Identification and characterization of GSK-9089 metabolites through high resolution-mass spectrometry based in vitro and in vivo rat biological sample analysis.

Estrogen related receptors (ERRs) agonist GSK-9089 (DY-131) reported to pose a potential in increasing exercise endurance. High resolution mass spectrometry (HRMS) based analysis has utmost importance in the detection, identification, or characterization of a molecule including its metabolites in human body. In this study, in vitro metabolism profile of GSK-9089 was investigated after incubation with liver microsomes and S9 fractions. Additionally, in vivo metabolites of the molecule were identified in plasma, urine, and faeces samples of rats. Structures of all the potential metabolites were revealed by employing an in silico tool and HRMS based analysis through data-dependent and data-independent mining strategies. Nine unknown metabolites of GSK-9089 have been identified which were found to be present in a trace amount in in vivo matrices. Most of the in vitro and in vivo phase I metabolites of the molecule were formed after imine bond hydrolysis followed by deamidation, oxidation, and N-oxidation. The molecule underwent phase II metabolism to generate more polar metabolites mainly through glucuronide, sulfate conjugation biotransformation reactions. The in vitro and in vivo metabolites of GSK-9089 could be useful to identify the abuse of this ERRs agonist in the future.

Countering Zoonotic Diseases: Current Scenario and Advances in Diagnostics, Monitoring, Prophylaxis and Therapeutic Strategies.

Human life and health have interacted reciprocally with the surrounding environment and animal fauna for ages. This relationship is evident in developing nations, where human life depends more on the animal population for food, transportation, clothing, draft power, and fuel sources, among others. This inseparable link is a potent source of public health issues, especially in outbreaks of zoonotic diseases transmitted from animals to humans. Zoonotic diseases are referred to as diseases that are naturally transmitted between vertebrate animals and humans. Among the globally emerging diseases in the last decade, 75% are of animal origin, most of which are life-threatening. Since most of them are caused by potent new pathogens capable of long-distance transmission, the impact is widespread and has serious public health and economic consequences. Various other factors also contribute to the transmission, spread, and outbreak of zoonotic diseases, among which industrialization-led globalization followed by ecological disruption and climate change play a critical role. In this regard, all the possible strategies, including advances in rapid and confirmatory disease diagnosis and surveillance/monitoring, immunization/vaccination, therapeutic approaches, appropriate prevention and control measures to be adapted, and awareness programs, need to be adopted collaboratively among different health sectors in medical, veterinary, and concerned departments to implement the necessary interventions for the effective restriction, minimization, and timely control of zoonotic threats. The present review focuses on the current scenario of zoonotic diseases and their counteracting approaches to safeguard their health impact on humans.

MediatorWeb: a protein-protein interaction network database for the RNA polymerase II Mediator complex.

The protein-protein interaction (PPI) network of the Mediator complex is very tightly regulated and depends on different developmental and environmental cues. Here, we present an interactive platform for comparative analysis of the Mediator subunits from humans, baker's yeast Saccharomyces cerevisiae, and model plant Arabidopsis thaliana in a user-friendly web-interface database called MediatorWeb. MediatorWeb provides an interface to visualize and analyze the PPI network of Mediator subunits. The database facilitates downloading the untargeted and unweighted network of Mediator complex, its submodules, and individual Mediator subunits to better visualize the importance of individual Mediator subunits or their submodules. Further, MediatorWeb offers network visualization of the Mediator complex and interacting proteins that are functionally annotated. This feature provides clues to understand functions of Mediator subunits in different processes. In an additional tab, MediatorWeb provides quick access to secondary and tertiary structures, as well as residue-level contact information for Mediator subunits in each of the three model organisms. Another useful feature of MediatorWeb is detection of interologs based on orthologous analyses, which can provide clues to understand the functions of Mediator complex in less explored kingdoms. Thus, MediatorWeb and its features can help the user to understand the role of Mediator complex and its subunits in the transcription regulation of gene expression.

Pd-catalyzed stereoselective synthesis of chromone C-glycosides.

