Unveiling Annona Reticulata's Bioactive Arsenal for Enhanced Antibiotic Effects.

OBJECTIVE: To study the antibacterial and phytochemical activities of bioactive elements in the leaves of Annona reticulata Linn, a historically used Bangladeshi medicinal plant. METHODS: Shade-dried and crushed plant leaves were soaked with various solvents to obtain samples for different chemical analyses. All extracts were selected for antimicrobial, physicochemical, and Pharmacological investigations. The antimicrobial activity was evaluated using disc diffusion assay, and broth microdilution methods determined potentiation of the activities of the antibiotic antibacterial activity of the plant extracts was investigated using either gram-positive or gram-negative pathogenic wild-type bacteria. RESULTS: From the initial phytochemical and pharmacological studies, it was clear that all extracts, methanol, chloroform, and ethyl acetate, of the leaves of A. reticulata, were proven to process potent bioactive constituents. While differential antimicrobial properties were found to be possessed by all extracts, methanolic extract was the most potent one against all tested microorganisms. It also has potentiated the activities of antibiotics in E. coli. CONCLUSION: Bioactive constituents in the plant extracts were shown to possess phytochemical and antimicrobial activities. More investigation is needed to segregate the chemical components responsible for the respective phytochemical and antimicrobial activities.

Natural flavonols: actions, mechanisms, and potential therapeutic utility for various diseases.

Background: Flavonols are phytoconstituents of biological and medicinal importance. In addition to functioning as antioxidants, flavonols may play a role in antagonizing diabetes, cancer, cardiovascular disease, and viral and bacterial diseases. Quercetin, myricetin, kaempferol, and fisetin are the major dietary flavonols. Quercetin is a potent scavenger of free radicals, providing protection from free radical damage and oxidation-associated diseases. Main body of the abstract: An extensive literature review of specific databases (e.g., Pubmed, google scholar, science direct) were conducted using the keywords "flavonol," "quercetin," "antidiabetic," "antiviral," "anticancer," and "myricetin." Some studies concluded that quercetin is a promising antioxidant agent while kaempferol could be effective against human gastric cancer. In addition, kaempferol prevents apoptosis of pancreatic beta-cells via boosting the function and survival rate of the beta-cells, leading to increased insulin secretion. Flavonols also show potential as alternatives to conventional antibiotics, restricting viral infection by antagonizing the envelope proteins to block viral entry. Short conclusion: There is substantial scientific evidence that high consumption of flavonols is associated with reduced risk of cancer and coronary diseases, free radical damage alleviation, tumor growth prevention, and insulin secretion improvement, among other diverse health benefits. Nevertheless, more studies are required to determine the appropriate dietary concentration, dose, and type of flavonol for a particular condition to prevent any adverse side effects.

Role of T cells in cancer immunotherapy: Opportunities and challenges.

Immunotherapies boosting the immune system's ability to target cancer cells are promising for the treatment of various tumor types, yet clinical responses differ among patients and cancers. Recently, there has been increasing interest in novel cancer immunotherapy practices aimed at triggering T cell-mediated anti-tumor responses. Antigen-directed cytotoxicity mediated by T lymphocytes has become a central focal point in the battle against cancer utilizing the immune system. The molecular and cellular mechanisms involved in the actions of T lymphocytes have directed new therapeutic approaches in cancer immunotherapy, including checkpoint blockade, adoptive and chimeric antigen receptor (CAR) T cell therapy, and cancer vaccinology. This review addresses all the strategies targeting tumor pathogenesis, including metabolic pathways, to evaluate the clinical significance of current and future immunotherapies for patients with cancer, which are further engaged in T cell activation, differentiation, and response against tumors.

Multidrug Resistance in Cancer: Understanding Molecular Mechanisms, Immunoprevention and Therapeutic Approaches.

