Hexaconazole exposure may lead to Parkinson via disrupting glucocerebrosidase and parkin: molecular interaction, dynamics, MMPBSA and DFT based in-silico predictive toxicology.

Hexaconazole is a known fungicide for agricultural purposes. It has bioaccumulation ability which makes it important for its toxicological characterization. There are various neurological impacts of pollutants on human health. Therefore, in this study, we have done predictive analyses of the interaction mechanism of hexaconazole by molecular interaction analysis, molecular dynamics simulation, and Poisson-Boltzmann surface area (MM-PBSA) to assess hexaconazole's potency to disrupt the homeostasis of glucocerebrosidase (-7.9 kcal/mol) and parkin (-5.67 kcal/mol) proteins which have significant roles in the manifestation of Parkinson disease. The findings reveal that hexaconazole has the potency to form stable interactions with glucocerebrosidase and parkin. This research provides a molecular and atomic-level understanding of how hexaconazole exposure may disrupt the homeostasis of glucocerebrosidase and parkin. The root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration, and hydrogen bonding exhibited the potent molecular interactions of hexaconazole, which may lead to neurological manifestations such as Parkinson disease.

Hexaconazole exposure disrupt acetylcholinesterase, leading to mental illness.

Hexaconazole is widely used in agricultural work, and it has been observed that it has potential to disrupt endocrine function and it has also capacity of bioaccumulation. In this study, we examined how the hexaconazole disrupts the usual balance of acetylcholinesterase. It has been already reported that heavy pesticide exposures may be a reason for several mental illnesses because these pesticides may disrupt normal balance of acetylcholinesterase. In this paper, we have done a complete molecular and dynamics analysis to understand the behavior of hexaconazole with acetylcholinesterase so that its toxicological aspect may be explored. Our findings revealed that hexaconazole has potency to interact with acetylcholinesterase in a stable manner. The binding energy of hexaconazole was found to be -7.95 kcal/mol. However, chlorpyrifos, known inhibitors of acetylcholinesterase, has binding energy of -7.17 kcal/mol. With respect to stability analysis, hexaconazole has similar stability like chlorpyrifos. Root-mean-square deviation, root-mean-square fluctuation, radius of gyration, hydrogen bonding, and solvent accessible surface area were similar to chlorpyrifos. In addition, density functional theory computations analysis reveals that hexaconazole is energetically stable like chlorpyrifos, which is necessary for establishing a stable ligand-protein complex. The result of this complete molecular analysis reveals that hexaconazole may disrupt the acetylcholinesterase balance, which leads to mental illness.

Formulation of lemongrass oil (Cymbopogon citratus)-loaded solid lipid nanoparticles: an in vitro assessment study.

Cymbopogon citratus (DC) stapf. (Gramineae) is a herb known worldwide as lemongrass. The oil obtained, i.e., lemongrass oil has emerged as one among the most relevant natural oils in the pharmaceutical industry owing to its extensive pharmacological and therapeutic benefits including antioxidant, antimicrobial, antiviral and anticancer properties. However, its usage in novel formulations is constrained because of its instability and volatility. To address these concerns, the present study aims to formulate lemongrass-loaded SLN (LGSLN) using hot water titration technique. In the Smix, Tween 80 was selected as a surfactant component, while ethanol was taken as a co-surfactant. Different ratios of Smix (1:1, 1:2, 1:3, 2:1 and 3:1) were utilized to formulate LG-loaded SLN. The results indicated the fact that the LGSLN formulation (abbreviated as LGSLN1), containing lipid phase 10% w/w (i.e., LG 3.33% and SA 6.67%), Tween 80 (20% w/w), ethanol (20% w/w) and distilled water (50% w/w), revealed suitable nanometric size (142.3 ± 5.96 nm) with a high zeta potential value (- 29.12 ± 1.7 mV) and a high entrapment efficiency (77.02 ± 8.12%). A rapid drug release (71.65 ± 5.33%) was observed for LGSLN1 in a time span of 24 h. Additionally, the highest values for steady-state flux (Jss; 0.6133 ± 0.0361 mg/cm2/h), permeability coefficient (Kp; 0.4573 ± 0.0141 (cm/h) × 102) and enhancement ratio (Er; 13.50) was also conferred by LGSLN1. Based on in vitro study results, the developed SLN appeared as a potential carrier for enhanced topical administration of lemongrass oil. The observed results also indicated the fact that the phyto-cosmeceutical prospective of the nanolipidic carrier for topical administration of lemongrass oil utilizing pharmaceutically acceptable components can be explored further for widespread clinical applicability. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03726-5.

