Targeting inflammation in glioblastoma: An updated review from pathophysiology to novel therapeutic approaches.

Glioblastoma (GBM) is a highly aggressive primary malignant brain tumor with a dismal prognosis despite current treatment strategies. Inflammation plays an essential role in GBM pathophysiology, contributing to tumor growth, invasion, immunosuppression, and angiogenesis. As a result, pharmacological intervention with anti-inflammatory drugs has been used as a potential approach for the management of GBM. To provide an overview of the current understanding of GBM pathophysiology, potential therapeutic applications of anti-inflammatory drugs in GBM, conventional treatments of glioblastoma and emerging therapeutic approaches currently under investigation. A narrative review was carried out, scanning publications from 2000 to 2023 on PubMed and Google Scholar. The search was not guided by a set research question or a specific search method but rather focused on the area of interest. Conventional treatments such as surgery, radiotherapy, and chemotherapy have shown some benefits, but their effectiveness is limited by various factors such as tumor heterogeneity and resistance.

Quillaja saponin mitigates methotrexate-provoked renal injury; insight into Nrf-2/Keap-1 pathway modulation with suppression of oxidative stress and inflammation.

BACKGROUND: Methotrexate (MTX) is an antineoplastic/immunosuppressive drug, whose clinical use is impeded owing to its serious adverse effects; one of which is acute kidney injury (AKI). Most of MTX complications emerged from the provoked pro-oxidant-, pro-inflammatory- and pro-apoptotic effects. Quillaja saponaria bark saponin (QBS) is a bioactive triterpene that has been traditionally used as an antitussive, anti-inflammatory supplement, and to boost the immune system due to its potent antioxidant- and anti-inflammatory activities. However, the protective/therapeutic potential of QBS against AKI has not been previously evaluated. This study aimed to assess the modulatory effect of QBS on MTX-induced reno-toxicity. METHODS: Thirty-two male rats were divided into 4-groups. Control rats received oral saline (group-I). In group-II, rats administered QBS orally for 10-days. In group-III, rats were injected with single i.p. MTX (20 mg/kg) on day-5. Rats in group-IV received QBS and MTX. Serum BUN/creatinine levels were measured, as kidney-damage-indicating biomarkers. Renal malondialdehyde (MDA), reduced-glutathione (GSH) and nitric-oxide (NOx) were determined, as oxidative-stress indices. Renal expression of TNF-α protein and Nrf-2/Keap-1 mRNAs were evaluated as regulators of inflammation. Renal Bcl-2/cleaved caspase-3 immunoreactivities were evaluated as apoptosis indicators. RESULTS: Exaggerated kidney injury upon MTX treatment was evidenced histologically and biochemically. QBS attenuated MTX-mediated renal degeneration, oxidant-burden enhancement, excessive inflammation, and proapoptotic induction. Histopathological analysis further confirmed the reno-protective microenvironment rendered by QBS. CONCLUSIONS: In conclusion, our results suggest the prophylactic and/or therapeutic effects of QBS in treating MTX-induced AKI. Such reno-protection is most-likely mediated via Nrf-2 induction that interferes with oxidant load, inflammatory pathways, and proapoptotic signaling.

Exploring the potential of Aspergillus wentii: secondary metabolites and biological properties.

Fungi are of considerable importance due to their capacity to biosynthesize various secondary metabolites with bioactive properties that draw high attention in new drug discovery with beneficial uses for improving human well-being and life quality. Aspergillus genus members are widespread and cosmopolitan species with varying economic significance in the fields of industry, medicine, and agriculture. Its species are renowned for their biosynthesis of secondary metabolites, characterized by both potent biological activity and structural novelty, making them a substantial reservoir for the development of new pharmaceuticals. The current work aimed at focusing on one species of this genus, Aspergillus wentii Wehmer, including its reported secondary metabolites in the period from 1951 to November 2023. A total of 97 compounds, including nitro-compounds, terpenoids, anthraquinones, xanthones, benzamides, and glucans. A summary of their bioactivities, as well as their biosynthesis was highlighted. Additionally, the reported applications of this fungus and its enzymes have been discussed. This review offers a useful reference that can direct future research into this fungus and its active metabolites, as well as their possible pharmacological and biotechnological applications.

