Countering Zoonotic Diseases: Current Scenario and Advances in Diagnostics, Monitoring, Prophylaxis and Therapeutic Strategies.

Human life and health have interacted reciprocally with the surrounding environment and animal fauna for ages. This relationship is evident in developing nations, where human life depends more on the animal population for food, transportation, clothing, draft power, and fuel sources, among others. This inseparable link is a potent source of public health issues, especially in outbreaks of zoonotic diseases transmitted from animals to humans. Zoonotic diseases are referred to as diseases that are naturally transmitted between vertebrate animals and humans. Among the globally emerging diseases in the last decade, 75% are of animal origin, most of which are life-threatening. Since most of them are caused by potent new pathogens capable of long-distance transmission, the impact is widespread and has serious public health and economic consequences. Various other factors also contribute to the transmission, spread, and outbreak of zoonotic diseases, among which industrialization-led globalization followed by ecological disruption and climate change play a critical role. In this regard, all the possible strategies, including advances in rapid and confirmatory disease diagnosis and surveillance/monitoring, immunization/vaccination, therapeutic approaches, appropriate prevention and control measures to be adapted, and awareness programs, need to be adopted collaboratively among different health sectors in medical, veterinary, and concerned departments to implement the necessary interventions for the effective restriction, minimization, and timely control of zoonotic threats. The present review focuses on the current scenario of zoonotic diseases and their counteracting approaches to safeguard their health impact on humans.

Exploring advancements in early detection of Alzheimer's disease with molecular assays and animal models.

Alzheimer's Disease (AD) is a challenging neurodegenerative condition, with overwhelming implications for affected individuals and healthcare systems worldwide. Animal models have played a crucial role in studying AD pathogenesis and testing therapeutic interventions. Remarkably, studies on the genetic factors affecting AD risk, such as APOE and TREM2, have provided valuable insights into disease mechanisms. Early diagnosis has emerged as a crucial factor in effective AD management, as demonstrated by clinical studies emphasizing the benefits of initiating treatment at early stages. Novel diagnostic technologies, including RNA sequencing of microglia, offer promising avenues for early detection and monitoring of AD progression. Therapeutic strategies remain to evolve, with a focus on targeting amyloid beta (Aß) and tau pathology. Advances in animal models, such as APP-KI mice, and the advancement of anti-Aß drugs signify progress towards more effective treatments. Therapeutically, the focus has shifted towards intricate approaches targeting multiple pathological pathways simultaneously. Strategies aimed at reducing Aß plaque accumulation, inhibiting tau hyperphosphorylation, and modulating neuroinflammation are actively being explored, both in preclinical models and clinical trials. While challenges continue in developing validated animal models and translating preclinical findings to clinical success, the continuing efforts in understanding AD at molecular, cellular, and clinical levels offer hope for improved management and eventual prevention of this devastating disease.

Sex differences in CGRP-induced vasodilation of human middle meningeal arteries but not human coronary arteries: implications for migraine.

BACKGROUND: Migraine prevalence and levels of calcitonin gene-related peptide (CGRP), a peptide involved in migraine pathophysiology, differ between men and women, and appear to be affected by changes in sex hormones. The present study investigated the sex-specific responses to CGRP in human isolated arteries. METHODS: CGRP-induced relaxation of 62 (28 men and 34 women) human isolated middle meningeal arteries (HMMA) and 139 (69 men and 70 women) human isolated coronary arteries (HCA) was compared between men and women in groups <50 years and ≥50 years of age as a proxy for pre- and postmenopausal status in women, as well as matched-age groups for men. RESULTS: In HCA, no differences were observed between male and female tissue, or between the different age groups. However, in HMMA, the maximum response was significantly smaller and CGRP was less potent in females <50 compared with males <50 years of age. No differences were observed between the older age groups. CONCLUSIONS: Sex differences were observed for CGRP-induced relaxation of HMMA, but not HCA. These differences could arise from differential receptor expression in the vascular beds combined with the effect of sex hormones on CGRP and subsequent receptor desensitization.

Case Report: Recurrent Type 2 Leprosy Reaction Associated with Multiple Nerve Function Impairments Refractory to Steroids: A Therapeutic Challenge.

