Exploring the Prevalence of Respiratory Failure in Adults Presenting With Acute Exacerbations of Chronic Obstructive Pulmonary Disease.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) poses a significant global health burden and is a leading cause of morbidity and mortality. Acute exacerbations of COPD often lead to respiratory failure, necessitating a thorough understanding of its prevalence. This study aimed to investigate the prevalence of respiratory failure among adult patients experiencing acute exacerbations of COPD. MATERIALS AND METHODS: A descriptive, cross-sectional study was conducted over a span of seven months at the internal medicine department of Hayatabad Medical Complex, Peshawar. A total of 255 adult patients with acute exacerbations of COPD were included, and their demographic data, as well as arterial blood gas (ABG) analysis results, were collected. The prevalence of respiratory failure was defined by specific arterial blood gas criteria. RESULTS: The study revealed a notable prevalence of respiratory failure (41.18%) among COPD patients presenting with acute exacerbations. Factors such as older age and male gender were identified as being associated with a heightened risk of respiratory failure. CONCLUSION: In conclusion, acute exacerbations of COPD predominantly affect middle-aged males (65.5%), with the 51-60 age group being the most impacted. Respiratory failure was present in over 41% of cases. ABG analysis indicated significant acid-base imbalances, hypoxemia, and hypercapnia, with compensatory chronic respiratory acidosis. These findings highlight the need for targeted interventions to manage and prevent COPD exacerbations, especially in middle-aged men.

The metabolic landscape of the bacteria Rhodococcus erythropolis used in the biodesulfurization of petroleum products: an emphasis on 2-hydroxybiphenyl.

Microorganisms produce diverse classes of metabolites under various physiological conditions. Many bacterial strains have been reported to carry out the process of desulfurization in a cost-effective manner by converting dibenzothiophene (DBT) into 2-hydroxybiphenyl (2-HBP) and then using the 2-HBP as a carbon source for growth and development. Key rate-limiting factors and an increased concentration of 2HBP (400 µM) affect the biodesulfurization activity of bacteria through the produced metabolites. Thus, this study was designed to explore the nature of the metabolites produced by Rhodococcus erythropolis in the presence of DBT and 2HBP supplemented with a culture medium. A total of 330 metabolites were detected, and the key metabolites identified were 11Z-eicosaenoyl-EA, 1-carboxyethylisoleucine, 1(3)-glyceryl-PGF2alpha, taurine, 2-hydroxynicotinic acid, 4,4-dimethyl-14alpha-hydroxymethyl-5alpha-cholest-8-en-3beta-ol, and 10-nitrooleic acid. The supplementation of DBT and DBT-2HBP resulted in the differential regulation of these metabolites, either through downregulation or overexpression. Furthermore, at high concentrations of 2-HBP, 1-carboxyethylisoleucine, taurine, 2-hydroxynicotinic acid, and nicotinic acid were upregulated. This work proposes that the identified metabolites may play a role in bacteria-mediated desulphurization and could be beneficial in developing a cost-effective method of desulphurization for refining petroleum.

Survivability and behavior of probiotic bacteria encapsulated by internal gelation in non-dairy matrix and In Vitro GIT conditions.

The primary objective of this investigation was to assess the viability of free and encapsulated Lactobacillus plantarum probiotics in mango juice and under simulated gastrointestinal conditions. Specifically, the probiotics were encapsulated using sodium alginate and alginate-soy protein isolate through the internal gelation method, and the obtained probiotics were characterized for various attributes. Both free and encapsulated probiotics were exposed to challenging conditions, including thermal stress, low temperature, and simulated gastrointestinal conditions. Additionally, both types of probiotics were incorporated into mango juice, and their survival was monitored over a 28-day storage period. Following viability under simulated gastrointestinal conditions, the count of free and encapsulated probiotic cells decreased from initial levels of 9.57 log CFU/mL, 9.55 log CFU/mL, and 9.53 log CFU/mL, 9.56 log CFU/mL to final levels of 6.14 log CFU/mL, 8.31 log CFU/mL, and 6.24 log CFU/mL, 8.62 log CFU/mL, respectively. Notably, encapsulated probiotics exhibited a decrease of 1.24 log CFU and 0.94 log CFU, while free cells experienced a reduction of 3.43 log CFU and 6.24 log CFU in mango juice over the storage period. Encapsulated probiotics demonstrated higher viability in mango juice compared to free probiotics throughout the 28-day storage period. These findings suggest that mango juice can be enriched with probiotics to create a health-promoting beverage.

