Multiple mechanisms contribute to skin barrier integrity, and emerging evidence suggests that acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) plays a key role in its regulation through both lipid and retinoid metabolism. Although DGAT1 deficiency leads to cutaneous abnormalities, the direct role of DGAT1 in keratinocyte biology remains unclear. Here, we show that DGAT1 deficiency drives extensive keratinocyte hyperproliferation and barrier dysfunction under homeostatic conditions. Transcriptomic profiling revealed upregulation of genes associated with proliferation, inflammation, and retinoic acid (RA) signaling, consistent with increased proliferation observed in vitro and in vivo. Unexpectedly, while DGAT1 expression was elevated in human psoriatic lesions and in a murine psoriasis model, DGAT1 loss reduced keratinocyte proliferation in this inflammatory condition. Further analyses identified dysregulated RA signaling as a central mediator of these effects. DGAT1-deficient keratinocytes exhibited elevated RA-target gene expression and increased expression of RA-binding proteins, indicating enhanced RA bioavailability. Our findings establish DGAT1 as a context-dependent regulator of keratinocyte proliferation, promoting growth in homeostasis while restraining it in psoriasis. By linking DGAT1 activity with RA signaling, this work uncovers a previously unrecognized pathway contributing to epidermal physiology and inflammatory skin disease.
Diabetic nephropathy (DN), a major microvascular complication of diabetes, remains a leading cause of end-stage renal disease. Tripartite motif protein 38 (TRIM38), a member of the TRIM family, plays critical roles in apoptosis, innate immunity, and inflammatory processes. Data of GEO database shows that TRIM38 is notably increased in the renal tubules of patients with DN. However, its functional significance in DN pathogenesis remains unexplored. In this study, streptozotocin (STZ)-induced diabetic mice and high glucose (HG)-treated HK-2 cells were employed to mimic DN conditions. Our results demonstrated that TRIM38 expression was significantly upregulated in renal tissues of DN patients, STZ-induced diabetic mice, and HG-stimulated HK-2 cells. Functionally, TRIM38 overexpression ameliorated renal dysfunction in diabetic mice and preserved the NAD+/NADH balance, while attenuating oxidative stress and inflammatory responses. Mechanistically, TRIM38 overexpression suppressed the NF-κB signaling activation. Further analysis revealed that TRIM38 physically interacted with receptor-interacting protein kinase 1 (RIPK1) and promoted its ubiquitination and degradation, thereby inhibiting the NF-κB pathway activation. Rescue experiments confirmed that RIPK1 overexpression abolished the protective effects of TRIM38 overexpression on HG-treated HK-2 cells. Our study identifies TRIM38 as a novel modulator of DN progression that exerts its protective effects by targeting RIPK1 degradation and subsequent inhibition of NF-κB signaling. These findings provide new insights into the molecular mechanisms underlying DN and highlight TRIM38 as a potential therapeutic target for DN treatment.
Non-alcoholic fatty liver disease (NAFLD) is a progressive disorder correlated with hepatic lipid homeostasis, gut dysbiosis, and inflammation. In this study, we propose a novel dietary therapy for NAFLD utilizing a conjugate of chitooligosaccharide (COS) and epigallocatechin gallate (EGCG), as the underlying mechanisms of NAFLD remain unclear. NAFLD was induced in male Wistar rats by administering a high-fat diet (HFD) for 16 weeks, followed by administration of COS-EGCG conjugate (150, 300, and 600 mg/kg) for an additional four weeks. The treatment alleviated metabolic parameters, liver steatosis, and injury. It also reduced hepatic lipid accumulation by downregulating the expression of CD36, fatty acid synthase (FASN), and sterol regulatory element-binding protein 1c (SREBP-1c), while upregulating peroxisome proliferator-activated receptor alpha (PPARα), carnitine palmitoyltransferase 1 A (CPT1A), and microsomal triglyceride transfer protein (MTTP). Regarding the gut-liver axis, the conjugate modulated gut microbiota, reduced serum lipopolysaccharide (LPS) levels, and restored the expression of intestinal tight junction proteins (zonula occludens-1; ZO-1 and occludin). It also prevented liver inflammation induced by gut-derived LPS by suppressing the Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling pathway. The results suggest that the COS-EGCG conjugate exerts therapeutic effects against NAFLD by regulating hepatic lipid metabolism, modulating the gut microbiota, and attenuating gut-derived LPS-induced liver inflammation. COS-EGCG conjugate alleviates hepatic lipid accumulation and hepatic damage in rats fed an HFD. COS-EGCG conjugate improves lipid homeostasis. COS-EGCG conjugate upregulates intestinal tight junction proteins. COS-EGCG conjugate modulates gut microbiota and restores gut-derived LPS-induced liver inflammation.
