Large, randomized trials testing omega-3 polyunsaturated fatty acid (ω-3 PUFA) supplementation to reduce cardiovascular events have reported contradictory results. Interpretation of these trials is challenging, because different dosages and formulations of ω-3 PUFA were tested. Furthermore, the exact mechanisms for the reduction in cardiovascular events are unclear. In this study, we investigated the effects of ω-3 PUFA on platelet adhesion, degranulation, and aggregation in vitro and in patients with cardiovascular disease using different formulations of ω-3 PUFA. We also investigated the effects of ω-3 PUFA in rodent models of arterial thrombosis and in tail bleeding assays, including in cyclooxygenase-1 (COX-1)–deficient animals. The ω-3 PUFA eicosapentaenoic acid (EPA) dose-dependently reduced platelet adhesion, degranulation, and aggregation in vitro. Moreover, arterial thrombus formation in wild-type mice was inhibited by oral EPA administration before thrombus formation. Photoaffinity labeling and in silico docking analyses suggested a direct, competitive interaction of EPA and arachidonic acid at the level of COX-1. The COX-1 dependency of EPA’s inhibitory effects was confirmed by platelet-specific COX-1–deficient animals that had no reduction of thrombus burden by EPA. In patients with cardiovascular disease, switching from 2 grams of EPA twice daily to 1 gram of docosahexaenoic acid (DHA) (460 milligrams of EPA and 380 milligrams of DHA) once daily completely blunted the platelet inhibition achieved by EPA. Our results may partially explain contradictory results with different ω-3 PUFA formulations in clinical trials.

Senescence is irreversible cell cycle arrest that results from therapy-induced stress such as DNA damage. It was initially thought to be a tumor-suppressive mechanism, but now getting attention to contribute to tumor progression and therapy resistance through the senescence-associated secretory phenotype (SASP). Remodeling the tumor microenvironment (TME), SASP can establish conditions conducive to tumor progression. In addition, senescence is being acknowledged increasingly as a crucial factor in inducing tumor dormancy, a state of reversible quiescence that allows cancer cells to evade therapeutic clearance and survive in protective niches. Eventually, both senescence and tumor dormancy significantly contribute to the maintenance of cancer stem cells (CSCs), enhancing their plasticity and tumor-initiating potential. Moreover, SASP can promote aggressive disease state in cancer cells, driving epithelial-to-mesenchymal transition (EMT) and metastasis. On the other hand, dormant cancer cells can act as a reservoir, serving as seeds for metastatic spread which reactivate to develop the tumor at secondary sites. Understanding senescence and tumor dormancy mechanisms holds promise for overcoming therapy resistance, cancer stemness and metastasis. Therapeutic strategies targeting cancer cell senescence and tumor dormancy include senolytics, senomorphics, dormancy-disrupting agents, and immunotherapies. Future preclinical and clinical research should prioritize integration of senescence- and dormancy-targeting agents with conventional treatments to achieve durable cancer control.

Objectives: Inflammatory pathways play a significant role in atherosclerosis that leads to acute coronary syndrome (ACS). The initial stages of atherosclerosis are often asymptomatic; when atherosclerotic plaques become unstable it leads to ACS. Therefore, early detection, diagnosis, and treatment of atherosclerosis must be sought. These circumstances underpin the need for diagnostic values of inflammatory markers, warranting their routine clinical application to develop anti-atherosclerotic therapeutic approaches. The aim of this case-control observational study was to evaluate the plasma levels of interleukin (IL)-6, IL-18, IL-1β, and IL-10. Methods: The research was conducted at Hasan Sadikin Hospital from September to December 2021. Patients were recruited based on the typical clinical history of ACS (non-ST-elevation myocardial infarction, ST-elevation myocardial infarction, and unstable angina) and electrocardiographic and cardiac enzyme data. Healthy subjects having no more than one cardiovascular disease risk factor at admission were included. A total of 43 subjects were included in the study, of which 23 subjects were patients diagnosed with ACS and 20 were healthy controls. Results: The results showed that the mean plasma levels of IL-6 (298.6±432.9 pg/mL) in ACS patients were significantly higher than the mean concentration of IL-6 (33.7±96.6 pg/mL) in the control group (p < 0.05). Similarly, the mean plasma level of IL-18 (181.4±81.4 pg/mL) in ACS patients was significantly higher compared to the mean concentration (125.0±29.8 pg/mL) in the control group (p < 0.05), suggesting that both IL-6 and IL-18 were associated with ACS. However, there is no statistically significant difference between IL-1β and IL-10 levels. A Pearson’s correlation analysis showed that a positive correlation exists between IL-6 and IL-18. Conclusions: Both IL-6 and IL-18 are associated with ACS.

