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The human microbiota represents the community and diverse population of microbes within the human body, which comprises approximately 100 trillion micro-organisms. They exist in the human gastrointestinal tract and various other organs and are now considered virtual body organs. It is mainly represented by bacteria but also includes viruses, fungi, and protozoa. Although there is a heritable component to the gut microbiota, environmental factors related to diet, drugs, and anthropometry determine the composition of the microbiota. Besides the gastrointestinal tract, the human body also harbours microbial communities in the skin, oral and nasal cavities, and reproductive tract. The current review demonstrates the role of gut microbiota and its involvement in processing food, drugs, and immune responses. The discussion focuses on the implications of human microbiota in developing several diseases, such as gastrointestinal infections, metabolic disorders, malignancies, etc., through symbiotic relationships. The microbial population may vary depending on the pathophysiological condition of an individual and thus may be exploited as a therapeutic and clinical player. Further, we need a more thorough investigation to establish the correlation between microbes and pathophysiology in humans and propose them as potential therapeutic targets.

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SARS-CoV-2 is one of the deadly outbreaks in the present era and still showing its presence around the globe. Researchers have produced various vaccines that offer protection against infection, but we have not yet found a cure for COVID-19. Currently, efforts are focused on identifying effective therapeutic approaches to treat this infectious disease. In the present work, we investigated the main protease (Mpro) protein, a crucial component in SARS-CoV-2 viral particle formation, as a drug target and proposed phytocompounds with therapeutic potential against SARS-CoV-2. Initially, several plant-based resources were exploited to screen around one thousand phytocompounds and further their physiochemical characterization and assessment of drug likeliness were performed using SwissADME. Eventually, we screened 95 compounds based on docking analysis using AutoDock Vina. Five compounds were selected having the highest affinity for Mpro for the analysis of ligand-receptor interaction using molecular dynamic (MD) simulation. Docking and MD simulation studies elucidated the promising stable interaction of selected 5 ligands with Mpro. During MD simulation of 100 ns, Abacopterin F showed the lowest binding energy (-37.13 kcal/mol) with the highest affinity towards Mpro and this compound may be proposed as a lead molecule for further investigation. This interaction may result in modulation of the Mpro activity, consequently leading to hindrance in viral particle formation. However, in-vitro and in-vivo experimental validation would be needed to process the selected phytomolecules as a therapeutic lead against SARS-CoV-2.

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Infectious disorders known as Neglected Tropical Diseases (NTDs) initially affect the world's underprivileged citizens. They have been disregarded for many years, first as a result of a general indifference to such a developing world and, more recently, as an outcome of the intense attention on AIDS, TB, and malaria. Tropical diseases mostly affect the region where health and hygiene are sacrificed, and most of the population lacks access to sufficient food and living resources. WHO has drafted and released the directions for regulation, pre-vention, and successful eradication of NTDs as per the revised roadmap of 2021-2030. This shifts from vertical disease programs to integrated cross-cutting methods. In the current work, we have provided comprehensive information on various aspects of neglected tropical dis-eases, including the clinical management of NTDs. This encompasses the causative agent of the diseases, their symptoms, pathogenesis, diagnosis, treatment, prognosis, and epidemio-logical perspective of major NTDs. This review will shed light on several perspectives of NTDs having influential roles in proposing strategies to control and treat them around the world.

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Mosquitoes are important vectors for the transmission of several infectious diseases that lead to huge morbidity and mortality. The exhaustive use of synthetic insecticides has led to widespread resistance and environmental pollution. Using essential oils and nano-emulsions as novel insecticides is a promising alternative approach for controlling vector borne diseases. In the current study, Lantana camara EO and NE were evaluated for their larvicidal and pupicidal activities against Anopheles culicifacies. The inhibitory effect of EO and NE on AChE, NSE (α/ß), and GST was also evaluated and compared. GC-MS analysis of oil displayed 61 major peaks. The stable nano-emulsion with an observed hydrodynamic diameter of 147.62 nm was formed using the o/w method. The nano-emulsion exhibited good larvicidal (LC50 50.35 ppm and LC90 222.84 ppm) and pupicidal (LC50 54.82 ppm and LC90 174.58 ppm) activities. Biochemical evaluations revealed that LCEO and LCNE inhibited AChE, NSE (α/ß), and GST, displaying LCNE to be a potent binder to AChE and NSE enzyme, whereas LCEO showed higher binding potency towards GST. The nano-emulsion provides us with novel opportunities to target different mosquito enzymes with improved insecticidal efficacy. Due to its natural origin, it can be further developed as a safer and more potent larvicide/insecticide capable of combating emerging insecticide resistance.