Potential of paracetamol for reproductive disruption: molecular interaction, dynamics, and MM-PBSA based in-silico assessment.

Paracetamol is generally recommended for pain and fever. However, as per experimental and epidemiological data, widespread and irrational or long-term use of paracetamol may be harmful to human endocrine homeostasis, especially during pregnancy. Some researchers suggest that prenatal exposure to paracetamol might alter fetal development and also enhance the risk of reproductive disorders. An imbalance in the levels of these hormones may play a significant role in the emergence of various diseases, including infertility. Therefore, in this study, the interaction mechanism of paracetamol with reproductive hormone receptors was investigated by molecular docking, molecular dynamics (MD) simulations, and Poisson-Boltzmann surface area (MM-PBSA) for assessing paracetamol's potency to disrupt reproductive hormones. The results indicate that paracetamol has the ability to interact with reproductive hormone receptors (estrogen 1XP9; 1QKM with binding energy of -5.61 kcal/mol; -5.77 kcal/mol; androgen 5CJ6 - 5.63 kcal/mol; and progesterone 4OAR -5.60 kcal/mol) by hydrogen bonds as well as hydrophobic and van der Waals interactions to maintain its stability. In addition, the results of the MD simulations and MM-PBSA confirm that paracetamol and reproductive receptor complexes are stable. This research provides a molecular and atomic level understanding of how paracetamols disrupt reproductive hormone synthesis. The root mean square deviation (RMSD), root mean square fluctuation (RMSF), Radius of Gyration and hydrogen bonding exhibited that paracetamol mimic at various attribute to bisphenol and native ligand.

Molecular Mechanisms of Oxidative Stress in Acute Kidney Injury: Targeting the Loci by Resveratrol.

Reactive oxygen species are a group of cellular molecules that stand as double-edged swords, their good and bad being discriminated by a precise balance. Several metabolic reactions in the biological system generate these molecules that interact with cellular atoms to regulate functions ranging from cell homeostasis to cell death. A prooxidative state of the cell concomitant with decreased clearance of such molecules leads to oxidative stress, which contributes as a prime pathophysiological mechanism in various diseases including renal disorders, such as acute kidney injury. However, targeting the generation of oxidative stress in renal disorders by an antioxidant, resveratrol, is gaining considerable therapeutic importance and is known to improve the condition in preclinical studies. This review aims to discuss molecular mechanisms of oxidative stress in acute kidney injury and its amelioration by resveratrol. The major sources of data were PubMed and Google Scholar, with studies from the last five years primarily included, with significant earlier data also considered. Mitochondrial dysfunction, various enzymatic reactions, and protein misfolding are the major sources of reactive oxygen species in acute kidney injury, and interrupting these loci of generation or intersection with other cellular components by resveratrol can mitigate the severity of the condition.

Global Prevalence and Associated Clinical Markers of Thrombocytopenia in People Living with HIV: Evidence from Meta-Analysis.

Thrombocytopenia is one of the complications in human immunodeficiency virus (HIV) patients. To improve the health outcomes of patients living with HIV, it is important to understand the prevalence and pattern of associated key clinical markers globally. This meta-analysis, therefore, aimed to estimate the pooled prevalence of and associated clinical marker of thrombocytopenia globally. Methodology: The meta-analysis was conducted as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. All statistical analyses were conducted using Stata. Twelve full-text papers out of 454 were eligible for meta-analysis. Results: Among 6686 participants, overall pooled prevalence of thrombocytopenia was 10.90% (95% CI: 7.91, 13.88) I2 = 93.62%. In addition, thrombocytopenia was more prevalent by 25.11% (95% CI: 13.33, 36.88) in patients with CD + T < 200 cells/µL, and less prevalent in patients with CD + T < 200 cells/µL 10.10% (95% CI: 7.37, 12.83), respectively. Conclusions and recommendations: This meta-analysis established the prevalence of thrombocytopenia among patients living with HIV, and that it may be more prevalent in patients with CD + T < 200 cells/µL indicating the necessity of routine screening for various haematological markers and a careful treatment plan for HIV patients.

