Unraveling the hepatic stellate cells mediated mechanisms in aging's influence on liver fibrosis.

Aging enhances numerous processes that compromise homeostasis and pathophysiological processes. Among these, activated HSCs play a pivotal role in advancing liver fibrosis. This research delved into how aging impacts liver fibrosis mechanisms. The study involved 32 albino rats categorized into four groups: Group I (young controls), Group II (young with liver fibrosis), Group III (old controls), and Group IV (old with liver fibrosis). Various parameters including serum ALT, adiponectin, leptin, and cholesterol levels were evaluated. Histopathological analysis was performed, alongside assessments of TGF-ß, FOXP3, and CD133 gene expressions. Markers of fibrosis and apoptosis were the highest in group IV. Adiponectin levels significantly decreased in Group IV compared to all other groups except Group II, while cholesterol levels were significantly higher in liver fibrosis groups than their respective control groups. Group III displayed high hepatic expression of desmin, α-SMA, GFAP and TGF- ß and in contrast to Group I. Increased TGF-ß and FOXP3 gene expressions were observed in Group IV relative to Group II, while CD133 gene expression decreased in Group IV compared to Group II. In conclusion, aging modulates immune responses, impairs regenerative capacities via HSC activation, and influences adipokine and cholesterol levels, elevating the susceptibility to liver fibrosis.

Dapagliflozin dampens liver fibrosis induced by common bile duct ligation in rats associated with the augmentation of the hepatic Sirt1/AMPK/PGC1α/FoxO1 axis.

Liver fibrosis is considered an epidemic health problem due to different insults that lead to death. Dapagliflozin (DAPA), a sodium-glucose cotransporter-2 (SGLT2) inhibitor, is one of the newer anti-diabetic drugs used to manage type 2 diabetes mellitus (T2DM). DAPA exerted beneficial effects in many human and rat models due to its antioxidant, anti-inflammatory and antifibrotic activities. AIM: Due to previously reported capabilities related to DAPA, we designed this study to clarify the beneficial role of DAPA in liver fibrosis triggered by common bile duct ligation (CBL) in male rats. METHODS: For 14 or 28 days after CBL procedures, DAPA was administered to the rats orally at a dose of 10 mg/kg once daily. The effects of DAPA were evaluated by assaying liver enzymes, hepatic oxidant/antioxidant parameters, serum levels of tumor necrotic factor alpha (TNF-α), and AMP-activated protein kinase (AMPK). In addition, we measured the hepatic expression of fibrosis regulator-related genes along with evaluating liver histological changes. KEY FINDINGS: DAPA successfully decreased hepatic enzymes and malondialdehyde levels, increased superoxide dismutase activity, elevated catalase levels, decreased serum levels of TNF-α, elevated serum levels of AMPK, decreased liver hydroxyproline content, upregulated Sirt1/PGC1α/FoxO1 liver gene expressions, down-regulated fibronectin-1 (Fn-1), collagen-1 genes in liver tissues, and improved the damaged liver tissues. Deteriorated biochemical parameters and histological liver insults associated with CBL were more pronounced after 28 days, but DAPA administration for 14 and 28 days showed significant improvement in most parameters and reflected positively in the histological structures of the liver. SIGNIFICANCE: The significance of this study lies in the observation that DAPA mitigated CBL-induced liver fibrosis in rats, most likely due to its antioxidant, anti-inflammatory, and antifibrotic effects. These results suggest that DAPA's beneficial impact on liver fibrosis might be attributed to its interaction with the Sirt1/AMPK/PGC1α/FoxO1 pathway, indicating a potential mechanistic action for future exploration.

Evaluation of Some Prognostic Biomarkers in Human Papillomavirus-Related Multiphenotypic Sinonasal Carcinoma.

Background: Human papillomavirus (HPV)-related multi phenotypic sinonasal carcinoma (HMSC) is a recently described tumor subtype with an unknown prognosis, often misdiagnosed with other sinonasal carcinomas, and associated with high-risk HPV (HR-HPV). The present study aimed to evaluate the expression of vascular endothelial growth factor (VEGF), Bcl-2-associated X protein (BAX), epidermal growth factor receptors (EGFR), ProExTMC, and human telomerase reverse transcriptase (hTERT) and assess their association with survival and clinicopathological characteristics. Methods: Between 2017 and 2022, 40 HMSC patients underwent surgical resection at the School of Medicine, Zagazig University Hospitals (Zagazig, Egypt). Tissue samples were examined for the presence of HR-HPV; absence of myeloblastosis (MYB), MYB proto-oncogene like 1 (MYBL1), and nuclear factor I/B (NFIB) fusions and the presence of myoepithelial proteins (calponin, S100, SMA), squamous differentiation markers (p63, p40, calponin), VEGF, BAX, ProExTMC, and hTERT by immunohistochemistry. All patients were followed up for about 54 months until death or the last known survival data. Data were analyzed using the Chi square test and Kaplan-Meier method. Results: The expression of VEGF, hTERT, and ProExTMC was significantly associated with age, advanced tumor stages, lymph node metastasis, tumor size, mortality, relapse, poor disease-free survival (DFS), and overall survival (OS) (P<0.001). BAX expression was significantly associated with tumor size, age, poor DFS, and relapse (P=0.01, P<0.001, P=0.035, and P=0.002, respectively). Conclusion: HMSC is strongly associated with HR-HPV. The expression of VEGF, EGFR, BAX, hTERT, and ProExTMC is associated with aggressive malignant behavior, poor survival, and poor prognosis, making them novel prognostic biomarkers for targeted therapeutics in HMSC.

