Genetic and Epigenetic Basis of Drug-Induced Liver Injury.

Drug-induced liver injury (DILI) is a rare but severe adverse drug reaction seen in pharmacotherapy and a major cause of postmarketing drug withdrawals. Advances in genome-wide studies indicate that genetic and epigenetic diversity can lead to inter-individual differences in drug response and toxicity. It is necessary to identify how the genetic variations, in the presence of environmental factors, can contribute to development and progression of DILI. Studies on microRNA, histone modification, DNA methylation, and single nucleotide polymorphisms related to DILI were retrieved from databases and were analyzed for the current research and updated to develop this narrative review. We have compiled some of the major genetic, epigenetic, and pharmacogenetic factors leading to DILI. Many validated genetic risk factors of DILI, such as variants of drug-metabolizing enzymes, HLA alleles, and some transporters were identified. In conclusion, these studies provide useful information in risk alleles identification and on implementation of personalized medicine.

An inclusive outlook on the fate and persistence of pesticides in the environment and integrated eco-technologies for their degradation.

Intensive and inefficient exploitation of pesticides through modernized agricultural practices has caused severe pesticide contamination problems to the environment and become a crucial problem over a few decades. Due to their highly toxic and persistent properties, they affect and get accumulated in non-target organisms, including microbes, algae, invertebrates, plants as well as humans, and cause severe issues. Considering pesticide problems as a significant issue, researchers have investigated several approaches to rectify the pesticide contamination problems. Several analyses have provided an extensive discussion on pesticide degradation but using specific technology for specific pesticides. However, in the middle of this time, cleaner techniques are essential for reducing pesticide contamination problems safely and environmentally friendly. As per the research findings, no single research finding provides concrete discussion on cleaner tactics for the remediation of contaminated sites. Therefore, in this review paper, we have critically discussed cleaner options for dealing with pesticide contamination problems as well as their advantages and disadvantages have also been reviewed. As evident from the literature, microbial remediation, phytoremediation, composting, and photocatalytic degradation methods are efficient and sustainable and can be used for treatment at a large scale in engineered systems and in situ. However, more study on the bio-integrated system is required which may be more effective than existing technologies.

Visible Light-Prompted Regioselective Synthesis of Novel 5-Aroyl/hetaroyl-2',4-dimethyl-2,4'-bithiazoles as DNA- and BSA-Targeting Agents.

Organic transformations mediated by visible light have gained popularity in recent years as they are green, renewable, inexpensive, and clean and yield excellent products. The present study describes cyclo-condensation of 2-methylthiazole-4-carbothioamide with differently substituted α-bromo-1,3-diketones achieved by utilizing a white light-emitting diode (LED) (9W) to accomplish the regioselective synthesis of novel 5-aroyl/hetaroyl-2',4-dimethyl-2,4'-bithiazole derivatives as DNA/bovine serum albumin (BSA)-targeting agents. The structure characterization of the exact regioisomer was achieved unequivocally by heteronuclear two-dimensional nuclear magnetic resonance (2D-NMR) spectroscopy [1H-13C] HMBC; [1H-13C] HMQC; and [1H-15N] HMBC. In silico toxicity studies indicated that the synthesized compounds exhibit low toxicity risks and adhere to the rules of oral bioavailability without any exception. Computational molecular modeling of the bithiazole derivatives with the dodecamer sequence of the DNA duplex and BSA identified 5-(4-chlorobenzoyl)-2',4-dimethyl-2,4'-bithiazole 7g as the most suitable derivative that can interact effectively with these biomolecules. Furthermore, theoretical results concurred with the ex vivo binding mode of the 7g with calf thymus DNA (ct-DNA) and BSA through a variety of spectroscopic techniques, viz., ultraviolet-visible (UV-visible), circular dichroism (CD), steady-state fluorescence, and competitive displacement assay, along with viscosity measurements.

An expeditious on-water regioselective synthesis of novel arylidene-hydrazinyl-thiazoles as DNA targeting agents.

