Renoprotective effects of zinc sulfate against transient liver ischemia/reperfusion injury in rats.

Objectives: Liver ischemia/reperfusion damage frequently occurs in setting of hepatic resection and liver transplantation. It leads to disturbance in remote organs such as heart, lung and kidneys. This study explored the consequences of hepatic ischemia/reperfusion on the oxidative stress parameters, biochemical factors, and histopathological alterations in the kidney's rats, as well as evaluated the role of zinc sulfate on above-mentioned parameters. Materials and methods: Twenty-eight male Wistar rats were accidently assigned into four groups (n = 7). They were Sham, ischemia/reperfusion, zinc sulfate pretreatment, and zinc sulfate pretreatment + ischemia/reperfusion groups. Sham group: obtained normal saline (2 ml/day, seven consecutive days), intraperitoneally, zinc sulfate pretreatment group: obtained zinc sulfate (5 mg/kg, seven consecutive days, intraperitoneally). Ischemia/reperfusion group: obtained normal saline as mentioned previous, then rats experienced the partial ischemia (%70) for 45 min followed by 60 min reperfusion. Zinc sulfate pretreatment group: obtained zinc sulfate as mentioned previous, then rats experience the partial ischemia/reperfusion as presented earlier. At the end of investigation, blood was withdrawn, liver and renal tissues were removed. Then, biochemical and oxidative stress parameters, and histological changes were evaluated in the mentioned tissues. Results: The findings of this experiment indicated that zinc sulfate markedly reduced the serum levels of liver and kidney function tests in relative to ischemia/reperfusion group. Also, antioxidant enzymes activity, ferric reducing antioxidant power, and nitric oxide significantly increased, while malondialdehyde level declined in the renal tissue of zinc sulfate + ischemia/reperfusion group compared to ischemia/reperfusion rats. Furthermore, zinc sulfate alleviated the liver and kidneys histopathological alterations following ischemia/reperfusion. Conclusion: Zinc sulfate ameliorated liver and kidney function, and improved oxidant-antioxidant balance in favor of antioxidants. It is suggested that zinc sulfate may be beneficial effects on hepato-renal injury after ischemia/reperfusion.

Molecular Mechanisms of Hawthorn Extracts in Multiple Organs Disorders in Underlying of Diabetes: A Review.

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.

Characterization of diet based nonalcoholic fatty liver disease/nonalcoholic steatohepatitis in rodent models: Histological and biochemical outcomes.

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.

Emerging roles of microRNAs in intestinal ischemia/reperfusion-induced injury: a review.

Intestinal ischemia/reperfusion (II/R) injury is a serious pathological phenomenon in underlying hemorrhagic shock, trauma, strangulated intestinal obstruction, and acute mesenteric ischemia which associated with high morbidity and mortality. MicroRNAs (miRNAs, miRs) are endogenous non-coding RNAs that regulate post-transcriptionally target mRNA translation via degrading it and/or suppressing protein synthesis. This review discusses on the role of some miRNAs in underlying II/R injury. Some of these miRNAs can have protective action through agomiR or specific antagomiR, and others can have destructive effects in the basal level of II/R insult. Based on these literature reviews, II/R injury affects several miRNAs and their specific target genes. Some miRNAs upregulate under condition of II/R injury, and multiple miRNAs downregulate following II/R damage. 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 2020. It is shown a correlation between changes in the expression of miRNAs and autophagy, inflammation, oxidative stress, apoptosis, and epithelial barrier function. Taken together, agomiR or antagomiR of some miRNAs can be considered as one new target for the research and development of innovative drugs to the prevention or treatment of II/R damage.

Role of crocin in several cancer cell lines: An updated review.

