Nrf2/HO‐1, NF‐κB and PI3K/Akt signalling pathways decipher the therapeutic mechanism of pitavastatin in early phase liver fibrosis in rats

Journal of Cellular and Molecular Medicine, Год журнала: 2024, Номер 28(3)

Опубликована: Янв. 12, 2024

Liver fibrosis is a common chronic hepatic disease. This study aimed to investigate the effect of pitavastatin (Pit) against thioacetamide (TAA)-induced liver fibrosis. Rats were divided into four groups: (1) control group; (2) TAA group (100 mg/kg, i.p.) three times weekly for 2 weeks; (3 and 4) TAA/Pit-treated group, in which Pit was administered orally (0.4 0.8 mg/kg/day) weeks following injections. caused damage manifested by elevated serum transaminases, reduced albumin histological alterations. Hepatic malondialdehyde (MDA) increased, glutathione (GSH) superoxide dismutase (SOD) decreased TAA-administered rats. upregulated inflammatory markers NF-κB, NF-κB p65, TNF-α IL-6. Treatment with ameliorated prevented histopathological changes TAA-intoxicated suppressed MDA, cytokines PI3K mRNA In addition, enhanced antioxidants boosted nuclear factor erythroid 2-related (Nrf2) heme oxygenase-1 (HO-1) mRNA. Moreover, immunohistological studies supported ability reduce via suppressing p-AKT expression. conclusion, effectively prevents TAA-induced attenuating oxidative stress response. The hepatoprotective efficacy associated upregulation Nrf2/HO-1 downregulation PI3K/Akt signalling pathways.

Язык: Английский

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Epigenetic modification in liver fibrosis: Promising therapeutic direction with significant challenges ahead

Acta Pharmaceutica Sinica B, Год журнала: 2023, Номер 14(3), С. 1009 - 1029

Опубликована: Ноя. 4, 2023

Liver fibrosis, characterized by scar tissue formation, can ultimately result in liver failure. It's a major cause of morbidity and mortality globally, often associated with chronic diseases like hepatitis or alcoholic non-alcoholic fatty diseases. However, current treatment options are limited, highlighting the urgent need for development new therapies. As reversible regulatory mechanism, epigenetic modification is implicated many biological processes, including fibrosis. Exploring mechanisms involved fibrosis could provide valuable insights into developing treatments diseases, although evidence still controversial. This review provides comprehensive summary critical targets modifications, DNA methylation, histone modification, RNA fibrotic The potential cooperation different modifications promoting fibrogenesis was also highlighted. Finally, available agonists inhibitors regulating these their application preventing were discussed. In summary, elucidating specific druggable more selective candidate medicines may represent promising approach bright prospects

Язык: Английский

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Hepatocardiorenal syndrome in liver cirrhosis: Recognition of a new entity?

World Journal of Gastroenterology, Год журнала: 2024, Номер 30(2), С. 128 - 136

Опубликована: Янв. 10, 2024

Emerging evidence and perspectives have pointed towards the heart playing an important role in hepatorenal syndrome (HRS), outside of conventional understanding that liver cirrhosis is traditionally considered sole origin a cascade pathophysiological mechanisms directly affecting kidneys this context. In absence established disease, cirrhotic cardiomyopathy may occur more frequently those with kidney disease. It specific form cardiac dysfunction characterized by blunted contractile responsiveness to stress stimuli altered diastolic relaxation electrophysiological abnormalities. Despite clinical description these potential cardiac-related complications liver, has been overlooked aspect circulatory HRS. Yet from physiological sense, temporality (prior onset) cardiorenal interactions HRS positive effects stemming portosystemic shunting demonstrated development progression patients. review, we discuss current concepts surrounding how influence HRS, systemic inflammation endothelial causing within setting. The will be discussed. For subgroup patients who receive shunting, dynamics following treatment reviewed. Continued research determine unknowns topic anticipated, hopefully further clarify intricacies liver-heart-kidney connection improve strategies for management.

