Synthesis, anticancer activity, molecular docking and molecular dynamics studies of some pyrazole-chalcone hybrids.

Four new hybrid compounds (H1-H4) bearing pyrazole (S1 and S2) and chalcone (P1 and P2) fragments were synthesized and characterized. Compounds were assayed for their ability to inhibit the proliferation of human lung (A549) and colon (Caco-2) cancer cell lines. Besides, toxicity against normal cells was determined using the human umbilical vein endothelial cells (HUVEC). In silico molecular docking, molecular dynamics (MD) simulation and absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies were carried out to predict the binding modes, protein stability, drug-likeness and toxicity of the reported compounds. The in vitro anticancer activity of the tested compounds revealed dose-dependent cell-specific cytotoxicity. In silico studies revealed that the compounds have a good binding affinity, possess appropriate drug-likeness properties and have low toxicity profiles.Communicated by Ramaswamy H. Sarma.

GLP-1/Sigma/RAGE receptors: An evolving picture of Alzheimer's disease pathology and treatment.

According to the facts and figures 2023stated that 6.7 million Americans over the age of 65 have Alzheimer's disease (AD). The scenario of AD has reached up to the maximum, of 4.1 million individuals, 2/3rd are female patients, and approximately 1 in 9 adults over the age of 65 have dementia with AD dementia. The fact that there are now no viable treatments for AD indicates that the underlying disease mechanisms are not fully understood. The progressive neurodegenerative disease, AD is characterized by amyloid plaques and neurofibrillary tangles (NFTs) of abnormally hyperphosphorylated tau protein and senile plaques (SPs), which are brought on by the buildup of amyloid beta (Aß). Numerous attempts have been made to produce compounds that interfere with these characteristics because of significant research efforts into the primary pathogenic hallmark of this disorder. Here, we summarize several research that highlights interesting therapy strategies and the neuroprotective effects of GLP-1, Sigma, and, AGE-RAGE receptors in pre-clinical and clinical AD models.

Reduced expression of miR-221 is associated with the pro-apoptotic pathways in spermatozoa of oligospermia men.

Oligospermia and asthenozoospermia, both frequent, can lead to male infertility. Oligospermia might be viewed as a milder form of azoospermia because the same mutations that produce azoospermia in some individuals also create oligospermia in other individuals. In this, we looked at different characteristics of oligospermia men, counting the level of apoptosis and a few related apoptotic and oxidative stress components, and compared them to solid controls. In this study, semen samples from healthy fertile men (n = 35) and oligospermia (n = 35) were collected, and sperm death rates in both groups were examined using flow cytometry. Also, gene expression of apoptotic and anti-apoptotic markers and miR-221 were investigated (Real-Time PCR). Moreover, for the evaluation of catalase and SOD activity and anti-inflammatory cytokines, including IL-10 and TGF-ß, the specific ELISA kits and procedures were applied. As a result, higher gene and protein expression levels of PTEN, P27, and P57 were observed in patients with oligospermia. In contrast, lower mRNA expression of AKT and miR-221 was detected in this group. In addition, IL-10, TGF-ß, and catalase activity were suppressed in the oligospermia group compared with healthy men samples. Moreover, the frequency of apoptosis of sperm cells is induced in patients. In conclusion, apoptosis-related markers, PTEN, and the measurement of significant and efficient oxidative stress markers like SOD and catalase in semen plasma could be considered as the critical diagnostic markers for oligospermia. Future studies will be better able to treat oligospermia by showing whether these indicators are rising or falling.

miR-199a-3p suppresses neuroinflammation by directly targeting MyD88 in a mouse model of bone cancer pain.

