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Archives of Biochemistry and Biophysics Aug 2023Defective autophagy-induced intracellular lipid degradation is causally associated with non-alcoholic fatty liver disease (NAFLD) development. Therefore, agents that can...
Defective autophagy-induced intracellular lipid degradation is causally associated with non-alcoholic fatty liver disease (NAFLD) development. Therefore, agents that can restore autophagy may have potential clinical application prospects on this public health issue. Galanin (GAL) is a pleiotropic peptide that regulates autophagy and is a potential drug for the treatment of NAFLD. In this study, we used an MCD-induced NAFLD mouse model in vivo and an FFA-induced HepG2 hepatocyte model in vitro to evaluate the anti-NAFLD effect of GAL. Exogenous GAL supplementation significantly attenuated lipid droplet accumulation and suppressed hepatocyte TG levels in mice and cell models. Mechanistically, Galanin-mediated reduction of lipid accumulation was positively correlated with upregulated p-AMPK, as evidenced by upregulated protein expressions of fatty acid oxidation-related gene markers (PPAR-α and CPT1A), upregulated expressions of the autophagy-related marker (LC3B), and downregulated autophagic substrate p62 levels. In FFA-treated HepG2 cells, activation of fatty acid oxidation and autophagy-related proteins by galanin was reversed by autophagy inhibitors, chloroquine, and the AMPK inhibitor. Galanin ameliorates hepatic fat accumulation by inducing autophagy and fatty acid oxidation via the AMPK/mTOR pathway.
Topics: Animals; Mice; AMP-Activated Protein Kinases; Galanin; TOR Serine-Threonine Kinases; Liver; Non-alcoholic Fatty Liver Disease; Lipid Metabolism; Autophagy; Fatty Acids; Lipids; Mice, Inbred C57BL; Diet, High-Fat
PubMed: 37429535
DOI: 10.1016/j.abb.2023.109689 -
Biomedicine & Pharmacotherapy =... Feb 2024Chronic kidney disease (CKD) development after acute kidney injury (AKI) involves multiple mechanisms, including inflammation, epithelial-mesenchymal transition (EMT),...
Chronic kidney disease (CKD) development after acute kidney injury (AKI) involves multiple mechanisms, including inflammation, epithelial-mesenchymal transition (EMT), and extracellular matrix deposition, leading to progressive tubulointerstitial fibrosis. Recently, a central role for peroxisome-proliferator activated receptor (PPAR)-α has been addressed in preserving kidney function during AKI. Among endogenous lipid mediators, oleoylethanolamide (OEA), a PPAR-α agonist, has been studied for its metabolic and anti-inflammatory effects. Here, we have investigated OEA effects on folic acid (FA)-induced kidney injury in mice and the underlying mechanisms. OEA improved kidney function, normalized urine output, and reduced serum BUN, creatinine, and albuminuria. Moreover, OEA attenuated tubular epithelial injury, as shown by histological analysis, and decreased expression of neutrophil gelatinase-associated lipocalin and kidney injury molecule-1. Gene expression analysis of kidney tissue indicated that OEA limited immune cell infiltration and inflammation. Moreover, OEA significantly inhibited Wnt7b and Catnb1 gene transcription and α-smooth muscle actin expression, indicating suppression of EMT. Accordingly, OEA exhibited an anti-fibrotic effect, as shown by Masson staining and the reduced levels of transforming growth factor (TGF)-β1, fibronectin, and collagen IV. Mechanistically, the nephroprotective effect of OEA was related to PPAR-α activation since OEA failed to exert its beneficial activity in FA-insulted PPAR-α mice. PPAR-α involvement was also confirmed in HK2 cells where GW6471, a PPAR-α antagonist, blunted OEA activity on the TGF-β1 signalling pathway and associated pro-inflammatory and fibrotic patterns. Our findings revealed that OEA counteracts kidney injury by controlling inflammation and fibrosis, making it an effective therapeutic tool for limiting AKI to CKD progression.
Topics: Mice; Animals; PPAR alpha; Kidney; Acute Kidney Injury; Fibrosis; Inflammation; Transforming Growth Factor beta1; Renal Insufficiency, Chronic; Oleic Acids; Endocannabinoids
PubMed: 38183745
DOI: 10.1016/j.biopha.2023.116094 -
Journal of Neuroinflammation Nov 2023Cyanidin-3-O-glucoside (C3G) is a natural anthocyanin with antioxidant, anti-inflammatory, and antitumor properties. However, as the effects of C3G on the amyloidogenic...
