Bariatric surgery is highly effective in achieving weight loss in children and adolescents with severe obesity, however the underlying mechanisms are incompletely understood, and gut microbiome changes are unknown. Here, we show that adolescents exhibit significant gut microbiome and metabolome shifts several months after laparoscopic vertical sleeve gastrectomy (VSG), with increased alpha diversity and notably with enrichment of oral-associated taxa. To assess causality of the microbiome/metabolome changes in phenotype, pre-VSG and post-VSG stool was transplanted into germ-free mice. Post-VSG stool was not associated with any beneficial outcomes such as adiposity reduction compared pre-VSG stool. However, post-VSG stool exhibited a potentially inflammatory phenotype with increased intestinal Th17 and decreased regulatory T cells. Concomitantly, we found elevated fecal calprotectin and an enrichment of proinflammatory pathways in a subset of adolescents post-VSG. We show that in some adolescents, microbiome changes post-VSG may have inflammatory potential, which may be of importance considering the increased incidence of inflammatory bowel disease post-VSG.

Chronic obstructive pulmonary disease (COPD) is one of the common chronic respiratory diseases, which causes a heavy burden to patients and society. Increasing studies suggest that ABCA1 plays an important role in COPD. ABCA1 belongs to a large class of ATP-binding (ABC) transporters. It is not only involved in the reverse transport of cholesterol, but also in the regulation of apoptosis, pyroptosis, cellular inflammation and cellular immunity. Meanwhile, ABCA1 is involved in several signaling pathways, such as SREBP pathway, LXR pathway, MAPK pathway, p62/mTOR pathway, CTRP1 pathway and so on. In addition, the ABCA1 participates in the disorder of lipid metabolism in COPD by regulating the formation of RCT and HDL, regulates the inflammation of COPD by removing excess cholesterol in macrophages, and promotes the differentiation of COPD phenotype into emphysema type. Accordingly, the ABCA1 may be a therapeutic target for COPD.

Apium graveolens L. (celery) is a dietary vegetable with anti-inflammatory properties. It has the potential to treat acute lung injury (ALI) caused by COVID-19 or other diseases.

To investigate the effects of Apium graveolens water extract (AGWE) on ALI in human lung A-549 cells induced by lipopolysaccharide (LPS).

A-549 cells were treated with AGWE for 24 h and then stimulated with 10 μg/mL LPS for another 24 h. The effects of AGWE on cell viability, the inflammatory response, oxidative stress, and apoptosis and their regulatory factors, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and NLR family pyrin domain containing 3 (NLRP3) inflammasome signaling activation were analyzed.

Treatment with 5-50 μg/mL AGWE reversed the decrease in cell viability caused by LPS (p < 0.05). AGWE can reduce interleukin (IL)-1β, IL-6, IL-18, and TNF-α levels; their EC50 values are 61.4, 65.7, 37.8, and 79.7 μg/mL, respectively. AGWE can reduce reactive oxygen species and thiobarbituric acid reactive substances in A-549 cells induced by LPS. AGWE also reduced the levels of apoptosis (EC50 of 74.8 μg/mL) and its regulators (Bid; Caspase-9, -8, and -3; Bax) and increased the levels of the mitochondrial membrane potential in A-549 cells induced by LPS. AGWE can also decrease the protein levels of NLRP3 and Caspase-1 and the activation of NF-κB signaling in A-549 cells induced by LPS.

These results show that 10 and 50 μg/mL AGWE can reduce the acute inflammation induced by LPS by reducing NF-κB and NLRP3 inflammasome signaling and mitochondria-dependent apoptosis pathways.

Vascular inflammation is a key process in the pathogenesis of atherosclerosis, which is regulated by NF-κB pathway. Yiqi Wenyang decoction (YQWY), a Traditional Chinese medicine (TCM) formula, has anti-inflammatory properties and may inhibit this pathway, potentially offering anti-atherosclerotic effects.

The purpose of this study is to investigate the effects of YQWY on atherosclerosis and the underlying mechanism. Materials and methods: ApoE-/- mice were fed a Western diet and administered with YQWY (low or high dose), atorvastatin, or vehicle for 13 weeks. The size of atherosclerotic plaques was assessed using ORO staining. Vascular inflammation was evaluated with IF or IHC staining. The mechanisms and signaling pathways underlying the effect of YQWY on vasculature were studied using transcriptomic analysis and were validated in vitro in endothelial cells and macrophages.

YQWY attenuated atherosclerotic plaque development which was associated with reduced vascular inflammation as demonstrated by transcriptomic analysis of aorta. This was verified by reduced expression of proinflammatory chemokines, adhesion molecules, and inflammatory cytokines in aortas from YQWY-treated mice at both mRNA and protein levels. Mechanistically, YQWY suppressed NF-κB activation in endothelial cells and, to a lesser extent, macrophages possibly.

YQWY protects against vascular inflammation and atherosclerosis by suppressing NF-κB pathway, suggesting the potential of YQWY and its active ingredients as novel anti-atherosclerotic therapeutics.

Stroke is classified as ischemic or hemorrhagic, and there are few effective treatments for either type. Immunologic mechanisms play a critical role in secondary brain injury following a stroke, which manifests as cytokine release, blood-brain barrier disruption, neuronal cell death, and ultimately behavioral impairment. Suppressing the inflammatory response has been shown to mitigate this cascade of events in experimental stroke models. However, in clinical trials of anti-inflammatory agents, long-term immunosuppression has not demonstrated significant clinical benefits for patients. This may be attributable to the dichotomous roles of inflammation in both tissue injury and repair, as well as the complex pathophysiologic inflammatory processes in stroke. Inhibiting acute harmful inflammatory responses or inducing a phenotypic shift from a pro-inflammatory to an anti-inflammatory state at specific time points after a stroke are alternative and promising therapeutic strategies. Identifying agents that can modulate inflammation requires a detailed understanding of the inflammatory processes of stroke. Furthermore, epigenetic reprogramming plays a crucial role in modulating post-stroke inflammation and can potentially be exploited for stroke management. In this review, we summarize current findings on the epigenetic regulation of the inflammatory response in stroke, focusing on key signaling pathways including nuclear factor-kappa B, Janus kinase/signal transducer and activator of transcription, and mitogen-activated protein kinase as well as inflammasome activation. We also discuss promising molecular targets for stroke treatment. The evidence to date indicates that therapeutic targeting of the epigenetic regulation of inflammation can shift the balance from inflammation-induced tissue injury to repair following stroke, leading to improved post-stroke outcomes.

Obesity is an important risk factor for incidence and death for many types of cancer. Vitamin D reduces risk of incidence and death for many types of cancer. This review outlines the mechanisms by which obesity increases risk of cancer, how vitamin D reduces risk of cancer, and the extent to which vitamin D counters the effects of obesity in cancer. Vitamin D is a partial ally against some of obesity's pro-carcinogenic effects, notably by reducing inflammation and regulating sex hormone receptors, leptin resistance, cellular energy metabolism, the microbiome, and hypoxia. However, it can act stronger in against the renin-angiotensin system, insulin resistance, and oxidative stress in cancer. Additionally, excess fat tissue sequesters vitamin D and, along with its dilution in increased body volume, further reduces its bioavailability and serum concentration, limiting its protective effects against cancer. In conclusion, while vitamin D cannot reverse obesity, it plays a significant role in mitigating its pro-carcinogenic effects by targeting several mechanisms.

