Impact of Juglone, a PIN1 Inhibitor, on Oral Carcinogenesis Induced by 4-Nitroquinoline-1-Oxide (4NQO) in Rat Model.

Background and Objectives: PIN1 is overexpressed in several human cancers, including prostate cancer, breast cancer, and oral squamous carcinomas. Juglone (J), derived from walnut, was reported to selectively inhibit PIN1 by modifying its sulfhydryl groups. In this study, the potential effects of juglone, also known as PIN1 inhibitor, on oral cancer and carcinogenesis were investigated at the molecular level. Materials and Methods: 4-Nitroquinoline N-oxide (4-NQO) was used to create an oral cancer model in animals. Wistar rats were divided into five groups: Control, NQO, Juglone, NQO+J, and NQO+J*. The control group received the basal diet and tap water throughout the experiment. The NQO group received 4-NQO for 8 weeks in drinking water only. The Juglone group was administered intraperitoneally in a juglone solution for 10 weeks (1 mg/kg/day). The NQO+J group received 4-NQO in drinking water for 8 weeks, starting 1 week after the cessation of 4-NQO treatment. They were then administered intraperitoneally in a juglone solution for 10 weeks. (1 mg/kg/day). NQO+J* group: received 4 NQO for 8 weeks in drinking water and administered intraperitoneally in a juglone solution for 10 weeks (1 mg/kg/day). They were sacrificed at the end of the 22-week experimental period. The tongue tissues of the rats were isolated after the experiment, morphological changes were investigated by histological examinations, and the molecular apoptotic process was investigated by rt-qPCR and western blot. Results: Histological results indicate that tumors are formed in the tongue tissue with 4-NQO, and juglone treatment largely corrects the epithelial changes that developed with 4-NQO. It has been determined that apoptotic factors p53, Bax, and caspases are induced by the effect of juglone, while antiapoptotic factors such as Bcl-2 are suppressed. However, it was observed that the positive effects were more pronounced in rats given juglone together with 4-NQO. Conclusions: The use of PIN1 inhibitors such as juglone in place of existing therapeutic approaches might be a promising and novel approach to the preservation and treatment of oral cancer and carcinogenesis. However, further research is required to investigate the practical application of such inhibitors.

Retrospective Evaluation of Survival and Prognostic Factors in Immune Thrombocytopenia: A Single-Center and Cross-Sectional Study.

Background and Objectives: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by the autoantibody-mediated destruction of platelets. The treatment of ITP aims to maintain a sufficient platelet count to prevent bleeding. First-line treatment options include corticosteroids and intravenous immunoglobulin (IVIg), while second-line treatments include splenectomy, rituximab and other immunosuppressive agents, and thrombopoietin (TPO) receptor agonists. This study aims to discuss the treatment methods and results from 100 patients with ITP at the Mugla Training and Research Hospital through a pharmacological approach. Materials and Methods: Demographic characteristics, clinical findings, bone marrow aspiration and biopsy results, and treatments and treatment responses at the time of diagnosis of the 100 patients with ITP who were treated and followed up in the period 2015-2023 were evaluated retrospectively. Results: In the third month after treatment, the overall response percentage was 100% in patients who received steroids only and 88% in patients who received IVIg treatment alone or in combination with steroids (p > 0.05). The most preferred second-line treatments were splenectomy (41%), eltrombopag (26%), and rituximab (10%). Bone marrow biopsy was performed in 54% of patients, where 35.1% showed increased megakaryocytes, 44.4% adequate megakaryocytes, and 14.8% decreased megakaryocytes. It is noted that eltrombopag and rituximab, in particular, yield higher complete remission rates than immunosuppressive drugs. Conclusions: Considering the side effects of immunosuppressive medications, IVIg, splenectomy, and steroid therapy, the use of new agents such as eltrombopag, which are easily tolerated and have a lower risk of side effects, is expected to increase.

Differential Expression and in Silico Functional Analysis of Plasma MicroRNAs in the Pathogenesis of Non-segmental Vitiligo.

Vitiligo is a disease characterized by acquired depigmentation, white macules, and patches on the skin due to the dysfunction of epidermal melanocytes. In this study, we attempt to profile the microRNA (miRNA) expression patterns and predict the potential targets, assessing the biological functions of differentially expressed miRNAs in the blood of generalized vitiligo patients. Peripheral blood samples were taken from all participants, and the expression levels of 89 identified miRNAs were analyzed with real-time quantitative polymerase chain reaction (PCR). The results indicated significant upregulation of six miRNAs and downregulation of 19 miRNAs in the plasma of vitiligo patients. The top three upregulated miRNAs were hsa-miR-451a, hsa-miR-25-3p, and hsa-miR-19a-3p, and the top three downregulated miRNAs were hsa-miR-146a-5p, hsa-miR-940, and hsa-miR-142-3p. Moreover, the miRNA expression profiles of patients with Type 3 and Type 4 phototypes were substantially different in such a way that the patients with Type 3 phototype would be more prone to the emergence of melanoma and cancer. While significant variations in the expression patterns of miRNAs in male and female vitiligo patients were demonstrated, miR-let-7i-5p, miR-19a-3p, miR-25-3p, and miR-451a were commonly upregulated, and miR-142-3p and miR-146a-5p were commonly repressed in both sexes. This study may shed light on the roles of differentially expressed miRNAs in vitiligo patients by examining the miRNA expression patterns and the combined effects of miRNA and their predicted targets.

