Ultra-performance liquid chromatography–tandem mass spectrometric determination of ramipril in human plasma

Purpose: To develop a sensitive and accurate ultra-performance liquid chromatography–tandem mass spectrometric (UPLC-MS) method for quantification of ramipril in human plasma.Methods: Ramipril was extracted from biological fluid using equal volumes of n-hexane and propanol (1:1, v/v), and then chromatographed in a suitable C18 column with methanol: 0.1 % HCOOH (4: 1, v/v) as mobile phase. Atorvastatin was used as an internal standard for the  chromatographic separation and quantification. The method was validated according to the United States Food and Drug Administration guidelines for standard indices.Results: Ramipril was determined in the concentration range 0.05 and 1000 ng/mL the validation procedure exhibited a correlation coefficient of 0.9979 + 0.002 (p = 0.05). The studied drug was quantified with lower ceiling of 0.05 ng/mL, and showed an accuracy of 105.00 %.Conclusion: A sensitive UPLC-MS analytical method has been successfully developed for the quantification of ramipril in human plasma. This method can be applied efficiently for the quantification of ramipril in bioavailability and pharmacokinetic studies. Keywords: Liquid chromatography–tandem mass, Ramipril, Stability, Biological fluids, Plasm

Microwave-assisted synthesis of novel Ti/BTB-MOFs as porous anticancer and antibacterial agents

Nano compounds, especially metal-organic frameworks (MOFs), have significant properties. Among the most important properties of these compounds, which depend on their specific surface area and porosity, are biological properties, such as anticancer and antibacterial properties. In this study, a new titanium/BTB metal-organic framework (Ti/BTB-MOF) was synthesized by using titanium nitrate and 1,3,5-Tris(4-carboxyphenyl)benzene (BTB) under microwave radiation. The structure of the synthesized Ti/BTB-MOF was characterized and confirmed using X-ray diffraction (XRD) patterns, X-ray photoelectron spectroscopy (XPS) analysis, Fourier transform infrared (FT-IR) spectra, energy-dispersive X-ray (EDAX) analysis mapping, scanning electron microscope (SEM) images, thermogravimetric analysis (TGA) curves, and Brunauer–Emmett–Teller (BET) analysis. The in vitro anticancer properties of Ti/BTB-MOF were evaluated using the MTT method against MG-63/bone cancer cells and A-431/skin cancer cells. The in vitro antibacterial activity was tested using the Clinical and Laboratory Standards Institute (CLSI) guidelines. In the anticancer activity, IC50 (half-maximal inhibitory concentration) values of 152 μg/mL and 201 μg/mL for MG-63/bone cancer cells and A-431/skin cancer cells, respectively, were observed. In the antibacterial activity, minimum inhibitory concentrations (MICs) of 2–64 μg/mL were observed against studied pathogenic strains. The antimicrobial activity of Ti/BTB-MOF was higher than that of penicillin and gentamicin. Therefore, the synthesized Ti/BTB-MOF could be introduced as a suitable bioactive candidate

System biology approach to identify the novel biomarkers in glioblastoma multiforme tumors by using computational analysis

Introduction: The most common primary brain tumor in adults is glioblastoma multiforme (GBM), accounting for 45.2% of all cases. The characteristics of GBM, a highly aggressive brain tumor, include rapid cell division and a propensity for necrosis. Regretfully, the prognosis is extremely poor, with only 5.5% of patients surviving after diagnosis.Methodology: To eradicate these kinds of complicated diseases, significant focus is placed on developing more effective drugs and pinpointing precise pharmacological targets. Finding appropriate biomarkers for drug discovery entails considering a variety of factors, including illness states, gene expression levels, and interactions between proteins. Using statistical techniques like p-values and false discovery rates, we identified differentially expressed genes (DEGs) as the first step in our research for identifying promising biomarkers in GBM. Of the 132 genes, 13 showed upregulation, and only 29 showed unique downregulation. No statistically significant changes in the expression of the remaining genes were observed.Results: Matrix metallopeptidase 9 (MMP9) had the greatest degree in the hub biomarker gene identification, followed by (periostin (POSTN) at 11 and Hes family BHLH transcription factor 5 (HES5) at 9. The significance of the identification of each hub biomarker gene in the initiation and advancement of glioblastoma multiforme was brought to light by the survival analysis. Many of these genes participate in signaling networks and function in extracellular areas, as demonstrated by the enrichment analysis.We also identified the transcription factors and kinases that control proteins in the proteinprotein interactions (PPIs) of the DEGs.Discussion: We discovered drugs connected to every hub biomarker. It is an appealing therapeutic target for inhibiting MMP9 involved in GBM. Molecular docking investigations indicated that the chosen complexes (carmustine, lomustine, marimastat, and temozolomide) had high binding affinities of −6.3, −7.4, −7.7, and −8.7 kcal/mol, respectively, the mean root-mean-square deviation (RMSD) value for the carmustine complex and marimastat complex was 4.2 Å and 4.9 Å, respectively, and the lomustine and temozolomide complex system showed an average RMSD of 1.2 Å and 1.6 Å, respectively. Additionally, high stability in root-mean-square fluctuation (RMSF) analysis was observed with no structural conformational changes among the atomic molecules. Thus, these in silico investigations develop a new way for experimentalists to target lethal diseases in future

