Silymarin and MSC-exosomes ameliorate thioacetamide-evoked renal fibrosis by inhibiting TGF-ß/SMAD pathway in rats.

BACKGROUND: TGF-ß1 and SMAD3 are particularly pathogenic in the progression of renal fibrosis. AIM: This study aimed to evaluate the kidney protective potentials of silymarin (SM) and exosomes of mesenchymal stem cells against the nephrotoxin thioacetamide (TAA) in rats. METHODS: 32 female rats were randomly assigned into four groups: the control group, the TAA group, the TAA + SM group, and the TAA + Exosomes group. The kidney homogenates from all groups were examined for expression levels of TGF-ß receptors I and II using real-time PCR, expression levels of collagen type I and CTGF proteins using ELISA, and the expression levels of nuclear SMAD2/3/4, cytoplasmic SMAD2/3, and cytoplasmic SMAD4 proteins using the western blot technique. RESULTS: Compared to the control group, the injection of TAA resulted in a significant increase in serum levels of urea and creatinine, gene expression levels of TßRI and TßRII, protein expression levels of both collagen I and CTGF proteins, cytoplasmic SMAD2/3 complex, and nuclear SMAD2/3/4 (p-value < 0.0001), with significantly decreased levels of the co-SMAD partner, SMAD4 (p-value < 0.0001). Those effects were reversed considerably in both treatment groups, with the superiority of the exosomal treatment regarding the SMAD proteins and the expression levels of the TßRI gene, collagen I, and CTGF proteins returning to near-control values (p-value > 0.05). CONCLUSION: Using in vitro and in vivo experimental approaches, the research discovered a reno-protective role of silymarin and exosomes of BM-MSCs after thioacetamide-induced renal fibrosis in rats, with the advantage of exosomes.

Caveolin-1's dual impact on endometrioid endometrial carcinoma: a histopathological and immunohistochemical study.

The objectives of this study are to evaluate caveolin-1 expression in endometrioid endometrial cancer and its correlation with clinicopathological parameters. Forty-four cases of endometrioid endometrial carcinomas underwent radical hysterectomy. The archived paraffin sections that were stained for caveolin-1 by immunohistochemistry, caveolin-1 expression were detected in cancerous epithelial cells in 18.2% of the cases, and stromal caveolin-1 was detected in 65.9% of the cases. Caveolin-1 expression in the epithelium showed a significant positive association with the T stage and the FIGO stage. Positive caveolin-1 expression in epithelium has a direct, positive and significant relationship with invasion of other organs and a direct and significant relationship with the advanced FIGO stage. As for caveolin-1 expression in the stroma, it showed a significant negative inversely significant association with myometrial invasion. Also, there is a significant negative association between caveolin-1 expression in the epithelium and its expression in the stroma. We conclude that caveolin-1 expression strongly plays a critical role in endometrioid endometrial carcinoma as a tumor suppressor or promoter of invasion. In early lesions, high stromal levels appear to be protective against progression. While decreased stromal expression and increased epithelial expression were associated with aggressive tumors.

Is Programmed Death-Ligand 1 of Prognostic Significance in Triple-Negative Female Mammary Carcinoma?

Introduction: The most widespread female malignancy is breast cancer (BC), considerable percentage of patients with triple-negative BC (TNBC) experience rapid progression, recurrence, and metastasis. BC has not historically been treated as an immunogenic cancer. Nonetheless, several researchers have started to concentrate on immunotherapy. Aim: The aim of the study is to investigate the immunohistochemical (IHC) expression of programmed death-ligand 1 (PD-L1) by stromal tumor-infiltrating lymphocytes (TILs) and tumor cells (TC) in female (TNBC) and to correlate with pathological features of such tumors, particularly those determine biologic behavior, such as the grade and stage the overall survival. Methodology: This is a retrospective study which includes 49 paraffin-embedded tumor tissue sections which were collected from breast surgery specimens either radical or conservative of female patients with TNBC. The samples were analyzed immunohistochemically for PD-L1 expression. Results: There were statistically significant relations among TC PD-L1 expression and TILs PD-L1 expression as well as relations among TILs PD-L1 expression with histologic grade, stromal TILs, and Ki-67 were statistically significant. Correlations between TC PD-L1 expression and N stage, histologic grade, and anatomic stage were statistically significant. Improved survival was detected within TILs PD-L1-positive cases; however, the correlation between the overall survival and PD-L1 expression in both TCs and stromal TIL was not statistically significant. Conclusion: PD-L1 expressed in tumors with poor prognostic features such as the high grade, advanced T stage, and high Ki-67 index, TILs PD-L1-positive cases experienced improved survival supporting its prognostic significance. However, the correlation with overall survival was not statistically significant.