Tendon injuries are often exacerbated by persistent inflammation, which hampers tissue regeneration. In this study, we developed a noninvasive, wirelessly controlled, and self-powered piezoelectric nanofilm fabricated by coaxial electrospinning of polycaprolactone (PCL) and tetragonal barium titanate nanoparticles (BTO), and investigated its roles in modulating inflammation and repairing Achilles tendon defects as well as the mechanism in a rat model. In vitro study and in vivo study upon subcutaneous implantation showed that the piezoelectric PCL/BTO nanofilms could inhibit M1 macrophage polarization and reduce the secretion of inflammatory factors. Moreover, when bridging an Achilles tendon defect, the nanofilms could promote tenogenic gene expression including collagen deposition, and collagen remodeling, facilitate functional tendon recovery and significantly reduce tissue inflammation by suppressing M1 macrophage polarization and promoting M2 polarization. Moreover, the piezoelectric stimulation could also enhance tendon regeneration by inhibiting angiogenesis, reducing lipid deposition, and decreasing ectopic ossification. Mechanistically, the piezoelectric nanofilms reduced tissue inflammation mainly via inhibiting the nuclear factor (NF)-κB signaling pathway that is mediated by interleukin (IL)-17A secreted from CD3+ T cells, and thus to reduce proinflammatory factors, such as IL-1β and IL-6, inducible nitric oxide synthase, monocyte chemoattractant protein-1, and tumor necrosis factor-α. These findings indicate the potential of piezoelectric stimulation in immunomodulation, and in promoting tendon regeneration via IL-17A/NF-κB-mediated pathway.

Sepsis is a life-threatening disease caused by the dysregulation of the immune response. It is important to identify influential genes modulating the immune response in sepsis. In this study, we used P-NET, a biologically informed explainable artificial intelligence model, to evaluate the gene importance for sepsis. About 688 important genes were identified, and these genes were enriched in pathways involved in inflammation and immune regulation, such as the PI3K-Akt signalling pathway, necroptosis and the NF-κB signalling pathway. We further selected differentially expressed genes both at bulk and single-cell levels and found TIMP1, GSTO1 and MYL6 exhibited significant different expressions in multiple cell types. Moreover, the expression levels of these 3 genes were correlated with the abundance of important immune cells, such as M-MDSC cells. Further analysis demonstrated that these three genes were highly expressed in sepsis patients with worse outcomes, such as severe, non-survived and shock sepsis patients. Using a drug repositioning strategy, we found navitoclax, curcumin and rotenone could down-regulate and bind to these genes. In conclusion, TIMP1, GSTO1 and MYL6 may serve as promising biomarkers and targets for sepsis treatment.

Zinc and several physiologically relevant ligands of the aryl hydrocarbon receptor (AHR) are nutrients that promote intestinal barrier function. We have identified that AHR activation upregulates the expression of zinc importers in the intestinal epithelium to increase intracellular zinc concentrations, which leads to improved epithelial barrier function. Here, we investigated if an amino acid chelate of zinc, in cooperation with AHR activation, can improve the barrier function of a differentiated Caco-2 cell epithelium. Functional assays of the Caco-2 cell epithelium demonstrate that both ZnSO4 and a lysine and glutamic acid chelate of Zn, in combination with the physiological AHR agonist 6-formylindolo[3,2-b]carbazole (FICZ), increase expression of tight junction proteins at the mRNA and protein levels. FICZ increases uptake of zinc into the epithelium in the presence of ZnSO4 or the amino acid Zn chelate in the medium to equal extents. We conclude that the lysine and glutamic acid chelate of Zn is as efficacious as ZnSO4 in reducing permeability of the Caco-2 cell epithelium in the presence of FICZ. The results suggest that dietary supplementation with bioavailable forms of zinc together with nutritional AHR agonists may be beneficial in improving gut barrier function and help prevent inflammatory bowel disease (IBD).

Calycosin (CA) is a flavonoid natural product that may effectively treats acute myocardial infarction (AMI), but its mechanism is unclear.

Targets related to AMI and CA were identified using the GEO database, SwissTargetPrediction, PharmMapper and literature searches. Protein-protein interactions analysis and Cytoscape were used to screen the core targets of CA for AMI treatment. Enrichment analysis identified biological pathways linked to AMI and potential mechanisms of CA. Immune infiltration analysis was used to explore the role of immune cells in AMI and the correlation between core targets and immune cells. And further validated in AMI rats with ligated left anterior descending.

Bioinformatics identified relevant targets and biological mechanisms of AMI, and network pharmacology revealed 31 potential targets affected by CA, with NLRP3, IL-18, IL-1β, MMP9, and TLR4 as core targets. Enrichment analysis demonstrated the biological roles of these potential targets and NLRP3, IL1β and IL18 were selected for further analysis. Immune infiltration analysis showed that both NLRP3 and IL-1β were closely associated with monocytes, mast cells activated and neutrophils, and IL-18 was closely associated with monocytes. CA exerted cardioprotective effects in AMI rats by inhibiting NLRP3 inflammasome activation and reducing IL-18 and IL-1β levels, improving cardiac function and attenuating myocardial injury and fibrosis.

CA effectively protects cardiac function and mitigates myocardial injury in post-AMI rats, probably through NLRP3 inflammasome inhibition.

Andrographolide, a labdane diterpenoid isolated from Andrographis paniculata, putatively functions through covalent inhibition of NF-κB, a transcription factor that modulates tumor survival and metastasis. Previous studies have found that functionalization of the C-19 hydroxyl alters the primary mode of action from inhibition of NF-κB to the modulation of the Wnt1/β-catenin signaling pathway. Here, we synthesized a series of twelve C-19 trityl and silyl ether analogs, including three novel substituted trityl analogs and four novel substituted silyl analogs of andrographolide. MTT assays revealed cell line selectivity between colorectal and breast cancer cells, which is consistent with known mechanisms of β-catenin-driven cell proliferation in colorectal cancer cell lines. Most compounds exhibited cell line specific antiproliferative activity in HCT-116 and HT-29 colorectal cancer cell lines. Specifically, within 24 h, C-19 analogs of andrographolide exhibit far more limited antiproliferative activity in MCF-7 breast cancer cells compared to HCT-116, HT-29, and MDA-MB-231 cells. Through in vitro TNF-α-dependent NF-κB reporter and Wnt1-dependent luciferase reporter assays, we observed that several analogs generally exhibit greater inhibitory activity compared to andrographolide. Fluorescence imaging demonstrated that cells treated with andrographolide and its C-19 analogs retained similar distributions of active β-catenin, but notable differences in antiproliferative potency upon co-delivery with GSK-3β inhibitor CHIR99021 indicate that several lead compounds exhibit attenuated biological activity selectively in HT-29 cells. Collectively, this work indicates that modest structural modifications at C-19 of andrographolide can have profound implications for its biological activity in mechanisms connected to its anticancer activity.

