Identification of Potent Inhibitors Targeting EGFR and HER3 for Effective Treatment of Chemoresistance in Non-Small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer. Despite the existence of various therapeutic options, NSCLC is still a major health concern due to its aggressive nature and high mutation rate. Consequently, HER3 has been selected as a target protein along with EGFR because of its limited tyrosine kinase activity and ability to activate PI3/AKT pathway responsible for therapy failure. We herein used a BioSolveIT suite to identify potent inhibitors of EGFR and HER3. The schematic process involves screening of databases for constructing compound library comprising of 903 synthetic compounds (602 for EGFR and 301 for HER3) followed by pharmacophore modeling. The best docked poses of compounds with the druggable binding site of respective proteins were selected according to pharmacophore designed by SeeSAR version 12.1.0. Subsequently, preclinical analysis was performed via an online server SwissADME and potent inhibitors were selected. Compound 4k and 4m were the most potent inhibitors of EGFR while 7x effectively inhibited the binding site of HER3. The binding energies of 4k, 4m, and 7x were −7.7, −6.3 and −5.7 kcal/mol, respectively. Collectively, 4k, 4m and 7x showed favorable interactions with the most druggable binding sites of their respective proteins. Finally, in silico pre-clinical testing by SwissADME validated the non-toxic nature of compounds 4k, 4m and 7x providing a promising treatment option for chemoresistant NSCLC

Designing multi-epitope monkeypox virus-specific vaccine using immunoinformatics approach

Background: Monkeypox virus is an enveloped DNA virus that belongs to Poxviridae family. The virus is transmitted from rodents to primates via infected body fluids, skin lesions, and respiratory droplets. After being infected with virus, the patients experience fever, myalgia, maculopapular rash, and fluid-filled blisters. It is necessary to differentiate monkeypox virus from other poxviruses during diagnosis which can be appropriately envisioned via DNA analysis from swab samples. During small outbreaks, the virus is treated with therapies administered in other orthopoxviruses infections and does not have its own specific therapy and vaccine. Consequently, in this article, two potential peptides have been designed. Methods: For the purpose of designing a vaccine, protein sequences were retrieved followed by the prediction of B- and T-cell epitopes. Afterward, vaccine structures were predicted which were docked with toll-like receptors. The docked complexes were analyzed with iMODS. Moreover, vaccine constructs nucleotide sequences were optimized and expressed in silico. Results: COP-B7R vaccine construct (V1) has antigenicity score of 0.5400, instability index of 29.33, z-score of − 2.11-, and 42.11% GC content whereas COP-A44L vaccine construct (V2) has an antigenicity score of 0.7784, instability index of 23.33, z-score of − 0.61, and 48.63% GC content. It was also observed that COP-A44L can be expressed as a soluble protein in Escherichia coli as compared to COP-B7R which requires a different expression system. Conclusion: The obtained results revealed that both vaccine constructs show satisfactory outcomes after in silico investigation and have significant potential to prevent the monkeypox virus. However, COP-A44L gave better results

Antioxidant and Gastroprotective Activity of <i>Suaeda fruticosa</i> Forssk. Ex J.F.Gmel

Suaeda fruticosa Forssk. Ex J.F.Gmel is traditionally used for inflammatory and digestive disorders, as a carminative, and for diarrhea. This plant is widely distributed in Asia, Africa, and the Mediterranean region. Aqueous methanolic extract of S. fruticosa (Sf.Cr) was prepared and screened for phytoconstituents through qualitative and GC-MS analysis. Quantification of total phenolic and flavonoid contents was performed, while antioxidant capacity was determined by DPPH, CUPRAC, FRAP, and ABTS assays. The gastroprotective activity was assessed in an ethanol-induced ulcer model. Gastric secretory parameters and macroscopic ulcerated lesions were analyzed and scored for ulcer severity. After scoring, histopathology was performed, and gastric mucus contents were determined. Oral pre-treatment of Sf.Cr demonstrated significant gastroprotection. The gastric ulcer severity score and ulcer index were reduced while the %-inhibition of ulcer was increased dose-dependently. The Sf.Cr significantly elevated the pH of gastric juice, while a decrease in total acidity and gastric juice volume was observed. Histopathology demonstrated less oedema and neutrophil infiltration in gastric mucosa of rats pre-treated with the Sf.Cr in comparison to ethanol-intoxicated animals. Furthermore, the gastric mucus contents were increased as determined by alcian blue binding. Sf.Cr showed marked gastroprotective activity, which can be attributed to antioxidant, antisecretory, and cytoprotective effects

