Inhibition of Acetylcholinesterase with Novel 1, 3, 4, Oxadiazole Derivatives: A Kinetic, In Silico, and In Vitro Approach.

Alzheimer's disease (AD) is a neurological disease that disturbs the memory, thinking skills, and behavior of the affected person. AD is a complex disease caused by the breakdown of acetylcholine via acetylcholinesterase (AChE). The present study aimed to assess the synthetic inhibitors of AChE that could be used to treat AD. For this purpose, synthetic compounds of oxadiazole derivatives (15-35) were evaluated and identified as promising inhibitors of AChE, exhibiting IC50 varying between 41.87 ± 0.67 and 1580.25 ± 0.7 µM. The kinetic parameters indicated that all the studied compounds bind to the allosteric site and decrease the efficiency of the AChE enzyme. In silico docking analysis showed that the majority of the compounds interact with the anionic subsite and Per-Arnt-Sim domain of AChE and are stabilized by various bonds including π-π and hydrogen bonding. The stability of the most potent compounds 16 and 17 with AChE interaction was confirmed by molecular dynamics simulations. Moreover, all compounds exhibited concentration-dependent calcium (Ca2+) antagonistic and spasmolytic activities. Among the whole series of oxadiazole derivatives, compounds 16 and 17 displayed the highest activities on spontaneous and potassium (K+)-induced contraction. Therefore, the AChE inhibitory potential, cytotoxicity safe profile, and Ca2+ antagonistic ability of these compounds make them potential therapeutic agents against AD and its associated problems in the future.

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.

Deciphering key genes involved in cisplatin resistance in kidney renal clear cell carcinoma through a combined in silico and in vitro approach.

The low survival rate of Kidney renal clear cell carcinoma (KIRC) patients is largely attributed to cisplatin resistance. Rather than focusing solely on individual proteins, exploring protein-protein interactions could offer greater insight into drug resistance. To this end, a series of in silico and in vitro experiments were conducted to identify hub genes in the intricate network of cisplatin resistance-related genes in KIRC chemotherapy. The genes involved in cisplatin resistance across KIRC were retrieved from the National Center for Biotechnology Information (NCBI) database using search terms as "Kidney renal clear cell carcinoma" and "Cisplatin resistance". The genes retrieved were analyzed for hub gene identification using the STRING database and Cytoscape tool. Expression and promoter methylation profiling of the hub genes was done using UALCAN, GEPIA, OncoDB, and HPA databases. Mutational, survival, functional enrichment, immune cell infiltration, and drug prediction analyses of the hub genes were performed using the cBioPortal, GEPIA, GSEA, TIMER, and DrugBank databases. Lastly, expression and methylation levels of the hub genes were validated on two cisplatin-resistant RCC cell lines (786-O and A-498) and a normal renal tubular epithelial cell line (HK-2) using two high throughput techniques, including targeted bisulfite sequencing (bisulfite-seq) and RT-qPCR. A total of 124 genes were identified as being associated with cisplatin resistance in KIRC. Out of these genes, MCL1, IGF1R, CCND1, and PTEN were identified as hub genes and were found to have significant (p < 0.05) variations in their mRNA and protein expressions and effects on the overall survival (OS) of the KIRC patients. Moreover, an aberrant promoter methylation pattern was found to be associated with the dysregulation of the hub genes. In addition to this, hub genes were also linked with different cisplatin resistance-causing pathways. Thus, hub genes can be targeted with Alvocidib, Estradiol, Tretinoin, Capsaicin, Dronabinol, Metribolone, Calcitriol, Acetaminophen, Acitretin, Cyclosporine, Azacitidine, Genistein, and Resveratrol drugs. As the pathogenesis of KIRC is complex, targeting hub genes and associated pathways involved in cisplatin resistance could bring a milestone change in the drug discovery and management of drug resistance, which might uplift overall survival among KIRC patients.

Genkwanin: An emerging natural compound with multifaceted pharmacological effects.

