Identification of Chemical Scaffolds Targeting Drug-Resistant and Latent Mycobacterium tuberculosis through High-Throughput Whole-Cell Screening.

Identification of structurally unique chemical entities targeting unexplored bacterial targets is a prerequisite to combat increasing drug resistance against Mycobacterium tuberculosis. This study employed a whole-cell screening approach as an initial filter to scrutinize a 10,000-compound chemical library, resulting in the discovery of seven potent compounds with MIC values ranging from 1.56 to 25 µM. These compounds were categorized into four distinct chemical groups. Remarkably, they demonstrated efficacy against drug-resistant and nonreplicating tuberculosis strains, highlighting their effectiveness across different infection states. With a favorable selectivity index (>10), these compounds showed a safe therapeutic range and exhibited potency in an intracellular model of Mtb infection, mimicking the in vivo setup. Combining these identified hits with established anti-TB drugs revealed additive effects with rifampicin, isoniazid, and bedaquiline. Notably, IIIM-IDD-01 exhibited synergy with isoniazid and bedaquiline, likely due to their complementary mechanisms of targeting Mtb. Most potent hits, IIIM-IDD-01 and IIIM-IDD-02, displayed time- and concentration-dependent killing of Mtb. Mechanistic insights were sought through SEM and docking studies, although comprehensive evaluation is ongoing to unravel the hits' specific targets and modes of action. The hits demonstrated favorable pharmacokinetic properties (ADME-Tox) and showed a low risk of adverse effects, along with a predicted high level of oral bioavailability. These promising hits can serve as an initial basis for subsequent medicinal chemistry endeavors aimed at developing a new series of anti-TB agents. Moreover, the study affirms the significance of high-throughput in vitro assays for the TB drug discovery. It also emphasizes the necessity of targeting diverse TB strains to address the heterogeneity of tuberculosis bacteria.

Harnessing host-pathogen interactions for innovative drug discovery and host-directed therapeutics to tackle tuberculosis.

Tuberculosis (TB) is a highly contagious bacterial infection caused by Mycobacterium tuberculosis (Mtb), which has been ranked as the second leading cause of death worldwide from a single infectious agent. As an intracellular pathogen, Mtb has well adapted to the phagocytic host microenvironment, influencing diverse host processes such as gene expression, trafficking, metabolism, and signaling pathways of the host to its advantage. These responses are the result of dynamic interactions of the bacteria with the host cell signaling pathways, whereby the bacteria attenuate the host cellular processes for their survival. Specific host genes and the mechanisms involved in the entry and subsequent stabilization of M. tuberculosis intracellularly have been identified in various genetic and chemical screens recently. The present understanding of the co-evolution of Mtb and macrophage system presented us the new possibilities for exploring host-directed therapeutics (HDT). Here, we discuss the host-pathogen interaction for Mtb, including the pathways adapted by Mtb to escape immunity. The review sheds light on different host-directed therapies (HDTs) such as repurposed drugs and vitamins, along with their targets such as granuloma, autophagy, extracellular matrix, lipids, and cytokines, among others. The article also examines the available clinical data on these drug molecules. In conclusion, the review presents a perspective on the current knowledge in the field of HDTs and the need for additional research to overcome the challenges associated HDTs.

Nanocapsules: An Emerging Drug Delivery System.

