Novel antiviral approaches for Marburg: a promising therapeutics in the pipeline.

Marburg virus disease (MVD) presents a significant global health threat, lacking effective antivirals and with current supportive care offering limited therapeutic options. This mini review explores the emerging landscape of novel antiviral strategies against MVD, focusing on promising therapeutics currently in the development pipeline. We delve into direct-acting antiviral approaches, including small molecule inhibitors targeting viral entry, replication, and assembly, alongside nucleic acid antisense and RNA interference strategies. Host-targeting antivirals are also considered, encompassing immune modulators like interferons and cytokine/chemokine modulators, broad-spectrum antivirals, and convalescent plasma and antibody-based therapies. The paper then examines preclinical and clinical development for the novel therapeutics, highlighting in vitro and in vivo models for antiviral evaluation, safety and efficacy assessments, and the critical stages of clinical trials. Recognizing the challenges of drug resistance and viral escape, the mini review underscores the potential of combination therapy strategies and emphasizes the need for rapid diagnostic tools to optimize treatment initiation. Finally, we discuss the importance of public health preparedness and equitable access to these promising therapeutics in achieving effective MVD control and global health security. This mini review presents a comprehensive overview of the burgeoning field of MVD antivirals, highlighting the potential of these novel approaches to reshape the future of MVD treatment and prevention.

Single nucleotide polymorphism-based biomarker in primary hypertension.

Primary hypertension is a multiplex and multifactorial disease influenced by various strong components including genetics. Extensive research such as Genome-wide association studies and candidate gene studies have revealed various single nucleotide polymorphisms (SNPs) related to hypertension, providing insights into the genetic basis of the condition. This review summarizes the current status of SNP research in primary hypertension, including examples of hypertension-related SNPs, their location, function, and frequency in different populations. The potential clinical implications of SNP research for primary hypertension management are also discussed, including disease risk prediction, personalized medicine, mechanistic understanding, and lifestyle modifications. Furthermore, this review highlights emerging technologies and methodologies that have the potential to revolutionize the vast understanding of the basis of genetics in primary hypertension. Gene editing holds the potential to target and correct any kind of genetic mutations that contribute to the development of hypertension or modify genes involved in blood pressure regulation to prevent or treat the condition. Advances in computational biology and machine learning enable researchers to analyze large datasets and identify complex genetic interactions contributing to hypertension risk. In conclusion, SNP research in primary hypertension is rapidly evolving with emerging technologies and methodologies that have the potential to transform the knowledge about genetic basis related to the condition. These advances hold promise for personalized prevention and treatment strategies tailored to an individual's genetic profile ultimately improving patient outcomes and reducing healthcare costs.

Predictive Modelling in pharmacokinetics: from in-silico simulations to personalized medicine.

INTRODUCTION: Pharmacokinetic parameters assessment is a critical aspect of drug discovery and development, yet challenges persist due to limited training data. Despite advancements in machine learning and in-silico predictions, scarcity of data hampers accurate prediction of drug candidates' pharmacokinetic properties. AREAS COVERED: The study highlights current developments in human pharmacokinetic prediction, talks about attempts to apply synthetic approaches for molecular design, and searches several databases, including Scopus, PubMed, Web of Science, and Google Scholar. The article stresses importance of rigorous analysis of machine learning model performance in assessing progress and explores molecular modeling (MM) techniques, descriptors, and mathematical approaches. Transitioning to clinical drug development, article highlights AI (Artificial Intelligence) based computer models optimizing trial design, patient selection, dosing strategies, and biomarker identification. In-silico models, including molecular interactomes and virtual patients, predict drug performance across diverse profiles, underlining the need to align model results with clinical studies for reliability. Specialized training for human specialists in navigating predictive models is deemed critical. Pharmacogenomics, integral to personalized medicine, utilizes predictive modeling to anticipate patient responses, contributing to more efficient healthcare system. Challenges in realizing potential of predictive modeling, including ethical considerations and data privacy concerns, are acknowledged. EXPERT OPINION: AI models are crucial in drug development, optimizing trials, patient selection, dosing, and biomarker identification and hold promise for streamlining clinical investigations.

Radiopharmaceuticals: navigating the frontier of precision medicine and therapeutic innovation.

