Objective: To generate a prognostic model prognosis based on anoikis-related genes (ANRGs) expression for Lung adenocarcinoma (LUAD), an exploration of the prognostic value of ANRGs in LUAD was conducted.
Methods: Based on the expression matrix of genes from the TCGA database, we built the co-expressed modules by weighted gene co-expression network analysis (WGCNA). Then we identified the differentially expressed ANRGs (DE-ANGs) between LUAD and normal samples by the WGCNA results, DEGs, and the 345 ANRGs. The biofunction of the DE-ANRGs was interpreted using the GO and KEGG databases. Univariate and multivariate regression models were used to verify whether the risk model could serve as an independent prognostic factor. A nomogram was utilized to predict overall survival (OS) in LUAD.
Results: The expression of 56 DE-ANRGs was significantly different in tumor tissues. We established a 4-ANRG prognostic signature. In the TCGA cohort and the external GSE31210 validation cohort, the OS of the high-risk group was lower than that of the low-risk group significantly. Moreover, the prediction performance of the risk model was excellently verified by the ROC curve. In addition, both univariate COX and multivariate Cox analyses indicated that risk score could act as an independent prognostic factor for LUAD patients. The calibration curve and C-index demonstrated that the nomogram was satisfactory in predicting 1, 3- and 5-year survival in LUAD patients.
Conclusions: Our study developed a novel prognostic signature of 4 ANRGs with Excellent prognostic performance for LUAD patients.
Aim of the study was designed for the design of novel indazole derivatives and evaluation of their docking against topoisomerase-II DNA gyrase enzyme for the antibacterial screening. Different novel substituted indazol-3-yl benzenesulfonamide derivatives were designed for the synthesis from o-chlorobenzonitrile and phenyl hydrazine reaction and further, with benzene sulphonyl chloride reaction. These were evaluated for their docking targeting topoisomerase-II DNA gyrase enzyme for the antibacterial screening. A range of binding affinity (-12.2 to -9.6 kcal/mol) was observed. Compound, 4-chloro-N-(1-phenyl-1H-indazol-3-yl)benzenesulfonamide had the highest binding affinity (-12.2 kcal/mol) which is better than the standard norfloxacin (-10.7 kcal/mol). Compounds (12a, 12c, 12e and 12g) with chloro-substitution at para position of sulfonamide had higher affinity as compared to the compounds (12b, 12d, 12f and 12h) with methyl substitution. A convenient method for the synthesis of indazole derivatives has been developed. 4-chloro-N-(1-phenyl-1H-indazol-3-yl)benzenesulfonamide had shown the best binding affinity. Further, more diverse bioactive moieties may be incorporated into indazole scaffold in the near future by future researchers and a great amount of effort may be dedicated to the exploration of medicinal approaches for their preparation and evaluation of their biological activities.
Objective: In recent years, the number of Gram-negative bacteria (GNB) resistant to ceftazidime-avibactam (CZA) isolated from clinic has been increasing. We aimed to evaluate the clinical efficacy in patients with CZA-resistant GNB infections, and analyze the risk factors for clinical treatment failure and death.
Methods: Clinical data of patients with CZA-resistant GNB infections were collected retrospectively, and the influencing factors were analyzed by binary logistic regression.
Results: A total of 75 patients with CZA-resistant GNB infections were enrolled in the study, and the clinical effective rate was 56% (42/75). Multivariate analysis showed that continuous renal replacement therapy (CRRT) during anti-infection treatment was an independent risk factor for clinical treatment failure (OR 0.177, 95% CI 0.05–0.63, p=0.008). The 28-day mortality rate in 75 patients was 18.7% (14/75). Multivariate analysis showed that the regimen of colistin E 750,000 U q12h (OR 0.020, 95% CI 0.00–0.56, p=0.021), co-administration of tigecycline (OR 8.851, 95% CI 2.38–1316.87, p=0.012) and CRRT during anti-infection treatment (OR 79.610, 95% CI 4.87–1300.26, p=0.002) were independent affecting factors for 28-day mortality in patients with CZA-resistant GNB infections.
