Drug Design, Discovery and Therapy
Trends on Novel Targets and Nanotechnology-Based Drug Delivery System in the Treatment of Parkinson's disease: Recent Advancement in Drug Development
Parkinson's disease (PD) is a progressive neurodegenerative disorder that impacts a significant portion of the population. Despite extensive research an effective cure for PD remains elusive and conventional pharmacological treatments often face limitations in efficacy and management of symptoms. There has been a lot of discussion about using nanotechnology to increase the bioavailability of small- molecule drugs to target cells in recent years. It is possible that PD treatment might become far more effective and have fewer side effects if medication delivery mechanisms were to be improved. Potential alternatives to pharmacological therapy for molecular imaging and treatment of PD may lie in abnormal proteins such as parkin α-synuclein leucine-rich repeat serine and threonine protein kinase 2. Published research has demonstrated encouraging outcomes when nanomedicine-based approaches are used to address the challenges of PD therapy. So to address the present difficulties of antiparkinsonian treatment this review outlines the key issues and limitations of antiparkinsonian medications new therapeutic strategies and the breadth of delivery based on nanomedicine. This review covers a wide range of subjects including drug distribution in the brain the efficacy of drug-loaded nano-carriers in crossing the blood-brain barrier and their release profiles. In PD the nano-carriers are also used. Novel techniques of pharmaceutical delivery are currently made possible by vesicular carriers which eliminate the requirement to cross the blood-brain barrier (BBB).
Advances in Protein-Ligand Binding Affinity Prediction via Deep Learning: A Comprehensive Study of Datasets, Data Preprocessing Techniques, and Model Architectures
Drug discovery is a complex and expensive procedure involving several timely and costly phases through which new potential pharmaceutical compounds must pass to get approved. One of these critical steps is the identification and optimization of lead compounds which has been made more accessible by the introduction of computational methods including deep learning (DL) techniques. Diverse DL model architectures have been put forward to learn the vast landscape of interaction between proteins and ligands and predict their affinity helping in the identification of lead compounds.
This survey fills a gap in previous research by comprehensively analyzing the most commonly used datasets and discussing their quality and limitations. It also offers a comprehensive classification of the most recent DL methods in the context of protein-ligand binding affinity prediction (BAP) providing a fresh perspective on this evolving field.
We thoroughly examine commonly used datasets for BAP and their inherent characteristics. Our exploration extends to various preprocessing steps and DL techniques including graph neural networks convolutional neural networks and transformers which are found in the literature. We conducted extensive literature research to ensure that the most recent deep learning approaches for BAP were included by the time of writing this manuscript.
The systematic approach used for the present study highlighted inherent challenges to BAP via DL such as data quality model interpretability and explainability and proposed considerations for future research directions. We present valuable insights to accelerate the development of more effective and reliable DL models for BAP within the research community.
The present study can considerably enhance future research on predicting affinity between protein and ligand molecules hence further improving the overall drug development process.
Therapeutic Correlation of TLR-4 Mediated NF-κB Inflammatory Pathways in Ischemic Injuries
Ischemia-reperfusion (I/R) injury refers to the tissue damage that happens when blood flow returns to tissue after a period of ischemia. I/R injuries are implicated in a large array of pathological conditions such as cerebral myocardial renal intestinal retinal and hepatic ischemia. The hallmark of these pathologies is excessive inflammation. Toll-like receptors (TLRs) are recognized as significant contributors to inflammation caused by pathogens and more recently inflammation caused by injury. TLR-4 activation initiates a series of events that results in activation of nuclear factor kappa-B (NF-κB) which stimulates the production of pro-inflammatory cytokines and chemokines exacerbating tissue injury. Therefore through a comprehensive review of current research and experimentation this investigation elucidates the TLRs signalling pathway and the role of TLR-4/NF-κB in the pathophysiology of I/R injuries. Furthermore this review highlights the various pharmacological agents (TLR-4/NF-κB inhibitors) with special emphasis on the various ischemic injuries (cerebral myocardial renal intestinal retinal and hepatic). Future research should prioritise investigating the specific molecular pathways that cause TLR-4/NF-κB- mediated inflammation in ischemic injuries. Additionally efforts should be made to enhance treatment approaches in order to enhance patient outcomes.