Nerve function impairment (NFI) in leprosy results in serious deformities of the face, hands, and feet and contributes significantly to the stigma associated with the disease. Most literature on NFI focuses on either type 1 reaction-associated NFI, or the silent neuropathy, whereas NFI associated with type 2 reaction (T2R) is less well researched. The latter, however, can be more refractory to conventional treatment, not solely owing to its recurrent nature. We present a therapeutically challenging case of a 31-year-old male with borderline lepromatous leprosy with recurrent T2R associated with recurrent and progressive sensorimotor NFI, largely unresponsive to oral steroids and multibacillary, multidrug therapy.

MicroRNAs in extracellular vesicles: A potential role in cancer progression.

Intercellular communication, an essential biological process in multicellular organisms, is mediated by direct cell-to-cell contact and cell secretary molecules. Emerging evidence identifies a third mechanism of intercellular communication- the release of extracellular vesicles (EVs). EVs are membrane-enclosed nanosized bodies, released from cells into the extracellular environment, often found in all biofluids. The growing body of research indicates that EVs carry bioactive molecules in the form of proteins, DNA, RNAs, microRNAs (miRNAs), lipids, metabolites, etc., and upon transferring them, alter the phenotypes of the target recipient cells. Interestingly, the abundance of EVs is found to be significantly higher in different diseased conditions, most importantly cancer. In the past few decades, numerous studies have identified EV miRNAs as an important contributor in the pathogenesis of different types of cancer. However, the underlying mechanism behind EV miRNA-associated cancer progression and how it could be used as a targeted therapy remain ill-defined. The present review highlights how EV miRNAs influence essential processes in cancer, such as growth, proliferation, metastasis, angiogenesis, apoptosis, stemness, immune evasion, resistance to therapy, etc. A special emphasis has been given to the potential role of EV miRNAs as cancer biomarkers. The final section of the review delineates the ongoing clinical trials on the role of miRNAs in the progression of different types of cancer. Targeting EV miRNAs could be a potential therapeutic means in the treatment of different forms of cancer alongside conventional therapeutic approaches.

Identification and Analysis of Atrial-Bronchial-Abdominal Disharmony in Patients with Isomeric Atrial Appendages.

Ideally, the morphology of atrial appendages should solely be used to identify and differentiate patients with isomeric right and left atrial appendages. However, in clinical practice, the segregation is often indirectly based on the arrangement of thoraco-abdominal structures. The correlation between thoraco-abdominal arrangement and atrial appendages, however, is imperfect. In this study, we sought to clarify the cardiovascular malformations in patients with isomeric atrial appendages with an emphasis on atrial-thoracic-abdominal disharmony. A retrospective review of all patients who underwent cardiac CT angiography between January 2014 and June 2023 and identified to have isomeric atrial appendages was performed. Of the 366 cases (median age: 2 years [interquartile range: 11 months-7 years]), 247 (67.5%) patients had isomeric right atrial appendages while 119 (32.5%) patients had isomeric left atrial appendages. In 316 (86.3%) patients, the thoraco-abdominal arrangement was as per atrial appendage morphology while the remaining 50 (13.6%) patients had disharmonious patterns. Compared to isomeric left atrial appendages, the disharmonious pattern was more frequent with isomeric right atrial appendages (5.9% vs. 17.4%; p 0.003). Irrespective of the type of isomerism, disharmony was mostly confined to the level of the abdomen. Not all patients with isomeric atrial appendages have a harmonious thoraco-abdominal arrangement. The atrial-bronchial-abdominal disharmony is more frequent with isomeric right atrial appendages and is mostly present at the level of the abdomen. A detailed sequential segmental analysis with an independent description of each organ system is, therefore, essential for the complete evaluation of patients with isomeric atrial appendages.

Extracellular Vesicular miRNA in Pancreatic Cancer: From Lab to Therapy.

