Sterol Regulatory Element-binding Protein Research Articles

Differential analysis of sorting nexin 10 and sterol regulatory element-binding protein 2 expression in inflammatory bowel disease.

Sorting nexin 10 (SNX10) expression induces intestinal barrier dysfunction and inflammatory responses; in contrast, its inhibition promotes intestinal mucosal healing through sterol regulatory element-binding protein 2 (SREBP2)-mediated cholesterol synthesis. However, its regulatory mechanism for the pathogenesis of inflammatory bowel disease (IBD) remains unclear. In this study, we examined SNX10 and SREBP2 expression in ulcerative colitis (UC) and Crohn's disease (CD). A total of 30 and 28 patients with UC and CD, respectively, were recruited. The expression of SNX10 and SREBP2 in the colonic mucosa was measured by immunohistochemistry (IHC). We discovered that patients with CD had significantly higher expression levels of SNX10 and SREBP2 than patients with UC and healthy controls. In addition, the expression of SREBP2 in patients with UC was significantly higher than that in healthy controls. In our study, we indicated that SNX10 and SREBP2 may serve as biomarkers for identifying patients with UC and CD, thereby providing a clinical therapeutic strategy for the treatment of IBD by inhibiting SNX10.

Molecular mechanism of ectopic lipid accumulation induced by methylglyoxal via activation of the NRF2/PI3K/AKT pathway implicates renal lipotoxicity caused by diabetes mellitus.

Patients with chronic kidney disease (CKD) have a high incidence of dyslipidemia comprising high triglyceride (TG) and low high-density lipoprotein (HDL)-cholesterol levels. An abnormal increase of TGs within cells can lead to intracellular lipid accumulation. In addition to dyslipidemia, hyperglycemia in diabetes may elicit ectopic lipid deposition in non-adipose tissues. Hyperglycemia increases intracellular levels of methylglyoxal (MG) leading to cellular dysfunction. A deficit of glyoxalase I (GLO1) contributes to dicarbonyl stress. Whether dicarbonyl stress induced by MG causes renal lipotoxicity through alteration of lipid metabolism signaling is still unknown. In this study, mice with high fat diet-induced diabetes were used to investigate the renal pathology induced by MG. NRK52E cells treated with MG were further used in vitro to delineate the involvement of lipogenic signaling. After treatment with MG for 12 weeks, plasma TG levels, renal fatty changes, and tubular injuries were aggravated in diabetic mice. In NRK52E cells, MG activated the nuclear factor erythroid 2-related factor 2 (Nrf2)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and sterol regulatory element-binding protein 1 (SREBP1), resulting in stimulation of fatty acid synthase. The intracellular accumulation of lipid droplets was mainly contributed by TGs, which increased the oxidative stress accompanied by high Nrf2 expression. In addition, MG time-dependently activated cyclin D, cyclin-dependent kinase 4 (CDK4), and cleaved caspase-3, evidencing that G0/G1 arrest was associated with apoptosis of NRK52E cells. In conclusion, our studies revealed the mechanism of lipotoxicity caused by MG. The target of such dicarbonyl stress may become a promising therapy for diabetic CKD.

GR113808, a serotonin receptor 4 antagonist, prevents high-fat-diet-induced obesity, fatty liver formation, and insulin resistance in C57BL/6J mice

BackgroundThe burden of nonalcoholic fatty liver disease is increasing, and limited therapeutic drugs are available for its treatment. Serotonin binds to approximately 14 serotonin receptors (HTR) and plays diverse roles in obesity and metabolic complications. In this study, we focused on the function of HTR4 on nonalcoholic fatty liver disease using GR113808, a selective HTR4 antagonist.MethodsMale C57BL/6J mice were fed high-fat diet for 12 weeks with intraperitoneal GR113808 injection, and HTR expression, weight changes, glucose and lipid metabolism, hepatic fat accumulation, changes in adipose tissue, the changes in transcriptional factors of signaling pathways, and inflammations were assessed. Hep3B cells and 3T3-L1 cells were treated with siRNA targeting HTR4 to downregulate its expression and then cultured with palmitate to mimic a high-fat diet. The changes in transcriptional factors of signaling pathways, and inflammations were assessed in those cells.ResultsAfter feeding a high-fat diet to male C57BL/6J mice, HTR4 expression in the liver and adipose tissues decreased. GR113808 suppressed body weight gain and improved glucose intolerance. Furthermore, GR113808 not only decreased fatty liver formation but also reduced adipose tissue size. Additionally, GR113808 reduced inflammatory cytokine serum levels and inflammasome complex formation in both tissues. Palmitate treatment in HTR4-downregulated Hep3B cells, also reduced peroxisome proliferator-activated receptor γ and sterol regulatory element-binding protein-1 pathway induction as well as inflammasome complex formation, thus decreasing inflammatory cytokine levels. HTR4 downregulation in 3T3-L1 cells also reduced palmitate-induced inflammasome complex formation and inflammatory cytokine production. Palmitate-induced insulin resistance in Hep3B cells, but not in 3T3-L1 cells, was improved by HTR4 downregulation.ConclusionsIn summary, GR113808 protected against fatty liver formation and improved inflammation in the liver and adipose tissue. Downregulation of HTR4 ameliorated insulin resistance in the liver. These results suggest that HTR4 could serve as a promising therapeutic target for metabolic diseases.