Rheumatoid arthritis (RA) is an autoimmune chronic inflammatory disease that imposes a heavy economic burden on patients and society. Bone and cartilage destruction is considered an important factor leading to RA, and inflammation, oxidative stress, and mitochondrial dysfunction are closely related to bone erosion and cartilage destruction in RA. Currently, there are limitations in the clinical treatment methods for RA, which urgently necessitates finding new effective treatments for patients. Nuclear transcription factor-κB (NF-κB) is a signaling transcription factor that is widely present in various cells. It plays an important role as a stress source in the cellular environment and regulates gene expression in processes such as immunity, inflammation, cell proliferation, and apoptosis. NF-κB has long been recognized as a pathogenic factor of RA, and its activation can exacerbate RA by promoting inflammation, oxidative stress, mitochondrial dysfunction, and bone destruction. Conversely, inhibiting the activity of the NF-κB pathway effectively inhibits these pathological processes, thereby alleviating RA. Therefore, NF-κB may be a potential therapeutic target for RA. This article describes the physiological structure of NF-κB and its important role in RA through the regulation of oxidative stress, inflammatory response, mitochondrial function, and bone destruction. Meanwhile, we also summarized the impact of NF-κB crosstalk with other signaling pathways on RA and the effect of related drugs or inhibitors targeting NF-κB on RA. The purpose of this article is to provide evidence for the role of NF-κB in RA and to emphasize its significant role in RA by elucidating the mechanisms, so as to provide a theoretical basis for targeting the NF-κB pathway as a treatment for RA.

Sepsis remains the leading cause of multiple-organ injury due to endotoxemia. Astaxanthin (ASTA), widely used in marine aquaculture, has an extraordinary potential for antioxidant and anti-inflammatory activity. Purinergic receptor (e.g., P2X7R) activation is a powerful signaling in the modulation of inflammation. The effect of ASTA was investigated on the regulation of oxidative stress, inflammatory response, apoptotic mediators, and P2X7R expression in the lung injury during lipopolysaccharide (LPS)-induced endotoxemia. Twenty-four rats were blocked into four groups as Control, LPS, ASTA, and LPS + ASTA. LPS was administered by intraperitoneal injection and ASTA by gavage. Blood and lung samples were taken 6 h after the administrations. The methods were ELISA, western blotting, histopathology, and immunohistochemistry. Sepsis was confirmed by the elevations of IL-1β, IL-6, IL-10, and TNF-α levels in bloodstream. Lung injury was determined by histopathological changes. There were increased P2X7R expression, malondialdehyde (MDA), IL-1β, TNF-α, nuclear factor kappa B (NF-κB), and Caspase-3 and decreased B-cell lymphoma 2 (Bcl-2) and glutathione (GSH) in the septic lung tissue (p < 0.05). ASTA treatment improved MDA, GSH, IL-1β, TNF-α, P2X7R, NF-κB, Caspase-3, and Bcl-2 levels and reduced P2X7R immunoreactivity and histological abnormalities in the lung (p < 0.05). The production of pro-inflammatory cytokines, oxidative stress, P2X7R expression, and apoptotic mediators in the lung is associated with LPS-induced endotoxemia. The ASTA administration appears to regulate the expressions of P2X7R, NF-κB, Bcl-2, and Caspase-3 improving the antioxidative and anti-inflammatory response of the lung tissue in sepsis, in vivo.

Dyslipidemia is recognized as one of the most prevalent metabolic disorders and is frequently associated with other prevalent conditions, particularly diabetes mellitus. There appears to be a bidirectional connection between these two metabolic disorders. While considerable research has focused on how insulin resistance can lead to lipid abnormalities, the reverse relationship specifically, how dyslipidemia could assist in developing insulin resistance and diabetes mellitus has received relatively less attention. This review aims to comprehensively evaluate the mechanisms through which dyslipidemia can induce insulin resistance. Dyslipidemia is primarily classified into three main categories: hypercholesterolemia, hypertriglyceridemia, and low levels of HDL. These conditions may promote insulin resistance across multiple pathways, including the accumulation of lipid metabolites, dysfunction of pancreatic β-cells, increased reactive oxygen species, endoplasmic reticulum stress and inflammation, endothelial dysfunction, alterations in adiponectin levels, changes in bile acid composition and concentration, and dysbiosis of gut microbiota. However, further investigation is required to fully elucidate the cellular and molecular mechanisms underlying the relationship between lipid disorders and insulin resistance. Emphasizing such research could facilitate the development of therapeutic strategies targeting both conditions simultaneously.

Neuroinflammation has been acknowledged as being one of the main pathologies that occur following chronic cerebral hypoperfusion (CCH). Since it significantly contributes to neuronal cell damage and thereby leads to cognitive impairment, the signals related to inflammation in hypoperfusion injury have been extensively investigated over the past few years. Toll-like receptor 4 (TLR4) is the key receptor responsible for immune and inflammatory reactions. It has been reported that TLR4 is involved in the pathology of several diseases and has emerged as a therapeutic target for developing a variety of anti-inflammatory compounds. This study explored the pathological roles of TLR4 that potentially cause the promotion of neuroinflammation in CCH damage. The evidence pertinent to the activation of TLR4 and its downstream inflammatory cascades following CCH are also summarized. This study also demonstrated the therapeutic potential of TLR4 inhibition, whether through drugs, substances, or other treatment strategies, in models of CCH-induced neurological dysfunction. The limitations of the accumulated evidence are addressed and discussed in this study. A deeper understanding of the roles of TLR4 in neuroinflammation following CCH damage may help inform the machinery behind pathological processes for advancing further neuroscientific research and developing therapeutic strategies for vascular dementia.

Metabolic profiling of the crude ethanolic extract of Gliricidia sepium (Jacq.) Kunth. ex. Walp. stem ethanolic extract (GSS) was conducted using ultra-high performance quadrupole time of flight mass spectrometry/mass spectrometry (UHPLC-QTOF-MS/MS) in negative mode, resulting in the identification of 23 compounds belonging to various classes such as flavonoids, fatty acids, triterpenoid saponins, and phenolic acids. Notably, eight flavonoids including kaempferol-3-O-robinoside-7-O-rhamnoside, isoquercitrin, kaempferol-3-O-rutinoside, apigenin-7-glucoside, kaempeferol-7-O-rhamnoside, luteolin, apigenin, and liquiritigenin, along with two phenolic acids (4-hydroxycinnamic acid and 2-hydroxyhydrocinnamic acid) and four triterpenoid saponins (soyasaponin I, soyasaponin II, soyasaponin III, and kaikasaponin III) were dereplicated. Additionally, nine fatty acid derivatives were identified, including azelaic acid and 2-isopropyl malic acid. Molecular networking analysis revealed the formation of clusters among compounds while others do not form clusters. Further analysis indicated that the GSS ethanolic extract exhibited a total phenolic content of 38.78 ± 1.609 µg of gallic acid equivalent/mg and a total flavonoid content of 5.62 ± 0.50 µg of rutin equivalent/mg. Biological evaluations showed that GSS ethanolic extract mitigated gastric tissue injury induced by pyloric ligation, with a notable reduction in oxidative stress marker reactive oxygen species levels and inflammatory cytokines interleukin-6 and tumor necrosis factor-alpha levels. Additionally, it enhanced superoxide dismutase and inhibitor of nuclear factor kappa B alpha levels, while lowering the expression of inducible nitric oxide synthase. Histopathological examination revealed significant improvements in gastric tissue morphology in GSS-treated groups compared to the control group. Molecular docking studies indicated potential interactions between GSS ethanolic extract compounds and various target proteins involved in oxidative stress, inflammation, and gastric protection in gastritis. This study aims to investigate the potential gastroprotective activity of GSS ethanolic extract against gastritis induced via pyloric ligation.