AIMS: Pain is a profoundly debilitating symptom in cancer patients, leading to disability, immobility, and a marked decline in their quality of life. This study aimed to investigate the potential roles of miR-199a-3p in a murine model of bone cancer pain induced by tumor cell implantation in the medullary cavity of the femur. MATERIALS AND METHODS: We assessed pain-related behaviors, including the paw withdrawal mechanical threshold (PWMT) and the number of spontaneous flinches (NSF). To investigate miRNA expression and its targets in astrocytes, we employed a combination of RNA-seq analysis, qRT-PCR, Western blotting, EdU, TUNEL, ChIP, ELISA, and luciferase reporter assays in mice (C3H/HeJ) with bone cancer pain and control groups. KEY FINDINGS: On days 10, 14, 21, and 28 post-surgery, we observed significant differences in PWTL, PWMT, and NSF when compared to the sham group (P < 0.001). qRT-PCR assays and miRNA sequencing results confirmed reduced miR-199a-3p expression in astrocytes of mice with bone cancer pain. Gain- and loss-of-function experiments demonstrated that miR-199a-3p suppressed astrocyte activation and the expression of inflammatory cytokines. In vitro investigations revealed that miR-199a-3p mimics reduced the levels of inflammatory factors in astrocytes and MyD88/NF-κB proteins. Furthermore, treatment with a miR-199a-3p agonist resulted in reduced expression of MyD88, TAK1, p-p65, and inflammatory mediators, along with decreased astrocyte activation in the spinal cord. SIGNIFICANCE: Collectively, these findings demonstrate that upregulation of miR-199a-3p may offer a therapeutic avenue for mitigating bone cancer pain in mice by suppressing neuroinflammation and inhibiting the MyD88/NF-κB signaling pathway.

Unravelling of molecular biomarkers in synaptic plasticity of Alzheimer's disease: Critical role of the restoration of neuronal circuits.

Learning and memory storage are the fundamental activities of the brain. Aberrant expression of synaptic molecular markers has been linked to memory impairment in AD. Aging is one of the risk factors linked to gradual memory loss. It is estimated that approximately 13 million people worldwide will have AD by 2050. A massive amount of oxidative stress is kept under control by a complex network of antioxidants, which occasionally fails and results in neuronal oxidative stress. Increasing evidence suggests that ROS may affect many pathological aspects of AD, including Aß accumulation, tau hyperphosphorylation, synaptic plasticity, and mitochondrial dysfunction, which may collectively result in neurodegeneration in the brain. Further investigation into the relationship between oxidative stress and AD may provide an avenue for effective preservation and pharmacological treatment of this neurodegenerative disease. In this review, we briefly summarize the cellular mechanism underlying Aß induced synaptic dysfunction. Since oxidative stress is common in the elderly and may contribute to the pathogenesis of AD, we also shed light on the role of antioxidant and inflammatory pathways in oxidative stress adaptation, which has a potential therapeutic target in neurodegenerative diseases.

Caenorhabditis elegans: A transgenic model for studying age-associated neurodegenerative diseases.

Neurodegenerative diseases (NDs) are a heterogeneous group of aging-associated ailments characterized by interrupting cellular proteostasic machinery and the misfolding of distinct proteins to form toxic aggregates in neurons. Neurodegenerative diseases, which include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and others, are becoming an increasing threat to human health worldwide. The degeneration and death of certain specific groups of neurons are the hallmarks of these diseases. Over the past decades, Caenorhabditis eleganshas beenwidely used as a transgenic model to investigate biological processes related to health and disease. The nematode Caenorhabditis elegans (C. elegans) has developed as a powerful tool for studying disease mechanisms due to its ease of genetic handling and instant cultivation while providing a whole-animal system amendable to several molecular and biochemical techniques. In this review, we elucidate the potential of C. elegans as a versatile platform for systematic dissection of the molecular basis of human disease, focusing on neurodegenerative disorders, and may help better our understanding of the disease mechanisms and search for new therapeutics for these devastating diseases.

Comparison of Clinical Characteristics and Outcome of COVID-19 Patients Between the 4th and 5th Wave in a Tertiary Care Hospital in Karachi, Pakistan.

