Triggering Breast Cancer Apoptosis via Cyclin-Dependent Kinase Inhibition and DNA Damage by Novel Pyrimidinone and 1,2,4-Triazolo[4,3-a]pyrimidinone Derivatives.

Combinations of apoptotic inducers are common clinical practice in breast cancer. However, their efficacy is limited by the heterogeneous pharmacokinetic profiles. An advantageous alternative is merging their molecular entities in hybrid multitargeted scaffolds exhibiting synergistic activities and uniform distribution. Herein, we report apoptotic inducers simultaneously targeting DNA and CDK-2 (cyclin-dependent kinase-2) inspired by studies revealing that CDK-2 inhibition sensitizes breast cancer to DNA-damaging agents. Accordingly, rationally substituted pyrimidines and triazolopyrimidines were synthesized and assayed by MTT against MCF-7, MDA-MB231, and Wi-38 cells compared to doxorubicin. The N-(4-amino-2-((2-hydrazinyl-2-oxoethyl)thio)-6-oxo-1,6-dihydropyrimidin-5-yl)acetamide 5 and its p-nitrophenylhydrazone 8 were the study hits against MCF-7 (IC50 = 0.050 and 0.146 µM) and MDA-MB231 (IC50 = 0.826 and 0.583 µM), induced DNA damage at 10.64 and 30.03 nM, and inhibited CDK-2 (IC50 = 0.172 and 0.189 µM). 5 induced MCF-7 apoptosis by 46.75% and disrupted cell cycle during S phase. Docking and MD simulations postulated their stable key interactions.

Involvement of Nrf2-PPAR-γ signaling in Coenzyme Q10 protecting effect against methotrexate-induced testicular oxidative damage.

Studies have identified Coenzyme Q10 (CoQ10) as a promising agent in improving idiopathic male infertility; however, its role in chemically or environmentally induced testicular dysfunction is not well-established. We investigated the potential of CoQ10 to attenuate methotrexate (MTX)-induced testicular damage and to identify molecular targets of CoQ10 effects. Wistar rats received a single intraperitoneal dose of 20 mg/kg MTX on the fifth day of the 10-day experimental protocol. 100 mg/kg CoQ10 was given orally daily for ten days, alone or combined with MTX. The testes of MTX-treated animals showed thickened tunica albuginea, distortion of seminiferous tubules with a marked reduction of germinal lining, a few primary spermatocytes with no spermatozoa, apoptotic cells, congested sub-capsular and interstitial blood vessels, and interstitial edema. Reduction of reproductive hormones and increased oxidative, inflammatory, and apoptotic biomarkers levels were also seen in the MTX-treated rats. CoQ10 + MTX-treated rats were protected against MTX-induced testicular histological changes and showed improvement in testosterone, luteinizing-, and follicle-stimulating hormone serum levels compared to the MTX group. The testes of the CoQ10 + MTX-treated rats showed reduced malondialdehyde, myloperoxidase, tumor necrosis factor -α, interleukin-6 and -1ß and Bax: Bcl2 ratio and enhanced glutathione, and catalase compared to MTX alone. CoQ10 enhanced MTX-induced downregulation of Nrf2 and PPAR-γ signaling and modulated its downstream targets, the inducible nitric oxide synthase, NF-κB, Bax, and Bcl2. In conclusion, CoQ10 targeted the Nrf2-PPAR-γ signaling loop and its downstream pathways, mitigating MTX-induced oxidative stress-related damages and alleviating the testicular dysfunction MTX caused. Our data suggest Nrf2-PPAR-γ signaling as a potential therapeutic target in testicular toxicity, where oxidative stress, inflammation, and apoptosis trigger damage.

Zinc's protective role against hydroxychloroquine-induced cardiac effects in adult male albino rats.