Phosgene, used in large-scale industrial production, is highly toxic and irritant. Accidental exposure can lead to varying degrees of injuries, with severe cases potentially resulting in acute lung injury or acute respiratory distress syndrome, resulting in a mortality rate of 40%-50%. The indirect damages of phosgene (inflammation and oxidative stress) are considered important factors in phosgene-induced acute lung injury (P-ALI). The expression of Liver X Receptor α (LXRα) significantly reduces during periods of inflammation. LXRs were initially discovered to be highly expressed in the liver, whereas LXRs are expressed in immune cells and vascular endothelial cells, playing a significant role in anti-inflammatory and antioxidant responses. LXRα may have pulmonary protection in P-ALI. However, evidence to verify this association is still lacking. In this study, rats were divided into six groups to explore the potential role of LXRα in P-ALI. This study found that GW3965 effectively activated LXRα, upregulated its expression and downregulated the levels of proinflammatory cytokines, inhibited malondialdehyde activity while enhancing superoxide dismutase activity, suppressed apoptosis and ameliorated the pathological processes of P-ALI, ultimately exerting pulmonary protection in P-ALI. Further validation revealed that the pulmonary protective effect of LXRα may be associated with the PI3K/Akt and NF-kB signalling pathways.

Cancer cachexia, a multifactorial syndrome characterized by body weight loss, muscle, and adipose tissue wasting, affects patients with cancer. Over time, the definition of cachexia has been modified, including inflammation as one of the main causal factors. Evidence has suggested that a range of proinflammatory mediators may be involved in the regulation of intracellular signaling, resulting in enhanced resting energy expenditure, metabolic changes, and muscle atrophy, all of which are typical features of cachexia. Physiologically speaking, however, inflammation is a response aimed at facing potentially damaging events. Along this line, its induction in the cancer hosts could be an attempt to restore the physiological homeostasis. Interesting observations have shown that cytokines such as interleukins 4 and 6 could improve muscle wasting, supporting the view that the same mediator may exert pro- or anti-inflammatory activity depending on the immune cells involved as well as on the tissue metabolic demand. In conclusion, whether inflammation is crucial to the occurrence of cachexia or just one contributor among others, is still unclear. Indeed, while inflammation is a trigger of cachexia, the alterations of energy and protein metabolism and of the hormonal homeostasis occurring in cachexia likely act as inflammatory stimuli on their own. Whether the causative role prevails over the compensatory one likely depends on the tumor type and stage, patient lifestyle, the presence of comorbidities, and the response to anticancer treatments paving the way to a holistic, personalized approach to cancer cachexia.

This study investigated the role of RAP1B in hepatic lipid metabolism and its implications in obesity and associated metabolic disorders, focusing on the molecular mechanisms through which RAP1B influences lipid accumulation, inflammation and oxidative stress in liver tissues and hepatocyte cell lines.

Liver-specific RAP1B-knockout (LKO) and overexpression (OE) mice were generated and fed a high-fat diet for 18 weeks to evaluate systemic and hepatic metabolic changes. Comprehensive metabolic phenotyping included measurements of body weight, body fat content, activity levels, energy expenditure (EE), respiratory exchange ratio (RER), glucose tolerance test and insulin tolerance test. RAP1B-knockdown AML12 hepatocytes were used for in vitro studies. Comprehensive transcriptome and metabolome analyses identified differentially expressed genes and key metabolic shifts. Biochemical and histological analyses were performed to assess lipid accumulation, oxidative stress and inflammatory markers.

We found that LKO mice exhibited significant reductions in body weight, fat pad size and liver mass, along with decreased hepatic lipid accumulation due to enhanced lipid breakdown. These mice demonstrated improved glucose tolerance and insulin sensitivity without changes in food intake. Liver histology showed reduced F4/80-positive macrophage infiltration, indicating decreased inflammatory cell recruitment. Additionally, markers of oxidative stress were significantly lower, and molecular analysis revealed downregulation of the MAPK(p38) and NF-κB signaling pathways, further supporting an anti-inflammatory hepatic environment. In contrast, OE mice showed increased liver weight, aggravated hepatic lipid accumulation driven by enhanced lipogenesis, worsened insulin resistance and elevated inflammation.

This study highlights RAP1B's pivotal role in hepatic metabolism and positions it as a potential therapeutic target for obesity and related metabolic disorders.

The Gene Ontology (GO) project has been pivotal in providing a structured framework for characterizing genes and annotating them to specific biological concepts. While traditional gene annotation primarily focuses on mapping genes to GO terms, descriptors of biological concepts, there is a growing need for tools facilitating reverse querying. This paper introduces GOReverseLookup, a novel tool designed to identify over- or underrepresented genes in researcher-defined states of interest (phenotypes), described by sets of GO terms. GOReverseLookup supplements the existing power of Gene Ontology by the possibility of orthologous gene querying across several databases, such as Ensembl and UniProtKB. This combination allows for a more nuanced identification of significant genes across a range of cross-species research contexts.

GOReverseLookup queries genes associated with input GO terms. Bundles of GO terms encapsulate user-defined states of interest, e.g., angiogenesis. In the second stage of the analysis, all GO terms associated with each gene are fetched, and finally, the statistical relevance of the genes being involved in one (or all) of the defined states of interests is computed.

The two presented use cases illustrate its utility in discovering genes related to rheumatoid arthritis and genes linked with chronic inflammation and tumorigenesis. In both cases, GOReverseLookup discovered a substantial number of genes significantly associated with the aforementioned states of interest.

GOReverseLookup proves to be a valuable resource for unraveling the genetic basis of phenotypes, with diverse practical potentials in functional genomics, systems biology, and drug discovery. We anticipate that GOReverseLookup will significantly aid in identifying potential gene targets during the initial research phases.