Herein, we present an efficient Pd-catalysed method for stereoselective synthesis of chromone C-glycosides from various glycals. We successfully applied this method to various glycals with different protecting groups, yielding the corresponding glycosides in 41-78% yields. Additionally, we investigated the potential of this approach for the late-stage modification of natural products and pharmaceutical compounds linked to glycals, leading to the synthesis of their respective glycosides. Furthermore, we extended our research to gram-scale synthesis and demonstrated its applicability in producing various valuable products, including 2-deoxy-chromone C-glycosides. In summary, our work introduces a novel library of chromone glycosides, which holds promise for advancing drug discovery efforts.

Experimental and computational studies on the corrosion inhibition potential of a novel synthesized thiophene and pyridine-based 1,3,4-oxadiazole hybrid against mild steel corrosion in 1 N HCl.

A convenient synthesis of a novel 1,3,4-oxadiazole derivative, specifically known as, 2-(5-methylthiophen-2-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole (MTPO), is reported along with a comprehensive evaluation of its ability to inhibit the corrosion of mild steel (MS) in a 1 N HCl environment using weight loss, EIS, PDP, SEM, EDX, and UV-Vis spectroscopy. The investigated inhibitor expressed excellent inhibition efficiency (99.05% at 500 ppm, 298 K) with a mixed-type inhibitory mechanism as demonstrated by the PDP technique. Furthermore, MTPO followed Langmuir adsorption isotherm, which provides insights into the adsorption phenomena, demonstrating that it exhibits superior adsorption behavior on the MS surface compared. In silico investigations, using DFT computation and MD simulation complements the experimental outcomes revealing strong adsorbing attributes of the MTPO hybrid with the ω - and ω + values of 8.8882 eV and 4.4787 eV, respectively. In addition, the radial distribution function also addressed the chemisorption behavior of MTPO. This article also takes into consideration the various ways in which the inhibitor interacts with the mild steel, offering potential insights for developing strategies to mitigate metal dissolution in acidic environments.

Public-Private Partnership for Treatment of Congenital Heart Diseases: Experiences From an Indian State.

Background: Treatment of congenital heart disease (CHD), being the most common congenital anomaly, puts immense financial burden in low- and middle-income countries (LMICs) and contributes significantly to infant mortality. We report experiences of treatment of CHD in the Indian state of West Bengal by a public-private partnership (PPP) model. Methods: Under the Rashtriya Bal Swasthya Karyakram, the government of the state of West Bengal in India launched a program called the "Sishu Sathi Scheme" to provide free treatment to children who need heart surgeries, irrespective of economic status. Treatment was provided in selected private hospitals and some public hospitals in a reimbursement model where government compensated the hospitals. Data were collected on such procedures from 2013 to 2022 and analyzed. Results: A total of 27,844 patients with CHD received treatment under the Sishu Sathi Scheme from August 2013 to December 2022. The average number of patients per year was 3,093. Detailed data of procedures from January 2016 to December 2022 showed a total of 22,572 procedures (6,249 device interventions, 4,840 cardiac catheterizations, and 11,483 surgical interventions). The in-hospital mortality of surgical procedures and catheterization lab procedures were 5.2% and 0.9%, respectively. Conclusions: A large number of patients with CHD were successfully treated under a PPP in the state of West Bengal in India. In spite of its inherent challenges, this model is of special relevance in LMICs where access and affordability for treatment of CHD always remain a challenge.

Effective corrosion inhibition of mild steel using novel 1,3,4-oxadiazole-pyridine hybrids: Synthesis, electrochemical, morphological, and computational insights.

An easy synthesis of two 1,3,4-oxadiazole derivatives, namely, 2-phenyl-5-(pyridin-3-yl)-1,3,4-oxadiazole (POX) and 2-(4-methoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole (4-PMOX), and their corrosion-inhibition efficacy against mild steel corrosion in 1 N HCl, is evaluated using weight loss from 303 to 323 K, Electrochemical Impedance Spectroscopy (EIS), Potentiodynamic Polarization (PDP), Scanning Electron Microscopy (SEM), Energy Dispersive X-ray (EDX), UV-Vis spectroscopy, along with theoretical evaluation. Both POX and 4-PMOX exhibit excellent inhibition efficiency, with values reaching 97.83% and 98% at 500 ppm, respectively. The PDP analysis reveals that both derivatives act as mixed-type inhibitors. The Langmuir adsorption isotherm provides insights into the adsorption phenomena, demonstrating that 4-PMOX exhibits superior adsorption behavior on the mild steel surface compared to POX. This finding is further supported by SEM, DFT, RDF, and MSD analyses. Quantum mechanical parameters, including EHOMO, ELUMO, dipole moment (µ), energy gap (ΔE), etc., are in good agreement with the effectiveness of inhibition performance revealing ΔE values of 3.10 and 2.75 for POX and 4-PMOX, respectively. The results obtained from this study hold significant implications for researchers aiming to design more efficient organic inhibitors to combat metal corrosion.