Plant bioactive molecules could play key preventive and therapeutic roles in chronological aging and the pathogenesis of many chronic diseases, often accompanied by increased oxidative stress and low-grade inflammation. Dietary antioxidants, including genkwanin, could decrease oxidative stress and the expression of pro-inflammatory cytokines or pathways. The present study is the first comprehensive review of genkwanin, a methoxyflavone found in several plant species. Indeed, natural sources, and pharmacokinetics of genkwanin, the biological properties were discussed and highlighted in detail. This review analyzed and considered all original studies related to identification, isolation, quantification, investigation of the biological and pharmacological properties of genkwanin. We consulted all published papers in peer-reviewed journals in the English language from the inception of each database to 12 May 2023. Different phytochemical demonstrated that genkwanin is a non-glycosylated flavone found and isolated from several medicinal plants such as Genkwa Flos, Rosmarinus officinalis, Salvia officinalis, and Leonurus sibiricus. In vitro and in vivo biological and pharmacological investigations showed that Genkwanin exhibits remarkable antioxidant and anti-inflammatory activities, genkwanin, via activation of glucokinase, has shown antihyperglycemic activity with a potential role against metabolic syndrome and diabetes. Additionally, it revealed cardioprotective and neuroprotective properties, thus reducing the risk of cardiovascular diseases and assisting against neurodegenerative diseases. Furthermore, genkwanin showed other biological properties like antitumor capability, antibacterial, antiviral, and dermato-protective effects. The involved mechanisms include sub-cellular, cellular and molecular actions at different levels such as inducing apoptosis and inhibiting the growth and proliferation of cancer cells. Despite the findings from preclinical studies that have demonstrated the effects of genkwanin and its diverse mechanisms of action, additional research is required to comprehensively explore its therapeutic potential. Primarily, extensive studies should be carried out to enhance our understanding of the molecule's pharmacodynamic actions and pharmacokinetic pathways. Moreover, toxicological and clinical investigations should be undertaken to assess the safety and clinical efficacy of genkwanin. These forthcoming studies are of utmost importance in fully unlocking the potential of this molecule in the realm of therapeutic applications.

Anticancer properties and mechanism insights of α-hederin.

α-Hederin is a natural bioactive molecule very abundant in aromatic and medicinal plants (AMP). It was identified, characterized, and isolated using different extraction and characterization technologies, such as HPLC, LC-MS and NMR. Biological tests have revealed that this natural molecule possesses different biological properties, particularly anticancer activity. Indeed, this activity has been investigated against several cancers (e.g., esophageal, hepatic, breast, colon, colorectal, lung, ovarian, and gastric). The underlying mechanisms are varied and include induction of apoptosis and cell cycle arrest, reduction of ATP generation, as well as inhibition of autophagy, cell proliferation, invasion, and metastasis. In fact, these anticancer mechanisms are considered the most targeted for new chemotherapeutic agents' development. In the light of all these data, α-hederin could be a very interesting candidate as an anticancer drug for chemotherapy, as well as it could be used in combination with other molecules already validated or possibly investigated as an agent sensitizing tumor cells to chemotherapeutic treatments.

Assessment of community pharmacists' knowledge about drug-drug interactions in Jeddah, Saudi Arabia.

Background: Drug-drug interactions (DDIs) have the potential to result in severe adverse drug events and profoundly affect patient outcomes. The pivotal role community pharmacists assume in recognizing and effectively managing these interactions necessitates a comprehensive understanding and heightened awareness of their implications. Such knowledge and awareness among community pharmacists are fundamental for ensuring the delivery of safe and efficacious care to patients. Aim: This study aimed to assess the knowledge of community pharmacists in Jeddah, Saudi Arabia, regarding drug-drug interactions (DDIs). Method: A cross-sectional survey was administered to a cohort of 147 community pharmacists through the utilization of a self-administered questionnaire. The questionnaire encompassed a comprehensive range of 30 multiple-choice questions, encompassing various facets pertaining to drug-drug interactions (DDIs). Results: A total of 147 community pharmacists working in Jeddah City, Saudi Arabia, completed the survey. The majority of them were male (89.1%, n = 131), and had bachelor's degrees in pharmacy. Results showed that the lowest correct response of DDIs was between Theophylline/Omeprazole, while the highest was between amoxicillin and acetaminophen. Results revealed that among the 28 drug pairs, only six pairs were determined correctly by most participants. The study found that majority of the studied community pharmacist could not determine the correct answer on drug-drug interaction knowledge, as also seen with the measured below half mean DDIs knowledge of 38.22 ± 22.0 (min = 0, max = 89.29, median = 35.71). Conclusion: The study highlights the need for ongoing training and education programs for community pharmacists in Saudi Arabia to enhance their knowledge and understanding of DDIs, ultimately leading to improved patient care and safety.