Conclusions: Patients with CZA-resistant GNB infections had a higher possibility of clinical treatment failure and death. The results of the study based on small sample size from a single center showed that clinical treatment failure and death were more likely to happen in patients on CRRT, and the regimen of colistin E 750,000 U q12h or co-administration of tigecycline may reduce or increase mortality, respectively. Further validation in rigorously designed multicenter clinical studies with larger sample sizes is needed.
Influenza A Virus (IAV) is a human respiratory pathogen prone to mutations and genome re-assortment leading to global pandemics. In this study, we applied the molecular modelling strategies such as, two-dimensional (2D), three-dimensional (3D)-quantitative structure-activity relationship (QSAR), and molecular docking simulation on a novel series of borneol compounds as influenza inhibitors. The best developed 2D-QSAR models, MLR (Q2 = 0.8735, R2(train) = 0.9096) and ANN [3-2-1] (Q2 = 0.8987, R2(train) = 0.9171) revealed good and acceptable statistical validation metrics for the inhibitory activity predictions. The 3D-QSAR models were generated using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), which showed CoMFA_S + E (Q2 = 0.559, R2(train) = 0.939) and CoMSIA_S + E (Q2 = 0.577, R2(train) = 0.941) as the best-observed models in accordance with the model acceptability standards. In addition, the contour maps generated from the CoMFA and CoMSIA models illustrates the steric and electrostatic molecular field relationships with the inhibitory effects of the studied molecules. Moreover, the binding modes of the active ligands were studied through molecular docking simulation with the Human Hemagglutinin (HA) receptor of influenza A virus (A/Puerto Rico/8/34(H1N1)). The studied compounds revealed the formation of H-bonds, CH-bonds, and hydrophobic interactions with the active amino acid residues such as Asn 543, Asn 614, Asn 617, Leu 618, Ser 540, Lys 539, and Lys 621 in the HA binding cavity. The prediction of drug-likeness and ADMET properties of the compounds revealed their good bioavailability and pharmacokinetic profiling. This study may provide a valuable in-silico guideline for discovering novel potent influenza inhibitors.
The emergence of multi-drug-resistant autoimmune diseases poses a significant risk to human health and has garnered global attention. In this study, metformin and sulfasalazine have been used as starting materials or control. This research has successfully designed a hundred compounds, to assess their efficacy against two autoimmune disease pathogens: type 1 diabetes and rheumatoid arthritis. The DFT method was engaged to calculate the vibrational frequencies and Frontier Molecular orbitals (FMOs) of the selected compounds. The reactivity and selectivity of the selected compounds are analyzed using parameters like MEP and global reactivity descriptors, which are calculated and interpreted. The Density of state (DOS) of the molecule has been plotted and interpreted. Furthermore, docking results showed favorable interactions of the designed compound D385 with catalytically important amino acid residues. The interactions of the best active D385 when compared with the template and the standard drugs show similar binding sites. DFT studies further confirm the presence of HOMO orbital centered on the isoxazole ring further highlighting its importance for receptor-ligand hydrogen and hydrophobic interactions. The molecular dynamics simulations and MM/GBSA analysis reveal that the inhibitory nature of the designed compound D385 is a proven inhibitor of diabetes type 1 and rheumatoid arthritis inhibitor activities. Our study suggested that the designed compounds showed comparable results to that of metformin and sulfasalazine and may be used for further experimental studies. It can also be used as a pipeline to search for and design new potential autoimmune disease inhibitors. The most promising candidates from computational trials can be examined in a wet laboratory experiment before moving on to clinical trials.
