Heavy metals toxicity on epigenetic modifications in the pathogenesis of Alzheimer's disease (AD).

Alzheimer's disease (AD) is a progressive decline in cognitive ability and behavior which eventually disrupts daily activities. AD has no cure and the progression rate varies unlikely. Among various causative factors, heavy metals are reported to be a significant hazard in AD pathogenesis. Metal-induced neurodegeneration has been focused globally with thorough research to unravel the mechanistic insights in AD. Recently, heavy metals suggested to play an important role in epigenetic alterations which might provide evidential results on AD pathology. Epigenetic modifications are known to play towards novel therapeutic approaches in treating AD. Though many studies focus on epigenetics and heavy metal implications in AD, there is a lack of research on heavy metal influence on epigenetic toxicity in neurological disorders. The current review aims to elucidate the plausible role of cadmium (Cd), iron (Fe), arsenic (As), copper (Cu), and lithium (Li) metals on epigenetic factors and the increase in amyloid beta and tau phosphorylation in AD. Also, the review discusses the common methods of heavy metal detection to implicate in AD pathogenesis. Hence, from this review, we can extend the need for future research on identifying the mechanistic behavior of heavy metals on epigenetic toxicity and to develop diagnostic and therapeutic markers in AD.

Molecular insights and promise of oncolytic virus based immunotherapy.

Discovering a therapeutic that can counteract the aggressiveness of this disease's mechanism is crucial for improving survival rates for cancer patients and for better understanding the most different types of cancer. In recent years, using these viruses as an anticancer therapy has been thought to be successful. They mostly work by directly destroying cancer cells, activating the immune system to fight cancer, and expressing exogenous effector genes. For the treatment of tumors, oncolytic viruses (OVs), which can be modified to reproduce only in tumor tissues and lyse them while preserving the healthy non-neoplastic host cells and reinstating antitumor immunity which present a novel immunotherapeutic strategy. OVs can exist naturally or be created in a lab by altering existing viruses. These changes heralded the beginning of a new era of less harmful virus-based cancer therapy. We discuss three different types of oncolytic viruses that have already received regulatory approval to treat cancer as well as clinical research using oncolytic adenoviruses. The primary therapeutic applications, mechanism of action of oncolytic virus updates, future views of this therapy will be covered in this chapter.

Microbiota-brain axis: Exploring the role of gut microbiota in psychiatric disorders - A comprehensive review.

Mental illness is a hidden epidemic in modern science that has gradually spread worldwide. According to estimates from the World Health Organization (WHO), approximately 10% of the world's population suffers from various mental diseases each year. Worldwide, financial and health burdens on society are increasing annually. Therefore, understanding the different factors that can influence mental illness is required to formulate novel and effective treatments and interventions to combat mental illness. Gut microbiota, consisting of diverse microbial communities residing in the gastrointestinal tract, exert profound effects on the central nervous system through the gut-brain axis. The gut-brain axis serves as a conduit for bidirectional communication between the two systems, enabling the gut microbiota to affect emotional and cognitive functions. Dysbiosis, or an imbalance in the gut microbiota, is associated with an increased susceptibility to mental health disorders and psychiatric illnesses. Gut microbiota is one of the most diverse and abundant groups of microbes that have been found to interact with the central nervous system and play important physiological functions in the human gut, thus greatly affecting the development of mental illnesses. The interaction between gut microbiota and mental health-related illnesses is a multifaceted and promising field of study. This review explores the mechanisms by which gut microbiota influences mental health, encompassing the modulation of neurotransmitter production, neuroinflammation, and integrity of the gut barrier. In addition, it emphasizes a thorough understanding of how the gut microbiome affects various psychiatric conditions.

Artificial intelligence and machine learning algorithms in the detection of heavy metals in water and wastewater: Methodological and ethical challenges.