Thrombosis is a frequent cause of cardiovascular mortality and hospitalization. Current antithrombotic strategies, however, target both thrombosis and physiological hemostasis and thereby increase bleeding risk. In recent years the pathophysiological understanding of thrombus formation has significantly advanced and inflammation has become a crucial element. Neutrophils as most frequent immune cells in the blood and their released mediators play a key role herein. Neutrophil-derived cathelicidin next to its strong antimicrobial properties has also shown to modulates thrombosis and thus presents a potential therapeutic target. In this article we review direct and indirect (immune- and endothelial cell-mediated) effects of cathelicidin on platelets and the coagulation system. Further we discuss its implications for large vessel thrombosis and consecutive thromboinflammation as well as immunothrombosis in sepsis and COVID-19 and give an outlook for potential therapeutic prospects.

The aim of the present study was to see how polymers effect on the rate of propranolol hydrochloride (propranolol HCl) release from a controlled release matrix tablet.Hydroxy propyl methyl cellulose (HPKMC K4M and HPMC K15M) and ethyl cellulose (EC) were used to retard the rate of propranolol HCl release.The UV (Ultraviolet) absorption, FTIR (Fourier transform infrared) spectroscopy and DSC (Differential scanning calorimetry) spectra showed that propranolol HCl is compatible with HPMC K4M, HPMC K15M and ethyl cellulose.Controlled release tablets were made using a wet granulation technique.Angle of repose, bulk density, tapped density and compressibility index of propranolol HCl were all assessed prior to compression.Prepared tablets were evaluated for thickness, hardness, content uniformity, % friability and disintegration time and % drug release.All the parameters of pre-compression and post compression comply with standard specification.The in vitro drug release study disclosed that a formulation containing HPMC K15M and ethyl cellulose retarded the drug release rate for maximum time.The results of this investigation manifested that a blend of hydrophilic and hydrophobic polymers might be used to successfully enhance delayed rate of propranolol hydrochloride release from its controlled release matrix tablet.

Ethnopharmacological relevance: Unani System of Medicine offers treatment for obesity and dyslipidaemia. Jawarish Falafili (JF) is a Unani polyherbal pharmacopoeial preparation. It has been used in the treatment of obesity for a long time. Dyslipidaemia is a recognised modifiable risk factor for hypertension, ischemic heart disease and stroke. Limitations of the current conventional therapy have provided scope for research of a potential drug in this medical condition. It was hypothesised that JF may ameliorate dyslipidaemia in human participants. Aim of the study: The main objective of this study was to evaluate the safety and efficacy of the JF. Materials and methods: This was a prospective randomized, active-controlled, open-label and parallel-group study. We randomized 74 participants of dyslipidaemia into treatment (n = 38) and control (n = 36) groups. Of them, 30 participants in each group completed the trial. The participants of any sex aged between 30 and 60 years, with serum total cholesterol (TC) >= 200 mg/dl and/or serum triglycerides (TG) >= 150 mg/dl and/or low-density lipoprotein cholesterol (LDL-C) level >= 130 mg/dl and/or high-density lipoprotein cholesterol (HDL-C) level <40 mg/dl were enrolled in this study. The participants of the treatment group were treated with JF (10 gm/day) once and atorvastatin (20 mg/day) was given to the control group for 90 days once at night daily. Results: We observed a significant reduction (treatment group versus control group) in mean serum TC by 22.89% versus 19.36%, TG by 29.90% versus 23.26% and LDL-C by 29.16% versus 27.92% from baseline (p < 0.05). But the change in mean serum HDL-C levels post-treatment was insignificant in both groups (p > 0.05). On inter-group comparison, the magnitude of the difference of mean TC, TG, LDL-C and HDL-C levels between the groups was not statistically significant (p > 0.00.05). Conclusions: This study concluded that JF and atorvastatin were equally effective in controlling dyslipidaemia. They were tolerated well by all participants and found safe during the course of treatment.