According to principles of Traditional Chinese Medicine, the nose is the passage for exogenous evil to invade the body, while essential or volatile oils extracted from herbs have the effects of dispelling melancholy, repelling foulness, and resuscitation with aromatics. Inhalation aromatherapy can target the brain and has a potential therapeutic effect on mood disorders. However, in particular, the mechanism of the effect of inhalation aromatherapy on the olfactory mucosa (OM) of the nasal cavity at the peripheral level, the first step in olfactory detection, where olfactory sensory neurons (OSNs) relay information to brain for signal processing, remains unclear. Here, we examined the roles of inhalation aromatherapy with compound essential oils derived from Bergamot, Peppermint and Rosa rugose on chronic unpredictable mild stress (CUMS)-induced depression and explored potential therapeutic targets in the peripheral OM. We found that inhalation aromatherapy effectively ameliorated CUMS-induced depression and olfactory dysfunction in rats. Strikingly, inhalation aromatherapy improved pathological changes, significantly reduced apoptosis levels, and promoted olfactory neurogenesis in the OM, which may contribute to the beneficial effects on the olfactory function of depressed rats. Further, inhalation aromatherapy significantly may reverse inflammation levels in the OM through Sirt1/FKBP5/GR/NF-κB signaling pathway, and prevented neuroinflammation in other parts of the olfactory system such as the hippocampus and prefrontal cortex, which may play a role in the olfactory impairments in rats with depression. Collectively, we have demonstrated that inhalation aromatherapy could efficiently prevent the local inflammatory responses in the OM of CUMS depression model rats. These findings provide new insights into the treatment of depression with aromatherapy, as well as new concept for the identification of novel antidepressant strategies.

Zinc oxide nanoparticles (nZnO) are increasingly utilized in industrial, medical, and personal care products, particularly as the main ingredient in sunscreens, raising concerns about their environmental impact, especially in coastal ecosystems. The Baltic Sea, experiencing severe eutrophication, faces persistent hypoxia due to excessive nutrient runoff and limited water exchange. Simultaneously, coastal pollution from industrial and urban activities introduces nZnO, a highly biotoxic nanopollutant. The combined effects of hypoxia and nZnO contamination may amplify environmental stress, yet their interactions remain insufficiently studied. This study investigates the combined effects of nZnO exposure and fluctuating dissolved oxygen regimes (specifically short- and long-term hypoxia and subsequent reoxygenation) on Mytilus edulis, a sentinel species in these ecosystems. By assessing a range of cellular and molecular markers, including oxidative stress, oxygen sensing, protein quality control, stress response, apoptosis, and inflammation, we show that nZnO exacerbates hypoxia-induced oxidative stress, delaying redox recovery and prolonging oxidative damage during reoxygenation. Specifically, nZnO exposure maintains elevated LPO and PC levels after reoxygenation, indicating prolonged oxidative imbalance. While M. edulis typically recovers from hypoxia-induced stress, nZnO disrupts this process by impairing antioxidant defenses, prolonging HIF-1α activation, and dysregulating p53, JNK, and p38 expression, thereby interfering with normal hypoxia-reoxygenation response. Additionally, nZnO alters HSP70, Lon protease, and caspase-3 regulation, disrupting protein-folding and apoptotic pathways. These findings suggest a synergistic interaction between nZnO and hypoxia, heightening the organism's vulnerability to environmental stress and suggesting risks for marine organisms in nanoparticle-polluted, hypoxia-prone coastal regions.

Ulcerative colitis (UC), a persistent immune-mediated disorder lacking effective treatment, is distinguished by gut microbiota dysbiosis, abnormal activation of the NLRP3 inflammasome pathway, and apoptosis. Despite growing attention to these factors, understanding their significance in UC pathogenesis remains a challenge. The present study explores the potential therapeutic impact of Bacillus clausii (Bc) spores in a murine UC model induced by drinking 4 % (w/v) dextran sulfate sodium (DSS) in C57BL/6 mice. Subsequently, the DSS-induced mice were orally administered either Bc at varying concentrations (105 and 1010 Colony forming unit, CFU) or sulfasalazine (SSZ) at a dosage of 200 mg/kg for 7 days. The disease-specific activity index (DAI) was calculated daily utilizing parameters such as body weight, diarrhea, and bloody stool. Changes in fecal Firmicutes and Bacteroidetes abundance, colonic TXNIP and NLRP3 contents, as well as colonic caspase-1, IL-1β, Bax, and Bcl-2 expression, were investigated. Additionally, markers related to oxidative stress and inflammation, histopathological changes and caspase-3 immunohistochemistry testing were conducted. DSS-treated mice had significantly higher DAI scores compared to controls, indicating severe colitis. However, SSZ treatment or Bc (105 CFU) dramatically lowered DAI scores, with the highest Bc dosage (1010 CFU) producing the greatest improvement. Furthermore, Bc (1010 CFU) substantially (p < 0.05) boosted fecal Firmicutes while decreased Bacteroidetes, indicating reversal of gut dysbiosis. Bc effectively reduced colonic oxidative stress and inflammation by replenishing GSH and catalase and modulating the NF-κB, Nrf2/HO-1, and TXNIP/NLRP3 pathways. Additionally, Bc (1010 CFU) exhibited histologically almost normal mucosa, with maintained architecture and reduced apoptosis, as seen by normalization of Bcl2 and Bax with decreased caspase-3. Collectively, these findings point to the potential usefulness of Bc spores in preventing and treating DSS-induced colitis, positioning them as a promising candidate for UC management.

Despite the identification of several pathogenic drivers, the molecular mechanisms underlying the development of acute myeloid leukemia (AML) remain largely unknown. Therefore, we sought to explore the key genes associated with leukemia and identified cluster of differentiation 40 (CD40) as a key mediator linked to the incidence and progression of AML. Higher levels of CD40 were detected in patients with AML compared to healthy donors. Moreover, elevated CD40 expression was associated with lower overall survival rates. Furthermore, anti-CD40 antibody significantly induced apoptosis and enhanced drug sensitivity in human AML cell lines. Conversely, ex vivo treatment of primary AML samples with a CD40 agonist significantly decreased cell apoptosis and drug sensitivity. In Kasumi-1 AML cells, CD40 knockout (KO) significantly impaired the engraftment ability of leukemia cells and reduced the leukemia burden in NSG mice compared to wild-type mice. RNA sequencing showed that differentially expressed genes were significantly enriched in the nuclear factor-kB (NF-kB) signaling pathway in CD40-KO cells, which was confirmed through Western blotting. Untargeted metabolomic analysis revealed 179 metabolites with differential expression between WT and CD40 KO cells. Subsequent analysis revealed significant changes in the main metabolic pathways, particularly the biosynthesis of unsaturated fatty acids and lipid metabolism. A targeted metabolomics study of fatty acid metabolism demonstrated that cis-5, 8, 11, 14, 17-eicosapentaenoic acid (EPA) was markedly downregulated in CD40-KO cells compared to wild-type cells. Remarkably, EPA reversed the apoptosis and cell cycle arrest induced by CD40 deletion, simultaneously reducing the drug sensitivity of CD40-KO cells. Together, our study highlights the potential of CD40 as a target in the treatment of AML.