Knowledge, Perception, and Self-Confidence of Antibiotic Resistance, Appropriate Antibiotic Therapy, and Antibiotic Stewardship Among Undergraduate Pharmacy Students in Sudan.

Background: Adequate training in infectious diseases and antibiotic resistance is crucial for pharmacy students to participate in antibiotic stewardship programs and understand microbiology careers. Aim: The study was carried out to assess the knowledge and self-reported confidence in antibiotic resistance, antibiotic therapy, and antimicrobial stewardship (AMS) among final-year undergraduate pharmacy students in Sudan. Methods: A cross-sectional study was conducted in three universities using a 57-item online questionnaire between April and May 2022. Results: A total of 109 students (response rate 36%) participated and showed average knowledge scores of 5.6±1.7 (out of 10.0) for antibiotic resistance, 4.9±2.0 (out of 5.0) for appropriate antibiotic therapy, and 3.1±1.4 (out of 5.0) for AMS. No significant differences were observed among schools. Some students reported poor knowledge about antibiotic therapy and the consequences of resistance. One-third of students lacked confidence in interpreting microbiological results. Knowledge of antibiotic resistance among students' practice area after graduation was higher (p=0.017) and those interested in ID careers (5.8 vs 4.8) (p=0.037). Male students (5.6 vs 4.5) and those interested in ID careers (4.3 vs 3.4) (p<0.001) had higher scores of appropriate antibiotic therapy. Students attended antibiotic resistance courses (51.5 vs 45.2), and those interested in ID significantly had higher self-confidence (55.3 vs 45.8) (p=0.008). Conclusion: Pharmacy students in Sudan have substantial knowledge of AMS and antibiotic resistance with poor knowledge of antibiotic therapy. Adequate training about infectious diseases and related topics is recommended to improve pharmacy students' understanding of microbiological findings, other competencies, and skills to incorporate in antimicrobial stewardship.

Integrating computational methods guided the discovery of phytochemicals as potential Pin1 inhibitors for cancer: pharmacophore modeling, molecular docking, MM-GBSA calculations and molecular dynamics studies.

Pin1 is a pivotal player in interactions with a diverse array of phosphorylated proteins closely linked to critical processes such as carcinogenesis and tumor suppression. Its axial role in cancer initiation and progression, coupled with its overexpression and activation in various cancers render it a potential candidate for the development of targeted therapeutics. While several known Pin1 inhibitors possess favorable enzymatic profiles, their cellular efficacy often falls short. Consequently, the pursuit of novel Pin1 inhibitors has gained considerable attention in the field of medicinal chemistry. In this study, we employed the Phase tool from Schrödinger to construct a structure-based pharmacophore model. Subsequently, 449,008 natural products (NPs) from the SN3 database underwent screening to identify compounds sharing pharmacophoric features with the native ligand. This resulted in 650 compounds, which then underwent molecular docking and binding free energy calculations. Among them, SN0021307, SN0449787 and SN0079231 showed better docking scores with values of -9.891, -7.579 and -7.097 kcal/mol, respectively than the reference compound (-6.064 kcal/mol). Also, SN0021307, SN0449787 and SN0079231 exhibited lower free binding energies (-57.12, -49.81 and -46.05 kcal/mol, respectively) than the reference ligand (-37.75 kcal/mol). Based on these studies, SN0021307, SN0449787, and SN0079231 showed better binding affinity that the reference compound. Further the validation of these findings, molecular dynamics simulations confirmed the stability of the ligand-receptor complex for 100 ns with RMSD ranging from 0.6 to 1.8 Å. Based on these promising results, these three phytochemicals emerge as promising lead compounds warranting comprehensive biological screening in future investigations. These compounds hold great potential for further exploration regarding their efficacy and safety as Pin1 inhibitors, which could usher in new avenues for combating cancer.

Exploring Promising Therapies for Non-Alcoholic Fatty Liver Disease: A ClinicalTrials.gov Analysis.