Effect of Aromatase Inhibitor Letrozole on the Placenta of Adult Albino Rats: A Histopathological, Immunohistochemical, and Biochemical Study.

Background: Letrozole, an aromatase inhibitor, has recently been introduced as the preferred treatment option for ectopic pregnancy. To date, no study has investigated the effect of letrozole alone on placental tissue. The present study aimed to evaluate the effect of different doses of letrozole on the placenta of rats and to clarify the underlying mechanism. Methods: Sixty pregnant female rats were equally divided into three groups, namely the control group (GI), low-dose (0.5 mg/Kg/day) letrozole group (GII), which is equivalent to the human daily dose (HED) of 5 mg, and high-dose (1 mg/Kg/day) letrozole group (GIII), equivalent to the HED of 10 mg. Letrozole was administered by oral gavage daily from day 6 to 16 of gestation. Data were analyzed using a one-way analysis of variance followed by Tukey's post hoc test and Chi square test. P<0.05 was considered statistically significant. Results: Compared to the GI and GII groups, high-dose letrozole significantly increased embryonic mortality with a high post-implantation loss rate (P<0.001) and significantly reduced the number of viable fetuses (P<0.001) and placental weight (P<0.001) of pregnant rats. Moreover, it significantly reduced placental estrogen receptor (ER) and progesterone receptor (PR) (P<0.001) and the expression of vascular endothelial growth factor (P<0.001), while increasing the apoptotic index of cleaved caspase-3 (P<0.001). Conclusion: Letrozole inhibited the expression of ER and PR in rat placenta. It interrupted stimulatory vascular signals causing significant apoptosis and placental vascular dysfunction. Letrozole in an equivalent human daily dose of 10 mg caused a high post-implantation loss rate without imposing severe side effects.

Epstein-Barr Virus Promotes Tumorigenicity and Worsens Hodgkin Lymphoma Prognosis by Activating JAK/STAT and NF-κB Signaling Pathways.

Background: Epstein-Barr virus (EBV) is detected in 40% of patients with Hodgkin lymphoma (HL). During latency, EBV induces epigenetic alterations to the host genome and decreases the expression of pro-apoptotic proteins. The present study aimed to evaluate the expression levels of mRNA molecules and the end product of proteins for the JAK/STAT and NF-κB pathways, and their association with clinicopathological and prognostic parameters in patients with EBV-positive and -negative classical Hodgkin lymphoma (CHL). Methods: A prospective cohort study was conducted from 2017 to 2022 at the Faculty of Medicine, Zagazig University Hospital (Zagazig, Egypt). Biopsy samples of 64 patients with CHL were divided into EBV-positive and EBV-negative groups. The expression levels of mRNA molecules (JAK2, STAT1, IRF-1, PD-L1, IFN-γ, NF-κB, Bcl-xL, COX-2) and the end product of proteins (PD-L1, Bcl-xL, COX-2) were determined and compared with clinicopathological and prognostic parameters. Data were analyzed using the Chi square test and Kaplan-Meier estimate. Results: EBV-positive CHL patients were significantly associated with positive expression of mRNAs molecules (P<0.001) and the end product of proteins (P<0.001) for the JAK/STAT and NF-κB pathways, B-symptoms (P=0.022), extra-nodal involvement (P=0.017), and advanced stage of CHL (P=0.018). These patients were more susceptible to cancer progression, higher incidence of relapse (P=0.008), poor disease-free survival rate (P=0.013), poor overall survival rate (P=0.028), and higher mortality rate (P=0.015). Conclusion: Through the activation of JAK/STAT and NF-κB signaling pathways, EBV-positive CHL is associated with poor clinicopathological parameters, higher incidence of disease progression, relapse, and poor overall survival. A preprint of this manuscript is available on research square (doi: 10.21203/rs.3.rs-1857436/v1).