Cancer is one of the leading causes of death worldwide. Several treatments are available for cancer treatment, but many treatment methods are ineffective against multidrug-resistant cancer. Multidrug resistance (MDR) represents a major obstacle to effective therapeutic interventions against cancer. This review describes the known MDR mechanisms in cancer cells and discusses ongoing laboratory approaches and novel therapeutic strategies that aim to inhibit, circumvent, or reverse MDR development in various cancer types. In this review, we discuss both intrinsic and acquired drug resistance, in addition to highlighting hypoxia- and autophagy-mediated drug resistance mechanisms. Several factors, including individual genetic differences, such as mutations, altered epigenetics, enhanced drug efflux, cell death inhibition, and various other molecular and cellular mechanisms, are responsible for the development of resistance against anticancer agents. Drug resistance can also depend on cellular autophagic and hypoxic status. The expression of drug-resistant genes and the regulatory mechanisms that determine drug resistance are also discussed. Methods to circumvent MDR, including immunoprevention, the use of microparticles and nanomedicine might result in better strategies for fighting cancer.

In-vitro antibacterial activity of commercially available probiotics on food-borne pathogens along with their synergistic effects with synthetic drugs.

Background: Probiotics are put forward as food to ensure the maintenance of the equilibrium of the intestinal flora. Prolonged usage of probiotics in food ingredients for human as well as in animal feed has not exposed any side effects yet. Present study attempted to justify the effects of some commercially available probiotics (Good-gut, Lubenna, Probio and Protein restro) and commonly used antibiotics (Streptomycin, Gentamycin, Ampicillin, Methicillin, Azithromycin, Erythromycin, Ceftrizone, Imepenem, Ciprofloxacin and Tetracycline) on the bacteria which were previously isolated from food samples. Methods: The anti-bacterial potential of the probiotics was aimed to be checked through the agar well diffusion method and the antibiogram of the synthetic drugs was determined by disc-diffusion method (Kirby Bauer technique). The minimum inhibitory concentration (MIC) of the probiotics were examined through broth micro dilution assay. Results: Almost all the probiotic samples exhibited antibacterial activity against the tested bacteria within the range of 10 mm-30 mm except Bacillus spp. and Salmonella spp. The lowest MIC values 3 mg/ml was determined with Luvena for Pseudomonas spp. and Shigella spp. while the maximum MIC 20 mg/ml was recorded for Good gut and Probio against Salmonella spp. and E. coli. Meanwhile, majority of the tested pathogens were detected to be resistant against more than one antibiotic as MDR strains except gentamycin, streptomycin and azithromycin. During the combination method, the zone diameter increased remarkably with a clear indication of synergistic effects compared to their individual activity. Conclusion: This study substantiated that the deployment of a combination of two antibacterial medications in order to combat the multi-drug resistant bacteria would rather be efficacious than the application of either antimicrobial agent alone.

A molecular modelling approach for identifying antiviral selenium-containing heterocyclic compounds that inhibit the main protease of SARS-CoV-2: an in silico investigation.

Coronavirus disease 2019 (COVID-19), an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been declared a global pandemic by the World Health Organization, and the situation worsens daily, associated with acute increases in case fatality rates. The main protease (Mpro) enzyme produced by SARS-CoV-2 was recently demonstrated to be responsible for not only viral reproduction but also impeding host immune responses. The element selenium (Se) plays a vital role in immune functions, both directly and indirectly. Thus, we hypothesised that Se-containing heterocyclic compounds might curb the activity of SARS-CoV-2 Mpro. We performed a molecular docking analysis and found that several of the selected selenocompounds showed potential binding affinities for SARS-CoV-2 Mpro, especially ethaselen (49), which exhibited a docking score of -6.7 kcal/mol compared with the -6.5 kcal/mol score for GC376 (positive control). Drug-likeness calculations suggested that these compounds are biologically active and possess the characteristics of ideal drug candidates. Based on the binding affinity and drug-likeness results, we selected the 16 most effective selenocompounds as potential anti-COVID-19 drug candidates. We also validated the structural integrity and stability of the drug candidate through molecular dynamics simulation. Using further in vitro and in vivo experiments, we believe that the targeted compound identified in this study (ethaselen) could pave the way for the development of prospective drugs to combat SARS-CoV-2 infections and trigger specific host immune responses.

Biochemical and Computational Approach of Selected Phytocompounds from Tinospora crispa in the Management of COVID-19.

