Musa sp. Leaves Extract Ameliorates the Hepato-Renal Toxicities Induced by Cadmium in Mice.

Heavy metals intoxication causes several health problems that necessitate finding new protective and therapeutic approaches. This study aimed to evaluate the impact of Musa sp. leaves extract (MLE) on hepato-renal toxicities induced by cadmium (Cd) in male mice. The phytochemical screening, metal chelating activity (MCA), and the median lethal dose (LD50) of MLE were determined. Fifty CD-1 male mice were used and intraperitoneally (i.p.) injected with MLE (1000 to 5000 mg/kg b.wt) for MLE LD50 determination. Another 50 mice were used for evaluating the effect of MLE on Cd toxicity. Blood samples were collected for hematological, liver, and kidney functions assessments. Liver tissue homogenates were used for determination of oxidant/antioxidant parameters. Liver and kidney tissues were harvested for histopathological and molecular investigations. MLE showed potent in vitro antioxidant activities. The MCA and LD50 of the MLE were 75 µg/mL and 3000 mg/kg b.wt, respectively. MLE showed beneficial therapeutic activity against hepato-renal toxicities in Cd-intoxicated mice, evidenced by improving the hematological, biochemical, histopathological, and molecular alterations.

Evaluation of the Expression EGFR, HER2/NEU and the End Effector ERK of the RAS/RAF/MAP Kinase Pathway in Prostatic Adenocarcinoma for a Possible Role as New Target Therapy.

The alterations of EGFR and HER2/neu as growth factor receptors and the cytoplasmic signal transduction proteins of RAS/RAF/MAP kinases including its end effector molecule (ERK) are important in the carcinogenesis of many tumors. The activation of these protooncogenes in prostate cancer is still under investigation. The aim of this work was to study EGFR, HER2- neu, inactive (non-phosphorylated) and active (phosphorylated) ERK expression in prostatic adenocarcinomas in correlation to the clinical and pathological parameters. METHODS: Immunohistochemistry- using tissue microarrays- for EGFR, HER2/neu, non-phosphorylated, and phosphor-ERK, was performed on tissues from 166 patients- with primary prostatic adenocarcinoma with no prior treatment-. The results of different markers expression were correlated with the clinical and pathological parameters and were analyzed statistically. RESULTS: The prostatic tissue showed EGFR, HER2 neu, phosphorylated and non-phosphorylated ERK expression in 8.4%, 1.4%, 78.2%, and 83.4% respectively whether low (patchy) or high expression (diffuse).  There were no significant correlations found between patient characteristics and expression of the tested markers. The negative immune reactivity for non-phosphorylated ERK and EGFR- was significantly correlated with high tumor stage (p values 0.03 and 0.01, respectively). CONCLUSION: EGFR and HER2/neu may play a limited role in prostatic adenocarcinoma as they showed positive expression in a limited number of the examined tissues specifically HER2neu. The expression of non-phosphorylated ERK (mostly weak to moderate) and phosphorylated ERK (mostly moderate to strong)- was appreciated in most cases. Thus, we suggest that anti-EGFR drugs may have a limited role in the treatment of castrate-resistant prostate cancer, but anti-MEK/ERK drugs may have more promising role as a target therapy. It is recommended to perform further molecular testing to elucidate the exact mechanism and significance of these markers.

Targeting Oxidative Stress, Autophagy, and Apoptosis by Quercetin to Ameliorate Cisplatin-induced Peripheral Neuropathy in Rats.

Background: Quercetin is a flavonoid, with antioxidant and autophagy-modulating activities. Cisplatin is one of the platinum-based anticancer drugs. Early development of peripheral neuropathy as an adverse effect of cisplatin interferes with the continuation of therapy. Oxidative stress and autophagy impairment may play a role. Aim: This study aimed to explore the possible protective effects of quercetin against cisplatin-induced peripheral neuropathy. Methods: Twenty-four male Wistar rats were divided into three groups: Group 1 (control group) and Group 2 (cisplatin group) where peripheral neuropathy was induced using single ip injection of cisplatin. Group 3 (cisplatin + quercetin group) received single ip injection of cisplatin and was then treated with quercetin for 14 days. At the end of the experiment, nociception was evaluated by tail immersion test, and then, blood was collected for analysis of nerve growth factor. Sciatic nerve was used to assess histopathological changes and light chain 3-II by immunohistochemical staining. Reduced glutathione, malondialdehyde, mTOR, and caspase-3 were estimated in sciatic nerve tissue homogenate. Results: This research work revealed that quercetin significantly improved cisplatin-induced nociceptive impairment, attenuated cisplatin-induced oxidative stress, autophagy, and apoptosis to protect against neuronal death. Conclusion: From the current study, quercetin can act as a promising protective agent against cisplatin-induced peripheral neuropathy.

Cloaca-Like Anomalies in the Male: A Report on Two Cases.

"Cloaca" is a term used to describe an anomaly in the female where a single orifice is located in the perineum draining both urogenital and gastrointestinal tracts. Few reports used the same term "cloaca" to describe the counterpart anomaly in the male. We present two "male" cases of anorectal anomalies associated with significant penile deformity (caudally displaced penis) that were managed during the period between January 2010 and September 2021. Characteristically, both cases had a single "central" perineal orifice. The latter was located anterior to the predestined site of the normal anus and just beneath a caudally positioned hypospadiac phallus. The caudal displacement of the penis was strikingly obvious by the presence of severe form of penoscrotal transposition. Both cases were associated with a perineal swelling (hamartoma) just beside the central perineal orifice. The urethra was very short (like that in the female), besides the single perineal orifice, which makes the presentation very similar to cloacal anomalies.

Fisetin ameliorates oxidative glutamate testicular toxicity in rats via central and peripheral mechanisms involving SIRT1 activation.