ABSTRACT       Objective: To compare the clinical parameters of 4th and 5th COVID waves in Karachi, Pakistan. STUDY DESIGN: Descriptive study. Place and Duration of the Study: PNS Shifa Hospital, Karachi, from July 2021 to February 2022. METHODOLOGY: All patients with COVID-19 in PNS Shifa Hospital were included in the study. The patients were divided into two groups, those who had COVID-19 during the 4th wave, and others who had it during the 5th wave. The patients' demographic details, comorbidities, vaccination status, initial presentation, the severity of disease, clinical progress, and final disposal from the hospital were noted. A comparison of severity, length of hospital stays, and mortality was made between the groups. RESULTS: There were 747 patients admitted during the Delta variant-dominated 4th wave of COVID-19, and 490 patients during the 5th wave, dominated by the Omicron variant. A vast majority of fifth-wave patients had the mild disease (87.35% vs. 49.39%), with significantly lower critical patients (2.04% vs. 7.09%). Vaccination was effective against both the Delta and the Omicron variant of the SARS-CoV-2 virus. The mean length of stay in the hospital for patients was significantly lesser (p < 0.001) during the 5th wave as compared to the 4th wave (6.43 ± 3.37 vs. 9.56 ± 5.45 days). The mortality rate was 7.09% among patients admitted in the 4th wave and 2.04% in the 5th wave. This difference was statistically significant (p < 0.001). CONCLUSION: The severity of disease, length of hospital stays, and mortality were higher in the Delta variant-dominated 4th wave of COVID-19 as compared to the Omicron variant-dominated 5th wave in Pakistan. The vaccination was effective against both the Delta and the Omicron variant of COVID 19, as the mortality rate among the vaccinated patients during the two waves was not significantly different. KEY WORDS: COVID 19, Vaccination, Disease outcome, Mortality.

Age-related pathophysiological alterations in molecular stress markers and key modulators of hypoxia.

Alzheimer's disease (AD) is characterized by an adverse cellular environment and pathological alterations in distinct brain regions. The development is triggered or facilitated by a condition such as hypoxia or ischemia, or inflammation and is associated with disruptions of fundamental cellular functions, including metabolic and ion homeostasis. Increasing evidence suggests that hypoxia may affect many pathological aspects of AD, including oxidative stress, mitochondrial dysfunction, ER stress, amyloidogenic processing of APP, and Aß accumulation, which may collectively result in neurodegeneration. Further investigation into the relationship between hypoxia and AD may provide an avenue for the effective preservation and pharmacological treatment of this neurodegenerative disease. This review summarizes the effects of normoxia and hypoxia on AD pathogenesis and discusses the underlying mechanisms. Regulation of HIF-1α and the role of its key players, including P53, VEGF, and GLUT1, are also discussed.

The role of Aedes aegypti in inducing/aggravating IgE-mediated allergic airway disease: extensive computational studies for identification of allergenic proteins.

Respiratory allergies have become a major public health concern and affect one-third of the world's population. Several factors like environmental changes, industrialization, and immunologic interactions are reported to contribute to allergic respiratory diseases. Immunological reactions because of mosquito bite (allergic proteins) have been reported to have a high contribution to IgE-mediated allergic airway disease but they are largely ignored. In this study, we aim to predict the potential allergens (proteins) from Aedes aegypti that might play a role in the reactions of IgE-mediated allergic airway diseases. The allergens are identified from an extensive literature search and the 3D structures were prepared using the SwissDock server. Computational studies were performed to identify the potential allergens that might be responsible for IgE-mediated allergies. Our docking and molecular dynamics (MD) simulation results suggest that ADE-3, an allergen from Aedes aegypti, has the highest docking score and is predicted to be responsible for IgE-mediated allergic reaction(s). Overall, this study highlights the importance of immunoinformatics, and the obtained information can be used for designing prophylactic peptide vaccine candidates and inhibitors for controlling IgE-mediated inflammations.Communicated by Ramaswamy H. Sarma.

Husk-like Zinc Oxide Nanoparticles Induce Apoptosis through ROS Generation in Epidermoid Carcinoma Cells: Effect of Incubation Period on Sol-Gel Synthesis and Anti-Cancerous Properties.