Background: Long exposure to Hydroxychloroquine (HCQ) has been complicated by some dangerous though infrequent cardiotoxicity. Methods: A total of 40 normal adult male albino rats dispersed into 4 groups were used. Group 1 (Control group), Group II (HCQ treated group), Group III (zinc [Zn]-treated group), and Group IV (HCQ and Zn treated group). Once the experimentation ended, rats were sacrificed and cardiac soft tissue sections were processed twenty-four hours at the end of the experiment for histological study. Results: Cardiac-stained sections revealed that HCQ induced widespread necrosis, dilatation, and vacuolar degeneration. However, the combination of HCQ with Zn ameliorated these damaging effects. Cardiac enzyme parameters were also studied in the 4 groups and revealed CK-MB and troponin were considerably elevated in groups II associated to the control group. Conclusion: It was concluded that Zn revealed a protective role against HCQ cardiomyopathy in adult male albino rats. This might signify an appreciated means for Zn-based treatment in the upcoming subsequent clinical records to adjust doses and guarantee patient safeguard.

The impact of oral ciprofloxacin on the structure and functions of rat gastric mucosa.

Ciprofloxacin (CPX), is a fluoroquinolone antibiotic used to treat a number of gram-negative and gram-positive bacterial infections. Ciprofloxacin can cause severe side effects, ranging from tendon problems, nerve damage, to serious mood or behavior changes. The purpose of this study was to investigate how ciprofloxacin affects gastric cell lines in rats with a distinctive emphasis on physiological, histopathological, and bacteriological changes. Male albino rats (n = 21) were distributed into three groups; control, CPX, and CPX-withdrawal groups. The treated rats were given CPX tablets (12.5 mg/kg) dissolved in carboxymethyl cellulose (CMC) 0.5% orally once daily via gavage for sixty consecutive days. Control rats received only the vehicle. The withdrawal group was treated for 60 days and the drug was withdrawn for another sixty days. After completion of the experiment, all rats were sacrificed and gastric tissues were treated for light, immunohistochemical, and scanning electron microscopic examination. Image J software was used to measure immune-labeled gastric epithelial cells. Blood samples were also collected for H. Pylori immunoglobulins IgM, IgA, and IgG. Results showed that treated rats acquired significantly strongly positive tumor necrosis factor (TNFα) and significant reduction of serum level of H. pylori IgM, IgA, and IgG in all the study groups. It could be concluded that prolonged oral CPX administration to albino rats changes the gastric mucosal architecture and bacteriology.

Thyroid cancer risk factors and Pakistani University students' awareness towards its preventive practice.

OBJECTIVES: Thyroid Cancer is one of the rarest cancers but its prevalence has been increasing worldwide for the last couple of decades. METHODS: The data collection tool was designed to assess knowledge, awareness, perception, and attitude towards preventive practices of thyroid cancer in Pakistani university students. The data were collected over a duration of six months and a total number of 3722 students participated. RESULTS: The knowledge of risk factors of thyroid cancer was an important parameter of this study. The students who knew all the early signs of thyroid cancer were 28.7%. In this study, the independent variables such as age, gender, demographic location, and financial status were found to be highly significant with knowledge, attitude towards warning signs of cancer, and the perception of students about developing thyroid cancer. CONCLUSIONS: The participants were found to have poor knowledge about early signs of thyroid cancer. The study participants perception, behavior, and attitude towards preventive practices of thyroid cancer were found inadequate and appropriate measures on a National level should be taken to enhance the knowledge about preventive practices of thyroid cancer. Increasing knowledge and awareness shall help decrease the overall morbidity and mortality linked with thyroid carcinomas and thyroid diseases.

Adherence of Geriatric Patients and Their Beliefs toward Their Medicines in the United Arab Emirates.

