Melatonin and metformin co-loaded nanoliposomes efficiently attenuate liver damage induced by bile duct ligation in rats.

In the current study, the therapeutic effectiveness of the metformin (Met) and melatonin (Mel) co-loaded liposomes was investigated on cholestasis induced by bile duct ligation (BDL) in male rats. Histopathological analysis, biochemical analysis, and oxidative stress markers were assayed to determine the therapeutic effect of Met and Mel co-loaded liposomes on cholestasis. Histopathological analysis revealed that the simultaneous administration of Met and Mel, whether in the free (C-Mel-Met) or liposomal (C-Lipo-Mel-Met) forms, reduced inflammation as well as proliferation of bile ducts; however, results were more prominent in the liposomal form of Mel and Met. Additionaly, serum levels of aspartate aminotransferase (AST) were significantly (p < 0.001) higher in (C-Mel-Met) treated rats compared with (BDL) rats; however, (C-Lipo-Mel-Met) treated rats exhibited significant (p < 0.05) lower AST rates in comparison to (BDL) rats. Moreover, a significant (p < 0.0001) drop in bilirubin levels was detected in (C-Lipo-Mel-Met) treated rats in comparison to (BDL) rats; it is noteworthy mentioning that bilirubin levels in (C-Lipo-Mel-Met) treated rats were insignificant in comparison to sham-control (SC) rats. Furthermore, rats concomitantly administered Met and Mel, exhibited significant downregulation in the expression levels of inflammatory cytokine genes such as TNF-α and IL-1 gene expression, where the downregulation was more prominent in the liposomal from. Our findings demonestrate that the concomitant administration of metformin and melatonin in the liposomal form had more therapeutic effect on liver injury than their free forms through improving histological changes, reducing biochemical markers and favoring oxidant- antioxidant balance.

Melatonin-Attenuated Oxidative Stress in High-Risk Pregnant Women Receiving Enoxaparin and Aspirin.

Objective: In pregnancy, reducing inflammation and oxidative stress is important. Administration of melatonin during pregnancy can improve reproductive performance by improving the placental antioxidant system and inflammatory response. This investigation was carried out to evaluate the beneficial impact of melatonin on the oxidative stress state among high-risk pregnant women receiving enoxaparin and aspirin. Methods: In this double-blind, placebo-controlled trial, 40 pregnant women, aged 15-45 years at 6 weeks of pregnancy, were randomly selected and divided into intervention and control groups. The control group received prophylaxis enoxaparin and aspirin once daily between 6 and 16 weeks of pregnancy. The intervention group was taken enoxaparin and aspirin for 9 weeks and melatonin once daily from the sixth week of pregnancy to delivery time. Blood samples were taken to measure some oxidative stress biomarkers including total antioxidant capacity (TAC), malondialdehyde (MDA), total thiol (T-SH), protein carbonyl (PCO), and nitric oxide (NO). The level of high-sensitivity C-reactive protein (hs-CRP) was also determined. Results: TAC and T-SH levels increased significantly in the intervention group in comparison with the control group. Melatonin administration compared to the control group led to a significantly decreased level of NO and an insignificant hs-CRP level. Conclusion: Melatonin supplementation in high-risk pregnancy had favorable effects on TAC, T-SH, NO, and hs-CRP levels, improved antioxidant activity, and reduced inflammation. More studies are needed in different pregnancy conditions along with the measurement of different biomarkers.

Evaluation of the Antioxidant and Anticancer Activities of Hydroalcoholic Extracts of Thymus daenensis Celak and Stachys pilifera Benth.

Herein, the effects of hydroalcoholic extracts of Thymus daenensis Celak (TDC) and Stachys pilifera Benth (SPB) plants on HepG2 cell line were investigated by using different analyses. Cytotoxicity and apoptosis of extracts were investigated by MTT method, AnnV/PI apoptosis assay, and their antioxidant capacity was evaluated by total thiol and glutathione peroxidase (GPX) assay. The results revealed that the SBP extract was more cytotoxic compared with the TDC extract and increased over time (128.49 µg/mL vs 107.11 µg/mL IC50 values for 24 and 72 h, respectively). Although, AnnV/PI apoptosis assay showed apoptosis induction for both extracts, but the caspase-3 activity assay revealed that TDC extract significantly increased caspase-3 activity compared with the control and SPB extract. Increasing the activity of GPX by SPB extract revealed that it has high antioxidant capacity. In conclusion, the TDC and SPB with high antioxidant capacity have high cytotoxicity against HepG2 cancer cells and have high capability as a medicinal plant.

Fluvoxamine ameliorates oxidative stress and inflammation induced by bile-duct ligation in male rats.

