqi 830017, China
- Xinjiang Key Laboratory of Biopharmaceuticals and Medical Devices, Urumqi 830017, China
- Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Ministry of Education, Urumqi 830017, China
| | - Alifeiye Aikebaier
- Department of Pharmacology, School of Pharmacy, Xinjiang Medical University, Urumqi 830017, China; (A.B.); (A.A.); (D.D.); (N.N.); (Y.P.); (S.H.); (N.M.)
- Xinjiang Key Laboratory of Natural Medicines Active Components and Drug Release Technology, Urumqi 830017, China
- Xinjiang Key Laboratory of Biopharmaceuticals and Medical Devices, Urumqi 830017, China
- Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Ministry of Education, Urumqi 830017, China
| | - Dilihuma Dilimulati
- Department of Pharmacology, School of Pharmacy, Xinjiang Medical University, Urumqi 830017, China; (A.B.); (A.A.); (D.D.); (N.N.); (Y.P.); (S.H.); (N.M.)
- Xinjiang Key Laboratory of Natural Medicines Active Components and Drug Release Technology, Urumqi 830017, China
- Xinjiang Key Laboratory of Biopharmaceuticals and Medical Devices, Urumqi 830017, China
- Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Ministry of Education, Urumqi 830017, China
| | - Nuerbiye Nueraihemaiti
- Department of Pharmacology, School of Pharmacy, Xinjiang Medical University, Urumqi 830017, China; (A.B.); (A.A.); (D.D.); (N.N.); (Y.P.); (S.H.); (N.M.)
- Xinjiang Key Laboratory of Natural Medicines Active Components and Drug Release Technology, Urumqi 830017, China
- Xinjiang Key Laboratory of Biopharmaceuticals and Medical Devices, Urumqi 830017, China
- Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Ministry of Education, Urumqi 830017, China
| | - Yipaerguli Paerhati
- Department of Pharmacology, School of Pharmacy, Xinjiang Medical University, Urumqi 830017, China; (A.B.); (A.A.); (D.D.); (N.N.); (Y.P.); (S.H.); (N.M.)
- Xinjiang Key Laboratory of Natural Medicines Active Components and Drug Release Technology, Urumqi 830017, China
- Xinjiang Key Laboratory of Biopharmaceuticals and Medical Devices, Urumqi 830017, China
- Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Ministry of Education, Urumqi 830017, China
| | - Sendaer Hailati
- Department of Pharmacology, School of Pharmacy, Xinjiang Medical University, Urumqi 830017, China; (A.B.); (A.A.); (D.D.); (N.N.); (Y.P.); (S.H.); (N.M.)
- Xinjiang Key Laboratory of Natural Medicines Active Components and Drug Release Technology, Urumqi 830017, China
- Xinjiang Key Laboratory of Biopharmaceuticals and Medical Devices, Urumqi 830017, China
- Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Ministry of Education, Urumqi 830017, China
| | - Nulibiya Maihemuti
- Department of Pharmacology, School of Pharmacy, Xinjiang Medical University, Urumqi 830017, China; (A.B.); (A.A.); (D.D.); (N.N.); (Y.P.); (S.H.); (N.M.)
- Xinjiang Key Laboratory of Natural Medicines Active Components and Drug Release Technology, Urumqi 830017, China
- Xinjiang Key Laboratory of Biopharmaceuticals and Medical Devices, Urumqi 830017, China
- Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Ministry of Education, Urumqi 830017, China
| | - Wenting Zhou
- Department of Pharmacology, School of Pharmacy, Xinjiang Medical University, Urumqi 830017, China; (A.B.); (A.A.); (D.D.); (N.N.); (Y.P.); (S.H.); (N.M.)
- Xinjiang Key Laboratory of Natural Medicines Active Components and Drug Release Technology, Urumqi 830017, China
- Xinjiang Key Laboratory of Biopharmaceuticals and Medical Devices, Urumqi 830017, China
- Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Ministry of Education, Urumqi 830017, China
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Yang K, Wu YT, He Y, Dai JX, Luo YL, Xie JH, Ding WJ. GLP-1 and IL-6 regulates obesity in the gut and brain. Life Sci 2025; 362:123339. [PMID: 39730038 DOI: 10.1016/j.lfs.2024.123339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 11/06/2024] [Accepted: 12/23/2024] [Indexed: 12/29/2024]
Abstract
Obesity is a chronic metabolic disease characterized by excessive nutrient intake leading to increased subcutaneous or visceral fat, resulting in pathological and physiological changes. The incidence rate of obesity, an important form of metabolic syndrome, is increasing worldwide. Excess appetite is a key pathogenesis of obesity, and the inflammatory response induced by obesity has received increasing attention. This review focuses on the role of appetite-regulating factor (Glucogan-like peptide 1) and inflammatory factor (Interleukin-6) in the gut and brain in individuals with obesity and draws insights from the current literature.
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Affiliation(s)
- Kun Yang
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yu-Ting Wu
- Chengdu University of Traditional Chinese Medicine, 1166 Luitai Avenue, Chengdu, Sichuan 611137, China
| | - Yan He
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Jin-Xiu Dai
- Chengdu University of Traditional Chinese Medicine, 1166 Luitai Avenue, Chengdu, Sichuan 611137, China
| | - Yu-Lu Luo
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Jing-Hui Xie
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Wei-Jun Ding
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
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Morena da Silva F, Esser KA, Murach KA, Greene NP. Inflammation o'clock: interactions of circadian rhythms with inflammation-induced skeletal muscle atrophy. J Physiol 2024; 602:6587-6607. [PMID: 37563881 PMCID: PMC10858298 DOI: 10.1113/jp284808] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 07/24/2023] [Indexed: 08/12/2023] Open
Abstract
Circadian rhythms are ∼24 h cycles evident in behaviour, physiology and metabolism. The molecular mechanism directing circadian rhythms is the circadian clock, which is composed of an interactive network of transcription-translation feedback loops. The core clock genes include Bmal1, Clock, Rev-erbα/β, Per and Cry. In addition to keeping time, the core clock regulates a daily programme of gene expression that is important for overall cell homeostasis. The circadian clock mechanism is present in all cells, including skeletal muscle fibres, and disruption of the muscle clock is associated with changes in muscle phenotype and function. Skeletal muscle atrophy is largely associated with a lower quality of life, frailty and reduced lifespan. Physiological and genetic modification of the core clock mechanism yields immune dysfunction, alters inflammatory factor expression and secretion and is associated with skeletal muscle atrophy in multiple conditions, such as ageing and cancer cachexia. Here, we summarize the possible interplay between the circadian clock modulation of immune cells, systemic inflammatory status and skeletal muscle atrophy in chronic inflammatory conditions. Although there is a clear disruption of circadian clocks in various models of atrophy, the mechanism behind such alterations remains unknown. Understanding the modulatory potential of muscle and immune circadian clocks in inflammation and skeletal muscle health is essential for the development of therapeutic strategies to protect skeletal muscle mass and function of patients with chronic inflammation.
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Affiliation(s)
- Francielly Morena da Silva
- Cachexia Research Laboratory, Exercise Science Research Center, Department of Health, Human Performance and Recreation, University of Arkansas, Fayetteville, AR, USA
| | - Karyn A Esser
- Department of Physiology and Ageing, College of Medicine, University of Florida, Gainesville, FL, USA
- Myology Institute, University of Florida, Gainesville, FL, USA
| | - Kevin A Murach
- Molecular Muscle Mass Regulation Laboratory, Exercise Science Research Center, Department of Health, Human Performance and Recreation, University of Arkansas, Fayetteville, AR, USA
| | - Nicholas P Greene
- Cachexia Research Laboratory, Exercise Science Research Center, Department of Health, Human Performance and Recreation, University of Arkansas, Fayetteville, AR, USA
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9
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Weston WC, Hales KH, Hales DB. Utilizing Flaxseed as an Antimicrobial Alternative in Chickens: Integrative Review for Salmonella enterica and Eimeria. Curr Issues Mol Biol 2024; 46:12322-12342. [PMID: 39590326 PMCID: PMC11592616 DOI: 10.3390/cimb46110732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 10/24/2024] [Indexed: 11/28/2024] Open
Abstract
This review provides an integrative framework for understanding flaxseed (Linum utassitissimum) as an antimicrobial alternative for poultry production. We begin by familiarizing the reader with the global legislation of antibiotics in animal husbandry; highlighting gaps and current issues for Salmonella enterica (S. enterica) and Eimeria (coccidiosis-inducing). We then discuss the natural, symbiotic characteristics of the Galliformes order (chicken-like birds) and Linum (the flaxes). The key immunological themes in this review include: (i) flaxseed's regulation of innate and adaptive immunity in chickens, (ii) flaxseed's ability to accelerate chicken recovery from infection with S. enterica and Eimeria, and (iii) flaxseed's strengthening of immunity via vitamin B6 antagonism. Research indicates that whole flaxseed increases adaptive immune capacity by augmenting cecal Bacteroides and short-chain fatty acids while also attenuating the heterophil to lymphocyte ratio in chickens. Moreover, flaxseed accelerates chicken recovery from infection with Salmonella Enteritidis or Eimeria tenella; however, future work is needed to better understand (i) defatted flaxseed's superior performance against Eimeria species and (ii) Eimeria maxima's resilience against whole flaxseed. In the context of vitamin B6 antagonism, we propose that 15% whole flaxseed overcomes S. enterica's insult to estrogen synthesis by sustaining the activity of phosphatidylethanolamine methyltransferase (PEMT) in liver. We also propose that 10% defatted flaxseed (as a metformin homologue) strengthens chicken immunity by safeguarding gonadal physiology and by increasing plasma thymidine bioavailability. The concepts in this review can be used as a template for conducting advanced immunological studies in poultry science.
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Affiliation(s)
- William C. Weston
- Department of Molecular, Cellular & Systemic Physiology, School of Medicine, Southern Illinois University, Carbondale, IL 62901, USA;
| | - Karen H. Hales
- Department of Obstetrics & Gynecology, School of Medicine, Southern Illinois University, Carbondale, IL 62901, USA;
| | - Dale B. Hales
- Department of Molecular, Cellular & Systemic Physiology, School of Medicine, Southern Illinois University, Carbondale, IL 62901, USA;
- Department of Obstetrics & Gynecology, School of Medicine, Southern Illinois University, Carbondale, IL 62901, USA;
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Aboul-Ella H, Gohar A, Ali AA, Ismail LM, Mahmoud AEER, Elkhatib WF, Aboul-Ella H. Monoclonal antibodies: From magic bullet to precision weapon. MOLECULAR BIOMEDICINE 2024; 5:47. [PMID: 39390211 PMCID: PMC11467159 DOI: 10.1186/s43556-024-00210-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Accepted: 09/19/2024] [Indexed: 10/12/2024] Open
Abstract
Monoclonal antibodies (mAbs) are used to prevent, detect, and treat a broad spectrum of non-communicable and communicable diseases. Over the past few years, the market for mAbs has grown exponentially with an expected compound annual growth rate (CAGR) of 11.07% from 2024 (237.64 billion USD estimated at the end of 2023) to 2033 (679.03 billion USD expected by the end of 2033). Ever since the advent of hybridoma technology introduced in 1975, antibody-based therapeutics were realized using murine antibodies which further progressed into humanized and fully human antibodies, reducing the risk of immunogenicity. Some benefits of using mAbs over conventional drugs include a drastic reduction in the chances of adverse reactions, interactions between drugs, and targeting specific proteins. While antibodies are very efficient, their higher production costs impede the process of commercialization. However, their cost factor has been improved by developing biosimilar antibodies as affordable versions of therapeutic antibodies. Along with the recent advancements and innovations in antibody engineering have helped and will furtherly help to design bio-better antibodies with improved efficacy than the conventional ones. These novel mAb-based therapeutics are set to revolutionize existing drug therapies targeting a wide spectrum of diseases, thereby meeting several unmet medical needs. This review provides comprehensive insights into the current fundamental landscape of mAbs development and applications and the key factors influencing the future projections, advancement, and incorporation of such promising immunotherapeutic candidates as a confrontation approach against a wide list of diseases, with a rationalistic mentioning of any limitations facing this field.
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Affiliation(s)
- Hassan Aboul-Ella
- Department of Microbiology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt.
| | - Asmaa Gohar
- Department of Microbiology and Immunology, Faculty of Pharmacy, Galala University, Suez, Egypt
- Department of Microbiology and Immunology, Faculty of Pharmacy, Ahram Canadian University (ACU), Giza, Egypt
- Egyptian Drug Authority (EDA), Giza, Egypt
| | - Aya Ahmed Ali
- Department of Microbiology and Immunology, Faculty of Pharmacy, Sinai University, Sinai, Egypt
| | - Lina M Ismail
- Department of Biotechnology and Molecular Chemistry, Faculty of Science, Cairo University, Giza, Egypt
- Creative Egyptian Biotechnologists (CEB), Giza, Egypt
| | | | - Walid F Elkhatib
- Department of Microbiology and Immunology, Faculty of Pharmacy, Galala University, Suez, Egypt
- Department of Microbiology and Immunology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Heba Aboul-Ella
- Department of Pharmacognosy, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University (ECU), Cairo, Egypt
- Scientific Research Group in Egypt (SRGE), Cairo, Egypt
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11
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Yang J, Liang J, Hu N, He N, Liu B, Liu G, Qin Y. The Gut Microbiota Modulates Neuroinflammation in Alzheimer's Disease: Elucidating Crucial Factors and Mechanistic Underpinnings. CNS Neurosci Ther 2024; 30:e70091. [PMID: 39460538 PMCID: PMC11512114 DOI: 10.1111/cns.70091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 09/18/2024] [Accepted: 10/08/2024] [Indexed: 10/28/2024] Open
Abstract
BACKGROUND AND PURPOSE Alzheimer's disease (AD) is characterized by progressive cognitive decline and neuronal loss, commonly linked to amyloid-β plaques, neurofibrillary tangles, and neuroinflammation. Recent research highlights the gut microbiota as a key player in modulating neuroinflammation, a critical pathological feature of AD. Understanding the role of the gut microbiota in this process is essential for uncovering new therapeutic avenues and gaining deeper insights into AD pathogenesis. METHODS This review provides a comprehensive analysis of how gut microbiota influences neuroinflammation and glial cell function in AD. A systematic literature search was conducted, covering studies from 2014 to 2024, including reviews, clinical trials, and animal studies. Keywords such as "gut microbiota," "Alzheimer's disease," "neuroinflammation," and "blood-brain barrier" were used. RESULTS Dysbiosis, or the imbalance in gut microbiota composition, has been implicated in the modulation of key AD-related mechanisms, including neuroinflammation, blood-brain barrier integrity, and neurotransmitter regulation. These disruptions may accelerate the onset and progression of AD. Additionally, therapeutic strategies targeting gut microbiota, such as probiotics, prebiotics, and fecal microbiota transplantation, show promise in modulating AD pathology. CONCLUSIONS The gut microbiota is a pivotal factor in AD pathogenesis, influencing neuroinflammation and disease progression. Understanding the role of gut microbiota in AD opens avenues for innovative diagnostic, preventive, and therapeutic strategies.