A series of twenty novel (E)-arylidene-hydrazinyl-thiazole derivatives has been synthesized employing α-bromo-ß-diketones, thiosemicarbazide, and aromatic/heteroaromatic aldehydes with a simple and facile one-pot multicomponent reaction passageway. This organic transformation proceeds efficiently in aqueous media and demonstrated a large functional group tolerance. The structures and stereochemistry of the regioisomeric product were rigorously characterized using heteronuclear 2D NMR experiments. The binding potential of the synthesized analogs with B-DNA dodecamer d(CGCGAATTCGCG)2 was primarily screened using molecular modeling tools and further, mechanistic investigations (either groove or intercalation) were performed using various spectroscopic techniques such as UV-Visible, Fluorescence, and Circular dichroism. The absorption spectra showed a hyperchromic shift in the absorption maxima of ctDNA with successive addition of thiazole derivatives, implying groove binding mode of interactions, further supported by displacement assay and circular dichroism analysis. Furthermore, steady-state fluorescence analysis revealed the static mode of quenching and moderate bindings between the ligand and DNA biomolecule. The competitive studies showed that the derivatives having a pyridinyl (heteroaromatic) group in their structure, bind with the nucleic acid of calf-thymus (ctDNA) more effectively in the minor groove region as compared with the aromatic substitutions.

Quality of Life Assessment in Diabetic Patients Using a Validated Tool in a Patient Population Visiting a Tertiary Care Center in Bhubaneswar, Odisha, India.

Odisha has 4.2 million diabetic patients against the country's 70 million with an urban prevalence of nearly 15.4%. Diabetes is affecting younger age groups, thus having a crucial impact on quality of life of the affected. A qualitative endeavour was attempted at the diabetic clinic of a tertiary care set up in the capital city of Bhubaneswar to create a diabetic surveillance data assembly, wherein subjects above 18 years of age and newly diagnosed or on follow-up, after obtaining informed consent, were made to respond to a quality of life (QOLID) validated tool. The pretested tool has 8-domain role limitation due to physical health, physical endurance, general health, treatment satisfaction, symptom botherness, financial worries, emotional/mental health, and diet advice tolerance. The validated tool had 34 items (questions) that were selected to represent these domains on the basis of extraction communality, factor loading, and interitem and item-total correlations. The final questionnaire had an overall Cronbach's alpha value of 0.894 (subscale: 0.55 to 0.85), showing high internal consistency in the current study population. A score for each domain was calculated by simple addition of items scores. Each individual domain score was then standardized by dividing by maximum possible domain score and multiplying by 100. All individual standardized domain scores were then added and divided by 8 (number of domain) to obtain an overall score. The data collection was done for 400 patients as an interim analysis. Univariate and subsequently multivariate analysis was performed to decide the predictors that affected quality of life. Age over 50 years (OR = 1.81, CI 1.12-2.93; p=0.014), female gender (OR = 2.05, CI 1.26-3.35; p=0.004), having foot complications (OR = 2.81, CI 1.73-4.55; p < 0.001), and having depression (OR = 1.88, CI 1.15-3.06, p=0.011) emerged as predictors of poor QOLID scores. The tool can be made a subtle part of chronic case management of diabetes to ensure patient's participation in the treatment of the disease and to create a database that can redefine diabetic care in India to suit the diverse regional settings in the country.

Multistage inhibitors of the malaria parasite: Emerging hope for chemoprotection and malaria eradication.

Over time, several exciting advances have been made in the treatment and prevention of malaria; however, this devastating disease continues to be a major global health problem and affects millions of people every year. Notably, the paucity of new efficient drug molecules and the inevitable drug resistance of the malaria parasite, Plasmodium falciparum, against frontline therapeutics are the foremost struggles facing malaria eradication initiatives. According to the malaria eradication agenda, the discovery of new chemical entities that can destroy the parasite at the liver stage, the asexual blood stage, the gametocyte stage, and the insect ookinete stage of the parasite life cycle (i.e., compounds exhibiting multistage activity) are in high demand, preferably with novel and multiple modes of action. Phenotypic screening of chemical libraries against the malaria parasite is certainly a crucial step toward overcoming these crises. In the last few years, various research groups, including industrial research laboratories, have performed large-scale phenotypic screenings that have identified a wealth of chemical entities active against multiple life stages of the malaria parasite. Vital scientific and technological developments have led to the discovery of multistage inhibitors of the malaria parasite; these compounds, considered highly valuable starting points for subsequent drug discovery and eradication of malaria, are reviewed.

Antiplasmodial activity of hydroxyethylamine analogs: Synthesis, biological activity and structure activity relationship of plasmepsin inhibitors.