Heavy metals (HMs) enter waterbodies through various means, which, when exceeding a threshold limit, cause toxic effects both on the environment and in humans upon entering their systems. Recent times have seen an increase in such HM influx incident rates. This requires an instant response in this regard to review the challenges in the available classical methods for HM detection and removal. As well as provide an opportunity to explore the applications of artificial intelligence (AI) and machine learning (ML) for the identification and further redemption of water and wastewater from the HMs. This review of research focuses on such applications in conjunction with the available in-silico models producing worldwide data for HM levels. Furthermore, the effect of HMs on various disease progressions has been provided, along with a brief account of prediction models analysing the health impact of HM intoxication. Also discussing the ethical and other challenges associated with the use of AI and ML in this field is the futuristic approach intended to follow, opening a wide scope of possibilities for improvement in wastewater treatment methodologies.

Does gut brain axis has an impact on Parkinson's disease (PD)?

Parkinson's Disease (PD) is becoming a growing global concern by being the second most prevalent disease next to Alzheimer's Disease (AD). Henceforth new exploration is needed in search of new aspects towards the disease mechanism and origin. Evidence from recent studies has clearly stated the role of Gut Microbiota (GM) in the maintenance of the brain and as a root cause of various diseases and disorders including other neurological conditions. In the case of PD, with an unknown etiology, the GM is said to have a larger impact on the disease pathophysiology. Although GM and its metabolites are crucial for maintaining the normal physiology of the host, it is an undeniable fact that there is an influence of GM in the pathophysiology of PD. As such the Enteroendocrine Cells (EECs) in the epithelium of the intestine are one of the significant regulators of the gut-brain axis and act as a communication mediator between the gut and the brain. The communication is established via the molecules of neuroendocrine which are said to have a crucial part in neurological diseases such as AD, PD, and other psychiatry-related disorders. This review is focused on understanding the proper role of GM and EECs in PD. Here, we also focus on some of the metabolites and compounds that can interact with the PD genes causing various dysfunctions in the cell and facilitating the disease conditions using bioinformatical tools. Various mechanisms concerning EECs and PD, their identification, the latest studies, and available current therapies have also been discussed.

Association of Biochemical Parameters and Screening for Mutations in the MCU Gene in Alzheimer's Disease Patients.

The most prevalent form of dementia, Alzheimer's disease (AD) is a chronic illness that is on the rise among the geriatric population. Even though research into its biochemical, genetic, and cytogenetic pathways has advanced, its aetiology is still unclear and complex. In this study, we recruited sixty-eight participants diagnosed with AD where the cytogenetic, biochemical parameters and genetic mutations were analysed. Our results revealed chromosomal aberrations such as aneuploidies in the peripheral blood of Alzheimer's disease patients. Biochemical parameters revealed no statistical significance in the study though a pattern could be observed in the serum levels. Further few novel mutations at the c.21 C > T, c.56G > A were observed in the MCU gene of mitochondrial calcium uniporter. All these findings reveal the need for a larger cohort study to gain a better and more detailed understanding of the aetiology of Alzheimer's disease.

A cooperativity between virus and bacteria during respiratory infections.

Respiratory tract infections remain the leading cause of morbidity and mortality worldwide. The burden is further increased by polymicrobial infection or viral and bacterial co-infection, often exacerbating the existing condition. Way back in 1918, high morbidity due to secondary pneumonia caused by bacterial infection was known, and a similar phenomenon was observed during the recent COVID-19 pandemic in which secondary bacterial infection worsens the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) condition. It has been observed that viruses paved the way for subsequent bacterial infection; similarly, bacteria have also been found to aid in viral infection. Viruses elevate bacterial infection by impairing the host's immune response, disrupting epithelial barrier integrity, expression of surface receptors and adhesion proteins, direct binding of virus to bacteria, altering nutritional immunity, and effecting the bacterial biofilm. Similarly, the bacteria enhance viral infection by altering the host's immune response, up-regulation of adhesion proteins, and activation of viral proteins. During co-infection, respiratory bacterial and viral pathogens were found to adapt and co-exist in the airways of their survival and to benefit from each other, i.e., there is a cooperative existence between the two. This review comprehensively reviews the mechanisms involved in the synergistic/cooperativity relationship between viruses and bacteria and their interaction in clinically relevant respiratory infections.