Revolutionizing Skin Cancer Treatment: The Rise of PD-1/PDL-1 and CTLA-4 as Key Therapeutic Targets
Skin cancer is a significant health concern affecting millions of individuals globally on an annual basis. According to data from the World Health Organization it stands as the most prevalent form of cancer within the white population. Current treatments for skin cancer typically involve a combination of chemotherapy radiation therapy and surgery. However these methods often come with drawbacks such as side effects and potential scarring. Therefore there is a growing need for alternative treatments that can offer effective results with fewer adverse effects driving ongoing research in skin cancer therapy. The advancement of immune checkpoint inhibitors has been facilitated by a more profound comprehension of the interplay between tumors and the immune system along with the regulatory mechanisms governing T-cells. As cancer treatment continues to evolve immunotherapy is emerging as a powerful strategy leading to a growing interest in the role of immunological checkpoints in skin cancer. Various types of immune checkpoints and their expression including PD-1 PDL-1 CTLA-4 lymphocyte activation gene 3 and B7-H3 along with their blockers and monoclonal antibodies have been established for various cancers. PD-1 PDL-1 and CTLA-4 are crucial immune system regulators acting as brakes to prevent T-cell overactivation and potential autoimmunity. However tumors can exploit these checkpoints to evade immune detection. Inhibiting these immune checkpoints can enhance the body's ability to recognize and attack cancer cells. This review focuses on the characteristics of PD-1 PDL-1 and CTLA-4 immune checkpoints their mechanism of action and their role in skin cancer. Additionally it summarizes the ongoing clinical trials sponsored or conducted by various pharmaceutical companies and provides insights into the latest patent data.
Role of Vitamins in Therapeutic and Targeting Approaches for Prostate Cancer: An Overview
Vitamins play a crucial role in cellular functions like cell cycling and proliferation differentiation and apoptosis. These also help in the induction of cell cycle arrest and/or apoptosis. They can inhibit normal prostatic epithelial cell growth and might be helpful for the prevention of prostate cancer (PCa). Many essential vitamins including the fat-soluble vitamins (vitamin A vitamin D vitamin E and vitamin K) and the water-soluble vitamins (vitamin B complexes and vitamin C) have a huge impact on the inhibition of growth and progression of PCa. Vitamins show anticancer properties and are involved in regulatory processes like the DNA repairing process which inhibit the growth of PCa. Consumption of multivitamins prevents methylation of cancer cells and possesses an enormous potential that can be applied for the prevention as well as in the management of PCa. They have a great role in the inhibition of different signalling pathways involved in PCa. Moreover they have also displayed a significant role in targeting of PCa with various nanocarrier systems. This review encompasses the recent studies about the individual actions of different vitamins and vitamin analogs the combination of vitamins and their efficient functions in various therapeutic and targeting approaches for PCa.
Endogenous Ligands of TLR4 in Microglia: Potential Targets for Related Neurological Diseases
Chronic inflammation mediated by microglia is a cause of some neuroinflammatory diseases. TLR4 a natural immune receptor on microglia plays an important role in the occurrence of inflammation and the process of diseases. TLR4 can be activated by a variety of ligands to trigger inflammatory responses including endogenous ligands HMGB1 S100A8/9 Heme and Fetuin-A. As ligands derived from the body itself they have the ability to bind directly to TLR4 and can be used as inducers of aseptic inflammation. In the past 20 years targeting ligands rather than receptors has become an emerging therapeutic strategy for the treatment of diseases so understanding the relationship between microglia TLR4 TLR4 ligands and corresponding diseases may have new implications for the treatment of diseases. In the article we will discuss the TLR4 and the endogenous substances that can activate the TLR4 signaling pathway and present literature support for their role in neuroinflammatory diseases.
Promising New Targets for the Treatment of Infections Caused by Acinetobacter baumannii: A Review
Acinetobacter baumannii is a globally disseminated Gram-negative bacterium that causes several types of serious nosocomial infections the most worrisome being ventilator-associated pneumonia and bacteremia related to using venous catheters. Due to its great ability to form biofilms combined with its survival for prolonged periods on abiotic surfaces and its potential to acquire and control the genes that determine antibiotic resistance A. baumannii is at the top of the World Health Organization’s priority list of pathogens in urgent need of new therapies. In this sense this review aimed to present and discuss new molecular targets present in A. baumannii with potential for promising treatment approaches. This review highlights crucial molecular targets including cell division proteins membrane synthesis enzymes and biofilm-associated components offering promising targets for novel antimicrobial drug development against A. baumannii infections.