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Affiliation(s)
- Jianshe Yang
- Harbin Institute of Physical EducationHarbinHeilongjiang ProvinceChina
| | - Junyi Liang
- Heilongjiang University of Traditional Chinese MedicineHarbinHeilongjiang ProvinceChina
| | - Niyuan Hu
- Harbin Institute of Physical EducationHarbinHeilongjiang ProvinceChina
| | - Ningjuan He
- Harbin Institute of Physical EducationHarbinHeilongjiang ProvinceChina
| | - Bin Liu
- Heilongjiang University of Traditional Chinese MedicineHarbinHeilongjiang ProvinceChina
| | - Guoliang Liu
- Harbin Institute of Physical EducationHarbinHeilongjiang ProvinceChina
| | - Ying Qin
- Harbin Institute of Physical EducationHarbinHeilongjiang ProvinceChina
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12
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Zhang L, Jin W, Hu M, Su Y, Zhang Y, Yuan F, Fang Y, Li Z, Li Y, Bu C, Zhou W. Silencing miR-155-5p expression improves intestinal damage through inhibiting inflammation and ferroptosis in necrotizing enterocolitis. Heliyon 2024; 10:e37087. [PMID: 39286078 PMCID: PMC11402723 DOI: 10.1016/j.heliyon.2024.e37087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 08/25/2024] [Accepted: 08/27/2024] [Indexed: 09/19/2024] Open
Abstract
Background Necrotizing enterocolitis (NEC) is a condition characterized by acquired damage to the mucosal lining, predominantly affecting premature infants. Bioinformatics assessments uncovered a notable rise in miR-155-5p expression in the intestinal tissues of infants suffering from NEC. Nevertheless, the development of NEC's underlying mechanisms and the role of miR-155-5p are still not well understood. This research aimed to explore the role of miR-155-5p in NEC and to elucidate its underlying mechanisms. Methods To replicate NEC in vitro, lipopolysaccharide (LPS) was employed, whereas an in vivo rat model of NEC was established using formula feeding and exposure to hypoxia. Subsequently, levels of inflammatory cytokines, cell survival, and apoptosis rates were assessed. Various biochemical indicators such as glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) were measured utilizing a purchased diagnostic kit. For the assessment of reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) within FHC cells, analysis by flow cytometry was conducted. Additionally, the technique of Western blotting was utilized to analyze the levels of ferroptosis-associated proteins. Moreover, hematoxylin and eosin (H&E) staining was carried out to observe the histopathological alterations in the intestinal tissue samples from rats with necrotizing enterocolitis (NEC). Results Reducing miR-155-5p improved the survival of FHC cells exposed to LPS, decreased cell apoptosis, inflammation, and ferroptosis, and mitigated intestinal damage in NEC rats. Furthermore, SLC7A11 was found to be a direct target of miR-155-5p. The inhibition of miR-155-5p decreased LPS-induced inflammation and ferroptosis in both FHC cells and NEC rats by promoting SLC7A11 expression. This effect was evidenced by increased levels of ferroptosis-related proteins FTH1 and GPX4, decreased COX-2 and ACSL4 levels, lower lipid peroxidation marker MDA, reduced antioxidant markers GSH, SOD, and CAT, fewer IL-6 and TNF-α, and suppression of the IκBα/NF-κB p65 signaling pathway. Conclusions In conclusion, reducing miR-155-5p could improve intestinal damage in NEC by inhibiting inflammation and ferroptosis. These findings may provide theoretical insights for the development of new therapies for NEC.
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Affiliation(s)
- Le Zhang
- Key Laboratory of Birth Defects, Children's Hospital, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
- Department of Neonatology, Affiliated Children's Hospital of Jiangnan University (Wuxi Children's Hospital), Wuxi, 214023, Jiangsu, China
| | - Weilai Jin
- Department of Neonatology, Affiliated Children's Hospital of Jiangnan University (Wuxi Children's Hospital), Wuxi, 214023, Jiangsu, China
| | - Mengyuan Hu
- Department of Neonatology, The Affiliated Wuxi Children's Hospital of Nanjing Medical University, Wuxi, 214023, Jiangsu, China
| | - Yinglin Su
- Department of Neonatology, Affiliated Children's Hospital of Jiangnan University (Wuxi Children's Hospital), Wuxi, 214023, Jiangsu, China
| | - Yiting Zhang
- Department of Neonatology, Affiliated Children's Hospital of Jiangnan University (Wuxi Children's Hospital), Wuxi, 214023, Jiangsu, China
| | - Fuqiang Yuan
- Department of Neonatology, Affiliated Children's Hospital of Jiangnan University (Wuxi Children's Hospital), Wuxi, 214023, Jiangsu, China
| | - Yuanyuan Fang
- Department of Neonatology, Affiliated Children's Hospital of Jiangnan University (Wuxi Children's Hospital), Wuxi, 214023, Jiangsu, China
| | - Zhengying Li
- Department of Neonatology, Affiliated Children's Hospital of Jiangnan University (Wuxi Children's Hospital), Wuxi, 214023, Jiangsu, China
| | - Yawen Li
- Department of Neonatology, Affiliated Children's Hospital of Jiangnan University (Wuxi Children's Hospital), Wuxi, 214023, Jiangsu, China
| | - Chaozhi Bu
- State Key Laboratory of Reproductive Medicine, Research Institute for Reproductive Health and Genetic Diseases, Wuxi Maternity and Child Health Care Hospital, Affiliated Women's Hospital of Jiangnan University, Wuxi, 214002, Jiangsu, China
| | - Wenhao Zhou
- Key Laboratory of Birth Defects, Children's Hospital, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
- Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
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13
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Wadop YN, Vasquez EL, Mathews JJ, Muhammad JAS, Mavarez RP, Satizabal C, Gonzales MM, Tanner J, Maestre G, Fonteh AN, Seshadri S, Kautz TF, Fongang B. Differential Patterns of Gut and Oral Microbiomes in Hispanic Individuals with Cognitive Impairment. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.27.605455. [PMID: 39211240 PMCID: PMC11361189 DOI: 10.1101/2024.07.27.605455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Alzheimer's disease and related dementias (ADRD) have been associated with alterations in both oral and gut microbiomes. While extensive research has focused on the role of gut dysbiosis in ADRD, the contribution of the oral microbiome remains relatively understudied. Furthermore, the potential synergistic interactions between oral and gut microbiomes in ADRD pathology are largely unexplored. This study aims to evaluate distinct patterns and potential synergistic effects of oral and gut microbiomes in a cohort of predominantly Hispanic individuals with cognitive impairment (CI) and without cognitive impairment (NC). We conducted 16S rRNA gene sequencing on stool and saliva samples from 32 participants (17 CI, 15 NC; 62.5% female, mean age = 70.4 ± 6.2 years) recruited in San Antonio, Texas, USA. Correlation analysis through MaAslin2 assessed the relationship between participants' clinical measurements (e.g., fasting glucose and blood cholesterol) and their gut and saliva microbial contents. Differential abundance analysis evaluated taxa with significant differences between CI and NC groups, and alpha and beta diversity metrics assessed within-sample and group compositional differences. Our analyses revealed no significant differences between NC and CI groups in fasting glucose or blood cholesterol levels. However, a clear association was observed between gut microbiome composition and levels of fasting glucose and blood cholesterol. While alpha and beta diversity metrics showed no significant differences between CI and NC groups, differential abundance analysis revealed an increased presence of oral genera such as Dialister , Fretibacterium , and Mycoplasma in CI participants. Conversely, CI individuals exhibited a decreased abundance of gut genera, including Shuttleworthia , Holdemania , and Subdoligranulum , which are known for their anti-inflammatory properties. No evidence was found for synergistic contributions between oral and gut microbiomes in the context of ADRD. Our findings suggest that similar to the gut microbiome, the oral microbiome undergoes significant modifications as individuals transition from NC to CI. Notably, the identified oral microbes have been previously associated with periodontal diseases and gingivitis. These results underscore the necessity for further investigations with larger sample sizes to validate our findings and elucidate the complex interplay between oral and gut microbiomes in ADRD pathogenesis.
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14
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Ran Z, Yang J, Liu L, Wu S, An Y, Hou W, Cheng T, Zhang Y, Zhang Y, Huang Y, Zhang Q, Wan J, Li X, Xing B, Ye Y, Xu P, Chen Z, Zhao J, Li R. Chronic PM 2.5 exposure disrupts intestinal barrier integrity via microbial dysbiosis-triggered TLR2/5-MyD88-NLRP3 inflammasome activation. ENVIRONMENTAL RESEARCH 2024; 258:119415. [PMID: 38906446 DOI: 10.1016/j.envres.2024.119415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 05/31/2024] [Accepted: 06/11/2024] [Indexed: 06/23/2024]
Abstract
BACKGROUND PM2.5, a known public health risk, is increasingly linked to intestinal disorders, however, the mechanisms of its impact are not fully understood. PURPOSE This study aimed to explore the impact of chronic PM2.5 exposure on intestinal barrier integrity and to uncover the underlying molecular mechanisms. METHODS C57BL/6 J mice were exposed to either concentrated ambient PM2.5 (CPM) or filtered air (FA) for six months to simulate urban pollution conditions. We evaluated intestinal barrier damage, microbial shifts, and metabolic changes through histopathology, metagenomics, and metabolomics. Analysis of the TLR signaling pathway was also conducted. RESULTS The mean concentration of PM2.5 in the CPM exposure chamber was consistently measured at 70.9 ± 26.8 μg/m³ throughout the study period. Our findings show that chronic CPM exposure significantly compromises intestinal barrier integrity, as indicated by reduced expression of the key tight junction proteins Occludin and Tjp1/Zo-1. Metagenomic sequencing revealed significant shifts in the microbial landscape, identifying 35 differentially abundant species. Notably, there was an increase in pro-inflammatory nongastric Helicobacter species and a decrease in beneficial bacteria, such as Lactobacillus intestinalis, Lactobacillus sp. ASF360, and Eubacterium rectale. Metabolomic analysis further identified 26 significantly altered metabolites commonly associated with intestinal diseases. A strong correlation between altered bacterial species and metabolites was also observed. For example, 4 Helicobacter species all showed positive correlations with 13 metabolites, including Lactate, Bile acids, Pyruvate and Glutamate. Additionally, increased expression levels of TLR2, TLR5, Myd88, and NLRP3 proteins were noted, and their expression patterns showed a strong correlation, suggesting a possible involvement of the TLR2/5-MyD88-NLRP3 signaling pathway. CONCLUSIONS Chronic CPM exposure induces intestinal barrier dysfunction, microbial dysbiosis, metabolic imbalance, and activation of the TLR2/5-MyD88-NLRP3 inflammasome. These findings highlight the urgent need for intervention strategies to mitigate the detrimental effects of air pollution on intestinal health and identify potential therapeutic targets.
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Affiliation(s)
- Zihan Ran
- Shanghai Key Laboratory of Molecular Imaging, Zhoupu Hospital, Department of Pathology, Shanghai University of Medicine and Health Sciences, 279 Zhouzhu Road, Shanghai 201318, China
| | - Jingcheng Yang
- State Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Science, Fudan University, 2005 Songhu Road, Shanghai 200438, China; Greater Bay Area Institute of Precision Medicine, 115 Jiaoxi Road, Guangzhou 511458, China
| | - Liang Liu
- Clinical Research Unit, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Shaobo Wu
- Department of Laboratory Medicine, Tinglin Hospital of Jinshan District, No. 80 Siping North Road, Shanghai 201505, China
| | - YanPeng An
- State Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Science, Fudan University, 2005 Songhu Road, Shanghai 200438, China
| | - Wanwan Hou
- State Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Science, Fudan University, 2005 Songhu Road, Shanghai 200438, China
| | - Tianyuan Cheng
- Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| | - Youyi Zhang
- School of Public Health and the Key Laboratory of Public Health Safety, Ministry of Education, Fudan University, Shanghai 200032, China
| | - Yiqing Zhang
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Yechao Huang
- State Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Science, Fudan University, 2005 Songhu Road, Shanghai 200438, China
| | - Qianyue Zhang
- The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostic & Endocrinology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine, Shanghai 200011, China
| | - Jiaping Wan
- The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostic & Endocrinology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine, Shanghai 200011, China
| | - Xuemei Li
- Shanghai Key Laboratory of Molecular Imaging, Zhoupu Hospital, Department of Pathology, Shanghai University of Medicine and Health Sciences, 279 Zhouzhu Road, Shanghai 201318, China
| | - Baoling Xing
- Shanghai Key Laboratory of Molecular Imaging, Zhoupu Hospital, Department of Pathology, Shanghai University of Medicine and Health Sciences, 279 Zhouzhu Road, Shanghai 201318, China
| | - Yuchen Ye
- Shanghai Key Laboratory of Molecular Imaging, Zhoupu Hospital, Department of Pathology, Shanghai University of Medicine and Health Sciences, 279 Zhouzhu Road, Shanghai 201318, China
| | - Penghao Xu
- School of Biological Sciences, Georgia Insitute of Technology, Atlanta, GA, USA
| | - Zhenghu Chen
- Shanghai Key Laboratory of Molecular Imaging, Zhoupu Hospital, Department of Pathology, Shanghai University of Medicine and Health Sciences, 279 Zhouzhu Road, Shanghai 201318, China.
| | - Jinzhuo Zhao
- School of Public Health and the Key Laboratory of Public Health Safety, Ministry of Education, Fudan University, Shanghai 200032, China.
| | - Rui Li
- The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostic & Endocrinology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine, Shanghai 200011, China.
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15
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Krzyżewska-Dudek E, Dulipati V, Kapczyńska K, Noszka M, Chen C, Kotimaa J, Książczyk M, Dudek B, Bugla-Płoskońska G, Pawlik K, Meri S, Rybka J. Lipopolysaccharide with long O-antigen is crucial for Salmonella Enteritidis to evade complement activity and to facilitate bacterial survival in vivo in the Galleria mellonella infection model. Med Microbiol Immunol 2024; 213:8. [PMID: 38767707 PMCID: PMC11106168 DOI: 10.1007/s00430-024-00790-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 04/19/2024] [Indexed: 05/22/2024]
Abstract
Bacterial resistance to serum is a key virulence factor for the development of systemic infections. The amount of lipopolysaccharide (LPS) and the O-antigen chain length distribution on the outer membrane, predispose Salmonella to escape complement-mediated killing. In Salmonella enterica serovar Enteritidis (S. Enteritidis) a modal distribution of the LPS O-antigen length can be observed. It is characterized by the presence of distinct fractions: low molecular weight LPS, long LPS and very long LPS. In the present work, we investigated the effect of the O-antigen modal length composition of LPS molecules on the surface of S. Enteritidis cells on its ability to evade host complement responses. Therefore, we examined systematically, by using specific deletion mutants, roles of different O-antigen fractions in complement evasion. We developed a method to analyze the average LPS lengths and investigated the interaction of the bacteria and isolated LPS molecules with complement components. Additionally, we assessed the aspect of LPS O-antigen chain length distribution in S. Enteritidis virulence in vivo in the Galleria mellonella infection model. The obtained results of the measurements of the average LPS length confirmed that the method is suitable for measuring the average LPS length in bacterial cells as well as isolated LPS molecules and allows the comparison between strains. In contrast to earlier studies we have used much more precise methodology to assess the LPS molecules average length and modal distribution, also conducted more subtle analysis of complement system activation by lipopolysaccharides of various molecular mass. Data obtained in the complement activation assays clearly demonstrated that S. Enteritidis bacteria require LPS with long O-antigen to resist the complement system and to survive in the G. mellonella infection model.