Multi-Epitope-Based Vaccine Candidate for Monkeypox: An In Silico Approach.

Currently, there are limited treatment options available for the monkeypox disease. We used a computational strategy to design a specific antigenic vaccine against pathogens. After using various immunoinformatic tools and filters, cytotoxic T-cell lymphocyte (CTL)-, helper T-cell lymphocyte (HTL)-, and interferon gamma (IFN-γ)-inducing epitopes, which comprised the vaccine, in addition to other parameters, such as antigenic and allergic profiles, were assessed to confirm the safety of the vaccine. However, vaccine interaction and stability with Toll-like receptors (TLRs) were assessed by dynamic simulation methods, and it was found that the constructed vaccine was stable. In addition, C-IMMSIM tools were used to determine the immune-response-triggering capabilities of the vaccine. These immunoinformatic findings reveal that constructed vaccine candidates may be capable of triggering an efficient immune response for monkeypox viral infections. However, experimental evaluation is required to verify the safety and immunogenic profile of constructed vaccines.

Sunscreen Ingredient Octocrylene's Potency to Disrupt Vitamin D Synthesis.

Octocrylene is a widely used ingredient in sunscreen products, and it has been observed that the use of sunscreen has been increasing over the last few decades. In this paper, we investigated the way in which sunscreen's ingredient octocrylene may disrupt normal vitamin D synthesis pathway, resulting in an imbalance in vitamin D levels in the body. The key techniques used for this insilico investigation were molecular docking, molecular dynamic (MD) simulation, and MMPBSA-based assessment. Vitamin D abnormalities have become very common in human health. Unknown exposure to chemicals may be one of the important risk factors. In molecular docking analysis, octocrylene exhibited a binding energy of -11.52 kcal/mol with vitamin D binding protein (1KXP) and -11.71 for the calcitriol native ligand. Octocrylene had a binding potency of -11.152 kcal/mol with the vitamin D receptor (1DB1), and calcitriol had a binding potency of -8.73 kcal/mol. In addition, octocrylene has shown binding energy of -8.96 kcal/mol with CYP2R1, and the calcitriol binding energy was -10.36 kcal/mol. Regarding stability, the root-mean-square deviation (RMSD), the root-mean-square fluctuation (RMSF), the radius of gyration, hydrogen bonding, and the solvent-accessible surface area (SASA) exhibited that octocrylene has a stable binding pattern similar to calcitriol. These findings revealed that incessant exposure to octocrylene may disrupt normal vitamin D synthesis.

Hexaconazole exposure ravages biosynthesis pathway of steroid hormones: revealed by molecular dynamics and interaction.

Widespread application of hexaconazole for agriculture purpose poses a threat to human health by disrupting normal endocrine homeostasis. To avoid adverse health effects on human, it is crucial to identify the effects of hexaconazole on key enzymes responsible for steroidal hormone synthesis. In view of this, present study was conducted to investigate the interaction mechanisms of hexaconazole with key enzymes in comparison with their food drug administration (FDA) approved inhibitor by molecular docking and molecular dynamics simulations. Results indicate that hexaconazole contacts with the active site of the key enzymes required for steroidal hormonal synthesis. Results pertaining to root-mean-square deviation, root-mean-square calculation, radius of gyration, hydrogen bonding and solvent accessible surface area exhibited that the interaction pattern and stability of interaction of hexaconazole was similar to enzyme specific inhibitor. In addition, ligand and enzyme complex interaction energy of hexaconazole was almost similar to key enzyme and FDA-approved enzyme specific inhibitor complex. This study offers a molecular level of understanding of hexaconazole with different enzymes required for steroidal hormonal synthesis. Findings of the study clearly suggest that hexaconazole has efficacy to stably interact with various enzyme required to progress the pathway of hormonal synthesis. If incessant exposure of hexaconazole occurs during agricultural work it may lead to ravage hormonal synthesis or potent endocrine disruption. The result of binding energy and complex interaction energy is depicted in the graphical abstract.