Ameliorative effects of androstenediol against acetic acid-induced colitis in male wistar rats via inhibiting TLR4-mediated PI3K/Akt and NF-κB pathways through estrogen receptor ß activation.

5-androstenediol (ADIOL) functions as a selective estrogen receptor ß (ERß) ligand with a protective effect against many diseases. So, we conducted a novel insight into its role in acetic acid (AA)-induced colitis and investigated its effect on TLR4-Mediated PI3K/Akt and NF-κB Pathways and the potential role of ERß as contributing mechanisms. METHODS: Rats were randomized into 5 Groups; Control, Colitis, Colitis + mesalazine (MLZ), Colitis + ADIOL, and Colitis + ADIOL + PHTPP (ER-ß antagonist). The colitis was induced through a rectal enema of acetic acid (AA) on the 8th day. At the end of treatment, colons were collected for macroscopic assessment. Tissue levels of malondialdehyde (MDA), superoxide dismutase (SOD), nuclear factor kappa b (NF-κB), toll-like receptor (TLR4), and phosphorylated Protein kinase B (pAKT) were measured. Besides, Gene expression of interleukin-1beta (IL-1ß), metalloproteases 9 (Mmp9), inositol 3 phosphate kinase (PI3K), Neutrophil gelatinase-associated lipocalin (NGAL), ERß and NLRP6 were assessed. Histopathological and immunohistochemical studies were also investigated. RESULTS: Compared to the untreated AA group, the disease activity index (DAI) and macroscopic assessment indicators significantly decreased with ADIOL injections. Indeed, ADIOL significantly decreased colonic tissue levels of MDA, TLR4, pAKT, and NF-κB immunostainig while increased SOD activity and ß catenin immunostainig. ADIOL mitigated the high genetic expressions of IL1ß, NGAL, MMP9, and PI3K while increased ERß and NLRP6 gene expression. Also, the pathological changes detected in AA groups were markedly ameliorated with ADIOL. The specific ERß antagonist, PHTPP, largely diminished these protective effects of ADIOL. CONCLUSION: ADIOL could be beneficial against AA-induced colitis mostly through activating ERß.

The protective effect of allium cepa against ethylene glycol-induced kidney stones in rats.

1Background: Kidney stones is one of the serious medical conditions affecting populations worldwide. So, we aimed in this study to investigate the protective effect of allium cepa administration against KSD. 2Methods: 24 adult male albino rats were assigned into 3 groups; group I: control group; group II: received ethylene glycol (EG) in the drinking water for 4 weeks; and group III received EG in the drinking water plus freshly prepared allium cepa extract (ACE) for 4 weeks. Renal function tests and urine analysis were done. Tissue oxidative stress markers (SOD and MDA) were assessed, and kidney expression of SIRT-1, Beclin, LC3, osteopontin, and Regucalcin were measured by RT-qPCR. Histopathological assessment and immunohistochemistry for Bax, Beclin-1 and TNF-α were performed. 3Results: There was a significant improved kidney function tests in the ACE received group compared to EG group (P < 0.001). The present study showed less stones formation and apoptosis with decreased osteopontin and autophagy genes expression in the ACE received group compared to EG group (P < 0.001). While, regucalcin and SIRT-1 genes showed higher expression in the former group than the later group (P < 0.001). 4 Conclusion: Alium Cepa extract administration has a significant protective effect against kidney stones formation.

Sleep deprivation disturbs uterine contractility and structure in pregnant rats: role of matrix metalloproteinase 9 and transforming growth factor-ß.

Sleep deprivation (SD) during pregnancy can impact the delivery procedure, with prolongation of the labor duration. Matrix metalloproteinase-9 (MMP9) and transforming growth factor-ß (TGF-ß) are regulators of uterine remodeling. Their dysregulation is vital for abnormal placentation and uterine enlargement in complicated pregnancies. Therefore, this study aims to explore the outcome of SD throughout pregnancy on ex vivo uterine contractility, MMP9 and TGF-ß, and uterine microscopic structure. A total of 24 pregnant rats were divided into two groups. From the first day of pregnancy, animals were exposed to partial SD/6 h/day. Uterine in vitro contractile responses to oxytocin, acetylcholine, and nifedipine were assessed. Additionally, uterine levels of superoxide dismutase and malondialdehyde and uterine mRNA expression of MMP9, TGF-ß, and apoptotic biomarkers were analyzed. The results showed that SD significantly reduced uterine contractile responses to oxytocin and acetylcholine, while it augmented the relaxing effect of nifedipine. In addition, it significantly increased oxidative stress status, MMP9, TGF-ß, and apoptotic biomarkers' mRNA expression. All were accompanied by degeneration of endometrial glands, vacuolization with apoptotic nuclei, and increased area% of collagen fibers. Finally, increased uterine MMP9 and TGF-ß mRNA expression during SD clarified their potential role in modulating uterine contractility and structure.

