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Yin J, Song Z, Zhang L, Cong J. Methylophiopogonanone A alleviates diabetic cardiomyopathy via inhibiting JNK1 signaling. Cell Signal 2025; 131:111762. [PMID: 40139620 DOI: 10.1016/j.cellsig.2025.111762] [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: 12/24/2024] [Revised: 03/13/2025] [Accepted: 03/23/2025] [Indexed: 03/29/2025]
Abstract
OBJECTIVE Diabetic cardiomyopathy (DCM) is a common complication of type 2 diabetes mellitus (T2DM). The effects of methylophiopogonanone A (MO-A), a natural homoisoflavonoid with anti-inflammatory effects, on DCM and its underlying mechanisms were investigated in this study. METHODS The T2DM mouse model was induced by intraperitoneal injection of 30 mg/kg streptozotocin for 7 consecutive days and fed with a high-fat diet for 12 weeks. T2DM mice received MO-A (2.5, 5, or 10 mg/kg) treatment for two weeks. Cardiac function, hypertrophy, fibrosis, and inflammation were evaluated. The binding energy between MO-A and JNK1 was analyzed using molecular docking. The underlying mechanism was further investigated in high glucose (HG)-induced H9C2 cells. The cytotoxic effects, cardiomyocyte hypertrophy, fibrosis, inflammation, and relevant signaling proteins were assessed. RESULTS MO-A treatment alleviated cardiac function and histopathological changes in DCM mice. Moreover, MO-A treatment significantly decreased COLI, TGF-β1, MYH7, and ANP expression levels in DCM mice. Furthermore, TNF-α, IL-6, and IL-1β expression levels were notably downregulated after treatment with MO-A in DCM mice. Similar results were also observed in vitro. Mechanistically, MO-A targets JNK1 and downregulates its phosphorylation levels in DCM mice. The protective properties of MO-A were reversed by JNK1 overexpression in HG-induced H9C2 cells. CONCLUSION Our results revealed that MO-A could alleviate cardiac function, hypertrophy, fibrosis, and inflammation in DCM via inhibiting JNK1 signaling.
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Affiliation(s)
- Jing Yin
- Department of Traditional Chinese Medicine, Yantaishan Hospital, Yantai 264003, Shandong, China
| | - Zhicheng Song
- Department of Integrated Chinese and Western Medicine, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai 264000, Shandong, China
| | - Lijun Zhang
- Department of Endocrinology, Longkou Traditional Chinese Medicine Hospital, Yantai 265701, Shandong, China
| | - Jialin Cong
- Department of Integrated Chinese and Western Medicine, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai 264000, Shandong, China.
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2
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Guo X, Li H, Zhu B, Wang X, Xu Q, Aquino E, Koo M, Li Q, Cai J, Glaser S, Wu C. HFD feeding for seven months abolishes STING disruption-driven but not female sex-based protection against hepatic steatosis and inflammation in mice. J Nutr Biochem 2025; 135:109770. [PMID: 39284534 PMCID: PMC11620956 DOI: 10.1016/j.jnutbio.2024.109770] [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: 07/02/2024] [Revised: 09/07/2024] [Accepted: 09/11/2024] [Indexed: 10/06/2024]
Abstract
Stimulator of interferon genes (STING) is positively correlated with the degrees of liver inflammation in human metabolic dysfunction-associated steatotic liver disease (MASLD). In addition, STING disruption alleviates MASLD in mice fed a high-fat diet (HFD) for 3 months (3-m-HFD). Here we investigated the role of the duration of dietary feeding in regulating MASLD in mice and explored the involvement of STING in sex differences in MASLD. Both male and female STING-disrupted (STINGgt) and wild-type C57BL/6J mice were fed an HFD for 3 or 7 months (7-m-HFD). Additionally, female STINGgt mice upon ovariectomy (OVX) and 3-m-HFD were analyzed for MASLD. Upon 3-m-HFD, STINGgt mice exhibited decreased severity of MASLD compared to control. However, upon 7-m-HFD, STINGgt mice were comparable with wild-type mice in body weight, fat mass, and MASLD. Regarding regulating the liver RNA transcriptome, 7-m-HFD increased the expression of genes indicating proinflammatory activation of various liver cells. Interestingly, the severity of MASLD in female mice was much lighter than in male mice, regardless of STING disruption. Upon OVX, female STINGgt mice showed significantly increased severity of MASLD relative to sham control but were comparable with male STINGgt mice. Upon treatment with 17-beta estradiol (E2), hepatocytes revealed decreased fat deposition while macrophages displayed decreases in lipopolysaccharide-induced phosphorylation of Nfkb p65 and Jnk p46 independent of STING. These results suggest that 7-m-HFD, without altering female sex-based protection, abolishes STING disruption-driven protection of MASLD, likely through causing proinflammatory activation of multiple types of liver cells to offset the effect of STING disruption.
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Affiliation(s)
- Xinlei Guo
- Department of Nutrition, Texas A&M University, College Station, Texas, USA
| | - Honggui Li
- Department of Nutrition, Texas A&M University, College Station, Texas, USA
| | - Bilian Zhu
- Department of Nutrition, Texas A&M University, College Station, Texas, USA
| | - Xiaoxiao Wang
- Department of Nutrition, Texas A&M University, College Station, Texas, USA
| | - Qian Xu
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas, USA
| | - Eduardo Aquino
- Department of Nutrition, Texas A&M University, College Station, Texas, USA
| | - Minji Koo
- Department of Nutrition, Texas A&M University, College Station, Texas, USA
| | - Qingsheng Li
- Nebraska Center for Virology, School of Biological Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska, USA
| | - James Cai
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas, USA
| | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University College of Medicine, Byran, Texas, USA.
| | - Chaodong Wu
- Department of Nutrition, Texas A&M University, College Station, Texas, USA.
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Fang CY, Rao A, Handorf EA, Deng M, Cheung P, Tseng M. Increases in Psychological Stress Are Associated With Higher Fasting Glucose in US Chinese Immigrants. Ann Behav Med 2024; 58:799-808. [PMID: 39316655 DOI: 10.1093/abm/kaae056] [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] [Indexed: 09/26/2024] Open
Abstract
BACKGROUND The majority of Chinese Americans is foreign-born, and it is well-documented that immigration to the United States (US) leads to increased risk for chronic diseases including type 2 diabetes. Increased disease risk has been attributed to changes in lifestyle behaviors following immigration, but few studies have considered the psychosocial impact of immigration upon biomarkers of disease risk. PURPOSE To examine associations of psychological stress and social isolation with markers of type 2 diabetes risk over time among US Chinese immigrants. METHODS In this longitudinal study of 614 Chinese immigrants, participants completed assessments of perceived stress, acculturative stress, negative life events, and social isolation annually at three time points. Fasting blood samples were obtained at each time point to measure blood glucose, glycated hemoglobin, and insulin resistance. Mean duration between baseline and follow-up assessments was approximately 2 years. RESULTS Increases in migration-related stress, perceived stress and social isolation were associated with significant increases in fasting glucose at follow-up independent of age, body mass index, length of US residence, and other potential covariates. Moreover, increases in glucose varied depending on perceived stress levels at baseline, such that those with higher baseline stress had a steeper increase in glucose over time. CONCLUSIONS Psychological stress and social isolation are associated with increases in fasting glucose in a sample of US Chinese immigrants. Findings suggest that the unique experiences of immigration may be involved in the risk of developing type 2 diabetes, a condition that is prevalent among US Chinese despite relatively low rates of obesity.
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Affiliation(s)
- Carolyn Y Fang
- Cancer Prevention & Control Program, Fox Chase Cancer Center, USA
| | - Ajay Rao
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, Lewis Katz School of Medicine, Temple University, USA
- Center for Metabolic Disease Research, Department of Medicine, Lewis Katz School of Medicine, Temple University, USA
| | | | - Mengying Deng
- Department of Biostatistics & Bioinformatics, Fox Chase Cancer Center, USA
| | - Peter Cheung
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, Lewis Katz School of Medicine, Temple University, USA
| | - Marilyn Tseng
- Department of Kinesiology and Public Health, California Polytechnic State University, USA
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Taranto D, Kloosterman DJ, Akkari L. Macrophages and T cells in metabolic disorder-associated cancers. Nat Rev Cancer 2024; 24:744-767. [PMID: 39354070 DOI: 10.1038/s41568-024-00743-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/16/2024] [Indexed: 10/03/2024]
Abstract
Cancer and metabolic disorders have emerged as major global health challenges, reaching epidemic levels in recent decades. Often viewed as separate issues, metabolic disorders are shown by mounting evidence to heighten cancer risk and incidence. The intricacies underlying this connection are still being unraveled and encompass a complex interplay between metabolites, cancer cells and immune cells within the tumour microenvironment (TME). Here, we outline the interplay between metabolic and immune cell dysfunction in the context of three highly prevalent metabolic disorders, namely obesity; two associated liver diseases, metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH); and type 2 diabetes. We focus primarily on macrophages and T cells, the critical roles of which in dictating inflammatory response and immune surveillance in metabolic disorder-associated cancers are widely reported. Moreover, considering the ever-increasing number of patients prescribed with metabolism disorder-altering drugs and diets in recent years, we discuss how these therapies modulate systemic and local immune phenotypes, consequently impacting cancer malignancy. Collectively, unraveling the determinants of metabolic disorder-associated immune landscape and their role in fuelling cancer malignancy will provide a framework essential to therapeutically address these highly prevalent diseases.
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Affiliation(s)
- Daniel Taranto
- Division of Tumour Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
- Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Daan J Kloosterman
- Division of Tumour Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
- Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Leila Akkari
- Division of Tumour Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
- Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
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Fukuda Y, Okada H, Tomita H, Suzuki K, Mori K, Takada C, Kawasaki Y, Fukuda H, Minamiyama T, Nishio A, Shimada T, Kuroda A, Uchida A, Suzuki K, Kamidani R, Kitagawa Y, Fukuta T, Miyake T, Yoshida T, Suzuki A, Tetsuka N, Yoshida S, Ogura S. Nafamostat mesylate decreases skin flap necrosis in a mouse model of type 2 diabetes by protecting the endothelial glycocalyx. Biochem Biophys Res Commun 2024; 710:149843. [PMID: 38593617 DOI: 10.1016/j.bbrc.2024.149843] [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: 01/31/2024] [Revised: 03/22/2024] [Accepted: 03/26/2024] [Indexed: 04/11/2024]
Abstract
The success rate of flap tissue reconstruction has increased in recent years owing to advancements in microsurgical techniques. However, complications, such as necrosis, are still more prevalent in diabetic patients compared to non-diabetic individuals, presenting an ongoing challenge. To address this issue, many previous studies have examined vascular anastomoses dilation and stability, primarily concerning surgical techniques or drugs. In contrast, in the present study, we focused on microvascular damage of the peripheral microvessels in patients with diabetes mellitus and the preventative impact of nafamostat mesylate. Herein, we aimed to investigate the effects of hyperglycemia on glycocalyx (GCX) levels in mice with type 2 diabetes. We examined the endothelial GCX (eGCX) in skin flap tissue of 9-12-week-old type 2 diabetic mice (db/db mice) using a perforator skin flap and explored treatment with nafamostat mesylate. The growth rates were compared after 1 week. Heterotype (db/+) mice were used as the control group. Morphological examination of postoperative tissues was performed at 1, 3, 5, and 7 days post-surgery. In addition, db/db mice were treated with 30 mg/kg/day of nafamostat mesylate daily and were evaluated on postoperative day 7. Seven days after surgery, all db/db mice showed significant partial flap necrosis. Temporal observation of the skin flaps revealed a stasis-like discoloration and necrosis starting from the contralateral side of the remaining perforating branch. The control group did not exhibit flap necrosis, and the flap remained intact. In the quantitative assessment of endothelial glycans using lectins, intensity scoring showed that the eGCX in the db/db group was significantly thinner than that in the db/+ group. These results were consistent with the scanning electron microscopy findings. In contrast, treatment with nafamostat mesylate significantly improved the flap engraftment rate and suppressed eGCX injury. In conclusion, treatment with nafamostat mesylate improves the disrupted eGCX structure of skin flap tissue in db/db mice, potentially ameliorating the impaired capillary-to-venous return in the skin flap tissue.
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Affiliation(s)
- Yohei Fukuda
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Japan
| | - Hideshi Okada
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Japan; Center for One Medicine Innovative Translational Research (COMIT), Gifu University, Gifu, Japan.
| | - Hiroyuki Tomita
- Center for One Medicine Innovative Translational Research (COMIT), Gifu University, Gifu, Japan; Department of Tumor Pathology, Gifu University Graduate School of Medicine, Japan.
| | - Kodai Suzuki
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Japan; Department of Infection Control, Gifu University Graduate School of Medicine, Japan
| | - Kosuke Mori
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Japan
| | - Chihiro Takada
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Japan
| | - Yuki Kawasaki
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Japan
| | - Hirotsugu Fukuda
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Japan
| | - Toru Minamiyama
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Japan
| | - Ayane Nishio
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Japan
| | - Takuto Shimada
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Japan
| | - Ayumi Kuroda
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Japan
| | - Akihiro Uchida
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Japan
| | - Keiko Suzuki
- Department of Infection Control, Gifu University Graduate School of Medicine, Japan; Department of Pharmacy, Gifu University Hospital, Japan
| | - Ryo Kamidani
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Japan
| | - Yuichiro Kitagawa
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Japan
| | - Tetsuya Fukuta
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Japan
| | - Takahito Miyake
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Japan
| | - Takahiro Yoshida
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Japan
| | - Akio Suzuki
- Department of Pharmacy, Gifu University Hospital, Japan
| | - Nobuyuki Tetsuka
- Department of Infection Control, Gifu University Graduate School of Medicine, Japan
| | - Shozo Yoshida
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Japan; Abuse Prevention Emergency Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Shinji Ogura
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Japan
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Kawanaka R, Jin H, Aoe T. Unraveling the Connection: Pain and Endoplasmic Reticulum Stress. Int J Mol Sci 2024; 25:4995. [PMID: 38732214 PMCID: PMC11084550 DOI: 10.3390/ijms25094995] [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: 04/03/2024] [Revised: 04/29/2024] [Accepted: 04/30/2024] [Indexed: 05/13/2024] Open
Abstract
Pain is a complex and multifaceted experience. Recent research has increasingly focused on the role of endoplasmic reticulum (ER) stress in the induction and modulation of pain. The ER is an essential organelle for cells and plays a key role in protein folding and calcium dynamics. Various pathological conditions, such as ischemia, hypoxia, toxic substances, and increased protein production, may disturb protein folding, causing an increase in misfolding proteins in the ER. Such an overload of the folding process leads to ER stress and causes the unfolded protein response (UPR), which increases folding capacity in the ER. Uncompensated ER stress impairs intracellular signaling and cell function, resulting in various diseases, such as diabetes and degenerative neurological diseases. ER stress may be a critical universal mechanism underlying human diseases. Pain sensations involve the central as well as peripheral nervous systems. Several preclinical studies indicate that ER stress in the nervous system is enhanced in various painful states, especially in neuropathic pain conditions. The purpose of this narrative review is to uncover the intricate relationship between ER stress and pain, exploring molecular pathways, implications for various pain conditions, and potential therapeutic strategies.