This study effectively reports the influence of experimental incubation period on the sol-gel production of husk-like zinc oxide nanoparticles (ZNPs) and their anti-cancerous abilities. The surface morphology of ZNPs was studied with the help of SEM. With the use of TEM, the diameter range of the ZNPs was estimated to be ~86 and ~231 nm for ZNPA and ZNPB, prepared by incubating zinc oxide for 2 and 10 weeks, respectively. The X-ray diffraction (XRD) investigation showed that ZNPs had a pure wurtzite crystal structure. On prolonging the experimental incubation, a relative drop in aspect ratio was observed, displaying a distinct blue-shift in the UV-visible spectrum. Furthermore, RBC lysis assay results concluded that ZNPA and ZNPB both demonstrated innoxious nature. As indicated by MTT assay, reactive oxygen species (ROS) release, and chromatin condensation investigations against the human epidermoid carcinoma (HEC) A431 cells, ZNPB demonstrated viable relevance to chemotherapy. Compared to ZNPB, ZNPA had a slightly lower IC50 against A431 cells due to its small size. This study conclusively describes a simple, affordable method to produce ZNP nano-formulations that display significant cytotoxicity against the skin cancer cell line A431, suggesting that ZNPs may be useful in the treatment of cancer.

Role of melatonin and quercetin as countermeasures to the mitochondrial dysfunction induced by titanium dioxide nanoparticles.

AIM: Due to the growing commercialization of titanium dioxide nanoparticles (TNPs), it is necessary to use these particles in a manner that is safe, healthy and environmental friendly. Through reactive oxygen species (ROS) generation, it has been discovered that TNPs have a harmful effect on the brain. The aim of this study is to provide valuable insights into the possible mechanisms of TNPs induced mitochondrial dysfunction in brain and its amelioration by nutraceuticals, quercetin (QR) and melatonin (Mel) in in vitro and in vivo conditions. MATERIALS AND METHODS: Whole brain mitochondrial sample was used for in-vitro evaluation. Pre-treatment of QR (30 µM) and Mel (100 µM) at 25 °C for 1 h was given prior to TNPs (50 µg/ml) exposure. For in-vivo study, male Wistar rats were divided into four groups. Group I was control and group II was exposed to TNPs (5 mg/kg b.wt., i.v.). QR (5 mg/kg b.wt.) and Mel (5 mg/kg b.wt.) were given orally as pre-treatment in groups III and IV, respectively. Biochemical parameters, neurobehavioural paradigms, mitochondrial respiration, neuronal architecture assessment were assessed. KEY FINDINGS: QR and Mel restored the mitochondrial oxidative stress biomarkers in both the studies. Additionally, these nutraceuticals resuscitated the neurobehavioural alterations and restored the neuronal architecture alterations in TNPs exposed rats. The mitochondrial dysfunction induced by TNPs was also ameliorated by QR and Mel by protecting the mitochondrial complex activity and mitochondrial respiration rate. SIGNIFICANCE: Results of the study demonstrated that QR and Mel ameliorated mitochondrial mediated neurotoxic effects induced by TNPs exposure.

Anticancer effect of zinc oxide nanoparticles prepared by varying entry time of ion carriers against A431 skin cancer cells in vitro.

Although, zinc oxide nanoparticles (ZRTs) as an anti-cancer agent have been the subject of numerous studies, none of the reports has investigated the impact of the reaction entry time of ion-carriers on the preparation of ZRTs. Therefore, we synthesized variants of ZRTs by extending the entry time of NaOH (that acts as a carrier of hydroxyl ions) in the reaction mixture. The anti-proliferative action, morphological changes, reactive oxygen species (ROS) production, and nuclear apoptosis of ZRTs on human A431 skin carcinoma cells were observed. The samples revealed crystallinity and purity by X-ray diffraction (XRD). Scanning electron microscopy (SEM) images of ZRT-1 (5 min ion carrier entry) and ZRT-2 (10 min ion carrier entry) revealed microtubule like morphology. On prolonging the entry time for ion carrier (NaOH) introduction in the reaction mixture, a relative ascent in the aspect ratio was seen. The typical ZnO band with a slight shift in the absorption maxima was evident with UV-visible spectroscopy. Both ZRT-1 and ZRT-2 exhibited non-toxic behavior as evident by RBC lysis assay. Additionally, ZRT-2 showed better anti-cancer potential against A431 cells as seen by MTT assay, ROS generation and chromatin condensation analyses. At 25 µM of ZRT-2, 5.56% cells were viable in MTT test, ROS production was enhanced to 166.71%, while 33.0% of apoptotic cells were observed. The IC50 for ZRT-2 was slightly lower (6 µM) than that for ZRT-1 (8 µM) against A431 cells. In conclusion, this paper presents a modest, economical procedure to generate ZRT nano-structures exhibiting strong cytotoxicity against the A431 cell line, indicating that ZRTs may have application in combating cancer.

