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Frontiers of Medicine Jun 2024Pathological cardiac hypertrophy, a major contributor to heart failure, is closely linked to mitochondrial function. The roles of long noncoding RNAs (lncRNAs), which...
Pathological cardiac hypertrophy, a major contributor to heart failure, is closely linked to mitochondrial function. The roles of long noncoding RNAs (lncRNAs), which regulate mitochondrial function, remain largely unexplored in this context. Herein, a previously unknown lncRNA, Gm20257, was identified. It markedly increased under hypertrophic stress in vivo and in vitro. The suppression of Gm20257 by using small interfering RNAs significantly induced cardiomyocyte hypertrophy. Conversely, the overexpression of Gm20257 through plasmid transfection or adeno-associated viral vector-9 mitigated angiotensin II-induced hypertrophic phenotypes in neonatal mouse ventricular cells or alleviated cardiac hypertrophy in a mouse TAC model respectively, thus restoring cardiac function. Importantly, Gm20257 restored mitochondrial complex IV level and enhanced mitochondrial function. Bioinformatics prediction showed that Gm20257 had a high binding score with peroxisome proliferator-activated receptor coactivator-1 (PGC-1α), which could increase mitochondrial complex IV. Subsequently, Western blot analysis results revealed that Gm20257 substantially affected the expression of PGC-1α. Further analyses through RNA immunoprecipitation and immunoblotting following RNA pull-down indicated that PGC-1α was a direct downstream target of Gm20257. This interaction was demonstrated to rescue the reduction of mitochondrial complex IV induced by hypertrophic stress and promote the generation of mitochondrial ATP. These findings suggest that Gm20257 improves mitochondrial function through the PGC-1α-mitochondrial complex IV axis, offering a novel approach for attenuating pathological cardiac hypertrophy.
PubMed: 38926249
DOI: 10.1007/s11684-024-1065-7 -
Discovery Medicine Jun 2024Metabolic dysfunction-associated steatotic liver disease (MASLD), and more specifically steatohepatitis may be associated with fat infiltration of skeletal muscles which... (Review)
Review
BACKGROUND
Metabolic dysfunction-associated steatotic liver disease (MASLD), and more specifically steatohepatitis may be associated with fat infiltration of skeletal muscles which is known as myosteatosis. Pan-peroxisome proliferator-activated receptor (PPAR) agonists have been shown to promote metabolic dysfunction-associated steatohepatitis (MASH) remission. However, the effect of PPAR agonists on myosteatosis remains to be determined. The aim of this review is to evaluate the effect that PPAR agonists alone or in combination, have on myosteatosis in the context of MASLD.
METHODS
Original research reports concerning the impact of PPAR agonists on muscle fat in MASLD were screened from PUBMED and EMBASE databases following the PRISMA methodology.
RESULTS
Eleven original manuscripts were included in this review. Two preclinical studies assessed the impact of the PPARα agonist on fat content in the quadriceps muscle and the liver by extracting triglycerides in rats fed a high-fat diet and in insulin-resistant mice. Both models showed muscle and liver triglyceride content reduction using WY14643. Fenofibrate had no significant impact on soleus intramyocellular lipids or liver fat content in insulin-resistant subjects based on proton magnetic resonance spectroscopy. Treatment with PPARδ agonists increased the expression of genes involved in fatty acid oxidation in two studies on muscle cell culture. PPARγ agonists were investigated in two preclinical studies and one clinical study using spectroscopy and computed tomography respectively. In the first preclinical study in Zucker diabetic fatty rats, rosiglitazone reduced muscle lipids and hepatic steatosis. In a second preclinical study using the same animal model, pioglitazone reduced tibialis anterior intramyocellular lipids. In contrast, computed tomography analyses in patients with type 2 diabetes revealed a surface area increase of low-density muscles (suggesting an increase in muscle fat content) after a one-year treatment with rosiglitazone. Varying combinations of PPAR agonists (cevoglitazar, fenofibrate/pioglitazone and muraglitazar) were evaluated in two preclinical studies and one clinical study. In rats, these treatments showed variable results for muscle and liver depending on the combinations studied. In type 2 diabetic patients, treatment with muraglitazar (a PPARα/γ agonist) reduced the intramyocellular lipid content of tibialis anterior as well as liver fat content following spectroscopy assessment.