BACKGROUND: Controlled drug release and site-specific delivery of drugs make nanocapsules the most approbative drug delivery system for various kinds of drugs, bioactive, protein, and peptide compounds. Nanocapsules (NCs) are spherical shape microscopic shells consisting of a core (solid or liquid) in which the drug is positioned in a cavity enclosed by a distinctive polymeric membrane. OBJECTIVES: The main objective of the present patent study is to elaborate on various formulation techniques and methods of nanocapsules (NCs). The review also spotlights various biomedical applications as well as on the patents of NCs to date. METHODS: The review was extracted from the searches performed using various search engines such as PubMed, Google Patents, Medline, Google Scholars, etc. In order to emphasize the importance of NCs, some published patents of NCs have also been reported in the review. RESULTS: NCs are tiny magical shells having incredible reproducibility. Various techniques can be used to formulate NCs. The pharmaceutical performance of the formulated NCs can be judged by evaluating their shape, size, entrapment efficiency, loading capacity, etc., using different analytical techniques. Their main applications are found in the field of agrochemicals, genetic manipulation, cosmetics, hygiene items, strategic distribution of drugs to tumors, nanocapsule bandages to combat infection, and radiotherapy. CONCLUSION: In the present review, our team made a deliberate effort to summarize the recent advances in the field of NCs and focus on new patents related to the implementation of NCs delivery systems in the area of some life-threatening disorders like diabetes, cancer, and cardiovascular diseases.

Nanocrystals: A Deep Insight into Formulation Aspects, Stabilization Strategies, and Biomedical Applications.

BACKGROUND: Drugs with poor solubility exhibit hurdles in their formulation due to poor dissolution and low bioavailability. Nanocrystallization is a great technique for incorporating poorly soluble drugs and is associated with many benefits. OBJECTIVE: The objective of the present review is to discuss formulation techniques for the generation of Nanocrystals (NCs) and illustrate the various advantages of NCs. It also explains commonly used stabilizers and guidelines for their safe use for enhancing NCs and provides a deep insight into various biomedical applications of NCs. METHODS: The review was extracted from the study carried out in the general literature to emphasize the importance of NCs in various formulations. RESULTS: NCs are a widely accepted approach to enhancing drug solubility. There are so many marketed products of nanocrystal drug formulations that are being used to treat life-threatening disorders. Two techniques can be used to formulate NCs, i.e., the bottom-up method and the top-down method. Their main biomedical applications are found in oral, parenteral, pulmonary, ocular, dermal, and mucosal formulations. CONCLUSION: In the present review, different formulation methods of NCs have been discussed in detail, followed by explaining the advantages and various targeted drug delivery systems covered by NCs formulations. The development of NCs-based formulation avoids the limitations of other systems used for targeted drug delivery.

Association between caregiver opposition to topical fluoride and COVID-19 vaccines.

PURPOSE: Caregivers who oppose topical fluoride in dental settings may be opposed to other preventive health treatments, including COVID-19 vaccines. The study objective was to examine the association between caregiver opposition to topical fluoride and COVID-19 vaccines. METHODS: The study took place at the University of Washington in Seattle, WA. English-speaking caregivers of children aged < 18 years were eligible to participate. An 85-item REDCap survey was administered from February to September 2021. The predictor variable was topical fluoride opposition (no/yes). The outcome was COVID-19 vaccine opposition (no/yes). The models included the following covariates: child and caregiver age; caregiver race and ethnicity, education level, dental insurance type, parenting style, political ideology, and religiosity; and household income. Logistic regression models generated odds ratios (OR) and 95 % confidence intervals (α = 0.05). RESULTS: Six-hundred-fifty-one caregivers participated, and 403 caregivers with complete data were included in the final regression model. Mean child age was 8.5 years (SD 4.2), mean caregiver age was 42.1 years (SD 9.1), 53.0 % of caregivers were female, 57.3 % self-reported as white, and 65.5 % were insured by Medicaid. There was a significant positive association between topical fluoride and COVID-19 vaccine opposition (OR = 3.13; 95 % CI: 1.87, 5.25; p < 0.001). Other factors associated with COVID-19 vaccine opposition included conservative political views (OR = 2.77; 95 % CI: 1.26, 6.08; p < 0.011) and lower education (OR = 3.47; 95 % CI: 1.44, 8.38; p < 0.006). CONCLUSIONS: Caregivers opposed to topical fluoride in dental settings were significantly more likely to oppose COVID-19 vaccines for their child. Future research should identify ways to address both topical fluoride and vaccine opposition to prevent diseases in children.

Shear Bond Strength of Glass Ionomer Cement to Silver Diamine Fluoride-Treated Artificial Dentinal Caries.