Cancer is a major public health problem worldwide. The most important considerable features of cancer cells are uncontrolled proliferation, up-regulated differentiation, and immortality. Crocin, as a bioactive compound of saffron and as a water-soluble carotenoid has radical scavenging, anti-hyperlipidemia, memory improving, and inhibition of tumor growth effects. The present review was designed to evaluate molecular mechanisms underlying crocin effects against cancer cell lines. Data of this review have been collected from the scientific articles published in databases such as Science Direct, Scopus, PubMed, and Scientific Information Database from 1982 to 2019. According to various literature, crocin inhibits tumor growth, and its spread in several types of cancer including colorectal, pancreatic, breast, and prostate, as well as chronic myelogenous and leukemia. It inhibits telomerase activity, microtubule polymerization, cyclin D1, nuclear factor kappa B (NF-kB), multidrug resistance-associated protein (MRP1), and MRP2 overexpression. Crocin can induce apoptosis through activation of caspase 8, up-regulation of p53 expression, Bax/Bcl-2 ratio, and down-regulation expression of Bcl-2, survivin, and cyclin D1. It also down-regulates matrix metalloproteinase 2 and 9 (MMP2 and MMP9), N-cadherin, and beta-catenin expression, which are involved in tumor invasion and metastasis. Tumor invasion was also inhibited by crocin through increasing E-cadherin expression, cell cycle suppression at G1, G0/G1, S, and G2/M phases. Crocin has therapeutic and preventive effects on cancer cells line. Therefore, it has been suggested that this agent can be administered in patients that suffer from this problem.

Effect of gallic acid on electrophysiological properties and ventricular arrhythmia following chemical-induced arrhythmia in rat.

OBJECTIVES: Ventricular arrhythmias including ventricular tachycardia (VT) and ventricular fibrillation (VF) are the most important causes of mortality rate. Gallic acid (GA) has beneficial effects on cardiovascular diseases. The aim of this study was to evaluate the effects of GA on electrophysiological parameters such as QRS complex, heart rate (HR), PR interval parameters, and ventricular arrhythmia following chemical induction in rat. MATERIALS AND METHODS: Seventy-two male rats were divided into 9 groups (n=8). Chronic groups pretreated by GA (10, 30, and 50 mg/kg, orally) and normal saline (N/S, 1 ml/kg, orally) for 10 days. At the start of the experiments (the first day) and on the final day of the experiments (tenth day), the electrocardiogram (lead II) was recorded. At acute group, GA (50 mg/kg), and anti-arrhythmic drugs such as propranolol, amiodarone, and verapamil injected via intravenous (IV). Then, arrhythmia induced by a CaCl2 2.5% solution (140 mg/kg, IV). Afterward, percentage of premature ventricular beats (PVB), VF, and VT were recorded at 1, and 3 min. RESULTS: These findings showed that chronic and acute doses of GA have positive inotropic and anti-dysrhythmic effects by significant reduction of PVB, VT and VF on comparison with the control group. These actions are comparable to anti-arrhythmic drugs such as quinidine, propranolol, amiodarone, and verapamil. GA has not significant effect on chronotropic and dromotropic properties. CONCLUSION: Findings showed that GA has antiarrhythmic, and inotropic characteristics that suggested GA has effective for mild congestive heart failure, and cardiovascular disorders patients which susceptible to incidence of arrhythmias.

Molecular mechanisms underlying gallic acid effects against cardiovascular diseases: An update review.

OBJECTIVE: The prevalence of cardiovascular diseases (CVDs) is growing. CVDs are the major cause of mortality and have become one of the most important health challenges in developing countries. Gallic acid (GA) is a natural phytochemical which has been widely used against multiple conditions. The present review was designed to evaluate molecular mechanisms underlying the protective effects of this agent against CVDs. MATERIALS AND METHODS: Data discussed in this review were collected from the articles published in databases such as Science Direct, Scopus, PubMed, and Scientific Information Database between 1993 and 2018. RESULTS: According to the experimental studies, GA has protective actions against CVDs through increasing antioxidant enzymes capacity, inhibition of lipid peroxidation and decreasing serum levels of cardiac marker enzymes, modulation of hemodynamic parameters, recovery of electrocardiogram aberrations, and preservation of histopathological changes. CONCLUSION: GA has potential cardioprotective action. Therefore, it has been suggested that this agent can be administered in underlying of CVDS.