CONCLUSION
The combination of different PPAR agonists could have a positive impact on reducing myosteatosis, in addition to their effect on the liver. Some discrepancies could be explained by the different techniques used to assess muscle lipid content, the muscles assessed and the possible adipogenic effect of PPARγ agonists. Further clinical research is needed to fully assess the efficacy of these treatments on both MASLD progression and associated myosteatosis.
Topics: Animals; Humans; Fatty Liver; Peroxisome Proliferator-Activated Receptors; Muscle, Skeletal; Rats; Mice; PPAR alpha
PubMed: 38926100
DOI: 10.24976/Discov.Med.202436185.104 -
The Journal of Biological Chemistry Jun 2024Diabetic nephropathy (DN) is one of the most important comorbidities for diabetic patients, which is the main factor leading to end-stage renal disease. Heparin...
Diabetic nephropathy (DN) is one of the most important comorbidities for diabetic patients, which is the main factor leading to end-stage renal disease. Heparin analogues can delay the progression of DN, but the mechanism is not fully understood. In this study, we found that low molecular weight heparin (LMWH) therapy significantly upregulated some downstream proteins of the peroxisome proliferator-activated receptor (PPAR) signaling pathway by label-free quantification of the mouse kidney proteome. Through cell model verification, LMWH can protect the heparan sulfate (HS) of renal tubular epithelial cells from being degraded by heparanase that is highly expressed in a high-glucose environment, enhance the endocytic recruitment of fatty acid-binding protein 1 (FABP1), a coactivator of the PPAR pathway, and then regulate the activation level of intracellular PPAR. In addition, we have elucidated for the first time the molecular mechanism of HS and FABP1 interaction. These findings provide new insights into understanding the role of heparin in the pathogenesis of DN and developing corresponding treatments.
PubMed: 38925330
DOI: 10.1016/j.jbc.2024.107493 -
Journal of Ethnopharmacology Jun 2024Meibomian gland dysfunction (MGD), complicated by type 2 diabetes, is associated with a high incidence of ocular surface disease, and no effective drug treatment exists....
ETHNOPHARMACOLOGICAL RELEVANCE
Meibomian gland dysfunction (MGD), complicated by type 2 diabetes, is associated with a high incidence of ocular surface disease, and no effective drug treatment exists. Diabetes mellitus (DM) MGD shows a notable disturbance in lipid metabolism. Er-Dong-Xiao-Ke decoction (EDXKD) has important functions in nourishing yin, clearing heat, and removing blood stasis, which are effective in the treatment of DM MGD.
AIM OF THE STUDY
To observe the therapeutic effect of EDXKD on DM MGD and its underlying molecular mechanism.
MATERIALS AND METHODS
After establishing a type 2 DM (T2DM)-induced MGD rat model, different doses of EDXKD and T0070907 were administered. The chemical constituents of EDXKD were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the molecular mechanism of EDXKD in treating DM MGD was predicted using network pharmacology. Lipid metabolism in DM meibomian glands (MGs) was analyzed using LC-MS/MS, and lipid biomarkers were screened and identified. Histological changes and lipid accumulation in MGs were detected by staining, and Peroxisome proliferator-activated receptor gamma (PPARG) expression in MG acinar cells was detected by immunofluorescence. The expression of lipid metabolism-related factors was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) or western blotting.
RESULTS
EDXKD reduced lipid accumulation in the MGs and improved the ocular surface index in DM MGD rats. The main active components of EDXKD had advantages in lipid regulation. Additionally, the PPARG signaling pathway was the key pathway of EDXKD in the treatment of DM MGD. Twelve lipid metabolites were biomarkers of EDXKD in the treatment of DM MGD, and glycerophospholipid metabolism was the main pathway of lipid regulation. Moreover, EDXKD improved lipid deposition in the acini and upregulated the expression of PPARG. Further, EDXKD regulated the PPARG-mediated UCP2/AMPK signaling network, inhibited lipid production, and promoted lipid transport.