INTRODUCTION: Drug adherence is a major factor in determining health outcomes of geriatric patients and is a growing concern for health-care systems as the geriatric population shows a steep rise due to improved health-care services in the UAE. AIM: We aimed to evaluate the adherence and beliefs of geriatric patients in the UAE toward their medicines and to explore the factors affecting them. METHODS: A cross-sectional study was performed including 163 geriatric patients. Surveys, direct observations, and interviews were used for primary data collection. Demographic data were computed using descriptive statistics method. The Statistical Package for the Social Sciences (SPSS) program, Version 19.0, SPSS Inc., Chicago, IL, USA, was used to analyze and code the raw data, whereas chi-squared test was used to analyze the responses. Secondary data were also collected. RESULTS: The results indicated that patient factors and medication factors are the main risk factors for medication nonadherence among geriatric patients in the UAE. The study found that drug regimen (91.4%, N = 149), forgetfulness (87.1%, N = 142), time constraints (67.5%, N = 110), and cost (55.2%, N = 90) were the main key factors affecting medication adherence. Also, poor communication (12.9%), the lack of trust (16.6%), confidence (20.2%), and patient involvement (43.6%) were shown to influence adherence behaviors to medication. The main habits, attitudes, and beliefs that were found to affect patient's adherence were follow-ups (73%), inadequate knowledge of medicine (60.1%), the lack of perceived benefits (18.4%), and limited knowledge on health conditions (19.6%). The study showed 161 patients among the total 163 participants forget taking their medications and others cease from taking their medications. To conclude, nonadherence to medications is a substantial problem among the elderly in the UAE. CONCLUSION: The study findings confirm the need for further research to examine the perspectives of at-risk population with a focus on knowledge, beliefs, and attitudes on medication nonadherence.

Testosterone therapy in hypogonadal patients and the associated risks of cardiovascular events.

Since the male secondary sex characters, libido and fertility are attributed to their major androgen hormone testosterone, the sub-optimum levels of testosterone in young adults may cause infertility and irregularities in their sexual behaviour. Such deficiency is often secondary to maladies involving testes, pituitary or hypothalamus that could be treated with an administration of exogenous testosterone. In the last few decades, the number of testosterone prescriptions has markedly increased to treat sub-optimal serum levels even though its administration in such conditions is not yet approved. On account of its associated cardiovascular hazards, the food and drug authority in the United States has issued safety alerts on testosterone replacement therapy (TRT). Owing to a great degree of conflict among their findings, the published clinical trials seem struggling in presenting a decisive opinion on the matter. Hence, the clinicians remain uncertain about the possible cardiovascular adversities while prescribing TRT in hypogonadal men. The uncertainty escalates even further while prescribing such therapy in older men with a previous history of cardiovascular ailments. In the current review, we analysed the pre-clinical and clinical studies to evaluate the physiological impact of testosterone on cardiovascular and related parameters. We have enlisted studies on the association of cardiovascular health and endogenous testosterone levels with a comprehensive analysis of epidemiological studies, clinical trials, and meta-analyses on the cardiovascular risk of TRT. The review is aimed to assist clinicians in making smart decisions regarding TRT in their patients.

Pathophysiology of the Risk Factors Associated with Osteoporosis and their Correlation to the T-score Value in Patients with Osteopenia and Osteoporosis in the United Arab Emirates.

INTRODUCTION: Osteoporosis is a growing major health problem with medical, social, and economic burden. The pathogenesis of osteoporosis involves excessive bone resorption by osteoclasts and decreased new bone formation by osteoblasts. Early diagnosis is the key to minimize the impact of osteoporosis on patients. Dual-energy X-ray absorptiometry at the hip or spine is the main standard test for measuring bone mineral density, and according to the World Health Organization, the T-score value of -2.5 or less determines osteoporosis. AIM: In this work, we aimed to study the risk factors associated with osteoporosis among a population sample of osteoporotic and controls in the United Arab Emirates (UAE) and relate them to the T-score value. MATERIAL AND METHODS: Two hundred male and female participants were recruited in the study. A questionnaire was used and data were correlated with the T-score value of the participants. RESULTS: Results showed a positive correlation between the T-score value of the patients with osteoporosis and their calcium intake, exercise duration, and the age at menopause of female patients, whereas a negative correlation was evident between the T-score value and both caffeine and nicotine consumption. Results also revealed that patients with osteoporosis have significantly low body mass index, low calcium intake, and shorter duration of exposure to the sun than the control group. CONCLUSION: In conclusion, more intervention should be directed toward changing the modifiable risk factors in patients with osteoporosis and more studies should be directed toward osteoporosis in the UAE.