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The appropriate growth of the neurons, accurate organization of their synapses, and successful neurotransmission are indispensable for sensorimotor activities. These processes are highly dynamic and tightly regulated. Extensive genetic, molecular, physiological, and behavioral studies have identified many molecular candidates and investigated their roles in various neuromuscular processes. In this article, we show that Beadex (Bx), the Drosophila LIM only (LMO) protein, is required for motor activities and neuromuscular growth of Drosophila. The larvae bearing Bx7, a null allele of Bx, and the RNAi-mediated neuronal-specific knockdown of Bx show drastically reduced crawling behavior, a diminished synaptic span of the neuromuscular junctions (NMJs) and an increased spontaneous neuronal firing with altered motor patterns in the central pattern generators (CPGs). Microarray studies identified multiple targets of Beadex that are involved in different cellular and molecular pathways, including those associated with the cytoskeleton and mitochondria that could be responsible for the observed neuromuscular defects. With genetic interaction studies, we further show that Highwire (Hiw), a negative regulator of synaptic growth at the NMJs, negatively regulates Bx, as the latter's deficiency was able to rescue the phenotype of the Hiw null mutant, HiwDN. Thus, our data indicate that Beadex functions downstream of Hiw to regulate the larval synaptic growth and physiology.NEW & NOTEWORTHY A novel role for Beadex (Bx) regulates the larval neuromuscular junction (NMJ) structure and function in a tissue-specific manner. Bx is expressed in a subset of Toll-6-expressing neurons and is involved in regulating synaptic span and physiology, possibly through its negative interaction with Highwire (Hiw). The findings of this study provide insights into the molecular mechanisms underlying NMJ development and function and warrant further investigation to understand the role of Bx in these processes fully.

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Acinetobacter baumannii is observed as a common species of Gram-negative bacteria that exist in soil and water. Despite being accepted as a typical component of human skin flora, it has become an important opportunistic pathogen, especially in healthcare settings. The pathogenicity of A. baumannii is attributed to its virulence factors, which include adhesins, pili, lipopolysaccharides, outer membrane proteins, iron uptake systems, autotransporter, secretion systems, phospholipases etc. These elements provide the bacterium the ability to cling to and penetrate host cells, get past the host immune system, and destroy tissue. Its infection is a major contributor to human pathophysiological conditions including pneumonia, bloodstream infections, urinary tract infections, and surgical site infections. It is challenging to treat infections brought on by this pathogen since this bacterium has evolved to withstand numerous drugs and further emergence of drug-resistant A. baumannii results in higher rates of morbidity and mortality. The long-term survival of this bacterium on surfaces of medical supplies and hospital furniture facilitates its frequent spread in humans from one habitat to another. There is a need for urgent investigations to find effective drug targets for A. baumannii as well as designing novel drugs to reduce the survival and spread of infection. In the current review, we represent the specific features, pathogenesis, and molecular intricacies of crucial drug targets of A. baumannii. This would also assist in proposing strategies and alternative therapies for the prevention and treatment of A. baumannii infections and their spread.