Efficacy of Patellar Taping and Electromyographic Biofeedback Training at Various Knee Angles on Quadriceps Strength and Functional Performance in Young Adult Male Athletes with Patellofemoral Pain Syndrome: A Randomized Controlled Trial.

Background: The severity of the articular lesion is the single most essential element in investigating the extent of flexion that is required for activities. However, a prior study found no differences in muscle strength gains of quadriceps muscles at different knee angles in people with patellofemoral pain syndrome (PFPS). Objective: The effects of patellar taping and electromyographic biofeedback (EMG-BF)-guided isometric quadriceps strengthening at different knee angles (e.g., 30°, 60°, and 90° of knee flexion) on quadriceps strength and functional performance in people with PFPS were compared in this single-blind randomized controlled parallel trial. Methods: Sixty adult male athletes with PFPS (age: 26.9 ± 1.4 years) were randomly divided into two groups. The experimental group (n = 30) received patellar taping and EMG-BF-guided isometric contraction exercise at 30°, 60°, and 90° angles, and the control group (n = 30) received sham patellar taping without EMG-BF-guided exercises for six weeks. Pain intensity, knee function, muscle strength, and the single-leg triple hop (SLTH) test were assessed. Results: The pain intensity and SLTH scores between the groups were significantly different at the end of the trial (p ≤ 0.001). The EMG-BF and control groups had mean pain scores of 1.3 (0.8) and 4.5 (0.8), respectively. The EMG-BF and control groups had mean functional scores of 80.4 (5.1) and 69.1 (6.1), respectively. The mean SLTH score for the EMG-BF group was 540.7 (51.2) and for the control group it was 509.4 (49.8) after the trial. Quadriceps muscle strength was significantly higher in those who performed quadriceps strength training at 60° of knee flexion after six weeks than in those who performed strength training at 30° or 90° of knee flexion. Conclusion: The findings indicated that individuals who trained their quadriceps at a 60° knee angle had significantly stronger quadriceps muscles than individuals who trained at 30° or 90° of knee flexion. Trial Registration. This trial is registered at Clinical Trials.gov under the identifier NCT05055284.

Effect of Date Palm (Phoenix dactylifera) Phytochemicals on Aß1-40 Amyloid Formation: An in-silico Analysis.

Alzheimer's disease (AD) is a neurodegenerative disease and the most prevalent form of dementia. The generation of oxygen free radicals and oxidative damage is believed to be involved in the pathogenesis of AD. It has been suggested that date palm, a plant rich in phenolic compounds and flavonoids, can provide an alternative treatment to fight memory loss and cognitive dysfunction due to its potent antioxidant activity. Thus, we studied the effect of flavonoids present in date palm on Aß1-40 amyloid formation using molecular docking and molecular dynamics simulation. AutoDock. Myricetin was used as a positive control drug. The flavonoids Diosmetin, Luteolin, and Rutin were found to be potent inhibitors of aggregation (docking energies ≤ -8.05 kcal mol-1) targeting Aß1-40 fibrils (both 2LMO and 6TI5), simultaneously. Further screening by physicochemical properties and drug-likeness analysis suggested that all flavonoids except Rutin followed Lipinski's rule of five. Rutin was, thus, taken as a negative control (due to its violation of Lipinski's rule) to compare its dynamics with Diosmetin. Diosmetin exhibited the highest positive scores for drug likeness. Since Luteolin exhibited moderate drug-likeness and better absorption properties, it was also included in molecular dynamics simulation. Molecular dynamics of shortlisted compounds (Rutin, Diosmetin, and Luteolin) were performed for 200 ns, and the results were analyzed by monitoring root mean square deviations (RMSD), root mean square fluctuation (RMSF) analysis, the radius of gyration (Rg), and solvent accessible surface area (SASA). The results proved the formation of a stable protein-compound complex. Based on binding energies and non-bonded interactions, Rutin and Luteolin emerged as better lead molecules than Diosmetin. However, high MW (610.5), lowest absorption rate (16.04%), and more than one violation of Lipinski's rule make Rutin a less likely candidate as an anti-amyloidogenic agent. Moreover, among non-violators of Lipinski's rule, Diosmetin exhibited a greater absorption rate than Luteolin as well as the highest positive scores for drug-likeness. Thus, we can conclude that Diosmetin and Luteolin may serve as a scaffold for the design of better inhibitors with higher affinities toward the target proteins. However, these results warrant in-vitro and in-vivo validation before practical use.