Euglycemic Diabetic Ketoacidosis With Acute Renal Failure: A Challenging Case for Clinicians.

Diabetic ketoacidosis (DKA) is a severe complication of diabetes mellitus characterized by hyperglycemia, metabolic acidosis, and ketosis. We present a challenging case of euglycemic DKA secondary to fasting and urinary tract infection with acute renal failure in a 50-year-old woman. Despite normal random blood sugar levels, the patient exhibited clinical signs of DKA, leading to further investigation. High anion gap metabolic acidosis with hyperkalemia and abnormal renal function tests were identified. After hemodialysis, serum ketones were found to be highly positive, confirming the diagnosis. Prompt management led to a complete clinical and laboratory resolution. This case underscores the importance of considering DKA in patients with suggestive symptoms, even with normal blood sugar levels.

Mechanistic insight into the mode of inhibition of dietary flavonoids; targeting macrophage migration inhibitory factor.

Introduction: The Macrophage Migration Inhibitory Factor (MIF), a key pro-inflammatory mediator, is responsible for modulating immune responses. An array of inflammatory and autoimmune diseases has been linked to the dysregulated activity of MIF. The significance in physiological as well as pathophysiological phenomena underscores the potential of MIF as an attractive target with pharmacological relevance. Extensive research in past has uncovered a number of inhibitors, while the ISO-1, or (S, R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester being recognized as a benchmark standard so far. Recent work by Yang and coworkers identified five promising dietary flavonoids, with superior activity compared to the standard ISO-1. Nevertheless, the exact atomic-level inhibitory mechanism is still elusive. Methods: To improve the dynamic research, and rigorously characterize, and compare molecular signatures of MIF complexes with ISO-1 and flavonoids, principal component analysis (PCA) was linked with molecular dynamics (MD) simulations and binding free energy calculations. Results: The results suggest that by blocking the tautomerase site these small molecule inhibitors could modify the MIF activity by disrupting the intrinsic dynamics in particular functional areas. The stability matrices revealed the average deviation values ranging from 0.27-0.32 nm while the residue level fluctuations indicated that binding of the selected flavonoids confer enhanced stability relative to the ISO-1. Furthermore, the gyration values extracted from the simulated trajectories were found in the range of 1.80-1.83 nm. Discussion: Although all the tested flavonoids demonstrated remarkable results, the one obtained for the potent inhibitors, particularly Morin and Amentoflavone exhibited a good correlation with biological activity. The PCA results featured relatively less variance and constricted conformational landscape than others. The stable ensembles and reduced variation in turns might be the possible reasons for their outstanding performance documented previously. The results from the present exploration provide a comprehensive understanding of the molecular complexes formed by flavonoids and MIF, shedding light on their potential roles and impacts. Future studies on MIF inhibitors may benefit from the knowledge gathered from this investigation.

Common mental disorders among adolescents in an urban area of Delhi.