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OBJECTIVE: DNA repair genes and their variants have been found to alter the risk of oral cancer. METHOD: The level of expression of XRCC3, NBS1, and OGG1 genes among 20 cases of oral cancer, 6 pre-oral cancer, and 50 healthy control subjects was measured with RT-PCR. All the subjects were also genotyped for XRCC3 rs861539 C>T, NBS1 rs1805794 C>G, and OGG1 rs1052133 C>G polymorphisms by the PCR-RFLP method; their genotypes were correlated with their level of expression. Further, a localized fold structure analysis of the mRNA sequence surrounding the studied SNPs was performed with RNAfold. RESULTS: Results showed increased expression of XRCC3, NBS1, and OGG1 transcripts among oral cancer (4.49 fold, 3.45 fold, and 3.27 fold) as well as pre-oral cancer (3.04 fold, 5.32 fold, and 1.74 fold) as compared to control subjects. The transcript level of OGG1 was found to be significantly increased (6.68 fold, p-value 0.009) with the GG genotype compared to the CC genotype. The C>T polymorphism of XRCC3 and the C>G polymorphism of OGG1 result in an apparent change in its mRNA secondary structure. Folding energy with the C allele for XRCC3 C>T polymorphism was lower than that of the T allele (MFE C vs T: -50.20 kcal/mol vs -48.70 kcal/mol). In the case of OGG1 C>G polymorphism MFE for the C allele was higher (-23.30 kcal/mole) than with the G allele (-24.80 kcal/mol). CONCLUSION: Our results showed elevated levels of XRCC3, NBS1, and OGG1 both in oral cancer and pre-oral cancer conditions, which indicates their role as prospective biomarkers of oral cancer and pre-cancerous lesions. SNPs in these genes alter their level of expression, possibly by altering the secondary structure of their transcript. However, due to the small sample size our study can only provide a suggestive conclusion and warned future study with large sample size to verify our findings.

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Na+/H+ antiporters facilitate the exchange of Na+ for H+ across the cytoplasmic membrane in prokaryotic and eukaryotic cells. These transporters are crucial to maintain the homeostasis of sodium ions, consequently pH, and volume of the cells. Therefore, sodium/proton antiporters are considered promising therapeutic targets in humans. The Na+/H+ antiporter in Escherichia coli (Ec-NhaA), a prototype of cation-proton antiporter (CPA) family, transports two protons and one sodium (or Li+) in opposite direction. Previous mutagenesis experiments on Ec-NhaA have proposed Asp164, Asp163, and Asp133 amino acids with the significant implication in functional and structural integrity and create site for ion-binding. However, the mechanism and the sites for the binding of the two protons remain unknown and controversial which could be critical for pH regulation. In this study, we have explored the role of Glu78 in the regulation of pH by Ec-NhaA. Although we have created various mutants, E78C has shown a considerable effect on the stoichiometry of NhaA and presented comparable phenotypes. The ITC experiment has shown the binding of ~ 5 protons in response to the transport of one lithium ion. The phenotype analysis on selective medium showed a significant expression compared to WT Ec-NhaA. This represents the importance of Glu78 in transporting the H+ across the membrane where a single mutation with Cys amino acid alters the number of H+ significantly maintaining the activity of the protein.

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We investigate the influence of varying confinement on the dynamics of polymer translocation through a cone-shaped channel. For this, a linear polymer chain is modeled using self-avoiding walks on a square lattice. The cis side of a cone-shaped channel has a finite volume, while the trans side has a semi-infinite space. The confining environment is varied either by changing the position of the back wall while keeping the apex angle fixed or altering the apex angle while keeping the position of the back wall fixed. In both cases, the effective space ϕ, which represents the number of monomers in a chain relative to the total number of accessible sites within the cone, is reduced due to the imposed confinement. Consequently, the translocation dynamics are affected. We analyze the entropy of the confined system as a function of ϕ, which exhibits nonmonotonic behavior. We also calculate the free energy associated with the confinement as a function of a virtual coordinate for different positions of the back wall (base of the cone) along the conical axis for various apex angles. Employing the Fokker-Planck equation, we calculate the translocation time as a function of ϕ for different solvent conditions across the channel. Our findings indicate that the translocation time decreases as ϕ increases, but it eventually reaches a saturation point at a certain value of ϕ. Moreover, we highlight the possibility of controlling the translocation dynamics by manipulating the solvent quality across the channel. Furthermore, our investigation delves into the intricacies of polymer translocation through a cone-shaped channel, considering both repulsive and neutral interactions with the channel wall. This exploration unveils nuanced dynamics and sheds light on the factors that significantly impact translocation within confined channels.