Masseter muscle and gingival tissue inflammatory response following treatment with high-fructose corn syrup in rats: Anti-inflammatory and antioxidant effects of kefir.

The aim of the study was to evaluate whether high-fructose corn syrup (HFCS) intake (20% beverages) impacts antioxidative structures and inflammation in the gingival tissue and masseter muscle of rats. Kefir was tested for its potential utility on changes induced by HFCS. Animals were randomly divided into four groups as control, kefir, HFCS, and HFCS plus kefir. HFCS was given as 20% solutions in drinking water while kefir supplementations were given by gastric gavage for 8 weeks. It has been clearly determined that the HFCS diet increased expressions of interleukin (IL)-6, IL-1ß, and tumor necrosis factor-α proinflammatory structures via lymphocyte infiltration by suppressing antioxidant enzymes such as catalase, superoxide dismutase, and glutathione peroxidase in both tissues. Kefir improved these undesirable changes in rats fed with HFCS. The results of this current study, the first investigation to examine the effects of kefir on masseter muscle and gingival tissue, may provide new access to the restorative effects of kefir consumption on oral health disorders caused by high fructose in the diet. PRACTICAL APPLICATIONS: In this study, at an early age, the effects of kefir on improving inflammation via antioxidation in the masseter muscle and gingival tissue were investigated for the first time. We showed that kefir feeding ameliorates lymphocyte infiltration on the high-fructose corn syrup (HFCS)-induced masseter muscle and gingival tissue inflammation in rats. The mRNA expressions of inflammatory parameters measured in the study were supported by protein measurements via ELISA or immunohistochemistry. In the present study, kefir may play an important role in the antioxidation and inflammation process on the masseter muscle and gingival tissue against HFCS.

Potential Anti-Tumor Activity of Kefir-Induced Juglone and Resveratrol Fractions Against Ehrlich Ascites Carcinoma-Bearing BALB/C Mice.

We investigated the potential influence of kefir-induced juglone and resveratrol fractions (JRK) against Ehrlich Ascites Carcinoma (EAC) bearing BALB/c male mice. Kefir yeast was grown in the cell culture supplemented with juglone and resveratrol (1:2). After 48 h incubation, JRK solution was applied (0.1 mL/day i.p.) to the EAC-bearing mice throughout five days. Molecular regulatory mechanisms of apoptotic and anti-apoptotic pathway components were evaluated in the plasma of mice and isolated EAC cells with ELISA, qRT-PCR, and immunocytchemical experiments. EAC-induced upregulation in Bcl-2 and downregulation in Caspase-3 were normalized with JRK in the plasma of mice. Additionally, JRK upregulated the expression levels of apoptotic Bax, p53, Caspase-3,8,9, and APAF-1 proteins together with BAX, CASPASE-8, and CASPASE-9 genes in isolated EAC cells. These changes were also associated with decreased expression levels of anti-apoptotic Bcl-2 and Bcl-xl proteins. Immunocytochemical studies also confirmed the activation of apoptotic pathways and repression of anti-apoptotic proteins in EAC cells with JRK treatment. JRK activates apoptotic pathway and inhibits anti-apoptotic genes and proteins in Ehrlich ascites carcinoma- bearing BALB/c mice that could be beneficial in cancer treatment.

Dietary Fructose-Induced Hepatic Injury in Male and Female Rats: Influence of Resveratrol.

Purpose: Relatively little is known about gender-dependent susceptibility to hepatic injury induced by nutritional factors. In the current study, we investigated dietary fructose-induced hepatic degeneration and roles of endothelial nitric oxide synthase (eNOS), insulin receptor (IRß) and substrate-1 (IRS-1) expressions in association with inflammatory markers in male and female rats. Moreover, we examined potential effect of resveratrol on fructose-induced changes. Methods: Male and female rats were divided into 4 groups as control, resveratrol, fructose and resveratrol plus fructose. All rats were fed with a standard diet with or without resveratrol (500 mg/kg). Fructose was given as 10% in drinking waterfor 24 weeks. Results: Long-term dietary fructose caused parenchymal degeneration and hyperemia in association with impaired eNOS mRNA/protein expressions in liver of male and female rats. This dietary intervention also led to increases in hepatic triglyceride content, TNFα and IL-1ß levels in both genders. Gender-related differences to consequence of fructose consumption were not obvious. Resveratrol supplementation markedly attenuated hepatic degeneration, hyperemia and triglyceride content in association with reduced TNFα and IL-1ß levels, but enhanced IRß mRNA and IRS-1 protein, in male and female rats upon fructose feeding. Conclusion: Long-term dietary fructose causes hepatic degeneration possibly via a decrease in eNOS, but increase in TNFα and IL-1ß, in both genders. Resveratrol supplementation improved fructose-induced hepatic injury.