Stem cell therapy: a novel approach against emerging and re-emerging viral infections with special reference to SARS-CoV-2.

The past several decades have witnessed the emergence and re-emergence of many infectious viral agents, flaviviruses, influenza, filoviruses, alphaviruses, and coronaviruses since the advent of human deficiency virus (HIV). Some of them even become serious threats to public health and have raised major global health concerns. Several different medicinal compounds such as anti-viral, anti-malarial, and anti-inflammatory agents, are under investigation for the treatment of these viral diseases. These therapies are effective improving recovery rates and overall survival of patients but are unable to heal lung damage caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, there is a critical need to identify effective treatments to combat this unmet clinical need. Due to its antioxidant and immunomodulatory properties, stem cell therapy is considered a novel approach to regenerate damaged lungs and reduce inflammation. Stem cell therapy uses a heterogeneous subset of regenerative cells that can be harvested from various adult tissue types and is gaining popularity due to its prodigious regenerative potential as well as immunomodulatory and anti-inflammatory properties. These cells retain expression of cluster of differentiation markers (CD markers), interferon-stimulated gene (ISG), reduce expression of pro-inflammatory cytokines and, show a rapid proliferation rate, which makes them an attractive tool for cellular therapies and to treat various inflammatory and viral-induced injuries. By examining various clinical studies, this review demonstrates positive considerations for the implications of stem cell therapy and presents a necessary approach for treating virally induced infections in patients.

Microfluidic nanodevices for drug sensing and screening applications.

The outbreak of pandemics (e.g., severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 in 2019), influenza A viruses (H1N1 in 2009), etc.), and worldwide spike in the aging population have created unprecedented urgency for developing new drugs to improve disease treatment. As a result, extensive efforts have been made to design novel techniques for efficient drug monitoring and screening, which form the backbone of drug development. Compared to traditional techniques, microfluidics-based platforms have emerged as promising alternatives for high-throughput drug screening due to their inherent miniaturization characteristics, low sample consumption, integration, and compatibility with diverse analytical strategies. Moreover, the microfluidic-based models utilizing human cells to produce in-vitro biomimetics of the human body pave new ways to predict more accurate drug effects in humans. This review provides a comprehensive summary of different microfluidics-based drug sensing and screening strategies and briefly discusses their advantages. Most importantly, an in-depth outlook of the commonly used detection techniques integrated with microfluidic chips for highly sensitive drug screening is provided. Then, the influence of critical parameters such as sensing materials and microfluidic platform geometries on screening performance is summarized. This review also outlines the recent applications of microfluidic approaches for screening therapeutic and illicit drugs. Moreover, the current challenges and the future perspective of this research field is elaborately highlighted, which we believe will contribute immensely towards significant achievements in all aspects of drug development.

Double left atrial appendage: A diagnostic dilemma.

We report a unique intraoperative finding of an additional double left atrial appendage (LAA) during an arterial switch operation with ventricular septal defect closure in a 4-month-old girl. Immediately after the procedure, a prolapsing mass within the left atrium (LA) on the transesophageal echocardiogram raised concerns of a possible thrombus. The LAA was clearly visible with a pressure monitoring line which was put intraoperatively. To investigate further, cardiopulmonary bypass was resumed, and the heart was arrested and explored. There was an appendage-like structure, separate from the one that had the pressure monitoring line, which was inverted inside. It was pulled out from outside clearly establishing a double LAA. This report illustrates an example of a diagnostic dilemma caused by a double atrial appendage which was invaginated into LA masquerading as a mass or thrombus.

Bioanalysis by LC-MS/MS and preclinical pharmacokinetic interaction study of ribociclib and oleanolic acid.