Zingiber officinale Roscoe (Ginger) and its Bioactive Compounds in Diabetes: A Systematic Review of Clinical Studies and Insight of Mechanism of Action

Background: Zingiber officinale Roscoe (Ginger) belongs to the Zingiberaceae family, which is renowned for its rich nutritional and phytochemical composition, and has been validated for its anti-diabetic and anti-inflammatory properties via in vitro, in vivo, and clinical studies. Nonetheless, a comprehensive review of these pharmacological studies, especially clinical studies, together with an analysis of the mechanism of action of the bioactive compounds is still lacking. This review provided a comprehensive and updated analysis of the anti-diabetic efficacy of Z. officinale and its compounds ginger enone, gingerol, paradol, shogaol, and zingerone. Methods: The present systematic review was conducted using the PRISMA guidelines. Scopus, ScienceDirect, Google Scholar, and PubMed were the main databases used for retrieving information from inception to March 2022. Results: From the findings obtained, Z. officinale can be regarded as a therapeutic species showing significant improvement in clinical studies on glycemic parameters (Fasting blood glucose (FBG), hemoglobin A1C (HbA1c), and insulin resistance). In addition, the bioactive compounds of Z. officinale act via several mechanisms as revealed by in vitro and in vivo studies. Overall, these mechanisms were by increasing glucose-stimulated insulin secretion, sensitising insulin receptors and raising glucose uptake, translocation of GLUT4, inhibition of advanced glycation end product-induced increase of reactive oxygen species, regulation of hepatic gene expression of enzymes associated with glucose metabolism, regulation of the level of pro-inflammatory cytokines, amelioration of the pathological injuries of kidneys, protective effect on the morphology of ß-cells as well as its antioxidant mechanisms, among others. Conclusion: Z. officinale and its bioactive compounds displayed promising results in in vitro and in vivo systems, nevertheless, it is highly recommended that human trials be conducted on these compounds since clinical studies are the core of medical research and considered the final stages of the drug development process.

Identification of novel peptide inhibitors for oncogenic KRAS G12D as therapeutic options using mutagenesis-based remodeling and MD simulations.

The Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) serves as a molecular switch, cycling between guanosine triphosphate (GTP)-bound and inactive guanosine diphosphate (GDP)-bound states. KRAS modulates numerous signal transduction pathways including the conventional RAF-MEK-ERK pathway. Mutations in the RAS genes have been linked to the formation of malignant tumors. Human malignancies typically show mutations in the Ras gene including HRAS, KRAS, and NRAS. Among all the mutations in exon 12 and exon 13 of the KRAS gene, the G12D mutation is more prevalent in pancreatic and lung cancer and accounts for around 41% of all G12 mutations, making them potential anticancer therapeutic targets. The present study is aimed at repurposing the peptide inhibitor KD2 of the KRAS G12D mutant. We employed an in-silico mutagenesis approach to design novel peptide inhibitors from the experimentally reported peptide inhibitor, and it was found that substitutions (N8W, N8I, and N8Y) might enhance the peptide's binding affinity toward the KRAS. Molecular dynamics simulations and binding energy calculations confirmed that the newly designed peptide inhibitors are stable and that their binding affinities are stronger as compared to the wild-type peptide. The detailed analysis revealed that newly designed peptides have the potential to inhibit KRAS/Raf interaction and the oncogenic signal of the KRAS G12D mutant. Our findings strongly suggest that these peptides should be tested and clinically validated to combat the oncogenic activity of KRAS.Communicated by Ramaswamy H. Sarma.

SARS-CoV-2 Detection and COVID-19 Diagnosis: A Bird's Eye View.