Morusflavone, a New Therapeutic Candidate for Prostate Cancer by CYP17A1 Inhibition: Exhibited by Molecular Docking and Dynamics Simulation.

Morusflavone, a flavonoid from Morus alba L., was evaluated for its interactive ability and stability with CYP17A1, in comparison with abiraterone, which is a Food and Drug Administration (FDA)-approved CYP17A1 inhibitor. CYP17A1 inhibition is an important therapeutic target for prostate cancer. The CHAMM36 force field was used to perform molecular dynamics (MD) simulations in this study. The results show that Morusflavone has significant interactive ability and stability for CYP17A1, in comparison with abiraterone. The final interaction energies for the Morusflavone-CYP17A1 and abiraterone-CYP17A1 complexes were -246.252 KJ/mol and -207.86 KJ/mol, respectively. Since there are only limited therapeutic agents available, such as abiraterone, galeterone, and seviteronel, which are being developed for prostate cancer, information on any potent natural anticancer compounds, such as vinca alkaloids, for prostate cancer treatment is limited. The results of this study show that CYP17A1 inhibition by Morusflavone could be an important therapeutic target for prostate cancer. Further preclinical and clinical evaluations of the lead compound Morusflavone are required to evaluate whether it can serve as a potential inhibitor of CYP17A1, which will be a new hope for prostate cancer treatment.

Severe cutaneous adverse reactions in Asians: Trends observed in culprit anti-seizure medicines using VigiBase®.

PURPOSE: Diverse ethnic genetic populations display variability in the risk regarding anti-seizure medicine (ASM)-induced severe cutaneous adverse reactions (SCARs). However, clinical and epidemiological data on ASM-induced SCARs in Asians is limited. METHODS: We conducted a retrospective, post-market study until April 30, 2020 using VigiBase® for demographic characteristics, causative ASMs, complications and mortality. The study included adverse events as classified by Standardized Medical Dictionary for Regulatory Activities (MedDRA) queries of SCARs, mainly Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS), and SJS/TEN overlap reported for ASMs. RESULTS: A total of 694,811 adverse events were reported across the world while using ASMs. Of this, skin and subcutaneous tissue adverse events were 122,885 (17.6%). Among ASM-induced skin and subcutaneous tissue adverse events, SJS, TEN, DRESS and SJS/TEN overlap represented 11,181 (9.1%), 3,645 (3.0%), 5,106 (4.1%) and 6 (0.004%) cases, respectively. Female SJS/TEN/DRESS patients were 54.1%, and 75% of them were adults (>18Y). Nearly 64% of the ASM-induced SCARs were serious and culminated in death (3.5%), life-threatening conditions (11.5%), and hospitalization/prolonged hospitalization (43.5%) of patients on ASM therapy. Carbamazepine (31.6%), phenytoin (29.6%), lamotrigine (24.3%), valproic acid (6.4%) and phenobarbital (5.7%) are the most commonly used ASMs linked with SCARs. ASMs associated with significantly higher risk of SCARs in Asians were carbamazepine [n = 3265, ROR 3.55 (95% CI 3.38-3.72, P < 0.0001)], lamotrigine [n = 1253, ROR 3.90 (95% CI 3.63-4.18, P < 0.0001)], gabapentin [n = 85, ROR 3.58 (95% CI 2.79-4.60, P < 0.0001)], pregabalin [n = 68, ROR 3.16 (95% CI 2.40-4.16, P < 0.0001)], clonazepam [n = 53, ROR 3.19 (95% CI 2.31-4.41, P < 0.0001)], lorazepam [n = 31, ROR 3.07 (95% CI 2.06-4.59, P < 0.0001)] and acetazolamide [n = 28, ROR 3.90 (95% CI 2.45-6.21, P < 0.0001)]. CONCLUSION: Based on our study, carbamazepine, lamotrigine, gabapentin, pregabalin, clonazepam, lorazepam, and acetazolamide are the most common causative ASMs for SCARs in the Asian population.