Malaria, particularly in endemic countries remains a threat to the human health and is the leading the cause of mortality in the tropical and sub-tropical areas. Herein, we explored new C2 symmetric hydroxyethylamine analogs as the potential inhibitors of Plasmodium falciparum (P. falciparum; 3D7) in in-vitro cultures. All the listed compounds were also evaluated against crucial drug targets, plasmepsin II (Plm II) and IV (Plm IV), enzymes found in the digestive vacuole of the P. falciparum. Analog 10f showed inhibitory activities against both the enzymes Plm II and Plm IV (Ki, 1.93 ±â€¯0.29 µM for Plm II; Ki, 1.99 ±â€¯0.05 µM for Plm IV). Among all these analogs, compounds 10g selectively inhibited the activity of Plm IV (Ki, 0.84 ±â€¯0.08 µM). In the in vitro screening assay, the growth inhibition of P. falciparum by both the analogs (IC50, 2.27 ±â€¯0.95 µM for 10f; IC50, 3.11 ±â€¯0.65 µM for 10g) displayed marked killing effect. A significant growth inhibition of the P. falciparum was displayed by analog 12c with IC50 value of 1.35 ±â€¯0.85 µM, however, it did not show inhibitory activity against either Plms. The hemolytic assay suggested that the active compounds selectively inhibit the growth of the parasite. Further, potent analogs (10f and 12c) were evaluated for their cytotoxicity towards mammalian HepG2 and vero cells. The selectivity index (SI) values were noticed greater than 10 for both the analogs that suggested their poor toxicity. The present study indicates these analogs as putative lead structures and could serve as crucial for the development of new drug molecules.

Hypothesizing the Oleic Acid-Mediated Enhanced and Sustained Transdermal Codelivery of Pregabalin and Diclofenac Adhesive Nanogel: A Proof of Concept.

Pregabalin and diclofenac diethylamine are anti-inflammatory molecules that are effective in relieving inflammation and pain associated with musculoskeletal disorders, arthritis, and post-traumatic pain, among others. Intravenous and oral delivery of these two molecules has their limitations. However, the transdermal route is believed to be an alternate viable option for the delivery of therapeutic molecules with desired physicochemical properties. To this end, it is vital to understand the physicochemical properties of these drugs, dosage, and strategies to enhance permeation, thereby surmounting the associated constraints and concurrently attaining a sustained release of these therapeutic molecules when administered in combination. The present work hypothesizes the enhanced permeation and sustained release of Pregabalin and diclofenac diethylamine across the skin, entrapped in the adhesive nano-organogel formulation, including permeation enhancers. The solubility studies of Pregabalin and diclofenac diethylamine in combination were performed in different permeation enhancers. Oleic acid was optimized as the best permeation enhancer based on in vitro studies. Pluronic organogel containing Pregabalin and diclofenac diethylamine with oleic acid was fabricated. Duro-Tak® (87-2196) was added to the organogel formulation as a pressure-sensitive adhesive to sustain the release profile of these two therapeutic molecules. The adhesive organogel was characterized for particle size, scanning electron microscopy, and contact angle measurement. The HPLC method developed for the quantification of the dual drug showed a retention time of 3.84 minutes and 9.69 minutes for pregabalin and diclofenac, respectively. The fabricated nanogel adhesive formulation showed the desired results with particle size and contact angle of 282 ± 57 nm and ≥120°, respectively. In vitro studies showed the percentage cumulative release of 24.90 ± 4.65% and 33.29 ± 4.81% for pregabalin and diclofenac, respectively. In order to accomplish transdermal permeation, the suggested hypothesis of fabricating PG and DEE nano-organogel in combination with permeation enhancers will be a viable drug delivery method. In comparison to a traditional gel formulation, oleic acid as a permeation enhancer increased the penetration of both PG and DEE from the organogel formulation. Notably, the studies showed that the use of pressure-sensitive adhesives enabled the sustained release of both PG and DEE.Therefore, the results anticipated the hypothesis that the transdermal delivery of adhesive PG and DEE-based nanogel across the human skin can be achieved to inhibit inflammation and pain.

Prognostic significance of circulating microparticles in IgA nephropathy.