Background: Common mental disorders (CMDs) among adolescents may hamper their psycho-social development. Aim: This study evaluated the prevalence and determinants of CMD like depression and anxiety among late adolescents of an age of 15--19 years residing in an urban resettlement colony of southeast Delhi. Methods: A community-based cross-sectional study was carried out among 556 randomly selected adolescents. CMD was assessed using Mini International Neuropsychiatry Interview - Kid version 6 (MINI-Kid) based on DSM-IV TR and compliant with ICD-10 definitions of CMD. The associated risk factors were studied using a self-developed semi-structured interview schedule and analyzed using multi-variable logistic regression. Results: A total of 491 adolescents were interviewed (a response rate of 88.3%), of whom 247 (50.3%) were female and 210 (42.8%) belonged to a lower-middle socio-economic status. The lifetime prevalence of CMD was 34% [95% confidence interval (CI): 29.8-38.2]. Of the total, 22.4% (95% CI: 18.7-6.1) of the participants reported depression and 6.7% (95% CI: 4.5-8.9) reported generalized anxiety disorder during their lifetime. Female sex [adjusted odds ratio (aOR) 2.1, 95% CI: 1.4-2.2], experiencing a stressful event in the past 6 months (aOR 4.7, 95% CI: 3.1-7.3), and smoking tobacco (aOR 2.0, 95% CI: 1.2-7.4) significantly increased the odds of having CMD in multi-variate analysis. Conclusion: There is a high prevalence of CMD among adolescents residing in urban resettlement colonies of Delhi, which is composed mostly of people belonging to lower socio-economic strata. Hence, tailored intervention at stress management with promotion of healthy lifestyle is needed for this age group.

Telerehabilitation: Exploring the Untapped Potential.

Telerehabilitation is a burgeoning field that holds immense promise in revolutionizing the delivery of rehabilitation services. Defined as a branch of telecommunication utilizing technologies such as the internet, it facilitates remote interaction between healthcare providers and patients, transcending geographical barriers. This method proves invaluable in patient assessment, counseling, and treatment across various medical domains, including physical therapy, speech therapy, psychotherapy, and occupational therapy. Particularly beneficial for individuals with disabilities or those unable to access traditional healthcare facilities, telerehabilitation mitigates the constraints of time and cost associated with travel. This paper explores the evolution, types, uses, and research findings in telerehabilitation, shedding light on its transformative potential in health care.

Myocardial SERCA2 Protects Against Cardiac Damage and Dysfunction Caused by Inhaled Bromine.

Myocardial sarcoendoplasmic reticulum calcium ATPase 2 (SERCA2) activity is critical for heart function. We have demonstrated that inhaled halogen (chlorine or bromine) gases inactivate SERCA2, impair calcium homeostasis, increase proteolysis, and damage the myocardium ultimately leading to cardiac dysfunction. To further elucidate the mechanistic role of SERCA2 in halogen-induced myocardial damage, we used bromine-exposed cardiac-specific SERCA2 knockout (KO) mice [tamoxifen-administered SERCA2 (flox/flox) Tg (αMHC-MerCreMer) mice] and compared them to the oil-administered controls. We performed echocardiography and hemodynamic analysis to investigate cardiac function 24 hours after bromine (600 ppm for 30 minutes) exposure and measured cardiac injury markers in plasma and proteolytic activity in cardiac tissue and performed electron microscopy of the left ventricle (LV). Cardiac-specific SERCA2 knockout mice demonstrated enhanced toxicity to bromine. Bromine exposure increased ultrastructural damage, perturbed LV shape geometry, and demonstrated acutely increased phosphorylation of phospholamban in the KO mice. Bromine-exposed KO mice revealed significantly enhanced mean arterial pressure and sphericity index and decreased LV end diastolic diameter and LV end systolic pressure when compared with the bromine-exposed control FF mice. Strain analysis showed loss of synchronicity, evidenced by an irregular endocardial shape in systole and irregular vector orientation of contractile motion across different segments of the LV in KO mice, both at baseline and after bromine exposure. These studies underscore the critical role of myocardial SERCA2 in preserving cardiac ultrastructure and function during toxic halogen gas exposures. SIGNIFICANCE STATEMENT: Due to their increased industrial production and transportation, halogens such as chlorine and bromine pose an enhanced risk of exposure to the public. Our studies have demonstrated that inhalation of these halogens leads to the inactivation of cardiopulmonary SERCA2 and results in calcium overload. Using cardiac-specific SERCA2 KO mice, these studies further validated the role of SERCA2 in bromine-induced myocardial injury. These studies highlight the increased susceptibility of individuals with pathological loss of cardiac SERCA2 to the effects of bromine.