Role of Zinc Supplementation on Ischemia/Reperfusion Injury in Various Organs.

Ischemia-reperfusion (I/R) injury is a serious condition which is associated with myocardial infarction, stroke, acute kidney injury, trauma, circulatory arrest, sickle cell disease, and sleep apnea and can lead to high morbidity and mortality. Salts of zinc (Zn) are commonly used by humans and have protective effects against gastric, renal, hepatic, muscle, myocardial, or neuronal ischemic injury. The present review evaluates molecular mechanisms underlying the protective effects of Zn supplement against I/R injury. Data of this review have been collected from the scientific articles published in databases such as Science Direct, Scopus, PubMed, and Scientific Information Database from 1991 to 2019. Zn supplementation increased the decreased parameters including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), glutathione (GSH), metallothionein (MT), protein sulfhydryl (P-SH), and nuclear factor-erythroid 2-related factor-2 (Nrf2) expression and decreased the increased elements such as endoplasmic reticulum (ER) stress, mitochondrial permeability transition pore (mPTP) opening, malondialdehyde (MDA), serum level of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and microRNAs-(122 and 34a), apoptotic factors, and histopathological changes. Zn also increases phosphatidylinositol 3-kinase (PI3K)/Akt and glycogen synthase kinase-3ß (GSK-3ß) phosphorylation and preserves protein kinase C isoforms. It is suggested that Zn can be administered before elective surgeries for prevention of side effects of I/R injury.

Gallic acid protects the liver in rats against injuries induced by transient ischemia-reperfusion through regulating microRNAs expressions.

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.

Effect of crocin on cardiac antioxidants, and hemodynamic parameters after injuries induced by hepatic ischemia-reperfusion in rats.

OBJECTIVES: This research aimed to test the impact of liver ischemia/reperfusion (IR) insult on the activity of antioxidant enzymes, functional enzymes, histological, and hemodynamic parameters of heart, as well as protective function of crocin on these variables in rats. MATERIALS AND METHODS: Thirty two rats were randomly assigned into 4 experimental groups (8 rats in each). I: sham-operated, II: IR induction, III: Crocin alone, and IV: Crocin+IR induction. Groups I and III received normal saline at 2 ml per day and crocin at 200 mg per kg on a daily basis for a week via intraperitoneally injection. Afterwards, laparotomy was performed. Groups II and IV was also received normal saline and crocin and then experienced a 45 min ischemia followed by 1 hr reperfusion. Tissue samples of heart and blood were taken to use for further microscopic and laboratories analysis. Hemodynamic parameters were measured by tail cuff method. RESULTS: Findings indicated that crocin dramatically elevated the activity of antioxidant enzymes, and attenuated serum concentrations of hepatic and cardiac enzymes. Crocin also inhibited histopathological disarrangements, and modulated hemodynamic parameters beyond IR-induced hepatic insult. CONCLUSION: Current experiment indicated that crocin has potential cardioprotective action following hepatic I/R-induced damage. Therefore, it can be administered before elective hepatic surgeries.

The Effect of Zinc Sulfate on miR-122, miR-34a, Atioxidants, Biochemical and Histopathological Parameters Following Hepatic Ischemia/Reperfusion Injury in Rats.