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Affiliation(s)
- Eva Krzyżewska-Dudek
- Department of Immunology of Infectious Diseases, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
- Department of Bacteriology and Immunology, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
| | - Vinaya Dulipati
- Department of Bacteriology and Immunology, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
| | - Katarzyna Kapczyńska
- Department of Immunology of Infectious Diseases, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
| | - Mateusz Noszka
- Department of Microbiology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
| | - Carmen Chen
- Department of Bacteriology and Immunology, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
| | - Juha Kotimaa
- Department of Bacteriology and Immunology, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
- VTT Technical Research Centre of Finland Ltd, Espoo, Finland
| | - Marta Książczyk
- Department of Microbiology, Faculty of Biological Sciences, University of Wrocław, Wrocław, Poland
| | - Bartłomiej Dudek
- Platform for Unique Models Application (P.U.M.A), Department of Pharmaceutical Microbiology and Parasitology, Faculty of Pharmacy, Wroclaw Medical University, Wrocław, Poland
| | | | - Krzysztof Pawlik
- Department of Microbiology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
| | - Seppo Meri
- Department of Bacteriology and Immunology, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
- HUSLAB Diagnostic Center, Helsinki University Central Hospital, Helsinki, Finland
| | - Jacek Rybka
- Department of Immunology of Infectious Diseases, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland.
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16
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Yang C, Rubin L, Yu X, Lazarovici P, Zheng W. Preclinical evidence using synthetic compounds and natural products indicates that AMPK represents a potential pharmacological target for the therapy of pulmonary diseases. Med Res Rev 2024; 44:1326-1369. [PMID: 38229486 DOI: 10.1002/med.22014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 12/07/2023] [Accepted: 12/30/2023] [Indexed: 01/18/2024]
Abstract
Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) is a highly conserved eukaryotic enzyme discovered as a key regulator of cellular energy homeostasis, with anti-inflammation, antioxidative stress, anticancer, and antifibrosis beneficial effects. AMPK is dysregulated in human pulmonary diseases such as acute lung injury, nonsmall cell lung cancer, pulmonary fibrosis, chronic obstructive pulmonary disease, and asthma. This review provides an overview of the beneficial role of natural, synthetic, and Chinese traditional medicines AMPK modulators in pulmonary diseases, and highlights the role of the AMPK signaling pathway in the lung, emphasizing the importance of finding lead compounds and drugs that can target and modulate AMPK to treat the lung diseases.
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Affiliation(s)
- Chao Yang
- Faculty of Health Sciences, University of Macau, Taipa, Macau, China
| | - Limor Rubin
- Allergy and Clinical Immunology Unit, Department of Medicine, Jerusalem, Israel
| | - Xiyong Yu
- School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Philip Lazarovici
- School of Pharmacy Institute for Drug Research, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Wenhua Zheng
- Faculty of Health Sciences, University of Macau, Taipa, Macau, China
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17
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Wen X, Ni J, Zeng S, Song Z, Qiu W. One-Pot Synthesis of Nanoflower-Like Zn 2SnS 4 as Nanozymes for Highly Sensitive Electrochemical Detection of H 2O 2 Released by Living Cells. Chemistry 2024:e202400700. [PMID: 38625164 DOI: 10.1002/chem.202400700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 04/07/2024] [Accepted: 04/08/2024] [Indexed: 04/17/2024]
Abstract
The sensitive and reliable nanozyme-based sensor enables the detection of low concentrations of H2O2 in biological microenvironments, it has potential applications as an in-situ monitoring platform for cellular H2O2 release. The uniformly dispersed bimetallic sulfide (Zn2SnS4) nanoflowers were synthesized via a one-pot hydrothermal method and the two kinds of metal ions can serve as morphology and structure directing agents for each other in the synthetic process. The nanoparticles were utilized as nanozyme materials to fabricate a novel electrochemical sensor, and it exhibits a distinct electrochemical response towards H2O2 with excellent stability and detection capability (with a minimum detection limit of 1.79 nM (S/N=3)), the excellent characteristics facilitate the precise detection of low concentrations of H2O2 in biological microenvironments. Use the macrophages differentiated from leukemia THP-1 cells as a representative sensing model, the sensor was successfully utilized for real-time monitoring of the release of H2O2 induced by living cells, which has significant potential applications in clinical diagnosis and cancer treatment.
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Affiliation(s)
- Xia Wen
- The Department of Chemistry and Environment Science, Fujian Provincial Key Laboratory of Modern Analytical Science and Separation Technology, Minnan Normal University, Zhangzhou, 363000, PR China
| | - Jiancong Ni
- The Department of Chemistry and Environment Science, Fujian Provincial Key Laboratory of Modern Analytical Science and Separation Technology, Minnan Normal University, Zhangzhou, 363000, PR China
| | - Shunmu Zeng
- The Department of Chemistry and Environment Science, Fujian Provincial Key Laboratory of Modern Analytical Science and Separation Technology, Minnan Normal University, Zhangzhou, 363000, PR China
| | - Zhiping Song
- The Department of Chemistry and Environment Science, Fujian Provincial Key Laboratory of Modern Analytical Science and Separation Technology, Minnan Normal University, Zhangzhou, 363000, PR China
| | - Weiwei Qiu
- The Department of Chemistry and Environment Science, Fujian Provincial Key Laboratory of Modern Analytical Science and Separation Technology, Minnan Normal University, Zhangzhou, 363000, PR China
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18
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Liang J, Wang Y, Liu B, Dong X, Cai W, Zhang N, Zhang H. Deciphering the intricate linkage between the gut microbiota and Alzheimer's disease: Elucidating mechanistic pathways promising therapeutic strategies. CNS Neurosci Ther 2024; 30:e14704. [PMID: 38584341 PMCID: PMC10999574 DOI: 10.1111/cns.14704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 12/15/2023] [Accepted: 03/25/2024] [Indexed: 04/09/2024] Open
Abstract
BACKGROUND The gut microbiome is composed of various microorganisms such as bacteria, fungi, and protozoa, and constitutes an important part of the human gut. Its composition is closely related to human health and disease. Alzheimer's disease (AD) is a neurodegenerative disease whose underlying mechanism has not been fully elucidated. Recent research has shown that there are significant differences in the gut microbiota between AD patients and healthy individuals. Changes in the composition of gut microbiota may lead to the development of harmful factors associated with AD. In addition, the gut microbiota may play a role in the development and progression of AD through the gut-brain axis. However, the exact nature of this relationship has not been fully understood. AIMS This review will elucidate the types and functions of gut microbiota and their relationship with AD and explore in depth the potential mechanisms of gut microbiota in the occurrence of AD and the prospects for treatment strategies. METHODS Reviewed literature from PubMed and Web of Science using key terminologies related to AD and the gut microbiome. RESULTS Research indicates that the gut microbiota can directly or indirectly influence the occurrence and progression of AD through metabolites, endotoxins, and the vagus nerve. DISCUSSION This review discusses the future challenges and research directions regarding the gut microbiota in AD. CONCLUSION While many unresolved issues remain regarding the gut microbiota and AD, the feasibility and immense potential of treating AD by modulating the gut microbiota are evident.
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Affiliation(s)
- Junyi Liang
- Heilongjiang University of Traditional Chinese MedicineHarbinHeilongjiang ProvinceChina
| | - Yueyang Wang
- Heilongjiang University of Traditional Chinese MedicineHarbinHeilongjiang ProvinceChina
| | - Bin Liu
- Heilongjiang University of Traditional Chinese MedicineHarbinHeilongjiang ProvinceChina
| | - Xiaohong Dong
- Jiamusi CollegeHeilongjiang University of Traditional Chinese MedicineJiamusiHeilongjiang ProvinceChina
| | - Wenhui Cai
- Heilongjiang University of Traditional Chinese MedicineHarbinHeilongjiang ProvinceChina
| | - Ning Zhang
- Heilongjiang University of Traditional Chinese MedicineHarbinHeilongjiang ProvinceChina
| | - Hong Zhang
- Heilongjiang Jiamusi Central HospitalJiamusiHeilongjiang ProvinceChina
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Fedulovs A, Pahirko L, Jekabsons K, Kunrade L, Valeinis J, Riekstina U, Pīrāgs V, Sokolovska J. Association of Endotoxemia with Low-Grade Inflammation, Metabolic Syndrome and Distinct Response to Lipopolysaccharide in Type 1 Diabetes. Biomedicines 2023; 11:3269. [PMID: 38137490 PMCID: PMC10740930 DOI: 10.3390/biomedicines11123269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 11/10/2023] [Accepted: 11/11/2023] [Indexed: 12/24/2023] Open
Abstract
The association of endotoxemia with metabolic syndrome (MS) and low-grade inflammation in type 1 diabetes (T1D) is little-studied. We investigated the levels of lipopolysaccharide (LPS), lipopolysaccharide-binding protein (LBP), endogenous anti-endotoxin core antibodies (EndoCAb IgG and IgM) and high-sensitivity C-reactive protein (hsCRP) in 74 T1D patients with different MS statuses and 33 control subjects. Within the T1D group, 31 patients had MS. These subjects had higher levels of LPS compared to patients without MS (MS 0.42 (0.35-0.56) or no MS 0.34 (0.3-0.4), p = 0.009). MS was associated with LPS/HDL (OR = 6.5 (2.1; 20.0), p = 0.036) and EndoCAb IgM (OR = 0.32 (0.11; 0.93), p = 0.036) in patients with T1D. LBP (β = 0.30 (0.09; 0.51), p = 0.005), EndoCAb IgG (β = 0.29 (0.07; 0.51), p = 0.008) and the LPS/HDL ratio (β = 0.19 (0.03; 0.41, p = 0.084) were significantly associated with log-transformed hsCRP in T1D. Higher levels of hsCRP and EndoCAb IgG were observed in T1D compared to the control (p = 0.002 and p = 0.091, respectively). In contrast to the situation in the control group, LPS did not correlate with LBP, EndoCAb, leukocytes or HDL in T1D. To conclude, endotoxemia is associated with low-grade inflammation, MS and a distinct response to LPS in T1D.
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Affiliation(s)
- Aleksejs Fedulovs
- Faculty of Medicine, University of Latvia, LV-1004 Riga, Latvia; (A.F.); (K.J.); (L.K.); (U.R.); (V.P.)
| | - Leonora Pahirko
- Faculty of Physics, Mathematics and Optometry, University of Latvia, LV-1004 Riga, Latvia; (L.P.); (J.V.)
| | - Kaspars Jekabsons
- Faculty of Medicine, University of Latvia, LV-1004 Riga, Latvia; (A.F.); (K.J.); (L.K.); (U.R.); (V.P.)
| | - Liga Kunrade
- Faculty of Medicine, University of Latvia, LV-1004 Riga, Latvia; (A.F.); (K.J.); (L.K.); (U.R.); (V.P.)
| | - Jānis Valeinis
- Faculty of Physics, Mathematics and Optometry, University of Latvia, LV-1004 Riga, Latvia; (L.P.); (J.V.)
| | - Una Riekstina
- Faculty of Medicine, University of Latvia, LV-1004 Riga, Latvia; (A.F.); (K.J.); (L.K.); (U.R.); (V.P.)
| | - Valdis Pīrāgs
- Faculty of Medicine, University of Latvia, LV-1004 Riga, Latvia; (A.F.); (K.J.); (L.K.); (U.R.); (V.P.)
- Pauls Stradins Clinical University Hospital, LV-1002 Riga, Latvia
| | - Jelizaveta Sokolovska
- Faculty of Medicine, University of Latvia, LV-1004 Riga, Latvia; (A.F.); (K.J.); (L.K.); (U.R.); (V.P.)
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20
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Gore R, Mohsenipour M, Wood JL, Balasuriya GK, Hill-Yardin EL, Franks AE. Hyperimmune bovine colostrum containing lipopolysaccharide antibodies (IMM124-E) has a nondetrimental effect on gut microbial communities in unchallenged mice. Infect Immun 2023; 91:e0009723. [PMID: 37830823 PMCID: PMC10652967 DOI: 10.1128/iai.00097-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 08/21/2023] [Indexed: 10/14/2023] Open
Abstract
Enterotoxigenic Escherichia coli (ETEC) is a leading cause of bacterial diarrhea with the potential to cause long-term gastrointestinal (GI) dysfunction. Preventative treatments for ETEC-induced diarrhea exist, yet the effects of these treatments on GI commensals in healthy individuals are unclear. Whether administration of a prophylactic preventative treatment for ETEC-induced diarrhea causes specific shifts in gut microbial populations in controlled environments is also unknown. Here, we studied the effects of a hyperimmune bovine colostrum (IMM-124E) used in the manufacture of Travelan (AUST L 106709) on GI bacteria in healthy C57BL/6 mice. Using next-generation sequencing, we aimed to test the onset and magnitude of potential changes to the mouse gut microbiome in response to the antidiarrheagenic hyperimmune bovine colostrum product, rich in immunoglobulins against select ETEC strains (Travelan, Immuron Ltd). We show that in mice administered colostrum containing lipopolysaccharide (LPS) antibodies, there was an increased abundance of potentially gut-beneficial bacteria, such as Akkermansia and Desulfovibrio, without disrupting the underlying ecology of the GI tract. Compared to controls, there was no difference in overall weight gain, body or cecal weights, or small intestine length following LPS antibody colostrum supplementation. Overall, dietary supplementation with colostrum containing LPS antibodies produced subtle alterations in the gut bacterial composition of mice. Primarily, Travelan LPS antibody treatment decreased the ratio of Firmicutes/Bacteroidetes in gut microbial populations in unchallenged healthy mice. Further studies are required to examine the effect of Travelan LPS antibody treatment to engineer the microbiome in a diseased state and during recovery.
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Affiliation(s)
- Rachele Gore
- Neurodevelopment in Health and Disease Research Program, School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
- Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Bundoora, Victoria, Australia
| | - Mitra Mohsenipour
- Neurodevelopment in Health and Disease Research Program, School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Jennifer L. Wood
- Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Bundoora, Victoria, Australia
| | - Gayathri K. Balasuriya
- Department of Physiology and Cell Biology, Kobe University School of Medicine, Kobe, Japan
| | - Elisa L. Hill-Yardin
- Neurodevelopment in Health and Disease Research Program, School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Ashley E. Franks
- Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Bundoora, Victoria, Australia
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21
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Tandoro Y, Chen BK, Ali A, Wang CK. Review of Phytochemical Potency as a Natural Anti- Helicobacter pylori and Neuroprotective Agent. Molecules 2023; 28:7150. [PMID: 37894629 PMCID: PMC10609179 DOI: 10.3390/molecules28207150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 10/13/2023] [Accepted: 10/13/2023] [Indexed: 10/29/2023] Open
Abstract
Phytochemicals are plant secondary metabolites that show health benefits for humans due to their bioactivity. There is a huge variety of phytochemicals that have already been identified, and these compounds can act as antimicrobial and neuroprotection agents. Due to their anti-microbial activity and neuroprotection, several phytochemicals might have the potency to be used as natural therapeutic agents, especially for Helicobacter pylori infection and neurodegenerative disease, which have become a global health concern nowadays. According to previous research, there are some connections between H. pylori infection and neurodegenerative diseases, especially Alzheimer's disease. Hence, this comprehensive review examines different kinds of phytochemicals from natural sources as potential therapeutic agents to reduce H. pylori infection and improve neurodegenerative disease. An additional large-scale study is needed to establish the connection between H. pylori infection and neurodegenerative disease and how phytochemicals could improve this condition.
