Mutations in S2 subunit of SARS-CoV-2 Omicron spike strongly influence its conformation, fusogenicity, and neutralization sensitivity.

IMPORTANCE: The Omicron subvariants have substantially evaded host-neutralizing antibodies and adopted an endosomal route of entry. The virus has acquired several mutations in the receptor binding domain and N-terminal domain of S1 subunit, but remarkably, also incorporated mutations in S2 which are fixed in Omicron sub-lineage. Here, we found that the mutations in the S2 subunit affect the structural and biological properties such as neutralization escape, entry route, fusogenicity, and protease requirement. In vivo, these mutations may have significant roles in tropism and replication. A detailed understanding of the effects of S2 mutations on Spike function, immune evasion, and viral entry would inform the vaccine design, as well as therapeutic interventions aiming to block the essential proteases for virus entry. Thus, our study has identified the crucial role of S2 mutations in stabilizing the Omicron spike and modulating neutralization resistance to antibodies targeting the S1 subunit.

Interplay between α-synuclein and parkin genes: Insights of Parkinson's disease.

Parkinson's disease (PD) is a complex and debilitating neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra. The pathogenesis of PD is intimately linked to the roles of two key molecular players, α-synuclein (α-syn) and Parkin. Understanding the intricate interplay between α-syn and Parkin is essential for unravelling the molecular underpinnings of PD. Their roles in synaptic function and protein quality control underscore their significance in neuronal health. Dysregulation of these processes, as seen in PD, highlights the potential for targeted therapeutic strategies aimed at restoring normal protein homeostasis and mitigating neurodegeneration. Investigating the connections between α-syn, Parkin, and various pathological mechanisms provides insights into the complex web of factors contributing to PD pathogenesis and offers hope for the development of more effective treatments for this devastating neurological disorder. The present compilation provides an overview of their structures, regional and cellular locations, associations, physiological functions, and pathological roles in the context of PD.

Treatment of diabetic complications: do flavonoids holds the keys?

Diabetes mellitus (DM) is an endocrinological disorder in which blood sugar levels get elevated and if unmanaged, it leads to several critical complications. Existing therapies or drugs are not able to attain absolute control of DM. Moreover, associated side/adverse effects associated with pharmacotherapy further worsen the Quality of life of patients. Present review is focused on therapeutical potential of flavonoids in management of diabetes and diabetic complications. Plenteous literature has established significant potential of flavonoids in the treatment of diabetes and diabetic complications. A number of flavonoids are found to be effective in treatment of not only diabetes but progression of diabetic complication was also found to be attenuated with the use of flavonoids. Moreover, SAR studies of some flavonoids also indicated the that efficacy of flavonoids is increased with a change in functional group of flavonoids in the treatment of diabetes and diabetic complications. A number of clinical trials are into action to investigate the therapeutic potential of flavonoids as first-line drugs or as adjuvants for treatment of diabetes and diabetic complications.. Owing to their diverse mechanism of action, efficacy and safety, flavonoids may be conscripted as potential candidate for treatment of diabetic complications.

Characterization of chicken eggs associated Escherichia coli and Staphylococcus aureus for biofilm production and antimicrobial resistance traits.

The present study assessed the prevalence, virulence characteristics, antimicrobial resistance and biofilm-forming ability of E. coli and S. aureus recovered from egg samples in Ludhiana, Punjab. A total of 393 samples from hatcheries (n = 238), retail shops (n = 94), and households (n = 61) were collected. The prevalence of E. coli was observed as 11.70% and 9.16% for S. aureus. A total of 41.30% of E. coli isolates were positive for aggR gene and 52.17% were for fimA gene; while 36.11% of the S. aureus isolates were positive for coa gene. A high proportion of E. coli (76.10%) and S. aureus (69.44%) isolates were resistant toward ≥3 tested antibiotic classes. A total of 39.13% of E. coli isolates were moderate biofilm former, whereas the majority of the S. aureus (41.67%) were weak biofilm former. No significant difference regarding biofilm formation was observed between MDR and non-MDR isolates of E. coli and S. aureus. Biofilm genes viz., fimC and crl were reported in 43.47% and 80.43% of E. coli isolates, respectively; while icaA and icaD genes were reported in 58.34% and 47.22% of S. aureus isolates, respectively. A strong metabolic activity among 52.17% of E. coli and 41.66% of S. aureus isolates was observed using XTT assay. The present study highlights the need for applied food safety measures across the egg production chain of the region to prevent the development of MDR strains and biofilms.