Pancreatic cancer is a prevalent lethal gastrointestinal cancer that generally does not show any symptoms until it reaches advanced stages, resulting in a high mortality rate. People at high risk, such as those with a family history or chronic pancreatitis, do not have a universally accepted screening protocol. Chemotherapy and radiotherapy demonstrate limited effectiveness in the management of pancreatic cancer, emphasizing the urgent need for innovative therapeutic strategies. Recent studies indicated that the complex interaction among pancreatic cancer cells within the dynamic microenvironment, comprising the extracellular matrix, cancer-associated cells, and diverse immune cells, intricately regulates the biological characteristics of the disease. Additionally, mounting evidence suggests that EVs play a crucial role as mediators in intercellular communication by the transportation of different biomolecules, such as miRNA, proteins, DNA, mRNA, and lipids, between heterogeneous cell subpopulations. This communication mediated by EVs significantly impacts multiple aspects of pancreatic cancer pathogenesis, including proliferation, angiogenesis, metastasis, and resistance to therapy. In this review, we delve into the pivotal role of EV-associated miRNAs in the progression, metastasis, and development of drug resistance in pancreatic cancer as well as their therapeutic potential as biomarkers and drug-delivery mechanisms for the management of pancreatic cancer.

Molecular targets and therapeutic potential of baicalein: a review.

Aim: Researchers using herbs and natural products to find new drugs often prefer flavonoids because of their potential as antioxidants and anti-inflammatories. The planned review addressed baicalein research findings in detail. This manuscript provides a complete review of baicalein's potential pharmacological effects along with several molecular targets for better understanding of its therapeutic activities. Materials and methods: We targeted the review on in vitro and in vivo studies reported on baicalein. For this, the literature is gathered from the database available on search engines like PubMed, ScienceDirect, Scopus, and Google Scholar up to 21 December 2023. The keywords "Scutellaria baicalensis", "Oroxylum indicum", "Neuroprotective", "Cardioprotective", "Toxicity studies", and "Baicalein" were used to fetch the content. Results: Baicalein's molecular receptor binding approach has shown anticancer, antidiabetic, antimicrobial, antiaging, neuroprotective, cardioprotective, respiratory protective, gastroprotective, hepatic protective, and renal protective effects. The synergistic effects of this drug with other selective herbs are also contributed towards significant therapeutic potential. Conclusion: This systematic review article from a contemporary and scientific perspective offers fresh insight into S. baicalensis, O. indicum, and its bioactive component baicalein as a potential complementary medicine. Baicalein may be transformed into more efficacious and acceptable evidence-based medicine. However, we recommend more clinical and mechanistic approaches to confirm safety and efficacy of baicalein.

Structure-based virtual screening methods for the identification of novel phytochemical inhibitors targeting furin protease for the management of COVID-19.

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, is a highly contagious respiratory disease with widespread societal impact. The symptoms range from cough, fever, and pneumonia to complications affecting various organs, including the heart, kidneys, and nervous system. Despite various ongoing efforts, no effective drug has been developed to stop the spread of the virus. Although various types of medications used to treat bacterial and viral diseases have previously been employed to treat COVID-19 patients, their side effects have also been observed. The way SARS-CoV-2 infects the human body is very specific, as its spike protein plays an important role. The S subunit of virus spike protein cleaved by human proteases, such as furin protein, is an initial and important step for its internalization into a human host. Keeping this context, we attempted to inhibit the furin using phytochemicals that could produce minimal side effects. For this, we screened 408 natural phytochemicals from various plants having antiviral properties, against furin protein, and molecular docking and dynamics simulations were performed. Based on the binding score, the top three compounds (robustaflavone, withanolide, and amentoflavone) were selected for further validation. MM/GBSA energy calculations revealed that withanolide has the lowest binding energy of -57.2 kcal/mol followed by robustaflavone and amentoflavone with a binding energy of -45.2 kcal/mol and -39.68 kcal/mol, respectively. Additionally, ADME analysis showed drug-like properties for these three lead compounds. Hence, these natural compounds robustaflavone, withanolide, and amentoflavone, may have therapeutic potential for the management of SARS-CoV-2 by targeting furin.

Short segment posterior fixation of unstable thoracolumbar vertebral fractures with fractured vertebra augmentation with intermediate pedicle screw - a clinicoradiological analysis.