Introduction: Cholestasis is a disorder that the bile ducts were narrowed and bile acids are not released simply. Bile acids-induced liver damage is exacerbated by inflammation and oxidative stress. The goal of the current study was to investigate the protective impacts of fluvoxamine (Flu) on oxidant-antioxidant balance and inflammatory cytokines in the bile duct ligated (BDL) rats. Methods: Thirty-two male rats were arbitrarily allocated in 4 groups; sham-control (SC), SC+ 150 mg/kg Flu (SCF), bile duct ligation (BDL), and BDL+ 150 mg/kg Flu (BDLF). The rats received distilled water and Flu orally for one week. Biochemical analysis, hematoxylin and eosin staining, as well as oxidant/antioxidant status were evaluated. Also, the mRNA expression of TGF-ß1, IL-1, TNF-α, and α-SMA were determined. Results: The findings indicated serum values of ALT, total bilirubin, and ALP slightly declined in the BDL + Flu group in contrast to BDL rats. The plasma protein carbonyl and inflammatory markers were markedly increased in the BDL group in contrast with SC group (P ≤ 0.05). Treatment with Flu in BDL rats markedly reduced the values of hepatic nitric oxide metabolite and malondialdehyde, plasma protein carbonyl, as well as TNF-α mRNA level (P ≤ 0.05). Histological parameters were improved in the BDL + Flu group in comparison to BDL merely rats. Conclusion: It seems that Flu declined oxidative stress probably by inhibiting lipid peroxidation, protein oxidation, and nitric oxide formation. Also, it reduced inflammation by decreasing TNF-α mRNA expression.

Liposome Extract of Stachys pilifera Benth Effectively Improved Liver Damage due to Bile Duct Ligation Rats.

Herbal medicines harbor essential therapeutic agents for the treatment of cholestasis. In this study, we have assessed the anticholestatic potential of Stachys pilifera Benth's (SPB's) hydroalcoholic extract encapsulated into liposomes using bile duct ligation- (BDL-) induced hepatic cholestasis in rats. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), malondialdehyde (MDA), total thiol (T-SH) content, protein carbonyl (PCO), total bilirubin (TBIL), albumin (ALB), and nitric oxide (NO) metabolite levels were measured in either liver tissue or plasma to assess liver damage. Moreover, expression of proinflammatory cytokines (IL-1ß and TNF-α) and liver fibrosis markers (TGF-ß and SM-α) which are driving forces of many liver disorders was also determined. The activity of AST, ALT, and ALP was significantly enhanced in the BDL group in comparison to the control group; however, treatment with liposomal (SPB) hydroalcoholic extract significantly reduced AST and ALT's activity. Increases in MDA, TBIL, and NO levels and T-SH content due to BDL were restored to control levels by liposomal (SPB) hydroalcoholic extract treatment. Similarly, hepatic and plasma oxidative marker MDA levels, significantly enhanced by BDL, were significantly decreased by liposomal (SPB) hydroalcoholic extract treatment. Moreover, histopathological findings further demonstrated a significant decrease in hepatic damage in the liposomal (SPB) hydroalcoholic extract-treated BDL group. In addition, liposomal (SPB) hydroalcoholic extract treatment decreased the liver expression of inflammatory cytokines (IL-1ß, TNF-α) and liver fibrosis markers (TGF-ß and SM-α). Since liposomal (SPB) hydroalcoholic extract treatment alleviated the BDL-induced injury of the liver and improved the hepatic structure and function more efficiently in comparison to free SPB hydroalcoholic extract, probable liposomal (SPB) hydroalcoholic extract exhibits required potential therapeutic value in protecting the liver against BDL-caused oxidative injury.

Portulaca oleracea methanolic extract attenuate bile duct ligation-induced acute liver injury through hepatoprotective and anti-inflammatory effects.

INTRODUCTION: Cholestasis is a liver disease caused by a malfunction of the hepato-biliary system. Oxidative stress as a systemic complication is the main characteristic of cholestasis. The aim of this study was to evaluate the anti-inflammatory and hepatoprotective effects of Portulaca oleracea (PO) methanolic extract on liver dysfunction and tissue damage induced by bile duct ligation (BDL) in rats. MATERIALS AND METHODS: Twenty-eight male Wistar rats were randomly divided into four groups: sham control (SC), BDL alone, SC plus 500 mg/kg methanolic extract of PO orally for 1 week, and BDL plus 500 mg/kg methanolic extract of PO orally for 1 week. After 1 week, the animals were anesthetized, and the liver and blood samples were taken from each animal. Biochemical parameters, oxidative stress biomarkers, histopathological changes, as well as the gene expression of IL-1, TNF-α, TGF-ß, and α-SMA have been evaluated. RESULTS: The methanolic extract of PO at a dose of 500 mg/kg significantly decreased the plasma levels of aminotransferases, alkaline phosphatase as compared to BDL group (P < 0.05), while it had no significant effect on the levels of oxidative stress markers in the hepatic tissue. The plasma level of malondialdehyde and ferric-reducing antioxidant power were markedly elevated in the BDL group in comparison to SC group (P < 0.05), while treatment with PO significantly reduced these markers (P < 0.05). The administration of PO attenuated hydroxyproline content, bile duct proliferation, and inflammation score in the cholestatic liver in contrast to non-treated BDL rats (P < 0.05). Moreover, the methanolic extract of PO markedly declined the expression of TNF-α and TGF-ß pro inflammatory genes in contrast to BDL rats. CONCLUSIONS: Taken together, our findings showed that PO attenuated liver injury by decreasing liver function tests, inflammation, and hydroxyproline content. As a result, it is suggested that PO can be applied in cholestatic liver damage as a therapeutic or adjuvant agent.