PURPOSE: Endothelial injury, involved in the pathogenesis of renal fibrosis, can generate microparticles (MPs). These are 0.1-1 µm membrane-bound vesicles shed from the damaged or activated cell surfaces. We analyzed the presence of circulating MPs and EnMPs in IgAN and correlated with markers of endothelial injury and disease activity. METHODS: The study included 30 IgAN (mean age 31.5 ± 9 years), 25 healthy controls and Lupus nephritis (n = 10) as disease controls. Circulating MPs were quantitated by Flow cytometry and EnMPs were analyzed using anti-CD31-FITC and anti-CD146-PE antibodies. Their levels were correlated with serum von Willebrand Factor, histological Oxford MEST-C score and renal outcome. A prospective validation group of 20 patients of biopsy-proven IgA nephropathy was also included. RESULTS: IgAN had significantly higher levels of MPs, EnMPs and vWF compared to controls. On multivariate analysis, plasma levels of total MPs, EnMPs and serum vWF correlated significantly with the presence of hypertension and E1 on histology. E1 and high MPs (> 130 counts/µl) were associated with shorter time to doubling of serum creatinine. MPs cutoff level of 130 counts/µl had a sensitivity of 75%, specificity of 93.3% and diagnostic accuracy of 89.5% for E1 in the validation cohort. CONCLUSION: Circulating MPs and EnMPs in IgAN correlate with E1 on histology and have a potential as non-invasive biomarkers to predict disease activity and renal outcome.

Synthesis and characterization of Fe3O4@SiO2@PDA@Ag core-shell nanoparticles and biological application on human lung cancer cell line and antibacterial strains.

Novel magnetic and metallic nanoparticles garner much attention of researchers due to their biological, chemical and catalytic properties in many chemical reactions. In this study, we have successfully prepared a core-shell Fe3O4@SiO2@PDA nanocomposite wrapped with Ag using a simple synthesis method, characterised and tested on small cell lung cancer and antibacterial strains. Incorporating Ag in Fe3O4@SiO2@PDA provides promising advantages in biomedical applications. The magnetic Fe3O4 nanoparticles were coated with SiO2 to obtain negatively charged surface which is then coated with polydopamine (PDA). Then silver nanoparticles were assembled on Fe3O4@SiO2@PDA surface, which results in the formation core-shell nanocomposite. The synthesised nanocomposite were characterized using SEM-EDAX, dynamic light scattering, XRD, FT-IR and TEM. In this work, we report the anticancer activity of silver nanoparticles against H1299 lung cancer cell line using MTT assay. The cytotoxicity data revealed that the IC50 of Fe3O4@SiO2@PDA@Ag against H1299 lung cancer nanocomposites cells was 21.52 µg/mL. Furthermore, the biological data of nanocomposites against Gram-negative 'Pseudomonas aeruginosa' and Gram-positive 'Staphylococcus aureus' were carried out. The range of minimum inhibitory concentration was found to be 115 µg/mL where gentamicin was used as a standard drug. The synthesized AgNPs proves its supremacy as an efficient biomedical agent and AgNPs may act as potential beneficial molecule in lung cancer chemoprevention and antibacterial strains.

In the present study, we have successfully prepared a core-shell Fe₃O₄@SiO₂@PDA@Ag nanocomposite.We have investigated the dose-dependent cellular toxicity of silver nanocomposite in the nonsmall cell lung cancer cell line H1299 using MTT assay.Also, we have evaluated the mode of cell death using apoptosis.We have also evaluated the bioactivity of AgNPs on both Gram-positive and Gram-negative bacterial cells with highly efficient antibacterial potency.

Mango Leaves (Mangifera indica)-Derived Highly Florescent Green Graphene Quantum Dot Nanoprobes for Enhanced On-Off Dual Detection of Cholesterol and Fe2+ Ions Based on Molecular Logic Operation.