Cyanidin-3-O-glucoside (C3G) is a natural anthocyanin with antioxidant, anti-inflammatory, and antitumor properties. However, as the effects of C3G on the amyloidogenic pathway, autophagy, tau phosphorylation, neuronal cell death, and synaptic plasticity in Alzheimer's disease models have not been reported, we attempted to investigate the same in the brains of APPswe/PS1ΔE9 mice were analyzed. After oral administration of C3G (30 mg/kg/day) for 16 weeks, the cortical and hippocampal regions in the brains of APPswe/PS1ΔE9 mice were analyzed. C3G treatment reduced the levels of soluble and insoluble Aβ (Aβ40 and Aβ42) peptides and reduced the protein expression of the amyloid precursor protein, presenilin-1, and β-secretase in the cortical and hippocampal regions. And C3G treatment upregulated the expression of autophagy-related markers, LC3B-II, LAMP-1, TFEB, and PPAR-α and downregulated that of SQSTM1/p62, improving the autophagy of Aβ plaques and neurofibrillary tangles. In addition, C3G increased the protein expression of phosphorylated-AMPK/AMPK and Sirtuin 1 and decreased that of mitogen-activated protein kinases, such as phosphorylated-Akt/Akt and phosphorylated-ERK/ERK, thus demonstrating its neuroprotective effects. Furthermore, C3G regulated the PI3K/Akt/GSK3β signaling by upregulating phosphorylated-Akt/Akt and phosphorylated-GSK3β/GSK3β expression. C3G administration mitigated tau phosphorylation and improved synaptic function and plasticity by upregulating the expression of synapse-associated proteins synaptophysin and postsynaptic density protein-95. Although the potential of C3G in the APPswe/PS1ΔE9 mouse models has not yet been reported, oral administration of the C3G is shown to protect the brain and improve cognitive behavior.
Topics: Mice; Animals; Mice, Transgenic; Anthocyanins; Glycogen Synthase Kinase 3 beta; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; AMP-Activated Protein Kinases; Alzheimer Disease; Cognition; Brain; Glucosides; Amyloid beta-Peptides
PubMed: 37978414
DOI: 10.1186/s12974-023-02950-3 -
Biomedicine & Pharmacotherapy =... Sep 2023One of the most significant chemotherapeutic side effects of cisplatin (Cis) that limits its use and efficacy is testicular toxicity. Thus, the objective of the present...
One of the most significant chemotherapeutic side effects of cisplatin (Cis) that limits its use and efficacy is testicular toxicity. Thus, the objective of the present study was to investigate the possible ameliorative effect of Fenofibrate (Fen), Diosmetin (D), and their combination against cis-mediated testicular damage. Fifty-four adult male albino rats were randomly allocated into nine groups (6 rats each): Control group, Fen (100 mg/kg), D20 (20 mg/kg), D40 (40 mg/kg), Cis group (7 mg/kg), Cis +Fen group (7 mg/kg+100 mg/kg), Cis+D20 group (7 mg/kg+20 mg/kg), Cis+D40 group (7 mg/kg+40 mg/kg), Cis+Fen+D40 treated group (7 mg/kg+100 mg/kg+40 mg/kg). Relative testicular weight, epididymal sperm count and viability, serum testosterone level, testicular oxidative stress indices, mRNA expression of peroxisome proliferator-activated receptor alpha (PPAR-α), nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1), histopathological, and immunohistochemical alterations were assessed. Our results revealed that cis administration induced testicular oxidative and inflammatory damage as indicated by a substantial reduction in relative testicular weight, sperm parameters, serum testosterone levels, the antioxidant enzyme activity of catalase, and Johnson's histopathological score, PPAR-α/NRF-2/HO-1 and proliferating cell nuclear antigen (PCNA) immunoexpression with marked increment in malondialdehyde (MDA), Cosentino's score, nuclear factor kappa B (NF-κβ p65), interleukin (IL)- 1β and caspase 3 in testicular tissue. Interestingly, Fen and D diminished the harmful effects of cis on testes via upregulation of the antioxidant activities and downregulation of lipid peroxidation, apoptosis, and inflammation. Moreover, the combination therapy Fen/D40 also exhibited a more pronounced enhancement of previous markers than either treatment alone. In conclusion, because of their antioxidant, anti-inflammatory, and anti-apoptotic properties, cotreatment with Fen or D or their combination could be beneficial in reducing the harmful impacts of cis on testicular tissue, particularly in patients that receive cis chemotherapy.