Exploring the role of exosomes in rheumatoid arthritis.

In prosperous countries, autoimmune illnesses affect minimum 7% of the community. Rheumatoid Arthritis (RA) as an autoimmune illness is thought to be induced through a variety of genomic, physiological, and biological factors. Many experts in the field of nanomedicine have looked to stem cells as a viable strategy to repair human tissue; however, exosomes have demonstrated greater potential in recent years. Exosomes, produced from stem cells in particular, have exhibited a high propensity to give therapeutic effects. To resist local cellular stress, they are secreted in a paracrine manner from cells. As a result, exosomes produced from stem cells can provide enormous health uses. If treatment is not given, autoantibodies produce synovial inflammation and arthritis, which can lead to chronic inflammation, and impairment. Exosomes could be administered for the treatment of RA, by acting as therapeutic vectors. Exosomes are murine extracellular vesicles that influence biological mechanisms and signal transduction by transporting genetic and protein components. Diseases like RA and bone fractures could be treated using cell-free therapeutic strategies if exosomes could be isolated from stem cells efficiently and packaged with specific restorative substances. To get to this position, many breakthroughs must be achieved, and the following review summarises the most recent developments in stem cell-derived exosomes, with a focus on the important literature on exosome dynamics in RA.

Design of a highly thermotolerant, immunogenic SARS-CoV-2 spike fragment.

Virtually all SARS-CoV-2 vaccines currently in clinical testing are stored in a refrigerated or frozen state prior to use. This is a major impediment to deployment in resource-poor settings. Furthermore, several of them use viral vectors or mRNA. In contrast to protein subunit vaccines, there is limited manufacturing expertise for these nucleic-acid-based modalities, especially in the developing world. Neutralizing antibodies, the clearest known correlate of protection against SARS-CoV-2, are primarily directed against the receptor-binding domain (RBD) of the viral spike protein, suggesting that a suitable RBD construct might serve as a more accessible vaccine ingredient. We describe a monomeric, glycan-engineered RBD protein fragment that is expressed at a purified yield of 214 mg/l in unoptimized, mammalian cell culture and, in contrast to a stabilized spike ectodomain, is tolerant of exposure to temperatures as high as 100 °C when lyophilized, up to 70 °C in solution and stable for over 4 weeks at 37 °C. In prime:boost guinea pig immunizations, when formulated with the MF59-like adjuvant AddaVax, the RBD derivative elicited neutralizing antibodies with an endpoint geometric mean titer of ∼415 against replicative virus, comparing favorably with several vaccine formulations currently in the clinic. These features of high yield, extreme thermotolerance, and satisfactory immunogenicity suggest that such RBD subunit vaccine formulations hold great promise to combat COVID-19.

Association between aflatoxin M1 excretion in milk and indicators of rumen fermentation in bovines.

Aflatoxins and its metabolites negatively impact the ruminant health and production. The present cross-sectional study was aimed to determine the effect of aflatoxins on rumen fermentation by deducing the correlation between the aflatoxin M1 (AFM1) excretion in milk and indicators of rumen fermentation in bovines. The indicators of rumen fermentation were taken into account and correlated with AFM1 concentration in milk of 120 bovines (cattle (n = 82) and buffalo (n = 38)). The AFM1 in milk samples (n = 120) was quantified by ELISA kit. The correlation analysis revealed that with increase in excretion of AFM1 in milk, the pH (r = 0.38), methylene blue reduction time (MBRT) (r = 0.43), sedimentation activity time (SAT) (r = 0.31) and ammonia nitrogen content (r = 0.34) of rumen liquor increase, whereas the total volatile fatty acid (TVFA) content (r = - 0.25), total bacterial count (TBC) (r = - 0.43) and total protozoal count (TPC) (r = - 0.14) of rumen liquor decrease. The results of the present study suggest that the presence of aflatoxins in rumen could have negative effect on the process of rumen fermentation. Therefore, the prevention of primary entry point(s) of AFB1 through the feed of bovines is important for the animal health as well as public health.