The battle against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) associated coronavirus disease 2019 (COVID-19) is continued worldwide by administering firsttime emergency authorized novel mRNA-based and conventional vector-antigen-based anti- COVID-19 vaccines to prevent further transmission of the virus as well as to reduce the severe respiratory complications of the infection in infected individuals. However; the emergence of numerous SARS-CoV-2 variants is of concern, and the identification of certain breakthrough and reinfection cases in vaccinated individuals as well as new cases soaring in some low-to-middle income countries (LMICs) and even in some resource-replete nations have raised concerns that only vaccine jabs would not be sufficient to control and vanquishing the pandemic. Lack of screening for asymptomatic COVID-19-infected subjects and inefficient management of diagnosed COVID-19 infections also pose some concerns and the need to fill the gaps among policies and strategies to reduce the pandemic in hospitals, healthcare services, and the general community. For this purpose, the development and deployment of rapid screening and diagnostic procedures are prerequisites in premises with high infection rates as well as to screen mass unaffected COVID-19 populations. Novel methods of variant identification and genome surveillance studies would be an asset to minimize virus transmission and infection severity. The proposition of this pragmatic review explores current paradigms for the screening of SARS-CoV-2 variants, identification, and diagnosis of COVID-19 infection, and insights into the late-stage development of new methods to better understand virus super spread variants and genome surveillance studies to predict pandemic trajectories.

Nutritional, medicinal and functional properties of different parts of the date palm and its fruit (Phoenix dactylifera L.) - A systematic review.

Appraised for being one of the oldest staple nutritive foods mainly in the Arabian Peninsula, the date palm tree (Phoenix dactylifera L.), is a crop native to the subtropical and tropical regions of Southern Asia and Africa. Different parts of the date tree have been extensively studied for their nutritional and therapeutic properties. Despite an array of publications on the date tree, there has been no attempt to compile in a single study the traditional uses, nutritive value, phytochemical profile, the medicinal properties as well as the potential of the different plant parts as a functional food. Therefore, this review endeavors to systematically review the scientific literature to highlight the traditional uses of date fruit and parts around the world, the nutritional profile of several parts and the medicinal properties. A total of 215 studies was retrieved (traditional uses (n = 26), nutritional (n = 52), and medicinal (n = 84)). Scientific articles were further categorized as in vitro (n = 33), in vivo (n = 35), and clinical (n = 16) evidences. Date seeds were found to be effective against E. coli and Staphylococcus aureus. Aqueous date pollen was used to manage hormonal problems and boost fertility. Palm leaves showed anti-hyperglycemic effects via inhibition of α-amylase and α-glucosidase. Unlike previous studies, this study highlighted the functional roles of all the plant parts of the palm tree and provided insights into the various mechanism of action of their bioactive compounds. Although scientific shreds of evidence have been growing over the years, there is still a dearth of studies concerning the clinical validation of the date fruit and other plant parts to provide strong evidence on their medicinal uses. In conclusion, P. dactylifera can be regarded as a potent medicinal plant with prophylactic potential and should be further explored to alleviate the burden of both communicable and non-communicable diseases.

Assessment of the Community Pharmacists' Knowledge and Attitudes Toward Pain and Pain Management in Saudi Arabia.

Background: Pain is a global health issue that affects an individual's quality of life. Its alleviation and management will enhance patients' experience. Community pharmacists can help manage pain severity through their valuable roles in medical teams and by managing the consequences of pain. Objective: This study aimed to evaluate community pharmacists' knowledge and attitudes toward pain and pain management in Saudi Arabia. Methods: A cross-sectional study was performed to evaluate community pharmacists' knowledge and attitudes toward pain and pain management in Saudi Arabia. Pharmacists aged ≥ 21 years, with a degree in pharmacy were included in this study. Each respondent participated in an online survey covering cancer-oriented pain and assessment of pain; pharmacology; abuse of substances; and physical dependence. An independent t-test and One-way ANOVA, with least significant difference as a post-hoc test, were employed, in addition to the General Linear Regression Model using Main Effect as the model. Results: This study revealed that the pain-related knowledge and attitude among community pharmacists in Saudi Arabia were inadequate. Age (p = 0.003), work experience (p = 0.036), nature of work (p = 0.001), and work location (p = 0.003) were determined as significant factors affecting their overall knowledge and attitude toward pain. Conclusion: Overall, attempts to expand community pharmacists' knowledge and foster an appropriate attitude toward pain management among them in Saudi Arabia are highly recommended. Additional academic courses, studies, and tailored neuroscience courses will improve their awareness and knowledge of pain and pain management.