Topics: Rats; Male; Animals; Testis; Fenofibrate; Antioxidants; Heme Oxygenase-1; Rats, Wistar; Semen; Cisplatin; Signal Transduction; Oxidative Stress; PPAR alpha; Testosterone
PubMed: 37413905
DOI: 10.1016/j.biopha.2023.115095 -
Hepatology (Baltimore, Md.) Nov 2023Liver fibrosis is the result of sustained chronic liver injury and inflammation leading to hepatocyte cell death followed by the formation of fibrous scars, which is the...
Liver fibrosis is the result of sustained chronic liver injury and inflammation leading to hepatocyte cell death followed by the formation of fibrous scars, which is the hallmark of NASH and alcoholic steatohepatitis and can lead to cirrhosis, HCC, and liver failure. Although progress has been made in understanding the pathogenesis and clinical consequences of hepatic fibrosis, therapeutic strategies for this disease are limited. Preclinical studies suggest that peroxisome proliferator-activated receptor alpha plays an important role in preventing the development of liver fibrosis by activating genes involved in detoxifying lipotoxicity and toxins, transrepressing genes involved in inflammation, and inhibiting activation of hepatic stellate cells. Given the robust preclinical data, several peroxisome proliferator-activated receptor alpha agonists have been tested in clinical trials for liver fibrosis. Here, we provide an update on recent progress in understanding the mechanisms by which peroxisome proliferator-activated receptor alpha prevents fibrosis and discuss the potential of targeting PPARα for the development of antifibrotic treatments.
Topics: Humans; Carcinoma, Hepatocellular; Fibrosis; Inflammation; Liver; Liver Cirrhosis; Liver Neoplasms; Non-alcoholic Fatty Liver Disease; PPAR alpha
PubMed: 36626642
DOI: 10.1097/HEP.0000000000000182 -
Computational Biology and Chemistry Aug 2024A new series of 2H-chromene-based sulfonamide derivatives 3-12 has been synthesized and characterized using different spectroscopic techniques. The synthesized...
Discovery of novel 6-(piperidin-1-ylsulfonyl)-2H-chromenes targeting α-glucosidase, α-amylase, and PPAR-γ: Design, synthesis, virtual screening, and anti-diabetic activity for type 2 diabetes mellitus.
A new series of 2H-chromene-based sulfonamide derivatives 3-12 has been synthesized and characterized using different spectroscopic techniques. The synthesized 2H-chromenes were synthesized by reacting activated methylene with 5-(piperidin-1-ylsulfonyl)salicylaldehyde through one-step condensation followed by intramolecular cyclization. Virtual screening of the designed molecules on α-glucosidase enzymes (PDB: 3W37 and 3A4A) exhibited good binding affinity suggesting that these derivatives may be potential α-glucosidase inhibitors. In-vitro α-glucosidase activity was conducted firstly at 100 µg/mL, and the results demonstrated good inhibitory potency with values ranging from 90.6% to 96.3% compared to IP = 95.8% for Acarbose. Furthermore, the IC values were determined, and the designed derivatives exhibited inhibitory potency less than 11 µg/mL. Surprisingly, two chromene derivatives 6 and 10 showed the highest potency with IC values of 0.975 ± 0.04 and 0.584 ± 0.02 µg/mL, respectively, compared to Acarbose (IC = 0.805 ± 0.03 µg/mL). Moreover, our work was extended to evaluate the in-vitro α-amylase and PPAR-γ activity as additional targets for diabetic activity. The results exhibited moderate activity on α-amylase and potency as PPAR-γ agonist making it a multiplet antidiabetic target. The most active 2H-chromenes 6 and 10 exhibited significant activity to PPAR-γ with IC values of 3.453 ± 0.14 and 4.653 ± 0.04 µg/mL compared to Pioglitazone (IC = 4.884±0.29 µg/mL) indicating that these derivatives improve insulin sensitivity by stimulating the production of small insulin-sensitive adipocytes. In-silico ADME profile analysis indicated compliance with Lipinski's and Veber's rules with excellent oral bioavailability properties. Finally, the docking simulation was conducted to explain the expected binding mode and binding affinity.