Outpatient Clinical Markers for Laryngopharyngeal Reflux Disease: A Correlational Study.

Laryngopharyngeal reflux disease (LPRD) is the result of retrograde flow of gastric contents to the laryngopharynx which comes in contact with tissues of the upper aerodigestive tract. Due to ill defined criteria for diagnosis & followup, LPRD patients are underdiagnosed & undertreated. Reflux Symptom Index (RSI) and the Reflux Finding Score (RFS) are two clinical methods which can be utilised especially in the outpatient setup. This study was done with the aim to assess various laryngoscopic findings in patients with LPRD diagnosed symptomatically and examine the correlation between the RSI & RFS by comparing these two indices. This prospective analytical study was conducted at a tertiary care centre in Bangalore in the Department of ENT for a period of 24 months between Dec 2020 to Dec 2022. The study included patients aged 18 to 60 years diagnosed with LPRD based on symptoms as per RSI score (> 13). RSI & RFS were assessed on diagnosis and patients were followed up for 1, 3 & 6 months for assessment. Total 96 patients were enrolled, with mean age of be 42.49 ± 11.33 years. Prevalence was found to be more in females (61.5%). The most common symptom according to RSI was frequent throat clearing & globus sensation (sensation of something sticking in throat) and most common finding according to RFS was erythema/hyperemia. The mean score of RSI and RFI was found to reduce with treatment at different intervals in follow-up visits. There was a significant strength of association between the RSI and RFS at baseline, 1st month, 3rd month and 6th month of follow-up (r = 0.568, r = 0.684, r = 0.774, r = 0.736 respectively) (p < 0.001).The RFS and RSI showed statistically significant strong relationships between total scores and sign and symptom characteristics. On follow-up, there was a significant reduction in the RSI which was also correlated with a reduction in RFS.

Revisiting the role of cyanobacteria-derived metabolites as antimicrobial agent: A 21st century perspective.

Cyanobacterial species are ancient photodiazotrophs prevalent in freshwater bodies and a natural reservoir of many metabolites (low to high molecular weight) such as non-ribosomal peptides, polyketides, ribosomal peptides, alkaloids, cyanotoxins, and isoprenoids with a well-established bioactivity potential. These metabolites enable cyanobacterial survival in extreme environments such as high salinity, heavy metals, cold, UV-B, etc. Recently, these metabolites are gaining the attention of researchers across the globe because of their tremendous applications as antimicrobial agents. Many reports claim the antimicrobial nature of these metabolites; unfortunately, the mode of action of such metabolites is not well understood and/or known limited. Henceforth, this review focuses on the properties and potential application, also critically highlighting the possible mechanism of action of these metabolites to offer further translational research. The review also aims to provide a comprehensive insight into current gaps in research on cyanobacterial biology as antimicrobials and hopes to shed light on the importance of continuing research on cyanobacteria metabolites in the search for novel antimicrobials.

Current Developments and Challenges in Plant Viral Diagnostics: A Systematic Review.

Plant viral diseases are the foremost threat to sustainable agriculture, leading to several billion dollars in losses every year. Many viruses infecting several crops have been described in the literature; however, new infectious viruses are emerging frequently through outbreaks. For the effective treatment and prevention of viral diseases, there is great demand for new techniques that can provide accurate identification on the causative agents. With the advancements in biochemical and molecular biology techniques, several diagnostic methods with improved sensitivity and specificity for the detection of prevalent and/or unknown plant viruses are being continuously developed. Currently, serological and nucleic acid methods are the most widely used for plant viral diagnosis. Nucleic acid-based techniques that amplify target DNA/RNA have been evolved with many variants. However, there is growing interest in developing techniques that can be based in real-time and thus facilitate in-field diagnosis. Next-generation sequencing (NGS)-based innovative methods have shown great potential to detect multiple viruses simultaneously; however, such techniques are in the preliminary stages in plant viral disease diagnostics. This review discusses the recent progress in the use of NGS-based techniques for the detection, diagnosis, and identification of plant viral diseases. New portable devices and technologies that could provide real-time analyses in a relatively short period of time are prime important for in-field diagnostics. Current development and application of such tools and techniques along with their potential limitations in plant virology are likewise discussed in detail.