The Impact of Body Resistance Training Exercise on Biomedical Profile at High Altitude: A Randomized Controlled Trial

Background. Obesity causes different diseases, eventually. In our study, the results of resistance exercises were examined on selected biochemical markers in Abha City, Saudi Arabia, which is at the height of 2,270 meters above sea level. Methods. A randomized controlled research was conducted with 60 participants equally divided into three groups, 20 subjects in each group: group 1 was composed of obese people who received resistance training exercise, group 2 was composed of the obese control group who did not receive resistance training exercise, and group 3 was composed of normal individuals who received resistance exercise training. The resistance exercises were done in the 6th and 12th weeks. Biochemical blood tests were done. Results. Comparing to the control group, glucose decreased very little with insulin also showing little difference. It has been seen that TC, TG, and LDL reduced to a reasonable extent after resistance exercise, while HDL was increased (p≤0.01). Plasma urea and creatinine showed no differences. Interleukin-6 and leptin decreased significantly (p≤0.01), while there was a significant elevation in adiponectin and testosterone (p≤0.01) once comparing group 1 with group 2 and group 3. Conclusion. We have seen that resistance exercise helps in reducing lipid profile which will result in a decrease of the cardiac and related risk factors when conducted in obese patients in high-altitude regions. Also, alterations of the levels of interleukin-6, leptin, adiponectin, and testosterone showed that resistance exercise is of benefit and favourable in obese persons in high-altitude regions, which can also pave the way for added development of drugs related to the above parameters

Synthesis, In Vitro Anti-Microbial Analysis and Molecular Docking Study of Aliphatic Hydrazide-Based Benzene Sulphonamide Derivatives as Potent Inhibitors of α-Glucosidase and Urease

A unique series of sulphonamide derivatives was attempted to be synthesized in this study using a new and effective method. All of the synthesized compounds were verified using several spectroscopic methods, including FTIR, 1H-NMR, 13C-NMR, and HREI-MS, and their binding interactions were studied using molecular docking. The enzymes urease and α-glucosidase were evaluated against each derivative (1–15). When compared to their respective standard drug such as acarbose and thiourea, almost all compounds were shown to have excellent activity. Among the screened series, analogs 5 (IC50 = 3.20 ± 0.40 and 2.10 ± 0.10 µM) and 6 (IC50 = 2.50 ± 0.40 and 5.30 ± 0.20 µM), emerged as potent molecules when compared to the standard drugs acarbose (IC50 = 8.24 ± 0.08 µM) and urease (IC50 = 7.80 ± 0.30). Moreover, an anti-microbial study also demonstrated that analogs 5 and 6 were found with minimum inhibitory concentrations (MICs) in the presence of standard drugs streptomycin and terinafine

Fabrication of Cr-ZnFe2O4/S-g-C3N4 Heterojunction Enriched Charge Separation for Sunlight Responsive Photocatalytic Performance and Antibacterial Study