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Affiliation(s)
- Ryoko Kawanaka
- Department of Anesthesiology, Chiba Medical Center, Teikyo University, Ichihara 299-0111, Japan
| | - Hisayo Jin
- Department of Anesthesiology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Tomohiko Aoe
- Pain Center, Chiba Medical Center, Teikyo University, Ichihara 299-0111, Japan
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Wang M, Liang Y, Qin Y, Ma R, Yu H, Wang W, Zhang X. Active Ingredients and Mechanism of Gegen Qinlian Decoction in the Treatment of Diabetic Cardiomyopathy: A Network Pharmacology Study. Curr Pharm Des 2024; 30:2896-2910. [PMID: 39136516 DOI: 10.2174/0113816128312242240722080551] [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: 03/18/2024] [Accepted: 05/27/2024] [Indexed: 10/22/2024]
Abstract
BACKGROUND Diabetic cardiomyopathy (DCM) is a common diabetes complication with limited medications. Gegen Qinlian decoction (GQD) has been used in the treatment of diabetes and its related complications in China for several decades. OBJECTIVE In this study, network pharmacology was employed to predict the active ingredients, key targets, and pathways involved in the treatment of DCM by GQD and to validate it by animal experiments. METHODS The active ingredients of GQD were retrieved from TCMSP and published literature. DCM-related gene targets were searched in Drugbank, Genecards, Disgenet, and OMIM disease databases. Protein-protein interaction networks were constructed using the STRING database and Cytoscape. GO analysis and KEGG pathway enrichment analysis were performed using the Metascape platform. Moreover, a diabetic mouse model was established to evaluate the therapeutic effects of GQD by measuring serum biochemical markers and inflammation levels. Finally, the expression of predicted key target genes was determined using real-time quantitative PCR. RESULTS A total of 129 active ingredients were screened from GQD. Moreover, 146 intersecting genes related to DCM were obtained, with key targets, including AKT1, TNF, IL6, and VEGFA. Lipid and atherosclerosis, AGE-RAGE, PI3K-AKT, and MAPK pathways were identified. Blood glucose control, decreased inflammatory factors, and serum CK-MB levels were restored after GQD intervention, and the same occurred with the expressions of PPAR-γ, AKT1, APOB, and GSK3B genes. CONCLUSION Quercetin, kaempferol, wogonin, 7-methoxy-2-methyl isoflavone, and formononetin may exert major therapeutic effects by regulating key factors, such as AKT1, APOB, and GSK3B, in the inflammatory reaction, glycolipid oxidation, and glycogen synthesis related signaling pathways.
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Affiliation(s)
- Min Wang
- Institute of Basic Medical Sciences, Guilin Medical University, Guilin 541004, China
| | - Yanbin Liang
- College of Pharmacy, Guilin Medical University, Guilin 541004, China
| | - Yuce Qin
- College of Pharmacy, Guilin Medical University, Guilin 541004, China
| | - Ruimian Ma
- Institute of Basic Medical Sciences, Guilin Medical University, Guilin 541004, China
| | - Huanting Yu
- College of Clinical Medicine, Guilin Medical University, Guilin 541004, China
| | - Weixue Wang
- Department of Traditional Chinese Medicine, Huai'an No. 3 People's Hospital, Huaian 223001, China
- Department of Traditional Chinese Medicine, Affiliated Hospital of Guilin Medical University, Guilin 541004, China
| | - Xiaoxi Zhang
- Institute of Basic Medical Sciences, Guilin Medical University, Guilin 541004, China
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Engin A. Reappraisal of Adipose Tissue Inflammation in Obesity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:297-327. [PMID: 39287856 DOI: 10.1007/978-3-031-63657-8_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
Chronic low-grade inflammation is a central component in the pathogenesis of obesity-related expansion of adipose tissue and complications in other metabolic tissues. Five different signaling pathways are defined as dominant determinants of adipose tissue inflammation: These are increased circulating endotoxin due to dysregulation in the microbiota-gut-brain axis, systemic oxidative stress, macrophage accumulation, and adipocyte death. Finally, the nucleotide-binding and oligomerization domain (NOD) leucine-rich repeat family pyrin domain-containing 3 (NLRP3) inflammasome pathway is noted to be a key regulator of metabolic inflammation. The NLRP3 inflammasome and associated metabolic inflammation play an important role in the relationships among fatty acids and obesity. Several highly active molecules, including primarily leptin, resistin, adiponectin, visfatin, and classical cytokines, are abundantly released from adipocytes. The most important cytokines that are released by inflammatory cells infiltrating obese adipose tissue are tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), monocyte chemoattractant protein 1 (MCP-1) (CCL-2), and IL-1. All these molecules mentioned above act on immune cells, causing local and then general inflammation. Three metabolic pathways are noteworthy in the development of adipose tissue inflammation: toll-like receptor 4 (TLR4)/phosphatidylinositol-3'-kinase (PI3K)/Protein kinase B (Akt) signaling pathway, endoplasmic reticulum (ER) stress-derived unfolded protein response (UPR), and inhibitor of nuclear factor kappa-B kinase beta (IKKβ)-nuclear factor kappa B (NF-κB) pathway. In fact, adipose tissue inflammation is an adaptive response that contributes to a visceral depot barrier that effectively filters gut-derived endotoxin. Excessive fatty acid release worsens adipose tissue inflammation and contributes to insulin resistance. However, suppression of adipose inflammation in obesity with anti-inflammatory drugs is not a rational solution and paradoxically promotes insulin resistance, despite beneficial effects on weight gain. Inflammatory pathways in adipocytes are indeed indispensable for maintaining systemic insulin sensitivity. Cannabinoid type 1 receptor (CB1R) is important in obesity-induced pro-inflammatory response; however, blockade of CB1R, contrary to anti-inflammatory drugs, breaks the links between insulin resistance and adipose tissue inflammation. Obesity, however, could be decreased by improving leptin signaling, white adipose tissue browning, gut microbiota interactions, and alleviating inflammation. Furthermore, capsaicin synthesized by chilies is thought to be a new and promising therapeutic option in obesity, as it prevents metabolic endotoxemia and systemic chronic low-grade inflammation caused by high-fat diet.
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Affiliation(s)
- Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey.
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey.
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Yu X, Mukwaya V, Mann S, Dou H. Signal Transduction in Artificial Cells. SMALL METHODS 2023; 7:e2300231. [PMID: 37116092 DOI: 10.1002/smtd.202300231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 04/06/2023] [Indexed: 06/19/2023]
Abstract
In recent years, significant progress has been made in the emerging field of constructing biomimetic soft compartments with life-like behaviors. Given that biological activities occur under a flux of energy and matter exchange, the implementation of rudimentary signaling pathways in artificial cells (protocells) is a prerequisite for the development of adaptive sense-response phenotypes in cytomimetic models. Herein, recent approaches to the integration of signal transduction modules in model protocells prepared by bottom-up construction are discussed. The approaches are classified into two categories involving invasive biochemical signals or non-invasive physical stimuli. In the former mechanism, transducers with intrinsic recognition capability respond with high specificity, while in the latter, artificial cells respond through intra-protocellular energy transduction. Although major challenges remain in the pursuit of a sophisticated artificial signaling network for the orchestration of higher-order cytomimetic models, significant advances have been made in establishing rudimentary protocell communication networks, providing novel organizational models for the development of life-like microsystems and new avenues in protoliving technologies.
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Affiliation(s)
- Xiaolei Yu
- State Key Laboratory of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
- Zhangjiang Institute for Advanced Study (ZIAS), Shanghai Jiao Tong University, Shanghai, 201203, China
| | - Vincent Mukwaya
- State Key Laboratory of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
- Zhangjiang Institute for Advanced Study (ZIAS), Shanghai Jiao Tong University, Shanghai, 201203, China
| | - Stephen Mann
- State Key Laboratory of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
- Zhangjiang Institute for Advanced Study (ZIAS), Shanghai Jiao Tong University, Shanghai, 201203, China
- Max Planck Bristol Centre for Minimal Biology and Centre for Protolife Research, School of Chemistry, University of Bristol, Bristol, BS8 1TS, UK
| | - Hongjing Dou
- State Key Laboratory of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
- Zhangjiang Institute for Advanced Study (ZIAS), Shanghai Jiao Tong University, Shanghai, 201203, China
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Bisht MK, Dahiya P, Ghosh S, Mukhopadhyay S. The cause-effect relation of tuberculosis on incidence of diabetes mellitus. Front Cell Infect Microbiol 2023; 13:1134036. [PMID: 37434784 PMCID: PMC10330781 DOI: 10.3389/fcimb.2023.1134036] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 05/25/2023] [Indexed: 07/13/2023] Open
Abstract
Tuberculosis (TB) is one of the oldest human diseases and is one of the major causes of mortality and morbidity across the Globe. Mycobacterium tuberculosis (Mtb), the causal agent of TB is one of the most successful pathogens known to mankind. Malnutrition, smoking, co-infection with other pathogens like human immunodeficiency virus (HIV), or conditions like diabetes further aggravate the tuberculosis pathogenesis. The association between type 2 diabetes mellitus (DM) and tuberculosis is well known and the immune-metabolic changes during diabetes are known to cause increased susceptibility to tuberculosis. Many epidemiological studies suggest the occurrence of hyperglycemia during active TB leading to impaired glucose tolerance and insulin resistance. However, the mechanisms underlying these effects is not well understood. In this review, we have described possible causal factors like inflammation, host metabolic changes triggered by tuberculosis that could contribute to the development of insulin resistance and type 2 diabetes. We have also discussed therapeutic management of type 2 diabetes during TB, which may help in designing future strategies to cope with TB-DM cases.
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Affiliation(s)
- Manoj Kumar Bisht
- Laboratory of Molecular Cell Biology, Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad, India
- Regional Centre for Biotechnology, Faridabad, India
| | - Priyanka Dahiya
- Laboratory of Molecular Cell Biology, Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad, India
- Regional Centre for Biotechnology, Faridabad, India
| | - Sudip Ghosh
- Molecular Biology Unit, Indian Council of Medical Research (ICMR)-National Institute of Nutrition, Jamai Osmania PO, Hyderabad, India
| | - Sangita Mukhopadhyay
- Laboratory of Molecular Cell Biology, Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad, India
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Naz R, Saqib F, Awadallah S, Wahid M, Latif MF, Iqbal I, Mubarak MS. Food Polyphenols and Type II Diabetes Mellitus: Pharmacology and Mechanisms. Molecules 2023; 28:molecules28103996. [PMID: 37241737 DOI: 10.3390/molecules28103996] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 05/04/2023] [Accepted: 05/07/2023] [Indexed: 05/28/2023] Open
Abstract
Type II diabetes mellitus and its related complications are growing public health problems. Many natural products present in our diet, including polyphenols, can be used in treating and managing type II diabetes mellitus and different diseases, owing to their numerous biological properties. Anthocyanins, flavonols, stilbenes, curcuminoids, hesperidin, hesperetin, naringenin, and phenolic acids are common polyphenols found in blueberries, chokeberries, sea-buckthorn, mulberries, turmeric, citrus fruits, and cereals. These compounds exhibit antidiabetic effects through different pathways. Accordingly, this review presents an overview of the most recent developments in using food polyphenols for managing and treating type II diabetes mellitus, along with various mechanisms. In addition, the present work summarizes the literature about the anti-diabetic effect of food polyphenols and evaluates their potential as complementary or alternative medicines to treat type II diabetes mellitus. Results obtained from this survey show that anthocyanins, flavonols, stilbenes, curcuminoids, and phenolic acids can manage diabetes mellitus by protecting pancreatic β-cells against glucose toxicity, promoting β-cell proliferation, reducing β-cell apoptosis, and inhibiting α-glucosidases or α-amylase. In addition, these phenolic compounds exhibit antioxidant anti-inflammatory activities, modulate carbohydrate and lipid metabolism, optimize oxidative stress, reduce insulin resistance, and stimulate the pancreas to secrete insulin. They also activate insulin signaling and inhibit digestive enzymes, regulate intestinal microbiota, improve adipose tissue metabolism, inhibit glucose absorption, and inhibit the formation of advanced glycation end products. However, insufficient data are available on the effective mechanisms necessary to manage diabetes.
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Affiliation(s)
- Rabia Naz
- Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60000, Pakistan
| | - Fatima Saqib
- Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60000, Pakistan
| | - Samir Awadallah
- Department of Medical Lab Sciences, Faculty of Allied Medical Sciences, Zarqa University, Zarqa 13110, Jordan
| | - Muqeet Wahid
- Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60000, Pakistan
| | - Muhammad Farhaj Latif
- Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60000, Pakistan
| | - Iram Iqbal
- Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60000, Pakistan
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12
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Barua A, Hatzikirou H. Cell Decision Making through the Lens of Bayesian Learning. ENTROPY (BASEL, SWITZERLAND) 2023; 25:e25040609. [PMID: 37190396 PMCID: PMC10137733 DOI: 10.3390/e25040609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 03/20/2023] [Accepted: 03/29/2023] [Indexed: 05/17/2023]
Abstract
Cell decision making refers to the process by which cells gather information from their local microenvironment and regulate their internal states to create appropriate responses. Microenvironmental cell sensing plays a key role in this process. Our hypothesis is that cell decision-making regulation is dictated by Bayesian learning. In this article, we explore the implications of this hypothesis for internal state temporal evolution. By using a timescale separation between internal and external variables on the mesoscopic scale, we derive a hierarchical Fokker-Planck equation for cell-microenvironment dynamics. By combining this with the Bayesian learning hypothesis, we find that changes in microenvironmental entropy dominate the cell state probability distribution. Finally, we use these ideas to understand how cell sensing impacts cell decision making. Notably, our formalism allows us to understand cell state dynamics even without exact biochemical information about cell sensing processes by considering a few key parameters.