Quality-based assessment of pharmaceuticals obviates the uncertainties concerning their quality, safety and efficacy for their regulatory purpose. A method was developed and validated for quality control assessment of cefadroxil for the pharmaceuticals or row material analysis. In-silico analysis wasperformedto evaluate the bioavailability, toxicity as well asanti-inflammatory potential of cefadroxil. The results showed that the developed method was found linear, accurate, precise and robust while the dissolution rate of each tablet was found comparable. In-silico docking analysis and network pharmacology analysis showed low bioavailability and toxicity as well as a significant anti-inflammatory potential of cefadroxil via regulation of genes such as TNF-α, IL-6, SLC15A1 and SLC15A2. However, due to its bioavailability barriers, further experimental strategies are necessary to re-purpose the therapeutic application of cefadroxil as a potent anti-inflammatory agent.

Intravascular neutrophils and platelets collaborate in maintaining host integrity, but their interaction can also trigger thrombotic complications. We report here that cooperation between neutrophil and platelet lineages extends to the earliest stages of platelet formation by megakaryocytes in the bone marrow. Using intravital microscopy, we show that neutrophils "plucked" intravascular megakaryocyte extensions, termed proplatelets, to control platelet production. Following CXCR4-CXCL12-dependent migration towards perisinusoidal megakaryocytes, plucking neutrophils actively pulled on proplatelets and triggered myosin light chain and extracellular-signal-regulated kinase activation through reactive oxygen species. By these mechanisms, neutrophils accelerate proplatelet growth and facilitate continuous release of platelets in steady state. Following myocardial infarction, plucking neutrophils drove excessive release of young, reticulated platelets and boosted the risk of recurrent ischemia. Ablation of neutrophil plucking normalized thrombopoiesis and reduced recurrent thrombosis after myocardial infarction and thrombus burden in venous thrombosis. We establish neutrophil plucking as a target to reduce thromboischemic events.

Bacterial infections and oxidative damage are becoming more concerning health problems to be addressed by health professionals due to the multidrug resistance of pharmaceuticals. Despite, topical preference, oral administration compliance, and bioavailability berries, still remains the opacity to developed an alternative topical formulation with better compatibility. The study is aimed to prepare different topical ointment formulations containing gallic acid as an active pharmaceutical ingredient, followed by optimization of the best formulation. In vitro drug release profile was determined followed by antibacterial evaluation against E. coli and S. aureus viability. DPPH assay, in silico pharmacokinetic and network pharmacology analysis were performed to determine antioxidant potential, bioavailable response and multi-mechanistic therapeutic role of formulation/gallic acid in alleviation of bacterial infection even oxidative damage. The outcomes of the study showed that the formulation F5 was found as an optimized formulation which showed 5.76 +/- 0.0207 pH, 1487.35 +/- 4.868 Pas viscosity, 139.42 +/- 1.665 g. cm/s spreadability index. In antibacterial activity, the average zone of inhibition was found 5.324 +/- 0.458 mm and 5.324 +/- 0.458 mm against the growth of E. coli and S. aureus, respectively. The developed formulation exhibited significant (p<0.001) antioxidant activity. In silico, pharmacokinetic showed good bioavailable response of gallic acid while network pharmacology analysis showed multi-mechanistic action of gallic acid in alleviation of inflammation and oxidative stress induced by the biological stimulus. Hence, it can be concluded that the developed optimized formulation can be used for the bacterial infection as well as oxidative damages induced by the biological stimulus.