Development and Optimization of Tamarind Gum-ß-Cyclodextrin-g-Poly(Methacrylate) pH-Responsive Hydrogels for Sustained Delivery of Acyclovir.

Acyclovir has a short half-life and offers poor bioavailability. Its daily dose is 200 mg five times a day. A tamarind gum and ß-cyclodextrin-based pH-responsive hydrogel network for sustained delivery of acyclovir was developed using the free-radical polymerization technique. Developed networks were characterized by FTIR, DSC, TGA, PXRD, EDX, and SEM. The effect of varying feed ratios of polymers, monomers, and crosslinker on the gel fraction, swelling, and release was also investigated. FTIR findings confirmed the compatibility of the ingredients in a new complex polymer. The thermal stability of acyclovir was increased within the newly synthesized polymer. SEM photomicrographs confirmed the porous texture of hydrogels. The gel fraction was improved (from 90.12% to 98.12%) with increased reactant concentrations. The pH of the dissolution medium and the reactant contents affected swelling dynamics and acyclovir release from the developed carrier system. Based on the R2 value, the best-fit model was zero-order kinetics with non-Fickian diffusion as a release mechanism. The biocompatibility of the developed network was confirmed through hematology, LFT, RFT, lipid profile, and histopathological examinations. No sign of pathology, necrosis, or abrasion was observed. Thus, a pH-responsive and biocompatible polymeric system was developed for sustained delivery of acyclovir to reduce the dosing frequency and improve patient compliance.

Evaluation of Substance Use Disorder Readmission and Length of Hospital Stay in a Major Rehabilitation Center in the Gulf States: a Retrospective Cohort Study.

Substance use disorders (SUDs) patients have longer lengths of hospital stay, and more unplanned readmissions than other hospitalized patients. We aim to evaluate SUD-related rehospitalization and length of hospital stay in a major rehabilitation center that serves countries of the Gulf States. In a retrospective cohort study for 16-year data set in Al-Amal Hospital Electronic Health Record in the city of Dammam, Eastern region of Saudi Arabia, patients received services from the SUD treatment programs in the period of January 1, 2005, to December 31, 2021. We used cause-specific Cox proportional hazards regression model to estimate risk of readmission, and general linear model to examine the association between substance use disorders and length of hospital stay. Of the total cohort, 4398 (30.17%) were readmitted within 1 year of discharge date. More than half of the cohort were unemployed patients (52.93%). Patients diagnosed with amphetamine use disorder were 1.36 higher risk of readmission compared to no amphetamine disorder (HR = 1.36; CI (1.04, 1.78) P.02). Patients diagnosed with mental disorder had 7.25 times higher risk of longer hospital stay compared to no mental health disorder (coefficient = 7.25; P < .0001). Amphetamine use disorder increased the risk of readmission. A secondary diagnosis of mental disorders among SUD patients increased length of hospital stay. As a targeted region of amphetamine smuggling in the world, policy and clinical decision-makers in Saudi Arabia and the Gulf States should consider taking proactive steps to minimize the future anticipated high demand for addiction treatment in the region.

Primary tumor location and survival among metastatic colorectal cancer patients treated with systemic chemotherapy and biologic therapies: Retrospective analysis.