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Affiliation(s)
- Arnab Barua
- Departement de Biochimie, Université de Montréal, Montréal, QC H3T 1C5, Canada
- Centre Robert-Cedergren en Bio-Informatique et Génomique, Université de Montréal, Montréal, QC H3C 3J7, Canada
| | - Haralampos Hatzikirou
- Center for Information Services and High Performance Computing, Technische Univesität Dresden, 01062 Dresden, Germany
- Mathematics Department, Khalifa University, Abu Dhabi P.O. Box 127788, United Arab Emirates
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13
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Guha Ray A, Odum OP, Wiseman D, Weinstock A. The diverse roles of macrophages in metabolic inflammation and its resolution. Front Cell Dev Biol 2023; 11:1147434. [PMID: 36994095 PMCID: PMC10041730 DOI: 10.3389/fcell.2023.1147434] [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: 01/18/2023] [Accepted: 02/14/2023] [Indexed: 03/14/2023] Open
Abstract
Macrophages are one of the most functionally diverse immune cells, indispensable to maintain tissue integrity and metabolic health. Macrophages perform a myriad of functions ranging from promoting inflammation, through inflammation resolution to restoring and maintaining tissue homeostasis. Metabolic diseases encompass a growing list of diseases which develop from a mix of genetics and environmental cues leading to metabolic dysregulation and subsequent inflammation. In this review, we summarize the contributions of macrophages to four metabolic conditions-insulin resistance and adipose tissue inflammation, atherosclerosis, non-alcoholic fatty liver disease and neurodegeneration. The role of macrophages is complex, yet they hold great promise as potential therapies to address these growing health concerns.
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Affiliation(s)
| | | | | | - Ada Weinstock
- Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, United States
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14
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Sanches JM, Zhao LN, Salehi A, Wollheim CB, Kaldis P. Pathophysiology of type 2 diabetes and the impact of altered metabolic interorgan crosstalk. FEBS J 2023; 290:620-648. [PMID: 34847289 DOI: 10.1111/febs.16306] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 10/14/2021] [Accepted: 11/29/2021] [Indexed: 02/06/2023]
Abstract
Diabetes is a complex and multifactorial disease that affects millions of people worldwide, reducing the quality of life significantly, and results in grave consequences for our health care system. In type 2 diabetes (T2D), the lack of β-cell compensatory mechanisms overcoming peripherally developed insulin resistance is a paramount factor leading to disturbed blood glucose levels and lipid metabolism. Impaired β-cell functions and insulin resistance have been studied extensively resulting in a good understanding of these pathways but much less is known about interorgan crosstalk, which we define as signaling between tissues by secreted factors. Besides hormones and organokines, dysregulated blood glucose and long-lasting hyperglycemia in T2D is associated with changes in metabolism with metabolites from different tissues contributing to the development of this disease. Recent data suggest that metabolites, such as lipids including free fatty acids and amino acids, play important roles in the interorgan crosstalk during the development of T2D. In general, metabolic remodeling affects physiological homeostasis and impacts the development of T2D. Hence, we highlight the importance of metabolic interorgan crosstalk in this review to gain enhanced knowledge of the pathophysiology of T2D, which may lead to new therapeutic approaches to treat this disease.
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Affiliation(s)
| | - Li Na Zhao
- Department of Clinical Sciences, Lund University, Malmö, Sweden
| | - Albert Salehi
- Department of Clinical Sciences, Lund University, Malmö, Sweden
| | - Claes B Wollheim
- Department of Clinical Sciences, Lund University, Malmö, Sweden.,Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
| | - Philipp Kaldis
- Department of Clinical Sciences, Lund University, Malmö, Sweden
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15
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Petrecca S, Quail DF. Mouse Models of Obesity to Study the Tumor-Immune Microenvironment. Methods Mol Biol 2023; 2614:121-138. [PMID: 36587123 DOI: 10.1007/978-1-0716-2914-7_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Obesity is associated with chronic, low-grade systemic inflammation and leads to changes in the immune microenvironment of various tissues. As a result, obesity is associated with increased risk of cancer and a worse prognosis in patients. Given the prevalence of obesity worldwide, understanding the fundamental biology governing the relationship between obesity and cancer is critical. In this chapter, we describe preclinical models of obesity that can be combined with standard tumor models and techniques to study the tumor-immune microenvironment. We also discuss important considerations when planning experiments involving these models.
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Affiliation(s)
- Sarah Petrecca
- Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC, Canada.,Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, QC, Canada
| | - Daniela F Quail
- Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC, Canada. .,Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, QC, Canada. .,Department of Physiology, Faculty of Medicine, McGill University, Montreal, QC, Canada.
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16
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Rani K, Ali SA, Kaul G, Behare PV. Protective effect of probiotic and prebiotic fermented milk containing Lactobacillus fermentum against obesity-induced hepatic steatosis and inflammation. J Food Biochem 2022; 46:e14509. [PMID: 36334279 DOI: 10.1111/jfbc.14509] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 10/17/2022] [Accepted: 10/21/2022] [Indexed: 11/08/2022]
Abstract
Obesity has reached epidemic proportions, with major economic and health implications. The complex pathophysiology of obesity explains the difficulty provided to health policy for its clinical management. Increasing data show that obesity and metabolic abnormalities are intimately connected to differences in consumption of probiotics, its relevance to gut microbiota activity and composition. The goal of this investigation was to assess the effect of oral delivery of indigenous probiotic Lactobacillus fermentum NCDC 400 and prebiotic fructo-oligosaccharide (FOS) on obesity-associated hepatic steatosis and inflammation produced by a high-fat diet (HFD). C57BL/6 mice treated with L. fermentum NCDC 400 either independently or in conjunction with FOS demonstrated reduced body weight and abdominal obesity after 24 weeks of treatment. Also, the anti-oxidative enzyme activity went down, and the inflammatory profile got better, with less fat getting into the hepatocytes. The lipid profile changed, with HDL cholesterol going up and LDL cholesterol and triglyceride levels going down. Further, L. fermentum NCDC 400 and FOS combinations decreased fasting glucose, gHbA1c, gastric inhibitory peptide, and insulin levels in mice fed with HFD, thus improving glucose homeostasis. Overall, consumption of L. fermentum NCDC 400 alone or its combinational effects had a protective role on obesity-associated hepatic steatosis. PRACTICAL APPLICATIONS: The potential indigenous probiotic Lactobacillus fermentum NCDC 400 and prebiotic FOS had a preventive role in obesity-induced hepatic steatosis and improves anti-oxidant and anti-inflammatory properties in HFD-fed obese mice. Our finding would be helpful to prevent obesity-associated hepatic steatosis and inflammation upon supplementation of pre- and pro-biotics (synbiotics).
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Affiliation(s)
- Kavita Rani
- Semen Biology Lab, Animal Biochemistry Division, ICAR-National Dairy Research Institute, Haryana, India
| | - Syed Azmal Ali
- German Cancer Research Center, Division Proteomics of Stem Cells and Cancer, Heidelberg, Germany.,Cell Biology and Proteomics Lab, Animal Biotechnology Center, ICAR-National Dairy Research Institute, Karnal, India
| | - Gautam Kaul
- Semen Biology Lab, Animal Biochemistry Division, ICAR-National Dairy Research Institute, Haryana, India
| | - Pradip V Behare
- National Collection of Dairy Cultures (NCDC) Lab, Dairy Microbiology Division, ICAR-National Dairy Research Institute, Karnal, India
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17
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Mukherjee A, Bilecz AJ, Lengyel E. The adipocyte microenvironment and cancer. Cancer Metastasis Rev 2022; 41:575-587. [PMID: 35941408 DOI: 10.1007/s10555-022-10059-x] [Citation(s) in RCA: 73] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 08/01/2022] [Indexed: 02/08/2023]
Abstract
Many epithelial tumors grow in the vicinity of or metastasize to adipose tissue. As tumors develop, crosstalk between adipose tissue and cancer cells leads to changes in adipocyte function and paracrine signaling, promoting a microenvironment that supports tumor growth. Over the last decade, it became clear that tumor cells co-opt adipocytes in the tumor microenvironment, converting them into cancer-associated adipocytes (CAA). As adipocytes and cancer cells engage, a metabolic symbiosis ensues that is driven by bi-directional signaling. Many cancers (colon, breast, prostate, lung, ovarian cancer, and hematologic malignancies) stimulate lipolysis in adipocytes, followed by the uptake of fatty acids (FA) from the surrounding adipose tissue. The FA enters the cancer cell through specific fatty acid receptors and binding proteins (e.g., CD36, FATP1) and are used for membrane synthesis, energy metabolism (β-oxidation), or lipid-derived cell signaling molecules (derivatives of arachidonic and linolenic acid). Therefore, blocking adipocyte-derived lipid uptake or lipid-associated metabolic pathways in cancer cells, either with a single agent or in combination with standard of care chemotherapy, might prove to be an effective strategy against cancers that grow in lipid-rich tumor microenvironments.
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Affiliation(s)
- Abir Mukherjee
- Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, Center for Integrative Science, University of Chicago, 5841 S. Maryland Avenue, Chicago, IL, 60637, USA
| | - Agnes J Bilecz
- Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, Center for Integrative Science, University of Chicago, 5841 S. Maryland Avenue, Chicago, IL, 60637, USA
| | - Ernst Lengyel
- Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, Center for Integrative Science, University of Chicago, 5841 S. Maryland Avenue, Chicago, IL, 60637, USA.
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18
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Busquets O, Espinosa-Jiménez T, Ettcheto M, Olloquequi J, Bulló M, Carro E, Cantero JL, Casadesús G, Folch J, Verdaguer E, Auladell C, Camins A. JNK1 and JNK3: divergent functions in hippocampal metabolic-cognitive function. Mol Med 2022; 28:48. [PMID: 35508978 PMCID: PMC9066854 DOI: 10.1186/s10020-022-00471-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Accepted: 04/08/2022] [Indexed: 11/21/2022] Open
Abstract
Background and aim The appearance of alterations in normal metabolic activity has been increasingly considered a risk factor for the development of sporadic and late-onset neurodegenerative diseases. In this report, we induced chronic metabolic stress by feeding of a high-fat diet (HFD) in order to study its consequences in cognition. We also studied the effects of a loss of function of isoforms 1 and 3 of the c-Jun N-terminal Kinases (JNK), stress and cell death response elements. Methods Animals were fed either with conventional chow or with HFD, from their weaning until their sacrifice at 9 months. Before sacrifice, body weight, intraperitoneal glucose and insulin tolerance test (IP-GTT and IP‑ITT) were performed to evaluate peripheral biometrics. Additionally, cognitive behavioral tests and analysis of spine density were performed to assess cognitive function. Molecular studies were carried out to confirm the effects of metabolic stressors in the hippocampus relative to cognitive loss. Results Our studies demonstrated that HFD in Jnk3−/− lead to synergetic responses. Loss of function of JNK3 led to increased body weight, especially when exposed to an HFD and they had significantly decreased response to insulin. These mice also showed increased stress in the endoplasmic reticulum and diminished cognitive capacity. However, loss of function of JNK1 promoted normal or heightened energetic metabolism and preserved cognitive function even when chronically metabolically stressed. Conclusions Downregulation of JNK3 does not seem to be a suitable target for the modulation of energetic-cognitive dysregulations while loss of function of JNK1 seems to promote a good metabolic-cognitive profile, just like resistance to the negative effects of chronic feeding with HFD. Supplementary Information The online version contains supplementary material available at 10.1186/s10020-022-00471-y.
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Affiliation(s)
- Oriol Busquets
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Pharmacy and Food Sciences Faculty, University of Barcelona, 08028, Barcelona, Spain.,Department of Biochemistry and Biotechnology, Medicine and Health Sciences Faculty, University Rovira i Virgili, 43201, Reus, Spain.,Centre for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, 28029, Madrid, Spain.,Institut de Neurociències, University of Barcelona, 08035, Barcelona, Spain.,Dominick P. Purpura Department of Neurosciences, Albert Einstein College of Medicine, New York City, 10461, USA
| | - Triana Espinosa-Jiménez
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Pharmacy and Food Sciences Faculty, University of Barcelona, 08028, Barcelona, Spain.,Centre for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, 28029, Madrid, Spain.,Institut de Neurociències, University of Barcelona, 08035, Barcelona, Spain
| | - Miren Ettcheto
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Pharmacy and Food Sciences Faculty, University of Barcelona, 08028, Barcelona, Spain.,Department of Biochemistry and Biotechnology, Medicine and Health Sciences Faculty, University Rovira i Virgili, 43201, Reus, Spain.,Centre for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, 28029, Madrid, Spain.,Institut de Neurociències, University of Barcelona, 08035, Barcelona, Spain
| | - Jordi Olloquequi
- Laboratory of Cellular and Molecular Pathology, Facultad de Ciencias de La Salud, Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Talca, Chile
| | - Mònica Bulló
- Department of Biochemistry and Biotechnology, Medicine and Health Sciences Faculty, University Rovira i Virgili, 43201, Reus, Spain.,Institut d'Investigació Sanitària Pere Virgili (IISPV), Hospital Universitari de Sant Joan de Reus, 43204, Reus, Spain.,CIBER de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, 28029, Madrid, Spain
| | - Eva Carro
- Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain.,Group of Neurodegenerative Diseases, Hospital Universitario 12 de Octubre Research Institute (imas12), Madrid, Spain
| | - José Luis Cantero
- Centre for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, 28029, Madrid, Spain.,Laboratory of Functional Neuroscience, Pablo de Olavide University, 41013, Seville, Spain
| | - Gemma Casadesús
- Department of Pharmacology & Therapeutics, College of Medicine, University of Florida, Gainesville, FL, 32610, USA
| | - Jaume Folch
- Department of Biochemistry and Biotechnology, Medicine and Health Sciences Faculty, University Rovira i Virgili, 43201, Reus, Spain.,Centre for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, 28029, Madrid, Spain
| | - Ester Verdaguer
- Centre for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, 28029, Madrid, Spain.,Institut de Neurociències, University of Barcelona, 08035, Barcelona, Spain.,Department of Cell Biology, Physiology and Immunology, Biology Faculty, University of Barcelona, 08028, Barcelona, Spain
| | - Carme Auladell
- Centre for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, 28029, Madrid, Spain.,Institut de Neurociències, University of Barcelona, 08035, Barcelona, Spain.,Department of Cell Biology, Physiology and Immunology, Biology Faculty, University of Barcelona, 08028, Barcelona, Spain
| | - Antoni Camins
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Pharmacy and Food Sciences Faculty, University of Barcelona, 08028, Barcelona, Spain. .,Centre for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, 28029, Madrid, Spain. .,Institut de Neurociències, University of Barcelona, 08035, Barcelona, Spain.