Role of Circ-ITCH Gene Polymorphisms and Its Expression in Breast Cancer Susceptibility and Prognosis.

INTRODUCTION/OBJECTIVE: Breast cancer (BC) is the first leading cause of cancer-related mortality in females worldwide. We have investigated the correlation between circ-ITCH gene polymorphisms, circ-ITCH expression, and their effect on ß-catenin levels and BC development. METHODS: Participants included 62 BC and 62 controls matched in terms of age. The circ-ITCH polymorphisms rs10485505 and rs4911154 were genotyped using whole blood samples. In addition, mRNA expression analysis of circ-ITCH was performed on BC tissues. The ß-catenin levels in serum samples were measured using ELISA. RESULTS: The qRT-PCR results demonstrated that circ-ITCH was significantly downregulated in BC compared to normal healthy tissues. The genotype distribution of rs10485505 and rs4911154 were significantly associated with BC risk. For rs10485505, genotype CT and TT were significantly associated with an increased BC risk. In contrast, there was a significant association between rs4911154, genotypes GA and AA, and an increased BC risk. Regarding the rs10485505 genotype, carriers of the T allele frequently have a poor prognosis compared to carriers of the CC genotype. Serum ß-catenin in the BC patients' group was significantly higher than in the control group. The relative expression levels of circ-ITCH were remarkably decreased in the BC samples of patients carrying the A allele at rs4911154 compared to patients with a GG genotype. Conversely, ß-catenin protein levels were increased in patients carrying the A allele, while rs10485505 genotype carriers of the CT and TT genotypes showed downregulation of circ-ITCH expression fold compared to the CC genotype. Contrarily, ß-catenin levels markedly increased in TT and CT genotypes compared with the CC genotype. CONCLUSIONS: Our research showed that the rs10485505 polymorphism (T allele) and the rs4911154 polymorphism (A allele) are associated with the risk and prognosis of BC. This finding may be due to the effect on the level of circ-ITCH mRNA expression in BC tissues as well as the level of ß-catenin in BC patients.

Histological and biochemical evaluation of the effects of silver nanoparticles (AgNps) versus titanium dioxide nanoparticles (TiO2NPs) on rat parotid gland.

The unlimited use of nanoparticles (NPs) results in toxic impacts on different tissues. The current study aimed to compare the adverse effects of AgNPs and TiO2NPs on the parotid gland of adult male albino rats as regards the histopathological, immunohistochemical, and biochemical changes, exploring the possible underlying mechanisms and the degree of improvement after cessation of administration. Fifty-four adult male albino rats were divided into control group (I), AgNPs-injected group (II), and TiO2NPs-injected group (III). We measured the levels of tumor necrosis factor-alpha (TNF-α) and interleukin (IL-6) in the serum, and levels of MDA and GSH in parotid tissue homogenate. Quantitative real-time polymerase-chain reaction (qRT-PCR) was used to measure the expression levels of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC1-α), nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4), mouse double minute 2 (MDM2), Caspase-3 Col1a1, and Occludin. Parotid tissue sections were examined by light microscope (Hematoxylin & Eosin and Mallory trichrome stains), electron microscope, and immunohistochemical examination of CD68 and anti-caspase-3 antibodies. Both NPs severely affected the acinar cells and damaged the tight junction between them by enhancing expression of the inflammatory cytokines, inducing oxidative stress, and disturbing the expression levels of the studied genes. They also stimulated fibrosis, acinar cell apoptosis, and inflammatory cells infiltration in parotid tissue. TiO2NPs effects were less severe than AgNPs. Cessation of exposure to both NPs, ameliorated the biochemical and structural findings with more improvement in TiO2NPs withdrawal. In conclusion: AgNPs and TiO2NPs adversely affected the parotid gland, but TiO2NPs were less toxic than AgNPs.

Repurposing of carvedilol to alleviate bleomycin-induced lung fibrosis in rats: Repressing of TGF-ß1/α-SMA/Smad2/3 and STAT3 gene expressions.