CONCLUSION
EDXKD is an effective treatment for MGD in patients with T2DM. EDXKD can regulate lipids by regulating the PPARG-mediated UCP2/AMPK signaling network, as it reduced lipid accumulation in the MGs of DM MGD rats, promoted lipid metabolism, and improved MG function and ocular surface indices.
PubMed: 38925318
DOI: 10.1016/j.jep.2024.118484 -
Science Advances Jun 2024Once considered as a "metabolic waste," lactate is now recognized as a major fuel for tricarboxylic acid (TCA) cycle. Our metabolic flux analysis reveals that skeletal...
Once considered as a "metabolic waste," lactate is now recognized as a major fuel for tricarboxylic acid (TCA) cycle. Our metabolic flux analysis reveals that skeletal muscle mainly uses lactate to fuel TCA cycle. Lactate is transported through the cell membrane via monocarboxylate transporters (MCTs) in which MCT1 is highly expressed in the muscle. We analyzed how MCT1 affects muscle functions using mice with specific deletion of MCT1 in skeletal muscle. MCT1 deletion enhances running performance, increases oxidative fibers while decreasing glycolytic fibers, and enhances flux of glucose to TCA cycle. MCT1 deficiency increases the expression of mitochondrial proteins, augments cell respiration rate, and elevates mitochondrial activity in the muscle. Mechanistically, the protein level of PGC-1α, a master regulator of mitochondrial biogenesis, is elevated upon loss of MCT1 via increases in cellular NAD level and SIRT1 activity. Collectively, these results demonstrate that MCT1-mediated lactate shuttle plays a key role in regulating muscle functions by modulating mitochondrial biogenesis and TCA flux.
Topics: Animals; Monocarboxylic Acid Transporters; Muscle, Skeletal; Symporters; Lactic Acid; Organelle Biogenesis; Mice; Citric Acid Cycle; Mitochondria; Sirtuin 1; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Mice, Knockout; Glycolysis
PubMed: 38924407
DOI: 10.1126/sciadv.adn4508 -
Phytotherapy Research : PTR Jun 2024Glucolipid metabolism disorder (GLMD) is a complex chronic disease characterized by glucose and lipid metabolism disorders with a complex and diverse etiology and... (Review)
Review
Glucolipid metabolism disorder (GLMD) is a complex chronic disease characterized by glucose and lipid metabolism disorders with a complex and diverse etiology and rapidly increasing incidence. Many studies have identified the role of flavonoids in ameliorating GLMD, with mechanisms related to peroxisome proliferator-activated receptors, nuclear factor kappa-B, AMP-activated protein kinase, nuclear factor (erythroid-derived 2)-like 2, glucose transporter type 4, and phosphatidylinositol-3-kinase/protein kinase B pathway. However, a comprehensive summary of the flavonoid effects on GLMD is lacking. This study reviewed the roles and mechanisms of natural flavonoids with different structures in the treatment of GLMD reported globally in the past 5 years and provides a reference for developing flavonoids as drugs for treating GLMD.
PubMed: 38924256
DOI: 10.1002/ptr.8276 -
Journal of Phycology Jun 2024The northward shift of Pyropia yezoensis aquaculture required the breeding of germplasms with tolerance to the oxidative stress due to the high light conditions of the...