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Li Z, Yang W, Yang Y, Wu J, Luo P, Liu Y. The Astragaloside IV Derivative LS-102 Ameliorates Obesity-Related Nephropathy. Drug Des Devel Ther 2022; 16:647-664. [PMID: 35308255 PMCID: PMC8932932 DOI: 10.2147/dddt.s346546] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Accepted: 01/20/2022] [Indexed: 12/23/2022] Open
Abstract
Background Astragaloside IV is the most important bioactive component of Radix Astragali. Previous studies have shown that astragaloside IV plays an important role in the control of early- and mid-stage diabetes and late diabetic nephropathy. However, it is disappointing that the in vivo solubility of astragaloside IV and its bioavailability after oral administration are very low. We recently obtained a new water-soluble derivative of astragaloside IV-astragaloside formic acid (LS-102), which has higher bioavailability than the parent compound. In our previous study, we found that there was a significant inflammatory response in the perirenal adipose tissue of mice with obesity-related nephropathy induced by a high-fat diet (HFD), which was related to macrophage infiltration. We hypothesized that in model mice with obesity-related nephropathy, LS-102 effectively regulated the inflammatory response and pathological changes in obesity-related nephropathy through macrophages in perirenal adipose tissue. If this hypothesis is true, the effects of LS-102 and astragaloside IV on TGF-β1/Smad signal transduction will be further investigated. Methods In this study, adipose stem cells and an HFD-induced obesity-related nephropathy mouse model were used to observe the regulatory effect of LS-102 on perirenal fat inflammation and the mechanism. Adipose mesenchymal stem cells were extracted from mice that were fed a normal diet and those with obesity-related nephropathy. The effects of LS-102 on the proliferation of two kinds of cells were measured by the CCK-8 method. The levels of tumor necrosis factor-α (TNF-a) and plasminogen activator inhibitor-1 (PAI-1) were measured by ELISA. Obesity-related nephropathy mice were randomly divided into five groups: the HFD group, the LAS group (HFD+low concentration of astragaloside IV [10 mg/kg], intragastrically [ig]), the HAS group (HFD+high concentration of astragaloside IV [40 mg/kg], ig), the L102 group (HFD+low concentration of LS-102 [10 mg/kg], ig) and the H102 group (HFD+high concentration of LS-102 [40 mg/kg], ig). Body weight was measured, and the levels of serum glucose, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglyceride (TG), total cholesterol (TC), serum creatinine (Crea) and blood urea were measured. The kidneys were stained with HE, PAS and Masson's trichrome. Perirenal adipose tissue was harvested to examine the expression of CD68, LCA, CD11C, TNF-a, TGF-β1, Fn1, Smad2, Smad3, Smad4, and Smad7 by immunohistochemical staining, and F4/80 was examined by immunofluorescence staining. Results LS-102 significantly inhibited the in vitro secretion of TNF-a and PAI-1 by adipose stem cells in a concentration-dependent manner (P < 0.05). In vivo, the body weights in the LAS group, HAS group, L102 group and H102 group were significantly lower than those in the HFD group (P < 0.05). Except for that in the HFD group, the volume of perirenal adipocytes in the other groups was small and uniform (P < 0.05). Compared with the LAS, HAS, L102 and H102 groups, the HFD group had a larger glomerular cross-sectional area, proliferation of mesangial cells and the mesangial matrix, and increased matrix area/glomerular area (P < 0.05). The effect of LS-102 was better than that of astragaloside IV at the same concentration (P < 0.05). Compared with those in the HFD group, glucose, HDL-C, LDL-C and urea levels in the LAS group, HAS group, L102 group and H102 group were significantly decreased (P < 0.05). The expression of F4/80, CD68, LCA, TNF-a, CD11C, and PAI-1 in perirenal adipose tissue in the HFD group was significantly higher than that in the LAS group, HAS group, L102 group and H102 group (P < 0.05). Compared with those in the HFD group, the expression levels of TGF-β1 and Fn1 in the HAS group, L102 group and H102 group were significantly increased (P < 0.05). Compared with the HFD group, the HAS group, L102 group and H102 group had decreased immunopositive rates of Smad2, Smad3 and Smad4 (P < 0.05). At the same concentration, the effect of LS-102 was better than that of astragaloside IV (P < 0.05). There was no significant difference in the expression of Smad7 among the different experimental groups (P > 0.05). Conclusion Astragaloside IV and LS-102 improved the inflammatory reaction in perirenal adipose tissue and renal pathological changes in obesity-related nephropathy model mice and inhibited the TGF-β1/Smad signaling cascade. At the same concentration, the effect of LS-102 was better than that of astragaloside IV. These results suggest that LS-102 has a better protective effect against obesity-related nephropathy. LS-102 may be a new type of traditional Chinese medicine for the clinical treatment of obesity and its related metabolic diseases.
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Affiliation(s)
- Ziyu Li
- Department of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
| | - Wei Yang
- Department of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
| | - Yong Yang
- Department of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
| | - Jianbo Wu
- Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
| | - Pei Luo
- State Key Laboratories for Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, People’s Republic of China
| | - Yong Liu
- Department of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
- Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, People’s Republic of China
- Medical Equipment Department, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
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20
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Lu B, Huang L, Cao J, Li L, Wu W, Chen X, Ding C. Adipose tissue macrophages in aging-associated adipose tissue function. J Physiol Sci 2021; 71:38. [PMID: 34863096 PMCID: PMC10717320 DOI: 10.1186/s12576-021-00820-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 11/04/2021] [Indexed: 12/29/2022]
Abstract
"Inflammaging" refers to the chronic, low-grade inflammation that characterizes aging. Aging, like obesity, is associated with visceral adiposity and insulin resistance. Adipose tissue macrophages (ATMs) have played a major role in obesity-associated inflammation and insulin resistance. Macrophages are elevated in adipose tissue in aging. However, the changes and also possibly functions of ATMs in aging and aging-related diseases are unclear. In this review, we will summarize recent advances in research on the role of adipose tissue macrophages with aging-associated insulin resistance and discuss their potential therapeutic targets for preventing and treating aging and aging-related diseases.
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Affiliation(s)
- Bangchao Lu
- Department of Geriatrics, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangshu, China
| | - Liang Huang
- Department of Geriatrics, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangshu, China
| | - Juan Cao
- Department of Geriatrics, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangshu, China
| | - Lingling Li
- Department of Geriatrics, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangshu, China
| | - Wenhui Wu
- Department of Geriatrics, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangshu, China
| | - Xiaolin Chen
- Department of Geriatrics, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangshu, China
| | - Congzhu Ding
- Department of Geriatrics, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangshu, China.
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21
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Resident and migratory adipose immune cells control systemic metabolism and thermogenesis. Cell Mol Immunol 2021; 19:421-431. [PMID: 34837070 PMCID: PMC8891307 DOI: 10.1038/s41423-021-00804-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 10/28/2021] [Indexed: 02/08/2023] Open
Abstract
Glucose is a vital source of energy for all mammals. The balance between glucose uptake, metabolism and storage determines the energy status of an individual, and perturbations in this balance can lead to metabolic diseases. The maintenance of organismal glucose metabolism is a complex process that involves multiple tissues, including adipose tissue, which is an endocrine and energy storage organ that is critical for the regulation of systemic metabolism. Adipose tissue consists of an array of different cell types, including specialized adipocytes and stromal and endothelial cells. In addition, adipose tissue harbors a wide range of immune cells that play vital roles in adipose tissue homeostasis and function. These cells contribute to the regulation of systemic metabolism by modulating the inflammatory tone of adipose tissue, which is directly linked to insulin sensitivity and signaling. Furthermore, these cells affect the control of thermogenesis. While lean adipose tissue is rich in type 2 and anti-inflammatory cytokines such as IL-10, obesity tips the balance in favor of a proinflammatory milieu, leading to the development of insulin resistance and the dysregulation of systemic metabolism. Notably, anti-inflammatory immune cells, including regulatory T cells and innate lymphocytes, protect against insulin resistance and have the characteristics of tissue-resident cells, while proinflammatory immune cells are recruited from the circulation to obese adipose tissue. Here, we review the key findings that have shaped our understanding of how immune cells regulate adipose tissue homeostasis to control organismal metabolism.
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22
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Insulin Resistance and Cancer: In Search for a Causal Link. Int J Mol Sci 2021; 22:ijms222011137. [PMID: 34681797 PMCID: PMC8540232 DOI: 10.3390/ijms222011137] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 10/11/2021] [Accepted: 10/12/2021] [Indexed: 12/12/2022] Open
Abstract
Insulin resistance (IR) is a condition which refers to individuals whose cells and tissues become insensitive to the peptide hormone, insulin. Over the recent years, a wealth of data has made it clear that a synergistic relationship exists between IR, type 2 diabetes mellitus, and cancer. Although the underlying mechanism(s) for this association remain unclear, it is well established that hyperinsulinemia, a hallmark of IR, may play a role in tumorigenesis. On the other hand, IR is strongly associated with visceral adiposity dysfunction and systemic inflammation, two conditions which favor the establishment of a pro-tumorigenic environment. Similarly, epigenetic modifications, such as DNA methylation, histone modifications, and non-coding RNA, in IR states, have been often associated with tumorigenesis in numerous types of human cancer. In addition to these observations, it is also broadly accepted that gut microbiota may play an intriguing role in the development of IR-related diseases, including type 2 diabetes and cancer, whereas potential chemopreventive properties have been attributed to some of the most commonly used antidiabetic medications. Herein we provide a concise overview of the most recent literature in this field and discuss how different but interrelated molecular pathways may impact on tumor development.
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23
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Aurones and Flavonols from Coreopsis lanceolata L. Flowers and Their Anti-Oxidant, Pro-Inflammatory Inhibition Effects, and Recovery Effects on Alloxan-Induced Pancreatic Islets in Zebrafish. Molecules 2021; 26:molecules26206098. [PMID: 34684679 PMCID: PMC8540554 DOI: 10.3390/molecules26206098] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/01/2021] [Accepted: 10/04/2021] [Indexed: 01/22/2023] Open
Abstract
(1) Background: Many flavonoids have been reported to exhibit pharmacological activity; a preparatory study confirmed that Coreopsis lanceolata flowers (CLFs) contained high flavonoid structure content; (2) Methods: CLFs were extracted in aqueous methanol (MeOH:H2O = 4:1) and fractionated into acetic ester (EtOAc), normal butanol (n-BuOH), and H2O fractions. Repeated column chromatographies for two fractions led to the isolation of two aurones and two flavonols; (3) Results: Four flavonoids were identified based on a variety of spectroscopic data analyses to be leptosidin (1), leptosin (2), isoquercetin (3), and astragalin (4), respectively. This is the first report for isolation of 2–4 from CLFs. High-performance liquid chromatography (HPLC) analysis determined the content levels of compounds 1–4 in the MeOH extract to be 2.8 ± 0.3 mg/g (1), 17.9 ± 0.9 mg/g (2), 3.0 ± 0.2 mg/g (3), and 10.9 ± 0.9 mg/g (4), respectively. All isolated compounds showed radical scavenging activities and recovery activities in Caco-2, RAW264.7, PC-12, and HepG2 cells against reactive oxygen species. MeOH extract, EtOAc fraction, and 1–3 suppressed NO formation in LPS-stimulated RAW 264.7 cells and decreased iNOS and COX-2 expression. Furthermore, all compounds recovered the pancreatic islets damaged by alloxan treatment in zebrafish; (4) Conclusions: The outcome proposes 1–4 to serve as components of CLFs in standardizing anti-oxidant, pro-inflammatory inhibition, and potential anti-diabetic agents.
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24
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Hou L, Jiang F, Huang B, Zheng W, Jiang Y, Cai G, Liu D, Hu CY, Wang C. Dihydromyricetin Ameliorates Inflammation-Induced Insulin Resistance via Phospholipase C-CaMKK-AMPK Signal Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:8542809. [PMID: 34650665 PMCID: PMC8510796 DOI: 10.1155/2021/8542809] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 08/07/2021] [Accepted: 08/26/2021] [Indexed: 12/19/2022]
Abstract
Patients with metabolic syndrome have a higher risk of type II diabetes and cardiovascular disease. The metabolic syndrome has become an urgent public health problem. Insulin resistance is the common pathophysiological basis of metabolic syndrome. The higher incidence of insulin resistance in obese groups is due to increased levels of inflammatory factors during obesity. Therefore, developing a therapeutic strategy for insulin resistance has great significance for the treatment of the metabolic syndrome. Dihydromyricetin, as a bioactive polyphenol, has been used for anti-inflammatory, antitumor, and improving insulin sensitivity. However, the target of DHM and molecular mechanism of DHM for preventing inflammation-induced insulin resistance is still unclear. In this study, we first confirmed the role of dihydromyricetin in inflammation-induced insulin resistance in vivo and in vitro. Then, we demonstrated that dihydromyricetin resisted inflammation-induced insulin resistance by activating Ca2+-CaMKK-AMPK using signal pathway blockers, Ca2+ probes, and immunofluorescence. Finally, we clarified that dihydromyricetin activated Ca2+-CaMKK-AMPK signaling pathway by interacting with the phospholipase C (PLC), its target protein, using drug affinity responsive target stability (DARTS) assay. Our results not only demonstrated that dihydromyricetin resisted inflammation-induced insulin resistance via the PLC-CaMKK-AMPK signal pathway but also discovered that the target protein of dihydromyricetin is the PLC. Our results provided experimental data for the development of dihydromyricetin as a functional food and new therapeutic strategies for treating or preventing PLC.
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Affiliation(s)
- Lianjie Hou
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, China
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan City People's Hospital, Qingyuan, 511518 Guangdong, China
| | - Fangyi Jiang
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, China
| | - Bo Huang
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, China
| | - Weijie Zheng
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, China
| | - Yufei Jiang
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, China
| | - Gengyuan Cai
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, China
| | - Dewu Liu
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, China
| | - Ching Yuan Hu
- Department of Human Nutrition, Food and Animal Sciences, College of Tropical Agriculture and Human Resources, University of Hawaii at Manoa, USA
| | - Chong Wang
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, China
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25
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Lefevre C, Chartoire D, Ferraz JC, Verdier T, Pinteur C, Chanon S, Pesenti S, Vieille-Marchiset A, Genestier L, Vidal H, Mey A. Obesity activates immunomodulating properties of mesenchymal stem cells in adipose tissue with differences between localizations. FASEB J 2021; 35:e21650. [PMID: 33993539 DOI: 10.1096/fj.202002046rr] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 04/21/2021] [Accepted: 04/21/2021] [Indexed: 01/02/2023]
Abstract
Mesenchymal stem cells from healthy adipose tissue are adipocytes progenitors with immunosuppressive potential that are used for years in cell therapy. Whether adipose stem cells (ASC) may prevent inflammation in early obesity is not known. To address this question, we performed a kinetic study of high-fat (HF) diet induced obesity in mice to follow the immune regulating functions of adipose stem cells (ASC) isolated from the subcutaneous (SAT) and the visceral adipose tissue (VAT). Our results show that, early in obesity and before inflammation was detected, HF diet durably and differently activated ASC from SAT and VAT. Subcutaneous ASC from HF-fed mice strongly inhibited the proliferation of activated T lymphocytes, whereas visceral ASC selectively inhibited TNFα expression by macrophages and simultaneously released higher concentrations of IL6. These depot specific differences may contribute to the low-grade inflammation that develops with obesity in VAT while inflammation in SAT is delayed. The mechanisms involved differ from those already described for naïve cells activation with inflammatory cytokines and probably engaged metabolic activation. These results evidence that adipose stem cells are metabolic sensors acquiring an obesity-primed immunocompetent state in answer to depot-specific intrinsic features with overnutrition, placing these cells ahead of inflammation in the local dialog with immune cells.