Idiopathic pulmonary fibrosis (IPF) is the most widely studied interstitial lung disease. IPF eventually leads to respiratory insufficiency, lung cancer, and death. Carvedilol (CAR) is a third-generation ß-adrenergic receptor antagonist with an α1-blocking effect. CAR demonstrates antifibrotic activities in various experimental models of organ fibrosis. AIMS: This work is designed to explore the possible alleviating effects of CAR on bleomycin (BLM)-induced lung fibrosis in rats. MAIN METHODS: The BLM rat model of lung fibrosis was achieved by intratracheal delivery of a single dose of 5 mg/kg of BLM. Seven days following BLM injection, either prednisolone or CAR was orally administered at doses of 10 mg/kg once daily for 21 days to the rats. The actions of CAR were evaluated by lung oxidant/antioxidant parameters, protein concentration and total leucocyte count (TLC) in bronchoalveolar lavage fluid (BALF), fibrosis regulator-related genes along with the coexistent lung histological changes. KEY FINDINGS: CAR effectively decreased lung malondialdehyde level, increased superoxide dismutase activity, declined both protein concentration and TLC in BALF, downregulated TGF-ß1/α-SMA/Smad2/3 and STAT3 gene expressions, and repaired the damaged lung tissues. SIGNIFICANCE: CAR conferred therapeutic potential against BLM-induced lung fibrosis in rats, at least in part, to its antioxidant, anti-inflammatory, and antifibrotic activities. CAR could be utilized as a prospective therapeutic option in patients with lung fibrosis in clinical practice.

Nicorandil and Bone Marrow-derived Mesenchymal Stem Cells Therapeutic Effect after Ureteral Obstruction in Adult Male Albino Rats.

BACKGROUND: Chronic kidney disease is a global health problem for which renal fibrogenesis is the final treatment target. OBJECTIVE: In our work, we have highlighted two new strategies, nicorandil and Bone marrow-derived mesenchymal stem cells (BM-MSCs), as effective in reversing renal fibrosis induced by partial unilateral ureteral obstruction (PUUO). METHODS: The current study included 96 male albino rats randomly divided into four groups, with 24 rats per group; Group I, the control group; Group II, PUUO, where two-thirds of the left ureter was entrenched in the psoas muscle; Group III, same surgical procedure as in Group II for 7 days, and then the rats received 15 mg/kg/day nicorandil once daily for 21 days; and Group IV, same surgical procedure as in Group II for 7 days, and then rats were given 3 × 106 of labeled MSCs injected intravenous, and left for 21 days. Blood and kidney tissues were collected for biochemical, histological, and molecular analyses. RESULTS: Both the nicorandil and BM-MSCs treatment groups could ameliorate kidney damage evidenced by inhibition of MDA elevation and total antioxidant capacity reduction caused by PUUO. Also, there was a significant reduction observed in TNF, TGF, IL6, collagen I, and α-SMA in addition to improvement in histological examination. However, a significant difference was found between the BM-MSCs and nicorandil-treated groups. CONCLUSION: Our results suggest that BM-MSCs and nicorandil improved renal fibrosis progression through their antiapoptotic, anti-inflammatory, and antifibrotic effects in male albino rats subjected to PUUO, with BM-MSCs being more effective compared to nicorandil.

Icosapent ethyl alleviates acetic acid-induced ulcerative colitis via modulation of SIRT1 signaling pathway in rats.

Ulcerative colitis (UC) is a global inflammatory bowel disease. This study aimed to assess the effects of icosapent ethyl on acetic acid-induced colitis in rats as well as the underlying mechanisms involved. 36 male Wister rats were equally divided into six groups: control, UC, mesalamine 100 mg/kg, icosapent 150mg/kg, icosapent 300 mg/kg, and EX527-icosapent 300 mg/kg groups. Except for control group, UC was induced by acetic acid instillation into colon. Drugs were administered once daily for one week then under thiopental anaesthesia, colons were excised. Colitis macroscopic and microscopic scores were assessed. A part of colon was homogenized for detection of malondialdehyde (MDA), inerleukin1 (IL-1ß), tumor necrosis factor (TNF-α), superoxide dismutase (SOD), phosphorylated Akt (pAkt) and caspase 3 levels. Silent information regulator 1 (SIRT1), heme oxygenase 1 (HO-1), and nuclear factor erythroid 2 (Nrf2) mRNA expressions were detected. Mallory-stained colonic sections were examined for collagen fibres detection. Immunohistochemistry of NF-κB and p53 expressionsin colonic sections were assessed. Acetic acid induced colitis with increments in MDA, IL-1ß, TNF-α, and caspase 3 levels while decreased SOD, pAkt, SIRT1, HO-1, and Nrf2 with increased collagen fibres as well as NF-κB and p53. Icosapent decreased macro& microscopic colitis scores, MDA, IL-1ß, TNF-α, and caspase 3 levels while increased SOD, pAkt, SIRT1, HO-1, and Nrf2 with decreased collagen fibres as well as NF-κB and p53. The effects of icosapent 300 mg/kg were similar to mesalamine. Icosapent effects were antagonized by EX527. Icosapent alleviated acetic acid-induced colitis via its anti-inflammatory, antioxidant, and anti-apoptotic effects mediated in part by SIRT1 pathway activation.

