Blackberry-Loaded AgNPs Attenuate Hepatic Ischemia/Reperfusion Injury via PI3K/Akt/mTOR Pathway.

Liver ischemia-reperfusion injury (IRI) is a pathophysiological insult that often occurs during liver surgery. Blackberry leaves are known for their anti-inflammatory and antioxidant activities. AIMS: To achieve site-specific delivery of blackberry leaves extract (BBE) loaded AgNPs to the hepatocyte in IRI and to verify possible molecular mechanisms. METHODS: IRI was induced in male Wister rats. Liver injury, hepatic histology, oxidative stress markers, hepatic expression of apoptosis-related proteins were evaluated. Non-targeted metabolomics for chemical characterization of blackberry leaves extract was performed. KEY FINDINGS: Pre-treatment with BBE protected against the deterioration caused by I/R, depicted by a significant improvement of liver functions and structure, as well as reduction of oxidative stress with a concomitant increase in antioxidants. Additionally, BBE promoted phosphorylation of antiapoptotic proteins; PI3K, Akt and mTOR, while apoptotic proteins; Bax, Casp-9 and cleaved Casp-3 expressions were decreased. LC-HRMS-based metabolomics identified a range of metabolites, mainly flavonoids and anthocyanins. Upon comprehensive virtual screening and molecular dynamics simulation, the major annotated anthocyanins, cyanidin and pelargonidin glucosides, were suggested to act as PLA2 inhibitors. SIGNIFICANCE: BBE can ameliorate hepatic IRI augmented by BBE-AgNPs nano-formulation via suppressing, oxidative stress and apoptosis as well as stimulation of PI3K/Akt/mTOR signaling pathway.

C-peptide corrects hepatocellular dysfunction in a rat model of type 1 diabetes.

C-peptide is gaining much interest recently due to its well-documented beneficial effects on multiple organ dysfunction induced by diabetes. Our study was designed to investigate the effect of C-peptide on hepatocellular dysfunction in diabetic rats. Wistar male rats were separated into four groups: control, diabetic, diabetic + insulin, and diabetic + C-peptide. Serum levels of glucose, insulin, and liver biomarkers were assessed. Liver sections were collected for histopathological examination and immuno-histochemical assessment of tumor necrosis factor alpha (TNF-α). Oxidative stress markers and gene expression of inducible nitric oxide synthase (iNOS), transforming growth factor beta 1 (TGF-ß1), and glucose-6-phosphatase (G6Pase) were also measured in liver tissues. C-peptide administration prevented hepatic dysfunction induced by diabetes to a similar extent as that of insulin which was confirmed microscopically. We concluded that C-peptide could be used as an alternative therapy to insulin to correct hepatocellular dysfunction associated with type 1 diabetes mellitus (T1DM).

Correction to: Caveolin-1 Expression Together with VEGF can be a Predictor for Lung Metastasis and Poor Prognosis in Osteosarcoma.

The original version of this article unfortunately contained an error. The Tables 1 and 2 were missing in the published paper.

Caveolin-1 Expression Together with VEGF can be a Predictor for Lung Metastasis and Poor Prognosis in Osteosarcoma.

Caveolin-1, the major protein component of caveolae, plays vital functions in tumorigenesis and metastasis. Previous evidence demonstrated the positive role of Caveolin-1 in the regulation of endothelial cell differentiation and the involvement of Caveolin-1 in vascular endothelial growth factor (VEGF) mediated angiogenesis. The correlation of Caveolin-1 expression and angiogenesis is not yet elucidated in osteosarcoma. This study aimed to investigate the expression levels of Caveolin-1 and VEGF in osteosarcoma and their associations with clinicopathological data. This study included 66 formalin-fixed and paraffin embedded osteosarcoma tissue samples. The expression levels of Caveolin-1 and VEGF were assessed by immunohistochemistry. Then associations with clinicopathological variables and the correlation between both markers were evaluated statistically. We also investigated the expression of Caveolin-1 and VEGF values in gene microarrays of osteosarcoma patients and cell lines by using GEO data sets on https://www.ncbi.nlm.nih.gov. Caveolin-1 and VEGF were expressed in 19.6% and 77.3%, respectively. Caveolin-1 expression was associated positively with osteoblastic histological subtype (P < 0.0001). VEGF expression showed positive association with patient age, histological grade and clinical stage (P = 0.031, P = 0.024 and P < 0.001; respectively). An inverse correlation between Caveolin-1 and VEGF expressions in osteosarcoma was found (r = 0.2 P = 0.04). In silico analysis of Caveolin-1 and VEGF expression supported our results. Our results suggest that Caveolin-1 may act as a tumor suppressor in osteosarcoma. Down-regulation of Caveolin-1 can be used as an indicator for poor prognosis in osteosarcoma patients. Meanwhile, overexpression of VEGF is a predictor of pulmonary metastasis and poor prognosis.

Comparing the preventive effect of sodium hydrosulfide, leptin, and curcumin against L-arginine induced acute pancreatitis in rats: role of corticosterone and inducible nitric oxide synthase.

