Accumulating evidence indicates that a hypomagnetic field (HMF, <5 μT) has a significant impact on various organ systems in animals. However, the cellular and molecular mechanisms underlying these biological effects remain unclear. Understanding the molecular mechanisms underlying mammalian responses to a HMF is crucial for addressing health and safety concerns associated with HMF exposure. In this study, we investigated the changes in intracellular protein phosphorylation under HMF conditions and validated the functional mechanisms by which HMF-induced protein phosphorylation affects cell behavior. We found that U2OS cells can rapidly sense changes in magnetic fields, leading to alterations in protein phosphorylation levels within the cell. The quantitative phosphoproteomics results revealed that the exposure of U2OS cells to the HMF environment for 0.5 h and 3 days resulted in the alteration of 1101 and 1543 phosphosites, respectively. Notably, HMF exposure enhanced the phosphorylation of β-Catenin at Ser552, and this increased phosphorylation-promoted U2OS proliferation and migration. Furthermore, quantitative proteomics showed that exposure to a HMF for 3 days upregulated the expression of LOX and FN1, while the knockdown of LOX or FN1 suppressed the proliferation and migration of the U2OS cells. These results suggest that a HMF enhances U2OS cell proliferation and migration by promoting β-Catenin phosphorylation and upregulating FN1 and LOX expression.

Acute liver injury (ALI) is a severe public health problem closely associated with oxidative stress, inflammation, and hepatocyte injury, leading to high mortality. Fucoxanthin (Fx), a marine carotenoid found in brown seaweeds, has various beneficial effects against multiple diseases. However, the potential role of Fx on ALI remains unclear. This study aims to explore the pharmacological potential of Fx in lipopolysaccharide (LPS)/D-galactosamine (D-Gal)-induced ALI. The therapeutic effect of Fx on ALI was primarily evaluated using a mouse model induced by LPS/D-Gal, focusing on pathological changes, oxidative stress, inflammation, and pyroptosis. Additionally, the effects of Fx on cell pyroptosis and its molecular mechanisms were explored in an in vitro pyroptosis model established by inducing macrophages with LPS/Nigericin. Fx significantly alleviated the LPS/D-Gal-induced histopathological progression and hepatocyte apoptosis, reducing plasma levels of ALT, AST, and LDH. It also obviously decreased hepatic MDA levels while increasing antioxidant enzyme activities and GSH concentration compared to LPS/D-Gal-treated mice. These antioxidant effects were linked to the upregulation of hepatic Nrf-2, HO-1, and GCLC expression. Furthermore, Fx treatment alleviated macrophage accumulation and downregulated the expression of pro-inflammatory factors in the liver. Importantly, Fx administration suppressed NLRP3 inflammasome-dependent canonical pyroptosis both in LPS/D-Gal-treated mice and LPS/Nigericin-stimulated macrophages, potentially mediated by the suppression of MAPKs and NF-κB pathways. These findings suggest that Fx could be an effective strategy to prevent ALI, particularly in cases associated with NLRP3 inflammasome-mediated pyroptosis.