BACKGROUND: Metastatic colorectal cancer (mCRC) is a genetically heterogeneous disease and different ethnicities might result in different chemotherapy treatment responses. The aim of the study is to evaluate whether survival outcomes for mCRC patients treated with systemic chemotherapy (SC) and, with and without biologic therapies (BT) are different between left and right-sided tumors. METHODS: A retrospective cohort study via the Ministry of National Guard- Health Affairs (MNG-HA) Cancer registry data was used to identify patients diagnosed with CRC between 2013 and 2016. Kaplan-Meier method and porosity score Cox proportional hazard models were used to assess survival for right and left-sided mCRC with and with BT. RESULTS: There was a total of 549 CRC patients and 196 mCRC patients with mean age of 64 years and 57.65% were males. The median survival for the left-sided was higher than the right-sided mCRC tumors (P 0.03). mCRC patients treated with SC+BT were associated with decreased mortality only among patients with left-sided mCRC compared to right-sided mCRC (HR, 0.21; 95% CI, 0.05-0.92; P 0.03). mCRC with no primary-tumor resection and CS+TB left-sided mCRC was significantly associated with decreased mortality compared to right-sided mCRC (HR, 0.15; 95% CI, 0.03-0.72; P 0.02). CONCLUSION: A significant decrease in mortality for the left-sided mCRC treated with SC + BT compared with the right-sided mCRC was observed. mCRC patients with unresectable metastases demonstrated survival benefits from left-sided SC + BT treatment. Randomized controlled trials are needed to determine the optimal treatment for mCRC patients.

Clinical Impact of Semaglutide, a Glucagon-Like Peptide-1 Receptor Agonist, on Obesity Management: A Review.

Purpose: Obesity and overweight pose a threat to health and are more common than undernutrition among adults. It is categorized by fat accumulation and a body mass index (BMI) of > 30. A significant increase in worldwide obesity has been ongoing over several decades. Over the past few years, several strategies have been followed for weight management and to counteract the increasing prevalence of the disease; however, room for improvement with pharmacological options still exists. This review aimed to digest selected past clinical and experimental studies and understand the role of semaglutide treatment for obesity. Methods: Articles related to the clinical uses of semaglutide, mechanism of action, pharmacokinetics, pharmacodynamics, and side effects of the drug were identified. Only studies with human subjects who used Semaglutide for obesity management were included and assessed. Results: Semaglutide promotes weight loss via appetite and hunger suppression, decreases energy intake, controls eating, and depresses the relative fondness for fatty, energy-dense foods. Moreover, the relationship between obesity and Semaglutide has been widely investigated, and most studies reveal the efficacy of Semaglutide on weight loss. Overall, the pharmacokinetics of semaglutide shows a drop in glycosylated hemoglobin A1c (HbA1c) and total body weight. The usual adverse effects observed in patients treated with Semaglutide include gastrointestinal adverse events, like nausea, vomiting, diarrhea, constipation, and abdominal cramps. Conclusion: The findings from the review suggest that semaglutide appears to be beneficial, most notably in its contribution to weight reduction.

Phytochemical, Cytotoxic, and Antimicrobial Evaluation of Tribulus terrestris L., Typha domingensis Pers., and Ricinus communis L.: Scientific Evidences for Folkloric Uses.

Many medicinal plants have been utilized for centuries despite the lack of scientific evidence of their therapeutic effects. This study evaluated the phytochemical and dual biological profiling, namely, antibacterial and cytotoxic properties, of three plant species, namely, Tribulus terrestris L., Typha domingensis Pers., and Ricinus communis L., in order to explore potential relationships (if any) with their ethnopharmacological uses. GC-MS was used to achieve phytochemical screening of two plant extracts (T. terrestris and T. domingensis). The primary chemicals detected in varying amounts in both extracts were siloxane derivatives, fatty acid esters, diisooctyl phthalate, phytosterol, and aromatic acid esters. According to the findings, the major component detected in both extracts was 1,2-benzenedicarboxylic acid and diisooctyl ester (antibacterial and antifungal). T. domingensis contained a low level of benzoic acid, methyl ester (antibacterial). Both extracts included stigmasterol and sitosterol, as well as six different forms of fatty acid esters. Antimicrobial, antioxidant, anticancer, thyroid inhibitor, and anti-inflammatory properties have all been described. Human breast adenocarcinoma (MCF7), human ovary adenocarcinoma (A2780), and human colon adenocarcinoma (HT29), as well as normal human fetal lung fibroblasts (MRC5), all showed cytotoxic activity. The most potent activity against A2780 cells was seen in T. terrestris and T. domingensis extracts (IC50: 3.69 and 5.87 g/mL, respectively). R. communis was more active against MCF7 cells (1.52 µg/mL) followed by A2780 and HT29 cells, respectively. R. communis showed a dose-dependent clonogenic effect against MCF7 cells. The antibacterial activity of all three plant extracts was tested against three standard Gram-positive, four standard Gram-negative, and two clinical bacterial strains. Among the three extracts examined, T. terrestris was the most effective, followed by R. communis, and finally, T. domingensis plant extract was effective against various isolated bacteria. This study, interestingly, sheds light on the bioactive components found in plant extracts that can be utilized for cytotoxic and antibacterial purposes.