In the present study, we have engineered a molecular logic gate system employing both Fe2+ ions and cholesterol as bioanalytes for innovative detection strategies. We utilized a green-synthesis method employing the mango leaves extract to create fluorescent graphene quantum dots termed "mGQDs". Through techniques like HR-TEM, i.e., high-resolution transmission electron microscopy, Raman spectroscopy, and XPS, i.e., X-ray photoelectron spectroscopy, the successful formation of mGQDs was confirmed. The photoluminescence (PL) characteristics of mGQDs were investigated for potential applications in metal ion detection, specifically Fe2+ traces in water, by using fluorescence techniques. Under 425 nm excitation, mGQDs exhibited emission bands at 495 and 677 nm in their PL spectrum. Fe2+-induced notable quenching of mGQDs' PL intensity decreased by 97% with 2.5 µM Fe2+ ions; however, adding 20 mM cholesterol resulted in a 92% recovery. Detection limits were established through a linear Stern-Volmer (S-V) plot at room temperature, yielding values of 4.07 µM for Fe2+ ions and 1.8 mM for cholesterol. Moreover, mGQDs demonstrated biocompatibility, aqueous solubility, and nontoxicity, facilitating the creation of a rapid nonenzymatic cholesterol detection method. Selectivity and detection studies underscored mGQDs' reliability in cholesterol level monitoring. Additionally, a molecular logic gate system employing Fe2+ metal ions and cholesterol as a bioanalyte was established for detection purposes. Overall, this research introduces an ecofriendly approach to craft mGQDs and highlights their effectiveness in detecting metal ions and cholesterol, suggesting their potential as versatile nanomaterials for diverse analytical and biomedical applications.

Design and development of efficient and compact 20 kW 325 MHz solid-state amplifier for superconducting accelerator applications.

An efficient and compact, 20 kW solid-state power amplifier (SSA) at 325 MHz has been designed and developed in-house, using single stage combining. It comprises of 24 nos. of 1 kW power amplifier (PA) modules, a 24-way Wilkinson power combiner and divider, and other peripheral systems. The typical gain and conversion efficiency of the PA modules at 1.0 kW output is 21.7 dB and 66.6%, respectively. It is demonstrated that overall power gain and AC to RF efficiency of this SSA at 20 kW is 88.5 dB and 54.8%, respectively, which matches closely with the design estimates. The harmonic content in the RF output is < -40 dBc for all the harmonics. The results of the Monte Carlo simulation are also presented, showing lower bound on combining efficiency with a degree of confidence if magnitude and phase data for 24 inputs are randomly chosen from a normal distribution's pre-defined interval. The salient features of this SSA include power density of 12.7 kW/m3, AC to RF efficiency of 54.8% at 20 kW, and guaranteed output of 20 kW with one failed PA module and 18.1 kW under two failed PA modules condition.

In vitro profiling and molecular dynamics simulation studies of berberine loaded MCM-41 mesoporous silica nanoparticles to prevent neuronal apoptosis.

Neuronal loss in Alzheimer's disease has been reported to display features of apoptosis, pyroptosis (programmed necrosis), or necroptosis. This study thoroughly examines the production and characterization of MCM-41 based berberine (BBR)-loaded porous silica nanoparticles (MSNs) by a modified Stöber method, focusing on their possible role in inhibiting the apoptotic process. Particle size, polydispersity index, morphology, drug loading, zeta potential, entrapment efficiency, and drug release were examined. The formulation was analyzed using various spectroscopic techniques. The surface area was computed by the Brunauer-Emmett-Teller plot. Computational models were developed for molecular dynamics simulation studies. A small PDI value indicated an even distribution of particles at nanoscale sizes (80-100 nm). Results from XRD and SEAD experiments confirmed the amorphous nature of BBR in nanoparticles. Nanoparticles had high entrapment (75.21 ± 1.55%) and drug loading (28.16 ± 2.5%) efficiencies. A negative zeta potential value (-36.861.1 mV) indicates the presence of silanol groups on the surface of silica. AFM findings reveal bumps due to the surface drug that contributed to the improved roughness of the MSNs-BBR surface. Thermal gravimetric analysis confirmed the presence of BBR in MSNs. Drug release was controlled by simple diffusion or quasi-diffusion. Molecular dynamics simulations confirmed the existence of diffused drug molecules. Cellular studies using SH-SY-5Y cells revealed dose-dependent growth inhibition. Fragmented cell nuclei and nuclear apoptotic bodies in DAPI-stained cells exposed to nanoparticles showed an increase in apoptotic cells. Flow cytometry analysis demonstrated a lower red-to-green ratio in SH-SY-5Y cells treated with nanoparticles. This suggests improved mitochondrial health, cellular viability restoration, and prevention of the apoptotic process. This study provides essential data on the synthesis and potential of MSNs loaded with BBR, which may serve as a viable therapeutic intervention for conditions associated with apoptosis.