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Affiliation(s)
- Camille Lefevre
- Univ Lyon, CarMeN Laboratory, INSERM U1060, INRAE 1397, INSA Lyon, Université Claude Bernard Lyon 1, Oullins Cedex, France.,Hospices Civils de Lyon, Faculté de Médecine, Hôpital Lyon Sud, Oullins Cedex, France
| | - Dimitri Chartoire
- CRCL, Equipe Labellisée Ligue Contre le Cancer, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Faculté de Médecine Lyon Sud, Université Claude Bernard Lyon I, Oullins Cedex, France
| | - Jose Candido Ferraz
- Department of Physical Education and Sports Science, CAV, Federal University of Pernambuco (UFPE), Vitoria de Santo Antão, Brazil
| | - Thomas Verdier
- Univ Lyon, CarMeN Laboratory, INSERM U1060, INRAE 1397, INSA Lyon, Université Claude Bernard Lyon 1, Oullins Cedex, France.,Hospices Civils de Lyon, Faculté de Médecine, Hôpital Lyon Sud, Oullins Cedex, France
| | - Claudie Pinteur
- Univ Lyon, CarMeN Laboratory, INSERM U1060, INRAE 1397, INSA Lyon, Université Claude Bernard Lyon 1, Oullins Cedex, France.,Hospices Civils de Lyon, Faculté de Médecine, Hôpital Lyon Sud, Oullins Cedex, France
| | - Stéphanie Chanon
- Univ Lyon, CarMeN Laboratory, INSERM U1060, INRAE 1397, INSA Lyon, Université Claude Bernard Lyon 1, Oullins Cedex, France.,Hospices Civils de Lyon, Faculté de Médecine, Hôpital Lyon Sud, Oullins Cedex, France
| | - Sandra Pesenti
- Univ Lyon, CarMeN Laboratory, INSERM U1060, INRAE 1397, INSA Lyon, Université Claude Bernard Lyon 1, Oullins Cedex, France.,Hospices Civils de Lyon, Faculté de Médecine, Hôpital Lyon Sud, Oullins Cedex, France
| | - Aurélie Vieille-Marchiset
- Univ Lyon, CarMeN Laboratory, INSERM U1060, INRAE 1397, INSA Lyon, Université Claude Bernard Lyon 1, Oullins Cedex, France.,Hospices Civils de Lyon, Faculté de Médecine, Hôpital Lyon Sud, Oullins Cedex, France
| | - Laurent Genestier
- CRCL, Equipe Labellisée Ligue Contre le Cancer, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Faculté de Médecine Lyon Sud, Université Claude Bernard Lyon I, Oullins Cedex, France
| | - Hubert Vidal
- Univ Lyon, CarMeN Laboratory, INSERM U1060, INRAE 1397, INSA Lyon, Université Claude Bernard Lyon 1, Oullins Cedex, France.,Hospices Civils de Lyon, Faculté de Médecine, Hôpital Lyon Sud, Oullins Cedex, France
| | - Anne Mey
- Univ Lyon, CarMeN Laboratory, INSERM U1060, INRAE 1397, INSA Lyon, Université Claude Bernard Lyon 1, Oullins Cedex, France.,Hospices Civils de Lyon, Faculté de Médecine, Hôpital Lyon Sud, Oullins Cedex, France
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26
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Desharnais L, Walsh LA, Quail DF. Exploiting the obesity-associated immune microenvironment for cancer therapeutics. Pharmacol Ther 2021; 229:107923. [PMID: 34171329 DOI: 10.1016/j.pharmthera.2021.107923] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 05/11/2021] [Accepted: 06/10/2021] [Indexed: 12/12/2022]
Abstract
Obesity causes chronic low-grade inflammation and leads to changes in the immune landscape of multiple organ systems. Given the link between chronic inflammatory conditions and cancer, it is not surprising that obesity is associated with increased risk and worse outcomes in many malignancies. Paradoxically, recent epidemiological studies have shown that high BMI is associated with increased efficacy of immune checkpoint inhibitors (ICI), and a causal relationship has been demonstrated in the preclinical setting. It has been proposed that obesity-associated immune dysregulation underlies this observation by inadvertently creating a favourable microenvironment for increased ICI efficacy. The recent success of ICIs in obese cancer patients raises the possibility that additional immune-targeted therapies may hold therapeutic value in this context. Here we review how obesity affects the immunological composition of the tumor microenvironment in ways that can be exploited for cancer immunotherapies. We discuss existing literature supporting a beneficial role for obesity during ICI therapy in cancer patients, potential opportunities for targeting the innate immune system to mitigate chronic inflammatory processes, and how to pinpoint obese patients who are most likely to benefit from immune interventions without relying solely on body mass index. Given that the incidence of obesity is expanding on an international scale, we propose that understanding obesity-associated inflammation is necessary to reduce cancer mortalities and capitalize on novel therapeutic opportunities in the era of cancer immunotherapy.
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Affiliation(s)
- Lysanne Desharnais
- Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada; Department of Human Genetics, McGill University, Montreal, QC, Canada
| | - Logan A Walsh
- Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada; Department of Human Genetics, McGill University, Montreal, QC, Canada.
| | - Daniela F Quail
- Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada; Department of Physiology, Faculty of Medicine, McGill University, Montreal, QC, Canada; Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, QC, Canada.
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27
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Thibaut R, Gage MC, Pineda-Torra I, Chabrier G, Venteclef N, Alzaid F. Liver macrophages and inflammation in physiology and physiopathology of non-alcoholic fatty liver disease. FEBS J 2021; 289:3024-3057. [PMID: 33860630 PMCID: PMC9290065 DOI: 10.1111/febs.15877] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 03/05/2021] [Accepted: 04/12/2021] [Indexed: 12/13/2022]
Abstract
Non‐alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, being a common comorbidity of type 2 diabetes and with important links to inflammation and insulin resistance. NAFLD represents a spectrum of liver conditions ranging from steatosis in the form of ectopic lipid storage, to inflammation and fibrosis in nonalcoholic steatohepatitis (NASH). Macrophages that populate the liver play important roles in maintaining liver homeostasis under normal physiology and in promoting inflammation and mediating fibrosis in the progression of NAFLD toward to NASH. Liver macrophages are a heterogenous group of innate immune cells, originating from the yolk sac or from circulating monocytes, that are required to maintain immune tolerance while being exposed portal and pancreatic blood flow rich in nutrients and hormones. Yet, liver macrophages retain a limited capacity to raise the alarm in response to danger signals. We now know that macrophages in the liver play both inflammatory and noninflammatory roles throughout the progression of NAFLD. Macrophage responses are mediated first at the level of cell surface receptors that integrate environmental stimuli, signals are transduced through multiple levels of regulation in the cell, and specific transcriptional programmes dictate effector functions. These effector functions play paramount roles in determining the course of disease in NAFLD and even more so in the progression towards NASH. The current review covers recent reports in the physiological and pathophysiological roles of liver macrophages in NAFLD. We emphasise the responses of liver macrophages to insulin resistance and the transcriptional machinery that dictates liver macrophage function.
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Affiliation(s)
- Ronan Thibaut
- Cordeliers Research Centre, INSERM, IMMEDIAB Laboratory, Sorbonne Université, Université de Paris, France
| | - Matthew C Gage
- Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK
| | - Inès Pineda-Torra
- Department of Medicine, Centre for Cardiometabolic and Vascular Science, University College London, UK
| | - Gwladys Chabrier
- Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK
| | - Nicolas Venteclef
- Cordeliers Research Centre, INSERM, IMMEDIAB Laboratory, Sorbonne Université, Université de Paris, France
| | - Fawaz Alzaid
- Cordeliers Research Centre, INSERM, IMMEDIAB Laboratory, Sorbonne Université, Université de Paris, France
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28
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Sampei S, Okada H, Tomita H, Takada C, Suzuki K, Kinoshita T, Kobayashi R, Fukuda H, Kawasaki Y, Nishio A, Yano H, Muraki I, Fukuda Y, Suzuki K, Miyazaki N, Watanabe T, Doi T, Yoshida T, Suzuki A, Yoshida S, Kushimoto S, Ogura S. Endothelial Glycocalyx Disorders May Be Associated With Extended Inflammation During Endotoxemia in a Diabetic Mouse Model. Front Cell Dev Biol 2021; 9:623582. [PMID: 33869173 PMCID: PMC8047120 DOI: 10.3389/fcell.2021.623582] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 02/03/2021] [Indexed: 01/07/2023] Open
Abstract
In diabetes mellitus (DM) patients, the morbidity of infectious disease is increased, and these infections can easily progress from local to systemic infection. Sepsis is a characteristic of organ failure related to microcirculation disorders resulting from endothelial cell injury, whose most frequent comorbidity in patients is DM. The aim of the present study was to evaluate the influence of infection on DM-induced microvascular damage on inflammation and pulmonary endothelial structure using an experimental endotoxemia model. Lipopolysaccharide (LPS; 15 mg/kg) was injected intraperitoneally into 10-week-old male C57BLKS/J Iar- + lepr db /lepr db (db/db) mice and into C57BLKS/J Iar-m + / + lepr db (db/ +) mice, which served as the littermate non-diabetic control. At 48 h after LPS administration, the survival rate of db/db mice (0%, 0/10) was markedly lower (P < 0.05) than that of the db/ + mice (75%, 18/24), whereas the survival rate was 100% in both groups 24 h after LPS administration. In control mice, CD11b-positive cells increased at 6 h after LPS administration; by comparison, the number of CD11b-positive cells increased gradually in db/db mice until 12 h after LPS injection. In the control group, the number of Iba-1-positive cells did not significantly increase before and at 6, 12, and 24 h after LPS injection. Conversely, Iba-1-positive cells continued to increase until 24 h after LPS administration, and this increase was significantly greater than that in the control mice. Expression of Ext1, Csgalnact1, and Vcan related to endothelial glycocalyx synthesis was significantly lower in db/db mice than in the control mice before LPS administration, indicating that endothelial glycocalyx synthesis is attenuated in db/db/mice. In addition, ultrastructural analysis revealed that endothelial glycocalyx was thinner in db/db mice before LPS injection. In conclusion, in db/db mice, the endothelial glycocalyx is already injured before LPS administration, and migration of inflammatory cells is both delayed and expanded. This extended inflammation may be involved in endothelial glycocalyx damage due to the attenuation of endothelial glycocalyx synthesis.
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Affiliation(s)
- So Sampei
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
- Division of Emergency and Critical Care Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hideshi Okada
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Hiroyuki Tomita
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Chihiro Takada
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Kodai Suzuki
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Takamasa Kinoshita
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan
- Department of Neurosurgery, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Ryo Kobayashi
- Department of Pharmacy, Gifu University Hospital, Gifu, Japan
| | - Hirotsugu Fukuda
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Yuki Kawasaki
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Ayane Nishio
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Hirohisa Yano
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Isamu Muraki
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Yohei Fukuda
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Keiko Suzuki
- Department of Pharmacy, Gifu University Hospital, Gifu, Japan
| | - Nagisa Miyazaki
- Department of Internal Medicine, Asahi University School of Dentistry, Mizuho, Japan
| | - Takatomo Watanabe
- Department of Clinical Laboratory, Gifu University Hospital, Gifu, Japan
| | - Tomoaki Doi
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Takahiro Yoshida
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Akio Suzuki
- Department of Pharmacy, Gifu University Hospital, Gifu, Japan
| | - Shozo Yoshida
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Shigeki Kushimoto
- Division of Emergency and Critical Care Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shinji Ogura
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
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29
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Zhou Y, Liu Z, Lynch EC, He L, Cheng H, Liu L, Li Z, Li J, Lawless L, Zhang KK, Xie L. Osr1 regulates hepatic inflammation and cell survival in the progression of non-alcoholic fatty liver disease. J Transl Med 2021; 101:477-489. [PMID: 33005011 PMCID: PMC7987871 DOI: 10.1038/s41374-020-00493-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 09/12/2020] [Accepted: 09/13/2020] [Indexed: 02/07/2023] Open
Abstract
Odd-skipped related 1 (Osr1) is a novel tumor suppressor gene in several cancer cell lines. Non-alcoholic steatohepatitis (NASH) is considered as a high-risk factor for hepatocellular carcinoma (HCC). This study is aimed to investigate the novel role of Osr1 in promoting the progression of hepatic steatosis to NASH. Following 12 weeks of diethylnitrosamine (DEN) and high-fat diet (HFD), wildtype (WT) and Osr1 heterozygous (Osr1+/-) male mice were examined for liver injuries. Osr1+/- mice displayed worsen liver injury with higher serum alanine aminotransferase levels than the WT mice. The Osr1+/- mice also revealed early signs of collagen deposition with increased hepatic Tgfb and Fn1 expression. There was overactivation of both JNK and NF-κB signaling in the Osr1+/- liver, along with accumulation of F4/80+ cells and enhanced hepatic expression of Il-1b and Il-6. Moreover, the Osr1+/- liver displayed hyperphosphorylation of AKT/mTOR signaling, associated with overexpression of Bcl-2. In addition, Osr1+/- and WT mice displayed differences in the DNA methylome of the liver cells. Specifically, Osr1-responsible CpG islands of Ccl3 and Pcgf2, genes for inflammation and macrophage infiltration, were further identified. Taken together, Osr1 plays an important role in regulating cell inflammation and survival through multiple signaling pathways and DNA methylation modification for NAFLD progression.