Mitochondria are important targets for preventing oxidative damage during the progression of sepsis-induced lung injury. Numerous studies have pointed out that maintaining the stabilization of Nrf-2, thereby activating its transcription, may combat pathological inflammation by sustaining the integrity of mitochondrial function. Our previous study found that protein interaction with C-kinase 1 (PICK1) deficiency disrupts the physiological anti-inflammatory mechanism by affecting Nrf-2 transcription. However, whether PICK1 participates in mitochondrial quality control regulation through Nrf-2 has not been explored, and the underlying interaction between PICK1 and Nrf-2 has not been fully elucidated. We found that PICK1 decreased mitochondria-derived ROS, upregulated MnSOD activity in endotoxin-induced acute lung injury mice, improved mitochondrial membrane potential, and restored the damaged structure of mitochondria in LPS-stimulated macrophages. Through in-depth studies, we demonstrated that PICK1 maintains the stability of Nrf-2 by preserving mitochondrial dynamic equilibrium, facilitating mitochondrial biogenesis, and participating in mitophagy by activating the PI3K/AKT/GSK-3β pathway. PICK1 also inhibits the β-TrCP-mediated ubiquitination of Nrf-2. Thus, PICK1 offers an unexplored alternative to current Nrf-2 activators by acting as a Nrf-2 activator that may have therapeutic value against septic inflammation. Our study demonstrated the protective effects of PICK1 overexpression in endotoxin-associated ALI. PICK1 overexpression and the subsequent PI3K/AKT/Nrf-2/HO-1 pathway-dependent and E3 ubiquitin ligase adapter β-TrCP-mediated mitochondrial quality control contribute to lung repair, which offers an unexplored alternative to current Nrf-2 activators by acting as a Nrf-2 activator that may have therapeutic value against septic inflammation.

Increased intestinal permeability can occur in patients with diabetes mellitus. Previous studies demonstrated a correlation between impaired intestinal barrier function, elevated blood glucose levels, and diminished protective capacity of intestinal epithelial cells. However, few studies have explored gut-barrier disruption using three-dimensional (3D) in vitro models. In this study, we developed and optimized a 3D intestinal organoid model that mimics diabetic conditions by exposing the organoids to high glucose (HG) and palmitic acid (PA) levels. Human intestinal organoids derived from samples of both healthy individuals and patients with diabetes mellitus were analyzed. We evaluated the transcript levels of tight junction proteins and inflammation-related genes in ex vivo mouse intestinal organoids cultured under HG and PA conditions for 48 h. Human intestinal organoids from patients with diabetes mellitus exhibited reduced expression of genes associated with intestinal function and barrier integrity compared with those from healthy individuals. In mouse intestinal organoids, PA treatment induced cytotoxicity and significantly reduced the expression of intestinal stem cells and tight junction proteins, including zonula occludens-1 and occludin, compared with the control and HG-treated groups. Furthermore, treatment with HG and PA resulted in increased levels of inflammatory factors compared with those in the control group. Our in vitro model using 3D intestinal organoids can be used to investigate the impact of diabetic conditions and provide insights into gut barrier disruption.

Oxidative stress and chronic inflammation are important drivers in the pathogenesis and progression of many chronic diseases, such as cancers of the breast, kidney, lung, and others, autoimmune diseases (rheumatoid arthritis), cardiovascular diseases (hypertension, atherosclerosis, arrhythmia), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease), mental disorders (depression, schizophrenia, bipolar disorder), gastrointestinal disorders (inflammatory bowel disease, colorectal cancer), and other disorders. With the increasing demand for less toxic and more tolerable therapies, flavonoids have the potential to effectively modulate the responsiveness to conventional therapy and radiotherapy. Flavonoids are polyphenolic compounds found in fruits, vegetables, grains, and plant-derived beverages. Six of the twelve structurally different flavonoid subgroups are of dietary significance and include anthocyanidins (e.g. pelargonidin, cyanidin), flavan-3-ols (e.g. epicatechin, epigallocatechin), flavonols (e.g. quercetin, kaempferol), flavones (e.g. luteolin, baicalein), flavanones (e.g. hesperetin, naringenin), and isoflavones (daidzein, genistein). The health benefits of flavonoids are related to their structural characteristics, such as the number and position of hydroxyl groups and the presence of C2C3 double bonds, which predetermine their ability to chelate metal ions, terminate ROS (e.g. hydroxyl radicals formed by the Fenton reaction), and interact with biological targets to trigger a biological response. Based on these structural characteristics, flavonoids can exert both antioxidant or prooxidant properties, modulate the activity of ROS-scavenging enzymes and the expression and activation of proinflammatory cytokines (e.g., interleukin-1beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α)), induce apoptosis and autophagy, and target key signaling pathways, such as the nuclear factor erythroid 2-related factor 2 (Nrf2) and Bcl-2 family of proteins. This review aims to briefly discuss the mutually interconnected aspects of oxidative and inflammatory mechanisms, such as lipid peroxidation, protein oxidation, DNA damage, and the mechanism and resolution of inflammation. The major part of this article discusses the role of flavonoids in alleviating oxidative stress and inflammation, two common components of many human diseases. The results of epidemiological studies on flavonoids are also presented.

Microcystin-LR (MC-LR) a cyclic toxin produced by cyanobacterial species is known to exert detrimental effects on various organs, including lung. Several investigators demonstrated that MC-LR exerts pulmonary toxicity, but the underlying mechanisms remain unclear. This study aimed to investigate whether exposure to MC-LR-induced lung inflammation and examine the underlying mechanisms. Thirty specific pathogen-free (SPF) male mice were allocated into control and MC-LR treatment groups. Mice were intraperitoneally injected with physiological saline or MC-LR (20 μg/kg) daily for a total of 21 days. Our findings indicated that exposure to MC-LR-produced histopathological changes in lung tissue, including thickening of alveolar walls and inflammatory infiltration. MC-LR was found to upregulate mRNA expression levels of pro-inflammatory cytokines TNFα, IL-6, IL-1β, and IL-18. Further, MC-LR significantly elevated the expression levels of proteins associated with the NF-κB/NLRP3 pathway p-NF-κB, NLRP3, Caspase-1, ASC. The activation of NF-κB/NLRP3 pathway further promoted the release of inflammatory cytokine IL-1β and cleavage of pyroptosis-associated GSDMD protein. These findings indicate that MC-LR may induce lung inflammation by promoting cell pyroptosis via the activation of the NF-κB/NLRP3 pathway.

Blockade of IL1RAP (interleukin 1 receptor associated protein) was recently shown to reduce atherosclerosis in mice, but the effect on human vascular cells is largely unknown. Targeting the IL1RAP coreceptor represents a novel strategy to block the IL1RAP-dependent cytokines IL (interleukin)-1, IL-33, and IL-36. In the present study, we aimed to evaluate the role of novel antibodies targeting IL1RAP to reduce the effects of IL-1β, IL-33, or IL-36γ in human vascular cells.