Glioblastoma multiforme (GBM) is considered the most aggressive and heterogeneous type of brain malignancy. The substantial invasion of the central nervous system parenchyma is a typical hallmark of all grades of glioma. To improve tumor localization and prevent unanticipated toxicity, anti-tumor drug delivery mechanisms must be upgraded in parallel with pharmacotherapeutics. Monocytes can easily pass the blood-brain barrier, and thus, drugs with difficulty entering the brain can be loaded into monocytes, resulting in the treatment of brain cancers. RNA as a natural and biocompatible polymer has many advantages for biomedical applications, and RNA-based therapies can provide regulated biological functions by highly selective and controlling means. In this context, macrophages are excellent carriers for distributing RNA-based treatments. However, developing an efficient macrophage-targeted RNA delivery has remained challenging. Several approaches have been introduced in the last decade to efficiently deliver RNA-based therapy via macrophages to treat GBM and inflammatory conditions. This review summarizes the most suitable nano-carrier systems to deliver RNA into immunocytes; also, different methods of synthesizing RNA-loaded nanoparticles and their application, with an emphasis on targeting GBM, are discussed. Furthermore, it focuses specifically on the stability of such nanoformulations and the effect of targeting moieties and adjuvants in determining the worth of the aroused immune response. Finally, the critical aspects of delivering RNA-lipid hybrid nanoparticles (LNPs) via oral, systemic, and local routes are highlighted. We hope that these findings will pave the way for more effective treatment of solid tumors, such as GBM, in the future.

Development of the novel formulation is critically needed for alleviating several acute and chronic ailments.Diabetes is acknowledged as one of the prevalent metabolic disorder affecting the global health and economy, vigorously.Based on the above facts, the study is aimed to develop SLNs (solid lipid nanoparticle) loaded with quercetin as the potential novel formulation for the management of diabetes.Preformulation and postformulation studies were conducted to determine the purity and compatibility of quercetin with the formulation bases used for its development.a-amylase and a-glucosidase inhibitory activity and DPPH (2, 2-diphenyl-1-picrylhydrazy) free radicals scavenging activity were performed of the developed formulation with the comparison of the control group quercetin to determine antidiabetic and antioxidant potential.Network pharmacology analysis was performed to determine the multimechanistic and therapeutic potential of quercetin for treatment of diabetes and its associated complications.The results showed that quercetin was found substantially compatible with the formulation bases used for its development.The particle size of the developed SLNs was found with no drug interaction with the formulation base which was evaluated from the FTIR (Fourier transform infrared spectroscopy) analysis.In antidiabetic analysis of the formulation, no significant (p<0.05)variance was found in the aamylase and a-glucosidase activity while DPPH activity of the developed SLNs was found 81% at the higher concentration.In network pharmacology analysis, it was found that quercetin regulates several genomes such as IRS-1, TLRs, ILs, CASPs, MAPKs, AKT1, AOX, etc., involved in the diabetes and its associated complication.Hence, it can be concluded that the developed SLNs not only regulates diabetes even effect for the diabetes associated complication.

Objective: To find out the association of demographic and biochemical markers in families of the patients with spinabifida. Study Design: Cross Sectional study. Setting: Arif Memorial Teaching Hospital, Lahore, Sheikh Zayed Hospital, Lahore, Hameed Latif Hospital Lahore. Period: July 2017 to January 2018. Material & Methods: Demographic data of the participants was obtained through a pre designed questionnaire with informed consent. Physical examination of weight and height for the calculation of BMI was done at spot. Biochemical markers such as HbA1c and folic acid were measured after collecting 5ml blood samples of participants through automated analyzers. Results: Results of this study showed 50% mothers bearing child with spina bifida being between the ages of 26 to 30 years. 50% of Fathers of subjects were between 35 to 40 years of age. 62.5% subject families belonged to rural area. 87.5% families having child with spina bifida belonged to low SES (Socioeconomic Statius). 50% Consanguinity found in subject families. BMI, HbA1c and folic acid of children were found to be significant p values respectively 0.046, 0.043 and 0.005. BMI of fathers also showed significant p value of 0.043. Conclusion: Demographic data such as age, location and socioeconomic status of parents of subjects were found to be significantly correlated with the occurrence of spina bifida, while BMI of fathers subjects were found having effect on the spina bifida in their children.