Age and sex are critical yet often overlooked variables in preclinical models of acute myocardial infarction (AMI), potentially limiting the translational relevance of molecular findings. In this study, we used the Senescence-Accelerated Mouse Prone 8 (SAMP8) strain, a model of age-related cardiovascular dysfunction, alongside age-matched SAMR1 controls, to investigate early expression patterns of four canonical circulating miRNA biomarkers of AMI: miR-1-3p, miR-133a-3p, miR-208a-3p, and miR-499-5p. Male and female mice underwent left anterior descending (LAD) coronary artery ligation, with serum and cardiac tissue collected at 1, 4, and 24 h post-injury. Results reveal a robust early induction of all four miRNAs in serum, with 4 h identified as the optimal profiling time point. Notably, miR-1-3p was significantly elevated in both male and female SAMP8 mice post-AMI, but not in SAMR1. miR-133a-3p increased only in aged females, while male SAMP8 and SAMR1 mice showed divergent responses. miR-208a-3p and miR-499-5p rose consistently across all groups. In cardiac tissue, SAMR1 mice exhibited downregulation of all four miRNAs, whereas only miR-1-3p was reduced in SAMP8 males. Baseline expression in sham-operated hearts revealed age-related differences, particularly in males, with lower levels of miR-133a-3p, miR-208a-3p, and miR-499-5p in SAMP8 versus SAMR1. These findings highlight pronounced age- and sex-dependent miRNA expression dynamics in both serum and cardiac tissue during the acute phase of AMI. These results validate the SAMP8/SAMR1 model as a valuable tool for dissecting molecular responses to myocardial injury and underscore the need to integrate age and sex into preclinical AMI research.
Aerobic exercise improves systemic insulin sensitivity by modulating muscle glucose metabolism. The CHRONO/BMAL1 pathway constitutes a core component of the endogenous molecular clock and participates in glucose metabolic regulation; however, whether it mediates exercise-induced metabolic benefits under high-fat diet (HFD) conditions remains unclear. We therefore investigated the role of this pathway in conferring protective effects of aerobic exercise against HFD-induced glucose metabolic dysfunction in skeletal muscle, by subjecting wild-type (WT) and inducible muscle-specific Chrono overexpression (Chrono IMOE) mice to an HFD with or without 12-week exercise. Unlike in WT mice, exercise failed to ameliorate adipose mass, dyslipidemia, and insulin resistance in HFD-fed Chrono IMOE mice. Mechanistically, in skeletal muscle of Chrono IMOE mice, Chrono overexpression suppressed exercise-induced reductions in CHRONO expression and CHRONO-BMAL1 binding, as well as the increase in BMAL1 levels. Consequently, despite elevated p-TBC1D1Ser237 and GLUT4 expression, exercise failed to promote GLUT4 sarcolemmal colocalization or upregulate gene expression of key enzymes for glycolysis and glycogen metabolism in skeletal muscle of Chrono IMOE mice. These findings demonstrate that preventing CHRONO‑BMAL1 dissociation via muscle-specific Chrono overexpression abrogates exercise-induced GLUT4 membrane trafficking, transcriptional activation of glycolytic/glycogen metabolic genes, and systemic insulin sensitivity improvements in HFD-fed mice, establishing CHRONO‑BMAL1 dissociation as a required step for these exercise adaptations. Chrono overexpression aggravates HFD-induced insulin resistance. Chrono overexpression blunts exercise-induced improvement in muscle glucose metabolism under HFD.