Interaction of Bioactive Compounds of Moringa oleifera Leaves with SARS-CoV-2 Proteins to Combat COVID-19 Pathogenesis: a Phytochemical and In Silico Analysis.

Novel SARS-CoV-2 claimed a large number of human lives. The main proteins for viral entry into host cells are SARS-CoV-2 spike glycoprotein (PDB ID: 6VYB) and spike receptor-binding domain bound with ACE2 (spike RBD-ACE2; PDB ID: 6M0J). Currently, specific therapies are lacking globally. This study was designed to investigate the bioactive components from Moringa oleifera leaf (MOL) extract by gas chromatography-mass spectroscopy (GC-MS) and their binding interactions with spike glycoprotein and spike RBD-ACE2 protein through computational analysis. GC-MS-based analysis unveiled the presence of thirty-seven bioactive components in MOL extract, viz. polyphenols, fatty acids, terpenes/triterpenes, phytosterols/steroids, and aliphatic hydrocarbons. These bioactive phytoconstituents showed potential binding with SARS-CoV-2 spike glycoprotein and spike RBD-ACE2 protein through the AutoDock 4.2 tool. Further by using AutoDock 4.2 and AutoDock Vina, the top sixteen hits (binding energy ≥ - 6.0 kcal/mol) were selected, and these might be considered as active biomolecules. Moreover, molecular dynamics simulation was determined by the Desmond module. Interestingly two biomolecules, namely ß-tocopherol with spike glycoprotein and ß-sitosterol with spike RBD-ACE2, displayed the best interacting complexes and low deviations during 100-ns simulation, implying their strong stability and compactness. Remarkably, both ß-tocopherol and ß-sitosterol also showed the drug- likeness with no predicted toxicity. In conclusion, these findings suggested that both compounds ß-tocopherol and ß-sitosterol may be developed as anti-SARS-CoV-2 drugs. The current findings of in silico approach need to be optimized using in vitro and clinical studies to prove the effectiveness of phytomolecules against SARS-CoV-2.

Nephroprotective effects of polyherbal extract via attenuation of the severity of kidney dysfunction and oxidative damage in the diabetic experimental model.

In view of many complications of diabetes, kidney failure is considered as one of the main complications. The oxidative stress-induced due to persistent hyperglycemic conditions is the major cause of kidney disease. The present study was designed to explore the nephroprotective efficacy of polyherbal (PH) extract in a diabetic model induced by streptozotocin (STZ). STZ (55 mg/kg body weight, intraperitoneal) was injected in overnight fasting rats to develop the diabetic experimental model. Effect on kidney injury was evaluated by investigating biochemical and histological evidences in renal tissue after 56 days of treatment of PH extract. Results showed the high glucose level in STZ treated rats that suggested hyperglycemia persistence along with the successful establishment of nephropathy in diabetic rats with altered renal function, inflammatory cytokines level as well as oxidative and nitrosative stress. Administration of PH extract significantly improved the glycemic condition, glomerular function and proximal reabsorptive markers. Further, elevated pro-inflammatory cytokines levels and disturbed redox status were restored. Moreover, findings were fostered and substantiated by histopathological examinations. Our work strongly proposes that the nephroprotective effect of the PH extract on renal damage could be attributed due to its anti-inflammatory and antioxidant properties. Thus, PH extract could have potential as a pharmaceutical drug for diabetes mellitus (DM). Additional long-term study or clinical trial is required for further investigations.