Eugenol is acknowledged as a potent anti-inflammatory and analgesic agent. Due to the opacity for the development of effective and affordable topical pharmaceuticals and lack of a multi-mechanistic approach, the present study is aimed to develop a eugenol-based topical formulation and explore the multi-mechanistic effect of eugenol-based gel formulation for analgesic and anti-inflammatory action. Pre-formulation and post formulation studies were conducted to evaluate the drug compatibility with certain bases. Furthermore, network pharmacology and gene ontology analysis were conducted to determine the multi-mechanistic role of eugenol in treating pain, inflammation and associated malfunctions. The results showed that among the four developed formulations, F3 formulation was found as the optimized formulation with the average drug content 1.584 +/- 0.070 mg/g. Evaluation of post-formulation parameters such as pH, spreadability, viscosity and FT-IR showed the optimistic characteristic of the optimized formulation. Furthermore, in network pharmacology and gene ontology (GO) study, it can be demonstrated that the developed eugenol based formulation play multiple physiological actions such as regulation of angiogenesis, inflammatory response, dopaminergic synapse, response to reactive oxygen species, etc., via regulation of genes such as ALOX5, BDKRB2, CASP3, MAOA, SCN10A, SCN11A, UGT1A7, VR1 etc., It can be demonstrated that the developed formulation provides an effective pharmaceutical formulation with potent analgesic and anti-inflammatory property.

Regardless of a plethora of advanced diagnostics, TB and drug resistance remains a principal killer. We proposed gold nanoparticles (AuNPs) attached with probes to enhance the efficiency of GeneXpert MTB/RIF assay instead of conventional dye probes for molecular detection. A total of 15,000 samples were collected from TB suspects and subjected to Xpert MTB/RIF assay, where 6800 (45.3%) were detected as MTB positive, 280 (4.3%) were detected to harbor mutations in the RRDR, while invalid /errors were found in 690 (4.6%) cases. The mutations were detected by probe E, 199 (71.1%), while probes B and D, 30 and 26 (10% and 9%), respectively. In the Xpert MTB/RIF Assay were found mutations picked by probes E and B codons 529–533 (71%) and 512–518 (10%), respectively. The fast-rising works of TB nano-diagnostics, of Xpert probes, may improve by the applications of gold nanoparticle probes.

Scientists worldwide struggle to identify suitable animal models to study SARS-CoV-2 infections. Interspecies-related differences, such as host specificity, divergent immune responses, or the unavailability of species-specific reagents hamper the research. Human-based models, such as micro-engineered multi-organs-on-chip, may hold the solution.

Host defense against infectious disease is a tormenting task considering not only the enormous pathogens diversity, but also their rapid genome replication and mutation rates. Front line and anti-microbial defense is accomplished by the innate immune system with the help of pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) in prompt pathogens detection. In this study, distribution of single nucleotide polymorphisms (SNPs) in TLR2 gene was studied in two cattle breeds Dhanni and locally adapted exotic Jersey. The complete sequences of TLR2 gene composed of 5'UTR 136 bp, coding sequence 2355 bp and 3'UTR 1316 bp. Phylogenetic analysis revealed clustering of Dhanni with Bos indicus and Jersey with Bos taurus as the nearest neighbor. Sequencing of TLR2 in Dhanni cattle showed the occurrence of 35 variable sites within coding region including 37% non-synonymous and 63% synonymous, while in Jersey cattle, 21 SNPs were identified within coding region including 48% non-synonymous and 52% synonymous. Mostly SNPs fell within the leucine-rich repeats (LRR) of extracellular domain, regions responsible for ligand recognition. The ratio of d S / d N substitutions was <1 at polymorphic-sites indicating purifying selection. The SNPs at position 681 (p.Leu227Phe in Jersey) and 521(p.Thr174Ile in Dhanni) were presumed to have possible damaging or functional altering effect. The predicted bovine TLR2 is a solenoid-like (coil-like) built from 20 LRRs bend into a horseshoe shaped structure. The polymorphisms in TLR2 can be useful in future research exploring its role in immunity and may be used as markers for disease resistance under selective breeding.