Chronic kidney disease is an increasing global public health concern, and the Developmental Origins of Health and Disease (DOHaD) concept proposes that adverse conditions during critical developmental windows predispose offspring to chronic disorders later in life. Maternal protein restriction (MPR), a well-established experimental model reflecting food insecurity, has been shown to impair nephrogenesis and promote long-term renal dysfunction. In this study, we investigated renal metabolic-epigenetic programming induced by gestational and lactational MPR in post-weaning male rats using a global kidney proteomic approach. MPR altered renal structure and profoundly dysregulated protein networks, characterized by downregulation of energy metabolism, ion transport, cytoskeletal organization, membrane integrity, and mitochondrial function, alongside upregulation of innate immune pathways, glutathione metabolism, vesicular trafficking, and cytoskeletal dynamics. Integrated pathway and disease enrichment analyses revealed the potential risk to hypertension, acid-base imbalance, renal tubular transport disorders, nephrosis, and renal failure. Key differentially expressed proteins (e.g., GPX1, CYCS, ATP1A2/ATP1B1, TUBB/TUBA isoforms, ANPEP, and metabolic enzymes) emerged as potential biomarkers of renal metabolic-epigenetic programming. Collectively, these findings identify molecular signatures that link early-life protein restriction to long-term risk of kidney disease and provide mechanistic insight into the nephron-and cell-specific consequences of MPR.
Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by lipid accumulation and inflammatory injury. Kupffer cells (KC) play a key role in the immune response and metabolic homeostasis in the liver. We evaluated the impact of hemin treatment on the phenotype of KC and on metabolism and mitochondrial dynamics of hepatocytes in a rat model of early-stage MASH induced by a high-carbohydrate diet. In the liver, HO-1 induction by hemin was associated with reduced tissue injury and apoptosis, restored oxidative balance, attenuated UPR activation, reinstated autophagic flux and improved mitochondrial dynamics. In addition, hemin treatment enhanced fatty acid oxidation and insulin sensitivity in a KC-independent manner. These results suggest that hemin treatment exerts hepatoprotective effects in a rat model of early-stage MASH, highlighting the potential of this treatment as a therapeutic approach for MASH.
Metabolic dysfunction-associated steatotic liver disease (MASLD), marked by excess fat in the liver, has become the most prevalent chronic liver disease worldwide, affecting over 30
The insidious onset and progression of sarcopenia make it vital to understand the early skeletal muscle changes and explore therapies to slow its progression. This study explored the gastrocnemius remodeling at an early stage of aging (14 months of age) and the effects of lifelong aerobic exercise. For that, 2-month-old male Wistar rats underwent a 12-month treadmill exercise program. Sedentary age-matched, young sedentary, and young exercised for 6 months rats were considered. The results highlighted an age-related decrease in the relative gastrocnemius muscle mass, suggestive of loss or atrophy of some fibers, which was mitigated by lifelong aerobic exercise. Consequently, an age-related compensatory hypertrophy was suggested to be triggered in the gastrocnemius muscle. Data proposed that aging reduced mitochondrial density, indicated by citrate synthase (CS) activity, which was prevented by lifelong aerobic exercise. The reduced CS activity correlated with increased ATP-dependent 6-phosphofructokinase (PFKM)/ATP synthase subunit beta (ATPB) ratio, suggesting that at an early stage of aging, the skeletal muscle favors the glycolytic metabolism in response to decreased mitochondrial content. The results also pointed to an age-induced AMP-activated protein kinase (AMPK) activation and an AMPK-related apoptosis inhibition, perchance to reduce fiber loss or atrophy. The basal phosphorylated AMPK/AMPK ratio decreased with lifelong aerobic exercise, possibly reflecting the exercise-induced increase in CS activity. This work highlights the importance of studying early skeletal muscle changes in aging for timely disease management and prevention.