Aim of the study was designed to investigate the antihyperlipidemic activity of carvedilol and pitavastatin in tyloxapol-induced hyperlipidemia in Wistar rats. The rats were randomly divided into 6 groups. The vehicle control group-I received 2 mL of normal saline for eight days. The pathological control group-II received tyloxapol (400 mg/kg) on 8th day. The treated group-III received 10 mg/kg carvedilol and group-IV received 20 mg/kg carvedilol for eight days and tyloxapol (400 mg/kg) on the 8th day. The group-V received pitavastatin (0.3 mg/ kg) for eight days and tyloxapol (400 mg/kg) on the 8th day. The group-VI received carvedilol (20 mg/kg) only for eight days. After eight days of treatment, triglycerides, total cholesterol, high-density lipoprotein, very lowdensity lipoprotein, thiobarbituric acid reactive substances, and glutathione were estimated in the serum and myocardial tissues along with DNA fragmentation of the liver tissue using gel-electrophoresis. Oral administration of carvedilol to tyloxapol-induced hyperlipidemic rats normalized the changes in the above parameters in a dose dependent manner. Hence, carvedilol with pitavastatin has antihyperlipidemic activity in tyloxapol-induced hyperlipidemia in Wistar rats.
Breast cancer, a deadly disease among women, demands effective interventions due to its global impact, with over one million annual cases. Current anti-breast cancer drugs displays several side effects, also most patients resists to these drugs during early treatment stage. Hence, global search for better drugs with less side effects became necessary. The objective of this study is to identify potential inhibitors of vascular endothelial growth factor receptor-2 (VEGFR-2), a critical target in breast cancer treatment. Molecular docking-based virtual screening of 45 benzoxazole/thiazole derivatives was conducted, followed by molecular dynamics simulations to explore ligandprotein interactions. Seven ligands (compounds 7, 10, 12, 13, 14, 20, and 26) demonstrated superior binding affinities ranging from -157.85 to -173.88 kcal/mol (MolDock scores) and -109.96 to -129.23 kcal/mol (Rerank scores) compared to Sorafenib (-156.35 kcal/mol MolDock score and -102.63 kcal/mol Re-rank score). Compound 7, identified as a potential hit, exhibited stability in a 100-ns dynamic simulation. It was chosen as a template for designing novel inhibitors, resulting in five compounds with improved binding affinities ranging from -177.84 to -184.69 kcal/mol (MolDock scores) and -137.34 to -143.44 kcal/mol (Re-rank scores). Pharmacological profiling confirmed the drug-like properties of both the potential hit molecules and the designed compounds, with 0–1 violations against Lipinski’s rule of five and favorable pharmacokinetics status. Density functional theory (DFT) studies illustrated the reactive nature of the designed compounds. These findings suggest the potential of these molecules as novel VEGFR-2 inhibitors for breast cancer treatment, providing promising prospects for future drug development.
Due to the unavailability of effective vaccines and treatments, mosquito-borne diseases continue to pose a threat to global public health. Insecticide-treated mosquito nets and room sprays have both been successfully treated with plant-based biopesticides to protect people from mosquito bites. The extensive use of chemical pesticides is known to cause serious harm to human and animal health. From this point of view, the demand for plant extracts has recently increased worldwide. The aim of the current study was to determine the effectiveness of a Solanum torvum (Sw.) leaf extract as a larvicidal, adulticidal and in silico study against the mosquito Aedes aegypti. The plant extract from S. torvum was obtained using a simple method. Preliminary qualitative analysis shows the presence of steroids, saponins, phenol, flavonoids, tannins, and anthraquinones in the aqueous leaf extract of S. torvum. A total, 15 compounds were identified using GC–MS. The larvicidal activity, observed during 24-h and 48-h exposure cycles of 4th instar larvae, exhibits a maximum (100 %) mortality rate at 200 µg/ml. The adulticidal activity, observed during the 24-h exposure cycle of adult mosquitoes, exhibits a maximum (92 %) mortality rate at 2 mg/mL. The molecular docking observation of Protease Sterol Carrier Protein-2 (IPZ4) was noted campesterol had the most favourable docking score with a value of -10. This finding suggests that campesterol may have a high affinity for the target molecule under study. Based on the results, the current study suggests that the use of S. torvum leaf extract could serve as an environmentally friendly alternative to chemical insecticides in controlling mosquito populations and controlling mosquito bone diseases.