Background: Ribociclib (RIBO), approved in 2017 for HR-positive and HER-2-negative metastatic breast cancer treatment is reported to have the potential to induce hepatobiliary toxicity in patients. Oleanolic acid (OLA) has hepatoprotective potential that can be beneficial if coadministered with RIBO. Methodology & results: The primary scope of this study was to develop quantitative bioanalytical methods for RIBO and OLA. Two methods (for +ve electrospray ionization [ESI] and -ve ESI) were developed and validated according to USFDA bioanalytical guidelines. Discussion/conclusion: A single and simple sample preparation method was developed with >75% recovery. The accuracy and precision for RIBO and OLA were within acceptable limits over the calibration range of 5-500 ng/ml. This work reports, for the first time, the drug-drug interaction potential between RIBO and OLA.

Late presentation of aortopulmonary window: a contemporary series.

Late presentation of aortopulmonary window (APW) beyond infancy is uncommon and many of these cases are inoperable due to development of progressive pulmonary hypertension and Eisenmenger syndrome. Outcome data in this cohort is thus sparse and the aim of this study was to analyze the outcomes in patients with APW operable beyond 1 year of age. Between September 2016 and March 2020, in a single center, 12 consecutive patients older than 1 year, undergoing surgery for APW, were included in the study. The median age and weight at presentation were 7.5 years (interquartile range (IQR) 4-9.5) and 15 kg (IQR 11.7-19.5). Ten (83.3%) patients had type 1 APW (proximal type) and 2 (16.6%) had a type 2 APW (distal type). Eight (66.6%) patients had associated lesions. Transaortic patch closure of APW was done in all cases. Seven (58.3%) patients were extubated within 3.5 h of admission in intensive care. There were no early deaths or during follow-up. The median follow-up duration was 20.5 months (IQR 7.5-24), and all patients were in New York Heart Association (NYHA) class I at last follow-up. Follow-up echocardiography did not reveal any significant residual shunts necessitating any additional procedure and a consistent decrease in pulmonary artery pressures. Surgery in patients with APW beyond 1 year of age is possible in selected patients. The early and intermediate surgical outcomes in patients who remain operable are excellent.

Green Synthesized Silver Nanoparticles as Silver Lining in Antimicrobial Resistance: A Review.

Unprincipled use of antibiotics has led to antimicrobial resistance (AMR) against mostly available compounds, and has now become a major cause of concern for the scientific community. However, in the past decade, green synthesized silver nanoparticles (AgNPs) have received greater attention for the development of newer therapies as antimicrobials by virtue of their unique physico- chemical properties. Unlike traditional antibiotics, AgNPs exert their action by acting on multiple mechanisms, which make them potential candidates against AMR. Green synthesis of AgNPs using various medicinal plants has demonstrated a broader spectrum of action against several microbes in a number of attempts. The present paper provides an insight into the scientific studies that have elucidated the positive role of plant extracts/phytochemicals during the green synthesis of AgNPs and their future perspectives. The studies conducted so far seem promising; still, a few factors like the precise mechanism of action of AgNPs, their synergistic interaction with biomolecules, and industrial scalability, need to be explored further till effective drug development using green synthesized AgNPs in healthcare systems against AMR is established.

A systematic UHPLC-Q-TOF-MS/MS based analytical approach for characterization of flibanserin metabolites and establishment of biotransformation pathway.

A systematic metabolite profiling approach has paramount importance in detecting, identifying, and characterizing drug metabolites. Till date, there is no report published on the comprehensive metabolic fate of flibanserin (FLB). In this study, the structure of entire potential metabolites of FLB has been elucidated by execution of in silico tool and high resolution mass spectrometry based metabolite profiling strategy employing data-dependent and data-independent approaches. In vitro metabolism profile was investigated after incubating FLB with liver microsomes (rat and human) and S9 fractions in presence of their respective co-factors. In vivo metabolites were identified from rat plasma, urine, feces, and brain tissue samples. An efficient extraction technique was developed that made it possible to identify the metabolites generated even in extremely low concentrations. Extraction was carried out by precipitating protein and thereafter solid-phase extraction to enrich their concentration in the sample before analysis. Fourteen new metabolites have been identified and characterized. Most of the metabolites of FLB were generated due to hydrolysis and oxidation followed by glucuronide, sulfate, and methyl conjugation. Additionally, a spiking study was employed to confirm the presence of N-oxide metabolite in human liver S9 fraction and rat urine samples. Moreover, we have established the probable biotransformation pathway of FLB and successfully analyzed the toxicity potential of the metabolites using Pro Tox-II software.