A review on fluoride contamination in groundwater and human health implications and its remediation: A sustainable approaches.

Contamination of drinking water due to fluoride (F-) is a major concern worldwide. Although fluoride is an essential trace element required for humans, it has severe human health implications if levels exceed 1.5 mg. L-1 in groundwater. Several treatment technologies have been adopted to remove fluoride and reduce the exposure risk. The present article highlights the source, geochemistry, spatial distribution, and health implications of high fluoride in groundwater. Also, it discusses the underlying mechanisms and controlling factors of fluoride contamination. The problem of fluoride-contaminated water is more severe in India's arid and semiarid regions than in other Asian countries. Treatment technologies like adsorption, ion exchange, precipitation, electrolysis, electrocoagulation, nanofiltration, coagulation-precipitation, and bioremediation have been summarized along with case studies to look for suitable technology for fluoride exposure reduction. Although present technologies are efficient enough to remove fluoride, they have specific limitations regarding cost, labour intensity, and regeneration requirements.

Primary Laryngeal Aspergillosis - Case Series, Reported in a Tertiary Care Hospital, Bhubaneswar, Odisha, India.

We report 2 vocal fold aspergillosis cases from Otolaryngology department of a tertiary hospital, Bhubaneswar. A 26 years old female visited the OPD with chief complaint of progressive hoarseness and pain while talking since 6 months. While another 29 years old female complained of having progressive hoarseness since 4 months preceded by an episode of sore throat. Both cases had microlaryngeal surgery/ endo laryngeal surgery followed by excisional biopsy.

Osteonecrosis of the Jaws: An Update and Review of Literature.

Aim: To provide a concise review on risk factors, stages, pathophysiology, prevention and possible treatment options for both MRONJ and ORN individually. Methods: The review was conducted according to the 'Preferred Reporting Items for Systematic Reviews and Meta-Analyses' (PRISMA) guidelines. A comprehensive search of the PUBMED, Ebsco, SCOPUS, WEB OF SCIENCE and NDH for articles published up until 2021 was performed. After screening and full text analyses, 44 studies were included in this review. Definition, risk factors, etiology, symptoms, stages, pathophysiology, prevention and possible management options were explored and highlighted in this article. Results: Three studies described osteonecrosis of jaw (ONJ) in general, 15 studies described ONJ associated with radiotherapy and 26 studies described ONJ associated with medications. Both the two conditions (ORN) and (MRONJ) have relatively similar clinical presentations clearing the fact that a resemblance in clinical presentations does not necessarily denote a similar pathophysiology. Conclusion: However, various advancements have been made in the control and management of ONJ, but until and unless need for high tumoricidal doses exists, ONJ will certainly continue to remain as a clinical challenge demanding satisfactory treatment to improve the quality of life of the patient.

Recent advancements on in vitro blood-brain barrier model: A reliable and efficient screening approach for preclinical and clinical investigation.

INTRODUCTION: The efficiency of brain therapeutics is greatly hindered by the blood-brain barrier (BBB). BBB's protective function, selective permeability, and dynamic functionality maintain the harmony between the brain and peripheral region. Thus, the design of any novel drug carrier system requires the complete study and investigation of BBB permeability, efflux transport, and the effect of associated cellular and non-vascular unit trafficking on BBB penetrability. The in vitro BBB models offer a most promising, and reliable mode of initial investigation of BBB permeability and associated factors as strong evidence for further preclinical and clinical investigation. AREA COVERED: This review work covers the structure and functions of BBB components and different types of in vitro BBB models along with factors affecting BBB model development and model selection criteria. EXPERT OPINION: In vivo models assume to reciprocate the physiological environment to the maximum extent. However, the interspecies variability, NVUs trafficking, dynamic behavior of BBB, etc., lead to non-reproducible results. The in vitro models are comparatively less complex, and flexible, as per the study design, could generate substantial evidence and help identify suitable in vivo animal model selection.

Biological activity and structure-activity relationship of dehydrodieugenol B analogues against visceral leishmaniasis.

