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Background: Organ ischemia-reperfusion (IR) is a common clinical condition associated with various situations such as trauma surgery, organ transplantation, and myocardial ischemia. Current therapeutic methods for IR injury have limitations, and nanotechnology, particularly zinc oxide nanoparticles (ZnO NPs), offers new approaches for disease diagnosis and treatment. In this study, we investigated the protective and anti-apoptotic effects of ZnO NPs in liver ischemia-reperfusion (IR) injury in rats. Methods: Forty-eight male rats were divided into six groups: sham, ZnO5, ZnO10, ischemia-reperfusion (IR), IR+ZnO5, and IR+ZnO10. The protective effect of ZnO NPs was evaluated by liver enzymes (AST, ALT, Bilirubin, ALP), biochemical (TAC, TNF-α, and MDA), molecular examinations (Bcl2, BAX), and histopathological evaluations (H&E, TUNEL). Results: Pre-treatment with ZnO5 and ZnO10 improved hepatic function in IR liver injury, attenuated the levels of oxidants (P = 0.03) and inflammatory mediators, and reduced apoptosis (P = 0). ZnO10 was found to have a greater effect on ischemic reperfusion injury than ZnO5 did. Histopathological examination also showed a dose-dependent decrease in alterations in the IR+ZnO5 and IR+ZnO10 groups. Conclusion: Administration of ZnO5 and ZnO10 improved liver function after IR. The findings of this study suggest that ZnO NPs have a protective effect against oxidative stress and apoptosis in liver ischemia-reperfusion injury in rats. These results may have important implications for developing advanced methods in ischemia-reperfusion treatment.
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Ischemia-reperfusion (I/R) injury, as a pathological phenomenon, takes place when blood supply to an organ is disrupted and then aggravated during restoration of blood flow. Ischemic preconditioning (IPC) is a potent method for attenuating subsequent events of IR damage in numerous organs. IPC protocol is determined by a brief and sequential time periods of I/R before the main ischemia. MicroRNAs are endogenous non-coding RNAs that regulate post-transcriptionally target mRNA translation via degrading it and/or suppressing protein synthesis. This review introduces the physiological and cellular mechanisms of ischemic preconditioning microRNAs-mediated after I/R insult in different organs such as the liver, kidney, heart, brain, and intestine. Data of this review have been collected from the scientific articles published in databases such as Science Direct, Scopus, PubMed, Web of Science, and Scientific Information Database from 2000 to 2023. Based on these literature studies, IPC/IR intervention can affect cellular mechanisms including oxidative stress, apoptosis, angiogenesis, and inflammation through up-regulation or down-regulation of multiple microRNAs and their target genes.
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Non-alcoholic steatohepatitis (NASH) is a subtype of nonalcoholic fatty liver disease and a progressive and chronic liver disorder with a significant risk for the development of liver-related morbidity and mortality. The complex and multifaceted pathophysiology of NASH makes its management challenging. Early identification of symptoms and management of patients through lifestyle modification is essential to prevent the development of advanced liver disease. Despite the increasing prevalence of NASH, there is no FDA-approved treatment for this disease. Currently, medications targeting metabolic disease risk factors and some antifibrotic medications are used for NASH patients but are not sufficiently effective. The beneficial effects of different drugs and phytochemicals represent new avenues for the development of safer and more effective treatments for NASH. In this review, different risk factors, clinical symptoms, diagnostic methods of NASH, and current treatment strategies for the management of patients with NASH are reviewed.