Molecular docking and dynamics simulation to screen interactive potency and stability of fungicide tebuconazole with thyroid and sex hormone-binding globulin: Implications of endocrine and reproductive interruptions.

Tebuconazole is a widely used fungicide in agriculture, and it may easily enter in the human food chain. In addition, tebuconzaol skin permeation coefficient (Log Kp) is -5.55 cm/s and it does not violate Lipinski's rule. It may mimic as a ligand for various endocrine and reproductive receptor leading to toxicological response or disease manifestation. We studied interactive potential of tebuconazole with thyroid and sex hormone-binding globulin. The main methods for this in silico analyses are molecular docking and molecular dynamic (MD) simulation. This paper explores how agriculture fungicide tebuconzaol exposure can be a risk for endocrine and reprotoxicity due to its stable interactive potency with thyroid and sex hormone-binding globulin (2CEO and 1D2S). Thyroid impairment is one of the most common endocrine issues in human health. In molecular docking analyses, tebuconazole exhibited binding potency of -6.28 kcal/mol with 2CEO compared to its native ligand thyroxin and inhibitor propylthiouracil which had the binding potency of -9.9 and -4.49 kcal/mol, respectively. The binding score of tebuconzaol with 1D2S was found to be -7.54 kcal/mol compared to native ligand dihydrotestosteron and inhibitor aminoglutethimide which exhibited the binding score of -6.84 and -11.41 kcal/mol, respectively. Therefore, each complex was subjected to MD simulation for comparative assessment of physical movement. The root mean square deviation (RMSD), root mean square fluctuation (RMSF), Radius of Gyration and hydrogen bonding exhibited that fluconazole had stable binding pattern with 2CEO and 1D2S which was almost similar to native ligand and its inhibitor. Study revealed that tebuconazole may lead to potent endocrine and reproductive disruptions.

S-allyl cysteine ameliorates cyclophosphamide-induced downregulation of urothelial uroplakin IIIa with a concomitant effect on expression and release of CCL11and TNF-α in mice.

BACKGROUND: The aim of this study was to evaluate the modulatory effect of S-allyl cysteine against cyclophosphamide-induced changes in uroplakin IIIa, CCL11 and TNF-α. METHODS: Mice were treated with cyclophosphamide (200mg/kg×7 d, ip). S-allyl cysteine (150mg/kg×7d, ip), and comparator compound mesna (40mg/kg×7d, ip) were administered 1h before and 4h after each cyclophosphamide dose. The urinary bladder was analysed for mRNA and protein changes in uroplakin IIIa (UPIIIa), CCL11 and TNF-α and histopathological findings. RESULTS: Cyclophosphamide caused hemorrhagic cystitis formation and downregulation of UPIIIa. These changes were accompanied by upregulation of CCL11 and TNF-α. S-allyl cysteine attenuated these changes including protection at histological level. Mesna which was used as a comparator drug also showed protection. However, relatively S-allyl cysteine showed a stronger protective effect than mesna. CONCLUSION: These findings highlight a correlation between downregulaion of UPIIIa and enhanced production of inflammatory biomarkers and protective effects of S-allyl cysteine which has been reported to be a potent uroprotective agent. The present study strengthens its role which could be clinically exploited in chemotherapy regimen.

The protective effect of α-lipoic acid against bisphenol A-induced neurobehavioral toxicity.