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Affiliation(s)
- Yohanes Tandoro
- Department of Nutrition, Chung Shan Medical University, 110, Section 1, Jianguo North Road, Taichung 40201, Taiwan; (Y.T.); (B.-K.C.); (A.A.)
- Faculty of Agricultural Technology, Widya Mandala Catholic University Surabaya, Surabaya 60265, Indonesia
| | - Bo-Kai Chen
- Department of Nutrition, Chung Shan Medical University, 110, Section 1, Jianguo North Road, Taichung 40201, Taiwan; (Y.T.); (B.-K.C.); (A.A.)
| | - Asif Ali
- Department of Nutrition, Chung Shan Medical University, 110, Section 1, Jianguo North Road, Taichung 40201, Taiwan; (Y.T.); (B.-K.C.); (A.A.)
| | - Chin-Kun Wang
- Department of Nutrition, Chung Shan Medical University, 110, Section 1, Jianguo North Road, Taichung 40201, Taiwan; (Y.T.); (B.-K.C.); (A.A.)
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22
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Tao R, Liu S, Crawford J, Tao F. Gut-Brain Crosstalk and the Central Mechanisms of Orofacial Pain. Brain Sci 2023; 13:1456. [PMID: 37891825 PMCID: PMC10605055 DOI: 10.3390/brainsci13101456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 09/21/2023] [Accepted: 10/11/2023] [Indexed: 10/29/2023] Open
Abstract
Accumulated evidence has demonstrated that the gut microbiome can contribute to pain modulation through the microbiome-gut-brain axis. Various relevant microbiome metabolites in the gut are involved in the regulation of pain signaling in the central nervous system. In this review, we summarize recent advances in gut-brain interactions by which the microbiome metabolites modulate pain, with a focus on orofacial pain, and we further discuss the role of gut-brain crosstalk in the central mechanisms of orofacial pain whereby the gut microbiome modulates orofacial pain via the vagus nerve-mediated direct pathway and the gut metabolites/molecules-mediated indirect pathway. The direct and indirect pathways both contribute to the central regulation of orofacial pain through different brain structures (such as the nucleus tractus solitarius and the parabrachial nucleus) and signaling transmission across the blood-brain barrier, respectively. Understanding the gut microbiome-regulated pain mechanisms in the brain could help us to develop non-opioid novel therapies for orofacial pain.
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Affiliation(s)
| | | | | | - Feng Tao
- Department of Biomedical Sciences, Texas A&M University School of Dentistry, 3302 Gaston Ave., Dallas, TX 75246, USA
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23
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Liang J, Liu B, Dong X, Wang Y, Cai W, Zhang N, Zhang H. Decoding the role of gut microbiota in Alzheimer's pathogenesis and envisioning future therapeutic avenues. Front Neurosci 2023; 17:1242254. [PMID: 37790586 PMCID: PMC10544353 DOI: 10.3389/fnins.2023.1242254] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Accepted: 09/04/2023] [Indexed: 10/05/2023] Open
Abstract
Alzheimer's disease (AD) emerges as a perturbing neurodegenerative malady, with a profound comprehension of its underlying pathogenic mechanisms continuing to evade our intellectual grasp. Within the intricate tapestry of human health and affliction, the enteric microbial consortium, ensconced within the milieu of the human gastrointestinal tract, assumes a role of cardinal significance. Recent epochs have borne witness to investigations that posit marked divergences in the composition of the gut microbiota between individuals grappling with AD and those favored by robust health. The composite vicissitudes in the configuration of the enteric microbial assembly are posited to choreograph a participatory role in the inception and progression of AD, facilitated by the intricate conduit acknowledged as the gut-brain axis. Notwithstanding, the precise nature of this interlaced relationship remains enshrouded within the recesses of obscurity, poised for an exhaustive revelation. This review embarks upon the endeavor to focalize meticulously upon the mechanistic sway exerted by the enteric microbiota upon AD, plunging profoundly into the execution of interventions that govern the milieu of enteric microorganisms. In doing so, it bestows relevance upon the therapeutic stratagems that form the bedrock of AD's management, all whilst casting a prospective gaze into the horizon of medical advancements.
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Affiliation(s)
- Junyi Liang
- Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang, China
| | - Bin Liu
- Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang, China
| | - Xiaohong Dong
- Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang, China
| | - Yueyang Wang
- Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang, China
| | - Wenhui Cai
- Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang, China
| | - Ning Zhang
- Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang, China
| | - Hong Zhang
- Heilongjiang Jiamusi Central Hospital, Jiamusi, Heilongjiang, China
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24
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Rangel K, Lechuga GC, Provance DW, Morel CM, De Simone SG. An Update on the Therapeutic Potential of Antimicrobial Peptides against Acinetobacter baumannii Infections. Pharmaceuticals (Basel) 2023; 16:1281. [PMID: 37765087 PMCID: PMC10537560 DOI: 10.3390/ph16091281] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Revised: 08/09/2023] [Accepted: 09/06/2023] [Indexed: 09/29/2023] Open
Abstract
The rise in antibiotic-resistant strains of clinically important pathogens is a major threat to global health. The World Health Organization (WHO) has recognized the urgent need to develop alternative treatments to address the growing list of priority pathogens. Antimicrobial peptides (AMPs) rank among the suggested options with proven activity and high potential to be developed into effective drugs. Many AMPs are naturally produced by living organisms protecting the host against pathogens as a part of their innate immunity. Mechanisms associated with AMP actions include cell membrane disruption, cell wall weakening, protein synthesis inhibition, and interference in nucleic acid dynamics, inducing apoptosis and necrosis. Acinetobacter baumannii is a critical pathogen, as severe clinical implications have developed from isolates resistant to current antibiotic treatments and conventional control procedures, such as UV light, disinfectants, and drying. Here, we review the natural AMPs representing primary candidates for new anti-A. baumannii drugs in post-antibiotic-era and present computational tools to develop the next generation of AMPs with greater microbicidal activity and reduced toxicity.
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Affiliation(s)
- Karyne Rangel
- Center for Technological Development in Health (CDTS), National Institute of Science and Technology for Innovation in Neglected Population Diseases (INCT-IDPN), Oswaldo Cruz Institut, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, RJ, Brazil; (K.R.); (G.C.L.); (D.W.P.J.); (C.M.M.)
- Epidemiology and Molecular Systematics Laboratory (LEMS), Oswaldo Cruz Institut, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, RJ, Brazil
| | - Guilherme Curty Lechuga
- Center for Technological Development in Health (CDTS), National Institute of Science and Technology for Innovation in Neglected Population Diseases (INCT-IDPN), Oswaldo Cruz Institut, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, RJ, Brazil; (K.R.); (G.C.L.); (D.W.P.J.); (C.M.M.)
- Epidemiology and Molecular Systematics Laboratory (LEMS), Oswaldo Cruz Institut, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, RJ, Brazil
| | - David W. Provance
- Center for Technological Development in Health (CDTS), National Institute of Science and Technology for Innovation in Neglected Population Diseases (INCT-IDPN), Oswaldo Cruz Institut, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, RJ, Brazil; (K.R.); (G.C.L.); (D.W.P.J.); (C.M.M.)
- Epidemiology and Molecular Systematics Laboratory (LEMS), Oswaldo Cruz Institut, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, RJ, Brazil
| | - Carlos M. Morel
- Center for Technological Development in Health (CDTS), National Institute of Science and Technology for Innovation in Neglected Population Diseases (INCT-IDPN), Oswaldo Cruz Institut, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, RJ, Brazil; (K.R.); (G.C.L.); (D.W.P.J.); (C.M.M.)
| | - Salvatore G. De Simone
- Center for Technological Development in Health (CDTS), National Institute of Science and Technology for Innovation in Neglected Population Diseases (INCT-IDPN), Oswaldo Cruz Institut, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, RJ, Brazil; (K.R.); (G.C.L.); (D.W.P.J.); (C.M.M.)
- Epidemiology and Molecular Systematics Laboratory (LEMS), Oswaldo Cruz Institut, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, RJ, Brazil
- Program of Post-Graduation on Science and Biotechnology, Department of Molecular and Cellular Biology, Biology Institute, Federal Fluminense University, Niterói 22040-036, RJ, Brazil
- Program of Post-Graduation on Parasitic Biology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, RJ, Brazil
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25
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Anthonymuthu S, Sabui S, Lee K, Sheikh A, Fleckenstein JM, Said HM. Bacterial lipopolysaccharide inhibits colonic carrier-mediated uptake of thiamin pyrophosphate: roles for TLR4 receptor and NF-κB/P38/JNK signaling pathway. Am J Physiol Cell Physiol 2023; 325:C758-C769. [PMID: 37519229 PMCID: PMC10635650 DOI: 10.1152/ajpcell.00272.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 07/20/2023] [Accepted: 07/20/2023] [Indexed: 08/01/2023]
Abstract
This study investigated the effect of the bacterial endotoxin lipopolysaccharide (LPS) on colonic uptake of thiamin pyrophosphate (TPP), the biologically active form of vitamin B1 that is generated by gut microbiota. We used three complementary models in our study: in vitro (human-derived colonic epithelial NCM460), ex vivo (human differentiated colonoid monolayers), and in vivo (mouse colonic tissue). The results showed that exposure of NCM460 cells to LPS leads to a significant inhibition of carrier-mediated TPP uptake as well as in decreased expression of the colonic TPP transporter (cTPPT) protein, mRNA, and heterologous nuclear RNA (hnRNA) compared with untreated controls. Similarly, exposure of human differentiated colonoid monolayers and mice to LPS caused significant inhibition in colonic carrier-mediated TPP uptake and in cTPPT protein, mRNA, and hnRNA expression. The effect of LPS on colonic TPP uptake and cTTPT expression was also found to be associated with a significant reduction in activity of the SLC44A4 promoter as well as in decreased expression of the nuclear factor Elf-3 (E74-like ETS transcription factor 3), which is needed for promoter activity. Finally, we found that knocking down the Toll-like receptor 4 (TLR4) and blocking the nuclear factor kappa B (NF-κB), JNK, and p38 signaling pathways with the use of pharmacological inhibitors lead to significant abrogation in the degree of LPS-mediated inhibition in TPP uptake and cTPPT expression. These results demonstrated that exposure of colonic epithelia to LPS inhibits colonic TPP uptake via transcriptional mechanism(s) and that the effect is mediated via TLR4 receptor and NF-κB/p38/JNK signaling pathways.NEW & NOTEWORTHY This study examined the effect of the bacterial lipopolysaccharide (LPS) on the colonic uptake of thiamin pyrophosphate (TPP), the biologically active form of vitamin B1. Three complementary models were used: in vitro (human NCM460 cells), ex vivo (human colonoids), and in vivo (mice). The results showed LPS to significantly suppress TPP uptake and the expression of its transporter, and that these effects are mediated via the membrane TLR4 receptor, and involve the NF-κB/p38/JNK signaling pathways.
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Affiliation(s)
- Selvaraj Anthonymuthu
- Department of Physiology & Biophysics, School of Medicine, University of California, Irvine, California, United States
| | - Subrata Sabui
- Department of Physiology & Biophysics, School of Medicine, University of California, Irvine, California, United States
- Department of Medical Research, Tibor Rubin VA Medical Center, Long Beach, California, United States
| | - Katherine Lee
- Department of Physiology & Biophysics, School of Medicine, University of California, Irvine, California, United States
| | - Alaullah Sheikh
- Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States
| | - James M Fleckenstein
- Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States
- Veterans Affairs Medical Center, St. Louis, Missouri, United States
| | - Hamid M Said
- Department of Physiology & Biophysics, School of Medicine, University of California, Irvine, California, United States
- Department of Medicine, School of Medicine, University of California, Irvine, California, United States
- Department of Medical Research, Tibor Rubin VA Medical Center, Long Beach, California, United States
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26
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Tanabe N, Tomita K, Manaka S, Ichikawa R, Takayama T, Kawato T, Ono M, Masai Y, Utsu A, Suzuki N, Sato S. Co-Stimulation of AGEs and LPS Induces Inflammatory Mediators through PLCγ1/JNK/NF-κB Pathway in MC3T3-E1 Cells. Cells 2023; 12:1383. [PMID: 37408216 PMCID: PMC10216316 DOI: 10.3390/cells12101383] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 04/28/2023] [Accepted: 05/09/2023] [Indexed: 07/07/2023] Open
Abstract
Advanced glycation end-products (AGEs) are increased under hyperglycemia in vivo and are associated with the onset of diabetes. According to previous studies, AGEs exacerbate inflammatory diseases. However, the mechanism by which AGEs aggravate osteoblast inflammation remains unknown. Therefore, the aim of this study was to determine the effects of AGEs on the production of inflammatory mediators in MC3T3-E1 cells and the underlying molecular mechanisms. Co-stimulation with AGEs and lipopolysaccharide (LPS) was found to increase the mRNA and protein levels of cyclooxygenase 2 (COX2), interleukin-1α (IL-1α), S100 calcium-binding protein A9 (S100A9), and the production of prostaglandin E2 (PGE2) compared to no stimulation (untreated control) or individual stimulation with LPS or AGEs. In contrast, the phospholipase C (PLC) inhibitor, U73122, inhibited these stimulatory effects. Co-stimulation with AGEs and LPS also increased the nuclear translocation of nuclear factor-kappa B (NF-κB) compared to no stimulation (untreated control) or individual stimulation with LPS or AGE. However, this increase was inhibited by U73122. Co-stimulation with AGEs and LPS-induced phosphorylated phospholipase Cγ1 (p-PLCγ1) and phosphorylated c-Jun N-terminal kinase (p-JNK) expression compared to no stimulation or individual stimulation with LPS or AGEs. U73122 inhibited the effects induced by co-stimulation. siPLCγ1 did not increase the expression of p-JNK and the translocation of NF-κB. Overall, co-stimulation with AGEs and LPS may promote inflammation mediators in MC3T3-E1 cells by activating the nuclear translocation of NF-κB via PLCγ1-JNK activation.