Combined Bazedoxifene and Genistein Ameliorate Ovariectomy-Induced Hippocampal Neuro-Alterations via Activating CREB/BDNF/TrkB Signaling Pathway.

OBJECTIVES: The scientific research community devotes stupendous efforts to control the arguable counterbalance between the undesirable effects of hormone replacement therapy (HRT) and post-menopausal syndrome. The recent emergence of 3rd generation selective estrogen receptor modulators and phytoestrogens has provided a promising alternative to HRT. Hence, we assessed the potential effects of combined Bazedoxifene and Genistein on hippocampal neuro-alterations induced by experimental ovariectomy. METHODS: For this purpose, we utilized forty-eight healthy sexually mature female Wistar rats assorted to control, ovariectomy (OVX), Genistein-treated ovariectomized (OVX+GEN) and Bazedoxifene and Genistein-treated ovariectomized (OVX+BZA+GEN) groups. Hippocampi samples from various groups were examined by H&E, silver stains and immunohistochemical examination for calbindin-D28k, GFAP, and BAX proteins. We also assessed hippocampal mRNA expression of ERK, CREB, BDNF and TrkB. RESULTS: Our histopathological results confirmed that combined BZA+GEN induced restoration of hippocampal neuronal architecture, significant reduction of GFAP and BAX mean area % and significant upregulation of calbindin-D28k immunoexpression. Furthermore, we observed significant upregulation of ERK, CREB, BDNF and TrkB mRNA expression in the BZA+GEN group compared to the OVX group. CONCLUSION: Taken together, our findings have provided a comprehensive assessment of histological, immunohistochemical and cyto-molecular basis of combined Genistein and Bazedoxifene ameliorative impacts on hippocampal neuro-alterations of OVX rats via upregulation of Calbindin, CERB, BDNF, Trk-B and ERK neuronal expression.

p53, Pirh2, and L1CAM as Promising Prognostic Biomarkers of Endometrial Carcinoma: An Immunohistochemical and Genetic Study.

Endometrial cancer (EC) is the most common gynecologic cancer and the current methods for the prediction of its prognosis and treatment response are unfortunately suboptimal. In this study, we evaluated the prognostic value of p53, Pirh2, and L1CAM in 60 cases of EC using immunohistochemistry (IHC) and polymerase chain reaction. TP53 missense mutations result in nuclear accumulation of p53 protein that can be detected as overexpression by IHC. This is in the form of diffuse strong nuclear positivity involving at least at least >50% of the tumor cells as a whole or if >50% of the tumor cells of a discrete geographical areas. Abnormal p53 IHC expression was expressed in 33.3% of the cases and significantly associated with the tumor grade, myometrial invasion (MI), lymphovascular invasion (LVSI), nodal metastasis, and FIGO stage, and the advanced European Society for Medical Oncology (ESMO) risk groups ( P <0.001 for each). High IHC Pirh2 expression was noted in 58.3% of the cases, and significantly associated with MI, LVSI, nodal metastasis, FIGO stage, and high-risk group ( P <0.001, P =0.011, P =0.010, P =0.024, P =0.005, respectively). There was a significant upregulation of Pirh2 mRNA expression in EC specimens as compared with the control adjacent tissues ( P =0.001). Upregulated Pirh2 mRNA expression had a significant association with Pirh2 immunostaining, tumor grade, tumor stage, MI, lymph node involvement, LVSI, and relapse ( P <0.001 for each). Positive L1CAM immunoexpression was noted in 26.7% and was significantly associated with grade, MI, LVSI, nodal metastasis, FIGO stage, and high-risk group ( P =0.003, P =0.023, P =0.003, P <0.001, P <0.001, P =0.002, respectively). Analysis of follow-up period revealed that EC with abnormal p53 IHC expression, high pirh2 and positive L1CAM expression exhibited a potent relation with tumor relapse, shorter overall survival and disease-specific survival ( P <0.001 for each). Mutant p53, high Pirh2, and L1CAM-positive EC are highly aggressive tumors with a shortened survival rate, dismal outcome, and high risk of relapse after the standard protocol of therapy.

The protective role of exogenous Ghrelin versus its combination with Zingerone on experimentally induced gastric ischemic-reperfusion in adult male albino rats.

