Genomic Insight of Leishmania Parasite: In-Depth Review of Drug Resistance Mechanisms and Genetic Mutations.

Leishmaniasis, which is caused by a parasitic protozoan of the genus Leishmania, is still a major threat to global health, impacting millions of individuals worldwide in endemic areas. Chemotherapy has been the principal method for managing leishmaniasis; nevertheless, the evolution of drug resistance offers a significant obstacle to therapeutic success. Drug-resistant behavior in these parasites is a complex phenomenon including both innate and acquired mechanisms. Resistance is frequently related to changes in drug transportation, drug target alterations, and enhanced efflux of the drug from the pathogen. This review has revealed specific genetic mutations in Leishmania parasites that are associated with resistance to commonly used antileishmanial drugs such as pentavalent antimonials, miltefosine, amphotericin B, and paromomycin, resulting in changes in gene expression along with the functioning of various proteins involved in drug uptake, metabolism, and efflux. Understanding the genetic changes linked to drug resistance in Leishmania parasites is essential for creating approaches for tackling and avoiding the spread of drug-resistant variants. Based on which specific treatments focus on mutations and pathways could potentially improve treatment efficacy and help long-term leishmaniasis control. More study is needed to uncover the complete range of genetic changes generating medication resistance and to develop new therapies based on available information.

14-3-3 proteins-a moonlight protein complex with therapeutic potential in neurological disorder: in-depth review with Alzheimer's disease.

Alzheimer's disease (AD) affects millions of people worldwide and is a gradually worsening neurodegenerative condition. The accumulation of abnormal proteins, such as tau and beta-amyloid, in the brain is a hallmark of AD pathology. 14-3-3 proteins have been implicated in AD pathology in several ways. One proposed mechanism is that 14-3-3 proteins interact with tau protein and modulate its phosphorylation, aggregation, and toxicity. Tau is a protein associated with microtubules, playing a role in maintaining the structural integrity of neuronal cytoskeleton. However, in the context of Alzheimer's disease (AD), an abnormal increase in its phosphorylation occurs. This leads to the aggregation of tau into neurofibrillary tangles, which is a distinctive feature of this condition. Studies have shown that 14-3-3 proteins can bind to phosphorylated tau and regulate its function and stability. In addition, 14-3-3 proteins have been shown to interact with beta-amyloid (Aß), the primary component of amyloid plaques in AD. 14-3-3 proteins can regulate the clearance of Aß through the lysosomal degradation pathway by interacting with the lysosomal membrane protein LAMP2A. Dysfunction of lysosomal degradation pathway is thought to contribute to the accumulation of Aß in the brain and the progression of AD. Furthermore, 14-3-3 proteins have been found to be downregulated in the brains of AD patients, suggesting that their dysregulation may contribute to AD pathology. For example, decreased levels of 14-3-3 proteins in cerebrospinal fluid have been suggested as a biomarker for AD. Overall, these findings suggest that 14-3-3 proteins may play an important role in AD pathology and may represent a potential therapeutic target for the disease. However, further research is needed to fully understand the mechanisms underlying the involvement of 14-3-3 proteins in AD and to explore their potential as a therapeutic target.

A pro-oxidant property of vitamin C to overcome the burden of latent Mycobacterium tuberculosis infection: A cross-talk review with Fenton reaction.

Tuberculosis (TB), caused by the bacillus M. tuberculosis, is one of the deadliest infectious illnesses of our day, along with HIV and malaria.Chemotherapy, the cornerstone of TB control efforts, is jeopardized by the advent of M. tuberculosis strains resistant to many, if not all, of the existing medications.Isoniazid (INH), rifampicin (RIF), pyrazinamide, and ethambutol are used to treat drug-susceptible TB for two months, followed by four months of INH and RIF, but chemotherapy with potentially harmful side effects is sometimes needed to treat multidrug-resistant (MDR) TB for up to two years. Chemotherapy might be greatly shortened by drugs that kill M. tuberculosis more quickly while simultaneously limiting the emergence of drug resistance.Regardless of their intended target, bactericidal medicines commonly kill pathogenic bacteria (gram-negative and gram-positive) by producing hydroxyl radicals via the Fenton reaction.Researchers have concentrated on vitamins with bactericidal properties to address the rising cases globally and have discovered that these vitamins are effective when given along with first-line drugs. The presence of elevated iron content, reactive oxygen species (ROS) generation, and DNA damage all contributed to VC's sterilizing action on M. tb in vitro. Moreover, it has a pleiotropic effect on a variety of biological processes such as detoxification, protein folding - chaperons, cell wall processes, information pathways, regulatory, virulence, metabolism etc.In this review report, the authors extensively discussed the effects of VC on M. tb., such as the generation of free radicals and bactericidal mechanisms with existing treatments, and their further drug development based on ROS production.

Leishmania species: A narrative review on surface proteins with structural aspects involved in host-pathogen interaction.

In tropical and subtropical regions of the world, leishmaniasis is endemic and causes a range of clinical symptoms in people, from severe tegumentary forms (such as cutaneous, mucocutaneous, and diffuse leishmaniasis) to lethal visceral forms. The protozoan parasite of the genus Leishmania causes leishmaniasis, which is still a significant public health issue, according to the World Health Organization 2022. The public's worry about the neglected tropical disease is growing as new foci of the illness arise, which are exacerbated by alterations in behavior, changes in the environment, and an enlarged range of sand fly vectors. Leishmania research has advanced significantly during the past three decades in a few different avenues. Despite several studies on Leishmania, many issues, such as illness control, parasite resistance, parasite clearance, etc., remain unresolved. The key virulence variables that play a role in the pathogenicity-host-pathogen relationship of the parasite are comprehensively discussed in this paper. The important Leishmania virulence factors, such as Kinetoplastid Membrane Protein-11 (KMP-11), Leishmanolysin (GP63), Proteophosphoglycan (PPG), Lipophosphoglycan (LPG), Glycosylinositol Phospholipids (GIPL), and others, have an impact on the pathophysiology of the disease and enable the parasite to spread the infection. Leishmania infection may arise from virulence factors; they are treatable with medications or vaccinations more promptly and might greatly shorten the duration of treatment. Additionally, our research sought to present a modeled structure of a few putative virulence factors that might aid in the development of new chemotherapeutic approaches for the treatment of leishmaniasis. The predicted virulence protein's structure is utilized to design novel drugs, therapeutic targets, and immunizations for considerable advantage from a higher understanding of the host immune response.