Qingshen granules inhibits dendritic cell glycolipid metabolism to alleviate renal fibrosis via PI3K-AKT-mTOR pathway

BackgroundQingshen exhibits anti-inflammatory and immunoregulation effects to renal damage. Dendritic cells (DCs) play a critical role in regulating the pathologic inflammatory environment in renal fibrosis (RF). PurposeTo investigate the immune modulation mechanism of qingshen granule (QSG) in RF, particularly focusing on the role of DCs. Methods/Study designAdenine-induced RF animal models were used to study the pharmacological effects of QSG and the immune cells differentiation and function. Glucose uptake, non-esterified fatty acids secretion, mitochondrial membrane potential (MMP) detection, and qPCR were used to explore the effect of QSG to glucose and lipid metabolism in DCs and T cells. The effect of QSG to PI3K-AKT-mTOR axis and the modulation of mTOR to PD-L1 were explored by co-culture experiments, co-immunoprecipitation and western blot assays. The interaction of DCs/CD8+T cells and renal tubular epithelial cells (RTECs) was investigated to demonstrate the direct action and/or the immune-mediated regulation of QSG to RF. The components of QSG in the serum were determined by HPLC. And the effect of active ingredients and formula to DCs and T cells was analyzed by cell experiments in vitro. ResultsQSG reduced nephritic histopathological damage and suppressed the release of proinflammatory cytokines in adenine-induced RF mice. Of note, QSG decreased the levels of CD86, MHC-II, and CCR7 on DCs, while, increased PD-L1 expression on DCs in RF. The results demonstrated that QSG promoted the maturation and inhibited the migration of DCs, and QSG decreased the antigen presenting of DCs to T cells. Additionally, QSG reduced the MMP and glucose/lipid utilization ratio in DCs. QSG also down-regulated the level of targeted metabolic genes included glucose transporter 1 (Glut1), sterol-regulatory element-binding protein 1 (Srebp1), acetyl-CoA carboxylase alpha (Acaca), phosphomevalonate kinase (Pmvk), and up-regulated sirtuin2 (Sirt2) in DCs. In terms of mechanism, QSG inhibited the metabolism-related PI3K-AKT-mTOR pathway, followed by regulating the interaction of mTOR with PD-L1 to enhance the membrane stability of PD-L1. Besides, HPLC analysis identified five active ingredients in QSG. The specific anti-inflammatory and immunosuppressive actions of these ingredients were found to be weaker than QSG as a whole. Finally, inhibiting DC function by QSG disrupted the communication among DCs, T cells, and RTECs. This disruption was associated with low expression of α-smooth muscle actin (α-SMA) and collagen type I (Col-I) in the kidney. ConclusionsQSG inhibits DC metabolism and function via the PI3K-AKT-mTOR pathway to alleviate RF. The study highlights the importance of the specific composition of the formula in targeting DC-mediated immune regulation.

Purple Butter Clam (Saxidomus Purpurata) as a Potential Functional Food Source for Obesity Treatment.

Saxidomus purpurata extract (SPE) is a highly consumable seafood worldwide with known health-related benefits. However, there are no reports of its' anti-obesity effect. This study explores the potential of SPE for anti-obesity effects by modulating adipogenesis and lipolysis. SPE reduced intracellular lipid and triglyceride accumulation while increasing free glycerol release in adipocytes. SPE inhibited lipogenesis protein expressions and increased the phosphorylation of hormone-sensitive lipase and Adenosine monophosphate-activated protein kinase (AMPK) to promote lipolysis. In addition, SPE suppressed adipogenesis by downregulating protein expression of key adipogenic markers, peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer-binding protein α (C/EBPα), and sterol regulatory element-binding protein 1 (SREBP1) via Wnt/β-catenin signaling. SPE augmented the heme oxygenase-1 (HO-1) expression. Thus, pharmacological intervention with Zinc protoporphyrin (ZnPP-HO-1 antagonist) was employed to validate the HO-1 role. The presence of ZnPP increased the lipid accumulation and reduced the free glycerol release. At the molecular level, adipogenic transcription factors (PPARγ, C/EBPα, and SREBP1) expressions were restored in the presence of ZnPP. GC-MS analysis revealed that SPE was comprised of several fatty acids, contributing to its anti-obesity activity. SPE is an effective nutraceutical that can be used to reduce the progression of obesity. HO-1 expression during adipogenesis might be the mechanism of action for the anti-obesity effect of SPE.