Background: Non-alcoholic fatty liver disease (NAFLD) is a common disease and has been increasing in recent years. To date, no FDA-approved drug specifically targets NAFLD. Methods: The terms "Non-alcoholic Fatty Liver Disease" and "NAFLD" were used in a search of ClinicalTrials.gov on August 24, 2023. Two evaluators independently examined the trials using predetermined eligibility criteria. Studies had to be interventional, NAFLD focused, in Phase IV, and completed to be eligible for this review. Results: The ClinicalTrials.gov database was searched for trials examining pharmacotherapeutics in NAFLD. The search revealed 1364 trials, with 31 meeting the inclusion criteria. Out of these, 19 were finalized for evaluation. The dominant intervention model was Parallel. The most prevalent studies were in Korea (26.3%) and China (21.1%). The most common intervention was metformin (12.1%), with others like Exenatide and Pioglitazone accounting for 9.1%. Conclusion: Therapeutics used to manage NAFLD are limited. However, various medications offer potential benefits. Further investigations are definitely warranted.

The Effect of Melatonin Supplement on High Arterial Blood Pressure: An Overview from Clinicaltrials.gov.

Background: Melatonin is a hormone produced by the pineal gland primarily at night. It has been suggested that melatonin may possess various cardiovascular benefits, including the potential to lower blood pressure. For this reason, we sought to identify and provide evidence of the effectiveness of melatonin on high arterial blood pressure in clinical trials. Methods: Using the search term "melatonin and hypertension", a search of the ClinicalTrials.gov database was performed on October 10th, 2023. I defined the exclusion and inclusion criteria to isolate appropriate clinical trials. Inclusion criteria for the search included hypertension that utilized melatonin as a treatment supplement; all non-related trials were omitted from the search. The data extractions, including study title, study type, study status, and intervention and outcome details, were compiled. Results: Of the 13 clinical trials identified, only three focused on examining the effects of melatonin. The study titles, enrollment numbers, conditions, statuses, interventions, and outcome measures have been explained in depth. Information gathered from these clinical trials will assist us in identifying the possible risks and benefits of melatonin with respect to high arterial blood pressure. Conclusion: Melatonin has been shown to be an effective treatment for lowering blood pressure. More research is required to fully establish the potential benefits and risks and highlight the mechanisms through which melatonin may influence blood pressure regulation.

The preventive effects of ondansetron on chemotherapy-induced nausea and vomiting in adult cancer patients: systematic review from ClinicalTrials.gov.

Purpose: Cancer is a neoplastic transformation that affects tissue. Among the many complications associated with cancer treatment, managing the distressing side effects of chemotherapy-induced nausea and vomiting (CINV) is of main concern. Ondansetron is a selective serotonin 5-HT3 receptor antagonist that has emerged as an essential medication against CINV in adult cancer patients. Ondansetron efficacy and tolerability have made it a primary medication in CINV prophylaxis and treatment regimens. The study aims to offer a detailed overview of ondansetron's effectiveness, safety, and impact on patients' lives, ultimately contributing to the ongoing research to enhance the quality of cancer care. Methods: On 4 September 2023, a search was conducted of the ClinicalTrials.gov database using the search terms "cancer," "ondansetron," and "Zofran." Inclusion and exclusion criteria were defined to select relevant clinical trials. Included trials were completed with results and interventional studies that assessed the preventive effects of ondansetron on CINV in adult cancer patients. Results: A total of 23 clinical trials were identified, with only 13 of them focusing on investigating the preventive effects of ondansetron on CINV in adult cancer patients. The collective findings from these trials showed an effective management of CINV using ondansetron. Conclusion: Through a comprehensive overview of clinical trials, the use of ondansetron in adult cancer patients represents a significant improvement in CINV management.

Estrogen/estrogen receptor activation protects against DEN-induced liver fibrosis in female rats via modulating TLR-4/NF-kß signaling.