Evaluation of the protective potential of hydroalcoholic extract of Thymus daenensis on acetaminophen-induced nephrotoxicity in rats.

BACKGROUND: Acetaminophen (APAP) is an antinociceptive and antipyretic drug that can be useful in therapeutic doses, although it can cause serious damage to the kidney if used overdose. The current study aimed to evaluate the protective effect of Thymus daenensis (TD) extract on APAP-induced kidney damage in rats. METHODS: Thirty female Wistar rats were randomly divided into 5 groups: control, APAP (3 g/kg), TD (500 mg/kg), APAP + TD (500 mg/kg), and APAP + N- acetylcysteine (140 mg/kg). The APAP groups received APAP on the 6th day and the rats were sacrificed on the 7th day. Plasma levels of creatinine (Cr) and urea were measured. Ferric reducing antioxidant power (FRAP), nitric oxide (NO) metabolite, total thiol (T-SH), tumor necrosis factor-α (TNF-α) and antioxidant enzymes activity of superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) were measured in kidney tissue. The gene expression of TNF-α was also measured by real-time PCR. The histological examination of kidney tissue was also performed. RESULTS: Results showed that urea, Cr and FRAP markers markedly elevated in the APAP rats compared with the control group. There was a significant decrease in T-SH levels in the APAP animals in comparison with the control group. CAT activity also augmented in the APAP group compared to the control group. Urea and Cr levels were significantly decreased in the APAP + TD group in comparison with the APAP group. The administration of TD extract significantly increased the SOD enzyme activity. Histological findings were improved in the group treated with TD extract. CONCLUSION: In general, the results indicate that TD extract can protect against APAP-induced nephrotoxicity by improving biochemical, histological and antioxidant effects. However, more studies are required to determine the mechanism of this extract.

Hepatoprotective and antioxidant activity of watercress extract on acetaminophen-induced hepatotoxicity in rats.

INTRODUCTION: Acetaminophen (APAP) as an analgesic and antipyretic drug can result to liver damages while using more than 4 g/day. Therefore, APAP toxicity causes the liver to dysfunction. This study aims to investigate the hepatoprotective and antioxidant activity of hydroalcoholic extract of watercress (WC) in APAP-induced hepatotoxicity in rats. MATERIALS AND METHODS: Randomly, twenty-four Wistar rats were divided into four groups of six each. Groups named as control, APAP, APAP + WC and APAP + S for group 1, 2, 3, and 4, respectively. Group 1 received distilled water 1 ml/kg for 7 days. In group 2, 3, and 4, rats pretreated by receiving distilled water (1 ml/kg), WC extract (500 mg/kg), silymarin extract (mg/kg) for 7 days, respectively. Of note, to induce acute hepatotoxicity in groups 2, 3, and 4, rats posttreated by orally intoxicated with single dose of APAP (2 g/kg) on the sixth day. The animals were sacrificed on the seventh day. Alanine amino transferase (ALT), aspartate amino transferase (AST), ferric reducing ability of plasma (FRAP), protein carbonyl (PCO), total thiol (T-SH), glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT) activities were measured in plasma. It should be noted that the chemical composition of WC extract was identified by GC-MS analysis. RESULTS: The results have shown that there was a significant increase in AST, ALT, FRAP and PCO content in APAP group in comparison to control. Also, there was a significant reduction in T-SH levels and GPx activity in APAP group compared to control. However, administration of WC extract and silymarin not only causes a significant decrease in AST activity, but they markedly increased T-SH content and GPx activity compared to APAP group. GC-MS analysis showed the major compositions were found to be benzenepropanenitrile (48.30 %), Phytol (10.10 %), α-cadinene (9.50%) and linolenic acid (8.0). CONCLUSIONS: It is concluded that the WC extract reduces APAP-induced toxicity through its hepatoprotective and antioxidant activity in rats.