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Affiliation(s)
- Yi Zhou
- Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA
- Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Zhimin Liu
- Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University (Gastrointestinal and Anal Hospital of Sun Yat-sen Unversity), Guangzhou, 510655, China
| | - Ernest C Lynch
- Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA
| | - Leya He
- Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA
- Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Henghui Cheng
- Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA
- Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Lin Liu
- Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA
| | - Zhen Li
- Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA
| | - Jiangyuan Li
- Department of Statistics, Texas A&M University, College Station, TX, 77843, USA
| | - Lauren Lawless
- Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA
| | - Ke K Zhang
- Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA
- Center for Epigenetics & Disease Prevention, Institute of Biosciences & Technology, College of Medicine, Texas A&M University, Houston, TX, USA
| | - Linglin Xie
- Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA.
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30
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Garg R, Kumariya S, Katekar R, Verma S, Goand UK, Gayen JR. JNK signaling pathway in metabolic disorders: An emerging therapeutic target. Eur J Pharmacol 2021; 901:174079. [PMID: 33812885 DOI: 10.1016/j.ejphar.2021.174079] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 03/18/2021] [Accepted: 03/25/2021] [Indexed: 02/08/2023]
Abstract
Metabolic Syndrome is a multifactorial disease associated with increased risk of cardiovascular disorders, type 2 diabetes mellitus, fatty liver disease, etc. Various stress stimuli such as reactive oxygen species, endoplasmic reticulum stress, mitochondrial dysfunction, increased cytokines, or free fatty acids are known to aggravate progressive development of hyperglycemia and hyperlipidemia. Although the exact mechanism contributing to altered metabolism is unclear. Evidence suggests stress kinase role to be a crucial one in metabolic syndrome. Stress kinase, c-jun N-terminal kinase activation (JNK) is involved in various metabolic manifestations including obesity, insulin resistance, fatty liver disease as well as cardiometabolic disorders. It emerged as a foremost mediator in regulating metabolism in the liver, skeletal muscle, adipose tissue as well as pancreatic β cells. It has three isoforms each having a unique and tissue-specific role in altered metabolism. Current findings based on genetic manipulation or chemical inhibition studies identified JNK isoforms to play a central role in the regulation of whole-body metabolism, suggesting it to be a novel therapeutic target. Hence, it is imperative to elucidate its role in metabolic syndrome onset and progression. The purpose of this review is to elucidate in vitro and in vivo implications of JNK signaling along with the therapeutic strategy to inhibit specific isoform. Since metabolic syndrome is an array of diseases and complex pathway, carefully examining each tissue will be important for specific treatment strategies.
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Affiliation(s)
- Richa Garg
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Sanjana Kumariya
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India
| | - Roshan Katekar
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Saurabh Verma
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Umesh K Goand
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Jiaur R Gayen
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India; Pharmacology Division, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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Zhu B, Guo X, Xu H, Jiang B, Li H, Wang Y, Yin Q, Zhou T, Cai JJ, Glaser S, Meng F, Francis H, Alpini G, Wu C. Adipose tissue inflammation and systemic insulin resistance in mice with diet-induced obesity is possibly associated with disruption of PFKFB3 in hematopoietic cells. J Transl Med 2021; 101:328-340. [PMID: 33462362 PMCID: PMC7897240 DOI: 10.1038/s41374-020-00523-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 10/13/2020] [Accepted: 11/28/2020] [Indexed: 02/06/2023] Open
Abstract
Obesity-associated inflammation in white adipose tissue (WAT) is a causal factor of systemic insulin resistance; however, precisely how immune cells regulate WAT inflammation in relation to systemic insulin resistance remains to be elucidated. The present study examined a role for 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in hematopoietic cells in regulating WAT inflammation and systemic insulin sensitivity. Male C57BL/6J mice were fed a high-fat diet (HFD) or low-fat diet (LFD) for 12 weeks and examined for WAT inducible 6-phosphofructo-2-kinase (iPFK2) content, while additional HFD-fed mice were treated with rosiglitazone and examined for PFKFB3 mRNAs in WAT stromal vascular cells (SVC). Also, chimeric mice in which PFKFB3 was disrupted only in hematopoietic cells and control chimeric mice were also fed an HFD and examined for HFD-induced WAT inflammation and systemic insulin resistance. In vitro, adipocytes were co-cultured with bone marrow-derived macrophages and examined for adipocyte proinflammatory responses and insulin signaling. Compared with their respective levels in controls, WAT iPFK2 amount in HFD-fed mice and WAT SVC PFKFB3 mRNAs in rosiglitazone-treated mice were significantly increased. When the inflammatory responses were analyzed, peritoneal macrophages from PFKFB3-disrputed mice revealed increased proinflammatory activation and decreased anti-inflammatory activation compared with control macrophages. At the whole animal level, hematopoietic cell-specific PFKFB3 disruption enhanced the effects of HFD feeding on promoting WAT inflammation, impairing WAT insulin signaling, and increasing systemic insulin resistance. In vitro, adipocytes co-cultured with PFKFB3-disrupted macrophages revealed increased proinflammatory responses and decreased insulin signaling compared with adipocytes co-cultured with control macrophages. These results suggest that PFKFB3 disruption in hematopoietic cells only exacerbates HFD-induced WAT inflammation and systemic insulin resistance.
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Affiliation(s)
- Bilian Zhu
- Department of Nutrition, Texas A&M University, College Station, TX, USA
- Department of VIP Medical Service Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xin Guo
- Department of Nutrition, Texas A&M University, College Station, TX, USA
- Department of Nutrition and Food Hygiene, School of Public Health, Cheeloo College of Medicine, Shandong University, Shandong, Jinan, China
| | - Hang Xu
- Department of Nutrition, Texas A&M University, College Station, TX, USA
| | - Boxiong Jiang
- Department of VIP Medical Service Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Honggui Li
- Department of Nutrition, Texas A&M University, College Station, TX, USA
| | - Yina Wang
- Department of VIP Medical Service Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Qiongli Yin
- Department of VIP Medical Service Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Tianhao Zhou
- Medical Physiology, Texas A&M University College of Medicine, Bryan, TX, USA
| | - James J Cai
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX, USA
| | - Shannon Glaser
- Medical Physiology, Texas A&M University College of Medicine, Bryan, TX, USA
| | - Fanyin Meng
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN, USA
- Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA
| | - Heather Francis
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN, USA
- Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA
| | - Gianfranco Alpini
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN, USA
- Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA
| | - Chaodong Wu
- Department of Nutrition, Texas A&M University, College Station, TX, USA.
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The Tumor Promotional Role of Adipocytes in the Breast Cancer Microenvironment and Macroenvironment. THE AMERICAN JOURNAL OF PATHOLOGY 2021; 191:1342-1352. [PMID: 33639102 DOI: 10.1016/j.ajpath.2021.02.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 01/23/2021] [Accepted: 02/02/2021] [Indexed: 12/12/2022]
Abstract
The role of the adipocyte in the tumor microenvironment has received significant attention as a critical mediator of the obesity-cancer relationship. Current estimates indicate that 650 million adults have obesity, and thirteen cancers, including breast cancer, are estimated to be associated with obesity. Even in people with a normal body mass index, adipocytes are key players in breast cancer progression because of the proximity of tumors to mammary adipose tissue. Outside the breast microenvironment, adipocytes influence metabolic and immune function and produce numerous signaling molecules, all of which affect breast cancer development and progression. The current epidemiologic data linking obesity, and importantly adipose tissue, to breast cancer risk and prognosis, focusing on metabolic health, weight gain, and adipose distribution as underlying drivers of obesity-associated breast cancer is presented here. Bioactive factors produced by adipocytes, both normal and cancer associated, such as cytokines, growth factors, and metabolites, and the potential mechanisms through which adipocytes influence different breast cancer subtypes are highlighted.
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Mazzoli A, Sardi C, Breasson L, Theilig F, Becattini B, Solinas G. JNK1 ablation improves pancreatic β-cell mass and function in db/db diabetic mice without affecting insulin sensitivity and adipose tissue inflammation. FASEB Bioadv 2021; 3:94-107. [PMID: 33615154 PMCID: PMC7876705 DOI: 10.1096/fba.2020-00081] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 12/12/2020] [Accepted: 12/16/2020] [Indexed: 12/15/2022] Open
Abstract
The cJun N‐terminal Kinases (JNK) emerged as a major link between obesity and insulin resistance, but their role in the loss of pancreatic β‐cell mass and function driving the progression from insulin resistance to type‐2 diabetes and in the complications of diabetes was not investigated to the same extent. Furthermore, it was shown that pan‐JNK inhibition exacerbates kidney damage in the db/db model of obesity‐driven diabetes. Here we investigate the role of JNK1 in the db/db model of obesity‐driven type‐2 diabetes. Mice with systemic ablation of JNK1 (JNK1−/−) were backcrossed for more than 10 generations in db/+ C57BL/KS mice to generate db/db‐JNK1−/− mice and db/db control mice. To define the role of JNK1 in the loss of β‐cell mass and function occurring during obesity‐driven diabetes we performed comprehensive metabolic phenotyping, evaluated steatosis and metabolic inflammation, performed morphometric and cellular composition analysis of pancreatic islets, and evaluated kidney function in db/db‐JNK1−/− mice and db/db controls. db/db‐JNK1−/− mice and db/db control mice developed insulin resistance, fatty liver, and metabolic inflammation to a similar extent. However, db/db‐JNK1−/− mice displayed better glucose tolerance and improved insulin levels during glucose tolerance test, higher pancreatic insulin content, and larger pancreatic islets with more β‐cells than db/db mice. Finally, albuminuria, kidney histopathology, kidney inflammation and oxidative stress in db/db‐JNK1−/− mice and in db/db mice were similar. Our data indicate that selective JNK1 ablation improves glucose tolerance in db/db mice by reducing the loss of functional β‐cells occurring in the db/db mouse model of obesity‐driven diabetes, without significantly affecting metabolic inflammation, steatosis, and insulin sensitivity. Furthermore, we have found that, differently from what previously reported for pan‐JNK inhibitors, selective JNK1 ablation does not exacerbate kidney dysfunction in db/db mice. We conclude that selective JNK1 inactivation may have a superior therapeutic index than pan‐JNK inhibition in obesity‐driven diabetes.
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Affiliation(s)
- Arianna Mazzoli
- The Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research Department of Molecular and Clinical Medicine Institute of Medicine University of Gothenburg Gothenburg Sweden
| | - Claudia Sardi
- The Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research Department of Molecular and Clinical Medicine Institute of Medicine University of Gothenburg Gothenburg Sweden
| | - Ludovic Breasson
- The Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research Department of Molecular and Clinical Medicine Institute of Medicine University of Gothenburg Gothenburg Sweden
| | - Franziska Theilig
- Institute of Anatomy Christian Albrechts-University Kiel Kiel Germany
| | - Barbara Becattini
- The Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research Department of Molecular and Clinical Medicine Institute of Medicine University of Gothenburg Gothenburg Sweden
| | - Giovanni Solinas
- The Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research Department of Molecular and Clinical Medicine Institute of Medicine University of Gothenburg Gothenburg Sweden
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Al-Fadhel SZ, Al-Ghuraibawi NHA, Mohammed Ali DM, Al-Hakeim HK. Serum cytokine dependent hematopoietic cell linker (CLNK) as a predictor for the duration of illness in type 2 diabetes mellitus. J Diabetes Metab Disord 2021; 19:959-966. [PMID: 33520815 DOI: 10.1007/s40200-020-00588-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 06/22/2020] [Accepted: 07/13/2020] [Indexed: 02/07/2023]
Abstract
Type 2 diabetes mellitus (T2DM) is an endocrine illness associated with various changes in the immune system and adaptor protein levels. Cytokine dependent hematopoietic cell linker (CLNK) is an adapter protein that regulates immune receptor signaling and acts as a regulator of the receptor signaling of T-cells and natural killer cells. The role of CLNK in T2DM is not studied previously. In the present study, serum CLNK level was measured and correlated with some sociodemographic and insulin resistance (IR) parameters. To achieve these goals, we measured CLNK level and insulin parameters (glucose, insulin, HbA1c, in addition to the calculation of the functions of IR (HOMA2IR), insulin sensitivity (HOMA%S), and beta-cell function (HOMA%B)) in 60 T2DM patients and 30 controls. The results indicated a significant increase (p < 0.05) in serum CLNK in patients group in comparison with the controls. Multivariate generalized linear model (GLM) analysis revealed no significant effect of age, BMI, and sex on the CLNK level. The results of tests for between-subjects showed that the CLNK affects diagnosis significantly (F = 7.445, p = 0.008, partial η2 = 0.081) and its effect is approximately the same as the effect of insulin (F = 8.107, p = 0.006, partial η2 = 0.087). The correlation study showed a highly significant positive correlation between CLNK and the duration of disease (rho = 0.420, p < 0.001). It can be concluded that the increase CLNK in T2DM revealing the role of the adaptor proteins level in the progression of the disease and may act as a predictor for diabetes complications, which deserves more investigations.
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Affiliation(s)
- Suhaer Zeki Al-Fadhel
- Department of Clinical Laboratory Science, College of Pharmacy, University of Kufa, Kufa, Iraq
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Favre G, Legueult K, Pradier C, Raffaelli C, Ichai C, Iannelli A, Redheuil A, Lucidarme O, Esnault V. Visceral fat is associated to the severity of COVID-19. Metabolism 2021; 115:154440. [PMID: 33246009 PMCID: PMC7685947 DOI: 10.1016/j.metabol.2020.154440] [Citation(s) in RCA: 96] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 11/17/2020] [Accepted: 11/19/2020] [Indexed: 02/01/2023]
Abstract
BACKGROUND Excess visceral fat (VF) or high body mass index (BMI) is risk factors for severe COVID-19. The receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is expressed at higher levels in the VF than in the subcutaneous fat (SCF) of obese patients. AIM To show that visceral fat accumulation better predicts severity of COVID-19 outcome compared to either SCF amounts or BMI. METHODS We selected patients with symptomatic COVID-19 and a computed tomography (CT) scan. Severe COVID-19 was defined as requirement for mechanical ventilation or death. Fat depots were quantified on abdominal CT scan slices and the measurements were correlated with the clinical outcomes. ACE 2 mRNA levels were quantified in fat depots of a separate group of non-COVID-19 subjects using RT-qPCR. RESULTS Among 165 patients with a mean BMI of 26.1 ± 5.4 kg/m2, VF was associated with severe COVID-19 (p = 0.022) and SCF was not (p = 0.640). Subcutaneous fat was not different in patients with mild or severe COVID-19 and the SCF/VF ratio was lower in patients with severe COVID-19 (p = 0.010). The best predictive value for severe COVID-19 was found for a VF area ≥128.5 cm2 (ROC curve), which was independently associated with COVID-19 severity (p < 0.001). In an exploratory analysis, ACE 2 mRNA positively correlated with BMI in VF but not in SCF of non-COVID-19 patients (r2 = 0.27 vs 0.0008). CONCLUSION Severe forms of COVID-19 are associated with high visceral adiposity in European adults. On the basis of an exploratory analysis ACE 2 in the visceral fat may be a trigger for the cytokine storm, and this needs to be clarified by future studies.