Overview On Surgical Management Of Overactive Bladder

Overactive bladder syndrome is a persistent and incapacitating disorder that has profound medical, psychological, and social implications, greatly impacting the wellbeing of countless individuals globally. A significant number of individuals experience urine urgency, which can be extremely bothersome. The primary indicator of overactive bladder (OAB) is a sense of urgency, often accompanied by increased urine frequency and nocturia. After ruling out other medical conditions with similar symptoms, the initial approach to managing OAB is providing guidance on fluid consumption and bladder training. If needed, antimuscarinic medicines may be added as a supplement. If patients have significant distress from OAB symptoms even after maximizing medicinal treatment, they may choose to undergo invasive procedures. There is currently a limited understanding of the hierarchical structure of central nervous system control. However, the use of functional imaging is starting to reveal the difficulties that need to be addressed in this area. Current research is exploring the use of botulinum neurotoxin-A injection, oral β3-adrenergic agonists, and innovative methods for nerve stimulation as potential therapies. The inherent subjectivity of urine urgency, the absence of animal models, and the complex pathophysiology of overactive bladder (OAB) pose substantial obstacles to achieving effective clinical therapy

A Multi-Target mechanism of Withania somnifera bioactive compounds in autism spectrum disorder (ASD) Treatment: Network pharmacology, molecular docking, and molecular dynamics simulations studies

Autism spectrum disorder (ASD) is a developmental disorder resulting from variations in brain structure and function. Individuals with ASD often experience challenges in communication and social interaction, along with engaging in repetitive or restricted patterns of behavior and interests. The lack of documented data and the wide range of pathophysiological processes associated with ASD make it challenging to work which causes a major financial burden on health care management. Withania somnifera, often referred to as ashwagandha is the tropical winter cherry in the Solanaceae family that can be used to treat several ailments such as asthma, stress, hypertension, diabetes, cancer, arthritic, and neural disorders including ASD. In this investigation, we examined the active compound-target-pathway network and discovered that Withanolide J, Withanone, and Withaferin A have a great role in the onset of ASD by influencing the IL6 gene. Later, the molecular docking method was applied for confirmation of the active compound's effective action against the prospective target. The molecular dynamics simulation exhibited that the complexes of Withanolide J and Withanone had stable intermolecular binding conformation and unveiled very stable dynamics during the simulation time. A combined network pharmacology and molecular docking approach demonstrated that W. somnifera exhibits a promising preventive impact on ASD by targeting relevant signaling pathways associated with the disorder. This establishes a foundation for comprehending the underlying mechanism of the anti-ASD activity of W. somnifera

Structure-Based Virtual Screening and Molecular Dynamics of Phytochemicals Derived from Saudi Medicinal Plants to Identify Potential COVID-19 Therapeutics

Coronavirus disease 2019 (COVID-19) has affected almost every country in the world by causing a global pandemic with a high mortality rate. Lack of an effective vaccine and/or antiviral drugs against SARS-CoV-2, the causative agent, has severely hampered the response to this novel coronavirus. Natural products have long been used in traditional medicines to treat various diseases, and purified phytochemicals from medicinal plants provide a valuable scaffold for the discovery of new drug leads. In the present study, we performed a computational screening of an in-house database composed of ~1000 phytochemicals derived from traditional Saudi medicinal plants with recognised antiviral activity. Structure-based virtual screening was carried out against three druggable SARS-CoV-2 targets, viral RNAdependent RNA polymerase (RdRp), 3-chymotrypsin-like cysteine protease (3CLpro) and papain like protease (PLpro) to identify putative inhibitors that could facilitate the development of potential anti-COVID-19 drug candidates. Computational analyses identified three compounds inhibiting each target, with binding affinity scores ranging from-9.9 to -6.5 kcal/mol. Among these, luteolin 7-rutinoside, chrysophanol 8-(6-galloylglucoside) and kaempferol 7-(6’’-galloylglucoside) bound efficiently to RdRp, while chrysophanol 8-(6galloylglucoside), 3,4,5-tri-O-galloylquinic acid and mulberrofuran G interacted strongly with 3CLpro, and withanolide A, isocodonocarpine and calonysterone bound tightly to PLpro. These potential drug candidates will be subjected to further in vitro and in vivo studies and may assist the development of effective anti-COVID-19 drugs