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Gallbladder cancer (GBC) is an uncommon condition in which malignant (cancer) cells are detected in gallbladder tissue. Cancer is often triggered when normal cells turn malignant and begin to spread. Cancer can also be caused by genetic anomalies that result in uncontrolled cell proliferation and tumor development. MicroRNAs (also known as miRNAs or miRs) are a group of small, endogenous, non-coding RNAs of 19-23 nucleotides in length, which play a key role in post-transcriptional gene regulation. These miRNAs serve as negative gene regulators by supervising target genes and regulating biological processes, including cell proliferation, migration, invasion, and apoptosis. Cancer development and progression relate to aberrant miRNA expression. This review demonstrated the implication of various genetic factors and microRNAs in developing and regulating GBC. This suggests the potential of genes and RNAs as the diagnostic, prognostic, and therapeutic targets in gallbladder cancer.

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We study the influence of confinement on the dynamics of translocation of a linear polymer chain in a good solvent through a cone-shaped pore. Using the Langevin dynamics simulations, we calculate both the first attempt time and translocation time as a function of the position of the back wall and apex angle α. As the in vivo confining environment is inherently dynamic, we extended the present study to explore the consequences of a periodically driven back wall and apex angles on the translocation dynamics. Our findings reveal that the translocation time initially decreases as the driving frequency increases, but increases after a certain frequency. The frequency at which the translocation time is found to be minimum is referred to as the resonance activation. Analyzing the distribution of translocation times around this frequency renders interesting information about the translocation process. We further explore the translocation dynamics by calculating the residence time of individual monomers, shedding light on the microscopic aspects of the process.

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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.

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Axotomized spinal motoneurons (MNs) lose presynaptic inputs following peripheral nerve injury; however, the cellular mechanisms that lead to this form of synapse loss are currently unknown. Here, we delineate a critical role for neuronal kinase dual leucine zipper kinase (DLK)/MAP3K12, which becomes activated in axotomized neurons. Studies with conditional knockout mice indicate that DLK signaling activation in injured MNs triggers the induction of phagocytic microglia and synapse loss. Aspects of the DLK-regulated response include expression of C1q first from the axotomized MN and then later in surrounding microglia, which subsequently phagocytose presynaptic components of upstream synapses. Pharmacological ablation of microglia inhibits the loss of cholinergic C boutons from axotomized MNs. Together, the observations implicate a neuronal mechanism, governed by the DLK, in the induction of inflammation and the removal of synapses.

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Cancer has a devastating impact globally regardless of gender, age, and community, which continues its severity to the population due to the lack of efficient strategy for the cancer diagnosis and treatment. According to the World Health Organisation report, one out of six people dies due to this deadly cancer and we need effective strategies to regulate it. In this context, trace element has a very hidden and unexplored role and require more attention from investigators. The variation in concentration of trace elements was observed during comparative studies on a cancer patient and a healthy person making them an effective target for cancer regulation. The percentage of trace elements present in the human body depends on environmental exposure, food habits, and habitats and could be instrumental in the early diagnosis of cancer. In this review, we have conducted inclusive analytics on trace elements associated with the various types of cancers and explored the several methods involved in their analysis. Further, intricacies in the correlation of trace elements with prominent cancers like prostate cancer, breast cancer, and leukaemia are represented in this review. This comprehensive information on trace elements proposes their role during cancer and as biomarkers in cancer diagnosis.

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Hepatitis C Virus (HCV) is a global health concern, chronically infecting over 70 million people worldwide. HCV is a bloodborne pathogen that primarily affects the liver, and chronic HCV infection can lead to cirrhosis, liver cancer, and liver failure over time. There is an urgent need for more effective approaches to prevent and treat HCV. This review summarizes current knowledge on the virology, transmission, diagnosis, and management of HCV infection. It also provides an in-depth analysis of HCV proteins as promising targets for antiviral drug and vaccine development. Specific HCV proteins discussed as potential drug targets include the NS5B polymerase, NS3/4A protease, entry receptors like CD81, and core proteins. The implications of HCV proteins as diagnostic and prognostic biomarkers are also explored. Current direct-acting antiviral therapies are effective but have cost, genotype specificity, and resistance limitations. This review aims to synthesize essential information on HCV biology and pathogenesis to inform future research on improved preventive, diagnostic, and therapeutic strategies against this global infectious disease threat.