Enzymatic Activity and Horizontal Gene Transfer of Heavy Metals and Antibiotic Resistant Proteus vulgaris from Hospital Wastewater: An Insight.

Globally, the issue of microbial resistance to medicines and heavy metals is getting worse. There are few reports or data available for Proteus vulgaris (P. vulgaris), particularly in India. This investigation intends to reveal the bacteria's ability to transmit genes and their level of resistance as well. The wastewater samples were taken from several hospitals in Lucknow City, India, and examined for the presence of Gram-negative bacteria that were resistant to antibiotics and heavy metals. The microbial population count in different hospital wastewaters decreases with increasing concentrations of metal and antibiotics. Among all the examined metals, Ni and Zn had the highest viable counts, whereas Hg, Cd, and Co had the lowest viable counts. Penicillin, ampicillin, and amoxicillin, among the antibiotics, demonstrated higher viable counts, whereas tetracycline and erythromycin exhibited lower viable counts. The MIC values for the P. vulgaris isolates tested ranged from 50 to 16,00 µg/ml for each metal tested. The multiple metal resistance (MMR) index, which ranged from 0.04 to 0.50, showed diverse heavy metal resistance patterns in all P. vulgaris isolates (in the case of 2-7 metals in various combinations). All of the tested isolates had methicillin resistance, whereas the least number of isolates had ofloxacin, gentamycin, or neomycin resistance. The P. vulgaris isolates displayed multidrug resistance patterns (2-12 drugs) in various antibiotic combinations. The MAR indexes were shown to be between (0.02-0.7). From the total isolates, 98%, 84%, and 80% had urease, gelatinase, and amylase activity, whereas 68% and 56% displayed protease and beta-lactamase activity. Plasmids were present in all the selected resistant isolates and varied in size from 42.5 to 57.0 kb and molecular weight from 27.2 to 37.0 MD. The transmission of the antibiotic/metal resistance genes was evaluated between a total of 7 pairs of isolates. A higher transfer frequency (4.4 × 10-1) was observed among antibiotics, although a lower transfer frequency (1.0 × 10-2) was observed against metals in both the media from the entire site tested. According to exponential decay, the population of hospital wastewater declined in the following order across all sites: Site II > Site IV > Site III > Site I for antibiotics and site IV > site II > site I >site III for metal. Different metal and antibiotic concentrations have varying effects on the population. The metal-tolerant P. vulgaris from hospital wastewater was studied in the current study had multiple distinct patterns of antibiotic resistance. It could provide cutting-edge methods for treating infectious diseases, which are essential for managing and assessing the risks associated with hospital wastewater, especially in the case of P. vulgaris.

Role of Natural plant extracts for potential Antileishmanial targets-In-depth review of the molecular mechanism.

A group of protozoan parasites known as Leishmania species can cause a variety of chronic illnesses, ranging from self-healing lesions to fatal outcomes. Drug-resistant pathogens have become common due to the lack of safe and effective medications, which has sparked the development of new therapeutic interventions, particularly plant-based natural extracts. As a way to avoid chemotherapy's side effects, natural herbal remedies have drawn more attention. In addition to having anti-inflammatory, anticancer, and cosmetic properties, the secondary metabolites of plants, such as phenolic compounds, flavonoids, alkaloids, and terpenes, have a number of positive effects on our health. Natural metabolites such as naphthoquinone, alkaloids, benzophenones, etc. that have antileishmanial and antiprotozoal activity have been the subject of extensive research. In this review paper, it can be concluded that these natural extracts can be developed into excellent therapeutic agents against Leishmaniasis.

Heterologous expression, purification and characterization of L-type lectin homologue from Leishmania donovani.

Leishmaniasis, a disease of the developing world affects about 12 million people and has limited therapeutic interventions available. L-type lectins, Endoplasmic Reticulum Golgi Intermediate Compartment/Vesicular Integral Proteins (ERGIC-53/VIP36) are involved in protein sorting in luminal compartments of animal cells and are important for parasite biology. A lectin homologue was identified through a bioinformatics analysis of Leishmania genome and it was found to have N-terminal conserved carbohydrate recognition domain (CRD) and a unique C-terminal region rich in repetitive amino acids and a poly glutamine tract. The N-terminal CRD region was cloned and expressed in Escherichia coli, but gave an insoluble expression which was re-solubilized by on column refolding. The fold integrity was checked through CD, fluorescence and functional assay of hemagglutination activity using rabbit erythrocyte. Bioinformatics analysis identified 15 members from Tritryps (Leishmania spp., Trypanosoma spp.) and they separate out as a distinct clade in the global phylogenetic analysis of all ERGIC-53/VIP36 sequences downloaded from Uniprot. Our analysis shows that the extended C-terminal regions with repeats is unique to Tritryps and this repeat pattern is different in sequences from Leishmania spp. and Trypanosoma spp. and all these features make this protein an interesting candidate for further detailed studies.