Beta-Hydroxybutyrate: A Supplemental Molecule for Various Diseases
β-hydroxybutyrate (BHB) is a ketone body that serves as an alternative energy source for various tissues including the brain heart and skeletal muscle. As a metabolic intermediate and signaling molecule BHB plays a crucial role in modulating cellular and physiological processes. Notably BHB supplementation offers a novel and promising strategy to induce nutritional ketosis without the need for strict dietary adherence or causing nutritional deficiencies. This review article provides an overview of BHB metabolism and explores its applications in age-related diseases. This review conducted a comprehensive search of PubMed ScienceDirect and other relevant English-language articles. The main findings were synthesized and discussed the challenges limitations and future directions of BHB supplementation. BHB supplementation holds potential benefits for various diseases and conditions including neurodegenerative disorders cardiovascular diseases cancers and inflammation. BHB acts through multiple mechanisms including interactions with cell surface receptors intracellular enzymes transcription factors signaling molecules and epigenetic modifications. Despite its promise BHB supplementation faces several challenges such as determining the optimal dosage ensuring long-term safety identifying the most effective type and formulation establishing biomarkers of response and conducting cost-effectiveness analyses. BHB supplementation opens exciting avenues for research including investigating molecular mechanisms refining optimization strategies exploring innovation opportunities and assessing healthspan and lifespan benefits. BHB supplementation represents a new frontier in health research offering a potential pathway to enhance well-being and extend lifespan.
Trends of Artificial Intelligence (AI) Use in Drug Targets, Discovery and Development: Current Status and Future Perspectives
The applications of artificial intelligence (AI) in pharmaceutical sectors have advanced drug discovery and development methods. AI has been applied in virtual drug design molecule synthesis advanced research various screening methods and decision-making processes. In the fourth industrial revolution when medical discoveries are happening swiftly AI technology is essential to reduce the costs effort and time in the pharmaceutical industry. Further it will aid “genome-based medicine” and “drug discovery.” AI may prepare proactive databases according to diseases disorders and appropriate usage of drugs which will facilitate the required data for the process of drug development. The application of AI has improved clinical trials on patient selection in a population stratification and sample assessment such as biomarkers effectiveness measures dosage selection and trial length. Various studies suggest AI could be perform better compared to conventional techniques in drug discovery. The present review focused on the positive impact of AI in drug discovery and development processes in the pharmaceutical industry and beneficial usage in health sectors as well.
Evaluation of a Kenaf Nanocrystalline Cellulose-based Hydrogel Containing Platelet Lysate for Full-thickness Wound Healing
Healing full-thickness wounds is often challenging and time-consuming with complications such as scarring and infections. The standard treatment split skin grafting has limitations due to the availability of healthy donors and suitability for immunocompromised patients.
Autologous platelet lysate (PL) has been popular for tissue regenerative potential because it contains growth factors (GF) and is a safer option for bedridden patients with weak immune systems. However PL has inconsistent clinical efficacy high costs and a short half-life. To address these issues this study explores a novel delivery system by fabricating a chitosan/nanocrystalline cellulose (CS/NCC) hydrogel to sustainably deliver autologous PL to the wound site. Notably NCC was prepared from kenaf bast fibers using acid hydrolysis and integrated into the CS matrix through physical entrapment without any chemical crosslinkers. The composite hydrogel was then enriched with autologous PL and further characterized for its physicochemical properties in vitro GF release and compatibility with skin cells. At the molecular level gene expression of wound healing genes was facilitated using qPCR revealing that the PL-supplemented hydrogel upregulated the expression of extracellular matrix genes. An in vivo study using a full-thickness wound model demonstrated that the CS-NCC-PL hydrogel dressing achieved 81.8% wound closure within 14 days compared to the control groups.
Histological analysis indicated enhanced re-epithelialization angiogenesis and collagen deposition. Particularly the CS-NCC-PL hydrogel group showed a significantly higher hydroxyproline content (60.62 ± 11.46 μg/100 mg) by day 14. Immunohistochemistry results revealed elevated levels of α-SMA and CD31 markers of myofibroblast presence and angiogenesis peaking at day 7.