Antimicrobial sensitivity profiling of bacterial communities recovered from effluents of municipal solid waste dumping site.

The diversity of antibiotic-resistance bacteria (ARB) from the effluents of Aizawl city municipal waste dumping site was studied using a culture-dependent method. The present study molecularly identified 73 isolates that were differentiated into three phyla (Proteobacteria, Actinobacteria, and Firmicutes) belonging to 17 family and 22 genera. Bacillus constitutes the most dominant genus comprising 16% of the total isolates. The topology of the phylogenetic tree differentiates them into five major clades. Corynebacterium and Rhodococcus which are morphologically alike were clustered together and the Gram-positive bacteria such as Staphylococcus, Bacillus, and Lysinibacillus formed a separate cluster. Antibiotic resistance of the identified bacterial isolates was performed using 19 different antibiotics. Among the isolates, 70 of them found resistant to polymixin B and nalidixic acid and 10 isolates exhibited resistance to 15 tested antibiotics. The present study revealed that bacteria with antibiotic resistance are extensively distributed in the effluents of the dumping site and may serve as a significant reservoir for the spreading of antibiotic resistance to opportunistic pathogens.

Intra-Operative Dermoscopy in Assessment of Melanonychia and as a Guide for Biopsy.

BACKGROUND AND AIMS: Melanonychia can be a manifestation of benign or malignant pathology and often poses a diagnostic challenge on clinical examination. Even with distinguishing dermoscopic features (nail plate), it can be quite difficult to determine the nature of pigmentation as complete assessment of nail bed and matrix is still not possible. Intraoperative dermoscopy (IOD) can serve as a useful tool to appreciate the bed and matrix changes. The aim here is to study the intraoperative dermoscopic features in patients with melanonychia and correlate with histopathology. METHODS: 20 consecutive patients with melanonychia were recruited. Inclusion criteria was melanonychia of sudden onset, progressive nature, irregular width/color/symmetry on dermoscopy, positive Hutchinson sign, solitary nail involvement or associated nail dystrophy. Preoperative dermoscopy was performed and recorded. Patients were planned for nail matrix biopsy, during which IOD was performed over nail matrix and bed after removal of the nail plate. Images were recorded and analyzed and correlated with the histopathology. RESULTS: Out of 20 patients, 12 were females and 8 males. On IOD-histopathological correlation, 2 patients were found to have melanoma of the nail unit, 5had nail lichen planus, 9 had benign melanocytic nevi, and 4 had fungal melanonychia. IOD revealed fine, parallel and regular lines of pigmentation localized to proximal nail bed and matrix in all patients with benign melanonychia, while dark thick bands with irregular borders, dots, globules, streaks and structureless areas in the two patients with melanoma. Fungal melanonychia revealed an unremarkable nail bed and matrix on IOD. CONCLUSION: Intraoperative dermoscopycan help in determining the nature of melanonychia and obviate the need to perform biopsy in certain cases. It can also aid in delineating the most suitable site for biopsy, along with grossly assessing the extent of involvement in case of malignancy.

Asian Sand Dust Particles Increased Pneumococcal Biofilm Formation in vitro and Colonization in Human Middle Ear Epithelial Cells and Rat Middle Ear Mucosa.