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The emergence of drug-resistant strains of pathogens becomes a major obstacle to treating human diseases. Antibiotics and antivirals are in the application for a long time but now these drugs are not much effective anymore against disease-causing drug-resistant microbes and gradually it is becoming a serious complication worldwide. The development of new antibiotics cannot be a stable solution to treat drug-resistant strains due to their evolving nature and escaping antibiotics. At this stage, antimicrobial peptides (AMPs) may provide us with novel therapeutic leads against drug-resistant pathogens. Structurally, antimicrobial peptides are mostly α-helical peptide molecules with amphiphilic properties that carry the positive charge (cationic) and it belong to host defence peptides. These positively charged AMPs can interact with negatively charged bacterial cell membranes and may cause the alteration in electrochemical potential on bacterial cell membranes and consequently lead to the death of microbial cells. In the present study, we will elaborate on the implication of AMPs in the treatment of various diseases along with their specific structural and functional properties. This review will provide information which assists in the development of new synthetic peptide analogues to natural AMPs. These analogues will eliminate the limitations of natural AMPs like toxicity and severe hemolytic activities.

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Tuberculosis (TB) is a prehistoric infection and major etiologic agent of TB, Mycobacterium tuberculosis, which is considered to have advanced from an early progenitor species found in Eastern Africa. By the 1800s, there were approximately 800 to 1000 fatality case reports per 100,000 people in Europe and North America. This research suggests an In-silico study to identify potential inhibitory compounds for the target Mycobacterial copper transport protein (Mctb). ADME-based virtual screening, molecular docking, and molecular dynamics simulations were conducted to find promising compounds to modulate the function of the target protein. Four chemical compounds, namely Anti-MCT1, Anti-MCT2, Anti-MCT3 and Anti-MCT4 out of 1500 small molecules from the Diverse-lib of MTiOpenScreen were observed to completely satisfy Lipinski rule of five and Veber's rule. Further, significantly steady interactions with the MctB target protein were observed. Docking experiments have presented 9 compounds with less than -9.0 kcal/mol free binding energies and further MD simulation eventually gave 4 compounds having potential interactions and affinity with target protein and favorable binding energy ranging from -9.2 to -9.3 kcal/mol. We may propose these compounds as an effective candidate to reduce the growth of M. tuberculosis and may also assist present a novel therapeutic approach for Tuberculosis. In vivo and In vitro validation would be needed to proceed further in this direction.Communicated by Ramaswamy H. Sarma.

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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.

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Sodium-Proton antiporter, NhaA is a ubiquitous protein found in cytoplasmic membranes of all the prokaryotic and eukaryotic systems. These antiporters have been widely studied in E. coli and their homologs, observed in humans, are found to be crucial for various pathophysiological conditions, such as hypertension, cardiac diseases, blood pressure fluctuation etc. NhaA is responsible for the virulent properties of many pathogens like Vibrio cholerae, Yersinia pestis etc. In the present work, we have exploited in silico approaches to find lead phytomolecules that have the efficacy to interfere with the activities of sodium-proton antiporters in E. coli. A database of the plant-based natural bioactive compounds was used to screen 350 phytochemicals from various plant sources as potential ligands for the Ec-NhaA protein (PDB ID: 4ATV). Further interactions between Ec-NhaA and ligands were analyzed by AutoDock Vina and proposed 46 ligands with a significant affinity for NhaA where the binding energy range from -7.5 to -9.3 kcal/mol. Physiochemical characterization suggested 26 ligands with non-BBB permeability, good GI absorption and solubility. As a final step, MD simulation for more than 100 ns duration suggested Luteolin, Apigenin and Rhamnocitrin with the best affinity and showing potential stable interaction with the target protein. This study proposed the potential compounds of natural origin as an interfering agent against sodium-proton transport activity that may lead to affect the survival of various pathogenic bacteria.Communicated by Ramaswamy H. Sarma.

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