INTRODUCTION: Unstable thoracolumbar burst fractures are routinely encountered in orthopedic practice. Recently, short-segment fixation with pedicle screw augmentation of the fractured vertebra for unstable thoracolumbar burst fractures has gained popularity. Nonetheless, the maintenance of the kyphotic correction during the follow-up period remains controversial. This study aimed to examine the clinical-radiological outcomes, complications, and functional outcomes of fractured vertebrae augmentation with intermediate pedicle screws in short-segment instrumentation in acute thoracolumbar spine fractures. METHODS: This retrospective study was conducted in the Department of Orthopedics, All India Institute of Medical Sciences, Jodhpur, using medical records from January 2021 to October 2022. Parameters such as local kyphosis correction, loss of kyphotic correction at final follow-up, anterior body height correction (%), and loss of correction (%) at final follow-up were measured as primary outcomes. Various other parameters such as operative time, blood loss, length of hospital stay, and visual analog scale were measured as secondary outcomes. RESULTS: The mean correction obtained via surgery in the immediate postoperative period was 13.7±2.3 degrees. The mean loss of correction at the final follow-up was 4.1±2.0 degrees, and the mean final local kyphotic angle was 7.2±2.4 degrees (P<0.05). The mean correction obtained via surgery in the immediate postoperative period was 37.2%±9.0%. The mean loss of correction at the final follow-up was 10.5%±5.3%, and the mean final anterior vertebral body height maintained was 72%±11.0% (P<0.05). CONCLUSION: Short-segment posterior fixation with pedicle screw augmentation achieves good correction of local kyphotic angle and anterior vertebral height in the immediate postoperative period, but some loss of correction at final follow-up is common. In our study, the loss of correction corresponded directly to the load-sharing score.

Non-coding RNA mediated regulation of PI3K/Akt pathway in hepatocellular carcinoma: Therapeutic perspectives.

Hepatocellular carcinoma (HCC) is among the primary reasons for fatalities caused by cancer globally, highlighting the need for comprehensive knowledge of its molecular aetiology to develop successful treatment approaches. The PI3K/Akt system is essential in the course of HCC, rendering it an intriguing candidate for treatment. Non-coding RNAs (ncRNAs), such as long ncRNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), are important mediators of the PI3K/Akt network in HCC. The article delves into the complex regulatory functions of ncRNAs in influencing the PI3K/Akt system in HCC. The study explores how lncRNAs, miRNAs, and circRNAs impact the expression as well as the function of the PI3K/Akt network, either supporting or preventing HCC growth. Additionally, treatment strategies focusing on ncRNAs in HCC are examined, such as antisense oligonucleotide-based methods, RNA interference, and small molecule inhibitor technologies. Emphasizing the necessity of ensuring safety and effectiveness in clinical settings, limitations, and future approaches in using ncRNAs as therapies for HCC are underlined. The present study offers useful insights into the complex regulation system of ncRNAs and the PI3K/Akt cascade in HCC, suggesting possible opportunities for developing innovative treatment approaches to address this lethal tumor.

Construction of Pseudomonas aeruginosa SDK-6 with synthetic lipase gene cassette and optimization of different parameters using response surface methodology for over-expression of recombinant lipase.

Lipases are industrially important enzymes having vast applications in various fields. Cloning and expression of lipase enzyme-encoding genes in suitable host lead to their widespread use in different fields. The present study represents the first attempt towards the expression of the synthetic lipase gene in Pseudomonas aeruginosa. An alkalophilic lipase gene (GenBank accession number: NP_388152) from Bacillus subtilis was synthetically designed and introduced in the pJN105 vector and subsequently cloned in Pseudomonas aeruginosa SDK-6. Agarose gel electrophoresis confirmed the transformation of SDK-6, exhibiting a band difference of ~ 700 bp between native and recombinant pJN105. Further amplification of cloned lipase gene was confirmed using PCR amplification with Lip 1 and Lip 2 primers respectively, followed by restriction analysis. Approximately 15-fold increase in lipase production was observed in recombinant Pseudomonas as compared to the native strain. One factor at a time (OFAT) analysis revealed L-arabinose, inoculum size (0.5%; v/v), and agitation (120 rpm) as significant factors affecting the over-expression of lipase enzyme. Optimization of enzyme induction conditions by central composite design (CCD) led to 1.60-fold increase in the production of lipase at 0.65% (w/v) inducer concentration, OD600-1.075 before induction and 35 °C post induction temperature with overall lipase production of 50.50 IU/mL. Statistical validation of observed value via ANOVA showed an F-value of 138.70 at p < 0.01 with R2 of 0.9921.

Bacterial cell death to overcome drug resistance with multitargeting bis-naphthalimides as potent antibacterial agents against Enterococcus faecalis.