Calcific aortic valve disease (CAVD) is a highly prevalent heart valve disorder in which mitochondria act as critical regulators of calcification, yet their precise pathogenic mechanisms remain unclear. To elucidate these mechanisms, we integrated single-cell transcriptomic datasets comparing normal and calcified human aortic valves to identify 200 differentially expressed mitochondria-related genes (DE-MRGs), each exhibiting distinct expression patterns across diverse cellular subpopulations. Pseudotime trajectory analysis revealed 18 DE-MRGs with dynamic changes during the endothelial-to-mesenchymal transition, and intercellular communication analysis highlighted enhanced signaling between valve interstitial cells (VICs) and macrophages. Specifically, we hypothesized that distinct mitochondrial hubs may modulate these interactions. Using machine learning and bulk transcriptomic data, we identified microsomal glutathione S-transferase 1 (MGST1), an enzyme located on the outer mitochondrial and endoplasmic reticulum membranes, as a hub gene with high predictive performance. Subsequent validation confirmed that MGST1 is functionally involved in calcification, as its expression was markedly upregulated under calcifying conditions. Molecular docking further predicted that ritlecitinib exhibits the highest binding affinity for MGST1, and this molecule was shown to ameliorate calcification. In conclusion, this study delineates a comprehensive molecular network of MRGs in CAVD pathogenesis and identifies MGST1 as a mitochondria‑related hub gene that is upregulated in CAVD and functionally promotes calcification in vitro.
Metabolic dysfunction–associated steatotic liver disease (MASLD) is a prevalent metabolic disorder with limited therapeutic options. This study aimed to investigate the therapeutic effects and underlying mechanisms of Bylvay (odevixibat) on high-fat diet (HFD)-induced MASLD in mice, focusing on liver pathology, gut barrier integrity, and the gut-liver axis via 16 S rRNA gene sequencing and untargeted metabolomics. Bylvay Odevixibat significantly ameliorated hepatic steatosis, inflammation, and liver injury markers. It restored gut barrier integrity, notably reversing HFD-induced dysbiosis, including Akkermansia and Desulfovibrio, and normalized key metabolites like LysoPC (20:5) and trichloroethanol glucuronide. Mechanistically, Bylvay treatment promoted the restructuring of the gut microbiota, which correlated with improved metabolic health. The abundance of trichloroethanol glucuronide was negatively correlated with Muribaculaceae and Lactobacillus abundance. The abundance of LysoPC (20:5(5Z,8Z,11Z,14Z,17Z)/0:0) exhibited a positive correlation with the abundance of Muribaculaceae, Alistipes, Lactobacillus, Alloprevotella and Desulfovibrio, and a negative correlation with Akkermansia and Bacteroides abundance. In summary, our findings reveal the therapeutic potential of Bylvay (odevixibat) in MASLD management, emphasizing the critical role of the interplay between gut microbiota, metabolites, and the gut-liver axis.
During postnatal development in mice there is a marked switch in the expression of AQP4 from white to grey matter regions. A microglial population, CD11c+, which has been shown to be involved in normal postnatal development of the corpus callosum (CC), prolongs its expression in this tissue in the absence of AQP4. Here, we investigated the correlation between the levels of AQP4 expression during the early postnatal period and the expression of marker genes related to oligodendrogenesis in the mouse CC. A microarray transcriptomic analysis of the CC of wild-type (WT) and AQP4-KO (KO) mice was performed, validation of differentially expressed genes was done by RT-qPCR, and protein expression was analyzed by immunofluorescence. Overexpression of genes associated with microglia and astrocytes and inhibition of genes associated with mature oligodendrocytes were observed in the KO animal compared to the WT. GFAP and CD11c signals were significantly higher in the CC of the KO animal, as was the number of OPCs (OLIG2+/PDGFRa+). However, the number of mature oligodendrocytes (OLIG2+/CC1+) was reduced in the KO mice, indicating a failure of the oligodendrogenesis process that results in a significant reduction in the number of myelinated axons in the CC of the KO animal. This mouse model of congenital AQP4 deficiency, which shows defects in the maturation of its oligodendrocytes in the CC, provides insight into the role of AQP4 in demyelinating pathology and could help in the development of new diagnostic and/or therapeutic strategies for such diseases.