ETHNOPHARMACOLOGICAL RELEVANCE:Morus alba L. (M. alba) also known as white mulberry is recognized in traditional Chinese medicine (TCM) and Ayurveda as a functional food and nutraceutical supplement for treating conditions such as hypertension, diabetes, and obesity. In TCM, mulberry leaves are specifically described as enhancing hepatic lipid metabolism, promoting lipid excretion to support obesity treatment. AIM OF THE STUDY:This study aimed to investigate the anti-obesity potential of M. alba leaf extract and its flavonoid component, astragalin (ASG), using a high-fat diet (HFD)-induced obese mouse model, and to elucidate the underlying molecular mechanisms. METHODS:HFD-fed mice were treated with M. alba aqueous extract or ASG using a curative treatment approach. Body weight, glucose tolerance, insulin sensitivity, serum lipid profiles, hepatic steatosis, and inflammatory cytokines were assessed. Systemic and hepatic inflammation was measured by enzyme-linked immunosorbent assay (ELISA), while glucose transporter (GLUT1 and GLUT2) transcripts and protein levels were measured by RT-PCR and Western blotting, respectively. Molecular interactions were evaluated using cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS), and molecular docking analyses, while AMP-activated protein kinase (AMPK), phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) and liver kinase B1 (LKB1) phosphorylation was also assessed by Western blotting. Pharmacologic inhibition with Compound C was performed to confirm AMPK involvement. RESULTS:Treatment with M. alba extract significantly reduced body weight gain, improved serum lipid profiles, and attenuated hepatic lipid accumulation in obese mice. Phytochemical analysis identified ASG as a major bioactive constituent. ASG recapitulated several beneficial effects of the extract, including improvements in body weight gain, glucose tolerance, insulin sensitivity, hepatic lipid burden, and inflammatory status. ASG reduced systemic and hepatic levels of pro-inflammatory cytokines and modulated hepatic and intestinal GLUT1/2 transcripts and protein levels. Mechanistically, ASG showed evidence of AMPK engagement in CETSA, DARTS, and docking analyses, and was associated with increased hepatic AMPK and PI3K/AKT phosphorylation. Co-administration of Compound C attenuated several metabolic benefits of ASG, supporting AMPK involvement. CONCLUSION:ASG ameliorates obesity-related metabolic abnormalities in HFD-fed mice and is associated with AMPK engagement and increased hepatic AMPK/PI3K/AKT phosphorylation. These findings support ASG as a promising natural lead compound for obesity-related metabolic dysfunction, although further studies are needed to define its direct target interaction and downstream signaling more conclusively.

Objective Acetaminophen (APAP)-induced liver injury (ALI), the major cause of acute drug-induced hepatotoxicity, lacks effective therapies. Berbamine (BBM), a bisbenzylisoquinoline alkaloid derived from the genus Berberis, exhibits diverse pharmacological properties but its efficacy against ALI and involvement in ferroptosis remains unexplored. This study aims to investigate the hepatoprotective effects and mechanisms of BBM against ALI and ferroptosis. Methods The in vivo model of ALI and the in vitro ferroptosis models were established using APAP and RSL3, respectively. Models received BBM or Ferrostatin-1 (Fer-1) treatment. The direct target of BBM was identified through molecular docking, cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) assays. Results In vivo, BBM pretreatment dose-dependently alleviated APAP-induced hepatic damage, inflammation, and ferroptosis markers, including lipid peroxidation, GSH depletion, and PTGS2 upregulation, while upregulating GPX4. Meanwhile, the hepatoprotective effects of BBM against ALI matched Fer-1, confirming ferroptosis as an ALI driver. In vitro, BBM inhibited RSL3-induced ferroptosis, reducing ROS, lipid peroxidation, and mitochondrial dysfunction. These effects were mediated by NRF2/GCLC/GPX4 axis activation and FSP1 upregulation. Crucially, BBM directly bound GCLC confirmed by Molecular docking, CETSA, and DARTS. Conclusion BBM protects against ALI by mitigating ferroptosis, oxidative stress, and inflammation, in part through direct modulation of GCLC and coordinated activation of the NRF2/GCLC/GPX4 axis together with FSP1. These findings provide pharmacological evidence supporting the potential of BBM as a promising therapeutic candidate for ALI.