AIM: Men are more susceptible to liver fibrosis (LF) than women. However, the underlying molecular mechanism, especially the role of estrogen/estrogen receptor (ER) activation in this sexual dimorphism is unclear. Therefore, the aim of the current study was to investigate the impact and the underlying molecular mechanisms of estrogen/ER activation on diethyl nitrosamine (DEN)-induced LF. MAIN METHODS: Thirty ovariectomized (OVX) female rats were randomly allocated into five groups (n = 6), and received no treatment, diethyl nitrosamine (DEN), DEN/fulvestrant, DEN/silymarin or DEN/estradiol benzoate (EB). In addition, three sham groups received no treatment, DEN or DEN/fulvestrant, and one control group that neither ovariectomized nor treated. Directly after treatment, liver injury biomarkers were measured. In addition, hepatic tissue hydroxyproline, TNF- α, TGF- ß, and IL-10 were evaluated. Expression of NF-kß, CD68 (a marker for macrophage infiltration), ER-ß and TLR-4 were measured. Finally, liver tissue histopathology was assessed. KEY FINDINGS: Ovariectomy aggravates DEN-induced LF, as it significantly elevated all liver tissue injury biomarkers. This effect has become even worse after blocking ER by fulvestrant, indicating a protective role of estrogen/ER activation against DEN-induced LF. Inhibition of TLR-4/NF-kß signaling pathway contributed to this protective effect, as estrogen deprivation or blocking of ER significantly activates this pathway during the onset of LF. While administration of EB or silymarin (selective ER-ß activator) improved LF indices and deactivated this pathway. SIGNIFICANCE: These results provide new insight into the pivotal role of estrogen/ER activation via modulation of TLR-4/NF-kß, in the alleviation of LF pathogenesis.

Tetraenone A: A New ß-Ionone Derivative from Tetraena aegyptia.

In this study, the chemical investigation of Tetraena aegyptia (Zygophyllaceae) led to the identification of a new megastigmene derivative, tetraenone A ((2S, 5R, 6R, 7E)-2-hydroxy-5,6-dihydro-ß-ionone) (1), along with (3S, 5R, 6S, 7E)-3-hydroxy-5,6-epoxy-5,6-dihydro-ß-ionone- (2), 3,4-dihydroxy-cinnamyl alcohol-4-glucoside (3), 3ß,19α-dihydroxy-ursan-28-oic acid (4), quinovic acid (5), p-coumaric acid (6), and ferulic acid (7), for the first time. The chemical structures of 1-7 were confirmed by analysis of their 1D and 2D NMR and HRESIMS spectra and by their comparison with the relevant literature. The absolute configurations of 1 and 2 were assigned based on NOESY interactions and ECD spectra. Conformational analysis showed that 1 existed exclusively in one of the two theoretically possible chair conformers with a predominant s-trans configuration for the 3-oxobut-1-en-1-yl group with the ring, while the half-chair conformer had a pseudo-axial hydroxy group that was predominant over the other half-chair conformation. Boat conformations were not among the most stable conformations, and the s-trans isomerism was in favor of s-cis configuration. In silico investigation revealed that 1 and 2 had more favorable binding interactions with Mpro rather than with TMPRSS2. Accordingly, molecular dynamic simulations were performed on the complexes of compounds 1 and 2 with Mpro to explore the stability of their interaction with the target protein structure. Compounds 1 and 2 might offer a possible starting point for developing covalent inhibitors of Mpro of SARS-CoV-2.

Efficacy and safety of ondansetron for morning sickness in pregnancy: a systematic review of clinical trials.

Background: Ondansetron is a selective antagonist of the serotonin 5-HT3 receptor that is commonly used to treat morning sickness. It is estimated that 70%-80% of pregnant women suffer from morning sickness, a condition characterized by nausea and vomiting. However, it is still controversial regarding its safety during pregnancy, and continued research will be necessary to fully understand the risks and benefits associated with its use. Therefore, we aimed to identify and provide details of the efficacy and safety of ondansetron in clinical trials. Methods: A search was conducted of the ClinicalTrials.gov database on 13 April 2023, using the search term "ondansetron and pregnancy." Inclusion and exclusion criteria were defined to identify relevant clinical trials. The inclusion criteria encompassed clinical trials related to pregnancy that utilized ondansetron as a treatment, while other clinical trials were excluded from consideration. All data extractions such as study title, study status, study type, intervention details, and outcome were collected. Results: A total of 18 clinical trials were identified, of which only 6 focused on studying the effects of ondansetron. Their respective study titles, statuses, conditions, interventions, outcome measures, and enrollment sizes have been written in detail. The information collected from these trials will contribute to our understanding of the potential benefits and risks of ondansetron in the context of pregnancy and its complications. Conclusion: Ondansetron has been shown to be an effective treatment for nausea and vomiting, including pregnancy-related morning sickness. Further research is needed to better understand the potential risks and benefits associated with its use in pregnant women. Systematic Review Registration: ClinicalTrials.gov, identifier.