These findings suggest that the CS-NCC-PL hydrogel is a promising personalized wound dressing for bedridden patients offering improved healing outcomes in hospital settings.
Phytovesicular Nanoconstructs for Advanced Delivery of Medicinal Metabolites: An In-Depth Review
Phytochemicals the bioactive compounds in plants possess therapeutic benefits such as antimicrobial antioxidant and pharmacological activities. However their clinical use is often hindered by poor bioavailability and stability. Phytosome technology enhances the absorption and efficacy of these compounds by integrating vesicular systems like liposomes niosomes transfersomes and ethosomes. Phytosomes offer diverse biological benefits including cardiovascular protection through improved endothelial function and oxidative stress reduction. They enhance cognitive function and protect against neurodegenerative diseases in the nervous system aid digestion and reduce inflammation in the gastrointestinal system and provide hepatoprotective effects by enhancing liver detoxification and protection against toxins. In the genitourinary system phytosomes improve renal function and exhibit anti-inflammatory properties. They also modulate the immune system by enhancing immune responses and reducing inflammation and oxidative stress. Additionally phytosomes promote skin health by protecting against UV radiation and improving hydration and elasticity. Recent patented phytosome technologies have led to innovative formulations that improve the stability bioavailability and therapeutic efficacy of phytochemicals although commercialization challenges like manufacturing scalability and regulatory hurdles remain. Secondary metabolites from natural products are classified into primary and secondary metabolites with a significant focus on terpenoids phenolic compounds and nitrogen-containing compounds. These metabolites have notable biological activities: antimicrobial antioxidant antibiotic antiviral anti-inflammatory and anticancer effects. In summary this review amalgamates the latest advancements in phytosome technology and secondary metabolite research presenting a holistic view of their potential to advance therapeutic interventions and contribute to the ever-evolving landscape of natural product-based medicine.
Prostaglandins in the Inflamed Central Nervous System: Potential Therapeutic Targets
The global burden of neurological disorders is evident yet there remains limited efficacious therapeutics for their treatment. There is a growing recognition of the role of inflammation in diseases of the central nervous system (CNS); among the numerous inflammatory mediators involved prostaglandins play a crucial role. Prostaglandins are small lipid mediators derived from arachidonic acid via multi-enzymatic pathways. The actions of prostaglandins are varied with each prostaglandin having a specific role in maintaining homeostasis. In the CNS prostaglandins can have neuroprotective or neurotoxic properties depending on their specific G-protein receptor. These G-protein receptors have varying subfamilies tissue distribution and signal transduction cascades. Further studies into the impact of prostaglandins in CNS-based diseases may contribute to the clarification of their actions hopefully leading to the development of efficacious therapeutic strategies. This review focuses on the roles played by prostaglandins in neural degeneration with a focus on Alzheimer’s Disease Multiple Sclerosis and Amyotrophic Lateral Sclerosis in both preclinical and clinical settings. We further discuss current prostaglandin-related agonists and antagonists concerning suggestions for their use as future therapeutics.
Comparative Analysis of Circular RNAs Expression and Function between Aortic and Intracranial Aneurysms
An aneurysm is an abnormal enlargement or bulging of the wall of a blood vessel. Most often aneurysms occur in large blood vessels - the aorta (Thoracic Aortic Aneurysm (TAA) and Abdominal Aortic Aneurysm (AAA)) and brain vessels (Intracranial Aneurysm (IA)). Despite the presence of significant differences in the pathogenesis of the development and progression of IA and TAA/AAA there are also similarities. For instance both have been shown to be strongly influenced by shear stress inflammatory processes and enzymatic destruction of the elastic lamellae and extracellular matrix (ECM) proteins of the vascular wall. Moreover although IA and TAA are predominantly considered arteriopathies with different pathological mechanisms they share risk factors with AAA such as hypertension and smoking. However there is a need for a more in-depth study of the key elements that may influence the formation and progression of a particular aneurysm to find ways of therapeutic intervention or search for a diagnostic tool. Today it is known that the disruption of gene expression is one of the main mechanisms that contribute to the development of aneurysms. At the same time growing evidence suggests that aberrant epigenetic regulation of gene function is strongly related to the genesis of aneurysms. Although much has been studied of the known protein-coding genes circular RNAs (circRNAs) a relatively new and rapidly evolving large family of transcripts have recently received much scientific attention. CircRNAs regulate gene expression through the sponging of microRNAs (miRNAs) and can also be used as therapeutic targets and biomarkers. Increasing evidence has implicated circRNAs in the pathogenesis of multiple cardiovascular diseases including the development of aneurysms. However the mechanism of dysregulation of certain circRNAs in a particular aneurysm remains to be studied. The discovery of circRNAs has recently advanced our understanding of the latest mode of miRNAs/target genes regulation in the development and progression of IA and TAA/AAA. The aim of this study is to compare the expression profiles of circRNAs to search for similar or different effects of certain circRNAs on the formation and progression of IA and TAA/AAA.