Ziziphus jujuba Mill., documented in Shennong Bencao Jing, demonstrates medicinal agents and enhanced longevity through sustained consumption. Yet their specific medicinal components and mechanisms of action require further exploration. In light of increasing radiation exposure from medical procedures, environmental hazards, and aerospace activities, this study aims to elucidate the radioprotective mechanisms of jujube aqueous extract (JAE). JAE effects were tested in UVC-irradiated A549 and HaCaT cells and x-ray-exposed mice. Cell viability, oxidative stress markers, hematological and histopathological parameters, and proteomic profiles were analyzed. Key apoptotic proteins and the core bioactive compound were identified. JAE demonstrated antioxidant activity in vitro, effectively scavenging free radicals (p < 0.01). In C57BL/6 mice subjected to 6 Gy x-ray irradiation, JAE significantly alleviated lymphocytopenia (p < 0.05, 74.31% alleviation), attenuated lung damage, and mitigated oxidative stress by enhancing SOD (41.70% increase) and CAT (10.43% increase) activities while suppressing MDA levels (13.59% decrease, all p < 0.05). Proteomic profiling further identified 58 apoptosis-associated proteins, demonstrating modulation of apoptotic pathways through upregulation of anti-apoptotic Bcl-XL and downregulation of pro-apoptotic Bax, Bik, and cytochrome c (p < 0.05). In A549 and HaCaT cells, JAE enhanced viability (p < 0.05, 37.06% and 14.08% increase), reduced ROS, and restored redox homeostasis (p < 0.05). Arbutin was identified as a key bioactive compound in JAE, conferring radioprotection by anti-apoptotic, anti-inflammatory, and stabilizing mitochondrial function. By combining proteomics with functional validation, this study reveals JAE's radioprotective mechanism via apoptosis modulation and antioxidant enhancement, highlighting arbutin as a key mediator. These findings provide a pharmacological foundation for developing jujube-based adjuvants in radiation oncology and aerospace medicine.

Monocrotaline (MCT), a major pyrrolizidine alkaloid, is well-known for its high liver toxicity. Dysregulation of autophagy induced apoptosis can lead to various liver diseases, including those induced by chemical compounds. Therefore, we aim to explore whether autophagy might serve as a potential strategy for addressing liver apoptosis caused by MCT. In primary rat hepatocytes (PRHs), MCT significantly increased the number of autophagosomes and the expression levels of LC3II, Becline-1, and Atg5, while it decreased the expression of p62 in a concentration-dependent manner at doses of 100, 200, 300, and 400 μM. Western blot assays revealed MCT inhibited the phosphorylation levels of the PI3K/AKT/mTOR pathway. To elucidate the role of autophagy in mediating MCT-induced apoptosis, we further pretreated PRHs with the autophagy agonist Rapamycin and the inhibitors Bafilomycin A1 and Chloroquine, respectively, and assessed the apoptosis of PRHs induced by MCT. The results displayed that Rapamycin increased the apoptosis rate and the expression of cleaved caspase-3, whereas Bafilomycin A1 and Chloroquine reduced the apoptosis and the expression of cleaved caspase-3 in PRHs. This study confirms that autophagy enhances PRHs apoptosis induced by MCT. In summary, this study demonstrates that MCT-induced autophagy via inhibition of the PI3K/AKT/mTOR pathway can lead to apoptosis in PRHs.

BackgroundAge-related visceral obesity could contribute to the development of cardiometabolic complications. The pathogenesis of visceral fat mass accumulation during the aging process remains complex and largely unknown. Interleukin-6 (IL-6) has emerged as one of the prominent inflammaging markers which are elevated in circulation during aging. However, the precise role of IL-6 in regulating age-related visceral adipose tissue accumulation remains uncertain.ResultsA cross-sectional study including 77 older adults (≥65 years of age) was initially conducted. There was a significant positive association between serum IL-6 levels and visceral fat mass. We subsequently validated a modest but significant elevation in serum IL-6 levels in aged mice. Furthermore, we demonstrated that compared to wildtype control, IL-6 deficiency (IL-6 KO) significantly attenuated the accumulation of visceral adipose tissue during aging. Further metabolic characterization suggested that IL-6 deficiency resulted in improved lipid metabolism parameters and energy expenditure in aged mice. Moreover, histological examinations of adipose depots revealed that the absence of IL-6 ameliorated adipocyte hypertrophy in visceral adipose tissue of aged mice. Mechanically, the ablation of IL-6 could promote the PKA-mediated lipolysis and consequently mitigate lipid accumulation in adipose tissue in aged mice.ConclusionOur findings identify a detrimental role of IL-6 during the aging process by promoting visceral adipose tissue accumulation through inhibition of lipolysis. Therefore, strategies aimed at preventing or reducing IL-6 levels may potentially ameliorate age-related obesity and improve metabolism during aging.