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Affiliation(s)
- Guillaume Favre
- University of Côte d'Azur, CNRS-UMR 7073 (LP2M), Department of Nephrology-Dialysis-Transplantation, Pasteur University Hospital, F-06002 CD1 Nice, France.
| | - Kevin Legueult
- University of Côte d'Azur, Department of Public Health, Archet University Hospital, F-06202 Nice, France
| | - Christian Pradier
- University of Côte d'Azur, Department of Public Health, Archet University Hospital, F-06202 Nice, France
| | - Charles Raffaelli
- Radiology Department, Pasteur University Hospital, F-06002 Nice, France
| | - Carole Ichai
- University of Côte d'Azur, Intensive Care Unit, Pasteur University Hospital, Nice F-06002, France
| | - Antonio Iannelli
- University of Côte d'Azur, INSERM-U1065, Digestive Surgery and Liver Transplantation Unit, Archet University Hospital, F-06202 Nice, France
| | - Alban Redheuil
- Sorbonne University, Pitié-Salpêtrière Hospital (AP-HP), ICT Cardiothoracic Imaging Unit & Radiology Department, LIB Biomedical Imaging Laboratory INSERM, CNRS, ICAN Institute of Cardiometabolism and Nutrition, Paris, France
| | - Olivier Lucidarme
- Sorbonne University, CNRS, INSERM, Laboratoire d'Imagerie Biomédicale, APHP, Pitié-Salpêtrière Hospital, F-750013 Paris, France
| | - Vincent Esnault
- University of Côte d'Azur, CNRS-UMR 7073 (LP2M), Department of Nephrology-Dialysis-Transplantation, Pasteur University Hospital, F-06002 CD1 Nice, France
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Cimini FA, Barchetta I, Ciccarelli G, Leonetti F, Silecchia G, Chiappetta C, Di Cristofano C, Capoccia D, Bertoccini L, Ceccarelli V, Carletti R, Fraioli A, Baroni MG, Morini S, Cavallo MG. Adipose tissue remodelling in obese subjects is a determinant of presence and severity of fatty liver disease. Diabetes Metab Res Rev 2021; 37:e3358. [PMID: 32469428 DOI: 10.1002/dmrr.3358] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 04/21/2020] [Accepted: 05/18/2020] [Indexed: 12/11/2022]
Abstract
AIMS Experimental data suggest that visceral adipose tissue (VAT) dysfunction contributes to non-alcoholic fatty liver disease (NAFLD) development in obesity, however, data on humans are limited. Aims of this study were to investigate the relationship between NAFLD and VAT morphofunctional impairment and to determine whether the extent of VAT remodelling is associated with liver damage and metabolic alterations in obesity. METHODS We analysed data from 40 obese individuals candidate to bariatric surgery in whom paired intraoperative liver and omental biopsies were performed for diagnosing NAFLD and VAT inflammation by immunohistochemistry and mRNA expression studies. RESULTS Within our study population, NAFLD was significantly associated with greater VAT CD68+ macrophages infiltration (P = .04), fibrosis (P = .04) and impaired microvascular density (P = .03) as well as increased expression of markers of local hypoxia, apoptosis and inflammation (UNC5B, CASP7, HIF1-α, IL-8, MIP2, WISP-1, all P < .01). The degree of VAT inflammation correlated with the severity of hepatic injury (steatosis, inflammation, fibrosis; all P < .01) and impaired gluco-metabolic profile. CONCLUSIONS In obese patients, NAFLD is associated in a dose-dependent manner with signs of VAT remodelling, which reflect more severe clinical metabolic impairment. Our study depicts morphological alterations and novel mediators of VAT dysfunction, adding knowledge for future therapeutic approaches to NAFLD and its metabolic complications.
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Affiliation(s)
- Flavia Agata Cimini
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Ilaria Barchetta
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Gea Ciccarelli
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Frida Leonetti
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Gianfranco Silecchia
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Caterina Chiappetta
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Claudio Di Cristofano
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Danila Capoccia
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Laura Bertoccini
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | | | - Raffaella Carletti
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Antonio Fraioli
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | - Marco Giorgio Baroni
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
- Neuroendocrinology and Metabolic Disease, IRCCS Neuromed, Pozzilli, Italy
| | - Sergio Morini
- Laboratory of Microscopic and Ultrastructural Anatomy, Faculty of Medicine, University Campus Bio-Medico, Rome, Italy
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Kölbl H, Bartl T. Obesity in Gynecologic Oncology. Geburtshilfe Frauenheilkd 2020; 80:1205-1211. [PMID: 33293728 PMCID: PMC7714555 DOI: 10.1055/a-1124-7139] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 07/25/2020] [Indexed: 12/31/2022] Open
Abstract
The decades-long global obesity epidemic has resulted in steady increase in the incidence of obesity-related malignancies. The associated diagnostic and therapeutic implications present a clinical challenge for gynecologic oncology treatment strategies. Recent studies have provided solid evidence for an independent, linear, positive correlation between a pathologically increased body mass index and the probability of developing endometrial or postmenopausal breast cancer. The pathogenesis is complex and the subject of current research. Proposed causes include pathologically increased serum levels of sexual steroids and adiponectin, obesity-induced insulin resistance, and systemic inflammatory processes. The scientific evidence for an association between obesity and other gynecological malignancies is, however, less solid. The clinical relevance of obesity as a risk factor for epithelial ovarian cancer, cervical cancer and vulvar cancer appears to be negligible.
Nevertheless, obesity appears to have a negative impact on prognosis and oncologic outcomes for all gynecological cancers. Whether or not this effect can be interpreted as correlative or causal is still a subject of ongoing debate.
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Affiliation(s)
- Heinz Kölbl
- Klinische Abteilung für Allgemeine Gynäkologie und Gynäkologische Onkologie, Universitätsklinik für Frauenheilkunde, Medizinische Universität Wien, Wien, Austria
| | - Thomas Bartl
- Klinische Abteilung für Allgemeine Gynäkologie und Gynäkologische Onkologie, Universitätsklinik für Frauenheilkunde, Medizinische Universität Wien, Wien, Austria
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Chen KHE, Lainez NM, Coss D. Sex Differences in Macrophage Responses to Obesity-Mediated Changes Determine Migratory and Inflammatory Traits. THE JOURNAL OF IMMUNOLOGY 2020; 206:141-153. [PMID: 33268480 DOI: 10.4049/jimmunol.2000490] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 11/02/2020] [Indexed: 12/18/2022]
Abstract
The mechanisms whereby obesity differentially affects males and females are unclear. Because macrophages are functionally the most important cells in obesity-induced inflammation, we sought to determine reasons for male-specific propensity in macrophage migration. We previously determined that male mice fed a high-fat diet exhibit macrophage infiltration into the hypothalamus, whereas females were protected irrespective of ovarian estrogen, in this study, we show that males accumulate more macrophages in adipose tissues that are also more inflammatory. Using bone marrow cells or macrophages differentiated in vitro from male and female mice fed control or high-fat diet, we demonstrated that macrophages derived from male mice are intrinsically more migratory. We determined that males have higher levels of leptin in serum and adipose tissue. Serum CCL2 levels, however, are the same in males and females, although they are increased in obese mice compared with lean mice of both sexes. Leptin receptor and free fatty acid (FFA) receptor, GPR120, are upregulated only in macrophages derived from male mice when cultured in the presence of FFA to mimic hyperlipidemia of obesity. Unless previously stimulated with LPS, CCL2 did not cause migration of macrophages. Leptin, however, elicited migration of macrophages from both sexes. Macrophages from male mice maintained migratory capacity when cultured with FFA, whereas female macrophages failed to migrate. Therefore, both hyperlipidemia and hyperleptinemia contribute to male macrophage-specific migration because increased FFA induce leptin receptors, whereas higher leptin causes migration. Our results may explain sex differences in obesity-mediated disorders caused by macrophage infiltration.
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Affiliation(s)
- Kuan-Hui Ethan Chen
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA 92521
| | - Nancy M Lainez
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA 92521
| | - Djurdjica Coss
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA 92521
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Scheithauer TPM, Rampanelli E, Nieuwdorp M, Vallance BA, Verchere CB, van Raalte DH, Herrema H. Gut Microbiota as a Trigger for Metabolic Inflammation in Obesity and Type 2 Diabetes. Front Immunol 2020; 11:571731. [PMID: 33178196 PMCID: PMC7596417 DOI: 10.3389/fimmu.2020.571731] [Citation(s) in RCA: 364] [Impact Index Per Article: 72.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 09/11/2020] [Indexed: 12/12/2022] Open
Abstract
The gut microbiota has been linked to the development of obesity and type 2 diabetes (T2D). The underlying mechanisms as to how intestinal microbiota may contribute to T2D are only partly understood. It becomes progressively clear that T2D is characterized by a chronic state of low-grade inflammation, which has been linked to the development of insulin resistance. Here, we review the current evidence that intestinal microbiota, and the metabolites they produce, could drive the development of insulin resistance in obesity and T2D, possibly by initiating an inflammatory response. First, we will summarize major findings about immunological and gut microbial changes in these metabolic diseases. Next, we will give a detailed view on how gut microbial changes have been implicated in low-grade inflammation. Lastly, we will critically discuss clinical studies that focus on the interaction between gut microbiota and the immune system in metabolic disease. Overall, there is strong evidence that the tripartite interaction between gut microbiota, host immune system and metabolism is a critical partaker in the pathophysiology of obesity and T2D.
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Affiliation(s)
- Torsten P M Scheithauer
- Department of Internal Medicine, Amsterdam University Medical Center (UMC), Vrije Universiteit (VU) University Medical Center, Amsterdam, Netherlands.,Department of Experimental Vascular Medicine, Amsterdam University Medical Center (UMC), Academic Medical Center, Amsterdam, Netherlands
| | - Elena Rampanelli
- Department of Experimental Vascular Medicine, Amsterdam University Medical Center (UMC), Academic Medical Center, Amsterdam, Netherlands
| | - Max Nieuwdorp
- Department of Internal Medicine, Amsterdam University Medical Center (UMC), Vrije Universiteit (VU) University Medical Center, Amsterdam, Netherlands.,Department of Experimental Vascular Medicine, Amsterdam University Medical Center (UMC), Academic Medical Center, Amsterdam, Netherlands
| | - Bruce A Vallance
- Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, Vancouver, BC, Canada
| | - C Bruce Verchere
- Department of Surgery, University of British Columbia and BC Children's Hospital Research Institute, Vancouver, BC, Canada
| | - Daniël H van Raalte
- Department of Internal Medicine, Amsterdam University Medical Center (UMC), Vrije Universiteit (VU) University Medical Center, Amsterdam, Netherlands.,Department of Experimental Vascular Medicine, Amsterdam University Medical Center (UMC), Academic Medical Center, Amsterdam, Netherlands
| | - Hilde Herrema
- Department of Experimental Vascular Medicine, Amsterdam University Medical Center (UMC), Academic Medical Center, Amsterdam, Netherlands
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Lee MR, Kim JE, Park JW, Kang MJ, Choi HJ, Bae SJ, Choi YW, Kim KM, Hong JT, Hwang DY. Fermented mulberry (Morus alba) leaves suppress high fat diet-induced hepatic steatosis through amelioration of the inflammatory response and autophagy pathway. BMC Complement Med Ther 2020; 20:283. [PMID: 32948162 PMCID: PMC7501671 DOI: 10.1186/s12906-020-03076-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 09/08/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND A novel extract of mulberry leaves fermented with Cordyceps militaris (EMfC) is reported to exert anti-obesity activity, although their molecular mechanism during hepatic steatosis has not verified. METHODS To investigate the role of inflammation and autophagy during the anti-hepatic steatosis effects of EMfC, we measured alterations in the key parameters for inflammatory response and autophagy pathway in liver tissues of the high fat diet (HFD) treated C57BL/6N mice after exposure to EMfC for 12 weeks. RESULTS Significant anti-hepatic steatosis effects, including decreased number of lipid droplets and expression of Klf2 mRNA, were detected in the liver of the HFD + EMfC treated group. The levels of mast cell infiltration, expression of two inflammatory mediators (iNOS and COX-2), and the MAPK signaling pathway were remarkably decreased in the liver of HFD + EMfC treated group as compared to the HFD + Vehicle treated group. Furthermore, a similar inhibitory effect was measured for the expression levels of pro-inflammatory cytokines, including IL-1β, IL-6, TNF-α and NF-κB. The expression level of members in the AKT/mTOR signaling pathway (a central regulator in autophagy) was recovered after treatment with EMfC, and autophagy-related proteins (Beclin and LC3-II) were remarkably decreased in the HFD + EMfC treated group compared to the HFD + Vehicle treated group. Moreover, the HFD + EMfC treated group showed decreased transcript levels of autophagy-regulated genes including Atg4b, Atg5, Atg7 and Atg12. CONCLUSIONS Taken together, findings of the present study provide novel evidences that the anti-hepatic steatosis of EMfC is tightly linked to the regulation of the inflammatory response and autophagy pathway in the liver tissue of HFD-induced obesity mice.
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Affiliation(s)
- Mi Rim Lee
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, 50463, South Korea
| | - Ji Eun Kim
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, 50463, South Korea
| | - Ji Won Park
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, 50463, South Korea
| | - Mi Ju Kang
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, 50463, South Korea
| | - Hyeon Jun Choi
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, 50463, South Korea
| | - Su Ji Bae
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, 50463, South Korea
| | - Young Whan Choi
- Department of Horticultural Bioscience, College of Natural Resources & Life Science/Life and Industry Convergence Research Institue, Pusan National University, Miryang, 50463, South Korea
| | - Kyung Mi Kim
- Life Science Research Institute, Novarex Co., Ltd, Chungju, 28126, South Korea
| | - Jin Tae Hong
- College of Pharmacy, Chungbuk National University, Chungju, 28644, South Korea
| | - Dae Youn Hwang
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, 50463, South Korea.