Clinical practice guidelines in multisystem inflammatory syndrome (MIS-C) related to COVID-19: a critical review and recommendations.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a serious health condition that develops from and is linked to coronavirus disease 2019. MIS-C is considered a multi-organ dysfunction involving cardiac, renal, respiratory, hematologic, gastrointestinal and neurological symptoms and groups of signs and symptoms such as rash or bilateral non-purulent conjunctivitis, hypotension or shock and acute gastrointestinal problems, which require immediate therapeutic intervention to prevent the aggravation of the patient's health condition. MIS-C is relatively new in the field of evidence-based medicine; however, there are several clinical guidelines for good clinical practice. For every disorder, the guidelines have different suggestions. Hence, based on the current status of the evidence, recommendations have been combined to form a unified guideline for therapeutic management. METHODS: This paper compares and evaluates the current MIS-C-specific clinical practice guidelines (namely, American Academy of Pediatrics, American College of Rheumatology, Helen DeVos Children's Hospital Foundation, Children's Hospital of The King's Daughters, and the Infectious Diseases Society of America). The compiled literature was then assessed by the authors separately, and an algorithm was proposed for each disorder, taking into consideration the various guidelines proposed for the management of the disorder. RESULTS: The features of MIS-C patients are unified; this is very helpful in managing its symptoms and decreasing mortality rates. In addition, recommendations for pharmacological treatment for MIS-C symptoms are formulated after cross-comparison across five different guidelines. CONCLUSIONS: This study provides a general interpretation of the results in the context of other evidence and implications for future research. It proposes a unified guideline based on the current evidence, with the best potential to maintain suitable clinical standards in the Saudi Arabian Ministry of Health.

Co-Inhibition of P-gp and Hsp90 by an Isatin-Derived Compound Contributes to the Increase of the Chemosensitivity of MCF7/ADR-Resistant Cells to Doxorubicin.

Breast cancer is a complex and multi-drug resistant (MDR) disease, which could result in the failure of many chemotherapeutic clinical agents. Discovering effective molecules from natural products or by derivatization from known compounds is the interest of many research studies. The first objective of the present study is to investigate the cytotoxic combinatorial, chemosensitizing, and apoptotic effects of an isatin derived compound (5,5-diphenylimidazolidine-2,4-dione conjugated with 5-substituted isatin, named HAA2021 in the present study) against breast cancer cells (MCF7) and breast cancer cells resistant to doxorubicin (MCF7/ADR) when combined with doxorubicin. The second objective is to investigate the binding mode of HAA2021 withP-glycoprotein (P-gp) and heat shock protein 90 (Hsp90), and to determine whether their co-inhibition by HAA2021 contribute to the increase of the chemosensitization of MCF7/ADR cells to doxorubicin. The combination of HAA2021, at non-toxic doses, with doxorubicin synergistically inhibited the proliferation while inducing significant apoptosis in MCF7 cells. Moreover, HAA2021 increased the chemosensitization of MCF7/ADR cells to doxorubicin, resulting in increased cytotoxicity/selectivity and apoptosis-inducing efficiency compared with the effect of doxorubicin or HAA2021 alone against MCF7/ADR cells. Molecular modeling showed that two molecules of HAA2021 bind to P-gp at the same time, causing P-gp inhibitory effect of the MDR efflux pump, and accumulation of Rhodamine-123 (Rho123) in MCF7/ADR cells. Furthermore, HAA2021 stably interacted with Hsp90α more efficiently compared with 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), which was confirmed with the surface plasmon resonance (SPR) and molecular modeling studies. Additionally, HAA2021 showed multi-target effects via the inhibition of Hsp90 and nuclear factor kappa B (NF-𝜅B) proteins in MCF7 and MCF7/ADR cells. Results of real time-PCR also confirmed the synergistic co-inhibition of P-gp/Hsp90α genes in MCF7/ADR cells. Further pharmacokinetic and in vivo studies are warranted for HAA2021 to confirm its anticancer capabilities.