OBJECTIVES: Acute pancreatitis (AP) is a life-threatening condition. Using antioxidants in AP is insufficient and conflicting. Therefore, this study compared the effect of hydrogen sulfide (H2S) donor, sodium hydrosulfide (NaHS), leptin or curcumin pretreatment on AP induced by L-arginine. METHODS: Forty adult male rats were used and classified into: 1) control; 2) AP group [each rat was intraperitoneally (i.p.) injected with 2 doses of L-arginine of 250 mg/100 g body weight (b.w.) with an interval of 1 h]; 3) NaHS+AP group (each rat was i.p. injected with 10 mg/kg b.w. of NaHS 1 h before induction of AP); 4) leptin+AP group (each rat was pretreated with 10 µg/kg b.w. of leptin 30 min before induction of AP; and 5) curcumin+AP group (in which rats were i.p. injected with 150 mg/kg b.w. of curcumin 30 min before induction of AP). Serum amylase, lipase, nitric oxide (NO), tumor necrosis factor alpha (TNF-α), and corticosterone (CORT) levels were assayed. In addition, pancreatic tissues were obtained for histopathological examination and malondialde-hyde (MDA), total antioxidant capacity (TAC), and inducible nitric oxide synthase (iNOS) levels were measured. RESULTS: All AP treated groups showed significant decrease in serum levels of pancreatic enzymes, NO, and TNF-α, and pancreatic MDA and iNOS levels, while TAC levels were significantly increased. NaHS caused more limitation of inflammation than leptin and curcumin by affecting iNOS. Leptin was more potent than curcumin due to the stimulatory effect of leptin on glucocorticoid release to counteract inflammation. CONCLUSIONS: NaHS was more effective in AP amelioration than the leptin and curcumin.

Pathophysiological changes in experimental polycystic ovary syndrome in female albino rats: Using either hemin or L-arginine.

Polycystic ovary syndrome (PCOS), one of the important endocrine disorders affecting females in the reproductive age, is caused mainly by an abnormal oxidation status that subsequently causes inflammatory conditions. Thus, this study aims to examine the possible individual prophylactic effects of gasotransmitters, hemin, or L-arginine in letrozole-induced PCOS. Fifty adult female albino rats were used and separated into a control group, which received the vehicle; a letrozole-induced PCOS group (L), which received letrozole orally at a dose level of 1 mg/kg for 21 days; a letrozole+hemin (L+H) group, which received letrozole plus hemin at a dose level of 25 mg/kg injected IP twice per week for 21 days; and a letrozole+L-arginine (L+A) group, which received letrozole plus L-arginine at a dose level of 200 mg/kg orally for 21 days. During PCO induction, the body weight and Lee index were measured. Serum glucose, insulin, lipid profile, gonadotrophic hormones, testosterone, estrogen, and tumor necrosis factor alpha were assayed, while ovarian tissues were analyzed to measure the oxidative state and histopathological changes. Our results proved that either hemin or L-arginine administration could improve the oxidative state, the inflammatory reaction, the hormonal imbalance, and the metabolic disturbances in PCO rats, which was confirmed by a histopathological examination of the rats' ovaries. In conclusion, either hemin or L-arginine had protective effects against PCOS with better pathophysiological changes with hemin.

Mechanisms underlying the protective effect of montelukast in prevention of endometrial hyperplasia in female rats.

OBJECTIVE: To study the possible protective role of montelukast in endometrial hyperplesia (EH) rat model, induced by estradiol valerate (EV). METHODS/MATERIALS: Thirty six female albino Wistar rats were classified into 7 groups: normal control, EV (2 mg/kg/day, p.o.), montelukast (10 mg/kg/day, p.o.), montelukast (1 mg/kg/day, p.o.) + EV (2 mg/kg/day, p.o.), montelukast (10 mg/kg/day, p.o.) + EV (2 mg/kg/day, p.o.), montelukast (20 mg/kg/day, p.o.) + EV (2 mg/kg/day, p.o.) groups. Uterine malondialdehyde (MDA), superoxide dismutase (SOD), total nitrites (NO) and serum total antioxidant capacity (TAC) were determined. Uterine, serum total cholesterol, high density lipoprotein (HDL) and tumor necrosis factor (TNF)-α were measured. Histopathological examination of the uterine tissue was also done. In addition, immunohistochemistry was done using Phosphatase and tensin homolog (PTEN) and inducible nitric oxide synthase (iNOS) antibodies. RESULTS: Our results showed that montelukast in dose dependant manner improves oxidative stress, lipids profile and TNF α which were affected by EV. Moreover, immunohistochemical examination revealed that montelukast markedly reduced iNOS expression, while expression of PTEN was markedly enhanced, as compared to EV group. The protective effects of montelukast were also verified histopathologically. CONCLUSIONS: Montelukast in dose dependant manner provided biochemical and histo-pathological improvement in EV induced EH, through its anti-inflammatory, antioxidant activity and inhibition of iNOS expression with induction of PTEN expression.