Despite the extraordinary use of silver nanoparticles (AgNPs) in medicinal purposes and the food industry, there is rising worry about potential hazards to human health and the environment. The existing study aims to assess the hepatotoxic effects of different dosages of AgNPs by evaluating hematobiochemical parameters, oxidative stress, liver morphological alterations, immunohistochemical staining, and gene expression to clarify the mechanism of AgNPs’ hepatic toxic potential. Forty male Sprague Dawley rats were randomly assigned into control and three AgNPs intraperitoneally treated groups 0.25, 0.5, and 1 mg/kg b.w. daily for 15 and 30 days. AgNP exposure reduced body weight, caused haematological abnormalities, and enhanced hepatic oxidative and nitrosative stress with depletion of the hepatic GSH level. Serum hepatic injury biomarkers with pathological hepatic lesions where cholangiopathy emerges as the main hepatic alteration in a dosage- and duration-dependent manner were also elevated. Furthermore, immunohistochemical labelling of apoptotic markers demonstrated that Bcl-2 was significantly downregulated while caspase-3 was significantly upregulated. In conclusion, the hepatotoxic impact of AgNPs may be regulated by two mechanisms, implying the apoptotic/antiapoptotic pathway via raising BAX and inhibiting Bcl-2 expression levels in a dose-dependent manner. The TGF-β1 and α-SMA pathway which triggered fibrosis with incorporation of iNOS which consequently activates the inflammatory process were also elevated. To our knowledge, there has been no prior report on the experimental administration of AgNPs in three different dosages for short and long durations in rats with the assessment of Bcl-2, BAX, iNOS, TGF-β1, and α-SMA gene expressions. Graphical abstract

Hepatocellular carcinoma (HCC) is the most common cancer in humans. Despite advances in its treatment, liver cancer remains one of the most difficult cancers to treat. This study aimed to investigate the ameliorative action and potential mechanism of Aspergillus awamori (ASP) administration against the initiation process of liver carcinogenesis induced by diethylnitrosamine (DEN) in male Wistar rats. Seventy-two male rats were divided equally into eight groups as follows, Group 1: untreated control; Group 2: DEN (200 mg/kg bw) intra-peritoneally for the initiation of HCC; Groups 3–5: DEN + ASP at a dose of 1, 0.5, and 0.25 mg/kg bw and groups 6–8: ASP at a dose of 1, 0.5, and 0.25 mg/kg bw. Supplementation of A. awamori significantly lightened the adverse impacts induced by DEN via restoring the leukogram to normal, lowering the elevated serum aspartate aminotransferase (AST), alanine transaminase (ALT), and γ-glutamyl transferase (GGT), and alkaline phosphatase (ALP). Furthermore, it enhanced the hepatic antioxidant capacity through increasing the reduced glutathione (GSH) level and catalase (CAT) activity with a marked reduction in malondialdehyde (MDA) level. In addition, it decreased the positive GST-P foci. Likewise, a significant alteration of DEN-associated hepatocarcinogenesis occurred through inhibiting cytochrome P450 (Cyp19) and activating p53 gene expression. In conclusion, supplementation of A. awamori counteracts the negative effects of DEN, inhibits the early development of GST-P-positive foci and could be used as a new alternative strategy for its chemo-preventive effect in liver cancer. To the best of our knowledge, the present study is the first to report the hepato-protective effect of A. awamori in induced hepatocarcinogenesis.

In medicine, silver nanoparticles (AgNPs) are employed often. They do, however, have negative impacts, particularly on the reproductive organs. This research aimed to assess AgNP impact on the testis and the possible intracellular mechanisms to induce testicular deteriorations in rats at various concentrations and different time intervals. Sprague Dawley rats (n = 40) were allocated into four equal groups: the control one, and three other groups injected intra-peritoneally with AgNP solution 0.25, 0.5, and 1 mg/kg b.w. respectively for 15 and 30 days. Our findings revealed that AgNPs reduced body and testicular weights, estradiol (E2) and testosterone (T) hormone levels, and sperm parameters while elevating the nitric oxide and malondialdehyde levels with inhibition of reduced glutathione contents in testicular tissue. Interestingly, AgNPs significantly upregulated the testicular inducible nitric oxide synthase, B cell lymphoma 2 (Bcl-2)-associated X, transforming growth factor, and alpha-smooth muscle actin (α-SMA) expression levels. However, apurinic/apyrimidinic endo deoxyribonuclease 1 (APE1), NAD (P) H quinone dehydrogenase 1 (NQO1), and Bcl-2 expression levels were all downregulated indicating exhaustion of body antioxidant and repairing defense mechanisms in testicles in comparison with the control rats. Various histological alterations were also detected which dramatically increased in rats sacrificed after 30 days such as loss of the lining cells of seminiferous tubules with no spermatozoa and tubular irregularities associated with thickening of their basement membranes. Immunolabeling implicated in the apoptotic pathway revealed a negative expression of Bcl-2 and marked immunoreactivity for caspase-3 after 30 days of AgNP treatment in comparison to the control rats. To our knowledge, there have been no previous publications on the role of the α-SMA, APE1, and NQO1 genes in the molecular pathogenesis of AgNP testicular cytotoxicity following AgNP acute and chronic exposure. Graphical Abstract

Ochratoxin A (OTA) is one of the most dangerous and that pollute agricultural products, inducing a variety of toxic effects in humans and animals. The current study explored the protective effect of different concentrations ofAspergillus awamori(A.awamori) against OTA (0.3 mg/kg diet) induced renal and cardiac damage by exploring its mechanism of action in 60 New Zealand white male rabbits. Dietary supplementation ofA.awamoriat the selected doses of 50, 100, and 150 mg/kg diet, respectively, for 2 months significantly improved the rabbit’s growth performance; modulated the suppressed immune response and restored the altered hematological parameters; reduced the elevated levels of renal injury biomarkers such as urea, creatinine, and alkaline phosphatase; and increased serum total proteins concentrations. Moreover, it also declined enzymatic activities of cardiac injury biomarkers, including AST, LDH, and CK-MB.A.awamorialleviated OTA-induced degenerative and necrotic changes in the kidney and heart of rabbits. Interestingly,A.awamoriupregulated Nrf2/OH-1 signaling pathway. Therefore enhanced TAC, CAT, and SOD enzyme activities and reduced OTA-induced oxidative and nitrosative stress by declining iNOS gene expression and consequently lowered MDA and NO levels. In addition to attenuating renal and cardiac inflammation via reducing IL-1β, TNF-α gene expressions in a dose-dependent response. In conclusion,this is the first report to pinpoint that dietary incorporation ofA.awamoricounteracted OTA-induced renal and cardiac damage by potentiating the rabbit’s antioxidant defense system through its potent antioxidant, free radical scavenging, and anti-inflammatory properties in a dose-dependent response. Based on our observations,A.awamoricould be utilized as a natural protective agent against ochratoxicosis in rabbits.Graphical abstract