A comparative in vitro study on the effect of SGLT2 inhibitors on chemosensitivity to doxorubicin in MCF-7 breast cancer cells.

Cancer frequently develops resistance to the majority of chemotherapy treatments. This study aimed to examine the synergistic cytotoxic and antitumor effects of SGLT2 inhibitors, specifically Canagliflozin (CAN), Dapagliflozin (DAP), Empagliflozin (EMP), and Doxorubicin (DOX), using in vitro experimentation. The precise combination of CAN+DOX has been found to greatly enhance the cytotoxic effects of doxorubicin (DOX) in MCF-7 cells. Interestingly, it was shown that cancer cells exhibit an increased demand for glucose and ATP in order to support their growth. Notably, when these medications were combined with DOX, there was a considerable inhibition of glucose consumption, as well as reductions in intracellular ATP and lactate levels. Moreover, this effect was found to be dependent on the dosages of the drugs. In addition to effectively inhibiting the cell cycle, the combination of CAN+DOX induces substantial modifications in both cell cycle and apoptotic gene expression. This work represents the initial report on the beneficial impact of SGLT2 inhibitor medications, namely CAN, DAP, and EMP, on the responsiveness to the anticancer properties of DOX. The underlying molecular mechanisms potentially involve the suppression of the function of SGLT2.

A Quality Improvement Initiative to Reduce Prescription Error in a Pediatrics Outpatient Department at a Secondary-Level Community Hospital.

Background Medication errors are common, especially by new trainees in primary care settings. Our study aimed at reducing the rate of prescription error in the pediatric outpatient department (OPD) of a secondary healthcare center in suburban north India using a quality improvement methodology. Methods Based on a survey and focused group discussion (FGD) involving all stakeholders, the identified problems and difficulties faced during outpatient prescriptions, interventions, and outcome parameters were drafted. The primary outcome measure was the prescription error rate evaluated by a senior resident (SR) of pediatrics, and the secondary outcome measures included the frequency of antibiotic prescriptions and investigations. Intervention Two cycles of Plan-Do-Study-Act (PDSA) were conducted on accessible drug formularies and standard treatment protocols for common pediatric conditions. Results The mean baseline prescription error was 72.2% (95% confidence interval (CI): 63.2-81.1). After the implementation of the first PDSA cycle, the mean error rate was 46.5% (95% CI: 36.6-56.5). There were eight consecutive points of prescription error below the control limit (63.2% and 81.1%) of the baseline. The PDSA-2 cycle showed the same shift to below the control limit (36.6% and 56.5%). The mean error rate found at the end of the PDSA-2 cycle was 22.5% (95% CI 15.7-29.5). There was no clinically significant difference in the number of investigations or antibiotics prescribed. Conclusion The application of standardized drug formularies and standard treatment protocols (STPs) can help reduce prescription errors, especially in a primary care setting. Expansion of such techniques to other centers could be particularly useful.

Concomitant Salmonella and Leptospira Meningitis: A Rare Case Report.

This study presents a unique case of concurrent salmonella and Leptospira meningitis in a 20-year-old woman with no prior medical history. Coinfection with endemic pathogens is plausible, especially in regions like Pakistan. While Salmonella meningitis is uncommon, it presents a significant medical emergency, particularly in immunocompromised adults. Neuroleptospirosis, though rare, can manifest in certain cases. The patient displayed persistent high fever, confusion, irritability, and a single seizure episode. Initial tests, including blood and cerebrospinal fluid (CSF) cultures and serological examinations, detected Salmonella typhi and positive leptospiral antibodies, respectively. Leptomeningeal enhancement was confirmed by an MRI. Treatment with azithromycin, meropenem, and ceftriaxone led to improvement after seven days. She was advised to complete a 28-day course for Salmonella meningitis. This case emphasizes the importance of considering multiple infectious causes, especially in endemic regions. Timely and thorough diagnostic evaluation, followed by appropriate antimicrobial therapy, is essential for effective management. Further research is warranted to enhance understanding of the epidemiology, clinical features, and optimal treatment strategies for such dual infections.