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Affiliation(s)
- Natsuko Tanabe
- Department of Biochemistry, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan
- Division of Functional Morphology, Dental Research Center, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan
| | - Keiko Tomita
- Department of Periodontology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan
| | - Soichiro Manaka
- Division of Functional Morphology, Dental Research Center, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan
- Department of Periodontology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan
| | - Risa Ichikawa
- Department of Periodontology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan
- Division of Applied Oral Sciences, Nihon University Graduate School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan
| | - Tadahiro Takayama
- Division of Functional Morphology, Dental Research Center, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan
- Department of Periodontology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan
| | - Takayuki Kawato
- Division of Functional Morphology, Dental Research Center, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan
- Department of Oral Health Sciences, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan
| | - Misae Ono
- Department of Periodontology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan
- Division of Applied Oral Sciences, Nihon University Graduate School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan
| | - Yuma Masai
- Department of Periodontology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan
- Division of Applied Oral Sciences, Nihon University Graduate School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan
| | - Akihisa Utsu
- Division of Oral Structural and Functional Biology, Nihon University Graduate School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan
- Department of Orthodontics, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan
| | - Naoto Suzuki
- Department of Biochemistry, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan
- Division of Functional Morphology, Dental Research Center, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan
| | - Shuichi Sato
- Division of Functional Morphology, Dental Research Center, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan
- Department of Periodontology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan
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27
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Cheataini F, Ballout N, Al Sagheer T. The effect of neuroinflammation on the cerebral metabolism at baseline and after neural stimulation in neurodegenerative diseases. J Neurosci Res 2023. [PMID: 37186320 DOI: 10.1002/jnr.25198] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 03/23/2023] [Accepted: 03/29/2023] [Indexed: 05/17/2023]
Abstract
Neuroinflammation is a reaction of nervous tissue to an attack caused by an infection, a toxin, or a neurodegenerative disease. It involves brain metabolism adaptation in order to meet the increased energy needs of glial cell activation, but the nature of these adaptations is still unknown. Increasing interest concerning neuroinflammation leads to the identification of its role in neurodegenerative diseases. Few reports studied the effect of metabolic alteration on neuroinflammation. Metabolic damage initiates a pro-inflammatory response by microglial activation. Moreover, the exact neuroinflammation effect on cerebral cell metabolism remains unknown. In this study, we reviewed systematically the neuroinflammation effect in animal models' brains. All articles showing the relationship of neuroinflammation with brain metabolism, or with neuronal stimulation in neurodegenerative diseases were considered. Moreover, this review examines also the mitochondrial damage effect in neurodegeneration diseases. Then, different biosensors are classified regarding their importance in the determination of metabolite change. Finally, some therapeutic drugs inhibiting neuroinflammation are cited. Neuroinflammation increases lymphocyte infiltration and cytokines' overproduction, altering cellular energy homeostasis. This review demonstrates the importance of neuroinflammation as a mediator of disease progression. Further, the spread of depolarization effects pro-inflammatory genes expression and microglial activation, which contribute to the degeneration of neurons, paving the road to better management and treatment of neurodegenerative diseases.
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Affiliation(s)
- Fatima Cheataini
- Neuroscience Research Center (NRC), Faculty of Medical Science, Lebanese University, Hadath, Beirut, Lebanon
| | - Nissrine Ballout
- Neuroscience Research Center (NRC), Faculty of Medical Science, Lebanese University, Hadath, Beirut, Lebanon
| | - Tareq Al Sagheer
- Neuroscience Research Center (NRC), Faculty of Medical Science, Lebanese University, Hadath, Beirut, Lebanon
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Iacoponi F, Cafarelli A, Fontana F, Pratellesi T, Dumont E, Barravecchia I, Angeloni D, Ricotti L. Optimal low-intensity pulsed ultrasound stimulation for promoting anti-inflammatory effects in macrophages. APL Bioeng 2023; 7:016114. [PMID: 36968453 PMCID: PMC10036142 DOI: 10.1063/5.0137881] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 02/24/2023] [Indexed: 03/24/2023] Open
Abstract
In this paper, we stimulated M1-like macrophages (obtained from U937 cells) with low-intensity pulsed ultrasound (LIPUS) to lower pro-inflammatory cytokine production. A systematic screening of different frequencies, intensities, duty cycles, and exposure times was performed. The optimal stimulation conditions leading to a marked decrease in the release of inflammatory cytokines were determined to be 38 kHz, 250 mW/cm2, 20%, and 90 min, respectively. Using these parameters, we verified that up to 72 h LIPUS did not affect cell viability, resulting in an increase in metabolic activity and in a reduction of reactive oxygen species (ROS) production. Moreover, we found that two mechanosensitive ion channels (PIEZO1 and TRPV1) were involved in the LIPUS-mediated cytokine release modulation. We also assessed the role of the nuclear factor κB (NF-κB) signaling pathway and observed an enhancement of actin polymerization. Finally, transcriptomic data suggested that the bioeffects of LIPUS treatment occur through the modulation of p38 MAPK signaling pathway.
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Affiliation(s)
| | | | | | | | | | - Ivana Barravecchia
- Scuola Superiore Sant'Anna, Piazza Martiri della Libertà 33, 56127 Pisa, Italy
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Haslea ostrearia Pigment Marennine Affects Key Actors of Neuroinflammation and Decreases Cell Migration in Murine Neuroglial Cell Model. Int J Mol Sci 2023; 24:ijms24065388. [PMID: 36982463 PMCID: PMC10049552 DOI: 10.3390/ijms24065388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 03/06/2023] [Accepted: 03/09/2023] [Indexed: 03/16/2023] Open
Abstract
Haslea ostrearia, a cosmopolitan marine pennate diatom, produces a characteristic blue pigment called marennine that causes the greening of filter-feeding organisms, such as oysters. Previous studies evidenced various biological activities of purified marennine extract, such as antibacterial, antioxidant and antiproliferative effects. These effects could be beneficial to human health. However, the specific biological activity of marennine remains to be characterized, especially regarding primary cultures of mammals. In the present study, we aimed to determine in vitro the effects of a purified extract of marennine on neuroinflammatory and cell migratory processes. These effects were assessed at non-cytotoxic concentrations of 10 and 50μg/mL on primary cultures of neuroglial cells. Marennine strongly interacts with neuroinflammatory processes in the immunocompetent cells of the central nervous system, represented by astrocytes and microglial cells. An anti-migratory activity based on a neurospheres migration assay has also been observed. These results encourage further study of Haslea blue pigment effects, particularly the identification of molecular and cellular targets affected by marennine, and strengthen previous studies suggesting that marennine has bioactivities which could be beneficial for human health applications.
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Multi-Species Probiotic Strain Mixture Enhances Intestinal Barrier Function by Regulating Inflammation and Tight Junctions in Lipopolysaccharides Stimulated Caco-2 Cells. Microorganisms 2023; 11:microorganisms11030656. [PMID: 36985228 PMCID: PMC10056128 DOI: 10.3390/microorganisms11030656] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 02/22/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023] Open
Abstract
Although leaky gut syndrome is not recognized as an official diagnosis for human diseases, it is now believed that dysfunction of the cell barrier causes increased permeability of intestinal epithelial cells leading to this condition. Probiotics have been widely used to improve gut health, and studies have investigated the relevance of protecting the intestinal barrier by taking probiotic strains in vitro and in vivo. However, most studies have restricted the use of single or several probiotic strains and do not consider commercially available probiotic products composed of multi-species. In this study, we provide experimental evidence that a multi-species probiotic mixture composed of eight different strains and a heat-treated probiotic strain is effective in preventing leaky gut conditions. We employed an in vitro co-culture model system utilizing two different differentiated cell lines to mimic human intestinal tissue. The integrity of epithelial barrier function was protected by the preserving the occludin protein level and activating the AMPK signaling pathway, associated with tight junctions (TJs), through treatment with the probiotic strain mixture in Caco-2 cells. Moreover, we confirmed that application of the multi-species probiotic mixture reduced the expression of proinflammatory cytokine genes by inhibiting NFκB signaling pathway when artificial inflammation was induced in an in vitro co-culture model system. Finally, we proved that the epithelial permeability measured by trans-epithelial electrical resistance (TEER) was significantly decreased in the probiotic mixture treated cells, indicating that the integrity of the epithelial barrier function was not compromised. The multi-species probiotic strain mixture exhibited the protective effect on the integrity of intestinal barrier function via enhancing TJ complexes and reducing inflammatory responses in the human intestinal cells.
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31
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Wang L, Zhang P, Chen J, Li C, Tian Y, Xu F. Prebiotic properties of the polysaccharide from Rosa roxburghii Tratt fruit and its protective effects in high-fat diet-induced intestinal barrier dysfunction: A fecal microbiota transplantation study. Food Res Int 2023; 164:112400. [PMID: 36737985 DOI: 10.1016/j.foodres.2022.112400] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 12/08/2022] [Accepted: 12/24/2022] [Indexed: 12/28/2022]
Abstract
Polysaccharide from Rosa roxburghii Tratt fruit (RTFP) ameliorates high-fat diet (HFD)-induced colitis in mice. However, it is still unknown whether the gut microbiota can mediate the anti-colitis effects of RTFP in mice. This research aims to investigate the role of gut microbes in modulating RTFP in colitis mice through fecal microbiota transplantation (FMT). The findings demonstrated that RTFP exhibited prebiotic effects on HFD-induced colitis mice. After FMT treatment (transplatation of the microbiota from the fecal sample to each recipient daily), the fecal microbiota of RTFP-treated donor mice remarkably alleviated colitis-related symptoms (e.g., colonic inflammation, loss of body weight, gut microbiota dysbiosis, and loss of barrier integrity) and upregulated the expression of tight junction proteins compared to the HFD-treated donor mice. Overall, RTFP can reduce the severity of HFD-induced colitis by regulating gut microbiota.
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Affiliation(s)
- Lei Wang
- College of Food Science and Engineering, Henan University of Technology, Zhengzhou 450001, China.
| | - Pan Zhang
- College of Food Science and Engineering, Henan University of Technology, Zhengzhou 450001, China
| | - Jie Chen
- College of Food Science and Engineering, Henan University of Technology, Zhengzhou 450001, China.
| | - Chao Li
- School of Food Science and Engineering, South China University of Technology, Guangzhou 510640, China
| | - Yingpeng Tian
- College of Food Science and Engineering, Henan University of Technology, Zhengzhou 450001, China
| | - Fei Xu
- College of Food Science and Engineering, Henan University of Technology, Zhengzhou 450001, China
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Shen K, Bao L, Liu M, Lei W, Zhou Q, Ding J, Fang P, Hu B, Wen C, Kumar V, Peng M, Yang G. Dietary supplementation of β-1, 3-glucan improves the intestinal health of white shrimp ( Litopenaeus vannamei) by modulating intestinal microbiota and inhibiting inflammatory response. Front Immunol 2023; 14:1119902. [PMID: 36793729 PMCID: PMC9922984 DOI: 10.3389/fimmu.2023.1119902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 01/19/2023] [Indexed: 01/31/2023] Open
Abstract
The phenomenon of intestinal dysfunction is widely observed in white shrimp (Litopenaeus vannamei) culture, and β-1,3-glucan has been confirmed to be beneficial in intestinal health with a lack understanding of its underlying mechanism. Proteobacteria, Firmicutes, and Actinobacteria served as the predominant phyla inhabiting the intestine of white shrimp, whilst a significant variation in their proportion was recorded in shrimp fed with basal and β-1,3-glucan supplementation diets in this study. Dietary supplementation of β-1,3-glucan could dramatically increase the microbial diversity and affect microbial composition, concurrent with a notable reduction in the ratio of opportunistic pathogen Aeromonas, gram-negative microbes, from Gammaproteobacteria compared to the basal diet group. The benefits for microbial diversity and composition by β-1,3-glucan improved the homeostasis of intestinal microbiota through the increase of specialists' number and inhibition of microbial competition caused by Aeromonas in ecological networks; afterward, the inhibition of Aeromonas by β-1,3-glucan diet dramatically suppressed microbial metabolism related to lipopolysaccharide biosynthesis, followed by a conspicuous decrease in the intestinal inflammatory response. The improvement of intestinal health referred to the elevation in intestinal immune and antioxidant capacity, ultimately contributing to the growth of shrimp fed β-1,3-glucan. These results suggested that β-1,3-glucan supplementation improved the intestinal health of white shrimp through the modulation of intestinal microbiota homeostasis, the suppression of intestinal inflammatory response, and the elevation of immune and antioxidant capacity, and subsequently promoted the growth of white shrimp.
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Affiliation(s)
- Kaikai Shen
- Department of Fisheries Science, School of Life Science, Nanchang University, Nanchang, China
| | - Lixin Bao
- Department of Fisheries Science, School of Life Science, Nanchang University, Nanchang, China
| | - Muxin Liu
- Department of Fisheries Science, School of Life Science, Nanchang University, Nanchang, China
| | - Wen Lei
- Department of Fisheries Science, School of Life Science, Nanchang University, Nanchang, China
| | - Qin Zhou
- Department of Fisheries Science, School of Life Science, Nanchang University, Nanchang, China
| | - Jiali Ding
- Department of Fisheries Science, School of Life Science, Nanchang University, Nanchang, China
| | - Peng Fang
- School of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, China
| | - Baoqing Hu
- Department of Fisheries Science, School of Life Science, Nanchang University, Nanchang, China
| | - Chungen Wen
- Department of Fisheries Science, School of Life Science, Nanchang University, Nanchang, China
| | - Vikas Kumar
- Aquaculture Research Institute, Department of Animal, Veterinary and Food Sciences, University of Idaho, Moscow, ID, United States
| | - Mo Peng
- School of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, China,*Correspondence: Gang Yang, ; Mo Peng,
| | - Gang Yang
- Department of Fisheries Science, School of Life Science, Nanchang University, Nanchang, China,*Correspondence: Gang Yang, ; Mo Peng,
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33
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Chen H, Cao T, Zhang B, Cai H. The regulatory effects of second-generation antipsychotics on lipid metabolism: Potential mechanisms mediated by the gut microbiota and therapeutic implications. Front Pharmacol 2023; 14:1097284. [PMID: 36762113 PMCID: PMC9905135 DOI: 10.3389/fphar.2023.1097284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Accepted: 01/12/2023] [Indexed: 01/26/2023] Open
Abstract
Second-generation antipsychotics (SGAs) are the mainstay of treatment for schizophrenia and other neuropsychiatric diseases but cause a high risk of disruption to lipid metabolism, which is an intractable therapeutic challenge worldwide. Although the exact mechanisms underlying this lipid disturbance are complex, an increasing body of evidence has suggested the involvement of the gut microbiota in SGA-induced lipid dysregulation since SGA treatment may alter the abundance and composition of the intestinal microflora. The subsequent effects involve the generation of different categories of signaling molecules by gut microbes such as endogenous cannabinoids, cholesterol, short-chain fatty acids (SCFAs), bile acids (BAs), and gut hormones that regulate lipid metabolism. On the one hand, these signaling molecules can directly activate the vagus nerve or be transported into the brain to influence appetite via the gut-brain axis. On the other hand, these molecules can also regulate related lipid metabolism via peripheral signaling pathways. Interestingly, therapeutic strategies directly targeting the gut microbiota and related metabolites seem to have promising efficacy in the treatment of SGA-induced lipid disturbances. Thus, this review provides a comprehensive understanding of how SGAs can induce disturbances in lipid metabolism by altering the gut microbiota.