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Background: Liver diseases and injuries are important medical problems worldwide. Acute liver failure (ALF) is a clinical syndrome characterized by severe functional impairment and widespread death of hepatocytes. Liver transplantation is the only treatment available so far. Exosomes are nanovesicles originating from intracellular organelles. They regulate the cellular and molecular mechanisms of their recipient cells and have promising potential for clinical application in acute and chronic liver injuries. This study compares the effect of Sodium hydrosulfide (NaHS) modified exosomes with non-modified exosomes in CCL4-induced acute liver injury to ascertain their role in ameliorating hepatic injury. Methods: Human Mesenchymal stem cells (MSCs) were treated with or without NaHS (1 µmol) and exosomes were isolated using an exosome isolation kit. Male mice (8-12 weeks old) were randomly divided into four groups (n=6): 1-control, 2-PBS, 3- MSC-Exo, and 4- H2S-Exo. Animals received 2.8 ml/kg body weight of CCL4 solution intraperitoneally, and 24 h later MSC-Exo (non-modified), H2S-Exo (NaHS-modified), or PBS, was injected in the tail vein. Moreover, 24 h after Exo administration, mice were sacrificed for tissue and blood collection. Results: Administration of both MSC-Exo and H2S-Exo reduced inflammatory cytokines (IL-6, TNF-α), total oxidant levels, liver aminotransferases, and cellular apoptosis. Conclusion: MSC-Exo and H2S-Exo had hepato-protective effects against CCL4-induced liver injury in mice. Modification of cell culture medium with NaHS as an H2S donor enhances the therapeutic effects of MSC exosomes.
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INTRODUCTION: Ischemia-reperfusion injury (IRI) by causing histopathological changes is considered one of the most important causes of liver failure and dysfunction after surgery which affect graft outcomes. Stem cells are new promising approaches to treating different diseases. One of the critical strategies to improve their function is the preconditioning of their culture medium. This study compared the effect of NaHS-modified and non-modified mesenchymal stem cell exosomes on liver ischemia-reperfusion injury in mice. METHODS: Human umbilical cord-derived MSC (MSC) cultured in a 75 cm3 flask and when confluency reached about 80%, the culture medium replaced with a serum-free medium, and 48 h later supernatants collected, concentrated, and then MSC-Exo extracted. To obtain H2S-Exo, MSC was treated with NaHS (1 µmol),the supernatant collected after 48 h, concentrated and exosomes extracted. Twenty-four male mice were randomly divided into four groups (n = 6) including: 1-ischemia, 2-sham-operated, 3- MSC-Exo, and 4- H2S-Exo. To induce ischemia, the hepatic artery and portal vein clamped using an atraumatic clip for 60 min followed by 3 h of reperfusion. Just upon ending the time of ischemia (removal of clamp artery), animals in MSC-Exo, and H2S-Exo groups received 100 µg exosomes in 100 µl PBS via tail vein. At the end of reperfusion, blood, and liver samples were collected for further serological, molecular, and histological analyses. RESULTS: Administration of both MSC-Exo and H2S-Exo improved liver function by reducing inflammatory cytokines, cellular apoptosis, liver levels of total oxidant status, and liver aminotransferases. The results showed that protecting effect of MSC exosomes enhanced following NaHS preconditioning of cell culture medium. CONCLUSION: MSC-Exo and H2S-Exo had hepato-protective effects against injuries induced by ischemia-reperfusion in mice. NaHS preconditioning of mesenchymal stem cells could enhance the therapeutic effects of MSC-derived exosomes.
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Exosomas , Células Madre Mesenquimatosas , Daño por Reperfusión , Animales , Humanos , Masculino , Ratones , Exosomas/patología , Isquemia/patología , Hígado/patología , Daño por Reperfusión/prevención & control , Daño por Reperfusión/patología , ARN Largo no CodificanteRESUMEN
BACKGROUND: The role of hepatocyte apoptosis and inflammation has been implicated in the progression of nonalcoholic steatohepatitis (NASH). Overproduction of reactive oxygen species (ROS) appears to accelerate these pathways through the activation of Fas receptor signaling. Therefore, we explored the hepatoprotective effects of crocin as a strong free radical scavenger against oxidative damages leading to NASH development. METHODS: Thirty-two male mice were randomly divided into control, NASH, NASH + crocin, and crocin groups. They received an intraperi- toneal injection of crocin twice a week, for 3 weeks. For NASH model induction, the animals were fed with a Western diet and exposed to cigarette smoke for 8 weeks. At the end of the experiment, liver histology, biochemical, and biomolecular analyses were done to evaluate the antioxidant, anti-inflammatory, and anti-apoptotic activities of crocin in the NASH model. RESULTS: Evaluation of the features of the NASH model revealed steatosis, inflammatory infiltrate, and ballooning degeneration. Metabolic dysfunction was associated with elevated serum levels of the lipid profile and decreased hepatic liver enzymes. The increased content of malondialdehyde (MDA) and reduced antioxidant activities confirmed hepatotoxicity induction. There was a significant increase in expression level of Fas, caspase 3, and NF-κB genes that was also associated with elevation in hepatic TNF-α content. Moreover, expression the of Fas receptor protein was significantly detected on the hepatocyte membrane. Treatment with crocin effectively improved NASH-related parameters, and the histopathological findings were also parallel with the resulting changes. CONCLUSION: Crocin can be introduced as a candidate hepatoprotective agent against NASH by virtue of its anti-inflammatory, antioxi- dant, and anti-apoptotic properties, possibly through regulation of the Fas death receptor pathway.