A case of partial anomalous systemic venous drainage and perioperative detection of cerebral arteriovenous malformations.

We report a case of 8-year-old boy with unexplained desaturation and clubbing. Echocardiography showed anomalous drainage of right superior vena cava into left atrium. He did not have any neurological symptoms preoperatively. Some perioperative observations and subtle postoperative behavioral changes prompted us to investigate him further. He was found to have extensive cerebral arteriovenous malformations and hemiatrophy of brain.

Cardioprotective effects of azilsartan compared with that of telmisartan on an in vivo model of myocardial ischemia-reperfusion injury.

Azilsartan is found to be more potent than other angiotensin receptor blockers in reducing blood pressure. However, its effect on the heart following myocardial infarction remains to be established. For the first time, we investigated the peroxisome proliferator-activated receptor-γ (PPAR-γ) agonistic and cardioprotective properties of azilsartan. Computational modeling studies of interactions between azilsartan and PPAR-γ revealed azilsartan as an agonist of PPAR-γ and showed the mechanism of azilsartan in cardioprotection. Our study compared the cardioprotective potential of telmisartan to that of azilsartan in a murine model of myocardial ischemia-reperfusion injury by comparing their antioxidant, ant apoptotic, anti-inflammatory, mitogen-activated protein kinase (MAPK)-modulating ability, and PPAR-γ agonistic activity. Male Wistar rats were grouped into four to receive vehicle (dimethyl sulfoxide [0.05%] 2 ml/kg) telmisartan (10 mg/kg p.o.), azilsartan (10 mg/kg p.o.) or azilsartan with specific PPAR-γ blocker, GW 9662 for 28 days. Ischemia was induced for 45 min on the 29th day followed by 60 min of reperfusion. Telmisartan and azilsartan pretreatment significantly nearly normalized cardiac parameters and preserved structural changes. Both drugs inhibited oxidative burst, inflammation, as well as cell death by modulating apoptotic protein expression along with reduction in 4',6-diamidino-2-phenylindole/terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells. An increment in pro-survival kinase ERK paralleled with a reduction in p38 and JNK was also revealed by MAPK pathway studies, after administration of these drugs. Interestingly, the aforementioned changes induced by both drugs were reversed by administration of the specific PPAR-γ antagonist, GW9662. However, we found that azilsartan upregulated PPAR-γ to a lesser extent as compared to telmisartan and the latter may be preferred in hypertensive patients at risk of myocardial infarction.

Congenital right ventricular diverticulum: An atypical presentation.

Congenital ventricular diverticulum is a rare congenital malformation of the heart. It remains mostly asymptomatic unless associated with other congenital cardiac defects. We present a case of a 4-month-old child who had dextrocardia, large inlet ventricular septal defect, amounting to single ventricle, and severe pulmonary artery hypertension. There was a right ventricular diverticulum which passed through the foramina of Morgagni to give rise to a pulsating lump in the epigastrium. Right ventricular diverticulum presenting with a pulsating mass in the abdomen is a rare entity. The confirmation of diverticulum was made with histopathology.

The molecular mechanism involved in cardioprotection by the dietary flavonoid fisetin as an agonist of PPAR-γ in a murine model of myocardial infarction.