Ghrelin is a gut hormone has stimulatory properties on food intake, fat deposition and growth hormone release. Zingerone is a component of ginger with multiple pharmacological activities. They were established that have protective roles against oxidative stress actions.  We planned this study to evaluate pretreatment exogenous Ghrelin alone and or accompanied with Zingerone on ischemia-reperfusion injury to gastric fundus wall. Fifty male albino rats were used and subdivided into control, ischemic- reperfusion, Ghrelin pretreated and Ghrelin Zingerone pretreated groups. Specimens from the stomach fundus were processed for histological, immunohistochemical study and gene expression using real time PCR. Morphometric and statistical analyses were also carried out in this research. In ischemic-reperfusion sections, there were deep erosion and distortion of the mucosa. Chief cells appeared with vacuolated cytoplasm and pyknotic nuclei. Congestion of blood vessels with extravasation and cellular infiltration was also noticed. There was a decrease in mucous secreted cells in PAS-stained sections. Sections from Ghrelin pretreated and Ghrelin Zingerone pretreated groups showed a great improvement. In addition, gastric tissues with the ischemia-reperfusion group showed a significant decrease in enos and nrf2 mRNA expression while there was a significant increase in HIF and VEGF, which is counteracted to Ghrelin pretreated and Ghrelin Zingerone pretreated groups. This study revealed the vital protective role of Ghrelin in concomitant with Zingerone than pretreated Ghrelin alone on attenuating the damage changes of fundus that occurred after experimentally induced gastric ischemia-reperfusion.

Evaluation of Different Doses of the Aromatase Inhibitor Letrozole for the Treatment of Ectopic Pregnancy and Its Effect on Villous Trophoblastic Tissue.

Letrozole, an aromatase inhibitor, has recently been introduced as a favorable medical treatment for ectopic pregnancy. We aimed at evaluating the effects of different doses of letrozole for termination of ectopic pregnancy and study their effects on villous trophoblastic tissue. Sixty patients with undisturbed ectopic pregnancy were classified into three equal groups. Group I: the control group that contained women who underwent laparoscopic salpingectomy, Group II: patients who received letrozole (5 mg day-1) for 10 days, and Group III: patients who received letrozole (10 mg day-1) for 10 days. Subsequently, the ß-hCG levels were determined on the first day and after 11 days of treatment. Group IV consisted of patients of GII and GIII; their ß-hCG did not drop below 100 mIU/ml within 11 days, and underwent salpingectomy. Placental tissues from patients undergoing salpingectomy either from the control group or GIV were processed for the evaluation of estrogen (ER) and progesterone (PR) receptors, vascular endothelial growth factor (VEGF), and cleaved caspase 3 (CC-3) expression. Cases exposed to high dose letrozole 10 mg day-1 resulted in a higher ectopic pregnancy resolution rate of 85% (17/20), while the resolution rate of the low dose letrozole-treated group (5 mg day-1) was 65% (13/20), and also showed a significant reduction in ß-hCG levels on the 11th day, 25.63 ± 4.29 compared to the low dose letrozole group 37.91 ± 7.18 (P < 0.001), Meanwhile, the letrozole-treated group GIV showed markedly reduced expression of ER, PR, and VEGF and a significant increase in the apoptotic index cleaved caspase-3 compared to the control group (P < 0.001). The utilization of letrozole at a dose of 10 mg day-1 for medical treatment of ectopic pregnancy results in a high-successful rate without any severe side effects. Letrozole depriving the placenta of estrogen that had vascular supporting signals resulted in destroying the vascular network with marked apoptosis.

Therapeutic effect of the mesenchymal stem cells on vigabatrin-induced retinopathy in adult male albino rat.

Vigabatrin (VGB) is an effective antiepileptic drug used mainly to treat infantile spasms and refractory complex partial seizures. However, using VGB was restricted as it was known to cause retinal toxicity that appears as a severe peripheral visual field defect. Accordingly, this study was conducted to examine the histopathological and biochemical effects of VGB on the retina in adult male albino rats and assess the possible therapeutic role of mesenchymal stem cells (MSCs) against this potential toxicity. The rats were divided into three groups (control group, VGB group, and VGB/MSCs group), one week after 65 days of VGB treatment ±MSCs. The right eyeballs were prepared for histological and immunohistochemical examination, whereas the left eyeballs were prepared for real-time polymerase chain reaction analysis. Our results demonstrated that MSCs ameliorated retinal pathological changes and downregulated the expression of glial fibrillary acidic protein, vascular endothelial growth factor, and synaptophysin after VGB administration suggesting MSCs function and vascular modulating effect. Moreover, MSCs regulate retinal tissue gene expression of BAX, Bcl-2, BDNF, NGF, synapsin, interleukin (IL)-6, IL-1ß, and occludin suggesting MSCs antiapoptotic and immunomodulating effect. In conclusion, MSCs administration could be a suitable therapeutic line to ameliorate VGB-induced retinopathy.