Topics: PPAR gamma; Benzopyrans; Hypoglycemic Agents; alpha-Glucosidases; Diabetes Mellitus, Type 2; Glycoside Hydrolase Inhibitors; alpha-Amylases; Drug Design; Humans; Structure-Activity Relationship; Molecular Structure; Molecular Docking Simulation; Drug Evaluation, Preclinical; Drug Discovery; Dose-Response Relationship, Drug
PubMed: 38772048
DOI: 10.1016/j.compbiolchem.2024.108097 -
Inflammation Research : Official... Dec 2023Kidney stones commonly occur with a 50% recurrence rate within 5 years, and can elevate the risk of chronic kidney disease. Macrophage-to-myofibroblast transition (MMT)...
OBJECTIVE AND DESIGN
Kidney stones commonly occur with a 50% recurrence rate within 5 years, and can elevate the risk of chronic kidney disease. Macrophage-to-myofibroblast transition (MMT) is a newly discovered mechanism that leads to progressive fibrosis in different forms of kidney disease. In this study, we aimed to investigate the role of MMT in renal fibrosis in glyoxylate-induced kidney stone mice and the mechanism by which signal transducer and activator of transcription 6 (STAT6) regulates MMT.
METHODS
We collected non-functioning kidneys from patients with stones, established glyoxylate-induced calcium oxalate stone mice model and treated AS1517499 every other day in the treatment group, and constructed a STAT6-knockout RAW264.7 cell line. We first screened the enrichment pathway of the model by transcriptome sequencing; detected renal injury and fibrosis by hematoxylin eosin staining, Von Kossa staining and Sirius red staining; detected MMT levels by multiplexed immunofluorescence and flow cytometry; and verified the binding site of STAT6 at the PPARα promoter by chromatin immunoprecipitation. Fatty acid oxidation (FAO) and fibrosis-related genes were detected by western blot and real-time quantitative polymerase chain reaction.
RESULTS
In this study, we found that FAO was downregulated, macrophages converted to myofibroblasts, and STAT6 expression was elevated in stone patients and glyoxylate-induced kidney stone mice. The promotion of FAO in macrophages attenuated MMT and upregulated fibrosis-related genes induced by calcium oxalate treatment. Further, inhibition of peroxisome proliferator-activated receptor-α (PPARα) eliminated the effect of STAT6 deletion on FAO and fibrosis-associated protein expression. Pharmacological inhibition of STAT6 also prevented the development of renal injury, lipid accumulation, MMT, and renal fibrosis. Mechanistically, STAT6 transcriptionally represses PPARα and FAO through cis-inducible elements located in the promoter region of the gene, thereby promoting MMT and renal fibrosis.
CONCLUSIONS
These findings establish a role for STAT6 in kidney stone injury-induced renal fibrosis, and suggest that STAT6 may be a therapeutic target for progressive renal fibrosis in patients with nephrolithiasis.