13-cis Retinoic Acid-Mediated Modulation of Human Meibomian Gland Epithelial Cells Development: Implications for In Vitro Modeling of Meibomian Gland Dysfunction.

Purpose: This study aimed to investigate the effect of 13-cis retinoic acid (13-cis RA) on human meibomian gland epithelial cells (HMGECs) and explore the potential of using this experimental model as an in vitro approach for studying meibomian gland dysfunction (MGD). Methods: First, HMGECs were cultured with 13-cis RA at different doses and times, and cell viability and proliferation rates were assessed to determine the appropriate stimulation concentration and time. Subsequently, during the proliferation stage, the expression of proliferation, inflammation, and oxidative stress genes and their products were evaluated. The meibum synthesis capacity was determined during the differentiation stage. Additionally, the peroxisome proliferator-activated receptor gamma (PPARγ) antagonist GW9662 was used as a control to assess the impact of 13-cis RA on PPARγ. Results: 13-cis RA significantly inhibited cell viability and proliferation in a time-dose response manner. Under the stimulation of 2 and 5 μM for 48 h during the proliferation stage, a significant decrease was observed in the expression of cell proliferation markers Ki67, antioxidant SOD-2, and Nrf-2. However, the expression of the pro-inflammatory factors IL-1β, IL-8, MMP9, and oxidative stress markers NOX-4 and reactive oxygen species increased. During the differentiation stage, it suppressed meibum synthesis and the expression of meibocyte differentiation-related proteins adipose differentiation-associated protein 4 (ADFP4), elongation of very long chain fatty acid protein 4 (ELOVL4), sterol regulatory element-binding protein 2 (SREBP-2), and PPARγ. Conclusion: 13-cis RA inhibited cell viability, promoted inflammation and oxidative stress, and suppressed meibum synthesis through the PPARγ pathway. Our study shed light on the effect of 13-cis RA on HMGECs and provided a promising direction for studying MGD in vitro.

Inflammatory profile of eosinophils in asthma-COPD overlap and eosinophilic COPD: a multi-omics study.

Elevated blood eosinophil levels in patients with chronic obstructive pulmonary disease (COPD) with or without asthma are linked to increased exacerbations and the effectiveness of inhaled corticosteroid treatment. This study aimed to delineate the inflammatory cellular properties of eosinophils in patients with asthma-COPD overlap (ACO) and eosinophilic COPD (eCOPD). Eosinophils were isolated from the peripheral blood of healthy volunteers, patients with non-eCOPD, and those with ACO/eCOPD. Multi-omics analysis involving transcriptomics, proteomics, and lipidomics was performed, followed by bioinformatic data analyses. In vitro experiments using eosinophils from healthy volunteers were conducted to investigate the molecular mechanisms underlying cellular alterations in eosinophils. Proteomics and transcriptomics analyses revealed cellular characteristics in overall COPD patients represented by viral infection (elevated expression of sterol regulatory element-binding protein-1) and inflammatory responses (elevated levels of IL1 receptor-like 1, Fc epsilon receptor Ig, and transmembrane protein 176B). Cholesterol metabolism enzymes were identified as ACO/eCOPD-related factors. Gene Ontology and pathway enrichment analyses demonstrated the key roles of antiviral responses, cholesterol metabolism, and inflammatory molecules-related signaling pathways in ACO/eCOPD. Lipidomics showed the impaired synthesis of cyclooxygenase-derived mediators including prostaglandin E2 (PGE2) in ACO/eCOPD. In vitro assessment confirmed that IL-33 or TNF-α stimulation combined with IL-5 and IFN-γ stimulation induced cellular signatures in eosinophils in ACO/eCOPD. Atorvastatin, dexamethasone, and PGE2 differentially modulated these inflammatory changes. ACO/eCOPD is associated with viral infection and an inflammatory milieu. Therapeutic strategies using statins and inhaled corticosteroids are recommended to control these pathogenic changes.

Coffee Bioactive N-Methylpyridinium: Unveiling Its Antilipogenic Effects by Targeting De Novo Lipogenesis in Human Hepatocytes.