This review article explores the dynamic field of radiopharmaceuticals, where innovative developments arise from combining radioisotopes and pharmaceuticals, opening up exciting therapeutic possibilities. The in-depth exploration covers targeted drug delivery, delving into passive targeting through enhanced permeability and retention, as well as active targeting using ligand-receptor strategies. The article also discusses stimulus-responsive release systems, which orchestrate controlled release, enhancing precision and therapeutic effectiveness. A significant focus is placed on the crucial role of radiopharmaceuticals in medical imaging and theranostics, highlighting their contribution to diagnostic accuracy and image-guided curative interventions. The review emphasizes safety considerations and strategies for mitigating side effects, providing valuable insights into addressing challenges and achieving precise drug delivery. Looking ahead, the article discusses nanoparticle formulations as cutting-edge innovations in next-generation radiopharmaceuticals, showcasing their potential applications. Real-world examples are presented through case studies, including the use of radiolabelled antibodies for solid tumors, peptide receptor radionuclide therapy for neuroendocrine tumors, and the intricate management of bone metastases. The concluding perspective envisions the future trajectory of radiopharmaceuticals, anticipating a harmonious integration of precision medicine and artificial intelligence. This vision foresees an era where therapeutic precision aligns seamlessly with scientific advancements, ushering in a new epoch marked by the fusion of therapeutic resonance and visionary progress.

Unveiling the potential of proteomic and genetic signatures for precision therapeutics in lung cancer management.

Lung cancer's enduring global significance necessitates ongoing advancements in diagnostics and therapeutics. Recent spotlight on proteomic and genetic biomarker research offers a promising avenue for understanding lung cancer biology and guiding treatments. This review elucidates genetic and proteomic lung cancer biomarker progress and their treatment implications. Technological strides in mass spectrometry-based proteomics and next-generation sequencing enable pinpointing of genetic abnormalities and abnormal protein expressions, furnishing vital data for precise diagnosis, patient classification, and customized treatments. Biomarker-driven personalized medicine yields substantial treatment improvements, elevating survival rates and minimizing adverse effects. Integrating omics data (genomics, proteomics, etc.) enhances understanding of lung cancer's intricate biological milieu, identifying novel treatment targets and biomarkers, fostering precision medicine. Liquid biopsies, non-invasive tools for real-time treatment monitoring and early resistance detection, gain popularity, promising enhanced management and personalized therapy. Despite advancements, biomarker repeatability and validation challenges persist, necessitating interdisciplinary efforts and large-scale clinical trials. Integrating artificial intelligence and machine learning aids analyzing vast omics datasets and predicting treatment responses. Single-cell omics reveal cellular connections and intratumoral heterogeneity, valuable for combination treatments. Biomarkers enable accurate diagnosis, tailored medicines, and treatment response tracking, significantly impacting personalized lung cancer care. This approach spurs patient-centered trials, empowering active patient engagement. Lung cancer proteomic and genetic biomarkers illuminate disease biology and treatment prospects. Progressing towards individualized efficient therapies is imminent, alleviating lung cancer's burden through ongoing research, omics integration, and technological strides.

Emergence of Marburg virus: a global perspective on fatal outbreaks and clinical challenges.

The Marburg virus (MV), identified in 1967, has caused deadly outbreaks worldwide, the mortality rate of Marburg virus disease (MVD) varies depending on the outbreak and virus strain, but the average case fatality rate is around 50%. However, case fatality rates have varied from 24 to 88% in past outbreaks depending on virus strain and case management. Designated a priority pathogen by the National Institute of Allergy and Infectious Diseases (NIAID), MV induces hemorrhagic fever, organ failure, and coagulation issues in both humans and non-human primates. This review presents an extensive exploration of MVD outbreak evolution, virus structure, and genome, as well as the sources and transmission routes of MV, including human-to-human spread and involvement of natural hosts such as the Egyptian fruit bat (Rousettus aegyptiacus) and other Chiroptera species. The disease progression involves early viral replication impacting immune cells like monocytes, macrophages, and dendritic cells, followed by damage to the spleen, liver, and secondary lymphoid organs. Subsequent spread occurs to hepatocytes, endothelial cells, fibroblasts, and epithelial cells. MV can evade host immune response by inhibiting interferon type I (IFN-1) synthesis. This comprehensive investigation aims to enhance understanding of pathophysiology, cellular tropism, and injury sites in the host, aiding insights into MVD causes. Clinical data and treatments are discussed, albeit current methods to halt MVD outbreaks remain elusive. By elucidating MV infection's history and mechanisms, this review seeks to advance MV disease treatment, drug development, and vaccine creation. The World Health Organization (WHO) considers MV a high-concern filovirus causing severe and fatal hemorrhagic fever, with a death rate ranging from 24 to 88%. The virus often spreads through contact with infected individuals, originating from animals. Visitors to bat habitats like caves or mines face higher risk. We tailored this search strategy for four databases: Scopus, Web of Science, Google Scholar, and PubMed. we primarily utilized search terms such as "Marburg virus," "Epidemiology," "Vaccine," "Outbreak," and "Transmission." To enhance comprehension of the virus and associated disease, this summary offers a comprehensive overview of MV outbreaks, pathophysiology, and management strategies. Continued research and learning hold promise for preventing and controlling future MVD outbreaks. GRAPHICAL ABSTRACT.