Liver ischemia-reperfusion (IR) injury is a situation which occurs in various conditions such as pringle maneuver and liver transplantation. The regulatory effect of zinc sulfate (ZnSO4) is an important trace element on several liver disorders well known, but its effects on microRNAS (miR-122 and miR-34a) have not been evaluated. The goal of this study was to identify the protective effects of ZnSO4 on IR-induced liver injury, in particular, microRNAS in rats. Thirty-two male Wistar rats were randomly assigned into four groups (eight each group): sham, IR, ZnSO4 pretreatment, and ZnSO4 + IR groups. In sham and ZnSO4 pretreatment groups, animals received normal saline (N/S, 2 ml/kg) and ZnSO4 (5 mg/kg) for 7 consecutive days intraperitoneally (ip), then only laparotomy was performed. In IR and ZnSO4 + IR groups, N/S and ZnSO4, respectively, were given with the same dose, time, and route, before induction of ischemia for 45 min followed by reperfusion for 60 min. Blood sample was taken for biochemical and microRNAs analysis. Tissue specimens also were obtained for the measurements of antioxidant activities and histopathological evaluations. Our results showed that ZnSO4 pretreatment ameliorated histopathological changes decreased the increased serum levels of liver enzymes, miR-122 and miR-34a, and enhanced the decreased activity of antioxidant enzymes following hepatic IR injury. The present study indicated that ZnSO4 had potential hepatoprotective action against IR-induced injury. Therefore, it has been suggested that it can be administered as an anti-miR before elective hepatic surgeries for prevention of this complication.

A comprehensive review on regulatory effects of crocin on ischemia/reperfusion injury in multiple organs.

Ischemia-reperfusion (I/R) injury affects o2-dependent organs including liver, kidneys, heart, brain, and intestine. I/R injury is described as the cellular injury in an organ caused by ischemia and then further aggravated during the reperfusion due to intracellular alterations. It is a process that happens in clinical settings such as organ transplantation, reperfusion after thrombolytic therapy, and coronary angioplasty. Crocus sativus L. known as saffron used in folk medicine for its beneficial effects. It contains multiple bioactive compounds including the crocin, crocetin, picrocrocin, and safranal. Crocin, a water-soluble carotenoid has antitumor, radical scavenging, anti hyperlipidemia and memory improving effects. Moreover, crocin has antioxidant, and protective effects on I/R models in rats at various organs such as heart, brain, kidney, stomach, liver, and kidney as described in detail in this review.

Sodium hydrosulfide upregulates mRNA and protein expression of TGF-α in gastric mucosa in experimental model of stimulated gastric acid secretion in rats.

OBJECTIVES: Transforming growth factor alpha (TGF-α) has been shown to modulate the gastric acid secretion. Therefore, the aim of the present study was to investigate the effect of sodium hydrosulfide (NaHS) on TGF-α expression in gastric mucosa in rats. MATERIALS AND METHODS: Eighteen rats were randomly divided into 3 groups (6 per group). To determine the effect of NaHS on gene and protein expression of TGF-α in gastric mucosa in response to gastric acid, the acid output induced by gastric distension. At the end of experiment, rats were euthanized by anesthetics, and gastric effluents, in addition to mucosa were collected to measure the pH of gastric effluents and to quantify protein and gene expression of TGF-α. RESULTS: The stimulated gastric acid upregulated expression levels of TGF-α in gastric mucosa. These levels were higher in animals pretreated with NaHS. CONCLUSION: TGF-α upregulatory effect of sodium hydrosulfate implied that TGF-α is involved in the acid inhibitory effect of NaHS.

Renoprotective effect of crocin following liver ischemia/ reperfusion injury in Wistar rats.

OBJECTIVES: The objectives of the current study were to evaluate the effects of hepatic ischemia/reperfusion (IR) injury on the activity of antioxidant enzymes, biochemical factors, and histopathological changes in rat kidney, and to investigate the effect of crocin on IR-related changes. MATERIALS AND METHODS: Thirty-two male Wistar rats were randomly allocated into four groups (n=8). They were sham-operated, IR, crocin pre-treatment, and crocin pretreatment+IR groups. Sham-operated and Crocin pre-treatment groups received normal saline (N/S, 2 ml/day) and crocin (200 mg/kg) for seven consecutive days intraperitoneally (IP), respectively, then rats underwent laparotomy, only. IR and crocin pretreatment+IR groups received N/S and crocin with the same dose, time, and route, respectively, then rats underwent partial (70%) ischemia for 45 min that was followed by reperfusion for 60 min. At the end of the experiment, kidney specimens were taken for histopathological and antioxidant evaluations and also blood samples were obtained for biochemical analysis. RESULTS: The results of the present study showed that crocin pre-treatment significantly increased the activity of antioxidants, decreased the serum levels of liver enzymes and blood urea nitrogen following IR-induced hepatic injury. Crocin also ameliorated kidney's histopathological disturbance beyond IR-induced hepatic injury. CONCLUSION: Crocin as an antioxidant agent protected renal insult following liver IR injury by increasing the activity of antioxidant enzymes, reducing serum levels of liver enzymes, and improving histopathological changes.