Backgrounds: Li Kun Zhi Ji (LKZJ) is a traditional Chinese medicine formula that effectively improves the immune system. However, the mechanism of its action against cancer remains unknown. Our study aimed to determine whether LKZJ inhibits the growth of the human colon cancer cell line HCT-116, and we performed in vitro experiments to further explore the associated molecular mechanisms. Objective: We explored the antitumor function and the mechanism of LKZJ against human colon cancer cells. Methods: We selected the effective components of LKZJ. Then, the potential targets of these components were obtained against colon cancer, and an “LKZJ-targets-colon cancer” network was constructed. After that, a CCK-8 assay was used to assess cell viability. Next, apoptosis was analyzed with PI/Annexin V assay using flow cytometry. Finally, western blotting was carried out to determine the expression levels of the protein. Results: We obtained 36 effective LKZJ components and identified 225 candidate targets acting on colon cancer. We demonstrated that the cell viability of HCT-116 cells had significantly decreased after treatment of LKZJ. The suppression of HCT-116 proliferation by LKZJ through inducing apoptosis was determined using Flow cytometry. In addition, mitochondria-associated apoptosis was stimulated, and the down-regulation of Bcl-2 and up-regulation of Bax and Bad were observed. LKZJ also attenuated the PI3K/Akt signaling pathway through western blotting. Conclusion: Our study revealed that LKZJ induced HCT-116 cell line apoptosis through the PI3K/Akt apoptotic pathway. Our results indicated that LKZJ could be a possible therapeutic agent against human colon cancer.

Non-alcoholic fatty liver disease (NAFLD) manifests as a persistent liver ailment marked by the excessive buildup of lipids within the hepatic organ accompanied by inflammatory responses and oxidative stress. Alanyl-glutamine (AG), a dipeptide comprising alanine and glutamine, is commonly employed as a nutritional supplement in clinical settings. This research aims to evaluate the impact of AG on NAFLD triggered by a high-fat diet (HFD), while concurrently delving into the potential mechanisms underlying its effects. The results presented herein demonstrate a notable reduction in the elevated body weight, liver mass, and liver index induced by a HFD upon AG administration. These alterations coincide with the amelioration of liver injury and the attenuation of hepatic histological advancement. Furthermore, AG treatment manifests a discernible diminution in oil-red-O-stained regions and triglyceride (TG) levels within the liver. Noteworthy alterations encompass lowered plasma total cholesterol (TC) and low-density lipoprotein cholesterol (LDLC) concentrations, coupled with elevated high-density lipoprotein cholesterol (HDLC) concentrations. The mitigation of hepatic lipid accumulation resultant from AG administration is aligned with the downregulation of ACC1, SCD1, PPAR-γ, and CD36 expression, in conjunction with the upregulation of FXR and SHP expression. Concomitantly, AG administration leads to a reduction in the accumulation of F4/80-positive macrophages within the liver, likely attributable to the downregulated expression of MCP-1. Furthermore, AG treatment yields a decline in hepatic MDA levels and a concurrent increase in the activities of SOD and GPX. A pivotal observation underscores the effect of AG in rectifying the imbalance of gut microbiota in HFD-fed mice. Consequently, this study sheds light on the protective attributes of AG against HFD-induced NAFLD through the modulation of gut microbiota composition.