Topics: Animals; Humans; Mice; Calcium Oxalate; Fatty Acids; Fibrosis; Glyoxylates; Kidney; Kidney Calculi; Macrophages; Myofibroblasts; Oxalates; PPAR alpha; STAT6 Transcription Factor
PubMed: 37924395
DOI: 10.1007/s00011-023-01803-2 -
European Journal of Heart Failure Dec 2023The active ingredients in many traditional Chinese medicines are isoprene oligomers with a diterpenoid or triterpenoid structure, which exert cardiovascular effects by... (Review)
Review
The active ingredients in many traditional Chinese medicines are isoprene oligomers with a diterpenoid or triterpenoid structure, which exert cardiovascular effects by signalling through nutrient surplus and nutrient deprivation pathways. Qiliqiangxin (QLQX) is a commercial formulation of 11 different plant ingredients, whose active compounds include astragaloside IV, tanshione IIA, ginsenosides (Rb1, Rg1 and Re) and periplocymarin. In the QUEST trial, QLQX reduced the combined risk of cardiovascular death or heart failure hospitalization (hazard ratio 0.78, 95% confidence interval 0.68-0.90), based on 859 events in 3119 patients over a median of 18.2 months; the benefits were seen in patients taking foundational drugs except for sodium-glucose cotransporter 2 (SGLT2) inhibitors. Numerous experimental studies of QLQX in diverse cardiac injuries have yielded highly consistent findings. In marked abrupt cardiac injury, QLQX mitigated cardiac injury by upregulating nutrient surplus signalling through the PI3K/Akt/mTOR/HIF-1α/NRF2 pathway; the benefits of QLQX were abrogated by suppression of PI3K, Akt, mTOR, HIF-1α or NRF2. In contrast, in prolonged measured cardiac stress (as in chronic heart failure), QLQX ameliorated oxidative stress, maladaptive hypertrophy, cardiomyocyte apoptosis, and proinflammatory and profibrotic pathways, while enhancing mitochondrial health and promoting glucose and fatty acid oxidation and ATP production. These effects are achieved by an action of QLQX to upregulate nutrient deprivation signalling through SIRT1/AMPK/PGC-1α and enhanced autophagic flux. In particular, QLQX appears to enhance the interaction of PGC-1α with PPARα, possibly by direct binding to RXRα; silencing of SIRT1, PGC-1α and RXRα abrogated the favourable effects of QLQX in the heart. Since PGC-1α/RXRα is also a downstream effector of Akt/mTOR signalling, the actions of QLQX on PGC-1α/RXRα may explain its favourable effects in both acute and chronic stress. Intriguingly, the individual ingredients in QLQX - astragaloside IV, ginsenosides, and tanshione IIA - share QLQX's effects on PGC-1α/RXRα/PPARα signalling. QXQL also contains periplocymarin, a cardiac glycoside that inhibits Na -K -ATPase. Taken collectively, these observations support a conceptual framework for understanding the mechanism of action for QLQX in heart failure. The high likelihood of overlap in the mechanism of action of QLQX and SGLT2 inhibitors requires additional experimental studies and clinical trials.
Topics: Humans; Heart Failure; Sirtuin 1; Proto-Oncogene Proteins c-akt; PPAR alpha; Ginsenosides; Phosphatidylinositol 3-Kinases; NF-E2-Related Factor 2; TOR Serine-Threonine Kinases; Glucose; Drugs, Chinese Herbal; Saponins; Triterpenes
PubMed: 37877337
DOI: 10.1002/ejhf.3068 -
Journal of Ethnopharmacology Dec 2023Ramulus Cinnamomi, the dried twig of Cinnamomum cassia (L.) J.Presl., is a traditional Chinese medicine (TCM) with anti-inflammatory effects. The medicinal functions of...
ETHNOPHARMACOLOGICAL RELEVANCE
Ramulus Cinnamomi, the dried twig of Cinnamomum cassia (L.) J.Presl., is a traditional Chinese medicine (TCM) with anti-inflammatory effects. The medicinal functions of Ramulus Cinnamomi essential oil (RCEO) have been confirmed, although the potential mechanisms by which RCEO exerts its anti-inflammatory effects have not been fully elucidated.
AIM OF THE STUDY
To investigate whether N-acylethanolamine acid amidase (NAAA) mediates the anti-inflammatory effects of RCEO.
MATERIALS AND METHODS
RCEO was extracted by steam distillation of Ramulus Cinnamomi, and NAAA activity was detected using HEK293 cells overexpressing NAAA. N-Palmitoylethanolamide (PEA) and N-oleoylethanolamide (OEA), both of which are NAAA endogenous substrates, were detected by liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). The anti-inflammatory effects of RCEO were analyzed in lipopolysaccharide (LPS)-stimulated RAW264.7 cells, and the cell viability was measured with a Cell Counting Kit-8 (CCK-8) kit. The nitric oxide (NO) in the cell supernatant was measured using the Griess method. The level of tumor necrosis factor-α (TNF-α) in the RAW264.7 cell supernatant was determined using an enzyme-linked immunosorbent assay (ELISA) kit. The chemical composition of RCEO was assessed by gas chromatography-mass spectroscopy (GC-MS). The molecular docking study for (E)-cinnamaldehyde and NAAA was performed by using Discovery Studio 2019 software (DS2019).