This research seeks to investigate the prognostic significance and molecular mechanisms of derived organoid-angiogenesis-related genes (DOARGs) in colorectal cancer (CRC). DOARGs associated with CRC prognosis were screened based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Machine learning techniques were employed to create and assess a signature based on DOARGs, and a nomogram was constructed. Additionally, assessments were conducted on the levels of tumor mutational burden (TMB), immune infiltration, potential chemotherapeutic agents, and immune therapy responses to assess variations between groups with varying risk levels. In vitro experiments, including quantitative reverse-transcription polymerase chain reaction (qRT-PCR), Western blot, CCK-8, and transwell assays were conducted to verify the expression and molecular mechanisms of the model genes. A total of 13 DOARGs significantly associated with prognosis were identified. Five model genes (tissue inhibitor of metalloproteinases 1 (TIMP1), matrix metalloproteinase-1 (MMP1), C-C motif chemokine ligand 24 (CCL24), melanotransferrin (MELTF), and lymphoid enhancer-binding factor 1 (LEF1)) were identified for prognostic signature establishment. This signature demonstrated robust predictive performance for CRC prognosis upon validation. Significant differences were observed in TMB, immune infiltration, potential chemotherapeutic responses, and immune therapy reactions between groups with varying risk levels. Subgroup analysis categorized tumor samples into C1 and C2 groups, with C1 exhibiting significantly lower survival rates compared to C2. qRT-PCR analysis indicated a marked upregulation in the expression of the five model genes in CRC cells, and low expression of CCL24 suppressed the biological functions of CRC cells. This study has developed a prognostic signature for CRC utilizing DOARGs. This signature offers novel targets for the prognosis and personalized treatment of CRC.
Ovarian cancer (OC) is the leading cause of death from reproductive system cancer among women worldwide. Ovarian cancer stem cells (OCSCs) are critically involved in metastasis, tumor recurrence, and chemoresistance, and are a significant bottleneck in the treatment. Several studies demonstrated metabolic rewiring and altered mitochondrial dynamics in CSCs. However, the role of Mfn1-mediated imbalanced mitochondrial dynamics in ovarian cancer stemness remains poorly understood. In this study, quantification of mtDNA indicates that CSCs have increased mitochondrial mass compared to the parental adherent cells. CD133+ enriched cells and cancer stem-like cells (spheroid cultured from OC cells) have higher Mfn1 expression and mitochondrial fusion activity. CSCs have increased oxidative phosphorylation (OXPHOS), ATP, and reduced ROS compared to the parental adherent cells. Disruption of mitochondrial dynamics by depletion of Mfn1 modulates the growth and size of spheroid formation and OC stemness. Seahorse analyzer analysis confirms the functional impact of Mfn1 knockdown on mitochondrial respiration. Overexpression of Mfn1 in SKOV-3 cells, which have a naturally low level of Mfn1, induces increased mitochondrial respiration. Furthermore, to elucidate the relationship between Mfn1 and OXPHOS complex activities and their role in OC stemness, we treated OC cells with 2-Deoxy-D-glucose (2DG), which induces OXPHOS and modulates the cancer stemness through Mfn1. During stemness acquisition, CSCs undergo Mfn1-mediated mitochondrial rearrangement, which could be a potential therapeutic strategy against ovarian cancer.