Liver fibrosis, a common liver dysfunction with high morbidity and mortality rates, is the leading cause of cirrhosis and hepatocellular carcinoma, for which there are no effective therapies. Ivermectin is an antiparasitic drug that also has been showing therapeutic actions in many other diseases, including antiviral and anticancer actions, as well as treating metabolic diseases. Herein, we evaluated the function of ivermectin in regulating liver fibrosis. Firstly, carbon tetrachloride (CCl4)-injected Balb/c mice were used to assess the antifibrosis effects of ivermectin in vivo. Further, CFSC, a rat hepatic stellate cell (HSC) line, was used to explore the function of ivermectin in HSC activation in vitro. The in vivo data showed that ivermectin administration alleviated histopathological changes, improved liver function, reduced collagen deposition, and downregulated the expression of profibrotic genes. Mechanistically, the ivermectin treatment inhibited intrahepatic macrophage accumulation and suppressed the production of proinflammatory factors. Importantly, the ivermectin administration significantly decreased the protein levels of α-smooth muscle actin (α-SMA) both in vivo and in vitro, suggesting that the antifibrotic effects of ivermectin are mainly due to the promotion of HSC deactivation. The present study demonstrates that ivermectin may be a potential therapeutic agent for the prevention of hepatic fibrosis.

Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease with increasing prevalence rates over years and is associated with hepatic lipid accumulation, liver injury, oxidative stress, hepatic inflammation, and liver fibrosis and lack of approved pharmacological therapy. Alanyl-glutamine (Ala-Gln) is a recognized gut-trophic nutrient that has multiple pharmacological effects in the prevention of inflammation- and oxidative-stress-associated diseases. Nevertheless, whether Ala-Gln has a protective effect on NASH still lacks evidence. The aim of this study is to explore the influence of Ala-Gln on NASH and its underlying mechanisms. Here, C57BL/6 mice were fed a methionine- and choline-deficient (MCD) diet to establish the model of NASH, and Ala-Gln at doses of 500 and 1500 mg/kg were intraperitoneally administered to mice along with a MCD diet. The results showed that Ala-Gln treatment significantly attenuated MCD-induced hepatic pathological changes, lowered NAFLD activity score, and reduced plasma alanine transaminase (ALT), aspartate transaminase (AST) and lactate dehydrogenase (LDH) levels. Ala-Gln dramatically alleviated lipid accumulation in liver through modulating the expression levels of fatty acid translocase (FAT/CD36) and farnesoid X receptor (FXR). In addition, Ala-Gln exerted an anti-oxidant effect by elevating the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPX). Moreover, Ala-Gln exhibited an anti-inflammatory effect via decreasing the accumulation of activated macrophages and suppressing the production of proinflammatory mediators. Notably, Ala-Gln suppressed the development of liver fibrosis in MCD-diet-fed mice, which may be due to the inhibition of hepatic stellate cells activation. In conclusion, these findings revealed that Ala-Gln prevents the progression of NASH through the modulation of oxidative stress and inflammation and provided the proof that Ala-Gln might be an effective pharmacological agent to treat NASH.

Background: The Chinese medicine, Huangqi Jianzhong Tang (HJT), is widely used to treat gastric cancer (GC). In this study, network pharmacological methods were used to analyze the potential therapeutic targets and pharmacological mechanisms of HJT in GC.Methods: Bioactive components and targets of HJT and GC-related targets were identified using public databases. The protein-protein interaction network of potential targets of HJT in GC was constructed using the Cytoscape plug-in (v3.8.0), CytoHubba. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed, in addition to molecular docking and animal experiments to verify the results of network pharmacology analysis.Results: A total of 538 GC-related targets were identified. The bioactive components of HJT were selected for drug-likeness evaluation and binomial statistical model screening, which revealed 63 bioactive components and 72 targets. Based on GO enrichment analysis, all targets in the protein-protein interaction network were mainly involved in the response to oxidative stress and neuronal death. Further, KEGG enrichment analysis suggested that the treatment of GC with HJT mainly involved the Wnt signaling pathway, PI3K-Akt signaling pathway, TGF-β signaling pathway, and MAPK signaling pathway, thereby providing insights into the mechanism of the effects of HJT on GC.Conclusion: This study revealed the potential bioactive components and molecular mechanisms of HJT, which may be useful for the treatment of GC, and provided insights into the development of new drugs for GC.