There has been a lot of interest in the manufacture of stable, high-efficiency photocatalysts. In this study, initially Cr doped ZnFe2O4 nanoparticles (NPs) were made via surfactant-assisted hydrothermal technique. Then Cr-ZnFe2O4 NPs were modified by incorporating S-g-C3N4 to enhance their photocatalytic efficiency. The morphological, structural, and bonding aspects were analyzed by XRD, FTIR, and SEM techniques. The photocatalytic efficiency of the functional Cr-ZnFe2O4/S-g-C3N4 (ZFG) heterostructure photocatalysts was examined against MB under sunlight. The produced ZFG-50 composite has the best photocatalytic performance, which is 2.4 and 3.5 times better than that of ZnFe2O4 and S-g-C3N4, respectively. Experiments revealed that the enhanced photocatalytic activity of the ZFG nanocomposite was caused by a more effective transfer and separation of photo-induced charges. The ZFG photocatalyst can use sunlight for treating polluted water, and the proposed modification of ZnFe2O4 using Cr and S-g-C3N4 is efficient, affordable, and environmentally benign. Under visible light, Gram-positive and Gram-negative bacteria were employed to ZFG-50 NCs&rsquo; antimicrobial activity. These ZFG-50 NCs also exhibit excellent antibacterial potential

Isolated and Combined Effect of Age and Gender on Neutrophil&ndash;Lymphocyte Ratio in the Hyperglycemic Saudi Population

Inflammation is pivotal to the pathogenesis of diabetes mellitus (DM), but pathological alterations of the neutrophil&ndash;lymphocyte ratio (NLR), an emerging inflammatory index in DM management, remains understudied. The aim of this study is to examine the relationship between NLR and glycemic control in the Saudi population. Gender, age, WBC count, and fasting blood glucose (FBG) were obtained from Al-Borg Medical Laboratories for 14,205 subjects. Means, prevalence, risk measures, and the diagnostic accuracy of elevated NLR and hyperglycemia (HG) were evaluated. Subjects with elevated NLR (&gt;3) had significantly higher FBG (105.10 &plusmn; 0.33 vs. 114.0 &plusmn; 2.81) and NLR was significantly elevated in impaired fasting glycemia (IFG; 1.21 &plusmn; 0.01 vs. 1.25 &plusmn; 0.01) and HG (1.21 &plusmn; 0.01 vs. 1.39 &plusmn; 0.02). Elevations of NLR in HG but not in IFG persisted across all age groups except young males and elderly females. The prevalence of elevated NLR in hyperglycemic subjects was 4.12% compared to 2.16% in subjects with normal FBG. HG was more prevalent in subjects with elevated NLR (17.33% vs. 12.46%) who had a relative risk (RR) of 1.68 (95% CI = 1.38&ndash;2.06, p &lt; 0.0001) and an odds ratio (OR) of 1.94 (95% CI = 1.48&ndash;2.56, p &lt; 0.0001) to be hyperglycemic. Nevertheless, NLR failed to discriminate individuals with normal FBG from those with HG based on ROC curve analysis. Pathological fluctuations in NLR may serve as supportive evidence in DM management

Comparative Evaluation of Various Extraction Techniques for Secondary Metabolites from Bombax ceiba L. Flowering Plants along with In Vitro Anti-Diabetic Performance

Bombax ceiba L. (Family: Malvaceae) was rightly called the &ldquo;silent doctor&rdquo; in the past as every part of it had medicinal value. For centuries, humans have used this plant according to the traditional medicinal systems of China, Ayurveda, and tribal communities. Recently, with an emerging interest in herbals, attention has been paid to scientifically validating medicinal claims for the treatment of diabetes using secondary metabolites of B. ceiba L. flowers. In the present study, specific secondary metabolites from the flowers of B. ceiba L. were isolated in good yield using the solvent extraction methodology, and their in vitro anti-diabetic efficacy was examined. Extraction efficiency of each solvent for secondary metabolites was found in following order: water &gt; ethanol&gt; methanol &gt; chloroform &gt; petroleum ether. Quantitative analysis of secondary metabolites showed 120.33 &plusmn; 2.33 mg/gm polyphenols, 60.77 &plusmn; 1.02 mg/g flavonoids, 60.26 &plusmn; 1.20 mg/g glycosaponins, 0.167 &plusmn; 0.02 mg/g polysaccharides for water extract; 91.00 &plusmn; 1.00 mg/g polyphenols, 9.22 &plusmn; 1.02 mg/g flavonoids, 43.90 &plusmn; 0.30 mg/g glycosaponins, 0.090 &plusmn; 0.03 mg/g poly saccharides for ethanol extract; 52.00 &plusmn; 2.64 mg/g polyphenols, 35.22 &plusmn; 0.38 mg/g flavonoids, 72.26 &plusmn; 1.05 mg/g glycosaponins, 0.147 &plusmn; 0.01 mg/g polysaccharides for methanol extract; 11.33 &plusmn; 0.58 mg/g polyphenols, 23.66 &plusmn; 1.76 mg/g flavonoids, 32.8 &plusmn; 0.75 mg/g glycosaponins, 0.013 &plusmn; 0.02 mg/g polysaccharides for chloroform extract; and 3.33 &plusmn; 1.53 mg/g polyphenols, 1.89 &plusmn; 1.39 mg/g flavonoids, 21.67 &plusmn; 1.24 mg/g glycosaponins, 0.005 &plusmn; 0.01 mg/g polysaccharides for petroleum ether extract. Glucose uptake by yeast cells increased 70.38 &plusmn; 2.17% by water extract