Expression of IL1RAP was observed in human atherosclerotic plaques by immunohistochemistry and microarray and in endothelial cells by flow cytometry. Endothelial cells were cultured with IL-1β, IL-33, or IL-36γ cytokines with or without IL1RAP antibodies and analyzed with Olink proteomics, ELISA, Western blot, and real-time quantitative polymerase chain reaction. The functional effect of IL1RAP antibodies on endothelial cells were analyzed with adhesion and permeability assays.

Olink proteomics showed inhibition of the inflammatory proteins LIF (leukemia inhibitory factor), OPG (osteoprotegerin), CCL4 (C-C motif chemokine ligand 4), and MCP-3 (monocyte chemoattractant protein 3) by IL1RAP-blockade in endothelial cells after IL-1β stimulation. In addition, the IL1RAP antibodies inhibited IL-1β, and IL-33 induced IL-6 and IL-8 secretion. Secretion of MCP-1 (monocyte chemoattractant protein 1) was induced by IL-1β, IL-33, and IL-36γ, and subsequently was inhibited by IL1RAP antibodies. Similar effects were found on mRNA expression level. Endothelial expression of the adhesion markers ICAM1, VCAM1, and SELE were significantly reduced by IL1RAP antibodies, and neutrophil adhesion to endothelial cells induced by IL-1β and IL-33 was reduced by IL1RAP blockade. In human atherosclerotic lesions, IL1RAP expression correlated with markers of inflammation like IL6, IL8, and MCP1.

IL1RAP-targeting antibodies can reduce the expression of inflammatory cytokines and markers of adhesion in endothelial cells, which may be of importance for future putative targeted treatments against cardiovascular disease.

This study investigated anti-inflammatory effects of exosomes derived from human fetal cartilage progenitor cells (hFCPC-Exo) and their microRNAs (miRNAs) on the osteoarthritis (OA) phenotype in vitro in comparison with exosomes from bone marrow mesenchymal stem cells (MSC-Exo).

SW982 cells (synoviocytes) or hFCPCs (chondrocytes) were stimulated with 10 ng/mL IL-1β to mimic OA phenotypes. The effects of hFCPC-Exo and MSC-Exo were compared by measuring the expression of inflammatory cytokines and an anti-inflammatory protein. miRNA profiles of hFCPC-Exo and MSC-Exo were analyzed using a 2588 human miRNA dataset, and miRNAs potentially involved in the anti-inflammatory effect of hFCPC-Exo were selected. miRNA mimics and antisense inhibitors were used to investigate the role of selected miRNAs in the IL-1β signaling pathways.

Both hFCPC-Exo and MSC-Exo significantly decreased the expression of inflammatory cytokines (IL-1β, IL-6, and MCP-1), while slightly increased an anti-inflammatory protein (SOCS1) in IL-1β-treated SW982 cells. miRNA sequencing revealed anti-inflammatory miRNAs present in large amounts in both hFCPC-Exo and MSC-Exo. Among them, miR-125b-5p mimic significantly suppressed the expression of inflammatory cytokines induced by IL-1β, while anti-sense inhibitor of miR-125b-5p efficiently blocked anti-inflammatory effects of hFCPC-Exo. Both hFCPC-Exo and miR-125b-5p inhibited IκBα down-regulation and -NF-κB stabilization in IL-1β-treated SW982 cells. Additionally, hFCPC-Exo and miR-125b-5p showed similar effects on IL-1β-treated hFCPCs as an OA model in chondrocytes by down-regulating the expression of IL-1β, MMP13, and ADAMTS-5 and up-regulating the expression of aggrecan (ACAN) and type II collagen (COL2A1).

This study demonstrated that hFCPC-Exo exhibits anti-inflammatory effects on IL-1β-treated synoviocytes and chondrocytes in vitro possibly by down-regulating the IL-1β-TRAF6-NF-κB pathway via anti-inflammatory miRNAs such as miR-125b-5p.

Aortic dissection (AD) is the separation of medial layers of the aorta and is a major cause of death in patients with connective tissue disorders such as Marfan syndrome. However, molecular triggers instigating AD, its temporospatial progression, and how vascular cells in each vessel layer interact and participate in the pathological process remain incompletely understood. To unravel the underlying molecular mechanisms of AD, we generated a spontaneous AD mouse model.

We incorporated a novel missense variant (p.G234D) in FBN1, the gene for fibrillin-1, identified in a patient with nonsyndromic familial AD into mice using the CRISPR/Cas9 system. We performed molecular pathological analyses of the aortic lesions by histology, immunofluorescence staining, electron microscopy, synchrotron-based imaging, and single-cell RNA sequencing. Biochemical analysis was performed to examine the binding capacity of mutant human FBN1G234D protein to LTBPs (latent TGFβ [transforming growth factor-beta] binding proteins), and signaling pathways in the mutant aortic wall were examined by the Western blot analysis.

Fifty percent of the Fbn1G234D/G234D mutant mice died within 5 weeks of age from multiple intimomedial tears that expanded longitudinally and progressed to aortic rupture accompanied by massive immune cell infiltration. Fbn1G234D/G234D endothelial cells exhibited altered mechanosensing with loss of parallel alignment to blood flow and upregulation of VCAM-1 and ICAM-1 as early as 1 week of age. Single-cell RNA sequencing, validated by immunostaining, revealed a cluster of monocyte/macrophage predominantly in the intima at 3 weeks of age before the dissection, and the second cluster of macrophages increased during the progression of intimomedial tears, exhibiting strong CCR2+ and both M1- and M2-like features. Consistently, upregulation of MMP2/9 was observed. Biochemically, FBN1G234D lost the ability to bind to LTBP-1, -2, and -4, resulting in the downregulation of TGFβ signaling in the aortic wall.

We show that interactions involving endothelial cells and macrophages/monocytes in the intima, where the ECM (extracellular matrix) microenvironment contains reduced TGFβ signaling, contribute to the initiation of AD. Our novel AD mouse model provides a unique opportunity to identify target molecules involved in the intimomedial tears that can be utilized for the development of therapeutic strategies.

Benzo(a)pyrene (BaP), a carcinogen prevalent in high-temperature processed foods, activates the aryl hydrocarbon receptor (AhR) and induces liver pyroptotic injury. MicroRNAs regulate mRNA expression and are involved in BaP toxicity. In this study, we investigated the essential role of microRNA in BaP-induced pyroptosis. In vivo, BaP induces liver pyroptotic injury by activating AhR, which may be attributed to AhR's influence on microRNA expression. The miRNA-382-5p/Akt and miRNA-382-5p/IκB pairs were predicted to post-transcriptionally regulate pyroptosis. In vitro, miRNA-382-5p activates the classical NF-κB/NLRP3/Caspase-1 pyroptosis signaling pathway by targeting and inhibiting the IκB gene. Furthermore, AhR activation by BaP could promote the high expression of miRNA-382-5p, thereby upregulating the NF-κB/NLRP3/Caspase-1 pyroptosis signaling pathway. In summary, we established that the AhR-mediated miR-382-5p/NF-κB/NLRP3/Caspase-1 axis is a key driver of BaP-induced pyroptosis in hepatocytes and elucidated the underlying mechanisms. These findings provide a valuable theoretical basis for considering miRNA-382-5p as a potential target for preventing BaP toxicity.