Targeting Autophagy, Apoptosis, and Oxidative Perturbations with Dapagliflozin Mitigates Cadmium-Induced Cognitive Dysfunction in Rats.

Cognitive decline and Alzheimer-like neuropathology are common manifestations of cadmium toxicity. Thanks to its antioxidant/anti-apoptotic features, dapagliflozin has demonstrated promising neuroprotective actions. However, its effect on cadmium-induced neurotoxicity is lacking. The present work aimed to examine whether dapagliflozin could protect rats from cadmium-evoked cognitive decline. In this study, the behavioral disturbances and hippocampal biomolecular alterations were studied after receiving dapagliflozin. Herein, cadmium-induced memory/learning decline was rescued in the Morris water maze, novel object recognition task, and Y-shaped maze by dapagliflozin. Meanwhile, the hippocampal histopathological abnormalities were mitigated. The molecular mechanisms revealed that dapagliflozin lowered hippocampal expression of p-tau and Aß42 neurotoxic proteins while augmenting acetylcholine. The cognitive enhancement was triggered by hippocampal autophagy stimulation, as indicated by decreased SQSTM-1/p62 and Beclin 1 upregulation. Meanwhile, a decrease in p-mTOR/total mTOR and an increase in p-AMPK/total AMPK ratio were observed in response to dapagliflozin, reflecting AMPK/mTOR cascade stimulation. Dapagliflozin, on the other hand, dampened the pro-apoptotic processes in the hippocampus by downregulating Bax, upregulating Bcl-2, and inactivating GSK-3ß. The hippocampal oxidative insult was mitigated by dapagliflozin as seen by lipid peroxide lowering, antioxidants augmentation, and SIRT1/Nrf2/HO-1 pathway activation. In conclusion, dapagliflozin's promising neuroprotection was triggered by its pro-autophagic, anti-apoptotic, and antioxidant properties.

Marine-Derived Compounds for CDK5 Inhibition in Cancer: Integrating Multi-Stage Virtual Screening, MM/GBSA Analysis and Molecular Dynamics Investigations.

Cyclin-dependent kinase 5 (CDK5) plays a crucial role in various biological processes, including immune response, insulin secretion regulation, apoptosis, DNA (deoxyribonucleic acid) damage response, epithelial-mesenchymal transition (EMT), cell migration and invasion, angiogenesis, and myogenesis. Overactivation of CDK5 is associated with the initiation and progression of cancer. Inhibiting CDK5 has shown potential in suppressing cancer development. Despite advancements in CDK5-targeted inhibitor research, the range of compounds available for clinical and preclinical trials remains limited. The marine environment has emerged as a prolific source of diverse natural products with noteworthy biological activities, including anti-cancer properties. In this study, we screened a library of 47,450 marine natural compounds from the comprehensive marine natural product database (CMNPD) to assess their binding affinity with CDK5. Marine compounds demonstrating superior binding affinity compared to a reference compound were identified through high-throughput virtual screening, standard precision and extra-precision Glide docking modes. Refinement of the selected molecules involved evaluating molecular mechanics-generalized born surface area (MM/GBSA) free binding energy. The three most promising compounds, (excoecariphenol B, excoecariphenol A, and zyzzyanone B), along with the reference, exhibiting favorable binding characteristics were chosen for molecular dynamics (MD) simulations for 200 nanoseconds. These compounds demonstrated interaction stability with the target during MD simulations. The marine compounds identified in this study hold potential as effective CDK5 inhibitors and warrant subsequent experimental validation.