Effect of Kaempferol isolated from seeds of Eruca sativa on changes of pain sensitivity in Streptozotocin-induced diabetic neuropathy.

Generation of excessive reactive oxygen species (ROS) and advanced glycation end products (AGEs), and cellular apoptosis are implicated in the pathogenesis of diabetic neuropathy. Present study was aimed to explore the effect of Eruca sativa and Kaempferol (KP) on hyperalgesia (thermal and mechanical); tactile allodynia, motor nerve conduction velocity (MNCV) and oxidative-nitrosative stress in streptozotocin (STZ) induced experimental diabetes. Neuropathy developed in diabetic rats was evident from a marked hyperalgesia and allodynia; reduced MNCV associated with excess formation of AGEs and ROS. Chronic treatment with E. sativa hydroalcoholic extract (EHA; 100, 200 and 400 mg/kg) and KP (5 and 10 mg/kg) for 30 days starting from the 60th day of STZ administration significantly ameliorated behavioral and biochemical changes linked to diabetic neuropathy. Present study suggested that EHA and KP corrected hyperglycemia and reversed the pain response partially in diabetic rats along via modulating oxidative and nitrosative stress along with reduction of AGEs formation in diabetic rats. Thus E. sativa might be beneficial in chronic diabetes, ameliorate the progression of diabetic neuropathy and may also find application in diabetic neuropathic pain.

Therapeutic effect of Linum usitatissimum L. in STZ-nicotinamide induced diabetic nephropathy via inhibition of AGE's and oxidative stress.

The present study was aimed to evaluate the potential of petroleum ether and hydro-alcoholic extract of Linum usitatissimum (FPE and FHE) in STZ-nicotinamide induced diabetic nephropathy. GC-MS analysis of FPE revealed the presence of different fatty acids, heterocyclic compounds etc. Moreover, chromatography of FHE isolated Secoisolariciresinol diglycoside. After 30 days of STZ-administration, 100, 200 and 400 mg/kg of FPE and FHE were administered for 45 days. FPE and FHE produced significant attenuation in the glycemic status, renal parameter, lipid profile and level of antioxidant enzymes proving efficacy in diabetic nephropathy. Moreover, FPE and FHE produced significant reduction in the formation of AGEs in kidney. The results indicated that via amelioration oxidative stress and formation of AGEs, FPE and FHE produced significant nephroprotective effect in STZ- induced diabetic nephropathy in rats.

Renoprotective effect of Bacopa monnieri via inhibition of advanced glycation end products and oxidative stress in STZ-nicotinamide-induced diabetic nephropathy.

Hyperglycemia and oxidative stress are involved in the development of diabetic nephropathy (DN). This study was designed to evaluate the effect of alcohol and hydroalcohol extract of Bacopa monnieri and stigmasterol isolated from B. monnieri in the treatment of DN. Diabetes was induced in male wistar rats by streptozotocin (65 mg/kg i.p.) 15 min after nicotinamide (230 mg/kg, i.p.) administration. After 30 days, the rats were treated with different doses of extracts (100, 200, and 400 mg/kg) and stigmasterol (5 and 10 mg/kg) for 45 days to analyze their nephroprotective effect and produced significant attenuation in the serum glucose level, uric acid, creatinine, and lipid levels. Moreover, there is improvement in the level of superoxide dismutase (SOD), glutathione (GSH), and decrease in lipid peroxidation in terms of TBARS. The formation of AGEs in kidneys was also significantly reduced. These findings suggest that B. monnieri and its isolate (stigmasterol) might inhibit the progression of DN.

Role of free radical in atherosclerosis, diabetes and dyslipidaemia: larger-than-life.