Effect of plyometric training and neuromuscular electrical stimulation assisted strength training on muscular, sprint, and functional performances in collegiate male football players.

Background: The study's objective was to analyze the influence of an 8-week neuromuscular electrical stimulation (NMES) with a plyometric (PT) and strength training (ST) program on muscular, sprint, and functional performances in collegiate male football players. Methods: Sixty collegiate male football players participated in this randomized controlled trial single-blind study. All the participants were randomly divided into two groups: (1) NMES group (Experimental, n = 30) who received NMES assisted ST and (2) sham NMES group (Control, n = 30) who received sham NMES assisted ST. In addition, participants from both groups received a PT program; both groups received intervention on three days a week for 8-weeks. The study's outcomes, such as muscular, sprint, and functional performances, were assessed using a strength test (STN) for quadriceps muscle, sprint test (ST), and single-leg triple hop test (SLTHT), respectively, at baseline pre-intervention and 8-week post-intervention. The interaction between group and time was identified using a mixed design (2 × 2) ANOVA. Results: Significant difference found across the two time points for the scores of STN: F (1.58) = 5,479.70, p < 0.05; SLTHT: F (1.58) = 118.17, p < 0.05; and ST: F (1.58) = 201.63, p < 0.05. Similarly, the significant differences were found between groups averaged across time for the scores of STN: F (1.58) = 759.62, p < 0.05 and ST: F (1.58) = 10.08, p < 0.05. In addition, after 8-week of training, Cohen's d observed between two groups a large to medium treatment's effect size for the outcome STN (d = 10.84) and ST (d = 1.31). However, a small effect size was observed only for the SLTHT (d = 0.613). Conclusions: Findings suggest that the effect of PT and ST with either NMES or sham NMES are equally capable of enhancing muscular, sprint, and functional performances in collegiate male football players. However, PT and ST with NMES have shown an advantage over PT and ST with sham NMES in improving muscular performance and sprint performance among the same participants.

Comparison of Clinical Characteristics and Outcome Between Vaccinated and Non-Vaccinated Patients of Covid-19 During the Delta Variant-Dominated Fourth Wave in a Tertiary Care Hospital in Karachi, Pakistan.

Introduction In Pakistan, the fourth wave of coronavirus disease 2019 (Covid-19) started around July 2021, which was dominated by the Delta variant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. The vaccination drive to immunize the people of Pakistan against Covid-19 was also going on during this period. There were multiple types of vaccines being administered to the people of Pakistan, as the vaccines had been procured from multiple sources. Some people had apprehensions about different vaccines being administered in the country. The purpose of this study was to compare the clinical characteristics and outcome of the patients vaccinated against Covid-19 with those of the non-vaccinated patients during the fourth wave of Covid-19 in Pakistan Naval Ship (PNS) Shifa Hospital. Methods The cross-sectional descriptive study was performed at PNS Shifa Hospital Karachi, from July to October 2021. All the Covid-19 patients treated in PNS Shifa Hospital during the "fourth Covid-19 wave" were interviewed. Their medical records were accessed, and they were followed up till their discharge from the hospital. The vaccinated and non-vaccinated patients were compared for differences in their age or gender distribution, the severity of illness, comorbidities, and mortality. Results There were 884 participants in the study: 664 (75.11%) men and 220 (24.89%) women. There were 493 patients below 40 years of age, 233 were 40-59 years old, and 158 were aged 60 and above. One hundred and sixty-nine patients had one or more comorbidities, including hypertension, diabetes mellitus, ischemic heart disease, various malignancies, bronchial asthma, and chronic kidney disease. There were 63 (7.13%) obese patients, 28 of whom developed severe disease. Five hundred and four (57%) patients were vaccinated and 380 (47%) were non-vaccinated. Among the vaccinated patients, the effect of Covid-19 was mild in 58.37%, moderate in 36.11%, severe in 0.79%, and critical in 4.37%. Among the non-vaccinated patients, the effect of Covid-19 was mild in 40.26%, moderate in 46.58%, severe in 3.16%, and critical in 10%. The difference in disease severity between the two groups was statistically significant (p<0.05). Conclusion Vaccinated Covid-19 patients had significantly lower severity of disease and displayed better outcomes when compared to non-vaccinated patients during the fourth Covid-19 wave dominated by the Delta variant of the SARS-CoV-2 virus.