The Impact of Intermittent Fasting on Non-Alcoholic Fatty Liver Disease in Older Adults: A Review of Clinicaltrials.gov Registry.

Background: Non-alcoholic fatty liver disease (NAFLD) is a predominant health condition across the world due to its rising prevalence and association with various metabolic disorders. Intermittent fasting (IF) has attracted increasing attention as a dietary approach to addressing weight management and enhancing metabolic well-being, and its potential effects on NAFLD have been a topic of growing research interest. Aim: This review aims to critically evaluate the current evidence on IF's impact on NAFLD, including the mechanisms underlying the observed effects in older adults (65+). Methods: A comprehensive search of Clinicaltrials.gov was conducted to identify relevant studies that investigated the effects of IF on NAFLD in older adults (65+). Data on study design, sample size, intervention details, and outcomes related to NAFLD were extracted and analyzed. Results: As of April 12th, 2023, there were 1304 clinical trials on NAFLD. Most of these were interventional studies. The investigation focused on completed studies and found that limited clinical trials were identified with limited interventional measures. Only five out of the 1304 studies on NAFLD involved IF. Basic and advanced outcome measures were examined. Conclusion: Although some studies suggest that IF may have potential benefits for NAFLD, the evidence is still limited and inconclusive.

Amphetamines in child medicine: a review of ClinicalTrials.gov.

Background: Globally, the use of amphetamines as therapeutic agents in pediatric medicine is a crucial area of concern, especially given the population's vulnerability. Methods: On 6 August 2023, a search was conducted on ClinicalTrials.gov using "amphetamine" as the keyword. Two independent examiners screened trials against set criteria, including a focus on amphetamine, completion status, an interventional approach, and included children. Ongoing or observational studies were excluded. Data extracted from the qualified trials encompassed primary objectives, participant counts, study duration, and outcomes, with the aim of analyzing children disorders treated by amphetamine. Results: On 6 August 2023, a search of the ClinicalTrials.gov database with the term "amphetamines" identified 179 clinical trials. After extensive exclusion criteria, 19 trials were ultimately selected for analysis. The predominant condition under investigation was attention deficit hyperactivity disorder (ADHD), present in 84.2% of studies. Key study characteristics included: phase 4 trials (36.8%), randomized allocation (63.2%), and the parallel intervention model (42.1%). Masking techniques varied, with no masking in 42.1% of studies, and double and quadruple masking both accounting for 21.1%. Geographically, 78.9% of the studies' participants were from the United States. Conclusion: This study highlights the notable therapeutic potential of amphetamines in pediatric ADHD populations and emphasizes the importance of recognizing potential side effects and addiction risks. As pharmacogenomics offers the prospect of personalized treatments, there is potential to increase therapeutic efficacy and decrease adverse reactions. It is vital to balance these benefits against the inherent risks, understanding the need for continued research to optimize the use of amphetamines in medicine.

Community pharmacists' skills and practice regarding dispensing fiscalized substances: a cross-sectional survey.

Background: The use of drugs containing fiscalized substances is essential in different medical areas, including pain management, obstetric emergencies, and the treatment of mental disorders. However, due to their potential for abuse and negative health effects, the dispensing of these substances demands pharmacists with the requisite skills and practice. Objective: This study assesses the skills and practices of pharmacy personnel in the United Arab Emirates (UAE) regarding the dispensing of tramadol, a medication containing fiscalized substances, in community pharmacies. Methodology: A cross-sectional study was conducted. Community Pharmacies were chosen via random sampling, and seven well-trained final year pharmacy students visited them and conducted face-to-face interviews. The survey tool covered items highlighting the demographic data of the subjects, and items on the practice and skills regarding dispensing the fiscalized substances. The content validity ratio values of all tool questions were more than 0.78, suggesting acceptable validity and the Cronbach's α of 0.75 showed as acceptable internal reliability. The primary outcome measures of interest were the skills and practice regarding dispensing Fiscalized substances. Results: A total of 612 pharmacists were recruited in the study. The average practice score was 80%. There was a statistically significant association (p < 0.05) between practices about dispensing fiscalized substances and gender, age group, pharmacy type, work experience, university of graduation, and receiving training on epilepsy and antiepileptic drugs. Conclusion: The results implied that competency and experience are vital factors for the dispensing of tramadol. Contextually, the majority of the pharmacists evidently have the requisite competencies to provide high-quality and proper medical care, with regards to dispensing tramadol, which will minimize drug abuse and medication errors, and assist outpatients to manage their drugs containing fiscalized substances.

