Zahida Parveen

A novel spirooxindole‐pyrrolidine clubbed thiochromene and pyrazole motifs were synthesized by [3+2] cycloaddition (32CA) reactions in one step process starting from the ethylene‐based thiochromene and pyrazole scaffolds with the secondary amino‐acids and substituted isatins in high yield. The 32CA reaction of AY 10 with ethylene derivative 6 has also been studied with Molecular Electron Density Theory. The high nucleophilic character of AY 10, N = 4.39 eV, allows explaining that the most favorable TS‐on is 13.9 kcal mol⁻¹ below the separated reagent. This 32CA, which takes place through a non‐concerted one‐step mechanism, presents a total ortho regio‐ and endo stereoselectivity, which is controlled by the formation of two intramolecular H^…O hydrogen bonds. The design of spirooxindole‐pyrrolidines engrafted thiochromene and pyrazole was tested for alpha‐amylase inhibition and show a high efficacy in nanoscale range of reactivity. The key interaction between the most active hybrids and the receptor was studied by molecular docking. The physiochemical properties of the designed spirooxindole‐pyrrolidines were carried out by in silico ADMET prediction. The newly synthesized most potent hybrid could be considered as a lead compound for drug discovery development for type 2 diabetes mellitus (T2DM).

Dihydropyrazole (1-22) derivatives were synthesized from already synthesized chalcones. The structures of all of the synthesized compounds were confirmed by elemental analysis and various spectroscopic techniques. Furthermore, the synthesized compounds were screened against α amylase as well as investigated for antioxidant activities. The synthesized compounds demonstrate good to excellent antioxidant activities with IC₅₀ values ranging between 30.03 and 913.58 μM. Among the 22 evaluated compounds, 11 compounds exhibit excellent activity relative to the standard ascorbic acid IC₅₀ = 287.30 μM. Interestingly, all of the evaluated compounds show good to excellent α amylase activity with IC₅₀ values lying in the range between 0.5509 and 810.73 μM as compared to the standard acarbose IC₅₀ = 73.12 μM. Among the investigated compounds, five compounds demonstrate better activity compared to the standard. In order to investigate the binding interactions of the evaluated compounds with amylase protein, molecular docking studies were conducted, which show an excellent docking score as compared to the standard. Furthermore, the physiochemical properties, drug likeness, and ADMET were investigated, and it was found that none of the compounds violate Lipiniski's rule of five, which shows that this class of compounds has enough potential to be used as a drug candidate in the near future.

Abiotic stressors are global limiting constraints for plant growth and development. The most severe abiotic factor for plant growth suppression is salt. Among many field crops, maize is more vulnerable to salt, which inhibits the growth and development of plants and results in low productivity or even crop loss under extreme salinity. Consequently, comprehending the effects of salt stress on maize crop improvement, while retaining high productivity and applying mitigation strategies, is essential for achieving the long-term objective of sustainable food security. This study aimed to exploit the endophytic fungal microbe; Aspergillus welwitschiae BK isolate for the growth promotion of maize under severe salinity stress. Current findings showed that salt stress (200 mM) negatively affected chlorophyll a and b, total chlorophyll, and endogenous IAA, with enhanced values of chlorophyll a/b ratio, carotenoids, total protein, total sugars, total lipids, secondary metabolites (phenol, flavonoids, tannins), antioxidant enzyme activity (catalase, ascorbate peroxidase), proline content, and lipid peroxidation in maize plants. However, BK inoculation reversed the negative impact of salt stress by rebalancing the chlorophyll a/b ratio, carotenoids, total protein, total sugars, total lipids, secondary metabolites (phenol, flavonoids, tannins), antioxidant enzyme activity (catalase, ascorbate peroxidase), and proline content to optimal levels suitable for growth promotion and ameliorating salt stress in maize plants. Furthermore, maize plants inoculated with BK under salt stress had lower Na⁺, Cl⁻ concentrations, lower Na^+/K⁺ and Na⁺/Ca²⁺ ratios, and higher N, P, Ca²⁺, K⁺, and Mg²⁺ content than non-inoculated plants. The BK isolate improved the salt tolerance by modulating physiochemical attributes, and the root-to-shoot translocation of ions and mineral elements, thereby rebalancing the Na⁺/K⁺, Na⁺/Ca²⁺ ratio of maize plants under salt stress.