Plant extract preparation and green synthesis of silver nanoparticles using Swertia chirata: Characterization and antimicrobial activity against selected human pathogens.

Herbal medicinal plants have been used for centuries in traditional medicine, and it is interesting to see how modern research has identified the active compounds responsible for their therapeutic effects. The green synthesis of silver nanoparticles using herbal medicinal plants, such as Swertia chirata, is particularly noteworthy due to its antimicrobial properties. In the current study, the Swertia chirata plant was collected for the first time from the region of Murree, Punjab, Pakistan. After collection, extracts were prepared in different solvents (ethanol, methanol, chloroform, and distilled water), and silver nanoparticles were synthesized by reducing silver nitrate (AgNO3). The UV-visible spectrophotometer, SEM, and EDX were used to characterize the synthesized nanoparticles in terms of their size and shape. The phytochemical analysis of crude extract was performed to determine the presence of different kinds of phytochemicals. The antibacterial activity of plant extracts and the silver nanoparticles were then assessed using the agar well diffusion method against various pathogenic bacteria. The results showed that the plant contains several phytochemicals with remarkable antioxidant potential. The antibacterial analysis revealed that silver nanoparticles and the plant extracts exhibited a significant zone of inhibition against human pathogenic bacteria (Escherichia coli, S. capitis, B. subtilis, and Pseudomonas aeruginosa) as compared to the cefixime and norfloxacin. This implies that the nanoparticles have the potential to be used in nano-medicine applications, such as drug delivery systems, as well as for their antibacterial, antifungal, and antiviral activities. Additionally, the development and application of materials and technologies at the nanometer scale opens possibilities for the creation of novel drugs and therapies. Overall, the study highlights the promising potential of herbal medicinal plants found in Murree, Punjab, Pakistan, and green-synthesized silver nanoparticles in various fields of medicine and nanotechnology.

Asymptomatic Salmonella Myocarditis: A Case Report of a Rare Entity.

Enteric fever typically displays symptoms like high fever, abdominal pain, constipation, and headaches, primarily affecting the digestive system. While it is commonly seen as a gastrointestinal infection, it can also lead to rare but significant cardiovascular issues. There have been only a few reported cases of enteric fever causing heart manifestations. We present a case of a young male with enteric fever-induced myocarditis, which, due to its rarity, can be challenging to diagnose and is essentially a diagnosis of exclusion. Cardiac MRI (CMR) is crucial for diagnosis, supported by ECG, echocardiograms, and troponin levels. The treatment involves standard approaches for cardiomyopathy, including angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and diuretics. However, our patient presented as a case of asymptomatic myocarditis and fully recovered with treatment without any long-lasting heart problems. Our study aims to contribute to the limited body of knowledge on heart-related complications of enteric fever, raising awareness among clinicians of such presentations in enteric fever cases.

Effectiveness and safety of the combination of sodium-glucose transport protein 2 inhibitors and glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes mellitus: a systematic review and meta-analysis of observational studies.