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TLR4/AP-1-Targeted Anti-Inflammatory Intervention Attenuates Insulin Sensitivity and Liver Steatosis. Mediators Inflamm 2020; 2020:2960517. [PMID: 33013197 PMCID: PMC7519185 DOI: 10.1155/2020/2960517] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 08/15/2020] [Accepted: 09/04/2020] [Indexed: 01/17/2023] Open
Abstract
Insulin resistance has been shown to be the common pathogenesis of many metabolic diseases. Metainflammation is one of the important characteristics of insulin resistance. Macrophage polarization mediates the production and development of metainflammation. Toll-like receptor 4 (TLR4) mediates macrophage activity and is probably the intersection of immunity and metabolism, but the detailed mechanism is probably not fully understood. Activated protein 1 (AP1) signaling pathway is very important in macrophage activation-mediated inflammation. However, it is unclear whether AP1 signaling pathway mediates metabolic inflammation in the liver. We aimed to investigate the effects of macrophage TLR4-AP1 signaling pathway on hepatocyte metabolic inflammation, insulin sensitivity, and lipid deposition, as well as to explore the potential of TLR4-AP1 as new intervention targets of insulin resistance and liver steatosis. TLR4 and AP1 were silenced in the RAW264.7 cells by lentiviral siRNA transfection. In vivo transduction of lentivirus was administered in mice fed with high-fat diet. Insulin sensitivity and inflammation were evaluated in the treated cells or animals. Our results indicated that TLR4/AP-1 siRNA transfection alleviated high-fat diet-induced systemic and hepatic inflammation, obesity, and insulin resistance in mice. Additionally, TLR4/AP-1 siRNA transfection mitigated palmitic acid- (PA-) induced inflammation in RAW264.7 cells and metabolic abnormalities in cocultured AML hepatocytes. Herein, we propose that TLR4-AP1 signaling pathway activation plays a crucial role in high fat- or PA-induced metabolic inflammation and insulin resistance in hepatocytes. Intervention of the TLR4 expression regulates macrophage polarization and metabolic inflammation and further alleviates insulin resistance and lipid deposition in hepatocytes.
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Abstract
Integrated immunometabolic responses link dietary intake, energy utilization, and storage to immune regulation of tissue function and is therefore essential for the maintenance and restoration of homeostasis. Adipose-resident leukocytes have non-traditional immunological functions that regulate organismal metabolism by controlling insulin action, lipolysis, and mitochondrial respiration to control the usage of substrates for production of heat versus ATP. Energetically expensive vital functions such as immunological responses might have thus evolved to respond accordingly to dietary surplus and deficit of macronutrient intake. Here, we review the interaction of dietary intake of macronutrients and their metabolism with the immune system. We discuss immunometabolic checkpoints that promote healthspan and highlight how dietary fate and regulation of glucose, fat, and protein metabolism might affect immunity.
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Affiliation(s)
- Aileen H Lee
- Department of Comparative Medicine, Yale School of Medicine, New Haven, CT 06520, USA; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Vishwa Deep Dixit
- Department of Comparative Medicine, Yale School of Medicine, New Haven, CT 06520, USA; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA; Yale Center for Research on Aging, Yale School of Medicine, New Haven, CT 06520, USA.
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Kassouf T, Sumara G. Impact of Conventional and Atypical MAPKs on the Development of Metabolic Diseases. Biomolecules 2020; 10:biom10091256. [PMID: 32872540 PMCID: PMC7563211 DOI: 10.3390/biom10091256] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/25/2020] [Accepted: 08/26/2020] [Indexed: 02/06/2023] Open
Abstract
The family of mitogen-activated protein kinases (MAPKs) consists of fourteen members and has been implicated in regulation of virtually all cellular processes. MAPKs are divided into two groups, conventional and atypical MAPKs. Conventional MAPKs are further classified into four sub-families: extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK1, 2 and 3), p38 (α, β, γ, δ), and extracellular signal-regulated kinase 5 (ERK5). Four kinases, extracellular signal-regulated kinase 3, 4, and 7 (ERK3, 4 and 7) as well as Nemo-like kinase (NLK) build a group of atypical MAPKs, which are activated by different upstream mechanisms than conventional MAPKs. Early studies identified JNK1/2 and ERK1/2 as well as p38α as a central mediators of inflammation-evoked insulin resistance. These kinases have been also implicated in the development of obesity and diabetes. Recently, other members of conventional MAPKs emerged as important mediators of liver, skeletal muscle, adipose tissue, and pancreatic β-cell metabolism. Moreover, latest studies indicate that atypical members of MAPK family play a central role in the regulation of adipose tissue function. In this review, we summarize early studies on conventional MAPKs as well as recent findings implicating previously ignored members of the MAPK family. Finally, we discuss the therapeutic potential of drugs targeting specific members of the MAPK family.
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Is Host Metabolism the Missing Link to Improving Cancer Outcomes? Cancers (Basel) 2020; 12:cancers12092338. [PMID: 32825010 PMCID: PMC7564800 DOI: 10.3390/cancers12092338] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 08/14/2020] [Accepted: 08/17/2020] [Indexed: 12/11/2022] Open
Abstract
For the past 100 years, oncologists have relentlessly pursued the destruction of tumor cells by surgical, chemotherapeutic or radiation oncological means. Consistent with this focus, treatment plans are typically based on key characteristics of the tumor itself such as disease site, histology and staging based on local, regional and systemic dissemination. Precision medicine is similarly built on the premise that detailed knowledge of molecular alterations of tumor cells themselves enables better and more effective tumor cell destruction. Recently, host factors within the tumor microenvironment including the vasculature and immune systems have been recognized as modifiers of disease progression and are being targeted for therapeutic gain. In this review, we argue that—to optimize the impact of old and new treatment options—we need to take account of an epidemic that occurs independently of—but has major impact on—the development and treatment of malignant diseases. This is the rapidly increasing number of patients with excess weight and its’ attendant metabolic consequences, commonly described as metabolic syndrome. It is well established that patients with altered metabolism manifesting as obesity, metabolic syndrome and chronic inflammation have an increased incidence of cancer. Here, we focus on evidence that these patients also respond differently to cancer therapy including radiation and provide a perspective how exercise, diet or pharmacological agents may be harnessed to improve therapeutic responses in this patient population.
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Aoe T. Pathological Aspects of COVID-19 as a Conformational Disease and the Use of Pharmacological Chaperones as a Potential Therapeutic Strategy. Front Pharmacol 2020; 11:1095. [PMID: 32754041 PMCID: PMC7366900 DOI: 10.3389/fphar.2020.01095] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 06/09/2020] [Indexed: 01/08/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19), the seventh human coronavirus infectious disease, was first reported in Wuhan, China, in December 2019, followed by its rapid spread globally (251,059 deaths, on May 5, 2020, by Johns Hopkins University). An early clinical report showed that fever, cough, fatigue, sputum production, and myalgia were initial symptoms, with the development of pneumonia as the disease progressed. Increases in the level of serum liver enzymes, D-dimer, cardiac troponin I, and creatinine have been observed in severely ill patients, indicating that multiple organ failure had occurred in these cases. Lymphopenia and an increase in interleukin-6 (IL-6) were also observed. Although COVID-19 patients are administered glucocorticoid therapy to treat the excessive immune response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, the efficacy of this form of therapy is unclear. Viremia is observed in severe cases, suggesting that in addition to type II alveolar epithelial cells, many cell types, such as vascular endothelial cells, cardiomyocytes, renal tubular cells, neuronal cells, and lymphocytes, may be damaged. The improvement of survival rates requires elucidation of the mechanism by which cellular damage occurs during viral infection. Cellular therapy, along with organ support systems such as oxygen therapy, artificial ventilation, extra corporeal membrane oxygenation and dialysis, as well as antiviral therapy, are required. Viral replication in infected host cells may perturb protein folding in the endoplasmic reticulum (ER), causing ER stress. Although an adaptive cellular response, i.e. the unfolded protein response, can compensate for the misfolded protein burden to some extent, continued viral proliferation may induce inflammation and cell death. Therefore, we propose that proteostasis dysfunction may cause conformational disorders in COVID-19. The application of pharmacological chaperone therapy to treat COVID-19 patients is additionally discussed.
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Affiliation(s)
- Tomohiko Aoe
- Pain Center, Teikyo University Chiba Medical Center, Ichihara, Japan.,Department of Medicine, Teikyo University, Tokyo, Japan
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Su J, Liu X, Li H, Cheng X, Shi S, Li N, Wu J, Xu Y, Liu R, Tian X, Wang H, Wang S. Hypoglycaemic effect and mechanism of an RG-II type polysaccharide purified from Aconitum coreanum in diet-induced obese mice. Int J Biol Macromol 2020; 149:359-370. [DOI: 10.1016/j.ijbiomac.2020.01.209] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 01/07/2020] [Accepted: 01/21/2020] [Indexed: 02/06/2023]
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Role of c-Jun N-terminal Kinase (JNK) in Obesity and Type 2 Diabetes. Cells 2020; 9:cells9030706. [PMID: 32183037 PMCID: PMC7140703 DOI: 10.3390/cells9030706] [Citation(s) in RCA: 145] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 02/16/2020] [Accepted: 03/11/2020] [Indexed: 12/13/2022] Open
Abstract
Obesity has been described as a global epidemic and is a low-grade chronic inflammatory disease that arises as a consequence of energy imbalance. Obesity increases the risk of type 2 diabetes (T2D), by mechanisms that are not entirely clarified. Elevated circulating pro-inflammatory cytokines and free fatty acids (FFA) during obesity cause insulin resistance and ß-cell dysfunction, the two main features of T2D, which are both aggravated with the progressive development of hyperglycemia. The inflammatory kinase c-jun N-terminal kinase (JNK) responds to various cellular stress signals activated by cytokines, free fatty acids and hyperglycemia, and is a key mediator in the transition between obesity and T2D. Specifically, JNK mediates both insulin resistance and ß-cell dysfunction, and is therefore a potential target for T2D therapy.
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Orliaguet L, Dalmas E, Drareni K, Venteclef N, Alzaid F. Mechanisms of Macrophage Polarization in Insulin Signaling and Sensitivity. Front Endocrinol (Lausanne) 2020; 11:62. [PMID: 32140136 PMCID: PMC7042402 DOI: 10.3389/fendo.2020.00062] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 01/30/2020] [Indexed: 12/11/2022] Open
Abstract
Type-2 diabetes (T2D) is a disease of two etiologies: metabolic and inflammatory. At the cross-section of these etiologies lays the phenomenon of metabolic inflammation. Whilst metabolic inflammation is characterized as systemic, a common starting point is the tissue-resident macrophage, who's successful physiological or aberrant pathological adaptation to its microenvironment determines disease course and severity. This review will highlight the key mechanisms in macrophage polarization, inflammatory and non-inflammatory signaling that dictates the development and progression of insulin resistance and T2D. We first describe the known homeostatic functions of tissue macrophages in insulin secreting and major insulin sensitive tissues. Importantly we highlight the known mechanisms of aberrant macrophage activation in these tissues and the ways in which this leads to impairment of insulin sensitivity/secretion and the development of T2D. We next describe the cellular mechanisms that are known to dictate macrophage polarization. We review recent progress in macrophage bio-energetics, an emerging field of research that places cellular metabolism at the center of immune-effector function. Importantly, following the advent of the metabolically-activated macrophage, we cover the known transcriptional and epigenetic factors that canonically and non-canonically dictate macrophage differentiation and inflammatory polarization. In closing perspectives, we discuss emerging research themes and highlight novel non-inflammatory or non-immune roles that tissue macrophages have in maintaining microenvironmental and systemic homeostasis.
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Affiliation(s)
- Lucie Orliaguet
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Paris, France
| | - Elise Dalmas
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Paris, France
| | - Karima Drareni
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Paris, France
- Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA, United States
| | - Nicolas Venteclef
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Paris, France
| | - Fawaz Alzaid
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Paris, France
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Purslow JA, Khatiwada B, Bayro MJ, Venditti V. NMR Methods for Structural Characterization of Protein-Protein Complexes. Front Mol Biosci 2020; 7:9. [PMID: 32047754 PMCID: PMC6997237 DOI: 10.3389/fmolb.2020.00009] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 01/10/2020] [Indexed: 01/21/2023] Open
Abstract
Protein-protein interactions and the complexes thus formed are critical elements in a wide variety of cellular events that require an atomic-level description to understand them in detail. Such complexes typically constitute challenging systems to characterize and drive the development of innovative biophysical methods. NMR spectroscopy techniques can be applied to extract atomic resolution information on the binding interfaces, intermolecular affinity, and binding-induced conformational changes in protein-protein complexes formed in solution, in the cell membrane, and in large macromolecular assemblies. Here we discuss experimental techniques for the characterization of protein-protein complexes in both solution NMR and solid-state NMR spectroscopy. The approaches include solvent paramagnetic relaxation enhancement and chemical shift perturbations (CSPs) for the identification of binding interfaces, and the application of intermolecular nuclear Overhauser effect spectroscopy and residual dipolar couplings to obtain structural constraints of protein-protein complexes in solution. Complementary methods in solid-state NMR are described, with emphasis on the versatility provided by heteronuclear dipolar recoupling to extract intermolecular constraints in differentially labeled protein complexes. The methods described are of particular relevance to the analysis of membrane proteins, such as those involved in signal transduction pathways, since they can potentially be characterized by both solution and solid-state NMR techniques, and thus outline key developments in this frontier of structural biology.
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Affiliation(s)
- Jeffrey A Purslow
- Department of Chemistry, Iowa State University, Ames, IA, United States
| | | | - Marvin J Bayro
- Department of Chemistry and Molecular Sciences Research Center, University of Puerto Rico, San Juan, Puerto Rico
| | - Vincenzo Venditti
- Department of Chemistry, Iowa State University, Ames, IA, United States.,Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, IA, United States
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Role of c-Jun N-Terminal Kinases (JNKs) in Epilepsy and Metabolic Cognitive Impairment. Int J Mol Sci 2019; 21:ijms21010255. [PMID: 31905931 PMCID: PMC6981493 DOI: 10.3390/ijms21010255] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 12/17/2019] [Accepted: 12/20/2019] [Indexed: 01/08/2023] Open
Abstract
Previous studies have reported that the regulatory function of the different c-Jun N-terminal kinases isoforms (JNK1, JNK2, and JNK3) play an essential role in neurological disorders, such as epilepsy and metabolic-cognitive alterations. Accordingly, JNKs have emerged as suitable therapeutic strategies. In fact, it has been demonstrated that some unspecific JNK inhibitors exert antidiabetic and neuroprotective effects, albeit they usually show high toxicity or lack therapeutic value. In this sense, natural specific JNK inhibitors, such as Licochalcone A, are promising candidates. Nonetheless, research on the understanding of the role of each of the JNKs remains mandatory in order to progress on the identification of new selective JNK isoform inhibitors. In the present review, a summary on the current gathered data on the role of JNKs in pathology is presented, as well as a discussion on their potential role in pathologies like epilepsy and metabolic-cognitive injury. Moreover, data on the effects of synthetic small molecule inhibitors that modulate JNK-dependent pathways in the brain and peripheral tissues is reviewed.
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