Circadian disruption exacerbates high-fat diet-induced metabolic disease, but whether the time-of-day exercise differentially remodels the hepatic clockwork and downstream metabolic circuits remains unclear. Male C57BL/6J mice were fed normal diet or a high-fat diet (HFD) and then underwent 8 weeks of morning or afternoon treadmill training. We evaluated glucose-lipid phenotypes and hepatic core clock proteins and conducted quantitative liver proteomics with trend-based clustering, followed by immunoblot validation. Both morning and afternoon exercise mitigated high-fat diet induced weight gain, improved glucose tolerance and insulin sensitivity, and reduced hepatic lipid accumulation relative to sedentary HFD controls, with greater benefits in the morning. HFD increased hepatic CLOCK, BMAL1, and CRY1 and suppressed REV-ERBα. Morning training preferentially normalized CLOCK, BMAL1, and CRY1, whereas afternoon training more prominently restored REV-ERBα. Proteomics identified two dynamic modules. Cluster 1 consists of proteins induced by diet and suppressed by exercise, including enzymes of bile acid synthesis such as CYP7A1 and components of protein N-glycosylation and endoplasmic reticulum proteostasis such as DAD1 and DPAGT1, which shifted toward control levels with exercise intervention. Cluster 7 comprises proteins reduced by diet and enhanced by exercise, including IDNK involved in nucleotide metabolism and ATP6V1G1 associated with autophagy and lysosomal function, with a stronger recovery after morning training. Immunoblotting corroborated these protein level changes. Exercise acts as a time-of-day-dependent modulator of the hepatic proteome. Morning exercise produced a more pronounced normalization of proteins implicated in bile acid metabolism, ER proteostasis, and autophagy-lysosome pathways, thereby nominating candidate mechanisms that may contribute to improved metabolic control under HFD. 1) Morning treadmill exercise more effectively improved glucose tolerance, insulin sensitivity, and hepatic steatosis in high-fat diet-fed mice than afternoon exercise. 2) Time-of-day exercise differentially modulated core hepatic clock proteins and partially normalized HFD-disrupted clock component abundance. 3) Liver proteomics identified timing-responsive protein clusters enriched for proteins annotated to bile acid metabolism, ER proteostasis, and autophagy-lysosome pathways, providing hypothesis-generating mechanistic candidates for the superior phenotype observed with morning training.
Mitochondrial dysfunction is associated with the age-related decline in skeletal muscle mass and strength. Aerobic exercise upregulate Sestrins protein expression in skeletal muscle, which plays a key role in maintaining mitochondrial homeostasis. This study aimed to elucidate the role of aerobic exercise in regulating mitochondrial dynamics and oxidative stress in aging skeletal muscle. We randomly assigned male C57BL/6J mice into four groups: Young Control Group (YC), Young Aerobic Exercise Group (YA), Old Control Group (OC) and Old Aerobic Exercise Group (OA). We confirmed that aerobic exercise significantly enhanced grip strength and running capacity in aged mice compared to the OC group. The OC group exhibited significantly elevated MDA levels in skeletal muscle compared to the YC group, whereas aerobic exercise reduced MDA levels while increasing SOD and CAT activities in exercise group. Compared to the YC group, aging significantly reduced Sestrin1 protein expression, while Sestrin2 and Sestrin3 levels remained unaffected. Notably, aerobic exercise intervention significantly elevated Sestrin1 expression in OA group, compared to OC group, while no observable effects on Sestrin2/3 expression. Additionally Phospho-AMPK (Thr172), and PGC-1α were significantly increased in both the YA and OA groups. Aging also caused a marked decline in SDH activity and an increase in PGAM5 and OPA1 protein levels in the OC group. In addition, aerobic exercise improved SDH activity and augmented MFN2, OPA1 and PINK1 expression in YA and OA groups. In conclusion, aging induces oxidative stress accumulation and mitochondrial dysfunction in skeletal muscle, whereas 8-week of aerobic exercise mitigates these effects by upregulating Sestrin1 and its downstream targets, thus enhancing mitochondrial dynamics and function in aged mice.