BACKGROUND: Randomized controlled trials and real-world studies suggest that combination therapy with sodium-glucose transport protein 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) is associated with improvement in fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), systolic blood pressure (SBP), body mass index (BMI), and total cholesterol levels. However, a systematic review of available real-world evidence may facilitate clinical decision-making in the real-world scenario. This meta-analysis assessed the safety and effectiveness of combinations of SGLT2is + GLP-1RAs with a focus on their cardioprotective effects along with glucose-lowering ability in patients with type 2 diabetes mellitus (T2DM) in a real-world setting. METHODS: Electronic searches were performed in the PubMed/MEDLINE, PROQuest, Scopus, CINAHL, and Google Scholar databases. Qualitative analyses and meta-analyses were performed using the Joanna Briggs Institute SUMARI software package and Review Manager v5.4, respectively. RESULTS: The initial database search yielded 1445 articles; of these, 13 were included in this study. The analyses indicated that SGLT2is + GLP-1RAs combinations were associated with significantly lower all-cause mortality when compared with individual therapies (odds ratio [95% confidence interval [CI] 0.49 [0.41, 0.60]; p < 0.00001). Significant reductions in BMI (- 1.71 [- 2.74, - 0.67]; p = 0.001), SBP (- 6.35 [- 10.17, - 2.53]; p = 0.001), HbA1c levels (- 1.48 [- 1.75, - 1.21]; p < 0.00001), and FPG (- 2.27 [- 2.78, - 1.76]; p < 0.00001) were associated with the simultaneous administration of the combination. Changes in total cholesterol levels and differences between simultaneous and sequential combination therapies for this outcome were not significant. CONCLUSION: This systematic review and meta-analysis based on real-world data suggests that the combination of SGLT2is + GLP-1RAs is associated with lower all-cause mortality and favorable improvements in cardiovascular, renal, and glycemic measurements. The findings drive a call-to-action to incorporate this combination early and simultaneously in managing T2DM patients and achieve potential cardiovascular benefits and renal protection.

Multidrug resistance among uropathogenic clonal group A E. Coli isolates from Pakistani women with uncomplicated urinary tract infections.

OBJECTIVE: Multi-drug resistance (MDR) has notably increased in community acquired uropathogens causing urinary tract infections (UTIs), predominantly Escherichia coli. Uropathogenic E. coli causes 80% of uncomplicated community acquired UTIs, particularly in pre-menopausal women. Considering this high prevalence and the potential to spread antimicrobial resistant genes, the current study was conducted to investigate the presence of clinically important strains of E. coli in Pakistani women having uncomplicated cystitis and pyelonephritis. Women belonging to low-income groups were exclusively included in the study. Seventy-four isolates from urine samples were processed, phylotyped, and screened for the presence of two Single Nucleotide Polymorphisms (SNPs) particularly associated with a clinically important clonal group A of E. coli (CgA) followed by antibiotic susceptibility testing and genome sequence analysis. RESULTS: Phylogroup B2 was most prevalent in patients and 44% of isolates were positive for the presence of CgA specific SNPs in Fumarate hydratase and DNA gyrase subunit B genes. Antibiotic susceptibility testing showed widespread resistance to trimethoprim-sulfamethoxazole and extended-spectrum beta-lactamase production. The infection analysis revealed the phylogroup B2 to be more pathogenic as compared to the other groups. The genome sequence of E. coli strain U17 revealed genes encoding virulence, multidrug resistance, and host colonization mechanisms. CONCLUSIONS: Our research findings not only validate the significant occurrence of multidrug-resistant clonal group A E. coli (CgA) in premenopausal Pakistani women suffering from cystitis and pyelonephritis but also reveal the presence of genes associated withvirulence, and drug efflux pumps. The detection of highly pathogenic, antimicrobial-resistant phylogroup B2 and CgA E. coli strains is likely to help in understanding the epidemiology of the pathogen and may ultimately help to reduce the impact of these strains on human health. Furthermore, the findings of this study will particularly help to reduce the prevalence of uncomplicated UTIs and the cost associated with their treatment in women belonging to low-income groups.

Nanophytosomal Gel of Heydotis corymbosa (L.) Extract against Psoriasis: Characterisation, In Vitro and In Vivo Biological Activity.