Hypoxia pretreatment enhances the therapeutic potential of mesenchymal stem cells (BMSCs) on ozone-induced lung injury in rats.

Ozone (O3) gas is a double-sided weapon. It provides a shield that protects life on earth from the harmful ultraviolet (UV) rays, but ground-level O3 is considered an urban air pollutant. So, a rat model of chronic O3 inhalation was established to assess the biochemical and morphological alterations in the lung tissue and to investigate the ameliorative effects of bone marrow-derived mesenchymal stem cells (BMSCs) with or without hypoxia pre-treatment. Forty-two adult male albino rats were divided into four groups: control, ozone-exposed, normoxic BMSC-treated, and hypoxic BMSC-treated groups. Lung tissue sections were processed for light and electron microscope examination, immunohistochemical staining for caspase 3, and iNOS. Quantitative real-time PCR for IL-1α, IL-17, TNF-α, and Nrf2 mRNA gene expression were also performed. Chronic O3 exposure caused elevated inflammatory cytokines and decreased antioxidant Nrf2 mRNA expression. Marked morphological alterations with increased collagen deposition and elevated apoptotic markers and iNOS were evident. BMSC treatment showed immunomodulatory (decreased inflammatory cytokine gene expression), antioxidant (increased Nrf2 expression and decreased iNOS), and anti-apoptotic (decreased caspase3 expression) effects. Consequently, ameliorated lung morphology with diminished collagen deposition was observed. Hypoxia pretreatment enhanced BMSC survival by MTT assay. It also augmented the previously mentioned effects of BMSCs on the lung tissue as proved by statistical analysis. Lung morphology was similar to that of control group. In conclusion, hypoxia pretreatment represents a valuable intervention to enhance the effects of MSCs on chronic lung injury.

Histomorphological changes and molecular mechanisms underlying the ameliorative effect of resveratrol on the liver of silver nanoparticles-exposed rats.

Exposure to the deleterious effects of silver nanoparticles (AgNPs) is inevitable due to their wide use in medicine and daily life. The current study aimed to delineate the histomorphological changes and the molecular mechanisms underlying the ameliorative effect of Resveratrol (RSV) on rats' livers exposed to AgNPs. Fifty healthy adult male Wistar albino rats were divided into four groups: control, AgNPs-exposed, RSV-treated after AgNPs exposure, and recovery groups. Liver sections were examined by light and electron microscopes, and immunohistochemistry was performed for detection of activated caspase3 and TNFα. Serum ALT and AST, plasma levels of TNFα, IL-6, GSH and SOD were measured. mRNA expression of SIRT1, ADORA3, PAI, CDK1, Nrf2 and NFκB genes in liver tissue homogenate was performed using qRT-PCR. AgNPs-exposure for 28 days caused marked liver tissue damage with trapping in hepatocytes and Kupffer cells, while RSV treatment ameliorated liver ultrastructure and function. Our results clarified the molecular basis of RSV ameliorative effect on liver tissue by significant upregulation of SIRT1-NrF2 signaling pathway with increased levels of the antioxidant GSH and SOD, which represent the antioxidant effect of RSV. Significant upregulation of the protective ADORA3 with downregulation of the proinflammatory PAI-1 and NFκB mRNA expression levels besides decreased plasma levels of TNFα, IL-6 and decreased immunoexpression of TNFα in liver tissue, represent the anti-inflammatory effect of RSV. In addition, decreased immunoexpression of caspase3 and downregulation of CDK1 expression, represent its antiapoptotic effect. In conclusion: RSV ameliorates AgNPs-induced liver damage by antioxidant, anti-inflammatory and antiapoptotic effects.Abbreviations: AgNPs: Silver nanoparticles, RSV: Resveratrol, ROS: Reactive oxygen species, ESR: Electron spin resonance, DMPO: 5,5-Dimethyl-1-pyrroline-N-oxide, H2O2: Hydrogen peroxide, SOD: Superoxide dismutase, CAT: Catalase, GPx: Glutathione peroxidase, MPTP: Methyl-4-phenyl-1.2.3.6-tetrahydropyridine, MDA: Malondialdehyde, TNF: Tumor necrosis factor, GSH: Glutathione, Nrf2: Nuclear factor-erythroid 2-related factor 2, ARE: Antioxidant response elements, KEAP1: Kelch-1ike ECH-associated protein l, AMPK: AMP-activated protein kinase, HO-1: Heme oxygenase-1, NF-κB: Nuclear factor-kappa B, SIRT1: Sirtuins, FOXO: Forkhead box, UCP2: Uncoupling protein 2, STZ: Streptozotocin nicotinamide, HSC: hepatic stellate cells, ECM: extracellular matrix.