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Enfermedad del Hígado Graso no Alcohólico , Animales , Antiinflamatorios , Antioxidantes/farmacología , Carotenoides , Masculino , Ratones , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Transducción de Señal , Receptor fasRESUMEN
Diabetes mellitus (DM) is one of the most important metabolic disorders associated with chronic hyperglycemia and occurs when the body cannot manage insulin secretion, insulin action, or both. Autoimmune destruction of pancreatic beta cells and insulin resistance are the major pathophysiological factors of types 1 and 2 of DM, respectively. Prolonged hyperglycemia leads to multiple organs dysfunctions, including nephropathy, neuropathy, cardiomyopathy, gastropathy, and micro- and macrovascular disorders. The basis of the metabolic abnormalities in carbohydrate, fat, and protein in diabetes is insufficient action of insulin on various target tissues. Medicinal plants are rich sources of bioactive chemical compounds with therapeutic effects. The beneficial effects of leaves, fruits, and flowers extracts of Crataegus oxyacantha, commonly called hawthorn, belonging to the Rosaceae family, are widely used as hawthorn-derived medicines. Data in this review have been collected from the scientific articles published in databases such as Science Direct, Scopus, PubMed, Web of Science, and Scientific Information Database from 2000 to 2021. Based on this review, hawthorn extracts appear both therapeutic and protective effects against diabetic-related complications in various organs through molecular mechanisms, such as decreasing triglyceride, cholesterol, very low density lipoprotein and increasing the antioxidant activity of superoxide dismutase, catalase, glutathione peroxidase, total antioxidant capacity, decreasing malondialdehyde level, and attenuating tumor necrosis factor alpha, interleukin 6 and sirtuin 1/AMP-activated protein kinase (AMPK)/nuclear factor kappa B (NF-κB) pathway and increasing the phosphorylation of glucose transporter 4, insulin receptor substrate 1, AKT and phosphoinositide 3-kinases, and attenuating blood sugar and regulation of insulin secretion, insulin resistance, and improvement of histopathological changes in pancreatic beta cells. Collectively, hawthorn can be considered as one new target for the research and development of innovative drugs for the prevention or treatment of DM and related problems.
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Nonalcoholic fatty liver disease (NAFLD), as the most common chronic liver disease, is rapidly increasing worldwide. This complex disorder can include simple liver steatosis to more serious stages of nonalcoholic fibrosis and steatohepatitis (NASH). One of the critical concerns in NASH research is selecting and confiding in relying on preclinical animal models and experimental methods that can accurately reflect the situation in human NASH. Recently, creating nutritional models of NASH with a closer dietary pattern in human has been providing reliable, simple, and reproducible tools that hope to create a better landscape for showing the recapitulation of disease pathophysiology. This review focuses on recent research on rodent models (mice, rats, and hamsters) in the induction of the dietary model of NAFLD /NASH. This research tries to compile the different dietary compositions of NASH, time frames required for disease development, and their impact on liver histological features as well as metabolic parameters.