Exploring the Binding Pattern of Geraniol with Acetylcholinesterase through In Silico Docking, Molecular Dynamics Simulation, and In Vitro Enzyme Inhibition Kinetics Studies.

Acetylcholinesterase (AChE) inhibition is a key element in enhancing cholinergic transmission and subsequently relieving major symptoms of several neurological and neuromuscular disorders. Here, the inhibitory potential of geraniol and its mechanism of inhibition against AChE were elucidated in vitro and validated via an in silico study. Our in vitro enzyme inhibition kinetics results show that at increasing concentrations of geraniol and substrate, Vmax did not change significantly, but Km increased, which indicates that geraniol is a competitive inhibitor against AChE with an IC50 value 98.06 ± 3.92 µM. All the parameters of the ADME study revealed that geraniol is an acceptable drug candidate. A docking study showed that the binding energy of geraniol (-5.6 kcal mol-1) was lower than that of acetylcholine (-4.1 kcal mol-1) with AChE, which exhibited around a 12.58-fold higher binding affinity of geraniol. Furthermore, molecular dynamics simulation revealed that the RMSD of AChE alone or in complex with geraniol fluctuated within acceptable limits throughout the simulation. The mean RMSF value of the complex ensures that the overall conformation of the protein remains conserved. The average values of Rg, MolSA, SASA, and PSA of the complex were 3.16 Å, 204.78, 9.13, and 51.58 Å2, respectively. We found that the total SSE of AChE in the complex was 38.84% (α-helix: 26.57% and ß-sheets: 12.27%) and remained consistent throughout the simulation. These findings suggest that geraniol remained inside the binding cavity of AChE in a stable conformation. Further in vivo investigation is required to fully characterize the pharmacokinetic properties, optimization of dose administration, and efficacy of this plant-based natural compound.

Effect of Resisted Sprint and Plyometric Training on Lower Limb Functional Performance in Collegiate Male Football Players: A Randomised Control Trial.

The main objectives of this study were to evaluate the short-term effects of resisted sprint and plyometric training on sprint performance together with lower limb physiological and functional performance in collegiate football players. Ninety collegiate football players participated in this three-arm, parallel group randomized controlled trial study. Participants were randomly divided into a control group and two experimental groups: resisted sprint training (RST) (n = 30), plyometric training (PT) (n = 30), and a control group (n = 30). Participants received their respective training program for six weeks on alternate days. The primary outcome measures were a knee extensor strength test (measured by an ISOMOVE dynamometer), a sprint test and a single leg triple hop test. Measurements were taken at baseline and after 6 weeks post-training. Participants, caregivers, and those assigning the outcomes were blinded to the group assignment. A mixed design analysis of variance was used to compare between groups, within-group and the interaction between time and group. A within-group analysis revealed a significant difference (p < 0.05) when compared to the baseline with the 6 weeks post-intervention scores for all the outcomes including STN (RST: d = 1.63; PT: d = 2.38; Control: d = 2.26), ST (RST: d = 1.21; PT: d = 1.36; Control: d = 0.38), and SLTHT (RST: d = 0.76; PT: d = 0.61; Control: d = 0.18). A sub-group analysis demonstrated an increase in strength in the plyometric training group (95% CI 14.73 to 15.09, p = 0.00), an increase in the single leg triple hop test in the resisted sprint training group (95% CI 516.41 to 538.4, p = 0.05), and the sprint test was also improved in both experimental groups (95% CI 8.54 to 8.82, p = 0.00). Our findings suggest that, during a short-term training period, RST or PT training are equally capable of enhancing the neuromechanical capacities of collegiate football players. No adverse events were reported by the participants.