Bisphenol A (BPA), a well-known xenoestrogen, is ubiquitously utilized in manufacturing of polycarbonated plastics. Convincing evidence suggests that BPA induces neurotoxicity and certain behavioral deficits. α-Lipoic acid (ALA) supplementation has shown protective effect against heart and liver diseases, diabetes, and neurological debility associated with aging. We studied the neuromodulatory effect of ALA against neurotoxicity of BPA in vitro in C8-D1A mouse astrocyte cell line and in vivo in C57BL/6J male mice. In vitro ALA (100 µM) protected cells from BPA (30 µM)-induced reactive oxygen species generation and increased activity of glial fibrillary acidic protein. ALA showed reduction in cell death in astrocytes treated with BPA. In vivo ALA (50 mg/kg) increased the neurospecific acetylcholinesterase activity and decreased the monoamine oxidase activity altered by BPA exposure (10 mg/kg, per os x 30 days). In addition to neuroprotective effects, ALA also showed protective effects against BPA-induced oxidative stress. We observed that ALA significantly replenished the declined neurobehavioral and cognitive performances, decreased muscle coordination and alerted short-term recognition memory in mice exposed to BPA. Our results suggest that ALA has a promising role in modulating BPA-induced neurotoxicity in C8-D1A mouse astrocyte cells as well as neurochemical and neurobehavioral deficits in C57BL/6J male mice and its antioxidant and free radical scavenging activities may in part be responsible for such an effect.

Cyclophosphamide-induced Down-Regulation of Uroplakin II in the Mouse Urinary Bladder Epithelium is Prevented by S-Allyl Cysteine.

The alkylating anticancer drug, cyclophosphamide (CP), induces a number of toxic effects including haemorrhagic cystitis (HC) in the urinary bladder. Uroplakins are unique urinary transmembrane proteins of urothelium, which may become potential targets of CP metabolites and reactive free radicals. Natural compounds, especially those rich in thiols, have shown protective effects against CP-induced HC. In this study, we studied the modulatory effect of the thiol-rich compound S-allyl cysteine (SAC) on the mRNA level of uroplakin II by real-time polymerase chain reaction and expression of uroplakin II protein by immunoblotting. SAC (150 mg/kg) showed significant (p < 0.001) protective effects against CP (200 mg/kg)-induced alteration in mRNA level and protein expression of uroplakin II. SAC also protected animals from CP-induced HC as assessed by gross morphological examination of urinary bladder. When compared with mercaptoethane sulphonic acid (mesna) (40 mg/kg), a known thiol-rich drug used in clinical application, SAC was found to be more efficacious in affording protection in urinary bladder tissues. Role of uroplakins in CP-induced urinary bladder toxicity has not been well investigated. This study demonstrated that uroplakins may be the potential target of toxic metabolites of CP and natural compounds such as SAC have the capacity to modulate their expression leading to reduced toxicity burden on the urinary bladder epithelium.

Study of drug utilization pattern of antihyperglycemic agents in a South Indian tertiary care teaching hospital.

OBJECTIVE: To determine the drug utilization pattern of antihyperglycemic agents (AHA) in a tertiary care teaching hospital. MATERIALS AND METHODS: This was a prospective observational study. All the relevant data were collected and drug utilization pattern of AHA was determined. Direct cost associated with the use of antihyperglycemic medicines was calculated and consumption of the antihyperglycemic medicines was measured as defined daily dose (DDD)/100 bed-days. The adverse drug reactions (ADRs) related to anti-diabetic medicines were monitored. STATISTICAL ANALYSIS USED: Chi square test (χ(2)), mean±standard deviation. RESULTS: During the study period, 350 patients diagnosed as diabetes mellitus (DM) were admitted. Insulin was prescribed as monotherapy to 81% and to 52% patients during hospital stay and discharge, respectively. Increase in utilization of insulin was recorded in majority of the patients due to presence of co-morbid conditions or resistance to oral hypoglycemic drugs. Use of insulin at the time of discharge decreased significantly (P<0.05) by 29%. Among the oral AHA, combination of glimepiride with metformin was more prevalent during hospital stay and at the time of discharge monotherapy of metformin followed by glimepiride was more prevalent. During hospital stay, cost of AHA was found to be Rs. 95.27 ± 119.03. The total antihyperglycemic drug consumption in the medicine ward during study period was 13.42 DDD/100 bed-days. Fifty ADRs were reported and descriptions of ADRs were found to be only hypoglycemia. CONCLUSION: The study exhibited a significant increase in the utilization of two drug combination therapies and monotherapy of oral AHA and decrease in the utilization of insulin at the time of discharge.