Diabetic retinopathy (DR) is a sight-threatening complication of diabetes, which involves metabolic dysfunction, oxidative stress, inflammation, and angiogenesis. Luteolin, a dietary flavonoid, was examined for pleiotropic protective effects in streptozotocin-induced diabetic rats. Adult male Sprague-Dawley rats were assigned to five groups (n = 6): Control, Diabetic, Diabetic + Luteolin 50 mg kg⁻¹, Diabetic + Luteolin 100 mg kg⁻¹, and Diabetic + Metformin (300 mg kg⁻¹); treatments were given orally for eight weeks. Luteolin normalized fasting blood glucose (reduced by 48
Fat acts as a “double-edged sword”—while serving as essential energy for the body, excessive long-term intake can lead to metabolic disorders and liver damage. With social progress and lifestyle changes, liver injury caused by chronic high-fat diet (HFD) has become a widespread and serious public health concern. In consideration of the unique role of exercise in lipid metabolism, we subjected mice to an HFD to investigate its effects on the livers of mice using RNA-Seq and other methods and comprehensively explore the mechanism of exercise’s regulatory effects on liver damage in HFD mice. Our results demonstrated that HFD could induce PPARα downregulation in the livers of mice, disrupt redox homeostasis, and trigger NF-κB-mediated inflammatory cascades, resulting in severe liver damage. Exercise can activate PPARα, inhibit NF-κB, reduce macrophage aggregation, as well as enhance HO-1 and SOD1 expression to regulate redox balance and inflammation. It is worth noting that HFD induces an increase in pro-oxidant activity and a decrease in antioxidant activity in the livers of mice, placing them in a state of oxidative stress. However, exercise simultaneously increases both pro-oxidant and antioxidant levels, alleviating oxidative stress. These results indicate that exercise can activate PPARα and regulate redox balance and inflammation, thereby protecting the livers of mice from the effects of HFD.
High glucose toxicity or hyperglycaemia manifests through various downstream processes, one of which is the elevation of oxidative stress. One of the consequences of increased reactive oxygen species production is mitochondrial damage, both metabolically and structurally. Arachidonic acid (AA) has been shown to salvage mitochondrial dysfunction in skeletal muscles. In this study, we explore the effects of lipoxin A4 (LXA4), a downstream anti-inflammatory metabolite of arachidonic acid, on mitigating hyperglycaemia-induced oxidative stress at the molecular level. We observed that LXA4 could substantially inhibit ROS production and restore Nrf2 expression (by 14%). Additionally, lipoxin A4 treatment was able to restore the mitochondrial potential and prevent mitochondrial fragmentation. Finally, due to the rescue of mitochondrial homeostasis and energetics, the process of myogenesis, an energy-extensive phenomenon, was also restored by the lipid treatment as evident from the differentiation parameters like myotube diameter and myonuclei fusion index, and the expression of MyoD, which drives the transition of myoblasts from proliferation to differentiation.
Perivascular adipose tissue (PVAT) dysfunction is associated with impaired vascular contractile properties, oxidative stress, and inflammation. We investigated the protective effect of exercise training against high-fat diet (HFD)-induced PVAT dysfunction, and explored the underlying molecular events in oxidative stress, endoplasmic reticulum (ER) stress and inflammation. Six-week-old male Sprague-Dawley rats were randomized into control, high-fat diet (HFD), and HFD plus exercise (HEx) groups. Following 6-week treatment, glycemic levels, vascular function, oxidative stress, ER stress, and inflammatory mediators were determined. We found that HFD-induced weight gain, hyperglycemia, and impaired vascular function were significantly attenuated by exercise training. HFD-induced redox imbalance in PVAT, represented by decreased antioxidant status and increased lipid peroxidation, was significantly inhibited by exercise. This was supported by a substantial restoration of UCP2 signaling and inhibition of p66shc, PKCβ, and Pin1 expressions in HEx group. Furthermore, exercise inhibited ER stress transducers, including IRE1, ATF6, eIF-2α, and GRP78, which were overexpressed with HFD. Inhibition of ER stress was accompanied by a significant inhibition of pro-inflammatory (NF-κB, TNF-α, IL-6, TXNIP, and NLRP3) and restoration of anti-inflammatory (FGF21) mediators against HFD. Exercise further reversed the transcriptional activation and deposition of NLRP3 inflammasome in PVAT. Exercise also reversed the HFD-induced macrophage polarization, as visualized by stabilized CD206 and iNOS levels. Exercise can restore HFD-induced vascular dysfunctions by promoting the UCP2 signaling and inhibiting the ER stress-associated TXNIP/NLRP3-mediated inflammatory response in PVAT.