Coronavirus Disease 2019 (COVID-19) caused by SARS-CoV-2 has become a global health issue. The clinical presentation of COVID-19 is highly variable, ranging from asymptomatic and mild disease to severe. However, the mechanisms for the high mortality induced by SARS-CoV-2 infection are still not well understood. Recent studies have indicated that the cytokine storm might play an essential role in the disease progression in patients with COVID-19, which is characterized by the uncontrolled release of cytokines and chemokines leading to acute respiratory distress syndrome (ARDS), multi-organ failure, and even death. Cell death, especially, inflammatory cell death, might be the initiation of a cytokine storm caused by SARS-CoV-2 infection. This review summarizes the forms of cell death caused by SARS-CoV-2 in vivo or in vitro and elaborates on the dedication of apoptosis, necroptosis, NETosis, pyroptosis of syncytia, and even SARS-CoV-2 E proteins forming channel induced cell death, providing insights into targets on the cell death pathway for the treatment of COVID-19.

Acute liver injury is a worldwide problem with a high rate of morbidity and mortality, and effective pharmacological therapies are still urgently needed. Alanyl-glutamine (Ala-Gln), a dipeptide formed from L-alanine and L-glutamine, is known as a protective compound that is involved in various tissue injuries, but there are limited reports regarding the effects of Ala-Gln in acute liver injury. This present study aimed to investigate the protective effects of Ala-Gln in lipopolysaccharide (LPS)-induced acute liver injury in mice, with a focus on inflammatory responses and oxidative stress. The acute liver injury induced using LPS (50 μg/kg) and D-galactosamine (D-Gal) (400 mg/kg) stimulation in mice was significantly attenuated after Ala-Gln treatment (500 and 1500 mg/kg), as evidenced by reduced plasma alanine transaminase (ALT) (p < 0.01, p < 0.001), aspartate transaminase (AST) (p < 0.05, p < 0.001), and lactate dehydrogenase (LDH) (p < 0.01, p < 0.001) levels, and accompanied by improved histopathological changes. In addition, LPS/D-Gal-induced hepatic apoptosis was also alleviated by Ala-Gln administration, as shown by a greatly decreased ratio of TUNEL-positive hepatocytes, from approximately 10% to 2%, and markedly reduced protein levels of cleaved caspase-3 (p < 0.05, p < 0.001) in liver. Moreover, we found that LPS/D-Gal-triggered oxidative stress was suppressed after Ala-Gln treatment, the effect of which might be dependent on the elevation of SOD and GPX activities, and on GSH levels in liver. Interestingly, we observed that Ala-Gln clearly inhibited LPS/D-Gal exposure-induced macrophage accumulation and the production of proinflammatory factors in the liver. Furthermore, Ala-Gln greatly regulated autophagy in the liver in LPS/D-Gal-treated mice. Using RAW264.7 cells, we confirmed the anti-inflammatory role of Ala-Gln-targeting macrophages.

Obesity is an expanding global public health problem and a leading cause of metabolic disorders. The hepatokine Fetuin B participates in regulating insulin resistance, glucose metabolism and liver steatosis. However, the mechanism underlying Fetuin B activation remains unclear. Our previous population-based study demonstrated a significant association between serum Fetuin B and body fat mass in an obese population, which indicates its potential in mediating obesity-related metabolic disorders. In the present study, we further revealed a significant correlation between Fetuin B and leptin, the classic adipokine released by expanding adipose tissue, in this obese population. Consistently, elevated Fetuin B and leptin levels were confirmed in diet-induced obese mice. Furthermore, an in vitro study demonstrated that the leptin signalling pathway directly activated the transcription and expression of Fetuin B in primary hepatocytes and AML12 cells in a STAT3-dependent manner. STAT3 binds to the response elements on FetuB promoter to directly activate FetuB transcription. Finally, the mediating effect of Fetuin B in insulin resistance induced by leptin was confirmed according to mediation analysis in this obese population. Therefore, our study identifies leptin-STAT3 as an upstream signalling pathway that activates Fetuin B and provides new insights into the pathogenic mechanisms of obesity-related metabolic disorders.