Background Thrips tabaci Lindeman (Thysanoptera: Thripidae) is the key pest of onions that causes economic yield losses in commercial onion production in Pakistan. In this study, potential of the entomopathogenic fungi (EPF), Beauveria bassiana and Metarhizium anisopliae, as a bio agent was evaluated to manage buildup of thrips population on onion crop. Results Efficacy tests for EPF were conducted against T. tabaci infesting 3 different onion varieties (Phulkara, Swat 1, and Virio 7). Commercial formulations of B. bassiana strain GHA and M. anisopilae strain ESC-1, were evaluated at 4 different concentrations (10(8), 10(9), 10(10), and 10(11) conidia/ml) under field conditions for 2 years. The efficacy was assessed 3, 5, 7, and 10 days after spray application of the whole onion plant. Efficacy expressed as T. tabaci (nymphs and adults) percent population reduction in comparison to controls. Maximum corrected percent population reduction was observed in onion plants treated with B. bassiana 10(11) conidia/ml, i.e., 86.62, 84.59, and 86% in Phulkara, Swat 1, and Virio 7 onion varieties respectively, after 10 days of spray application. While onion plants treated with M. anisopliae 10(8) conidia/ml showed minimum corrected percent population reduction, i.e., 69.42, 68.45, and 69.11% in Phulkara, Swat 1, and Virio 7 onion varieties respectively, after 10 days of spray. Conclusions Beauveria bassiana could significantly reduce thrips population and could provide a better long-term management of T. tabaci on onion. B. bassiana had a high toxic effect against offspring production of the T. tabaci under field conditions than M. anisopliae.

Aim: The main aim of this study was to compare the quality of groundwater on the basis of its physical and chemical parameters analyzed. For this purpose, different areas of Varanasi, Ghaziabad and Noida. Introduction: One the oldest Indian ancient cities, Varanasi, known for the Hindu spiritual practices has now topped the country’s list of the most polluted city and Ghaziabad, considered as one of the most developed areas of the state Uttar Pradesh had highest pollution level among the 42 cities of the country in the previous year, 2017. Despite being the developed towns of the state, people have to suffer for basic needs, particularly the water needs. Contamination of underground water is one of the biggest hazards that the world will witness sooner or later. Underground water contamination in the present scenario is done more by the indirect pollution methods which include inadequate treatment of the waste product before their disposal into the water bodies. Ions transported by the rivers are an essential source of almost all the elements found on Earth. The major ions which are responsible to maintain the quality of water, particularly the groundwater includes sundry cations and anions like: carbonate (CO32-), PhosPhosphate (PO43-), Nitrate (NO3-), Bicarbonate (HCO3-), Chloride (Cl-), Sulphate (SO42-), Calcium (Ca++), Magnesium (Mg++), Cupper (Cu++ ), Fluoride (F-), Sodium (Na+) and Potassium (K+). Among the above-listed ions, Calcium (Ca++) and Magnesium (Mg++) are particularly responsible for the hardness of water, intake of this hard water by humans and animals can result in sundry medical complications like diarrhea and Gastrointestinal Disorders. Materials and Methods: Water samples from nine different areas of Ghaziabad (NCR) and Varanasi (East UP) were collected and analyzed various physical and chemical parameters. Conclusion: Comparison of groundwater quality showed higher values of observed parameters at Salarpur and Kavi Nagar area of NCR re