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Affiliation(s)
- Hui Chen
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China,Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China,Institute of Clinical Pharmacy, Central South University, Changsha, China,International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, Hunan, China
| | - Ting Cao
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China,Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China,Institute of Clinical Pharmacy, Central South University, Changsha, China,International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, Hunan, China
| | - Bikui Zhang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China,Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China,Institute of Clinical Pharmacy, Central South University, Changsha, China,International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, Hunan, China,*Correspondence: Bikui Zhang, ; Hualin Cai,
| | - Hualin Cai
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China,Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China,Institute of Clinical Pharmacy, Central South University, Changsha, China,International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, Hunan, China,*Correspondence: Bikui Zhang, ; Hualin Cai,
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Manilla V, Di Tommaso N, Santopaolo F, Gasbarrini A, Ponziani FR. Endotoxemia and Gastrointestinal Cancers: Insight into the Mechanisms Underlying a Dangerous Relationship. Microorganisms 2023; 11:microorganisms11020267. [PMID: 36838231 PMCID: PMC9963870 DOI: 10.3390/microorganisms11020267] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 01/14/2023] [Accepted: 01/17/2023] [Indexed: 01/21/2023] Open
Abstract
Lipopolysaccharide (LPS), also known as endotoxin, is a component of the membrane of gram-negative bacteria and a well-recognized marker of sepsis. In case of disruption of the intestinal barrier, as occurs with unhealthy diets, alcohol consumption, or during chronic diseases, the microbiota residing in the gastrointestinal tract becomes a crucial factor in amplifying the systemic inflammatory response. Indeed, the translocation of LPS into the bloodstream and its interaction with toll-like receptors (TLRs) triggers molecular pathways involved in cytokine release and immune dysregulation. This is a critical step in the exacerbation of many diseases, including metabolic disorders and cancer. Indeed, the role of LPS in cancer development is widely recognized, and examples include gastric tumor related to Helicobacter pylori infection and hepatocellular carcinoma, both of which are preceded by a prolonged inflammatory injury; in addition, the risk of recurrence and development of metastasis appears to be associated with endotoxemia. Here, we review the mechanisms that link the promotion and progression of tumorigenesis with endotoxemia, and the possible therapeutic interventions that can be deployed to counteract these events.
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Affiliation(s)
- Vittoria Manilla
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Natalia Di Tommaso
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Francesco Santopaolo
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Translational Medicine and Surgery Department, Catholic University of the Sacred Heart, 00168 Rome, Italy
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Translational Medicine and Surgery Department, Catholic University of the Sacred Heart, 00168 Rome, Italy
- Correspondence:
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Tomassen MMM, Govers C, Vos AP, de Wit NJW. Dietary fat induced chylomicron-mediated LPS translocation in a bicameral Caco-2cell model. Lipids Health Dis 2023; 22:4. [PMID: 36635716 PMCID: PMC9835336 DOI: 10.1186/s12944-022-01754-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 12/08/2022] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND There is increasing evidence that dietary fat, especially saturated fat, promotes the translocation of lipopolysaccharide (LPS) via chylomicron production in the gut. Chylomicrons can subsequently transport LPS to other parts of the body, where they can induce low-grade chronic inflammation that is linked to various metabolic and gut-related diseases. To identify promising (food) compounds that can prevent or ameliorate LPS-related low-grade inflammation, we developed and optimized a bicameral in vitro model for dietary fat-induced LPS translocation that closely mimics the in vivo situation and facilitates high-throughput screening. METHODS Caco-2 cells were cultured in monolayers and differentiated to a small intestinal phenotype in 21 days. Thereafter, optimal conditions for fat-induced chylomicron production were determined by apical exposure of Caco-2 cells to a dilution range of in vitro digested palm oil and sunflower oil, optionally preceded by a 1-week apical FBS deprivation (cultured without apical fetal bovine serum). Chylomicron production was assessed by measuring basolateral levels of the chylomicron-related marker apolipoprotein B. Next, LPS was coincubated at various concentrations with the digested oils, and fat-induced LPS translocation to the basolateral side was assessed. RESULTS We found that dietary fat-induced LPS translocation in Caco-2 cells was optimal after apical exposure to digested oils at a 1:50 dilution in combination with 750 ng/mL LPS, preceded by 1 week of apical FBS deprivation. Coincubation with the chylomicron blocker Pluronic L81 confirmed that fat-induced LPS translocation is mediated via chylomicron production in this Caco-2 cell model. CONCLUSION We developed a robust Caco-2 cell model for dietary fat-induced LPS translocation that can be used for high-throughput screening of (food) compounds that can reduce LPS-related low-grade inflammation.
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Affiliation(s)
- Monic M. M. Tomassen
- grid.4818.50000 0001 0791 5666Wageningen Food & Biobased Research, Wageningen University & Research, Wageningen, The Netherlands ,grid.4818.50000 0001 0791 5666Wageningen Food & Biobased Research – Food Health & Consumer Research group, Bornse Weilanden 9, 6708 WG Wageningen, The Netherlands
| | - Coen Govers
- grid.4818.50000 0001 0791 5666Wageningen Food & Biobased Research, Wageningen University & Research, Wageningen, The Netherlands ,grid.4818.50000 0001 0791 5666Cell Biology and Immunology Group, Wageningen University & Research, Wageningen, The Netherlands
| | - A. Paul Vos
- grid.4818.50000 0001 0791 5666Wageningen Food & Biobased Research, Wageningen University & Research, Wageningen, The Netherlands
| | - Nicole J. W. de Wit
- grid.4818.50000 0001 0791 5666Wageningen Food & Biobased Research, Wageningen University & Research, Wageningen, The Netherlands
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Liang H, Song H, Zhang X, Song G, Wang Y, Ding X, Duan X, Li L, Sun T, Kan Q. Metformin attenuated sepsis-related liver injury by modulating gut microbiota. Emerg Microbes Infect 2022; 11:815-828. [PMID: 35191819 PMCID: PMC8928825 DOI: 10.1080/22221751.2022.2045876] [Citation(s) in RCA: 97] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 02/13/2022] [Accepted: 02/19/2022] [Indexed: 12/13/2022]
Abstract
Increased evidence shows that gut microbiota acts as the primary regulator of the liver; however, its role in sepsis-related liver injury (SLI) in the elderly is unclear. This study assessed whether metformin could attenuate SLI by modulating gut microbiota in septic-aged rats. Cecal ligation and puncture (CLP) was used to induce SLI in aged rats. Fecal microbiota transplantation (FMT) was used to validate the roles of gut microbiota in these pathologies. The composition of gut microbiota was analysed by 16S rRNA sequencing. Moreover, the liver and colon tissues were analysed by histopathology, immunofluorescence, immunohistochemistry, and reverse transcription polymerase chain reaction (RT-PCR). Metformin improved liver damage, colon barrier dysfunction in aged SLI rats. Moreover, metformin improved sepsis-induced liver inflammation and damage under gut microbiota. Importantly, FMT assay showed that rats gavaged with faeces from metformin-treated SLI rats displayed less severe liver damage and colon barrier dysfunctions than those gavaged with faeces from SLI rats. The gut microbiota composition among the sham-operated, CLP-operated and metformin-treated SLI rats was different. In particular, the proportion of Klebsiella and Escherichia_Shigella was higher in SLI rats than sham-operated and metformin-treated SLI rats; while metformin could increase the proportion of Bifidobacterium, Muribaculaceae, Parabacteroides_distasonis and Alloprevitella in aged SLI rats. Additionally, Klebsiella and Escherichia_Shigella correlated positively with the inflammatory factors in the liver. Our findings suggest that metformin may improve liver injury by regulating the gut microbiota and alleviating colon barrier dysfunction in septic-aged rats, which may be an effective therapy for SLI.
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Affiliation(s)
- Huoyan Liang
- General ICU, The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Critical Care Medicine, Zhengzhou Key Laboratory of Sepsis, Henan Engineering Research Center for Critical Care Medicine, Zhengzhou, People’s Republic of China
- Academy of Medical Sciences, Zhengzhou University, Zhengzhou, People’s Republic of China
| | - Heng Song
- General ICU, The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Critical Care Medicine, Zhengzhou Key Laboratory of Sepsis, Henan Engineering Research Center for Critical Care Medicine, Zhengzhou, People’s Republic of China
- Academy of Medical Sciences, Zhengzhou University, Zhengzhou, People’s Republic of China
| | - Xiaojuan Zhang
- General ICU, The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Critical Care Medicine, Zhengzhou Key Laboratory of Sepsis, Henan Engineering Research Center for Critical Care Medicine, Zhengzhou, People’s Republic of China
| | - Gaofei Song
- General ICU, The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Critical Care Medicine, Zhengzhou Key Laboratory of Sepsis, Henan Engineering Research Center for Critical Care Medicine, Zhengzhou, People’s Republic of China
- Academy of Medical Sciences, Zhengzhou University, Zhengzhou, People’s Republic of China
| | - Yuze Wang
- General ICU, The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Critical Care Medicine, Zhengzhou Key Laboratory of Sepsis, Henan Engineering Research Center for Critical Care Medicine, Zhengzhou, People’s Republic of China
| | - Xianfei Ding
- General ICU, The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Critical Care Medicine, Zhengzhou Key Laboratory of Sepsis, Henan Engineering Research Center for Critical Care Medicine, Zhengzhou, People’s Republic of China
| | - Xiaoguang Duan
- General ICU, The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Critical Care Medicine, Zhengzhou Key Laboratory of Sepsis, Henan Engineering Research Center for Critical Care Medicine, Zhengzhou, People’s Republic of China
| | - Lifeng Li
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Internet Medical and System Applications of National Engineering Laboratory, Zhengzhou, People’s Republic of China
| | - Tongwen Sun
- General ICU, The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Critical Care Medicine, Zhengzhou Key Laboratory of Sepsis, Henan Engineering Research Center for Critical Care Medicine, Zhengzhou, People’s Republic of China
- Academy of Medical Sciences, Zhengzhou University, Zhengzhou, People’s Republic of China
| | - Quancheng Kan
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China
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Chen N, Fu Y, Wang ZX, Zhao XH. Casein Lactose-Glycation of the Maillard-Type Attenuates the Anti-Inflammatory Potential of Casein Hydrolysate to IEC-6 Cells with Lipopolysaccharide Stimulation. Nutrients 2022; 14:nu14235067. [PMID: 36501097 PMCID: PMC9741451 DOI: 10.3390/nu14235067] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 11/09/2022] [Accepted: 11/27/2022] [Indexed: 11/30/2022] Open
Abstract
During the thermal processing of dairy products, the Maillard reaction occurs between milk proteins and lactose, resulting in the formation of various products including glycated proteins. In this study, lactose-glycated casein was generated through the Maillard reaction between casein and lactose and then hydrolyzed by a trypsin preparation. The anti-inflammatory effect of the resultant glycated casein hydrolysate (GCH) was investigated using the lipopolysaccharide (LPS)-sitmulated rat intestinal epithelial (IEC-6) cells as a cell model and corresponding casein hydrolysate (CH) as a control. The results indicated that the preformed glycation enabled lactose conjugation to casein, which endowed GCH with a lactose content of 12.61 g/kg protein together with a lower activity than CH to enhance the viability value of the IEC-6 cells. The cells with LPS stimulation showed significant inflammatory responses, while a pre-treatment of the cells with GCH before LPS stimulation consistently led to a decreased secretion of three pro-inflammatory mediators, namely, IL-6, IL-1β and tumor necrosis factor-α (TNF-α) but an increased secretion of two anti-inflammatory mediators, including IL-10 and transforming growth factor-β (TGF-β), demonstrating the anti-inflammatory potential of GCH in LPS-stimulated cells. In addition, GCH up-regulated the expression of TLR4, p-p38, and p-p65 proteins in the stimulated cells, resulting in the suppression of NF-κB and MAPK signaling pathways. Collectively, GCH was mostly less efficient than CH to exert these assessed anti-inflammatory activities in the cells and more importantly, GCH also showed an ability to cause cell inflammation by promoting IL-6 secretion and up-regulating the expression of TLR4 and p-p65. The casein lactose-glycation of the Maillard-type was thereby concluded to attenuate the anti-inflammatory potential of the resultant casein hydrolysate. It is highlighted that the casein lactose-glycation of the Maillard-type might cause a negative impact on the bioactivity of casein in the intestine, because the glycated casein after digestion could release GCH with reduced anti-inflammatory activity.
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Affiliation(s)
- Na Chen
- Maoming Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong University of Petrochemical Technology, Maoming 525000, China
- School of Biological and Food Engineering, Guangdong University of Petrochemical Technology, Maoming 525000, China
- Research Centre of Food Nutrition and Human Healthcare, Guangdong University of Petrochemical, Maoming 525000, China
| | - Yu Fu
- College of Food Science, Southwest University, Chongqing 400715, China
| | - Zhen-Xing Wang
- Maoming Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong University of Petrochemical Technology, Maoming 525000, China
- School of Biological and Food Engineering, Guangdong University of Petrochemical Technology, Maoming 525000, China
- Research Centre of Food Nutrition and Human Healthcare, Guangdong University of Petrochemical, Maoming 525000, China
| | - Xin-Huai Zhao
- Maoming Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong University of Petrochemical Technology, Maoming 525000, China
- School of Biological and Food Engineering, Guangdong University of Petrochemical Technology, Maoming 525000, China
- Research Centre of Food Nutrition and Human Healthcare, Guangdong University of Petrochemical, Maoming 525000, China
- Correspondence: or ; Tel.: +86-668-2923716
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Wang W, Jiang S, Xu C, Tang L, Liang Y, Zhao Y, Zhu G. Interactions between gut microbiota and Parkinson's disease: The role of microbiota-derived amino acid metabolism. Front Aging Neurosci 2022; 14:976316. [PMID: 36408101 PMCID: PMC9667037 DOI: 10.3389/fnagi.2022.976316] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 08/29/2022] [Indexed: 11/05/2022] Open
Abstract
Non-motor symptoms (NMS) of Parkinson's disease (PD), such as constipation, sleep disorders, and olfactory deficits, may emerge up to 20 years earlier than motor symptoms. A series of evidence indicates that the pathology of PD may occur from the gastrointestinal tract to the brain. Numerous studies support that the gut microbiota communicates with the brain through the immune system, special amino acid metabolism, and the nervous system in PD. Recently, there is growing recognition that the gut microbiota plays a vital role in the modulation of multiple neurochemical pathways via the “gut microbiota-brain axis” (GMBA). Many gut microbiota metabolites, such as fatty acids, amino acids, and bile acids, convey signaling functions as they mediate the crosstalk between gut microbiota and host physiology. Amino acids' abundance and species alteration, including glutamate and tryptophan, may disturb the signaling transmission between nerve cells and disrupt the normal basal ganglia function in PD. Specific amino acids and their receptors are considered new potential targets for ameliorating PD. The present study aimed to systematically summarize all available evidence on the gut microbiota-derived amino acid metabolism alterations associated with PD.