DRP1 Association in Inflammation and Metastasis: A Review
In recent years mitochondria have gained significant interest in the field of biomedical research due to their impact on aging human health and other advanced findings in metabolic functions. The latest finding shows that metabolic interventions are a leading cause of several diseases which has sparked interest in finding new therapeutic treatments. Apart from this the unique inheritance of genetic material from mother to offspring can help scientists find ways to prevent mitochondrial inherited diseases. Additionally the anti-aging benefits of controlling mitochondrial functions are also being researched. The present study aims to provide a cohesive overview of the latest findings in mitochondrial research focusing on the role of DRP1 (Dynamin-related protein 1) a member of the GTPase family in mediating mitochondrial fission. The first section of this paper provides a concise explanation of how DRP1 controls processes such as mitophagy and mitochondrial fission. Subsequently the paper delves into the topic of inflammation discussing the current findings regarding the inflammatory response mediated by DRP1. Finally the role of mitochondrial fission mediated by DRP1 in cancer is examined reviewing ongoing research on various types of cancer and their recurrence. Moreover this review also covers the epigenetic regulation of mitochondrial fission. The studies were selected and evaluated and the information was collected to present an overview of the key findings. By exploring various aspects of research and potential links we hope to contribute to a deeper understanding of the intricate relationship between the fields of cancer research and inflammation studies with respect to mitochondrial-based research.
Trends on Nanomedicines as Novel therapeutics Approach in Targeting Nociceptors for Relieving Pain
An important sensation that warns of potential harm to a specific area of the body is pain. The prevalence of pain-related conditions globally is a significant and growing public health issue. Chronic pain affects an estimated 1.5 billion people worldwide with prevalence rates varying by region and demographic factors. Along with diabetes cardiovascular disease and cancer pain is among the most frequent medical diseases. Opioid analgesics are the mainstay of current pain therapies which are ineffective. Opioid addiction and its potentially fatal side effects necessitate novel treatment strategies. Nanotechnology offers potential advantages in pain management by enabling targeted drug delivery which can enhance the efficacy and reduce the side effects of analgesic medications. Additionally nanoparticles can be designed to release drugs in a controlled manner improving pain relief duration and consistency. This approach also allows for the delivery of therapeutics across biological barriers potentially enhancing treatment outcomes for chronic pain conditions. Nanomedicine enables sensitive and focused treatments with fewer side effects than existing clinical pain medicines; it is worth exploring as a potential solution to these problems. Furthermore medication delivery systems that use nanomaterials are being used to treat pain. Whether it's the distribution of a single medication or a combination of therapies this review seeks to summarise the ways in which drug delivery systems based on nanomaterials can be utilised to successfully treat and alleviate pain. For the purpose of writing this paper we consulted several online libraries including Pubmed Science Direct Pubmed Prime and the Cochrane Library to gather fresh and up-to-date material. This overview delves into the ins and outs of pain's pathophysiology the present state of pain treatment potential new pain treatment targets and the various initiatives that have been launched and are still in the works to address pain with nanotechnology. Recent developments in nanomaterials-based scavenging gene therapy for pain aetiology and nanoparticle-based medicine delivery for side effect reduction are highlighted. Analgesics have been further covered in our discussion on FDA-approved pharmaceuticals and clinical advancements.
Joint Screening and Identification of Potential Targets of Nitazoxanide by Affinity Chromatography and Label-Free Techniques
Nitazoxanide not only exhibits a broad spectrum of activities against various pathogens infecting animals and humans but also induces cellular autophagy. Currently the pattern of action and subcellular targets of nitazoxanide-induced cellular autophagy are still unclear.