During the past few decades, there have been numerous studies related to free radical chemistry. Free radicals including reactive oxygen species (ROS) and reactive nitrogen species are generated by the human body by various endogenous systems, exposure to different physiochemical conditions, or pathological states, and have been implicated in the pathogenesis of many diseases. These free radicals are also the common by-products of many oxidative biochemical reactions in cells. When free radicals overwhelm the body's ability to regulate them, a condition known as oxidative stress ensues. They adversely alter lipids, proteins, and DNA, which trigger a number of human diseases. In a number of pathophysiological conditions, the delicate equilibrium between free radical production and antioxidant capability is distorted, leading to oxidative stress and increased tissue injury. ROS which are mainly produced by vascular cells are implicated as possible underlying pathogenic mechanisms in a progression of cardiovascular diseases including ischemic heart disease, atherosclerosis, cardiac arrhythmia, hypertension, and diabetes. This review summarizes the key roles played by free radicals in the pathogenesis of atherosclerosis, diabetes, and dyslipidaemia. Although not comprehensive, this review also provides a brief perspective on some of the current research being conducted in this area for a better understanding of the role free radicals play in the pathogenesis of atherosclerosis, diabetes, and dyslipidaemia.

Ameliorative role of gemfibrozil against partial abdominal aortic constriction-induced cardiac hypertrophy in rats.

Fibrates are peroxisome proliferator-activated receptor-α agonists and are clinically used for treatment of dyslipidemia and hypertriglyceridemia. Fenofibrate is reported as a cardioprotective agent in various models of cardiac dysfunction; however, limited literature is available regarding the role of gemfibrozil as a possible cardioprotective agent, especially in a non-obese model of cardiac remodelling. The present study investigated the role of gemfibrozil against partial abdominal aortic constriction-induced cardiac hypertrophy in rats. Cardiac hypertrophy was induced by partial abdominal aortic constriction in rats and they survived for 4 weeks. The cardiac hypertrophy was assessed by measuring left ventricular weight to body weight ratio, left ventricular wall thickness, and protein and collagen content. The oxidative stress in the cardiac tissues was assessed by measuring thiobarbituric acid-reactive substances, superoxide anion generation, and reduced glutathione level. The haematoxylin-eosin and picrosirius red staining was used to observe cardiomyocyte diameter and collagen deposition, respectively. Moreover, serum levels of cholesterol, high-density lipoproteins, triglycerides, and glucose were also measured. Gemfibrozil (30 mg/kg, p.o.) was administered since the first day of partial abdominal aortic constriction and continued for 4 weeks. The partial abdominal aortic constriction-induced cardiac oxidative stress and hypertrophy are indicated by significant change in various parameters used in the present study that were ameliorated with gemfibrozil treatment in rats. No significant change in serum parameters was observed between various groups used in the present study. It is concluded that gemfibrozil ameliorates partial abdominal aortic constriction-induced cardiac oxidative stress and hypertrophy and in rats.

Diabetic peripheral neuropathy: current perspective and future directions.

Diabetic neuropathy is a heterogeneous group of disorders with extremely complex pathophysiology and affects both somatic and autonomic components of the nervous system. Neuropathy is the most common chronic complication of diabetes mellitus. Metabolic disruptions in the peripheral nervous system, including altered protein kinase C activity, and increased polyol pathway activity in neurons and Schwann cells resulting from hyperglycemia plays a key role in the development of diabetic neuropathy. These pathways are related to the metabolic and/or redox state of the cell and are the major source of damage. Activation of these metabolic pathways leads to oxidative stress, which is a mediator of hyperglycemia induced cell injury and a unifying theme for all mechanisms of diabetic neuropathy. The therapeutic intervention of these metabolic pathways is capable of ameliorating diabetic neuropathy but therapeutics which target one particular mechanism may have a limited success. Available therapeutic approaches are based upon the agents that modulate pathogenetic mechanisms (glycemic control) and relieve the symptoms of diabetic neuropathy. This review emphasizes the pathogenesis, presently available therapeutic approaches and future directions for the management of diabetic neuropathy.