Type 2 diabetes and nonalcoholic fatty liver diseases (NAFLDs) are promoted by insulin resistance (IR), which alters lipid homeostasis in the liver. This study aims to investigate the effect of N-methylpyridinium (NMP), a bioactive alkaloid of coffee brew, on lipid metabolism in hepatocytes. The effect of NMP in modulating lipid metabolism is evaluated at physiological concentrations in a diabetes cell model represented by HepG2 cells cultured in a high-glucose medium. Hyperglycemia triggers lipid droplet accumulation in cells and enhances the lipogenic gene expression, which is transactivated by sterol regulatory element binding protein-1 (SREBP-1). Lipid droplet accumulation alters the redox status and endoplasmic reticulum (ER) stress, leading to the activation of the unfolded protein response and antioxidative pathways by X-Box Binding Protein 1(XBP-1)/eukaryotic Initiation Factor 2 alpha (eIF2α) Protein Kinase RNA-Like ER Kinase and nuclear factor erythroid 2-related factor 2 (NRF2), respectively. NMP induces the phosphorylation of AMP-dependent protein kinase (AMPK) and acetyl-CoA carboxylase α (ACACA), and improves the redox status and ER homeostasis, essential steps to reduce lipogenesis and lipid droplet accumulation. These results suggest that NMP may be beneficial for the management of T2D and NAFLD by ameliorating the cell oxidative and ER homeostasis and lipid metabolism.

Androgen-ablative therapies inducing CXCL8 regulates mTORC1/SREBP2-dependent cholesterol biosynthesis to support progression of androgen receptor negative prostate cancer cells.

Treatment with androgen-ablative therapies effectively inhibited androgen receptor (AR)-positive (AR+) prostate cancer (PCa) cell subtypes, but it resulted in an increase in AR-negative (AR-) PCa cell subtypes. The present study aimed to investigate the debated mechanisms responsible for the changing proportion of cell types, identifying CXCL8 as a synthetic essential effector of AR- PCa cells. AR- PCa cells were found to be susceptible to CXCL8 depletion or inhibition, which impaired their survival. Mechanistically, androgen-ablative therapies resulted in the suppression of AR signaling, leading to the upregulation of CXCL8 gene transcription. CXCL8, in turn, activated the mTORC1 pathway, which increased de novo cholesterol synthesis by activating sterol regulatory element-binding protein-2 (SREBP2). Together, these results suggested that the CXCL8-mTORC1-SREBP2 axis contributed to the exacerbation of tumorigenicity in AR- PCa cells under androgen-ablative therapies.

Canola Oil Ameliorates Obesity by Suppressing Lipogenesis and Reprogramming the Gut Microbiota in Mice via the AMPK Pathway.

obesity is a worldwide problem that seriously endangers human health. Canola oil (Col) has been reported to regulate hepatic steatosis by influencing oxidative stress and lipid metabolism in Kunming mice. However, whether Col exhibits an anti-obesity effect by altering the gut microbiota remains unknown. in this study, we observed that a high-fat diet increased lipogenesis and gut microbiota disorder in C57BL/6J male mice, while the administration of Col suppressed lipogenesis and improved gut microbiota disorder. the results show that Col markedly reduced the final body weight and subcutaneous adipose tissue of C57BL/6J male mice fed a high-fat diet (HFD) after 6 weeks of administration. However, although Col did not effectively increase the serum concentration of HDL, we found that treatment with Col notably inhibited the low-density lipoprotein (LDL), total cholesterol (TC), and triglycerides (TGs) in HFD mice. Furthermore, Col ameliorated obesity in the liver compared to mice that were only fed a high-fat diet. We also found that Col significantly inhibited the relative expression of sterol regulatory element binding protein (SREBP1/2), peroxisome proliferator-activated receptor γ (PPARγ), and insulin-induced genes (Insig1/2) that proved to be closely associated with lipogenesis in HFD mice. In addition, the concentration of acetic acid was significantly increased in Col-treatment HFD mice. Further, we noted that Col contributed to the reprogramming of the intestinal microbiota. The relative abundances of Akkermansia, Dubosiella, and Alistipes were enhanced under treatment with Col in HFD mice. The results also imply that Col markedly elevated the phosphorylation level of the AMP-activated protein kinase (AMPK) pathway in HFD mice. the results of our study show that Col ameliorates obesity and suppresses lipogenesis in HFD mice. The underlying mechanisms are possibly associated with the reprogramming of the gut microbiota, in particular, the acetic acid-mediated increased expression of Alistipes via the AMPK signaling pathway.

Clitoria ternatea L. flower-derived anthocyanins and flavonoids inhibit bladder cancer growth by suppressing SREBP1 pathway-mediated fatty acid synthesis.