A pandemic caused by the novel coronavirus (SARS-CoV-2 or COVID-19) began in December 2019 in Wuhan, China, and the number of newly reported cases continues to increase. More than 19.7 million cases have been reported globally and about 728,000 have died as of this writing (10 August 2020). Recently, it has been confirmed that the SARS-CoV-2 main protease (Mpro) enzyme is responsible not only for viral reproduction but also impedes host immune responses. The Mpro provides a highly favorable pharmacological target for the discovery and design of inhibitors. Currently, no specific therapies are available, and investigations into the treatment of COVID-19 are lacking. Therefore, herein, we analyzed the bioactive phytocompounds isolated by gas chromatography-mass spectroscopy (GC-MS) from Tinospora crispa as potential COVID-19 Mpro inhibitors, using molecular docking study. Our analyses unveiled that the top nine hits might serve as potential anti-SARS-CoV-2 lead molecules, with three of them exerting biological activity and warranting further optimization and drug development to combat COVID-19.

Immunoinformatics-guided design of an epitope-based vaccine against severe acute respiratory syndrome coronavirus 2 spike glycoprotein.

AIMS: With a large number of fatalities, coronavirus disease-2019 (COVID-19) has greatly affected human health worldwide. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that causes COVID-19. The World Health Organization has declared a global pandemic of this contagious disease. Researchers across the world are collaborating in a quest for remedies to combat this deadly virus. It has recently been demonstrated that the spike glycoprotein (SGP) of SARS-CoV-2 is the mediator by which the virus enters host cells. MAIN METHODS: Our group comprehensibly analyzed the SGP of SARS-CoV-2 through multiple sequence analysis and a phylogenetic analysis. We predicted the strongest immunogenic epitopes of the SGP for both B cells and T cells. KEY FINDINGS: We focused on predicting peptides that would bind major histocompatibility complex class I. Two optimal epitopes were identified, WTAGAAAYY and GAAAYYVGY. They interact with the HLA-B*15:01 allele, which was further validated by molecular docking simulation. This study also found that the selected epitopes are able to be recognized in a large percentage of the world's population. Furthermore, we predicted CD4+ T-cell epitopes and B-cell epitopes. SIGNIFICANCE: Our study provides a strong basis for designing vaccine candidates against SARS-CoV-2. However, laboratory work is required to validate our theoretical results, which would lay the foundation for the appropriate vaccine manufacturing and testing processes.

Correlation between biofilm formation and antimicrobial susceptibility pattern toward extended spectrum ß-lactamase (ESBL)- and non-ESBL-producing uropathogenic bacteria.

BACKGROUND: Urinary tract infections (UTIs) are the most common bacterial infection encountered worldwide and are associated with significant morbidity and mortality. METHODS: The present study was undertaken to investigate the biofilm-forming ability, antibiotic susceptibility patterns and extended spectrum ß-lactamase (ESBL) production of seven uropathogenic isolates comprising both Escherichia coli and Klebsiella pneumoniae. The morphological, cultural and biochemical tests for the identification of the isolates, antibiotic susceptibility test, detection of ESBL production, biofilm formation on 96-well microtiter plate and Congo red agar (CRA) media are performed. RESULTS: The antimicrobial susceptibility profiles obtained in this study showed that the most active drugs gentamicin, amikacin and imipenem (100% sensitivity) were followed by amoxicillin-clavulanic acid (85% sensitivity), co-trimoxazole, ciprofloxacin (57% sensitivity) ceftazidime and kanamycin (50% sensitivity). All the isolates showed resistance to amoxicillin followed by ceftriaxone and cefotaxime (71% resistance), and the scenario gets more complicated because of the production of ESBL by five isolates (three E. coli isolates and two K. pneumoniae). The strains were also able to form biofilm as tested on CRA medium and by microtiter plate assay. The correlation between ESBL, non-ESBL and biofilm-producing E. coli and K. pneumonia was determined along with the multiple drug resistance patterns of E. coli and K. pneumonia. CONCLUSIONS: The findings of the study indicate that the emergence and rapid spread of such multidrug-resistant pathogens are of great concern. Early detection of ESBL-producing pathogen is of paramount clinical importance; therefore, strict infection control practices as well as therapeutic guidance for confirmed infection can be rapidly initiated.