Introduction Exercise training has been shown to be the most effective strategy to combat obesity and non-alcoholic fatty liver disease. However, exercise promotes loss of adipose tissue mass and improves obesity-related hepatic steatosis through mechanisms that remain obscure. Research design and methods To study the role of interleukin-6 (IL-6) in high-fat diet (HFD)-induced adiposity and hepatic steatosis during treadmill running, IL-6 knockout (IL-6 KO) mice and wild-type (WT) mice were randomly divided into lean, obese (fed a HFD) and trained obese groups (fed a HFD and exercise trained). Results After 20 weeks of HFD feeding and 8 weeks of treadmill running, we found that exercise obviously reduced HFD-induced body weight gain, inhibited visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) expansion and almost completely reversed obesity-related intrahepatic fat accumulation in WT mice. However, IL-6 knockout (IL-6 KO) mice are refractory to the benefits of treadmill training on body weight, VAT and SAT mass elevation, and hepatic steatosis. Moreover, a panel of lipolytic-related and thermogenic-related genes, including ATGL, HSL and PGC-1α, was upregulated in the VAT and SAT of WT mice that received exercise training compared with untrained mice, which was not observed in IL-6 KO mice. In addition, exercise training resulted in a significant inhibition of hepatic peroxisome proliferator-activated receptor gamma (PPAR-γ) expression in WT mice, and these effects were not noted in IL-6 KO mice. Conclusion These results revealed that IL-6 is involved in the prevention of obesity and hepatic fat accumulation during exercise training. The mechanisms underlying these antiobesity effects may be associated with enhanced lipolysis and thermogenesis in white adipose tissue. The improvement in hepatic steatosis by exercise training may benefit from the marked inhibition of PPAR-γ expression by IL-6.

Acute liver injury is a rapidly deteriorating clinical condition with markedly high morbidity and mortality. Oleoylethanolamide (OEA) is an endogenous lipid messenger with multiple bioactivities, and has therapeutic effects on various liver diseases. However, effects of OEA on acute liver injury remains unknown. In this study, effects and mechanisms of OEA in lipopolysaccharide (LPS)/ d -galactosamine (D-Gal)-induced acute liver injury in mice were investigated. We found that OEA treatment significantly attenuated LPS/D-Gal-induced hepatocytes damage, reduced liver index (liver weight/body weight), decreased plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) levels. Moreover, mechanism study suggested that OEA pretreatment significantly reduced hepatic MDA levels, increased Superoxide dismutase (SOD) and Glutathione peroxidase (GSH-PX) activities via up-regulate Nrf-2 and HO-1 expression to exert anti-oxidation activity. Additionally, OEA markedly reduced the expression levels of Bax, Bcl-2 and cleaved caspase-3 to suppress hepatocyte apoptosis. Meanwhile, OEA remarkedly reduced the number of activated intrahepatic macrophages, and alleviated the mRNA expression of pro-inflammatory factors, including TNF-α, IL-6, MCP1 and RANTES. Furthermore, OEA obviously reduced the expression of IL-1β in liver and plasma through inhibit protein levels of NLRP3 and caspase-1, which indicated that OEA could suppress NLRP3 inflammasome pathway. We further determined the protein expression of PPAR-α in liver and found that OEA significantly increase hepatic PPAR-α expression. In addition, HO-1 inhibitor ZnPP blocked the therapeutic effects of OEA on LPS/D-Gal-induced liver damage and oxidative stress, suggesting crucial role of Nrf-2/HO-1 pathway in the protective effects of OEA in acute liver injury. Together, these findings demonstrated that OEA protect against the LPS/D-Gal-induced acute liver injury in mice through the inhibition of apoptosis, oxidative stress and inflammation, and its mechanisms might be associated with the Nrf-2/HO-1 and NLRP3 inflammasome signaling pathways.