Approximate solution of Urysohn integral equations using the Adomian decomposition method.

We apply Adomian decomposition method (ADM) for obtaining approximate series solution of Urysohn integral equations. The ADM provides a direct recursive scheme for solving such problems approximately. The approximations of the solution are obtained in the form of series with easily calculable components. Furthermore, we also discuss the convergence and error analysis of the ADM. Moreover, three numerical examples are included to demonstrate the accuracy and applicability of the method.

Approximate series solution of nonlinear singular boundary value problems arising in physiology.

We introduce an efficient recursive scheme based on Adomian decomposition method (ADM) for solving nonlinear singular boundary value problems. This approach is based on a modification of the ADM; here we use all the boundary conditions to derive an integral equation before establishing the recursive scheme for the solution components. In fact, we develop the recursive scheme without any undetermined coefficients while computing the solution components. Unlike the classical ADM, the proposed method avoids solving a sequence of nonlinear algebraic or transcendental equations for the undetermined coefficients. The approximate solution is obtained in the form of series with easily calculable components. The uniqueness of the solution is discussed. The convergence and error analysis of the proposed method are also established. The accuracy and reliability of the proposed method are examined by four numerical examples.

Rapid identification of Campylobacter jejuni from poultry carcasses and slaughtering environment samples by real-time PCR.

The objective of this study was to develop a real-time PCR assay for rapid identification of Campylobacter jejuni and to apply the method in analyzing samples from poultry processing. A C. jejuni-specific primer set targeting a portion of the C. jejuni hippuricase gene was developed. The specificity of the newly designed primer pair was verified using 5 C. jejuni strains and 20 other bacterial strains. Sensitivity was determined to be as low as 1 genome copy per reaction. A total of 73 samples were collected at different sites along the processing line during 2 visits to a poultry slaughterhouse and were examined by direct plating onto modified charcoal cefoperazone deoxycholate agar or after enrichment in Bolton broth followed by plating on modified charcoal cefoperazone deoxycholate agar. The newly developed real-time PCR assay was used to identify the presumptive colonies as belonging to C. jejuni. A real-time PCR assay targeting 16S ribosomal RNA was also applied to determine Campylobacter spp. prevalence. Results from the real-time PCR analysis indicated considerable variability in Campylobacter contamination, with incidence rates of 72.7 and 27.6% for sampling days A and B, respectively. Campylobacter was isolated from 100% of prescalded and preeviscerated carcasses on sampling day A. In contrast, on sampling day B, the highest number of Campylobacter-positive carcasses was recovered after evisceration (60%). The chilling process significantly reduced (P < 0.05) Campylobacter population, but the percentage of positive samples on sampling day A increased to 80%. All samples collected from the processing environment, except scalding tank 3 and the prechiller and chiller tanks, were 100% positive on day A, whereas no campylobacters were isolated from machinery on sampling day B. Our results revealed the widespread of C. jejuni in poultry processing and proved that the newly developed real-time PCR assay is a simple, specific, and inexpensive method for rapid C. jejuni identification. The newly developed PCR method can be easily used in laboratories for reliable and unambiguous identification of C. jejuni in poultry samples.

Therapeutic Viewpoint on Rat Models of Locomotion Abnormalities and Neurobiological Indicators in Parkinson's Disease.

BACKGROUND: Locomotion problems in Parkinson's syndrome are still a research and treatment difficulty. With the recent introduction of brain stimulation or neuromodulation equipment that is sufficient to monitor activity in the brain using electrodes placed on the scalp, new locomotion investigations in patients having the capacity to move freely have sprung up. OBJECTIVE: This study aimed to find rat models and locomotion-connected neuronal indicators and use them all over a closed-loop system to enhance the future and present treatment options available for Parkinson's disease. METHODS: Various publications on locomotor abnormalities, Parkinson's disease, animal models, and other topics have been searched using several search engines, such as Google Scholar, Web of Science, Research Gate, and PubMed. RESULTS: Based on the literature, we can conclude that animal models are used for further investigating the locomotion connectivity deficiencies of many biological measuring devices and attempting to address unanswered concerns from clinical and non-clinical research. However, translational validity is required for rat models to contribute to the improvement of upcoming neurostimulation-based medicines. This review discusses the most successful methods for modelling Parkinson's locomotion in rats. CONCLUSION: This review article has examined how scientific clinical experiments lead to localised central nervous system injuries in rats, as well as how the associated motor deficits and connection oscillations reflect this. This evolutionary process of therapeutic interventions may help to improve locomotion- based treatment and management of Parkinson's syndrome in the upcoming years.