To identify potential targets of nitazoxanide in mammalian cells we developed an affinity chromatography system using tizoxanide a deacetyl derivative of nitazoxanide as a ligand. Affinity chromatography was performed using VERO cell extracts on tizoxanide-biotin and the isolated binding proteins were identified by mass spectrometry. Candidate target proteins obtained using affinity chromatography were co-analysed with the drug affinity response target stability method. Fluorescent probes obtained by coupling rhodamine B to nitazoxanide were used for intracellular localisation of the binding targets. Solvent-induced protein precipitation profiling and thermal proteome profiling were used to further validate the binding proteins.
The joint analysis of the drug affinity response target stability method and affinity chromatography resulted in the screening of six possible candidate target proteins. Fluorescent probes localised the nitazoxanide-binding protein around the nuclear membrane. Molecular docking revealed that the binding proteins mainly formed hydrogen bonds with the nitro group of nitazoxanide. Solvent-induced protein precipitation profiling and thermal proteome profiling further validated SEC61A PSMD12 and PRKAG1 as potential target proteins of nitazoxanide.
The data supports the idea that nitazoxanide is a multifunctional compound with multiple targets.
Recent Advances in the Development of Alpha-Glucosidase and Alpha-Amylase Inhibitors in Type 2 Diabetes Management: Insights from In silico to In vitro Studies
Diabetes is a metabolic disorder caused by high glucose levels leading to serious threats such as diabetic neuropathy and cardiovascular diseases. One of the most reliable measures for controlling postprandial hyperglycemia is to reduce the glucose level by inhibiting enzymes in the digestive system such as Alpha-Glucosidase and Alpha-Amylase. Here we have investigated the use of inhibitors to inhibit carbohydrate metabolism in order to restrict glucose levels in diabetic patients. Acarbose Voglibose and Miglitol are three inhibitors approved by the FDA that efficiently inhibit these two enzymes and thereby minimising hyperglycemia but are also significantly helpful in reducing the risk of cardiovascular effects. We also provide insight into the other known inhibitors currently available in the market. The adverse effects associated with other inhibitors emphasise the demand for the latest in silico screening and in vitro validation in the development of potent inhibitors with greater efficacy and safety for the treatment of Type 2 diabetes. The recent findings suggest that Alpha-Glucosidase and Alpha-Amylase play a major role in carbohydrate metabolism and triggering the increase in glucose levels. This review provides the latest scientific literature findings related to these two enzymes as well as the role of primary and secondary inhibitors as potential candidates. Moreover this review elaborates the framework on the mechanism of action different plant sources of extraction of these enzymes as well as kinetic assay of inhibitors and their interaction that can be used in future prospects to develop potential leads to combat Type 2 diabetes.
In Vivo Models of Steroid-Induced Intraocular Hypertension
Corticosteroids are widely utilized for their anti-inflammatory and immunosuppressive properties but often lead to ocular complications including ocular hypertension. If untreated ocular hypertension can progress to optic nerve atrophy and eventually result in steroid-induced glaucoma which poses a risk of irreversible visual damage. Approximately 40% of individuals experience increased intraocular pressure after steroid use and around 6% develop glaucoma. Although steroid-induced glaucoma is usually temporary and reversible if the treatment duration is under a year prolonged exposure can cause permanent vision impairment. The pathogenesis of steroid-induced glaucoma is suggested to arise from increased outflow resistance of aqueous humor primarily due to decreased expression of matrix metalloproteinases. This deficiency promotes the deposition of extracellular matrix and the dysfunction of trabecular meshwork cells. Additionally modifications in the actin cytoskeleton increase the stiffness and alter the morphology of trabecular meshwork further impeding aqueous humor outflow. Molecular changes such as elevated expression of the MYOC gene have also been implicated in restricting aqueous outflow. Various animal models including rats mice primates rabbits cattle sheep cats and dogs have been developed to study steroid-induced glaucoma. These models exhibit pathological pathophysiological and molecular similarities to human disease making them valuable for research. This review aims to summarize common animal models of steroid-induced ocular hypertension discussing their advantages and limitations. The goal is to help researchers select appropriate models for future studies thereby advancing the understanding of disease mechanisms and developing preventive strategies.