Biodegradable Electrospun Scaffolds as an Emerging Tool for Skin Wound Regeneration: A Comprehensive Review.

Skin is designed to protect various tissues, and because it is the largest and first human bodily organ to sustain damage, it has an incredible ability to regenerate. On account of extreme injuries or extensive surface loss, the normal injury recuperating interaction might be inadequate or deficient, bringing about risky and disagreeable circumstances that request the utilization of fixed adjuvants and tissue substitutes. Due to their remarkable biocompatibility, biodegradability, and bioactive abilities, such as antibacterial, immunomodulatory, cell proliferative, and wound mending properties, biodegradable polymers, both synthetic and natural, are experiencing remarkable progress. Furthermore, the ability to convert these polymers into submicrometric filaments has further enhanced their potential (e.g., by means of electrospinning) to impersonate the stringy extracellular grid and permit neo-tissue creation, which is a basic component for delivering a mending milieu. Together with natural biomaterial, synthetic polymers are used to solve stability problems and make scaffolds that can dramatically improve wound healing. Biodegradable polymers, commonly referred to as biopolymers, are increasingly used in other industrial sectors to reduce the environmental impact of material and energy usage as they are fabricated using renewable biological sources. Electrospinning is one of the best ways to fabricate nanofibers and membranes that are very thin and one of the best ways to fabricate continuous nanomaterials with a wide range of biological, chemical, and physical properties. This review paper concludes with a summary of the electrospinning (applied electric field, needle-to-collector distance, and flow rate), solution (solvent, polymer concentration, viscosity, and solution conductivity), and environmental (humidity and temperature) factors that affect the production of nanofibers and the use of bio-based natural and synthetic electrospun scaffolds in wound healing.

The Global Monkeypox (Mpox) Outbreak: A Comprehensive Review.

Monkeypox (Mpox) is a contagious illness that is caused by the monkeypox virus, which is part of the same family of viruses as variola, vaccinia, and cowpox. It was first detected in the Democratic Republic of the Congo in 1970 and has since caused sporadic cases and outbreaks in a few countries in West and Central Africa. In July 2022, the World Health Organization (WHO) declared a public-health emergency of international concern due to the unprecedented global spread of the disease. Despite breakthroughs in medical treatments, vaccines, and diagnostics, diseases like monkeypox still cause death and suffering around the world and have a heavy economic impact. The 85,189 reported cases of Mpox as of 29 January 2023 have raised alarm bells. Vaccines for the vaccinia virus can protect against monkeypox, but these immunizations were stopped after smallpox was eradicated. There are, however, treatments available once the illness has taken hold. During the 2022 outbreak, most cases occurred among men who had sex with men, and there was a range of 7-10 days between exposure and the onset of symptoms. Three vaccines are currently used against the Monkeypox virus. Two of these vaccines were initially developed for smallpox, and the third is specifically designed for biological-terrorism protection. The first vaccine is an attenuated, nonreplicating smallpox vaccine that can also be used for immunocompromised individuals, marketed under different names in different regions. The second vaccine, ACAM2000, is a recombinant second-generation vaccine initially developed for smallpox. It is recommended for use in preventing monkeypox infection but is not recommended for individuals with certain health conditions or during pregnancy. The third vaccine, LC16m8, is a licensed attenuated smallpox vaccine designed to lack the B5R envelope-protein gene to reduce neurotoxicity. It generates neutralizing antibodies to multiple poxviruses and broad T-cell responses. The immune response takes 14 days after the second dose of the first two vaccines and 4 weeks after the ACAM2000 dose for maximal immunity development. The efficacy of these vaccines in the current outbreak of monkeypox is uncertain. Adverse events have been reported, and a next generation of safer and specific vaccines is needed. Although some experts claim that developing vaccines with a large spectrum of specificity can be advantageous, epitope-focused immunogens are often more effective in enhancing neutralization.

Wnt/ß-catenin antagonist pyrvinium rescues high dose isoproterenol induced cardiotoxicity in rats: Biochemical and immunohistological evidences.