Clitoria ternatea L. flowers are used as traditional herbal medicines and are known for their advanced pharmacological activities. Flavonoids and anthocyanins reportedly contribute to the therapeutic properties of C. ternatea flowers; however, their potential anti-bladder cancer effects and molecular mechanisms remain unknown. In this study, flavonoid- and anthocyanin-rich samples from C. ternatea flowers (DDH) are prepared via macroporous resin-based extraction coupled with an efficient and reliable two-dimensional UPLC-DAD-MS/MS method. In vitro and in vivo studies reveal that DDH can inhibit bladder cancer cell growth and enhance the anti-bladder cancer activity of cisplatin. RNA-seq combined with KEGG analysis reveals that fatty acid synthesis is closely related to the anti-bladder cancer effect of DDH. Furthermore, DDH dose-dependently reduces cellular fatty acid levels in bladder cancer cells, and the addition of fatty acids significantly mitigates DDH-induced cell growth inhibition. Subsequent findings reveal that DDH downregulates sterol regulatory element-binding protein 1 (SREBP1), a key transcriptional regulator of de novo fatty acid synthesis in cancer cells, and its downstream targets (FASN, SCD1, and ACC). Additionally, this study demonstrates that gallic acid not only enhances the stability of DDH but also synergistically potentiates its anti-bladder cancer activity. Our study suggests that targeting the SREBP1 pathway is an effective strategy in bladder cancer therapy, and the ability of DDH to induce cell death by inhibiting the SREBP1 pathway and its good tolerance in mice make it a promising strategy for preventing and treating bladder cancer.

Targeting Cholesterol Biosynthesis with Statins Synergizes with AKT Inhibitors in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is responsible for a disproportionate number of breast cancer patient deaths due to extensive molecular heterogeneity, high recurrence rates, and lack of targeted therapies. Dysregulation of the phosphoinositide 3-kinase (PI3K)/AKT pathway occurs in approximately 50% of TNBC patients. Here, we performed a genome-wide CRISPR/Cas9 screen with PI3Kα and AKT inhibitors to find targetable synthetic lethalities in TNBC. Cholesterol homeostasis was identified as a collateral vulnerability with AKT inhibition. Disruption of cholesterol homeostasis with pitavastatin synergized with AKT inhibition to induce TNBC cytotoxicity in vitro in mouse TNBC xenografts and in patient-derived estrogen receptor (ER)-negative breast cancer organoids. Neither ER-positive breast cancer cell lines nor ER-positive organoids were sensitive to combined AKT inhibitor and pitavastatin. Mechanistically, TNBC cells showed impaired sterol regulatory element-binding protein 2 (SREBP-2) activation in response to single-agent or combination treatment with AKT inhibitor and pitavastatin, which was rescued by inhibition of the cholesterol-trafficking protein Niemann-Pick C1 (NPC1). NPC1 loss caused lysosomal cholesterol accumulation, decreased endoplasmic reticulum cholesterol levels, and promoted SREBP-2 activation. Taken together, these data identify a TNBC-specific vulnerability to the combination of AKT inhibitors and pitavastatin mediated by dysregulated cholesterol trafficking. These findings support combining AKT inhibitors with pitavastatin as a therapeutic modality in TNBC. Significance: Two FDA-approved compounds, AKT inhibitors and pitavastatin, synergize to induce cell death in triple-negative breast cancer, motivating evaluation of the efficacy of this combination in clinical trials.

Oral administration of PIISVYWK and FSVVPSPK peptides attenuates obesity, oxidative stress, and inflammation in high fat diet-induced obese mice

The bioactive peptides PIISVYWK (P1) and FSVVPSPK (P2), derived from the blue mussel Mytilus edulis, exhibit significant benefits in combating obesity, oxidative stress, and inflammation. This study demonstrates that these peptides inhibit the differentiation of bone marrow-derived mesenchymal stem cells (BMMSCs) into adipocytes by downregulating the adipogenic transcription factors peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer-binding protein alpha (C/EBPα), and sterol regulatory element-binding protein 1 (SREBP-1). Furthermore, P1 and P2 reduce lipogenesis and enhance lipolysis through the activation of AMP-activated protein kinase (AMPK) and hormone-sensitive lipase (HSL). These peptides also decrease intracellular reactive oxygen species (ROS) generation during adipogenesis and inhibit the mitogen-activated protein kinase (MAPK) pathway, thereby reducing inflammation. The involvement of heme oxygenase-1 (HO-1) in this mechanism is confirmed by the reversal of these effects upon HO-1 inhibition. In vivo, oral administration of P1 and P2 in high-fat diet (HFD) obese mice prevents weight gain, reduces adipose tissue accumulation, lowers adipogenic and lipogenic biomarkers, improves serum cholesterol levels, enhances lipolysis, and decreases pro-inflammatory cytokine production. These findings suggest that P1 and P2 peptides may effectively prevent obesity and related metabolic disorders by activating the HO-1/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway.

Black Ginger Extract Suppresses Fat Accumulation by Regulating Lipid Metabolism in High-Fat Diet-Fed Mice.