The northward shift of Pyropia yezoensis aquaculture required the breeding of germplasms with tolerance to the oxidative stress due to the high light conditions of the North Yellow Sea area. The MPV17/PMP22 family proteins were identified as a molecule related to reactive oxygen species (ROS) metabolism. Here, one of the MPV17 homolog genes designated as PyM-LP2 was selected for functional identification by introducing the encoding sequence region/reverse complementary fragment into the Py. yezoensis genome. Although the photosynthetic activity, the respiratory rate, and the ROS level in wild type (WT) and different gene-transformed algal strains showed similar levels under normal conditions, the overexpression (OE) strain exhibited higher values of photosynthesis, respiration, and reducing equivalents pool size but lower intracellular ROS production under stress conditions compared with the WT. Conversely, all the above parameters showed opposite variation trends in RNAi strain as those in the OE strain. This implied that the PyM-LP2 protein was involved in the mitigation of the oxidative stress. Sequence analysis revealed that this PyM-LP2 protein was assorted to peroxisomes and might serve as a poring channel for transferring malate (Mal) to peroxisomes. By overexpressing PyM-LP2, the transfer of Mal from chloroplasts to peroxisomes was enhanced under stress conditions, which promoted photorespiration and ultimately alleviated excessive reduction of the photosynthetic electron chain. This research lays the groundwork for the breeding of algae with enhanced resistance to oxidative stresses.
PubMed: 38924097
DOI: 10.1111/jpy.13474 -
PloS One 2024Spilanthes filicaulis (Schumach. & Thonn.) C. D Adam is a shrubby plant of the Asteraceae family that has medicinal benefits for the pharmaceutical and cosmetic...
Spilanthes filicaulis (Schumach. & Thonn.) C. D Adam leaf extract prevents assault of streptozotocin on liver cells via inhibition of oxidative stress and activation of the NrF2/Keap1, PPARγ, and PTP1B signaling pathways.
BACKGROUND
Spilanthes filicaulis (Schumach. & Thonn.) C. D Adam is a shrubby plant of the Asteraceae family that has medicinal benefits for the pharmaceutical and cosmetic industries.
PURPOSE
The purpose of this study was to assess the effectiveness of Spilanthes filicaulis leaf extract in a streptozotocin (STZ)-induced rat model and the associated signaling pathways.
METHODS
A sample of 25 male Wistar rats was randomly assigned to groups I, II, III, IV, and V. Each group included five animals, i.e., control rats, diabetic control rats, diabetic rats treated with metformin, and diabetic rats treated with 150 mg/kg/bw and 300 mg/kg/bw of the methanolic extract of S. filicaulis leaves (MESFL). Treatment was administered for 15 successive days via oral gavage. After 15 days, the rats were evaluated for fasting blood glucose (FBG), glycated hemoglobin (HbA1c), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), reduced glutathione (GSH), glutathione-S-transferase (GST), superoxide dismutase (SOD), catalase (CAT), lipid peroxidation (MDA), hexokinase, and glucose-6-phosphatase activities. Gene expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2), peroxisome proliferator-activated receptor gamma (PPAR-γ), kelch-like ECH-associated protein 1 (Keap1), protein tyrosine phosphatase 1B (PTP1B) and the antiapoptotic protein caspase-3 were examined.
RESULTS
MESFL was administered to diabetic rats, and changes in body weight, fasting blood glucose (FBG) and HbA1c were restored. Furthermore, in diabetic rats, S. filicaulis significantly reduced the levels of triglycerides (TGs), total cholesterol (TC), low-density lipoprotein (LDL), and very low-density lipoprotein (VLDL) and significantly increased HDL. S. filicaulis improved ALT, AST, and ALP enzyme activity in diabetic rats. MDA levels decreased considerably with increasing activity of antioxidant enzymes, such as GST, SOD, CAT and GSH, in diabetic liver rats treated with S. filicaulis. Diabetic rats treated with MESFL and metformin exhibited upregulated mRNA expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and peroxisome proliferator-activated receptor gamma (PPAR-γ). Kelch-like ECH-associated protein 1 (Keap1) and protein tyrosine phosphatase 1B (PTP1B) mRNA expression in the liver was downregulated in diabetic rats treated with MESFL and metformin. In addition, MESFL downregulated the mRNA expression of caspase-3 in diabetic rats.
CONCLUSION
It can be concluded from the data presented in this study that MESFL exerts a protective effect on diabetic rats due to its antidiabetic, antioxidant, antihyperlipidemic and antiapoptotic effects and may be considered a treatment for T2DM.