About 25 years ago it became apparent that TPN had value in the management of critically ill patients who were not being normally nourished because they either had gastrointestinal failure or could not tolerate the enteral preparations offered. Total parenteral nutrition (TPN) is a type of medication that provides nutrition to critically ill patients for whom enteral feeding is not possible. TPN is given through I.V route. Parenteral means outside of the digestive tract. TPN may be administered as peripheral parenteral nutrition (PPN) or via a central line, depending on the components and osmolality. TPN administered protein, fats, carbohydrates, vitamins and minerals. TPN plays a vital role in the growth and development of preterm neonates in NICU to provide micro nutrients, macro nutrients and electrolytes. TPN has extended the life of a small number of children born with non-existent or severely birth-deformed guts. Parenteral nutrition plays a major role in treating COVID-19 infection-related malnutrition in patients across the globe. Home parenteral nutrition (HPN) support has been an advancing therapy in the past 30 years. Patients who previously had no options to sustain their lives are now able to live at home, maintain employment, and continue with most daily activities. Although this therapy has been innovative and successful, it requires great financial and professional resources. Parenteral nutrition can be given for long periods of time. A large variety of complications can occur, related especially to the equipment or the nutrients. When the nutrition is given via a central venous catheter, then sepsis is a serious and possibly life-threatening complication. In case of administration via an arteriovenous shunt, thrombosis of the shunt is the most frequent problem.
The level of evidence is a fundamental structure for assessing the excellence of evidence while making healthcare choices. It assesses medical research according to its structure, credibility, and relevance. The different degrees of proof are frequently represented as a triangle shape, with the most powerful proof on the highest point. The pyramid is divided into two primary parts: refined data (systematic reviews, meta-analyses) that combines information from multiple studies, and raw data (randomized trials, cohort studies, case series) that consists of original research. Systematic evaluations condense results from various investigations on a subject using thorough, replicable approaches. Meta-analyses mathematically integrate information from similar research studies. Case studies provide information about a specific patient. Case-control studies examine the occurrences in separate groups of people who have a particular illness and those who do not. Randomly assigned intervention and control groups are compared in randomized controlled experiments to observe the differences in their outcomes. Cohort studies track groups over a period to investigate connections between factors and results. The upper levels of the pyramid are typically seen as more trustworthy proof because of thorough combination or research structure. However, every level provides valuable information. Recognizing the positive aspects of various research methods enables individuals to assess the credibility of information when making choices related to healthcare.
Background: The pitcher plant, Nepenthes khasiana is utilized by several indigenous groups in Meghalaya, India owing to its medicinal properties. Due to their therapeutic qualities, a pioneer work was undertaken where the GC–MS technique was used to detect and identify the phytochemical substances present in the unopened pitcher fluids of N. khasiana.
Materials and methods: Sample preparation and extraction of the methanol fraction of N. khasiana pitcher fluid were done following standard methods and exposed to GC–MS for phytochemical profiling.
Results: The GC–MS study revealed 22 compounds in total, each of which had different phytochemical properties. The metabolites present were coronavirus inhibitors, antioxidants, antimicrobials, cure urolithiasis, hypocholesterolemic, and can cure cancer. Lipinski’s Rule of 5 also depicted that 19 compounds of 22 have the potential to make active oral drugs for humans.
Conclusion: The metabolites present in pitcher fluids could be used in drug formulation in pharmacology. Even, the fluids can be used as raw medicine for poor people owing to their medicinal properties as depicted in GC–MS however, further research on quantitative and qualitative investigation, its clinical trial on animals along with cytotoxic study are required for a concrete conclusion.