This study investigated the antiobesity effects of black ginger extract (BGE) in high-fat diet (HFD)-induced obese mice. Mice were divided into six groups: normal diet control (NC, AIN-93G normal diet), 60% HFD control (HFD), HFD containing metformin at 250 mg/kg b.w. (Met, positive control), and HFD containing BGE at 5, 10, or 20 mg/kg b.w. for 15 weeks. BGE administration significantly prevented HFD-induced increases in weight gain, organ weight, and adipose tissue mass. Furthermore, it resulted in decreased adipogenesis and lipogenesis-related factors, including phosphorylated mitogen-activated protein kinase, peroxisome proliferator-activated receptor gamma, CCAAT/enhancer-binding proteins, sterol regulatory element-binding protein 1, phosphorylated cAMP response element-binding protein, glucose-6-phosphate dehydrogenase, fatty acid synthase, dephosphorylated ATP-citrate lyase, dephosphorylated acetyl-CoA carboxylase, and lipoprotein lipase, in white adipose tissues. Moreover, BGE administration enhanced lipolysis in white adipose tissue, as evidenced by elevated levels of adipose triglyceride lipase, phosphorylated hormone-sensitive lipase, and protein kinase A, along with reduced levels of perilipin and phosphodiesterase 3B. BGE induced thermogenesis in brown adipose tissues, as reflected by the increased expression of AMP-activated protein kinase, uncoupling protein 1, and carnitine palmitoyltransferase 1 and decreased levels of fatty acid-binding protein 4. In conclusion, this study provides comprehensive evidence supporting the antiobesity effects of BGE, elucidating the underlying molecular mechanisms involved in preventing weight gain, suppressing adipogenesis, promoting lipolysis, and stimulating thermogenesis. These findings suggest the potential therapeutic utility of BGE in combating obesity and associated metabolic disorders (KHGASP-2023-034).

Dendrobium Officinale Kimura & Migo Attenuates High Cholesterol Diet-Induced Atherosclerosis

Objectives: This study aimed to investigate the potential of Dendrobium officinale Kimura & Migo (DOKM) in ameliorating high cholesterol-induced atherosclerosis (AS) in zebrafish, focusing on the development of safe and effective drugs with low toxicity for AS treatment. Methods: A zebrafish AS model was established by feeding zebrafish a high cholesterol diet (HCD). Treatment was administered using 1 mg/L and 10 mg/L DOKM water extract. Fluorescence microscopy was utilised to observe the effects of DOKM on HCD-induced cholesterol accumulation, neutrophil accumulation, and macrophage infiltration in the vasculature. The impact of DOKM on HCD-induced disorders of lipid metabolism was assessed using Nile red staining. Total cholesterol (TC), triglycerides (TG), and low-density lipoprotein (LDL-C) levels in zebrafish were measured using kits. The expression of pcsk9, srebf2, and hmgcr genes in zebrafish was determined using RT-PCR. HE staining and Elvitegravir (EVG) staining were employed to assess the effect of DOKM on plaque formation in the blood vessels of AS zebrafish. Results: A total of 145 compounds were collected from Dendrobium officinale, along with 680 corresponding targets. Additionally, 1583 atherosclerosis-related targets were identified, with 202 representing interaction targets between Dendrobium officinale and atherosclerosis-related targets. Key compounds identified included Gigantol, Chrysotobibenzyl, Naringenin Chalcone, Hesperetin, and Tangeretin. The core targets of Dendrobium officinale for atherosclerosis treatment were STAT3, PTPN11, JAK2, epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor alpha (PDGFRA), proto-oncogene tyrosine-protein kinase Src (SRC), STAT1, TP53, ESR1, and AKT1. GO functional enrichment analysis revealed a total of 2090 GO biological functional entries. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed 200 AS signalling pathways associated with DOKM treatment for atherosclerosis. DOKM significantly attenuated cholesterol accumulation, neutrophil aggregation, and macrophage infiltration in the blood vessels of AS zebrafish, ultimately leading to reduced plaque formation. AS zebrafish exhibited lipid metabolism disorders, characterised by significant increases in TC, TG, and LDL-C levels, as well as mRNA expression of pcsk9, srebf2, and hmgcr genes. Treatment with DOKM significantly improved these lipid metabolism disorders. Conclusion: DOKM effectively attenuates HCD-induced AS, and this therapeutic effect on AS may be related to its role in improving lipid metabolism dysfunction.

Polyoxometalates Ameliorate Metabolic Dysfunction-Associated Steatotic Liver Disease by Activating the AMPK Signaling Pathway.