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Enfermedad del Hígado Graso no Alcohólico , Humanos , Ratones , Ratas , Animales , Enfermedad del Hígado Graso no Alcohólico/patología , Roedores , Hígado/patología , Dieta , Cirrosis Hepática/patología , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: General overnutrition is one of the key factors involved in the development of nonalcoholic fatty liver disease (NAFLD) as the most common liver disease occur by two steps of liver injury ranges from steatosis to nonalcoholic steatohepatitis (NASH). Here the effect of fructose, fat-rich and western diet (WD) feeding was studied along with aggravative effect of cigarette smoking on liver status in mice. METHODS: Sixty-four male NMRI mice were included in this study and assigned into 4 groups that fed standard, fructose-rich, high fat-, and western-diet for 8 weeks and then each group divided in two smoker and nonsmoker subgroups according to smoke exposing in the last 4 weeks of feeding time (n = 8). Histopathological studies, serum biochemical analyses and hepatic TNF-α level were evaluated in mice to compare alone or combination effects of dietary regimen and cigarette smoking. RESULTS: Serum liver enzymes and lipid profile levels in WD fed mice were significantly higher than in other studied diets. Exposing to cigarette smoke led to more elevation of serum biochemical parameters that was also accompanied by a significant increase in hepatic damage shown as more severe fat accumulation, hepatocyte ballooning and inflammation infiltrate. Elevated TNF-α level confirmed incidence of liver injury. CONCLUSION: The finding of this study demonstrated that a combination of cigarette smoke exposure and WD (rich in fat, fructose, and cholesterol) could induce a more reliable mouse model of NASH.
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Dieta Alta en Grasa/efectos adversos , Dieta Occidental/efectos adversos , Modelos Animales de Enfermedad , Fructosa , Hígado , Enfermedad del Hígado Graso no Alcohólico/etiología , Contaminación por Humo de Tabaco/efectos adversos , Animales , Fructosa/administración & dosificación , Fructosa/efectos adversos , Hígado/metabolismo , Hígado/patología , Pruebas de Función Hepática , Masculino , Ratones , Edulcorantes/administración & dosificación , Edulcorantes/efectos adversos , Factor de Necrosis Tumoral alfa/análisisRESUMEN
OBJECTIVES: Gallic acid (GA) is a highly effective antioxidant, which its beneficial effects are well known, but its impact on expression of microRNAs (miRs) following hepatic ischemia-reperfusion (I/R) is not well recognized. Therefore, the current research was designed to specify the beneficial effect of GA on miRs (122 and 34a), liver functional tests, and histopathological alterations beyond I/R-induced hepatic injury. MATERIALS AND METHODS: Thirty-two rats were randomly divided into four groups (8 per group) including: sham-operated (S), I/R, and GA+I/R pretreated groups. Rats in sham-operated group received physiologic saline (N/S, 2 ml/kg), on a weekly basis, once a day via intraperitoneally route), then a midline abdominal surgery was performed. IR, and GA+IR pretreated groups received physiologic saline (2 ml/kg), and GA (50, and 100 mg per kg) for same time, IP, respectively, before induction of transient ischemia. One hour after reperfusion, biochemical, and histopathological evaluations were performed and expression of miRs were evaluated. RESULTS: The results showed that GA reduced the concentrations of liver enzymes, miR-122, and miR-34a in serum, and preserved liver cells changes induced by I/R injury. CONCLUSION: These findings showed that GA has beneficial effect on liver damage induced by I/R. Therefore, it is suggested that GA can be administered as an anti-miR before elective hepatic surgeries for prevention of this complication.
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Aim: Stimulation of Fas death receptor is introduced as a major cause of non-alcoholic steatohepatitis (NASH) progression through suppression of cell viability. Therefore, the blocking of death pathways is hypothesised to be express new approaches to NASH therapy. For this purpose, current experiment applied synthetic small interference RNA (SiRNA) to trigger Fas death receptor and to show its potential therapeutic role in designed NASH model. Methods: Male mice were placed on a western diet (WD) for 8 weeks and exposed to cigarette smoke during the last 4 weeks of feeding to induce NASH model. In the next step, Fas SiRNA was injected to mice aiming to examine specific Fas gene silencing, after 8 weeks. As a control, mice received scrambled SiRNA. Reversible possibility of disease was examined by 3 weeks of recovery. Results: Analysis of data is accompanied with the significant histopathological changes (steatosis, ballooning and inflammation), increased lipid profile and hepatic enzyme activities (AST, ALT, ALP) plus TBARS as well as decreased antioxidants levels in NASH model. Upon Fas-SiRNA injection, almost all measured parameters of NASH such as overexpression of Fas receptor, caspase3, NF-kB genes and marked increase of hepatic TNF-α were significantly restored and were remained nearly unchanged following recovery liking as scrambled groups. Conclusions: The suppression of Fas receptor signalling subsequent RNAi therapy may represent an applicable strategy to decline hepatocyte damages and so NASH progression in mice.