Inflammatory bowel disease (IBD) represents chronic recurrent intestinal inflammation resulting from various factors. Crohn’s disease (CD) and ulcerative colitis (UC) have been identified as the two major types of IBD. Currently, most of the drugs for IBD used commonly in the clinic have adverse reactions, and only a few drugs present long-lasting treatment effects. Moreover, issues of drug resistance and disease recurrence are frequent and difficult to resolve. Together, these issues cause difficulties in treating patients with IBD. Therefore, the development of novel therapeutic agents for the prevention and treatment of IBD is of significance. In this context, research on natural compounds exhibiting anti-inflammatory activity could be a novel approach to developing effective therapeutic strategies for IBD. Phytochemicals such as astragalus polysaccharide (APS), quercetin, limonin, ginsenoside Rd, luteolin, kaempferol, and icariin are reported to be effective in IBD treatment. In brief, natural compounds with anti-inflammatory activities are considered important candidate drugs for IBD treatment. The present review discusses the potential of certain natural compounds and their synthetic derivatives in the prevention and treatment of IBD.

Nonalcoholic steatohepatitis (NASH) has become one of the serious causes of chronic liver diseases, characterized by hepatic steatosis, hepatocellular injury, inflammation and fibrosis, and lack of efficient therapeutic agents. Palmitoylethanolamide (PEA) is an endogenous bioactive lipid with various pharmacological activities, including anti-inflammatory, analgesic, and neuroprotective effects. However, the effect of PEA on nonalcoholic steatohepatitis is still unknown. Our study aims to explore the potential protective role of PEA on NASH and to reveal the underlying mechanism. In this study, the C57BL/6 mice were used to establish the NASH model through methionine- and choline-deficient (MCD) diet feeding. Here, we found that PEA treatment significantly improved liver function, alleviated hepatic pathological changes, and attenuated the lipid accumulation and hepatic fibrosis in NASH mice induced by MCD diet feeding. Mechanistically, the anti-steatosis effect of PEA may be due to the suppressed expression of ACC1 and CD36, elevated expression of PPAR-α, and the phosphorylation levels of AMPK. In addition, hepatic oxidative stress was greatly inhibited in MCD-fed mice treated with PEA via enhancing the expression and activities of antioxidant enzymes, including GSH-px and SOD. Moreover, PEA exerted a clear anti-inflammatory effect though ameliorating the expression of inflammatory mediators and suppressing the NLRP3 inflammasome pathway activation. Furthermore, the impaired autophagy in MCD-induced mice was reactivated with PEA treatment. Taken together, our research suggested that PEA protects against NASH through the inhibition of inflammation and restoration of autophagy. Thus, PEA may represent an efficient therapeutic agent to treat NASH.

SARS-Cov-2 infected cells fused with the ACE2-positive neighboring cells forming syncytia. However, the effect of syncytia in disease development is largely unknown. We established an in vitro cell-cell fusion system and used it to mimic the fusion of SARS-CoV-2 infected cells with ACE2-expressing cells to form syncytia. We found that Caspase-9 was activated after syncytia formation, and Caspase-3/7 was activated downstream of Caspase-9, but it triggered GSDME-dependent pyroptosis rather than apoptosis. What is more, single cell RNA-sequencing data showed that both ACE2 and GSDME were expression in alveolar type 2 cells in human lung. We propose that pyroptosis is the fate of syncytia formed by SARS-CoV-2 infected host cells and ACE2-positive cells, which indicated that lytic death of syncytia may contribute to the excessive inflammatory responses in severe COVID-19 patients.