Metabolic dysfunction-associated steatotic liver disease (MASLD), the most prevalent chronic liver disorder, has garnered increasing attention globally owing to its associated health complications. However, the lack of available therapeutic medications and inadequate management of complications in metabolic dysfunction-associated steatohepatitis (MASH) present significant challenges. There are little studies evaluating the effectiveness of POM in treating MASLD. In this study, we synthesized polyoxometalates (POM) for potential treatment of MASLD. We induced liver disease in mice using two approaches: feeding a high-fat diet (HFD) to establish MASLD or feeding a methionine-choline deficient (MCD) diet to induce hepatic lipotoxicity and MASH. Various metabolic parameters were detected, and biochemical and histological evaluations were conducted on MASLD. Western blotting, qRT-PCR and immunofluorescence assays were used to elucidate the molecular mechanism of POM in the treatment of MASLD. POM therapy resulted in significant improvements in weight gain, dyslipidemia, liver injury, and hepatic steatosis in mice fed a HFD. Notably, in a more severe dietary-induced MASH model with MCD diet, POM significantly attenuated hepatic lipid accumulation, inflammation, and fibrosis. POM treatment effectively attenuated palmitic acid and oleic acid-induced lipid accumulation in HepG2 and Huh7 cells by targeting the AMPK pathway to regulate lipid metabolism, which was confirmed by AMPK inhibitor. Additionally, the activation of AMPK signaling by POM suppressed the expression of lipid synthesis genes, including sterol regulatory element-binding protein 1c (SREBP1c) and SREBP2, while concurrently upregulating the expression of sirtuin 1 (SIRT1) to promote fatty acid oxidation. These findings suggest that POM is a promising therapeutic strategy with high efficacy in multiple MASLD models.

Sterol regulatory element-binding proteins mediate intrinsic fungicide tolerance and antagonism in the fungal biocontrol agent Clonostachys rosea IK726

Sterol regulatory element-binding proteins (SREBPs) are transcription factors governing various biological processes in fungi, including virulence and fungicide tolerance, by regulating ergosterol biosynthesis and homeostasis. While studied in model fungal species, their role in fungal species used for biocontrol remains elusive. This study delves into the biological and regulatory function of SREBPs in the fungal biocontrol agent (BCA) Clonostachys rosea IK726, with a specific focus on fungicide tolerance and antagonism. Clonostachys rosea genome contains two SREBP coding genes (sre1 and sre2) with distinct characteristics. Deletion of sre1 resulted in mutant strains with pleiotropic phenotypes, including reduced C. rosea growth on medium supplemented with prothioconazole and boscalid fungicides, hypoxia mimicking agent CoCl2 and cell wall stressor SDS, and altered antagonistic abilities against Botrytis cinerea and Rhizoctonia solani. However, Δsre2 strains showed no significant effect. Consistent with the gene deletion results, overexpression of sre1 in Saccharomyces cerevisiae enhanced tolerance to prothioconazole. The functional differentiation between SRE1 and SRE2 was elucidated by the yeast-two-hybridization assay, which showed an interaction between SREBP cleavage-activating protein (SCAP) and SRE1 but not between SRE2 and SCAP. Transcriptome analysis of the Δsre1 strain unveiled SRE1-mediated expression regulation of genes involved in lipid metabolism, respiration, and xenobiotic tolerance. Notably, genes coding for antimicrobial compounds chitinases and polyketide synthases were downregulated, aligning with the altered antagonism phenotype. This study uncovers the role of SREBPs in fungal BCAs, providing insights for C. rosea IK726 application into integrated pest management strategies.

The human milk oligosaccharide 3'sialyllactose reduces low-grade inflammation and atherosclerosis development in mice.

Macrophages contribute to the induction and resolution of inflammation and play a central role in chronic low-grade inflammation in cardiovascular diseases caused by atherosclerosis. Human milk oligosaccharides (HMOs) are complex unconjugated glycans unique to human milk that benefit infant health and act as innate immune modulators. Here, we identify the HMO 3'sialyllactose (3'SL) as a natural inhibitor of Toll-Like Receptor (TLR) 4-induced low-grade inflammation in macrophages and endothelium. Transcriptome analysis in macrophages revealed that 3'SL attenuates mRNA levels of a selected set of inflammatory genes and promotes the activity of Liver X Receptor (LXR) and Sterol Regulatory Element-binding Protein-1 (SREBP). These acute anti-inflammatory effects of 3'SL were associated with reduced histone H3K27 acetylation at a subset of lipopolysaccharide (LPS)-inducible enhancers distinguished by preferential enrichment for CCCTC-binding factor (CTCF), Interferon Regulatory Factor 2 (IRF2), B-cell lymphoma 6 (BCL6), and other transcription factor recognition motifs. In a murine atherosclerosis model, both subcutaneous and oral administration of 3'SL significantly reduced atherosclerosis development and the associated inflammation. This study provides evidence that 3'SL attenuates inflammation by a transcriptional mechanism to reduce atherosclerosis development in the context of cardiovascular disease.