Topics: Animals; NF-E2-Related Factor 2; Male; Plant Extracts; Kelch-Like ECH-Associated Protein 1; Oxidative Stress; Plant Leaves; Signal Transduction; Rats; Rats, Wistar; Diabetes Mellitus, Experimental; PPAR gamma; Liver; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Asteraceae; Streptozocin; Hypoglycemic Agents
PubMed: 38924022
DOI: 10.1371/journal.pone.0306039 -
Cancer Medicine Jun 2024A neurotrophic tropomyosin receptor kinase (NTRK)-tyrosine kinase inhibitor (TKI) has shown dramatic efficacy against malignant tumors harboring an NTRK fusion gene....
INTRODUCTION
A neurotrophic tropomyosin receptor kinase (NTRK)-tyrosine kinase inhibitor (TKI) has shown dramatic efficacy against malignant tumors harboring an NTRK fusion gene. However, almost all tumors eventually acquire resistance to NTRK-TKIs.
METHOD
To investigate the mechanism of resistance to NTRK-TKIs, we established cells resistant to three types of NTRK-TKIs (larotrectinib, entrectinib, and selitrectinib) using KM12 colon cancer cells with a TPM3-NTRK1 rearrangement.
RESULT
Overexpression of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) was observed in three resistant cells (KM12-LR, KM12-ER, and KM12-SR) by microarray analysis. Lower expression of sterol regulatory element-binding protein 2 (SREBP2) and peroxisome proliferator activated receptor α (PPARα) was found in two cells (KM12-ER and KM12-SR) in which HMGCS2 was overexpressed compared to the parental KM12 and KM12-LR cells. In resistant cells, knockdown of HMGCS2 using small interfering RNA improved the sensitivity to NTRK-TKI. Further treatment with mevalonolactone after HMGCS2 knockdown reintroduced the NTRK-TKI resistance. In addition, simvastatin and silibinin had a synergistic effect with NTRK-TKIs in resistant cells, and delayed tolerance was observed after sustained exposure to clinical concentrations of NTRK-TKI and simvastatin in KM12 cells. In xenograft mouse models, combination treatment with entrectinib and simvastatin reduced resistant tumor growth compared with entrectinib alone.
CONCLUSION
These results suggest that HMGCS2 overexpression induces resistance to NTRK-TKIs via the mevalonate pathway in colon cancer cells. Statin inhibition of the mevalonate pathway may be useful for overcoming this mechanistic resistance.
Topics: Humans; Animals; Drug Resistance, Neoplasm; Mice; Cell Line, Tumor; Protein Kinase Inhibitors; Mevalonic Acid; Xenograft Model Antitumor Assays; Colonic Neoplasms; Receptor, trkA; Hydroxymethylglutaryl-CoA Synthase; Benzamides; Pyrimidines; Pyrazoles; Indazoles
PubMed: 38923428
DOI: 10.1002/cam4.7393 -
Chemistry & Biodiversity Jun 2024Myricetin (1), quercetin (2), kaempferol (3) and kaempferide (4) were flavonoids with phenolic hydroxyl groups. The antioxidant and pharmacological mechanisms of them...
Myricetin (1), quercetin (2), kaempferol (3) and kaempferide (4) were flavonoids with phenolic hydroxyl groups. The antioxidant and pharmacological mechanisms of them were investigated in detail. The lowest hydroxyl dissociation enthalpies of 1, 2, 3 and 4 were calculated by DFT, respectively. The hydroxyl dissociation enthalpies of the four flavonoids at the O2 site are the highest. By analyzing the intramolecular hydrogen bonds and HOMO-LUMO orbitals of the four flavonoids, the reasons for their divergence of hydroxyl dissociation enthalpies and antioxidant mechanisms were further investigated. The UV-vis and IR spectra of four flavonoids were compared. The interactions about electrostatic attraction, p-π conjugation and hydrogen bond combined the flavonoid with the target protein closely. The root mean square deviation of peroxisome proliferator-activated receptor γ combined with 1, 2 and 3 increased, while that of PPARγ combined with 4 decreased.
PubMed: 38923373
DOI: 10.1002/cbdv.202400752