Alzheimer's disease (AD) is a neurodegenerative disorder that affects 35 million people worldwide. However, no potential therapeutics currently are available for AD because of the multiple factors involved in it, such as regulatory factors with their candidate genes, factors associated with the expression levels of its corresponding genes, and many others. To date, 29 novel loci from GWAS have been reported for AD by the Psychiatric Genomics Consortium (PGC2). Nevertheless, the main challenge of the post-GWAS era, namely to detect significant variants of the target disease, has not been conducted for AD. N6-methyladenosine (m6a) is reported as the most prevalent mRNA modification that exists in eukaryotes and that influences mRNA nuclear export, translation, splicing, and the stability of mRNA. Furthermore, studies have also reported m6a's association with neurogenesis and brain development. We carried out an integrative genomic analysis of AD variants from GWAS and m6a-SNPs from m6AVAR to identify the effects of m6a-SNPs on AD and identified the significant variants using the statistically significance value (p-value p-value p-value <0.05 in two datasets of AD gene expression profiles. A follow-up study to elucidate the impact of our identified m6a-SNPs in the experimental study would validate our findings for AD, which would contribute to the etiology of AD.

Coronary Artery Diseases (CAD) remains the top among Non-communicable Diseases (NCDs). Variations in Apolipoprotein E (APOE) and Paroxonase 1 (PON1) have been associated with Myocardial Infarction (MI) in several populations. However, despite the high prevalence of CAD, no such study has been reported in the Pashtun ethnic population of Pakistan. We have conducted a two-stage (i.e., screening and validation) case-control study in which 200 cases and 100 control subjects have been recruited. In the first stage, Whole Exome Sequencing (WES) was used to screen for pathogenic variants of Myocardial Infarction (MI). In the second stage, selected variants of both APOE and PON1 genes (rs7412, rs429358, rs854560, and rs662) were analyzed through MassARRAY genotyping. Risk Allele Frequencies (RAFs) distribution and association of the selected SNPs with MI were determined using the Chi-square test and logistic regression analysis. WES identified a total of 12 sequence variants in APOE and 16 in PON1. Genotyping results revealed that APOE variant rs429358 (ɛ4 allele and ɛ3/ɛ4 genotype) showed significant association in MI patients (OR = 2.11, p value = 0.03; 95% CI = 1.25–2.43); whereas no significant difference (p˃ 0.05) was observed for rs7412. Similarly, the R allele of PON1 Q192R (rs662) was significantly associated with cases (OR = 1.353, p value = 0.048; 95% CI = 0.959–1.91), with particular mention of RR genotype (OR = 1.523, p value = 0.006; 95% CI = 1.087–2.132). Multiple logistic regression analysis showed that rs429358 (C allele) and rs662 (R allele) have a significantly higher risk of MI after adjustment for the conventional risk factors. Our study findings suggested that the rs429358 variant of APOE and PON1 Q192R are associated with MI susceptibility in the Pashtun ethnic population of Pakistan.

The intake of various types and amounts of dietary fats influences metabolic and cardiovascular health. Hence, this study evaluated the impact of routinely consumed Pakistani dietary fats on their cardiometabolic impact. For this, we made four groups of mice, each comprising 5 animals: (1) C-ND: Control mice on a normal diet, (2) HFD-DG: High-fat diet mice on a normal diet plus 10% (w/w) desi ghee, (3) HFD-O: Mice on normal diet plus 10% (w/w) plant oil (4) HFD-BG: Mice on normal diet plus 10% (w/w) banaspati ghee. Mice were fed for 16 weeks, and blood, liver, and heart samples were collected for biochemical, histological, and electron microscopic analysis. The physical factors indicated that mice fed on HFD gained more body weight than the C-ND group. Blood parameters do not show significant differences, but overall, the glucose and cholesterol concentrations were raised in the mice fed with a fat-rich diet, with the highest concentrations in the HFD-BG group. The mice fed with HFD-BG and HFD-O had more lipid droplets in the liver, compared to HFD-DG and C-ND.

The present study was carried out to determine various phytochemicals from Swertia chirayita and to evaluate antimicrobial and antioxidant properties of the extracted phytochemicals. Phytochemical determination i.e., flavonoids, tannins, β-carotene and lycopene, and alkaloids was carried out using different methods. Among the phytochemicals, flavonoids i.e., 67.4 mg/ml were present in higher concentrations, tannins i.e., 38.2 mg/ml in moderate concentrations, while β-carotene i.e., 0.678 mg/50 ml, lycopene i.e., 0.150 mg/50 ml and alkaloids i.e., 0.073 mg were found in trace amounts. Among various extracts, acetone extract had shown antimicrobial activity against Klebsiella pneumonia, Haemophilus influenza, Acinetobacter baumanii and Morganella morganii, while it was inactive against Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa. Ethanol extract showed activity only against Haemophilus influenza and all other microorganisms showed resistance against ethanol extract. Other all the tested extracts showed no notable activity against the microorganisms. Flavonoid and tannin showed significant antioxidant activity and among the extracts ethanol and methanol showed higher antioxidant activity, n-hexane, acetone and chloroform showed moderate activity followed by butanol and water showing the lowest activity. Thus, S. chirayita possesses significant antimicrobial and antioxidant properties and can be used to treat pathogenic infections.

Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) is considered a global public health concern since it causes high morbidity and mortality. Recently, it has been reported that repurposed anti-COVID-19 drugs might interact with multidrug resistance ABC transporter, particularly ABCB1. In the current study, a series of thiourea derivatives were screened as potential inhibitors against SARS-CoV-2 by targeting the attachment of receptor binding domain (RBD) of spike protein with ACE2 and their interaction with human ABCB1 has also been explored. The results indicated strong impairment of RBD-ACE2 attachment by BB IV-46 with a percentage inhibition of 95.73 ± 1.79% relative to the positive control, while BB V-19 was proven inactive with a percentage inhibition of 50.90 ± 0.84%. The same compound (BB IV-46) interacted with ABCB1 and potentially inhibited cell proliferation of P-gp overexpressing cell line with an IC₅₀ value of 4.651 ± 0.06 μM. BB V-19, which was inactive against SARS-CoV-2, was inactive against ABCB1 with a higher IC₅₀ value of 35.72 ± 0.09 μM. Furthermore, molecular dynamics simulations followed by binding free-energy analysis explored the binding interaction of BB IV-46 and BB V-19 to RBD region of spike protein of SARS-CoV-2. The results confirmed that compound BB IV-46 interacted strongly with RBD with a significant binding energy (-127.0 kJ/mol), while BB V-19 interacted weakly (-29.30 kJ/mol). The key interacting residues of the RBD involved in binding included Leu441, Lys444, and Tyr449. This study highlights the importance of BB IV-46 against SARS-CoV-2; however, further pharmacokinetic and pharmacodynamics studies are needed to be done.

Implantation of cardiac implantable electronic devices (CIEDs) is an art of science. As the volume of implantation has increased worldwide, so has the rate of complications. Infection, fibrosis, lead and device erosion, lead displacement, right ventricle perforation, lead fracture, and insulation break are the common complications in the implantation process. This exposes the patient for reopening and threatens the implantation for further complication due to infection, fibrosis of veins, failure to retrieve the implanted wire, and failure to re-implant the device on the same site. We slightly changed our implantation technique to preserve the implantation site for future implantation and reduce the rate of complication in the index implantation. This randomized control trial was conducted from January 2016 to September 2019 at Hayatabad Medical Complex Peshawar, Pakistan. A consecutive sampling technique was used to obtain a sample size of 602 patients keeping a 95% confidence interval and a 5% margin error. We adopted a strategy to take prick, for implantation of devices, inside the pocket, which reduces the number of sutures, hastens the procedure, prevents erosion, and minimizes the chance of subclavian crush syndrome and insulation break. We also selected the minimum possible length of leads. This will possibly decrease the chances of cumbersome fibrosis around the lead and device and will make future implantation convenient. There was a total of 602 procedures in the study period. About 253 (42%) procedures were done in the newly adopted strategy and 349 (58%) were performed in the conventional way. Our complication rate grossly reduces in the novel way of implantation in which we took our prick inside the pocket. A slight modification in the implantation of CIEDs not only prevents the rate of complication in the index implantation but will also possibly preserve the site for future implantation.

Morchella conica (M. conica) Pers. is one of six wild edible mushrooms that are widely used by Asian and European countries for their nutritional value. The present study assessed the anti-diabetic potential of M. conica methanolic extract (100 mg/kg body weight) on streptozotocin (STZ)-induced diabetic mice. STZ was used in a single dose of 65 mg/kg to establish diabetic models. Body weights, water/food intake and fasting blood glucose levels were measured. Histopathological analysis of the pancreas and liver were performed to evaluate STZ-induced tissue injuries. In addition, in vitro assays such as α-amylase and protein tyrosine phosphatase 1B (PTP1B) inhibitory, antiglycation, antioxidant and cytotoxicity were performed. The in vitro study indicated potent PTP1B inhibitory potential of M. conica with an IC₅₀ value of 26.5 μg/ml as compared to the positive control, oleanolic acid (IC₅₀ 36.2 μg/ml). In vivo investigation showed a gradual decrease in blood sugar level in M. conica-treated mice (132 mg/dl) at a concentration of 100 mg/kg as compared to diabetic mice (346 mg/dl). The extract positively improved liver and kidney damages as were shown by their serum glutamic pyruvic transaminase, serum glutamic oxaloacetate, alkaline phosphatase, serum creatinine and urea levels. Histopathological analysis revealed slight liver and pancreas improvement of mice treated with extract. Cytotoxicity assays displayed lower IC₅₀ values. Based on the present results of the study, it may be inferred that M. conica are rich in bioactive compounds responsible for antidiabetic activity and this mushroom may be a potential source of antidiabetic drug. However, further studies are required in terms of isolation of bioactive compounds to validate the observed results.