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Affiliation(s)
- Wang Wang
- Department of Neurology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Shujun Jiang
- Chinese Medicine Modernization and Big Data Research Center, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Chengcheng Xu
- Department of Neurology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Lili Tang
- Department of Neurology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yan Liang
- Department of Neurology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yang Zhao
- Department of Neurology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- *Correspondence: Yang Zhao
| | - Guoxue Zhu
- Department of Neurology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Chinese Medicine Modernization and Big Data Research Center, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Guoxue Zhu
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Yu HJ, Wang LJ, Huang K, Guo QF, Lin BY, Liu YY, Yu M, Ma GP. PPAR-γ agonist pioglitazone alleviates inflammatory response induced by lipopolysaccharides in osteoblast cells. J Orthop Res 2022; 40:2471-2479. [PMID: 35072290 DOI: 10.1002/jor.25279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 10/19/2021] [Accepted: 01/16/2022] [Indexed: 02/04/2023]
Abstract
Osteomyelitis is an acute or chronic inflammatory bone disease with a high disability rate. As an anti-inflammatory factor, peroxisome proliferator activated receptor-γ (PPAR-γ) is not only implicated in a variety of inflammatory responses but also regulates osteoblast differentiation and bone mass. However, the role of PPAR-γ in osteomyelitis is not fully understood. In the present study, we demonstrated that PPAR-γ showed a lower expression level in infected bone tissue of osteomyelitis patients as compared with uninfected bone tissue from nonosteomyelitis patients with fracture of the hip. We applied lipopolysaccharides (LPSs) in MC3T3-E1 osteoblast precursor cell line as an in vitro model for osteomyelitis. LPS treatment increased osteomyelitis-associated inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), whereas PPAR-γ levels and cell viability in MC3T3-E1 cells were suppressed. PPAR-γ antagonist GW9662 further enhanced IL-6 and TNF-α levels, and decreased cell viability in the presence of LPS treatment. In contrast, PPAR-γ agonist pioglitazone antagonized the effect of LPS treatment in MC3T3-E1 cells. These findings suggest that PPAR-γ downregulation is associated with the inflammation and progression of osteomyelitis, and PPAR-γ agonist could serve as a therapeutic strategy to attenuate inflammatory responses. This study provides novel insights into the physiopathogenesis of osteomyelitis and future study is required to validate the findings in animal model and uncover the molecular mechanism of PPAR-γ-dependent anti-inflammation in osteoblasts.
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Affiliation(s)
- Hua-Jun Yu
- Department of Orthopaedics, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Lai-Jie Wang
- Department of Orthopaedics, Huai'An People's Hospital Of Hongze District Jiangsu Province, Huai'An, China
| | - Kai Huang
- Department of Orthopaedics, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Qiao-Feng Guo
- Department of Orthopaedics, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Bing-Yuan Lin
- Department of Orthopaedics, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Yi-Yang Liu
- Department of Orthopaedics, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Ming Yu
- Department of Orthopedics, Haihe Hospital of Tianjin University, Tianjin, China
| | - Gou-Ping Ma
- Department of Orthopaedics, Tongde Hospital of Zhejiang Province, Hangzhou, China
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Dudek B, Rybka J, Bugla-Płoskońska G, Korzeniowska-Kowal A, Futoma-Kołoch B, Pawlak A, Gamian A. Biological functions of sialic acid as a component of bacterial endotoxin. Front Microbiol 2022; 13:1028796. [PMID: 36338080 PMCID: PMC9631793 DOI: 10.3389/fmicb.2022.1028796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 10/05/2022] [Indexed: 11/28/2022] Open
Abstract
Lipopolysaccharide (endotoxin, LPS) is an important Gram-negative bacteria antigen. LPS of some bacteria contains sialic acid (Neu5Ac) as a component of O-antigen (O-Ag), in this review we present an overview of bacteria in which the presence of Neu5Ac has been confirmed in their outer envelope and the possible ways that bacteria can acquire Neu5Ac. We explain the role of Neu5Ac in bacterial pathogenesis, and also involvement of Neu5Ac in bacterial evading the host innate immunity response and molecular mimicry phenomenon. We also highlight the role of sialic acid in the mechanism of bacterial resistance to action of serum complement. Despite a number of studies on involvement of Neu5Ac in bacterial pathogenesis many aspects of this phenomenon are still not understood.
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Affiliation(s)
- Bartłomiej Dudek
- Department of Microbiology, University of Wrocław, Wrocław, Poland
- *Correspondence: Bartłomiej Dudek,
| | - Jacek Rybka
- Department of Immunology of Infectious Diseases, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
| | | | - Agnieszka Korzeniowska-Kowal
- Department of Immunology of Infectious Diseases, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
| | | | | | - Andrzej Gamian
- Department of Immunology of Infectious Diseases, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
- Andrzej Gamian,
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Li J, Fang P, Yi X, Kumar V, Peng M. Probiotics Bacillus cereus and B. subtilis reshape the intestinal microbiota of Pengze crucian carp (Carassius auratus var. Pengze) fed with high plant protein diets. Front Nutr 2022; 9:1027641. [PMID: 36337612 PMCID: PMC9627213 DOI: 10.3389/fnut.2022.1027641] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 10/03/2022] [Indexed: 11/19/2022] Open
Abstract
The intestinal dysfunction induced by high plant protein diets is frequently observed in farmed fish, and probiotics of Bacillus genus were documented to benefit the intestinal health through the modulation of intestinal microbiota without clearness in its underlying mechanism yet. Fusobacteria, Proteobacteria, and Firmicutes were observed to be the dominate phyla, but their proportion differentiated in the intestinal bacterial community of Pengze crucian carp (Carassius auratus var. Pengze) fed different diets in this study. Dietary supplementation of B. cereus and B. subtilis could reshape the intestinal bacterial community altered by high plant protein diets through a notable reduction in opportunistic pathogen Aeromonas together with an increase in Romboutsia and/or Clostridium_sensu_stricto from Firmicutes. Due to the alteration in the composition of bacterial community, Pengze crucian carp exhibited characteristic ecological networks dominated by cooperative interactions. Nevertheless, the increase in Aeromonas intensified the competition within bacterial communities and reduced the number of specialists within ecological network, contributing to the microbial dysbiosis induced by high plant protein diets. Two probiotics diets promoted the cooperation within the intestinal bacterial community and increased the number of specialists preferred to module hubs, and then further improved the homeostasis of the intestinal microbiota. Microbial dysbiosis lead to microbial dysfunction, and microbial lipopolysaccharide biosynthesis was observed to be elevated in high plant protein diets due to the increase in Aeromonas, gram-negative microbe. Probiotics B. cereus and B. subtilis restored the microbial function by elevating their amino acid and carbohydrate metabolism together with the promotion in the synthesis of primary and secondary bile acids. These results suggested that dietary supplementation of probiotics B. cereus and B. subtilis could restore the homeostasis and functions of intestinal microbiota in Pengze crucian carp fed high plant protein diets.
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Affiliation(s)
- Jiamin Li
- School of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, China
| | - Peng Fang
- School of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, China
| | - Xinwen Yi
- Shenzhen Aohua Group Co., Ltd., Shenzhen, China
| | - Vikas Kumar
- Department of Animal, Veterinary and Food Sciences, Aquaculture Research Institute, University of Idaho, Moscow, ID, United States
| | - Mo Peng
- School of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, China
- *Correspondence: Mo Peng
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Clerbaux LA, Mayasich SA, Muñoz A, Soares H, Petrillo M, Albertini MC, Lanthier N, Grenga L, Amorim MJ. Gut as an Alternative Entry Route for SARS-CoV-2: Current Evidence and Uncertainties of Productive Enteric Infection in COVID-19. J Clin Med 2022; 11:5691. [PMID: 36233559 PMCID: PMC9573230 DOI: 10.3390/jcm11195691] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/17/2022] [Accepted: 09/20/2022] [Indexed: 12/15/2022] Open
Abstract
The gut has been proposed as a potential alternative entry route for SARS-CoV-2. This was mainly based on the high levels of SARS-CoV-2 receptor expressed in the gastrointestinal (GI) tract, the observations of GI disorders (such as diarrhea) in some COVID-19 patients and the detection of SARS-CoV-2 RNA in feces. However, the underlying mechanisms remain poorly understood. It has been proposed that SARS-CoV-2 can productively infect enterocytes, damaging the intestinal barrier and contributing to inflammatory response, which might lead to GI manifestations, including diarrhea. Here, we report a methodological approach to assess the evidence supporting the sequence of events driving SARS-CoV-2 enteric infection up to gut adverse outcomes. Exploring evidence permits to highlight knowledge gaps and current inconsistencies in the literature and to guide further research. Based on the current insights on SARS-CoV-2 intestinal infection and transmission, we then discuss the potential implication on clinical practice, including on long COVID. A better understanding of the GI implication in COVID-19 is still needed to improve disease management and could help identify innovative therapies or preventive actions targeting the GI tract.
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Affiliation(s)
| | - Sally A. Mayasich
- University of Wisconsin-Madison Aquatic Sciences Center at US EPA, Duluth, MN 55804, USA
| | - Amalia Muñoz
- European Commission, Joint Research Centre (JRC), 2440 Geel, Belgium
| | - Helena Soares
- Laboratory of Human Immunobiology and Pathogenesis, iNOVA4Health, Faculdade de Ciências Médicas—Nova Medical School, Universidade Nova de Lisboa, 1099-085 Lisbon, Portugal
| | | | | | - Nicolas Lanthier
- Laboratory of Hepatogastroenterology, Service d’Hépato-Gastroentérologie, Cliniques Universitaires Saint-Luc, UCLouvain, 1200 Brussels, Belgium
| | - Lucia Grenga
- Département Médicaments et Technologies pour la Santé, Commissariat à l’Énergie Atomique et aux Énergies Alternatives (CEA), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Paris-Saclay, 91190 Paris, France
| | - Maria-Joao Amorim
- Instituto Gulbenkian de Ciência, 2780-156 Lisbon, Portugal
- Católica Biomedical Research Centre, Católica Medical School, Universidade Católica Portuguesa, 1649-023 Lisbon, Portugal
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Luo J, Lu J, Zeng J, Ma Y, Gong Q, Wang Z, Zhang X, Quan J. Single-cell RNA analysis of chemokine expression in heterogeneous CD14 + monocytes with lipopolysaccharide-induced bone resorption. Exp Cell Res 2022; 420:113343. [PMID: 36088998 DOI: 10.1016/j.yexcr.2022.113343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 08/31/2022] [Accepted: 09/04/2022] [Indexed: 11/27/2022]
Abstract
Lipopolysaccharide (LPS)-induced bone resorption has normally been found in inflammatory bone diseases, but the underlying mechanism is currently unclear. Since LPS binds to CD14 and activates Toll-like receptor 4 (TLR4) in monocytes, the present study focused on CD14+ monocytes and observed their responses after LPS treatment during the progression of local bone destruction. CD14+ monocytes were obtained from human peripheral blood mononuclear cells (PBMCs) by magnetic cell separation (MACS), and their classification was confirmed by fluorescence-activated cell sorting (FACS). Single-cell RNA sequencing (scRNA-seq) was further utilized to analyze their subpopulations, and the results showed that physiological CD14+ monocytes were heterogeneous and divided into 6 subsets, that could be easily agitated. After priming with a suitable concentration of LPS, heterogeneous CD14+ monocytes became pathological and expressed a large number of chemokines as a "cascade effect". Some of these chemokines have been validated in an animal model of mouse calvarial bone invasion. Taken together, our research has linked enhanced chemokine expression with stimulation of heterogeneous CD14+ monocytes, and indicated that inflammatory responses caused by microbiome infection are responsible for the recruitment and mobilization of CD14+ monocytes into bone resorption sites, which may explain the pathogenesis of LPS-associated bone diseases.
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Affiliation(s)
- Junpan Luo
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University and Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong, 510080, PR China
| | - Jiarui Lu
- Department of Stomatology, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025 Shennan Middle Road, Shenzhen, Guangdong, 518033, PR China
| | - Jie Zeng
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yuanyuan Ma
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University and Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong, 510080, PR China
| | - Qimei Gong
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University and Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong, 510080, PR China
| | - Zhuyu Wang
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University and Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong, 510080, PR China
| | - Xiaolei Zhang
- Department of Stomatology, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025 Shennan Middle Road, Shenzhen, Guangdong, 518033, PR China.
| | - Jingjing Quan
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University and Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong, 510080, PR China.
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Aschner M, Skalny AV, Ke T, da Rocha JBT, Paoliello MMB, Santamaria A, Bornhorst J, Rongzhu L, Svistunov AA, Djordevic AB, Tinkov AA. Hydrogen Sulfide (H 2S) Signaling as a Protective Mechanism against Endogenous and Exogenous Neurotoxicants. Curr Neuropharmacol 2022; 20:1908-1924. [PMID: 35236265 PMCID: PMC9886801 DOI: 10.2174/1570159x20666220302101854] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 02/10/2022] [Accepted: 02/27/2022] [Indexed: 11/22/2022] Open
Abstract
In view of the significant role of H2S in brain functioning, it is proposed that H2S may also possess protective effects against adverse effects of neurotoxicants. Therefore, the objective of the present review is to discuss the neuroprotective effects of H2S against toxicity of a wide spectrum of endogenous and exogenous agents involved in the pathogenesis of neurological diseases as etiological factors or key players in disease pathogenesis. Generally, the existing data demonstrate that H2S possesses neuroprotective effects upon exposure to endogenous (amyloid β, glucose, and advanced-glycation end-products, homocysteine, lipopolysaccharide, and ammonia) and exogenous (alcohol, formaldehyde, acrylonitrile, metals, 6-hydroxydopamine, as well as 1-methyl-4-phenyl- 1,2,3,6- tetrahydropyridine (MPTP) and its metabolite 1-methyl-4-phenyl pyridine ion (MPP)) neurotoxicants. On the one hand, neuroprotective effects are mediated by S-sulfhydration of key regulators of antioxidant (Sirt1, Nrf2) and inflammatory response (NF-κB), resulting in the modulation of the downstream signaling, such as SIRT1/TORC1/CREB/BDNF-TrkB, Nrf2/ARE/HO-1, or other pathways. On the other hand, H2S appears to possess a direct detoxicative effect by binding endogenous (ROS, AGEs, Aβ) and exogenous (MeHg) neurotoxicants, thus reducing their toxicity. Moreover, the alteration of H2S metabolism through the inhibition of H2S-synthetizing enzymes in the brain (CBS, 3-MST) may be considered a significant mechanism of neurotoxicity. Taken together, the existing data indicate that the modulation of cerebral H2S metabolism may be used as a neuroprotective strategy to counteract neurotoxicity of a wide spectrum of endogenous and exogenous neurotoxicants associated with neurodegeneration (Alzheimer's and Parkinson's disease), fetal alcohol syndrome, hepatic encephalopathy, environmental neurotoxicant exposure, etc. In this particular case, modulation of H2S-synthetizing enzymes or the use of H2S-releasing drugs should be considered as the potential tools, although the particular efficiency and safety of such interventions are to be addressed in further studies.
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Affiliation(s)
- Michael Aschner
- Address correspondence to this author at the Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; E-mail
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Monoclonal Antibodies for Bacterial Pathogens: Mechanisms of Action and Engineering Approaches for Enhanced Effector Functions. Biomedicines 2022; 10:biomedicines10092126. [PMID: 36140226 PMCID: PMC9496014 DOI: 10.3390/biomedicines10092126] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 08/04/2022] [Accepted: 08/11/2022] [Indexed: 11/17/2022] Open
Abstract
Monoclonal antibody (mAb) therapy has opened a new era in the pharmaceutical field, finding application in various areas of research, from cancer to infectious diseases. The IgG isoform is the most used therapeutic, given its long half-life, high serum abundance, and most importantly, the presence of the Fc domain, which can be easily engineered. In the infectious diseases field, there has been a rising interest in mAbs research to counteract the emerging crisis of antibiotic resistance in bacteria. Various pathogens are acquiring resistance mechanisms, inhibiting any chance of success of antibiotics, and thus may become critically untreatable in the near future. Therefore, mAbs represent a new treatment option which may complement or even replace antibiotics. However, very few antibacterial mAbs have succeeded clinical trials, and until now, only three mAbs have been approved by the FDA. These failures highlight the need of improving the efficacy of mAb therapeutic activity, which can also be achieved with Fc engineering. In the first part of this review, we will describe the mechanisms of action of mAbs against bacteria, while in the second part, we will discuss the recent advances in antibody engineering to increase efficacy of pre-existing anti-bacterial mAbs.