Targeting Autophagy, Apoptosis, and SIRT1/Nrf2 Axis with Topiramate Underlies Its Neuroprotective Effect against Cadmium-Evoked Cognitive Deficits in Rats.

Cadmium is an environmental toxicant that instigates cognitive deficits with excessive glutamate excitatory neuroactivity in the brain. Topiramate, a glutamate receptor antagonist, has displayed favorable neuroprotection against epilepsy, cerebral ischemia, and Huntington's disease; however, its effect on cadmium neurotoxicity remains to be investigated. In this study, topiramate was tested for its potential to combat the cognitive deficits induced by cadmium in rats with an emphasis on hippocampal oxidative insult, apoptosis, and autophagy. After topiramate intake (50 mg/kg/day; p.o.) for 8 weeks, behavioral disturbances and molecular changes in the hippocampal area were explored. Herein, Morris water maze, Y-maze, and novel object recognition test revealed that topiramate rescued cadmium-induced memory/learning deficits. Moreover, topiramate significantly lowered hippocampal histopathological damage scores. Mechanistically, topiramate significantly replenished hippocampal GLP-1 and dampened Aß42 and p-tau neurotoxic cues. Notably, it significantly diminished hippocampal glutamate content and enhanced acetylcholine and GABA neurotransmitters. The behavioral recovery was prompted by hippocampal suppression of the pro-oxidant events with notable activation of SIRT1/Nrf2/HO-1 axis. Moreover, topiramate inactivated GSK-3ß and dampened the hippocampal apoptotic changes. In tandem, stimulation of hippocampal pro-autophagy events, including Beclin 1 upregulation, was triggered by topiramate that also activated AMPK/mTOR pathway. Together, the pro-autophagic, antioxidant, and anti-apoptotic features of topiramate contributed to its neuroprotective properties in rats intoxicated with cadmium. Therefore, it may be useful to mitigate cadmium-induced cognitive deficits.

Factors influencing community pharmacists' knowledge about women's issues in epilepsy.

Background: Previous studies have highlighted instances where pharmacists lacked knowledge regarding women's health issues related to epilepsy. Objectives: To assess UAE community pharmacists' knowledge, toward women's issues in epilepsy. Methods: a cross-sectional research method was employed. A team of seven pharmacy students in their final year visited a randomly selected sample of community pharmacies in the UAE and face-to-face interviews were conducted with the pharmacists using a structured questionnaire. The questionnaire includes two parts; Eight questions designed to elicit data about the demographics of the study participants and 12 questions eliciting insights into the participants' knowledge of women's issues in epilepsy. Results: A total of 412 community pharmacist were recruited in the study. The overall level of knowledge about women's issues in epilepsy was good and the average knowledge score was 81% with a 95% confidence interval (CI) [79.1, 82.7%]. The results of multivariate analysis showed higher knowledge scores in chain pharmacies (OR 1.37; 95% CI 1.12-1.67), Chief pharmacists (OR 1.44; 95% CI 1.01-2.06), Pharmacists in charge (OR 3.46; 95% CI 2.7-4.45), pharmacists with 1-5 Years of experience (OR 2.87; 95% CI 1.71-4.82), pharmacists with 6-10 Years (OR 2.63; 95% CI 1.58-4.38), pharmacists with >10 years (OR 3.13; 95% CI 2.03-4.83), graduation form regional universities (OR 1.37; 95% CI 1.12-1.67), graduation form international universities (OR 1.73; 95% CI 1.36-2.20) and receiving a training on epilepsy (OR 1.36; 95% CI 1.12-1.67). Conclusion: While the findings reveal an overall promising level of knowledge among community pharmacists regarding the issues faced by women with epilepsy, pinpointing which clinical and demographic factors have the most significant impact on this knowledge would permit the implementation of tailored educational interventions. Workshops and modules targeting the issues faced by women with epilepsy would further raise the knowledge and competence among community pharmacists in this area, ensuring better pharmaceutical care for this population.