Язык: Английский

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Development of novel bosentan analogues as endothelin receptor antagonists for pulmonary arterial hypertension

European Journal of Medicinal Chemistry, Год журнала: 2023, Номер 259, С. 115681 - 115681

Опубликована: Июль 25, 2023

Язык: Английский

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Sinapic Acid Attenuate Liver Injury by Modulating Antioxidant Activity and Inflammatory Cytokines in Thioacetamide-Induced Liver Cirrhosis in Rats

Biomedicines, Год журнала: 2023, Номер 11(5), С. 1447 - 1447

Опубликована: Май 15, 2023

Sinapic acid (SA) is a natural pharmacological active compound found in berries, nuts, and cereals. The current study aimed to investigate the protective effects of SA against thioacetamide (TAA) fibrosis rats by histopathological immunohistochemical assays. albino (30) were randomly divided into five groups (G). G1 was injected with distilled water 3 times/week fed orally daily 10% Tween 20 for two months. G2–5 200 mg/kg TAA three times weekly months 20, 50 silymarin, 40 2 months, respectively. results showed that treated had fewer hepatocyte injuries lower liver index (serum bilirubin, total protein, albumin, enzymes (ALP, ALT, AST) similar control silymarin-treated rats. Acute toxicity 4 g/kg be safe without any toxic signs Macroscopic examination hepatotoxic an irregular, rough surface micro macro nodules histopathology expressed Hematoxylin Eosin, Masson Trichrome revealed severe inflammation infiltration focal necrosis, fibrosis, lymphocytes, proliferation bile duct. In contrast, significantly gross histology tissues as presented less tissue disruption, lesser minimum filtered hepatocytes. Immunohistochemistry receiving significant up-regulation HSP 70% down-regulation alpha-smooth muscle actin (α-SMA) protein expression compared positive homogenized notable rise antioxidant (SOD CAT) actions malondialdehyde (MDA) levels group. Furthermore, SA-treated TNF-a, IL-6, higher IL-10 than Thus, findings suggest hepatoprotective due its inhibitory on hepatotoxicity, cell proliferation, 70, downregulation α-SMA expression, inhibiting lipid peroxidation (MDA), while retaining normal.

Язык: Английский

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Ameliorative effect of curcuminoids in liver fibrosis rat model via regulating GIPC1 gene and modulating MMP-8/TIMP-3 balance mediated by miR-483-5p

Beni-Suef University Journal of Basic and Applied Sciences, Год журнала: 2025, Номер 14(1)

Опубликована: Янв. 3, 2025

Abstract Background Liver fibrosis is a worldwide disease that develops from activation and propagation of hepatic stellate cells, subsequent extracellular matrix accumulation. associated with multiple pathways, however, the dysregulation GIPC1 gene (GIPC PDZ domain containing family member 1) disruption in balance MMPs (matrix metalloproteinases) TIMPs (tissue inhibitor remain as key factors this disease. Curcuminoids, especially curcumin (CURC), are medicinal extracts proved their antioxidative, anti-inflammatory, antifibrotic actions, showed wide epigenetic regulatory effects. We aimed to explore CURC’s effect on declining inflammatory cytokines TNF-α (tumor necrosis factor-alpha), IL-6 (interleukin-6), TGF-β1 (transforming growth factor beta1), regulating expression, adjusting MMP-8/TIMP-3 mediated by miRNA-483-5p (microRNA-483-5p) TAA (thioacetamide)-induced liver fibrotic albino Wistar rat model. Results The attained results revealed significant regressions livers’ relative weights, serum ALT (alanine aminotransferase), AST (aspartate ALP (alkaline phosphatase) LDH (lactate dehydrogenase), plasma PDGF (platelet-derived factor), TOC (total oxidative capacity), TNF-α, IL-6, TGF-β1, downregulation besides, elevation TAC antioxidant capacity) CURC-treated rats. Surprisingly, upregulation miRNA-483 expression was obtained rats which consequentially enhanced form an MMP-8/reduction TIMP-3 levels, along confirming novel pathway through conducting bioinformatics analysis. All these enhancements were mirrored Annexin V/PI (Annexin V Propidium Iodide) assay massive improvements % apoptotic necrotic plus, H&E (hematoxylin eosin) Masson’s trichrome histopathological examinations near normal architecture no collagen bands deposition. Conclusions This study concludes CURC can modulate miRNA-483-5p/MMP-8/TIMP-3 regulate thus providing new perception effective therapeutic agent capable lowering inflammation remodeling damage. Graphical

