ncRNAs and Their Impact on Dopaminergic Neurons: Autophagy Pathways in Parkinson's Disease.

Parkinson's Disease (PD) is a complex neurological illness that causes severe motor and non-motor symptoms due to a gradual loss of dopaminergic neurons in the substantia nigra. The aetiology of PD is influenced by a variety of genetic, environmental, and cellular variables. One important aspect of this pathophysiology is autophagy, a crucial cellular homeostasis process that breaks down and recycles cytoplasmic components. Recent advances in genomic technologies have unravelled a significant impact of ncRNAs on the regulation of autophagy pathways, thereby implicating their roles in PD onset and progression. They are members of a family of RNAs that include miRNAs, circRNA and lncRNAs that have been shown to play novel pleiotropic functions in the pathogenesis of PD by modulating the expression of genes linked to autophagic activities and dopaminergic neuron survival. This review aims to integrate the current genetic paradigms with the therapeutic prospect of autophagy-associated ncRNAs in PD. By synthesizing the findings of recent genetic studies, we underscore the importance of ncRNAs in the regulation of autophagy, how they are dysregulated in PD, and how they represent novel dimensions for therapeutic intervention. The therapeutic promise of targeting ncRNAs in PD is discussed, including the barriers that need to be overcome and future directions that must be embraced to funnel these ncRNA molecules for the treatment and management of PD.

Mechanistic correlation of molecular pathways in obesity-mediated stroke pathogenesis.

Obesity, a prominent risk factor for the development of heart attacks and several cardiovascular ailments. Obesity ranks as the second most significant avoidable contributor to mortality, whereas stroke stands as the second leading cause of death on a global scale. While changes in lifestyle have been demonstrated to have significant impacts on weight management, the long-term weight loss remains challenging, and the global prevalence of obesity continues to rise. The pathophysiology of obesity has been extensively studied during the last few decades, and an increasing number of signal transduction pathways have been linked to obesity preclinically. This review is focused on signaling pathways, and their respective functions in regulating the consumption of fatty food as well as accumulation of adipose tissue, and the resulting morphological and cognitive changes in the brain of individuals with obesity. We have also emphasized the recent progress in the mechanisms behind the emergence of obesity, as elucidated by both experimental and clinical investigations. The mounting understanding of signaling transduction may shed light on the future course of obesity research as we move into a new era of precision medicine.

Exploring ncRNA-mediated regulation of EGFR signalling in glioblastoma: From mechanisms to therapeutics.

Glioblastoma (GBM) is the most prevalent and deadly primary brain tumor type, with a discouragingly low survival rate and few effective treatments. An important function of the EGFR signalling pathway in the development of GBM is to affect tumor proliferation, persistence, and treatment resistance. Advances in molecular biology in the last several years have shown how important ncRNAs are for controlling a wide range of biological activities, including cancer progression and development. NcRNAs have become important post-transcriptional regulators of gene expression, and they may affect the EGFR pathway by either directly targeting EGFR or by modifying important transcription factors and downstream signalling molecules. The EGFR pathway is aberrantly activated in response to the dysregulation of certain ncRNAs, which has been linked to GBM carcinogenesis, treatment resistance, and unfavourable patient outcomes. We review the literature on miRNAs, circRNAs and lncRNAs that are implicated in the regulation of EGFR signalling in GBM, discussing their mechanisms of action, interactions with the signalling pathway, and implications for GBM therapy. Furthermore, we explore the potential of ncRNA-based strategies to overcome resistance to EGFR-targeted therapies, including the use of ncRNA mimics or inhibitors to modulate the activity of key regulators within the pathway.

Unveiling the Role of PAR 1: A Crucial Link with Inflammation in Diabetic Subjects with COVID-19.