Synthesis, In Vitro Biological Evaluation and In Silico Molecular Docking Studies of Indole Based Thiadiazole Derivatives as Dual Inhibitor of Acetylcholinesterase and Butyrylchloinesterase

The current study was conducted to obtain hybrid analogues of indole-based thiadiazole derivatives (1–16) in which a number of reaction steps were involved. To examine their biological activity in the presence of the reference drug Donepezil (0.21 ± 0.12 and 0.30 ± 0.32 M, respectively), the inhibitory potentials of AChE and BuChE were determined for these compounds. Different substituted derivatives showing a varied range of inhibitory profiles, when compared to the reference drug, analogue 8 was shown to have potent activity, with IC50 values for AchE 0.15 ± 0.050 M and BuChE 0.20 ± 0.10, respectively, while other substituted compounds displayed good to moderate potentials. Varied spectroscopic techniques including 1H, 13CNMR and HREI-MS were used to identify the basic skeleton of these compounds. Furthermore, all analogues have a known structure–activity relationship (SAR), and molecular docking investigations have verified the binding interactions of molecule to the active site of enzymes

New Biologically Hybrid Pharmacophore Thiazolidinone-Based Indole Derivatives: Synthesis, In Vitro &Alpha;lpha-Amylase and &Alpha;lpha-Glucosidase Along with Molecular Docking Investigations

Amylase and glucosidase enzymes are the primary harmful source in the development of the chronic condition known as diabetes mellitus. The main function of these enzymes is to break the macromolecules into simple sugar units which are directly involved in the solubility of blood, hence increasing blood glucose levels. To overcome this effect, there is a need for a potent and effective inhibitor that inhibits the conversion of macromolecules of sugar into its smaller units. In this regard, we synthesized thiazolidinone-based indole derivatives (1&ndash;20). The synthesized derivatives were evaluated for &alpha;-amylase and &alpha;-glucosidase inhibitory activity. Different substituted derivatives were found with moderate to good potentials having IC50 values ranging, for &alpha;-amylase, from 1.50 &plusmn; 0.05 to 29.60 &plusmn; 0.40 &mu;M and, for &alpha;-glucosidase, from IC50 = 2.40 &plusmn; 0.10 to 31.50 &plusmn; 0.50 &mu;M. Among the varied substituted compounds, the most active analogs four (1.80 &plusmn; 0.70 and 2.70 &plusmn; 0.70), five (1.50 &plusmn; 0.05 and 2.40 &plusmn; 0.10, respectively) of the series showed few folds better inhibitory activity than standard drug acarbose (IC50 = 10.20 &plusmn; 0.10 and 11.70 &plusmn; 0.10 &mu;M, respectively). Moreover, structure&ndash;activity relationship (SAR) was established and binding interactions were analyzed for ligands and proteins (&alpha;-amylase and &alpha;-glucosidase) through a molecular docking study.&nbsp