Visceral leishmaniasis is a neglected protozoan disease with high mortality. Existing treatments exhibit a number of limitations, resulting in a significant challenge for public health, especially in developing countries in which the disease is endemic. With a limited pipeline of potential drugs in clinical trials, natural products could offer an attractive source of new pharmaceutical prototypes, not least due to their high chemodiversity. In the present work, a study of anti-L. (L.) infantum potential was carried out for a series of 39 synthetic compounds based on the core scaffold of the neolignan dehydrodieugenol B. Of these, 14 compounds exhibited activity against intracellular amastigotes, with 50% inhibitory concentration (IC50) values between 3.0 and 32.7 µM. A structure-activity relationship (SAR) analysis demonstrated a requirement for polar functionalities to improve activity. Lacking mammalian cytotoxicity and presenting the highest potency against the clinically relevant form of the parasite, compound 24 emerged as the most promising, fulfilling the hit criteria for visceral leishmaniasis defined by the Drugs for Neglected Diseases initiative (DNDi). This study emphasizes the potential of dehydrodieugenol B analogues as new candidates for the treatment of visceral leishmaniasis and suggests 24 to be a suitable compound for future optimization, including mechanism of action and pharmacokinetic studies.

Insight into the environmental fate, hazard, detection, and sustainable degradation technologies of chlorpyrifos-an organophosphorus pesticide.

Pesticides play a critical role in terms of agricultural output nowadays. On top of that, pesticides provide economic support to our farmers. However, the usage of pesticides has created a public health issue and environmental hazard. Chlorpyrifos (CPY), an organophosphate pesticide, is extensively applied as an insecticide, acaricide, and termiticide against pests in various applications. Environmental pollution has occurred because of the widespread usage of CPY, harming several ecosystems, including soil, sediment, water, air, and biogeochemical cycles. While residual levels in soil, water, vegetables, foodstuffs, and human fluids have been discovered, CPY has also been found in the sediment, soil, and water. The irrefutable pieces of evidence indicate that CPY exposure inhibits the choline esterase enzyme, which impairs the ability of the body to use choline. As a result, neurological, immunological, and psychological consequences are seen in people and the natural environment. Several research studies have been conducted worldwide to identify and develop CPY remediation approaches and its derivatives from the environment. Currently, many detoxification methods are available for pesticides, such as CPY. However, recent research has shown that the breakdown of CPY using bacteria is the most proficient, cost-effective, and sustainable. This current article aims to outline relevant research events, summarize the possible breakdown of CPY into various compounds, and discuss analytical summaries of current research findings on bacterial degradation of CPY and the potential degradation mechanism.

Blood-based biomarkers for diagnosis, prognosis, and severity prediction of COVID-19: Opportunities and challenges.

The reasons for high morbidity and mortality with Corona virus disease (COVID-19) disease remain unanswered with extremes of manifestation and uncertainty of modes of transmission for which biomarkers are urgently needed for early prediction of severity and prompt treatment. We have reviewed publications from PubMed (years 2019-2021) analysing the biochemical, immune-inflammatory, nucleic acid, and cellular biomarkers that predict infection, disease progression in COVID-19 with emphasis on organ-specific damage. Our analysis of 65 biomarkers assessing the impact of SCoV-2 infection on five organs (lung, liver, cardiac, kidney, and neural) reported that increased levels of CRP, TNF-α, ferritin, IL-6, D-dimer, Procalcitonin, Fibrinogen to Albumin Ratio (FAR), and decrease platelet count (PC), lymphocyte count, leukocyte count, and CD4+/CD8 + ratio shows promising association in the early diagnosis, prediction of prognosis and severity disease and also correlates with cytokine storm a cardinal feature of COVID-19 progression. In the above scenario, this review has put forth the most promising biomarkers for COVID diagnosis and prognosis based on the reported literature. In recent year's chemically synthesized antibody-like biomolecules, aptamers were also used in the diagnosis of COVID-19 which could be preferably used for diagnosis over antibodies. Biomarkers including increase in free DNA and Fibrinogen-to-Albumin Ratio, CRP, PCT, and Ferritin along with a consequential decrease of CD3+ T, CD4+ T, CD8+ T, NK cells with corresponding increase in CD4+/CD8+ ratio following SARS CoV-2 infection has been consistently correlated with disease severity. Despite the two waves of COVID-19 pandemic, currently there is no standard clinical practice guideline for evaluating the severity of the devastating pandemic of COVID-19, hence these biomarkers will have immense relevance for the third and subsequent wave of COVID-19 and related pandemic.