Structural basis of SARS-CoV-2 3CLpro and anti-COVID-19 drug discovery from medicinal plants

The recent outbreak of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 in December 2019 raised global health concerns. The viral 3-chymotrypsin-like cysteine protease (3CLpro) enzyme controls coronavirus replication and is essential for its life cycle. 3CLpro is a proven drug discovery target in the case of severe acute respiratory syndrome coronavirus (SARS-CoV) and middle east respiratory syndrome coronavirus (MERS-CoV). Recent studies revealed that the genome sequence of SARS-CoV-2 is very similar to that of SARS-CoV. Therefore, herein, we analysed the 3CLpro sequence, constructed its 3D homology model, and screened it against a medicinal plant library containing 32,297 potential anti-viral phytochemicals/traditional Chinese medicinal compounds. Our analyses revealed that the top nine hits might serve as potential anti- SARS-CoV-2 lead molecules for further optimisation and drug development process to combat COVID-19

Burnout Syndrome among Emergency Physicians and Nurses in Abha and Khamis Mushait Cities, Aseer Region, Southwestern Saudi Arabia

Objectives. To explore the magnitude and determinants of burnout among emergency physicians and nurses working at emergency departments of hospitals in Abha and Khamis Mushait cities. Subjects and Methods. A cross-sectional hospital-based study was conducted in emergency departments of hospitals in Abha and Khamis Mushait cities belonging to Ministry of Health. All physicians (n=95) and nurses (n=187) currently working at these sites were invited to participate in the study by filling a validated self-administered questionnaire including two main sections: personal and professional characteristics of physicians and nurses as well as Maslach burnout inventory (MBI) to assess the three components of the burnout syndrome: emotional exhaustion, depersonalization, and reduced personal accomplishment. Results. The study included 282 physicians and nurses. The age of more than half of them (54.3%) ranged between 31 and 35 years. Most of them (70.9%) were females. About two-thirds of the respondents (66.3%) were nurses while the remaining 33.7% were physicians. Majority of the emergency healthcare professionals (88.7%) had high emotional exhaustion. The prevalence of high depersonalization (cynicism) was 20.6% whereas that of low personal accomplishment was 41.1% among emergency healthcare professionals. The overall prevalence of burnout among healthcare professionals was 16.3%. Multivariate logistic regression analysis revealed that male healthcare professionals were at almost higher three-folded risk for developing burnout compared to females (aOR=2.76; 95% confidence interval (CI): 1.21-6.28, p=0.017)). Smokers were at higher significant risk for burnout compared to nonsmokers (aOR=15.37; 95% CI: 7.06-33.45, p<0.001). Healthcare professionals who reported a history of taking medications for sleep disorders expressed higher risk for burnout opposed to those with no history of sleep disorder medication (aOR=6.59; 95% CI: 2.08-20.81, p=0.001). Conclusion. A considerable proportion of physicians and nurses working at emergency departments of hospitals in Abha and Khamis Mushait cities had burnout syndrome, particularly high emotional exhaustion and low personal accomplishment

Discovery of human coronaviruses pan-papain-like protease inhibitors using computational approaches

The papain-like protease (PLpro) is vital for the replication of coronaviruses (CoVs), as well as for escaping innate-immune responses of the host. Hence, it has emerged as an attractive antiviral drug-target. In this study, computational approaches were employed, mainly the structure-based virtual screening coupled with all-atom molecular dynamics (MD) simulations to computationally identify specific inhibitors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PLpro, which can be further developed as potential pan-PLpro based broad-spectrum antiviral drugs. The sequence, structure, and functional conserveness of most deadly human CoVs PLpro were explored, and it was revealed that functionally important catalytic triad residues are well conserved among SARS-CoV, SARS-CoV-2, and middle east respiratory syndrome coronavirus (MERS-CoV). The subsequent screening of a focused protease inhibitors database composed of ∼7,000 compounds resulted in the identification of three candidate compounds, ADM_13083841, LMG_15521745, and SYN_15517940. These three compounds established conserved interactions which were further explored through MD simulations, free energy calculations, and residual energy contribution estimated by MM-PB(GB)SA method. All these compounds showed stable conformation and interacted well with the active residues of SARS-CoV-2 PLpro, and showed consistent interaction profile with SARS-CoV PLpro and MERS-CoV PLpro as well. Conclusively, the reported SARS-CoV-2 PLpro specific compounds could serve as seeds for developing potent pan-PLpro based broad-spectrum antiviral drugs against deadly human coronaviruses. Moreover, the presented information related to binding site residual energy contribution could lead to further optimization of these compounds.status: publishe