The increasing frequency of drug-resistant pathogens poses serious health issues to humans around the globe, leading to the development of new antibacterial agents to conquer drug resistance and bacterial infections. In view of this, we have synthesized a series of bis-naphthalimides to respond to awful drug resistance. Bioactivity assay and structure-activity relationship disclosed that compounds 5d and 5o exhibit potent antibacterial activity against E. faecalis, outperforming the marketed antibiotics. These drug candidates not only inhibit the biofilm formation of E. faecalis but also display rapid bactericidal properties, thus delaying the development of drug resistance within 20 passages. To explore the mechanism of antibacterial activity against E. faecalis, biofunctional examination was carried out which unveiled that 5d and 5o effectively disrupt bacterial cell membranes, causing the leakage of cytoplasmic contents and metabolic activity loss. Concurrently, 5d and 5o effectively intercalate with DNA to block DNA replication, causing the build-up of excessive reactive oxygen species and inhibiting the glutathione activity, ultimately leading to oxidative damage of E. faecalis and cell death. In addition, these compounds readily bind with HSA with a high binding constant, indicating that these drug candidates could be easily delivered to the target site. The above finding manifested that these newly synthesized bis-naphthalimides with multitargeting antibacterial properties offer a new prospect to overcome drug resistance.

Dietary anti-inflammatory and anti-bacterial medicinal plants and its compounds in bovine mastitis associated impact on human life.

Bovine mastitis (BM) is the most common bacterial mediated inflammatory disease in the dairy cattle that causes huge economic loss to the dairy industry due to decreased milk quality and quantity. Milk is the essential food in the human diet, and rich in crucial nutrients that helps in lowering the risk of diseases like hypertension, cardiovascular diseases and type 2 diabetes. The main causative agents of the disease include various gram negative, and positive bacteria, along with other risk factors such as udder shape, age, genetic, and environmental factors also contributes much for the disease. Currently, antibiotics, immunotherapy, probiotics, dry cow, and lactation therapy are commonly recommended for BM. However, these treatments can only decrease the rise of new cases but can't eliminate the causative agents, and they also exhibit several limitations. Hence, there is an urgent need of a potential source that can generate a typical and ideal treatment to overcome the limitations and eliminate the pathogens. Among the various sources, medicinal plants and its derived products always play a significant role in drug discovery against several diseases. In addition, they are also known for its low toxicity and minimum resistance features. Therefore, plants and its compounds that possess anti-inflammatory and anti-bacterial properties can serve better in bovine mastitis. In addition, the plants that are serving as a food source and possessing pharmacological properties can act even better in bovine mastitis. Hence, in this evidence-based study, we particularly review the dietary medicinal plants and derived products that are proven for anti-inflammatory and anti-bacterial effects. Moreover, the role of each dietary plant and its compounds along with possible role in the management of bovine mastitis are delineated. In this way, this article serves as a standalone source for the researchers working in this area to help in the management of BM.

Investigating the Potential Therapeutic Mechanisms of Puerarin in Neurological Diseases.

Plants and their derived phytochemicals have a long history of treating a wide range of illnesses for several decades. They are believed to be the origin of a diverse array of medicinal compounds. One of the compounds found in kudzu root is puerarin, a isoflavone glycoside commonly used as an alternative medicine to treat various diseases. From a biological perspective, puerarin can be described as a white needle crystal with the chemical name of 7-hydroxy-3-(4-hydroxyphenyl)-1-benzopyran-4-one-8-D-glucopyranoside. Besides, puerarin is sparingly soluble in water and produces no color or light yellow solution. Multiple experimental and clinical studies have confirmed the significant therapeutic effects of puerarin. These effects span a wide range of pharmacological effects, including neuroprotection, hepatoprotection, cardioprotection, immunomodulation, anticancer properties, anti-diabetic properties, anti-osteoporosis properties, and more. Puerarin achieves these effects by interacting with various cellular and molecular pathways, such as MAPK, AMPK, NF-κB, mTOR, ß-catenin, and PKB/Akt, as well as different receptors, enzymes, and growth factors. The current review highlights the molecular mechanism of puerarin as a neuroprotective agent in the treatment of various neurodegenerative and neurological diseases. Extensive cellular, animal, and clinical research has provided valuable insights into its effectiveness in conditions such as Alzheimer's disease, Parkinson's disease, epilepsy, cerebral stroke, depression, and more.