Resveratrol Ameliorates the Components of Hepatic Inflammation and Apoptosis in a Rat Model of Streptozotocin-Induced Diabetes.

Preclinical Research Trans-resveratrol has a wide range of biological effects that reflect its antioxidant, anti-inflammatory, anticarcinogenic and cardioprotective properties. This study was conducted to elucidate the potential role of resveratrol on hepatic inflammation and the apoptotic pathway components Bcl-2, Bax and p53 in a streptozotocin (STZ)-induced rat model of diabetes mellitus. Inflammatory and apoptotic biomarkers indicated a reduction in hepatic erythropoietin (1.26-fold) and increased asymmetric dimethylarginine (3.9-fold), visfatin (1.6-fold), inflammatory interleukins and TNF-α contents (approximately twofold each) in the diabetic animals. Induction of inducible nitric oxide synthase gene (2.04-fold) and protein expression (1.24-fold) was also observed. Immunohistochemical studies showed enhancement of the apoptotic biomarkers Bax and p53 in diabetic animals. STZ-induced diabetic male Wistar rats were treated with resveratrol (20 mg/kg/day i.p.). Resveratrol succeeded to recover most of these inflammatory and apoptotic elements. Therefore, inflammatory and apoptotic pathways were proved to be affected by STZ-induced diabetes in several aspects and resveratrol might contribute hepatoprotective effects as evidenced from this study.

Nebivolol compared with metoprolol for erectile function in males undergoing coronary artery bypass graft.

OBJECTIVE: The aim of this study was to evaluate erectile function in males undergoing coronary artery bypass graft (CABG) while on two different adrenoceptor beta-blocker regimens, namely nebivolol and metoprolol. We hypothesize that the negative effects of cardiopulmonary bypass on erectile function may be possibly attenuated by preferring a vasodilating selective ß1-blocker, nebivolol, to metoprolol as an anti-ischemic and antiarrhythmic agent in males undergoing CABG. METHODS: This randomized, double-blind, prospective clinical study was conducted in patients scheduled for CABG surgery between February 2012 and June 2014. A total of 60 consecutive patients who met inclusion criteria were randomized and divided into the following two groups: N group, which received 5 mg of nebivolol orally for 2 weeks before surgery plus 12 weeks after surgery or M group, which received 50 mg of metoprolol orally for the same period. All patients were evaluated by the erectile function domain of the International Index of Erectile Function-5 (IIEF-5) at the time of admission (before starting the beta-blocker) and 3 months after surgery. RESULTS: In the metoprolol group, the mean IIEF-5 score decreased significantly from a baseline of 15.2±5.8 to 12.9±5.8 (p<0.001), but in the nebivolol group, this difference was not significant (from a baseline 12.9±5.5 to 12.4±5.5, p=0.053). In all patients, the mean IIEF-5 score decreased significantly from a baseline of 14.0±5.7 to 12.6±5.6 (p<0.001). CONCLUSION: Although erectile function in males undergoing CABG surgery decreases when metoprolol is used, nebivolol exerts protective effects on erectile function against the disruptive effects of cardiopulmonary bypass in patients undergoing CABG.

L-Carnitine Supplementation Reduces Short-Term Neutrophil-Lymphocyte Ratio in Patients Undergoing Coronary Artery Bypass Grafting.

This study aims to investigate whether preoperative L-carnitine supplementation affects the neutrophil-to-lymphocyte ratio (NLR) in patients undergoing coronary artery bypass grafting surgery. The neutrophil-to-lymphocyte ratio is an inflammatory marker that has proven usefulness for predicting postoperative complications in coronary artery bypass surgery. A lot of studies concerning the role of L-carnitine in the immune system have been performed, contradictory results have been reported on its effects on absolute numbers of WBC subtypes. This randomized, double-blinded, placebo-controlled study was conducted among patients scheduled for coronary artery bypass grafting surgery between June 2012 and December 2013 in our cardiovascular surgery clinic. A total of 60 consecutive patients were randomized and divided into 2 groups. The first group received 2 g of L-carnitine in 1000 mL of 0.9% saline solution infused over 24 hours for each of the 3 preoperative days (L-carnitine group, n = 30), or only 1000 mL of 0.9% saline solution for the same time period (placebo group, n = 30). The basal values of leukocyte, neutrophil, lymphocyte counts, and neutrophil to lymphocyte ratio were similar in the 2 groups. After L-carnitine supplementation (just before surgery), leukocyte and neutrophil counts of the L-carnitine group were significantly lower than those of the placebo group (7.7 ± 1.5 versus 9.7 ± 2.6, P < 0.001 and 4.6 ± 1.3 versus 6.5 ± 2.2, P < 0.001). On postoperative day 1, lymphocyte counts were significantly higher in the L-carnitine group (1.1 ± 0.6 versus 0.8 ± 0.9, P < 0.001). Moreover, the increase in NLR was significantly lower in the L-carnitine group at postoperative day 1 (20.7 ± 13.8 versus 10.8 ± 4.1, P < 0.001). Preoperative L-carnitine supplementation may reduce neutrophil-lymphocyte ratio during the early postoperative period of coronary artery bypass grafting surgery.