OBJECTIVES: This study aimed to evaluate the potential mitigating effect of fisetin on monosodium glutamate (MSG)-induced testicular toxicity and investigate the possible involvement of silent mating type information regulation 2 homolog 1 (SIRT1) in this effect. METHODS: Forty male rats were divided into normal control, fisetin-treated, MSG-treated, and fisetin + MSG-treated groups. Testosterone, GnRH, FSH, and LH were measured in plasma, as well as SIRT1 and phosphorylated AMP-activated protein kinase (pAMPK) levels in testicular tissues using ELISA. Hydrogen peroxide (H2O2), nitric oxide (NO), and reduced glutathione (GSH) were measured colorimetrically, while Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) expression was relatively quantified using RT-PCR in testicular tissues. RESULTS: After 30 days, fisetin could ameliorate MSG-induced testicular toxicity by acting centrally on the hypothalamic-pituitary-gonadal axis, increasing plasma levels of GnRH, FSH, LH, and testosterone. Peripheral actions of fisetin on the testis were indicated as it increased testicular SIRT1 and pAMPK. Furthermore, it antagonized glutamate-induced oxidative stress by significantly lowering H2O2, NO, and relative NOX4 expression while significantly increasing reduced GSH levels. It also improved the architecture of the seminiferous tubules, reduced sperm abnormality, and increased sperm count. DISCUSSION: Fisetin ameliorates MSG-induced testicular toxicity via central and peripheral mechanisms making it a promising therapeutic target for male infertility.

The role of hepatic progenitor cells in predicting response to therapy in Egyptian patients with chronic hepatitis C, genotype 4.

BACKGROUND: Interferon therapy is used as a line of treatment of chronic hepatitis C virus (HCV) in several areas of the world including Egypt. OBJECTIVE: Our aim was to investigate the value of hepatic progenitor cells (HPCs) in predicting response of patients with chronic HCV, genotype 4 to pegylated interferon (PEGIFN) plus ribavirin (RBV) therapy. METHODS: Pre-treatment liver biopsies obtained from 110 patients with chronic HCV, genotype 4 were examined immunohistochemically for HPCs using cytokeratin19. The mean number of HPCs as ductular reaction (DR) and as isolated progenitor cells (IPCs) was counted in each case. The patients were classified into: those with sustained virological response (SVR) and those who did not achieve SVR. The results were compared between the two groups. Also, the relationships between HPCs and other clinico-pathologic variables were estimated using multivariate analysis. RESULTS: The mean number of HPCs was the only independent predictor of therapeutic response, being significantly higher in non-responders (P = 0 for DR and P = 0.03 for IPCs). On the other hand, fibrosis stage and steatosis were the only independent factors which showed a significant direct association with the mean number of HPCs in the form of DR and IPCs (P = 0 for each). CONCLUSION: The number of HPCs provides prognostic information in chronic HCV since it is significantly associated with stage of fibrosis. More importantly, it can be used as a marker to predict response of patients with chronic HCV to PEGIFN plus RBV therapy.

Cyclophosphamide eradicates murine immunogenic tumor coding for a non-self-antigen and induces antitumor immunity.

Although the majority of cancers respond to chemotherapy, most cancer types relapse, at least in part, due to the poor immunogenicity of most tumor. We have reported before that treatment of tumor bearing mice with a combination of the anti-cancer chemotherapy cyclophosphamide (CTX) and immunotherapy can result in complete tumor regression using T-cell receptor (TCR) transgenic CD8+ T cells specific to antigens. This study aimed to determine whether chemotherapy can cure immunogenic tumor which expresses non-self-tumor antigen and result in antitumor immunity. Either EL4 cell line, a poorly immunogenic thymoma, or EG7, a clone of EL4 cells transfected with ovalbumin (OVA), as a non-self-antigen were inoculated subcutaneously into wild type or splenectomized C57BL/6 mice and then treated once with intraperitoneal (i.p.) injection of 4 mg CTX/mouse. In certain experiments, the mice were rechallenged with the same tumor type 1-2 months after the primary challenge. Treatment of EL4 bearing mice with CTX induced transient antitumor effect followed by tumor progression. Interestingly, however, treatment of EG7-bearing mice with CTX resulted in regression of early and advanced tumors. EG7 tumor-free mice rejected the second and the third challenges with EG7 cells, but not with challenge EL4 cells. These antitumor effects did not require spleen, since splenectomized mice showed similar antitumor effects of CTX on EG7 cells. Taken together, these data indicate that expression of non-self-antigen by poorly immunogenic tumor might be a reliable means to increase its immunogenicity and its response to chemotherapy.

Taurine is more effective than melatonin on cytochrome P450 2E1 and some oxidative stress markers in streptozotocin-induced diabetic rats.

Melatonin and taurine have alleviative effects in streptozotocin (STZ)-induced diabetic rats. Male Wistar rats were divided into nondiabetic, diabetic, diabetic melatonin supplemented and diabetic taurine supplemented groups. At the end of the study, both blood and liver were collected for determination of some oxidative stress parameters, and hepatic cytochrome P450 2E1 (CYP2E1) enzyme activity and gene expression. An increased CYP2E1 activity and expression level with a concomitant significant change in oxidative stress parameters were found in STZ-induced diabetic rats. Taurine or melatonin supplementation to the diabetic rats alleviated these experimental parameters with a more significant effect for taurine than that of melatonin. Suppression of ß-hydroxybutyrate (ß-HB) production by taurine can be one of the mechanisms of a reduction in CYP2E1. Taurine was effective more than melatonin in reducing CYP2E1 activity and expression; therefore antioxidants might prove beneficial in type 1 diabetes associated with manifestations of liver injury.