The methodology exploring the cardioprotective potential of the flavonoid Fisetin through its ability to modulate PPAR-γ was unraveled in the present study. Computational modelling through molecular docking based binding study of interactions between Fiestin and PPAR-γ revealed the potential role of Fisetin as an agonist of PPAR-γ. A murine model of cardiac ischemia-reperfusion injury was used to explore this further. Male Wistar Rats were randomly assigned to five groups. Fisetin (20 mg/kg; p. o) was administered for 28 days. Ischemia was induced for 45 min on the 29th day followed by 60 min of reperfusion. Fisetin pretreatment upregulated the expression of PPAR-γ in heart tissue significantly Cardioprotection was assessed by measurement of hemodynamic parameters, infarct size, ELISA for oxidative stress, immunohistochemistry and TUNEL assay for apoptosis, and western blot analysis for MAPK proteins and inflammation. PPAR-γ activation by fisetin led to significantly reduced infarct size, suppression of oxidative stress, reduction of cardiac injury markers, alleviation of inflammation, and inhibition of apoptosis The MAPK-based molecular mechanism showed a rise in a key prosurvival kinase, ERK1/ERK2 and suppression of JNK and p38 proteins. The aforementioned beneficial findings of fisetin were reversed on the administration of a specific antagonist of PPAR-γ. In conclusion, through our experiments, we have proved that fisetin protects the heart against ischemia-reperfusion injury and the evident cardioprotection is PPAR-γ dependant. In conclusion, our study has revealed a prime mechanism involved in the cardioprotective effects of fisetin. Hence, Fisetin may be evaluated in further clinical studies as a cardioprotective agent in patients undergoing reperfusion interventions.

Simultaneous quantification of abemaciclib and letrozole in rat plasma: method development, validation and pharmacokinetic application.

Treatment through a combination of drugs involving cyclin D-dependent kinase inhibitors like abemaciclib and aromatase inhibitor like letrozole proved to be a potential therapeutic regimen and first-line treatment in estrogen receptor-positive breast cancer. In this study, we developed a simple and simultaneous RP-HPLC bioanalytical method for quantifying abemaciclib and letrozole in rat plasma. Abemaciclib and letrozole were separated on Zorbax Eclipse C18 column employing a gradient elution method comprising 10 mM ammonium acetate (pH 5) and acetonitrile as mobile phase. The method was found to have acceptable selectivity, accuracy (97.20-118.17%), precision (1.10-9.39%) and stability in the validation experiment performed as per the US Food and Drug Administration guidelines. The method sensitivity was low at a concentration level of 100 ng/ml. The applicability of the method has been verified through a single-dose oral pharmacokinetic study in rat. The developed method will be useful to quantitate the analytes in rat plasma samples of different preclinical studies including their pharmacokinetic drug-drug interactions in the future. To date, no method has been reported for the quantification of abemaciclib and letrozole simultaneously in any type of biological matrices. Therefore, this study makes a definite significant contribution in the field of bioanalytical research.

Mass Spectrometry-Based Rapid Quantitative Bioanalysis of Flibanserin: Pharmacokinetic and Brain Tissue Distribution Study in Female Rats.

Flibanserin (FLB) is the first United States Food and Drug Administration (USFDA) approved serotonin modulator recently marketed to treat acquired generalized women hypoactive sexual desire disorder. The scope of this study was to develop and validate a sensitive, selective and reliable ultra-performance liquid chromatography-mass spectroscopy/mass spectroscopy-based quantification method for FLB in rat plasma as well as brain tissue samples. The method includes a simple liquid-liquid sample extraction procedure. FLB was subjected to chromatographic separation using a poroshell C18 column with the mobile phase comprising a mixture of acetonitrile (ACN), 10 mM ammonium acetate and acetic acid (90:10:0.1, v/v/v). Detection and quantification of FLB after positive electrospray ionization were carried out in selective ion monitoring mode. The fragment ions (m/z) of FLB (parent ion: 391.1741) and IS (parent ion: 448.1550) were monitored at 161.0704 and 285.0917, respectively. A linear response of FLB was observed over a concentration range of 2.5-600 ng/mL in plasma and 5-500 ng/mL in brain tissue homogenate. The intra- and inter-day precision and accuracy of the method met the acceptable limits specified in the USFDA bioanalytical method validation guideline. The analyte was found to be stable in benchtop, freeze-thaw, auto-injector and dry extract stability studies. The developed method was used to quantitate FLB in the plasma and brain tissue of a single-dose oral pharmacokinetic and brain tissue distribution study in female rats. Maximum FLB concentration in plasma and brain was achieved within an hour; however, the total amount of the drug that reached the brain was significantly less than in plasma. Rate of elimination of FLB from brain was also faster resulting in a lesser half-life in brain compared to the plasma.