Neuroprotective Impact of Linagliptin against Cadmium-Induced Cognitive Impairment and Neuropathological Aberrations: Targeting SIRT1/Nrf2 Axis, Apoptosis, and Autophagy.

Cadmium is an environmental contaminant associated with marked neurotoxicity and cognitive impairment. Linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, has demonstrated promising neuroprotection against cerebral ischemia and diabetic dementia. However, there has been no study of its effect on cadmium-induced cognitive deficits. In the present work, linagliptin's prospective neuroprotective effects against cadmium-evoked cognitive decline were examined in vivo in rats. The molecular pathways related to oxidative stress, apoptosis, and autophagy were investigated. Histology, immunohistochemistry, ELISA, and biochemical assays were performed on brain hippocampi after receiving linagliptin (5 mg/kg/day). The current findings revealed that cadmium-induced learning and memory impairment were improved by linagliptin as seen in the Morris water maze, Y-maze, and novel object recognition test. Moreover, linagliptin lowered hippocampal neurodegeneration as seen in histopathology. At the molecular level, linagliptin curtailed hippocampal DPP-4 and augmented GLP-1 levels, triggering dampening of the hippocampal neurotoxic signals Aß42 and p-tau in rats. Meanwhile, it enhanced hippocampal acetylcholine and GABA and diminished the glutamate spike. The behavioral recovery was associated with dampening of the hippocampal pro-oxidant response alongside SIRT1/Nrf2/HO-1 axis stimulation. Meanwhile, linagliptin counteracted hippocampal apoptosis markers and inhibited the pro-apoptotic kinase GSK-3ß. In tandem, linagliptin activated hippocampal autophagy by lowering SQSTM-1/p62 accumulation, upregulating Beclin 1, and stimulating AMPK/mTOR pathway. In conclusion, linagliptin's antioxidant, antiapoptotic, and pro-autophagic properties advocated its promising neuroprotective impact. Thus, linagliptin may serve as a management approach against cadmium-induced cognitive deficits.

Exploring the potential of approved drugs for triple-negative breast cancer treatment by targeting casein kinase 2: Insights from computational studies.

Triple-negative breast cancer (TNBC) is an aggressive malignancy that requires effective targeted drug therapy. In this study, we employed in silico methods to evaluate the efficacy of seven approved drugs against human ck2 alpha kinase, a significant modulator of TNBC metastasis and invasiveness. Molecular docking revealed that the co-crystallized reference inhibitor 108600 achieved a docking score of (-7.390 kcal/mol). Notably, among the seven approved drugs tested, sunitinib, bazedoxifene, and etravirine exhibited superior docking scores compared to the reference inhibitor. Specifically, their respective docking scores were -10.401, -7.937, and -7.743 kcal/mol. Further analysis using MM/GBSA demonstrated that these three top-ranked drugs possessed better binding energies than the reference ligand. Subsequent molecular dynamics simulations identified etravirine, an FDA-approved antiviral drug, as the only repurposed drug that demonstrated a stable and reliable binding mode with the human ck2 alpha protein, based on various analysis measures including RMSD, RMSF, and radius of gyration. Principal component analysis indicated that etravirine exhibited comparable stability of motion as a complex with human ck2 alpha protein, similar to the co-crystallized inhibitor. Additionally, Density functional theory (DFT) calculations were performed on a complex of etravirine and a representative gold atom positioned at different sites relative to the heteroatoms of etravirine. The results of the DFT calculations revealed low-energy complexes that could potentially serve as guides for experimental trials involving gold nanocarriers of etravirine, enhancing its delivery to malignant cells and introducing a new drug delivery route. Based on the results obtained in this research study, etravirine shows promise as a potential antitumor agent targeting TNBC, warranting further investigation through experimental and clinical assessments.