The up-regulation of Wnt/ß-catenin pathway induces cardiac function abnormalities, hypertrophy, and fibrosis in diabetic hypertensive and pressure overload models. The present study investigates the cardioprotective effects of Wnt/ß-catenin inhibition on isoproterenol (ISO) induced cardiotoxicity in rats. ISO was administered at a dose of 85 mg/kg (s.c) for 2 days. Wnt/ß-catenin inhibitor pyrvinium (60 µg/kg, p.o) was given 2h prior and glibenclamide at a dose of 5 mg/kg; p.o, 2 h after ISO injection. Cardiac function parameters were assessed on isolated hearts by using automated Biopac apparatus. The ß-catenin transcription and expression was detected by RT-PCR technique and immunohistochemical method. Serum and cardiac tissue biochemical changes including cardiac troponin-I, CK-MB, LDH, anti-oxidant enzyme levels, inflammatory cytokines, and membrane associated Na+/K + ATPase and Ca2+ATPase and caspase-3 activity, collagen content, fibronectin protein levels were evaluated in various study groups. Histological studies were also carried out to analyze the cardiomyocyte damage, hypertrophy, fibrosis, and necrosis, while α-SMA, TGF-ß expression was checked by immunostaining. ISO administration enhanced ß-catenin gene expression and transcription which promoted oxidative and nitrosative stress, inflammatory cytokine release, reduced ATP levels, induced over-expression of fibrotic proteins resulting in cardiac hypertrophy, myocardial necrosis, functional and histological changes. However, antagonism of Wnt/ß-catenin pathway attenuated these ISO induced pathological manifestations. Notably, the co-treatment with ATP-sensitive K+ channel inhibitor partially, reduced the cardioprotective effects of Wnt/ß-catenin blocker pyrvinium in ISO rats. Thus Wnt/ß-catenin inhibition exhibits cardioprotective in ISO model by anti-oxidant, anti-inflammatory, anti-fibrotic properties and by possible involvement of ATP-sensitive potassium channel activation.

Platelet-rich plasma exhibits anti-inflammatory effect and attenuates cardiomyocyte damage by reducing NF-κB and enhancing VEGF expression in isoproterenol induced cardiotoxicity model.

The present study investigated the cardioprotective effects of activated platelet-rich plasma (PRP) on high dose isoproterenol (ISO) induced cardiotoxicity. ISO was injected at a dose of 85 mg/kg/day, s.c. for 2 days. Cardiac function parameters including dp/dt max/min, left ventricular end diastolic pressure (LVEDP), relaxation constant (tau) and electrocardiogram (ECG) changes, anti-oxidant and membrane bound enzymes assays, pro-inflammatory cytokine levels, collagen content, immunohistochemical staining/gene expression of vascular endothelial growth factor (VEGF), cTnI (cardiac troponin I), NF-κB (nuclear factor kappa B), Smad-2/3, TGF-ß (transforming growth factor), collagen-1/3 proteins were evaluated. PRP and platelet-poor plasma (PPP) were injected intramyocardially (200 µl in each ventricle region) 3 h after first dose of ISO under anesthesia. ISO injection induced cardiac dysfunction, hypertrophy, fibrosis, necrosis due to decline in anti-oxidant capacity, enhanced NF-κB and reduced cTnI immunostaining. However, the PRP injection attenuated these cardiac pathological changes by exerting anti-inflammatory properties and promoting cardiomyocyte repair.

Evolution of ß-catenin-independent Wnt-GSK3-mTOR signalling in regulation of energy metabolism in isoproterenol-induced cardiotoxicity model.

OBJECTIVE: Isoproterenol (ISO) is widely used agent to study the effects of interventions which could prevent or attenuate the development of myocardial infarction. The sequence of pathological event's revealed that increased myocardial tissue oxygen demand and energy dysregulation exist early during Iso-induced cardiac toxicity. Later, tissue hypoxia results in increased oxidative stress, inflammation and fibrosis along with cardiac dysfunction in this model. The canonical Wnt/ß-catenin pathway has been reported to directly implicate in inducing cardiomyocyte hypertrophy and remodelling. However, less is known about the role of non-canonical Wnt signalling in cardiac diseases. METHOD: Certain evidences have suggested that the activation of Wnt could up-regulate key energy sensor and cell growth regulator mTOR (Mechanistic target of rapamycin) by inhibition of GSK-3ß mediator. RESULT: The GSK-3ß could negatively influence the mTOR activity and produce energy dysregulation during stress or hypoxic conditions. This suggests that the inhibition of GSK-3ß by Wnt signalling could up-regulate mTOR levels and thereby restore early myocardial tissue energy balance and prevent cardiac toxicity in rodents. CONCLUSION: We hereby discuss a novel therapeutic role of the ß-catenin independent, Wnt-GSK3-mTOR axis in attenuation of Iso-induced cardiotoxicity in rodents.