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Clerbaux LA, Albertini MC, Amigó N, Beronius A, Bezemer GFG, Coecke S, Daskalopoulos EP, del Giudice G, Greco D, Grenga L, Mantovani A, Muñoz A, Omeragic E, Parissis N, Petrillo M, Saarimäki LA, Soares H, Sullivan K, Landesmann B. Factors Modulating COVID-19: A Mechanistic Understanding Based on the Adverse Outcome Pathway Framework. J Clin Med 2022; 11:4464. [PMID: 35956081 PMCID: PMC9369763 DOI: 10.3390/jcm11154464] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 07/05/2022] [Accepted: 07/06/2022] [Indexed: 12/10/2022] Open
Abstract
Addressing factors modulating COVID-19 is crucial since abundant clinical evidence shows that outcomes are markedly heterogeneous between patients. This requires identifying the factors and understanding how they mechanistically influence COVID-19. Here, we describe how eleven selected factors (age, sex, genetic factors, lipid disorders, heart failure, gut dysbiosis, diet, vitamin D deficiency, air pollution and exposure to chemicals) influence COVID-19 by applying the Adverse Outcome Pathway (AOP), which is well-established in regulatory toxicology. This framework aims to model the sequence of events leading to an adverse health outcome. Several linear AOPs depicting pathways from the binding of the virus to ACE2 up to clinical outcomes observed in COVID-19 have been developed and integrated into a network offering a unique overview of the mechanisms underlying the disease. As SARS-CoV-2 infectibility and ACE2 activity are the major starting points and inflammatory response is central in the development of COVID-19, we evaluated how those eleven intrinsic and extrinsic factors modulate those processes impacting clinical outcomes. Applying this AOP-aligned approach enables the identification of current knowledge gaps orientating for further research and allows to propose biomarkers to identify of high-risk patients. This approach also facilitates expertise synergy from different disciplines to address public health issues.
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Affiliation(s)
- Laure-Alix Clerbaux
- European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy; (S.C.); (E.P.D.); (N.P.); (M.P.); (B.L.)
| | | | - Núria Amigó
- Biosfer Teslab SL., 43204 Reus, Spain;
- Department of Basic Medical Sciences, Universitat Rovira i Virgili (URV), 23204 Reus, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Anna Beronius
- Institute of Environmental Medicine, Karolinska Institutet, 17177 Stockholm, Sweden;
| | - Gillina F. G. Bezemer
- Impact Station, 1223 JR Hilversum, The Netherlands;
- Department of Pharmaceutical Sciences, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands
| | - Sandra Coecke
- European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy; (S.C.); (E.P.D.); (N.P.); (M.P.); (B.L.)
| | - Evangelos P. Daskalopoulos
- European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy; (S.C.); (E.P.D.); (N.P.); (M.P.); (B.L.)
| | - Giusy del Giudice
- Finnish Hub for Development and Validation of Integrated Approaches (FHAIVE), Faculty of Medicine and Health Technology, Tampere University, 33100 Tampere, Finland; (G.d.G.); (D.G.); (L.A.S.)
| | - Dario Greco
- Finnish Hub for Development and Validation of Integrated Approaches (FHAIVE), Faculty of Medicine and Health Technology, Tampere University, 33100 Tampere, Finland; (G.d.G.); (D.G.); (L.A.S.)
| | - Lucia Grenga
- Département Médicaments et Technologies pour la Santé (DMTS), Université Paris-Saclay, CEA, INRAE, SPI, F-30200 Bagnols-sur-Ceze, France;
| | - Alberto Mantovani
- Department of Food Safety, Nutrition and Veterinary Public Health, Istituto Superiore di Sanità, 00161 Rome, Italy;
| | - Amalia Muñoz
- European Commission, Joint Research Centre (JRC), 2440 Geel, Belgium;
| | - Elma Omeragic
- Faculty of Pharmacy, University of Sarajevo, 71000 Sarajevo, Bosnia and Herzegovina;
| | - Nikolaos Parissis
- European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy; (S.C.); (E.P.D.); (N.P.); (M.P.); (B.L.)
| | - Mauro Petrillo
- European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy; (S.C.); (E.P.D.); (N.P.); (M.P.); (B.L.)
| | - Laura A. Saarimäki
- Finnish Hub for Development and Validation of Integrated Approaches (FHAIVE), Faculty of Medicine and Health Technology, Tampere University, 33100 Tampere, Finland; (G.d.G.); (D.G.); (L.A.S.)
| | - Helena Soares
- Laboratory of Immunobiology and Pathogenesis, Chronic Diseases Research Centre, Faculdade de Ciências Médicas Medical School, University of Lisbon, 1649-004 Lisbon, Portugal;
| | - Kristie Sullivan
- Physicians Committee for Responsible Medicine, Washington, DC 20016, USA;
| | - Brigitte Landesmann
- European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy; (S.C.); (E.P.D.); (N.P.); (M.P.); (B.L.)
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Hao W, Li K, Ge X, Yang H, Xu C, Liu S, Yu H, Li P, Xing R. The Effect of N-Acetylation on the Anti-Inflammatory Activity of Chitooligosaccharides and Its Potential for Relieving Endotoxemia. Int J Mol Sci 2022; 23:ijms23158205. [PMID: 35897781 PMCID: PMC9330575 DOI: 10.3390/ijms23158205] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 07/18/2022] [Accepted: 07/22/2022] [Indexed: 02/05/2023] Open
Abstract
Endotoxemia is mainly caused by a massive burst of inflammatory cytokines as a result of lipopolysaccharide (LPS) invasion. Chitooligosaccharides (COS) is expected to be a potential drug for relieving endotoxemia due to its anti-inflammatory properties. However, the structural parameters of COS are often ambiguous, and the effect of degree of acetylation (DA) of COS on its anti-inflammatory remains unknown. In this study, four COSs with different DAs (0%, 12%, 50% and 85%) and the same oligomers distribution were successfully obtained. Their structures were confirmed by 1H NMR and MS analysis. Then, the effect of DA on the anti-inflammatory activity and relieving endotoxemia potential of COS was researched. The results revealed that COS with a DA of 12% had better anti-inflammatory activity than COSs with other DAs, mainly in inhibiting LPS-induced inflammatory cytokines burst, down-regulating its mRNA expression and reducing phosphorylation of IκBα. Furthermore, this COS showed an obviously protective effect on endotoxemia mice, such as inhibiting the increase in inflammatory cytokines and transaminases, alleviating the injury of liver and intestinal tissue. This study explored the effect of DA on the anti-inflammatory activity of COS for the first time and lays the foundation for the development of COS as an anti-inflammatory drug against endotoxemia.
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Affiliation(s)
- Wentong Hao
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China; (W.H.); (X.G.); (H.Y.); (C.X.); (S.L.); (H.Y.); (P.L.)
- Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), No. 1 Wenhai Road, Qingdao 266237, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Kecheng Li
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China; (W.H.); (X.G.); (H.Y.); (C.X.); (S.L.); (H.Y.); (P.L.)
- Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), No. 1 Wenhai Road, Qingdao 266237, China
- Correspondence: (K.L.); (R.X.); Tel.: +86-0532-82898512 (K.L.); +86-0532-82898780 (R.X.)
| | - Xiangyun Ge
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China; (W.H.); (X.G.); (H.Y.); (C.X.); (S.L.); (H.Y.); (P.L.)
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao 266109, China
| | - Haoyue Yang
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China; (W.H.); (X.G.); (H.Y.); (C.X.); (S.L.); (H.Y.); (P.L.)
- Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), No. 1 Wenhai Road, Qingdao 266237, China
| | - Chaojie Xu
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China; (W.H.); (X.G.); (H.Y.); (C.X.); (S.L.); (H.Y.); (P.L.)
- Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), No. 1 Wenhai Road, Qingdao 266237, China
| | - Song Liu
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China; (W.H.); (X.G.); (H.Y.); (C.X.); (S.L.); (H.Y.); (P.L.)
- Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), No. 1 Wenhai Road, Qingdao 266237, China
| | - Huahua Yu
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China; (W.H.); (X.G.); (H.Y.); (C.X.); (S.L.); (H.Y.); (P.L.)
- Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), No. 1 Wenhai Road, Qingdao 266237, China
| | - Pengcheng Li
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China; (W.H.); (X.G.); (H.Y.); (C.X.); (S.L.); (H.Y.); (P.L.)
- Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), No. 1 Wenhai Road, Qingdao 266237, China
| | - Ronge Xing
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China; (W.H.); (X.G.); (H.Y.); (C.X.); (S.L.); (H.Y.); (P.L.)
- Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), No. 1 Wenhai Road, Qingdao 266237, China
- Correspondence: (K.L.); (R.X.); Tel.: +86-0532-82898512 (K.L.); +86-0532-82898780 (R.X.)
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Anti-Inflammatory Effects of Mitrephora sirikitiae Leaf Extract and Isolated Lignans in RAW 264.7 Cells. Molecules 2022; 27:molecules27103313. [PMID: 35630789 PMCID: PMC9147141 DOI: 10.3390/molecules27103313] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 05/17/2022] [Accepted: 05/20/2022] [Indexed: 12/05/2022] Open
Abstract
Mitrephora sirikitiae Weeras., Chalermglin & R.M.K. Saunders has been reported as a rich source of lignans that contribute to biological activities and health benefits. However, cellular anti-inflammatory effects of M. sirikitiae leaves and their lignan compounds have not been fully elucidated. Therefore, this study aimed to investigate the anti-inflammatory activities of methanol extract of M. sirikitiae leaves and their lignan constituents on lipopolysaccharide (LPS)-induced inflammation in RAW 264.7 mouse macrophage cells. Treatment of RAW 264.7 cells with the methanol extract of M. sirikitiae leaves and its isolated lignans, including (−)-phylligenin (2) and 3′,4-O-dimethylcedrusin (6) significantly decreased LPS-induced prostaglandin E2 (PGE2) and nitric oxide (NO) productions. These inhibitory effects of the extract and isolated lignans on LPS-induced upregulation of PGE2 and NO productions were derived from the suppression of cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS) production, respectively. In addition, treatment with 2-(3,4-dimethoxyphenyl)-6-(3,5-dimethoxyphenyl)-3,7-dioxabicyclo[3.3.0]octane (3) and mitrephoran (5) was able to suppress LPS-induced tumor necrosis factor alpha (TNF-α) secretion and synthesis in RAW 264.7 cells. These results demonstrated that M. sirikitiae leaves and some isolated lignans exhibited potent anti-inflammatory activity through the inhibition of secretion and synthesis of PGE2, NO, and TNF-α.
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Zhao H, Lyu Y, Zhai R, Sun G, Ding X. Metformin Mitigates Sepsis-Related Neuroinflammation via Modulating Gut Microbiota and Metabolites. Front Immunol 2022; 13:797312. [PMID: 35572534 PMCID: PMC9102391 DOI: 10.3389/fimmu.2022.797312] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 04/05/2022] [Indexed: 12/04/2022] Open
Abstract
Gut microbiota affects the functions of brains. However, its mechanism in sepsis remains unclear. This study evaluated the effect of metformin on ameliorating sepsis-related neurodamage by regulating gut microbiota and metabolites in septic rats. Cecal ligation and puncture (CLP) was used to establish the sepsis-related neurodamage animal models. Metformin therapy by gavage at 1 h after CLP administration was followed by fecal microbiota transplantation (FMT) to ensure the efficacy and safety of metformin on the sepsis-related neurodamage by regulating gut microbiota. The gut microbiota and metabolites were conducted by 16S rRNA sequencing and liquid chromatography-tandem mass spectrometry metabolomic analysis. The brain tissue inflammation response was analyzed by histopathology and reverse transcription-polymerase chain reaction (RT-PCR). This study reported brain inflammatory response, hemorrhage in sepsis-related neurodamage rats compared with the control group (C group). Surprisingly, the abundance of gut microbiota slightly increased in sepsis-related neurodamage rats than C group. The ratio of Firmicutes/Bacteroidetes was significantly increased in the CLP group than the C group. However, no difference was observed between the CLP and the metformin-treated rats (MET group). Interestingly, the abundance of Escherichia_Shigella increased in the MET group than the C and CLP groups, while Lactobacillaceae abundance decreased. Furthermore, Prevotella_9, Muribaculaceae, and Alloprevotella related to short-chain fatty acids production increased in the sepsis-related neurodamage of metformin-treated rats. Additionally, Prevotella_9 and Muribaculaceae correlated positively to 29 metabolites that might affect the inflammatory factors in the brain. The FMT assay showed that metformin improved sepsis-related neurodamage by regulating the gut microbiota and metabolites in septic rats. The findings suggest that metformin improves the sepsis-related neurodamage through modulating the gut microbiota and metabolites in septic rats, which may be an effective therapy for patients with sepsis-related neurodamage.
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Affiliation(s)
- Huayan Zhao
- Department of Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yuanjun Lyu
- Department of Respiratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ruiqing Zhai
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Guiying Sun
- Epidemiology and Statistics, College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Xianfei Ding
- General Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- *Correspondence: Xianfei Ding,
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50
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Pussinen PJ, Kopra E, Pietiäinen M, Lehto M, Zaric S, Paju S, Salminen A. Periodontitis and cardiometabolic disorders: The role of lipopolysaccharide and endotoxemia. Periodontol 2000 2022; 89:19-40. [PMID: 35244966 PMCID: PMC9314839 DOI: 10.1111/prd.12433] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Lipopolysaccharide is a virulence factor of gram-negative bacteria with a crucial importance to the bacterial surface integrity. From the host's perspective, lipopolysaccharide plays a role in both local and systemic inflammation, activates both innate and adaptive immunity, and can trigger inflammation either directly (as a microbe-associated molecular pattern) or indirectly (by inducing the generation of nonmicrobial, danger-associated molecular patterns). Translocation of lipopolysaccharide into the circulation causes endotoxemia, which is typically measured as the biological activity of lipopolysaccharide to induce coagulation of an aqueous extract of blood cells of the assay. Apparently healthy subjects have a low circulating lipopolysaccharide activity, since it is neutralized and cleared rapidly. However, chronic endotoxemia is involved in the pathogenesis of many inflammation-driven conditions, especially cardiometabolic disorders. These include atherosclerotic cardiovascular diseases, obesity, liver diseases, diabetes, and metabolic syndrome, where endotoxemia has been recognized as a risk factor. The main source of endotoxemia is thought to be the gut microbiota. However, the oral dysbiosis in periodontitis, which is typically enriched with gram-negative bacterial species, may also contribute to endotoxemia. As endotoxemia is associated with an increased risk of cardiometabolic disorders, lipopolysaccharide could be considered as a molecular link between periodontal microbiota and cardiometabolic diseases.
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Affiliation(s)
- Pirkko J Pussinen
- Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Elisa Kopra
- Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Milla Pietiäinen
- Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Markku Lehto
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.,Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Clinical and Molecular Metabolism, Faculty of Medicine Research Programs, University of Helsinki, Helsinki, Finland
| | - Svetislav Zaric
- Faculty of Dentistry, Oral & Craniofacial Sciences, Kings College London, London, UK
| | - Susanna Paju
- Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Aino Salminen
- Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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