Protective effects of crocin and zinc sulfate on hepatic ischemia-reperfusion injury in rats: a comparative experimental model study.

OBJECTIVES: The aim of this study was to investigate the comparative protective effects of separate and combined pretreatment with Cr and ZnSO4 on serum levels of miR-122, miR-34a, liver function tests, protein expression of Nrf2 and p53, and histopathological changes following IR-induced hepatic injury. MATERIALS AND METHODS: Fifty-six male Wistar rats randomly assigned into seven groups (n=8). Sham (S), IR, crocin pretreatment (Cr), and crocin pretreatment+IR (Cr+IR), ZnSO4 pretreatment (ZnSO4), ZnSO4 pretreatment+IR (ZnSO4+IR) and their combination (Cr+ZnSO4+IR) groups. In sham, ZnSO4 and Cr groups, animals received normal saline (N/S, 2ml/day), Cr (200mg/kg) and ZnSO4 (5mg/kg) for 7 consecutive days (intraperitoneally; i.p), then only laparotomy was performed. In IR, Cr+IR, ZnSO4+IR and Cr+ZnSO4+IR groups, rats received N/S, Cr and ZnSO4 with same dose and time, then underwent a partial (70%) ischemia for 45min that followed by reperfusion for 60min. Blood sample was taken for biochemical and microRNAs assay, tissue specimens were obtained for antioxidants, protein expression, histopathological and immunohistochemical evaluations. RESULTS: The results showed that Cr and ZnSO4 increased antioxidants activity and expression of Nrf2, decreased serum levels of liver enzymes, miR-122, miR-34a, p53 expression and also ameliorated histopathological abnormality. However, their combination caused more improvement on IR-induced liver injury. CONCLUSION: This study demonstrated that Cr, ZnSO4 and their combination through increasing antioxidant activity and Nrf2 expression, decreasing the serum levels of liver enzymes, miR-122, 34a, p53 expression, and amelioration of histopathological changes, protected liver against IR-induced injury.

The Hepatoprotective and MicroRNAs Downregulatory Effects of Crocin Following Hepatic Ischemia-Reperfusion Injury in Rats.

Background. Liver ischemia-reperfusion (IR) injury is one of the chief etiologies of tissue damage during liver transplantation, hypovolemic shock, and so forth. This study aimed to evaluate hepatoprotective effect of crocin on IR injury and on microRNAs (miR-122 and miR-34a) expression. Materials and Methods. 32 rats were randomly divided into four groups: sham, IR, crocin pretreatment (Cr), and crocin pretreatment + IR (Cr + IR) groups. In sham and Cr groups, animals were given normal saline (N/S) and Cr (200 mg/Kg) for 7 consecutive days, respectively, and laparotomy without inducing IR was done. In IR and Cr + IR groups, N/S and Cr were given for 7 consecutive days and rats underwent a partial (70%) ischemia for 45 min/reperfusion for 60 min. Blood and tissue samples were taken for biochemical, molecular, and histopathological examinations. Results. The results showed decreased levels of antioxidants activity and increased levels of liver enzymes improved by crocin. The expression of miR-122, miR-34a, and p53 decreased, while Nrf2 increased by crocin. Crocin ameliorated histopathological changes. Conclusion. The results demonstrated that crocin protected the liver against IR injury through increasing the activity of antioxidant enzymes, improving serum levels of liver enzymes, downregulating miR-122, miR-34a, and p53, and upregulating Nrf2 expression.