RESULTS
We established a cell model for evaluating NAAA activity, and we found that RCEO inhibited the NAAA activity with an IC of 5.64 ± 0.62 μg/mL. RCEO significantly elevated PEA and OEA levels in NAAA-overexpressing HEK293 cells, suggesting that RCEO might prevent the degradation of cellular PEA and OEA by inhibiting the NAAA activity in NAAA-overexpressing HEK293 cells. In addition, RCEO also decreased NO and TNF-α cytokines in lipopolysaccharide (LPS)-stimulated macrophages. Interestingly, the GC-MS assay revealed that more than 93 components were identified in RCEO, of which (E)-cinnamaldehyde accounted for 64.88%. Further experiments showed that (E)-cinnamaldehyde and O-methoxycinnamaldehyde inhibited NAAA activity with an IC of 3.21 ± 0.03 and 9.62 ± 0.30 μg/mL, respectively, which may represent key components of RCEO that inhibit NAAA activity. Meanwhile, docking assays revealed that (E)-cinnamaldehyde occupies the catalytic cavity of NAAA and engages in a hydrogen bond interaction with the TRP181 and hydrophobic-related interactions with LEU152 of human NAAA.
CONCLUSIONS
RCEO showed anti-inflammatory effects by inhibiting NAAA activity and elevating cellular PEA and OEA levels in NAAA-overexpressing HEK293 cells. (E)-cinnamaldehyde and O-methoxycinnamaldehyde, two components in RCEO, were identified as the main contributors of the anti-inflammatory effects of RCEO by modulating cellular PEA levels through NAAA inhibition.
Topics: Humans; Lipopolysaccharides; Tumor Necrosis Factor-alpha; Oils, Volatile; Tandem Mass Spectrometry; HEK293 Cells; Molecular Docking Simulation; Anti-Inflammatory Agents; Amidohydrolases
PubMed: 37311500
DOI: 10.1016/j.jep.2023.116747 -
Molecules and Cells Aug 2023A fructose-enriched diet is thought to contribute to hepatic injury in developing non-alcoholic steatohepatitis (NASH). However, the cellular mechanism of...
A fructose-enriched diet is thought to contribute to hepatic injury in developing non-alcoholic steatohepatitis (NASH). However, the cellular mechanism of fructose-induced hepatic damage remains poorly understood. This study aimed to determine whether fructose induces cell death in primary hepatocytes, and if so, to establish the underlying cellular mechanisms. Our results revealed that treatment with high fructose concentrations for 48 h induced mitochondria-mediated apoptotic death in mouse primary hepatocytes (MPHs). Endoplasmic reticulum stress responses were involved in fructose-induced death as the levels of phosho-eIF2α, phospho-C-Jun-N-terminal kinase (JNK), and homologous protein (CHOP) increased, and a chemical chaperone tauroursodeoxycholic acid (TUDCA) prevented cell death. The impaired oxidation metabolism of fatty acids was also possibly involved in the fructose-induced toxicity as treatment with an AMP-activated kinase (AMPK) activator and a PPAR-α agonist significantly protected against fructose-induced death, while carnitine palmitoyl transferase I inhibitor exacerbated the toxicity. However, uric acid-mediated toxicity was not involved in fructose-induced death as uric acid was not toxic to MPHs, and the inhibition of xanthine oxidase (a key enzyme in uric acid synthesis) did not affect cell death. On the other hand, treatment with inhibitors of the nicotinamide adenine dinucleotide (NAD)-consuming enzyme CD38 or CD38 gene knockdown significantly protected against fructose-induced toxicity in MPHs, and fructose treatment increased CD38 levels. These data suggest that CD38 upregulation plays a role in hepatic injury in the fructose-enriched diet-mediated NASH. Thus, CD38 inhibition may be a promising therapeutic strategy to prevent fructose-enriched diet-mediated NASH.
Topics: Mice; Animals; Non-alcoholic Fatty Liver Disease; Hepatocytes; Cell Death; Endoplasmic Reticulum Stress
PubMed: 37497588
DOI: 10.14348/molcells.2023.0045