Immunohistochemical expression of immune check point protein PDL-1 in hepatocellular carcinoma denotes its prognostic significance and association with survival.

This study was designed to evaluate the immunohistochemical expression of programmed death ligand-1 (PD-L1) in tumor cells (TCs) and tumor-infiltrating immune cells (TICs) in hepatocellular carcinoma (HCC) and to correlate its expression with clinicopathological parameters. Seventy-two formalin-fixed paraffin-embedded blocks of HCC were collected. The data were collected from the patients' records. The blocks were stained with hematoxylin and eosin. Additionally, they were immunostained with PD-L1. Membranous staining was considered positive expression including the entire membrane or part of it ± cytoplasmic staining, and the percentage of total cancer cells ≥ 5% was evaluated as positive staining for TCs. The TICs were considered positive if they expressed membranous ± cytoplasmic staining of PD-L1 ≥ 1%. Of the total cases, 34.7% expressed PD-L1 positively in TCs and 15.3% expressed PD-L1 positively in TICs. Significant associations were observed between PD-L1 expression in TCs and tumor grade, capsular and/or vascular invasion, tumor stage, nodal metastasis, and the expression of PD-L1 in paracancerous tissue. The cases that positively expressed PD-L1 exhibited reduced overall survival (OS). PD-L1 was expressed in HCC TCs and TICs. Its expression in TCs was associated with higher HCC grades, advanced stages, capsular and/or vascular invasion, and nodal metastasis, and cases that expressed PD-L1 displayed reduced OS. Therefore, PD-L1 might serve as a poor prognostic indicator and a tumor immunotherapy target.

Molecular and hormonal changes caused by long-term use of high dose pregabalin on testicular tissue: the role of p38 MAPK, oxidative stress and apoptosis.

In 1990, pregabalin was introduced as a novel antiepileptic drug that acts by binding selectively to the alpha-2-delta subunits of voltage-gated calcium channels resulting in increasing neuronal GABA levels and inhibiting the release of exciting neurotransmitters. The aim of our study is to assess the hazardous effects of prolonged high-dose pregabalin (like that abused by addicts) on testes and to clarify the potential causative mechanisms. The current study was conducted on 70 adult male Wistar albino rats which were divided into 7 groups. In our study we evaluated the effect of pregabalin, at concentrations 150 and 300 mg/kg/day for 90 days, on hormones; FSH, LH, testosterone and prolactin secretion. Our study also evaluated the expression of apoptosis-related genes BAX and BCL2 in testicular tissue in addition to the western blotted analysis of p38 Mitogen activated protein kinases (p38 MAPK). The levels of reduced glutathione, malondialdehyde and superoxide dismutase were also measured. Pregabalin decreased testosterone level while FSH, LH and prolactin showed a significant increase. It also produced genotoxicity through reversal of the BAX/BCL2 ratio; increased p38 MAPK level and induction of oxidative stress markers. The concomitant administration of vitamin E significantly reduced all the previously mentioned biochemical and hormonal adverse effects caused by pregabalin. Pregabalin can adversely affect male fertility particularly in addicts and patients who are being treated with it for long periods as those suffering from neuropathies and seizures. Antioxidants like vitamin E could have a role in amelioration.