Purpose: The purpose of this study was to measure the shear bond strength (SBS) of glass ionomer cement (GIC) to artificial carious dentin with and without silver diamine fluoride (SDF) treatment. Methods: Permanent molars were sectioned and demineralized to create artificial carious lesions. In five groups, the demineralization of dentin, application of SDF, use of conditioner, and elapsed time between the placement of SDF and restoration were tested for differences in SBS using an UltraTester machine. Statistical analysis was done using the Kruskal-Wallis test and Tukey-Kramer multiple comparison tests. Results: The highest bond strength was found when GIC was placed on conditioned and demineralized dentin treated with SDF one week earlier. Treatment with SDF and use of conditioner did not statistically affect the SBS of GIC to demineralized dentin. Statistically significant increases in bond strength were found when one week elapsed between SDF application and GIC placement. The lowest bond strength was found with immediate GIC application onto SDF-treated demineralized dentin. Conclusions: These in vitro findings suggest that silver diamine fluoride treatment does not significantly affect the bond strength of glass ionomer cement to dentin lesions, and improved retention is obtained by allowing SDF solution to set for one week prior to GIC placement.

Immunomodulatory Properties of Chitosan: Impact on Wound Healing and Tissue Repair.

OBJECTIVE: Chitosan, a natural polymer from shelled crustaceans, has been employed in an array of biomedical applications as it possesses a combination of fascinating attributes such as biocompatibility, biodegradability, non-toxicity and ease of chemical alteration into different active derivatives. The ability of chitosan to be tailored into different shapes has made it a very popular polymer for designing novel drug delivery systems for topical, transdermal and gene delivery. Recently, the multifunctional and immunomodulatory properties of chitosan have attracted a lot of attention. Since there are many patents and publications on medicated scaffolds, films and other topical dressings containing chitosan, an effort has been made to collate and synchronize the immunomodulatory properties of chitosan with its wound healing potential. METHODS: Literature and patent search was done using major search engines and websites. Based on the studies conducted by various research groups, the information was classified into important subheadings. RESULTS: Most of the studies suggested that due to remarkable immuno-stimulatory activities, chitosan stimulates the release of anti-inflammatory cytokines, chemokines, growth factors and hence promotes and supports every phase of wound healing, including hemostasis, inflammation, cell migration, proliferation, tissue repair and cell regeneration. CONCLUSION: An understanding of the immunomodulatory activities of chitosan can help the researchers and formulation scientists to use this natural polymer and its derivatives to design controlled release, medicated, self-decomposable, environment-friendly scaffolds for better patient compliance and promising wound-healing effects.

An Appraisal on Various Methods of Nano Particulate Formulations.

BACKGROUND: Nanotechnology has immense significance in the field of medicine, agriculture, business, public health sector due to wide applicability of the nano products. Basically, nanotechnology is the incorporation of nanoscale structures into larger material components to improve the properties of constructed system. METHOD: Nanotechnology serves as an alternative drug delivery system to the liposomes drug delivery system as the stability of the product in biological fluids is the main problem associated with the liposomal drug delivery system. In the present review, nanoparticles, their applications, various techniques of preparation of nanoparticles and research update on nano particulate drug delivery system have been discussed. RESULTS: The main complication associated with biodegradable polymer is uncertainty in their absorption pathway in gastrointestinal tract. Sometimes, harmful by-products after metabolism are released. However, the polymeric nanoparticles (synthetic or semi-synthetic) have a defined structure therefore; get absorbed in intact form in gastrointestinal tract. CONCLUSION: Nano-particulate drug delivery system using natural/synthetic polymer may enhance the therapeutic activity of some anti-cancer drug by increasing the host's immune mechanism and antitumor role through improving the body's immune function. It has been observed that despite the technological challenges, nanoparticulate drug delivery system is the most promising drug delivery system in case of anticancer drugs because polymer based nanostructures enhance the bio-adhesiveness and as well as local accumulation of chemotherapeutic agent.