Язык: Английский

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Hypoxia-inducible factor-1 alpha (HIF-1α) inhibitor AMSP-30m attenuates CCl4-induced liver fibrosis in mice by inhibiting the sonic hedgehog pathway

Chemico-Biological Interactions, Год журнала: 2025, Номер unknown, С. 111480 - 111480

Опубликована: Март 1, 2025

Язык: Английский

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Empagliflozin Plays Vasoprotective Role in Spontaneously Hypertensive Rats via Activation of the SIRT1/AMPK Pathway

Cells, Год журнала: 2025, Номер 14(7), С. 507 - 507

Опубликована: Март 29, 2025

Empagliflozin (EMPA), a sodium-glucose co-transporter 2 (SGLT2) inhibitor, prevents endothelial dysfunction, but its effects on vascular tone in hypertension remain unclear. This study investigated whether EMPA modulates vasomotor via sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK) pathways spontaneously hypertensive rats (SHR) controls (Wistar Kyoto rats, WKY). Functional (wire myography, organ bath) biochemical (Western blot) studies were conducted the third-order of superior mesenteric arteries (sMAs) and/or aortas. induced concentration-dependent relaxation preconstricted sMAs both groups. In SHR, enhanced acetylcholine (Ach)-induced aortas reduced constriction by phenylephrine (Phe) U46619 sMAs. The SIRT1 inhibitor (EX527) abolished EMPA’s Ach-mediated U46619-induced vasoconstriction, while AMPK inhibition Phe-induced vasoconstriction. SHR showed increased SGLT2 expression decreased pAMPK/AMPK levels conclusion, might exert vasoprotective enhancing endothelium-dependent reducing AMPK/SIRT1 pathways. These properties could improve health patients with related conditions. Further are needed to explore new indications for inhibitors.

Язык: Английский

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Carbon Nitride‐Based siRNA Vectors with Self‐Produced O₂ Effects for Targeting Combination Therapy of Liver Fibrosis via HIF‐1α‐Mediated TGF‐β1/Smad Pathway

Advanced Healthcare Materials, Год журнала: 2023, Номер 12(29)

Опубликована: Июль 19, 2023

Hypoxia is an important feature, which can upregulate the hypoxia-inducible factor-1α (HIF-1α) expression and promote activation of hepatic stellate cells (HSCs), leading to liver fibrosis. Currently, effective treatment for fibrosis extremely lacking. Herein, a safe method established downregulate HIF-1α in HSCs via targeted delivery VA-PEG-modified CNs-based nanosheets-encapsulated (VA-PEG-CN@GQDs) small interfering RNA (HIF-1α-siRNA). Due presence lipase liver, reversible release siRNA be promoted complete transfection process. Simultaneously, VA-PEG-CN@GQD nanosheets enable trigger water splitting process produce O2 under near-infrared (NIR) irradiation, thereby improving hypoxic environment site maximizing downregulation improve therapeutic effect, as demonstrated mice. Such combination therapy inhibit HIF-1α-mediated TGF-β1/Smad pathway, achieving outstanding effects In conclusion, this study proposes novel strategy by regulating at lesion site.

Язык: Английский

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Empagliflozin attenuates liver fibrosis in high‐fat diet/streptozotocin‐induced mice by modulating gut microbiota

Clinical and Experimental Pharmacology and Physiology, Год журнала: 2024, Номер 51(3)

Опубликована: Янв. 28, 2024

Abstract The effects of SGLT2 inhibitors on hepatic fibrosis in diabetes remain unclear. This study aimed to investigate the empagliflozin liver high‐fat diet/streptozotocin‐induced mice and correlation with gut microbiota. After application for 6 weeks, we performed oral glucose tolerance intraperitoneal insulin tests assess resistance, stained sections evaluate histochemical pathological markers fibrosis. Moreover, 16S rRNA amplicon sequencing was stool samples explore changes composition intestinal bacteria. We finally analysed between microbiome scores or indicators metabolism. results showed that intervention improved metabolism function reduced fibrosis, which might be related In addition, abundance probiotic Lactobacillus increased, while Ruminococcus Adlercreutzia decreased after treatment, analysis microbiota were positively correlated Overall, considering contribution metabolism, have beneficial balance bacteria composition. present provides evidence indicates involvement gut–liver axis by T2DM

Язык: Английский

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