Therapeutic potential of nicorandil beyond anti-anginal drug: A review on current and future perspectives.

Nicorandil (NIC) is a well-known anti-anginal agent, which has been recommended as one of the second-line treatments for chronic stable angina as justified by the European guidelines. It shows an efficacy equivalent to that of classic anti-anginal agents. NIC has also been used clinically in various cardiovascular diseases such as variant or unstable angina and reperfusion-induced damage following coronary angioplasty or thrombolysis. Different mechanisms have been involved in the protective effects of nicorandil in various diseases, including opening of adenosine triphosphate-sensitive potassium (KATP) channel and donation of nitric oxide (NO). In recent years, NIC has been found to show numerous pharmacological activities such as neuroprotective, nephroprotective, hepatoprotective, cardioprotective, and testicular protective effects, among other beneficial effects on the body. The present review dwells on the pharmacological potentials of NIC beyond its anti-anginal action.

Potential Antidiabetic Activity of ß-sitosterol from Zingiber roseum Rosc. via Modulation of Peroxisome Proliferator-activated Receptor Gamma (PPARγ).

AIM: To evaluate the antidiabetic potential of ß-sitosterol from Zingiber roseum. BACKGROUND: Diabetes mellitus is a cluster of metabolic disorders, and 90% of diabetic patients are affected with Type II diabetes (DM2). For the treatment of DM2, thiazolidinedione drugs (TZDs) were proposed, but recent studies have shown that TZDs have several detrimental effects, such as weight gain, kidney enlargement (hypertrophy), fluid retention, increased risk of bone fractures, and potential harm to the liver (hepatotoxicity). That is why a new molecule is needed to treat DM2. OBJECTIVE: The current research aimed to assess the efficacy of ß-Sitosterol from methanolic extract of Zingiber roseum in managing diabetes via PPARγ modulation. METHODS: Zingiber roseum was extracted using methanol, and GC-MS was employed to analyze the extract. Through homology modeling, PPARγ structure was predicted. Molecular docking, MD simulation, free binding energies, QSAR, ADMET, and bioactivity and toxicity scores were all used during the in-depth computer-based research. RESULTS: Clinically, agonists of synthetic thiazolidinedione (TZDs) have been used therapeutically to treat DM2, but these TZDs are associated with significant risks. Hence, GC-MS identified phytochemicals to search for a new PPAR-γ agonist. Based on the in-silico investigation, ß-sitosterol was found to have a higher binding affinity (-8.9 kcal/mol) than standard drugs. MD simulations and MMGBSA analysis also demonstrated that ß-sitosterol bound to the PPAR-γ active site stably. CONCLUSION: It can be concluded that ß-sitosterol from Z. roseum attenuates Type-II diabetes by modulating PPARγ activity.

Cross Talks between CNS and CVS Diseases: An Alliance to Annihilate.

Cardiovascular and neurological diseases cause substantial morbidity and mortality globally. Moreover, cardiovascular diseases are the leading cause of death globally. About 17.9 million people are affected by cardiovascular diseases and 6.8 million people die every year due to neurological diseases. The common neurologic manifestations of cardiovascular illness include stroke syndrome which is responsible for unconsciousness and several other morbidities significantly diminished the quality of life of patients. Therefore, it is prudent need to explore the mechanistic and molecular connection between cardiovascular disorders and neurological disorders. The present review emphasizes the association between cardiovascular and neurological diseases specifically Parkinson's disease, Alzheimer's disease, and Huntington's disease.