INTRODUCTION: Air pollutants such as Asian sand dust (ASD) and Streptococcus pneumoniae are risk factors for otitis media (OM). In this study, we evaluate the role of ASD in pneumococcal in vitro biofilm growth and colonization on human middle ear epithelium cells (HMEECs) and rat middle ear using the rat OM model. METHODS: S. pneumoniae D39 in vitro biofilm growth in the presence of ASD (50-300 µg/ml) was evaluated in metal ion-free BHI medium using CV-microplate assay, colony-forming unit (cfu) counts, resazurin staining, scanning electron microscopy (SEM), and confocal microscopy (CF). Biofilm gene expression analysis was performed using real-time RT-PCR. The effects of ASD or S. pneumoniae individually or on co-treatment on HMEECs were evaluated by detecting HMEEC viability, apoptosis, and reactive oxygen species (ROS) production. In vivo colonization of S. pneumoniae in the presence of ASD was evaluated using the rat OM model, and RNA-Seq was used to evaluate the alterations in gene expression in rat middle ear mucosa. RESULTS: S. pneumoniae biofilm growth was significantly (P < 0.05) elevated in the presence of ASD. SEM and CF analysis revealed thick and organized pneumococcal biofilms in the presence of ASD (300 µg/ml). However, in the absence of ASD, bacteria were unable to form organized biofilms, the cell size was smaller than normal, and long chain-like structures were formed. Biofilms grown in the presence of ASD showed elevated expression levels of genes involved in biofilm formation (luxS), competence (comA, comB, ciaR), and toxin production (lytA and ply). Prior exposure of HMEECs to ASD, followed by treatment for pneumococci, significantly (P < 0.05) decreased cell viability and increased apoptosis, and ROS production. In vivo experiment results showed significantly (P < 0.05) more than 65% increased bacteria colonization in rat middle ear mucosa in the presence of ASD. The apoptosis, cell death, DNA repair, inflammation and immune response were differentially regulated in three treatments; however, number of genes expressed in co-treatments was higher than single treatment. In co-treatment, antimicrobial protein/peptide-related genes (S100A family, Np4, DEFB family, and RATNP-3B) and OM-related genes (CYLD, SMAD, FBXO11, and CD14) were down regulated, and inflammatory cytokines and interleukins, such as IL1ß, and TNF-related gene expression were elevated. CONCLUSION: ASD presence increased the generation of pneumococcal biofilms and colonization.

Urban Particles Elevated Streptococcus pneumoniae Biofilms, Colonization of the Human Middle Ear Epithelial Cells, Mouse Nasopharynx and Transit to the Middle Ear and Lungs.

Air-pollutants containing toxic particulate matters (PM) deposit in the respiratory tract and increases microbial infections. However, the mechanism by which this occurs is not well understood. This study evaluated the effect of urban particles (UP) on Streptococcus pneumoniae (pneumococcus) in vitro biofilm formation, colonization of human middle ear epithelium cells (HMEECs) as well as mouse nasal cavity and its transition to the middle ear and lungs. The in vitro biofilms and planktonic growth of S. pneumoniae were evaluated in metal ion free medium in the presence of UP. Biofilms were quantified by crystal violet (CV) microplate assay, colony forming unit (cfu) counts and resazurin staining. Biofilm structures were analyzed using a scanning electron microscope (SEM) and confocal microscopy (CM). Gene expressions of biofilms were evaluated using real time RT-PCR. Effects of UP exposure on S. pneumoniae colonization to HMEECs were evaluated using fluorescent in-situ hybridization (FISH), cell viability was detected using the Ezcyto kit, apoptosis in HMEECs were evaluated using Annexin-V/PI based cytometry analysis and reactive oxygen species (ROS) production were evaluated using the Oxiselect kit. Alteration of HMEECs gene expressions on UP exposure or pneumococci colonization was evaluated using microarray. In vivo colonization of pneumococci in the presence of UP and transition to middle ear and lungs were evaluated using an intranasal mice colonization model. The UP exposure significantly increased (*p < 0.05) pneumococcal in vitro biofilms and planktonic growth. In the presence of UP, pneumococci formed organized biofilms with a matrix, while in absence of UP bacteria were unable to form biofilms. The luxS, ply, lytA, comA, comB and ciaR genes involved in bacterial pathogenesis, biofilm formation and quorum sensing were up-regulated in pneumococci biofilms grown in the presence of UP. The HMEECs viability was significantly decreased (p < 0.05) and bacteria colonization was significantly elevated (p < 0.05) in co-treatment (UP + S. pneumoniae) when compared to single treatment. Similarly, increased apoptosis and ROS production were detected in HMEECs treated with UP + pneumococci. The microarray analysis of HMEECs revealed that the genes involve in apoptosis and cell death, inflammation, and immune response, were up-regulated in co-treatment and were unchanged or expressed in less fold in single treatments of UP or S. pneumoniae. The in vivo study showed an increased pneumococcal colonization of the nasopharynx in the presence of UP and a higher transition of bacteria to the middle ear and lungs in the presence of UP. The UP exposure elevated S. pneumoniae in vitro biofilm and colonization of HMEECs, and in vivo mouse nasopharyngeal colonization, and increased dissemination to mouse middle ear and lungs.