Self-assembling peptides (SAPs) are fully defined nanobiomaterials offering unprecedented opportunities to control nanostructure and chemical attributes to investigate and manipulate cellular signals. To investigate the influence of chemical and morphological characteristics on inflammatory signaling in native immunity, we designed five β-sheet SAPs: EFEFKFEFK (EF8), YEFEFKFEFK (YEF8), EFEFKFEFKY (EF8Y), YEFEFKFEFKY (YEF8Y), and EYEFKFEFK (EYF8) (F: phenylalanine; E: glutamic acid; K: lysine, Y: tyrosine). The position of tyrosine in the peptide sequence dictated the self-assembly into nanostructures, with all SAPs self-assembling into thin constituent nanofibers with d ≈ 3.8 ± 0.4 nm, and sequences YEF8 and EF8 showing a propensity for associative bundling. These distinct SAPs induced contrasting inflammatory responses of monocytic model THP-1 cells-derived macrophages (MΦs). Presence of soluble EF8 nanofibers (at 2 mM) induced an anti-inflammatory response and polarization toward an M2 state, whereas YEF8 (at 2 mM) displayed a tendency for inducing a pro-inflammatory response and polarization toward an M1 state. EF8Y, YEF8Y, and EYF8 SAPs did not induce an inflammatory response in our models. These results were validated using peripheral blood mononuclear cells (PBMCs)-derived MΦs from human donors, confirming the critical role of EF8 and YEF8 SAPs as possible orchestrators of the repair of tissues or inducers of pro-inflammatory state, respectively. The same MΦs polarization responses from THP-1-derived MΦs cultured on 20 mM hydrogels were obtained. These findings will facilitate the utilization of this family of SAPs as immunomodulatory nanobiomaterials potentially changing the course of inflammation during the progression of various diseases.

Type 2 diabetes mellitus (T2DM) represents a significant risk factor for cardiovascular disease, particularly heart failure with preserved ejection fraction (HFpEF). HFpEF predominantly affects elderly individuals and women, and is characterized by dysfunctions associated with metabolic, inflammatory, and oxidative stress pathways. Despite HFpEF being the most prevalent heart failure phenotype in patients with T2DM, its underlying pathophysiological mechanisms remain inadequately elucidated.

This study aims to investigate the effects of diabetes mellitus on myocardial inflammation, oxidative stress, and protein quality control (PQC) mechanisms in HFpEF, with particular emphasis on insulin signaling, autophagy, and chaperone-mediated stress responses.

We conducted an analysis of left ventricular myocardial tissue from HFpEF patients, both with and without diabetes, employing a range of molecular, biochemical, and functional assays. The passive stiffness of cardiomyocytes (Fpassive) was assessed in demembranated cardiomyocytes before and after implementing treatments aimed at reducing inflammation (IL-6 inhibition), oxidative stress (Mito-TEMPO), and enhancing PQC (HSP27, HSP70). Inflammatory markers (NF-κB, IL-6, TNF-α, ICAM-1, VCAM-1, NLRP3), oxidative stress markers (ROS, GSH/GSSG ratio, lipid peroxidation), and components of signaling pathways (PI3K/AKT/mTOR, AMPK, MAPK, and PKG) were evaluated using western blotting, immunofluorescence, and ELISA techniques.

Hearts from diabetic HFpEF patients exhibited significantly heightened inflammation, characterized by the upregulation of NF-κB, IL-6, and the NLRP3 inflammasome. This increase in inflammation was accompanied by elevated oxidative stress, diminished nitric oxide (NO) bioavailability, and impaired activation of the NO-sGC-cGMP-PKG signaling pathway. Notably, dysregulation of insulin signaling was observed, as indicated by decreased AKT phosphorylation and impaired autophagy regulation mediated by AMPK and mTOR. Additionally, PQC dysfunction was evidenced by reduced expression levels of HSP27 and HSP70, which correlated with increased cardiomyocyte passive stiffness. Targeted therapeutic interventions effectively reduced Fpassive, with IL-6 inhibition, Mito-TEMPO, and HSP administration leading to improvements in cardiomyocyte mechanical properties.

The findings of this study elucidate a mechanistic relationship among diabetes, inflammation, oxidative stress, and PQC impairment in the context of HFpEF. Therapeutic strategies that target these dysregulated pathways, including IL-6 inhibition, mitochondrial antioxidants, and chaperone-mediated protection, may enhance myocardial function in HFpEF patients with T2DM. Addressing these molecular dysfunctions could facilitate the development of novel interventions specifically tailored to the diabetic HFpEF population.

Cuproptosis represents a novel mechanism of cellular demise characterized by the intracellular buildup of copper ions. Unlike other cell death mechanisms, its distinct process has drawn considerable interest for its promising applications in managing inflammatory bowel disease (IBD) and colorectal cancer (CRC). Emerging evidence indicates that copper metabolism and cuproptosis may exert dual regulatory effects within pathological cellular environments, specifically modulating oxidative stress responses, metabolic reprogramming, and immunotherapeutic efficacy. An appropriate level of copper may promote disease progression and exert synergistic effects, but exceeding a certain threshold, copper can inhibit disease development by inducing cuproptosis in pathological cells. This makes abnormal copper levels a potential new therapeutic target for IBD and CRC. This review emphasizes the dual function of copper metabolism and cuproptosis in the progression of IBD and CRC, while also exploring the potential application of copper-based therapies in disease treatment. The analysis further delineates the modulatory influence of tumor immune microenvironment on cuproptosis dynamics, while establishing the therapeutic potential of cuproptosis-targeted strategies in circumventing resistance to both conventional chemotherapeutic agents and emerging immunotherapies. This provides new research directions for the development of future cuproptosis inducers. Finally, this article discusses the latest advances in potential molecular targets of cuproptosis and their related genes in the treatment of IBD and CRC, highlighting future research priorities and unresolved issues.

The pathogenesis of enteric viral infections is attributed to both viral replication and the resultant immune-inflammatory response. To recapitulate this complex pathophysiology, we engineer macrophage-augmented organoids (MaugOs) by integrating human macrophages into primary intestinal organoids. Echovirus 1, echovirus 6, rotavirus, seasonal coronavirus OC43 and SARS-CoV-2- known to directly invade the intestine- are used as disease modalities. We demonstrate that these viruses efficiently propagate in MaugOs and stimulate the host antiviral response. However, rotavirus, coronavirus OC43 and SARS-CoV-2, but not the two echoviruses, trigger inflammatory responses. Acetate, a microbial metabolite abundantly present in the intestine, potently inhibits virus-induced inflammatory responses in MaugOs, while differentially affecting viral replication in macrophages and organoids. Furthermore, we provide a proof-of-concept of combining antiviral agent with either anti-inflammatory regimen or acetate to simultaneously inhibit viral infection and inflammatory response in MaugOs. Collectively, these findings demonstrate that MaugOs are innovative tools for studying the complex virus-host interactions and advancing therapeutic development.