Neurite outgrowth inhibitory levels of organophosphates induce tissue transglutaminase activity in differentiating N2a cells: evidence for covalent adduct formation.

Organophosphate compounds (OPs) induce both acute and delayed neurotoxic effects, the latter of which is believed to involve their interaction with proteins other than acetylcholinesterase. However, few OP-binding proteins have been identified that may have a direct role in OP-induced delayed neurotoxicity. Given their ability to disrupt Ca2+ homeostasis, a key aim of the current work was to investigate the effects of sub-lethal neurite outgrowth inhibitory levels of OPs on the Ca2+-dependent enzyme tissue transglutaminase (TG2). At 1-10 µM, the OPs phenyl saligenin phosphate (PSP) and chlorpyrifos oxon (CPO) had no effect cell viability but induced concentration-dependent decreases in neurite outgrowth in differentiating N2a neuroblastoma cells. The activity of TG2 increased in cell lysates of differentiating cells exposed for 24 h to PSP and chlorpyrifos oxon CPO (10 µM), as determined by biotin-cadaverine incorporation assays. Exposure to both OPs (3 and/or 10 µM) also enhanced in situ incorporation of the membrane permeable substrate biotin-X-cadaverine, as indicated by Western blot analysis of treated cell lysates probed with ExtrAvidin peroxidase and fluorescence microscopy of cell monolayers incubated with FITC-streptavidin. Both OPs (10 µM) stimulated the activity of human and mouse recombinant TG2 and covalent labelling of TG2 with dansylamine-labelled PSP was demonstrated by fluorescence imaging following SDS-PAGE. A number of TG2 substrates were tentatively identified by mass spectrometry, including cytoskeletal proteins, chaperones and proteins involved protein synthesis and gene regulation. We propose that the elevated TG2 activity observed is due to the formation of a novel covalent adduct between TG2 and OPs.

Activation of transglutaminase 2 by nerve growth factor in differentiating neuroblastoma cells: A role in cell survival and neurite outgrowth.

NGF (nerve growth factor) and tissue transglutaminase (TG2) play important roles in neurite outgrowth and modulation of neuronal cell survival. In this study, we investigated the regulation of TG2 transamidase activity by NGF in retinoic acid-induced differentiating mouse N2a and human SH-SY5Y neuroblastoma cells. TG2 transamidase activity was determined using an amine incorporation and a peptide cross linking assay. In situ TG2 activity was assessed by visualising the incorporation of biotin-X-cadaverine using confocal microscopy. The role of TG2 in NGF-induced cytoprotection and neurite outgrowth was investigated by monitoring hypoxia-induced cell death and appearance of axonal-like processes, respectively. The amine incorporation and protein crosslinking activity of TG2 increased in a time and concentration-dependent manner following stimulation with NGF in N2a and SH-SY5Y cells. NGF mediated increases in TG2 activity were abolished by the TG2 inhibitors Z-DON (Z-ZON-Val-Pro-Leu-OMe; Benzyloxycarbonyl-(6-Diazo-5-oxonorleucinyl)-l-valinyl-l-prolinyl-l-leucinmethylester) and R283 (1,3,dimethyl-2[2-oxo-propyl]thio)imidazole chloride) and by pharmacological inhibition of extracellular signal-regulated kinases 1 and 2 (ERK1/2), protein kinase B (PKB) and protein kinase C (PKC), and removal of extracellular Ca2+. Fluorescence microscopy demonstrated NGF induced in situ TG2 activity. TG2 inhibition blocked NGF-induced attenuation of hypoxia-induced cell death and neurite outgrowth in both cell lines. Together, these results demonstrate that NGF stimulates TG2 transamidase activity via a ERK1/2, PKB and PKC-dependent pathway in differentiating mouse N2a and human SH-SY5Y neuroblastoma cells. Furthermore, NGF-induced cytoprotection and neurite outgrowth are dependent upon TG2. These results suggest a novel and important role of TG2 in the cellular functions of NGF.