Inorganic clay nanocomposite system for improved cholinesterase inhibition and brain pharmacokinetics of donepezil.

Objective: Brain drug delivery for effective treatment of neurodegenerative disorders is limited due to the selective permeability of blood brain barrier (BBB). During the past few years, development of novel delivery system has attracted considerable attention of formulation scientists to overcome the permeability limitation caused by BBB.Significance: Based on the outcomes of this study and taking into consideration of the unique characteristics of laponite, it can be further explored to deliver many other central nervous system acting drugs.Methods: In the present study, laponite (LAP) nanocomposites were exploited for the improved brain delivery of donepezil (DZ) following encapsulation approach due to their nano-size and positive charge at pH <9.Result: The size of prepared nanocomposites was 53.7 ± 4.0 to 137.7 ± 11.0 nm. The drug was released in a sustained manner till 120 h in phosphate buffer saline (pH 7.4) and acid phthalate buffer (pH 4.0). LAPDZ formulations inhibited acetylcholinesterase approximately by 82%, significantly higher (p < 0.05) than plain DZ (30%). Swiss albino mice exhibited enhanced brain uptake of LAPDZ administered via intravenous route. Promising pharmacokinetic parameters were observed in animals treated with LAPDZ. LAPDZ formulation showed half-life (t1/2), volume of distribution (Vd) and clearance (Cl) as 5.53 ± 0.40 h-1, 0.129 ± 0.02 L, 0.015 ± 0.002 L/h, respectively. While DZ solution showed the same parameters as 1.06 ± 0.12 h-1, 0.168 ± 0.01 L, 0.106 ± 0.013 L/h, respectively. The brain uptake of LAPDZ formulation was improved with quintuplet t1/2.Conclusion: Based on the results of present study, it is proposed that the formulated nanocomposite would result in improved patient compliance with therapeutic effect at lower doses.

Primary Yolk Sac Tumor of the Liver in an Adult Man.

Primary yolk sac tumor of the liver is extremely rare in adults. We report a case of a young man with an unresectable primary yolk sac tumor of the liver, who had a platinum-refractory disease that progressed despite 2 lines of chemotherapy. We review the literature pertaining to primary yolk sac tumor of the liver and its management.

Ruthenium Chloride-Induced Oxidative Cyclization of Trans-Resveratrol to (±)-ε-Viniferin and Antimicrobial and Antibiofilm Activity Against Streptococcus pneumoniae.

Polyphenol ε-viniferin (2) is a protective phytochemical found in several plant families. Here, we report a simple and effective method for the synthesis of (±)-ε-viniferin (2) as major product and (±)-(E)-ω-viniferin (3) as a minor product. Synthesized viniferin compounds and standard viniferin were analyzed for antibacterial and antibiofilm activity against Gram-positive bacteria Streptococcus pneumoniae. The minimum inhibitory concentrations (MICs) of (±)-ε-viniferin (2) and standard viniferin were 20 µm. However, the MICs of (±)-(E)-ω-viniferin (3) and compound 8 were 40 µm. Although viniferin significantly (p < 0.05) reduced pre-established in vitro biofilms and killed bacteria within the biofilm, it was unable to prevent biofilm formation at sub-MIC concentrations. The time kill experiment revealed that viniferin killed bacteria and reduced 2.8 log10 bacteria at 2 × MIC concentration after 24 h. Scanning electron microscope (SEM) analysis and live/dead biofilm staining of pre-established biofilms revealed that viniferin treatment disrupts membrane integrity of biofilm bacteria. Crystal violet absorption, total protein, and DNA and RNA release revealed that viniferin alters bacterial cell permeability, eventually killing bacteria.