The current study was conducted to examine the possible advantages of Heydotis corymbosa (L.) Lam. extract nanogel as a perspective for enhanced permeation and extended skin deposition in psoriasis-like dermatitis. Optimised nanophytosomes (NPs) were embedded in a pluronic gel base to obtain nanogel and tested ex vivo (skin penetration and dermatokinetics) and in vivo. The optimised NPs had a spherical form and entrapment efficiency of 73.05 ± 1.45% with a nanosized and zeta potential of 86.11 nm and -10.40 mV, respectively. Structural evaluations confirmed encapsulation of the drug in the NPs. Topical administration of prepared nanogel to a rat model of psoriasis-like dermatitis revealed its specific in vivo anti-psoriatic efficacy in terms of drug activity compared to the control and other formulations. Nanogel had improved skin integrity and downregulation of inflammatory cytokines. These findings suggest that developed phytoconstituent-based nanogel has the potential to alleviate psoriasis-like dermatitis with better skin retention and effectiveness.

Uncovering PPAR-γ agonists: An integrated computational approach driven by machine learning.

Peroxisome proliferator-activated receptor gamma (PPAR-γ) serves as a nuclear receptor with a pivotal function in governing diverse facets of metabolic processes. In diabetes, the prime physiological role of PPAR-γ is to enhance insulin sensitivity and regulate glucose metabolism. Although PPAR-γ agonists such as Thiazolidinediones are effective in addressing diabetes complications, it is vital to be mindful that they are associated with substantial side effects that could potentially give rise to health challenges. The recent surge in the discovery of selective modulators of PPAR-γ inspired us to formulate an integrated computational strategy by leveraging the promising capabilities of both machine learning and in silico drug design approaches. In pursuit of our objectives, the initial stage of our work involved constructing an advanced machine learning classification model, which was trained utilizing chemical information and physicochemical descriptors obtained from known PPAR-γ modulators. The subsequent application of machine learning-based virtual screening, using a library of 31,750 compounds, allowed us to identify 68 compounds having suitable characteristics for further investigation. A total of four compounds were identified and the most favorable configurations were complemented with docking scores ranging from -8.0 to -9.1 kcal/mol. Additionally, the compounds engaged in hydrogen bond interactions with essential conserved residues including His323, Leu330, Phe363, His449 and Tyr473 that describe the ligand binding site. The stability indices investigated herein for instance root-mean-square fluctuations in the backbone atoms indicated higher mobility in the region of orthosteric site in the presence of agonist with the deviation peaks in the range of 0.07-0.69 nm, signifying moderate conformational changes. The deviations at global level revealed that the average values lie in the range of 0.25-0.32 nm. In conclusion, our identified hits particularly, CHEMBL-3185642 and CHEMBL-3554847 presented outstanding results and highlighted the stable conformation within the orthosteric site of PPAR-γ to positively modulate the activity.

Computational Approaches to Evaluate the Acetylcholinesterase Binding Interaction with Taxifolin for the Management of Alzheimer's Disease.

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are enzymes that break down and reduce the level of the neurotransmitter acetylcholine (ACh). This can cause a variety of cognitive and neurological problems, including Alzheimer's disease. Taxifolin is a natural phytochemical generally found in yew tree bark and has significant pharmacological properties, such as being anti-cancer, anti-inflammatory, and antioxidant. The binding affinity and inhibitory potency of taxifolin to these enzymes were evaluated through molecular docking and molecular dynamics simulations followed by the MMPBSA approach, and the results were significant. Taxifolin's affinity for binding to the AChE-taxifolin complex was -8.85 kcal/mol, with an inhibition constant of 326.70 nM. It was observed to interact through hydrogen bonds. In contrast, the BChE-taxifolin complex binding energy was observed to be -7.42 kcal/mol, and it was significantly nearly equal to the standard inhibitor donepezil. The molecular dynamics and simulation signified the observed interactions of taxifolin with the studied enzymes. The MMPBSA total free energy of binding for AChE-taxifolin was -24.34 kcal/mol, while BChE-taxifolin was -16.14 kcal/mol. The present research suggests that taxifolin has a strong ability to bind and inhibit AChE and BChE and could be used to manage neuron-associated problems; however, further research is required to explore taxifolin's neurological therapeutic potential using animal models of Alzheimer's disease.