Non-alcoholic fatty liver disease: Genetic susceptibility

The prevalence of Non-alcoholic Fatty Liver Disease (NAFLD) is increasing, particularly in individuals who consume minimal to no alcohol. Currently, NAFLD affects at least 32% of the global population. Although not all but approximately 5-10% cases of NAFLD progress to non-alcoholic steatohepatitis (NASH), a condition arising from lipotoxicity. Patients with NASH may further develop liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). However, it is important to note that progression from NAFLD to NASH and HCC is not inevitable for all patients. The pathogenesis of HCC in the context of NAFLD and NASH remains poorly understood, however, fat accumulation, often due to obesity or metabolic syndrome, leads to lipotoxicity. In individuals with type 2 diabetes (T2D), elevated insulin levels promote lipolysis in adipose tissue and activate lipid-synthesizing enzymes such as fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD1), which contribute to lipid accumulation in the liver. Additionally, high glucose levels in T2D can alter gene regulation by activating carbohydrate response-element binding protein (ChREBP) and insulin can increase the activity of sterol regulatory element binding protein (SREBP-1c). These lipogenic transcription factors are known to directly or indirectly activate patatin-like phospholipase domain-containing protein 3 (PNPLA3). Recent research has found elevated levels of angiotensinogen (AGT) and des-angiotensin in both experimental animals and patients with NAFLD. Emerging evidence highlights the significance of genetic factors in the risk of developing NAFLD. Here we explore the association between specific genes and hepatosteatosis, detailing the roles of T2D and obesity in the progression from NAFLD to NASH, and involvement of hepatic stellate cells in liver fibrosis. Additionally, we examine the impact of genes such as PNPLA3, MBOAT7, TM6SF2, GKRP, CCN3, and AGT as well as role of single nucleotide polymorphisms in gene regulation and their contribution to the risk of NAFLD.

Antidiabetic and Antihyperlipidemic Activities and Molecular Mechanisms of Phyllanthus emblica L. Extract in Mice on a High-Fat Diet.

We planned to explore the protective activities of extract of Phyllanthus emblica L. (EPE) on insulin resistance and metabolic disorders including hyperlipidemia, visceral obesity, and renal dysfunction in high-fat diet (HFD)-progressed T2DM mice. Mice treatments included 7 weeks of HFD induction followed by EPE, fenofibrate (Feno), or metformin (Metf) treatment daily for another 4-week HFD in HFD-fed mice. Finally, we harvested blood to analyze some tests on circulating glycemia and blood lipid levels. Western blotting analysis was performed on target gene expressions in peripheral tissues. The present findings indicated that EPE treatment reversed the HFD-induced increases in blood glucose, glycosylated HbA1C, and insulin levels. Our findings proved that treatment with EPE in HFD mice effectively controls hyperglycemia and hyperinsulinemia. Our results showed that EPE reduced blood lipid levels, including a reduction in blood triglyceride (TG), total cholesterol (TC), and free fatty acid (FFA); moreover, EPE reduced blood leptin levels and enhanced adiponectin concentrations. EPE treatment in HFD mice reduced BUN and creatinine in both blood and urine and lowered albumin levels in urine; moreover, EPE decreased circulating concentrations of inflammatory NLR family pyrin domain containing 3 (NLRP3) and kidney injury molecule-1 (KIM-1). These results indicated that EPE displayed antihyperglycemic and antihyperlipidemic activities but alleviated renal dysfunction in HFD mice. The histology examinations indicated that EPE treatment decreased adipose hypertrophy and hepatic ballooning, thus contributing to amelioration of lipid accumulation. EPE treatment decreased visceral fat amounts and led to improved systemic insulin resistance. For target gene expression levels, EPE enhanced AMP-activated protein kinase (AMPK) phosphorylation expressions both in livers and skeletal muscles and elevated the muscular membrane glucose transporter 4 (GLUT4) expressions. Treatment with EPE reduced hepatic glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) expressions to suppress glucose production in the livers and decreased phosphorylation of glycogen synthase kinase 3β (GSK3β) expressions to affect hepatic glycogen synthesis, thus convergently contributing to an antidiabetic effect and improving insulin resistance. The mechanism of the antihyperlipidemic activity of EPE involved a decrease in the hepatic phosphorylation of mammalian target of rapamycin complex C1 (mTORC1) and p70 S6 kinase 1 (S6K1) expressions to improve insulin resistance but also a reduction in hepatic sterol regulatory element binding protein (SREBP)-1c expressions, and suppression of ACC activity, thus resulting in the decreased fatty acid synthesis but elevated hepatic peroxisome proliferator-activated receptor (PPAR) α and SREBP-2 expressions, resulting in lowering TG and TC concentrations. Our results demonstrated that EPE improves insulin resistance and ameliorates hyperlipidemia in HFD mice.