Inflammation is a distinguished clinical manifestation of COVID-19 and type 2 diabetes mellitus (T2DM), often associated with inflammatory dysfunctions, insulin resistance, metabolic dysregulation, and other complications. The present study aims to test the hypothesis that serum concentrations of PAR-1 levels differ between COVID-19 diabetic patients (T2DM) and non-diabetic COVID-19 patients and determine their association with different biochemical parameters and inflammatory biomarkers. T2DM patients with COVID-19 (n = 50) with glycated hemoglobin (HbA1c) levels of (9.23 ± 1.66) and non-diabetic COVID-19 patients (n = 50) with HbA1c levels (4.39 ± 0.57) were recruited in this study. The serum PAR-1 levels (ELISA method) were determined in both groups and correlated with parameters such as age, BMI, inflammatory markers including CRP, interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), D-dimer, homocysteine, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Demographic variables such as BMI (29.21 ± 3.52 vs. controls 21.30 ± 2.11) and HbA1c (9.23 ± 1.66 vs. controls 4.39 ± 0.57) were found to be statistically elevated in COVID-19 T2DM patients compared to non-diabetic COVID-19 patients. The concentrations of several inflammatory biomarkers and PAR-1 were remarkably increased in the COVID-19 T2DM group when compared with the non-diabetic COVID-19 group. The univariate analysis revealed that increased serum PAR-1 estimations were positively correlated with enhanced HbA1c, BMI, inflammatory cytokines, D-dimer, homocysteine, and NT-proBNP. The findings in the current study suggest that increased levels of serum PAR-1 in the bloodstream could potentially serve as an independent biomarker of inflammation in COVID-19 patients with T2DM.

Cross Talks between CNS and CVS Diseases: An Alliance to Annihilate.

Cardiovascular and neurological diseases cause substantial morbidity and mortality globally. Moreover, cardiovascular diseases are the leading cause of death globally. About 17.9 million people are affected by cardiovascular diseases and 6.8 million people die every year due to neurological diseases. The common neurologic manifestations of cardiovascular illness include stroke syndrome which is responsible for unconsciousness and several other morbidities significantly diminished the quality of life of patients. Therefore, it is prudent need to explore the mechanistic and molecular connection between cardiovascular disorders and neurological disorders. The present review emphasizes the association between cardiovascular and neurological diseases specifically Parkinson's disease, Alzheimer's disease, and Huntington's disease.

Sirtuin dysregulation in Parkinson's disease: Implications of acetylation and deacetylation processes.

Parkinson's disease (PD) is a progressive neurodegenerative condition that primarily affects motor function and is caused by a gradual decline of dopaminergic neurons in the brain's substantia pars compacta (Snpc) region. Multiple molecular pathways are involved in the pathogenesis, which results in impaired cellular functions and neuronal degeneration. However, the role of sirtuins, a type of NAD+-dependent deacetylase, in the pathogenesis of Parkinson's disease has recently been investigated. Sirtuins are essential for preserving cellular homeostasis because they control a number of biological processes, such as metabolism, apoptosis, and DNA repair. This review shed lights on the dysregulation of sirtuin activity in PD, highlighting the role that acetylation and deacetylation processes play in the development of the disease. Key regulators of protein acetylation, sirtuins have been found to be involved in the aberrant acetylation of vital substrates linked to PD pathology when their balance is out of balance. The hallmark characteristics of PD such as neuroinflammation, oxidative stress, and mitochondrial dysfunction have all been linked to the dysregulation of sirtuin expression and activity. Furthermore, we have also explored how the modulators of sirtuins can be a promising therapeutic intervention in the treatment of PD.

Pyrazoline Derivatives as Promising MAO-A Targeting Antidepressants: An Update.

Depression is one of the key conditions addressed by the Mental Health Gap Action Programme (mhGAP) of WHO that can lead to self-harm and suicide. Depression is associated with low levels of neurotransmitters, which eventually play a key role in the progression and development of mental illness. The nitrogen-containing heterocyclic compounds exhibit the most prominent pharmacological profile as antidepressants. Pyrazoline, a dihydro derivative of pyrazole, is a well-known five-membered heterocyclic moiety that exhibits a broad spectrum of biological activities. Many researchers have reported pyrazoline scaffold-containing molecules as potential antidepressant agents with selectivity for monoamine oxidase enzyme (MAO) isoforms. Several studies indicated a better affinity of pyrazoline-based moiety as (monoamine oxidase inhibitors) MAOIs. In this review, we have focused on the recent advancements (2019-2023) in the development of pyrazoline-containing derivatives exhibiting promising inhibition of MAO-A enzyme to treat depression. This review provides structural insights on pyrazoline-based molecules along with their SAR analysis, in silico exploration of binding interactions between pyrazoline derivatives and MAO-A enzyme, and clinical trial status of various drug molecules against depression. The in-silico exploration of potent pyrazoline derivatives at the active site of the MAOA enzyme will provide further insights into the development of new potential MAO-A inhibitors for the treatment of depression.

Opening avenues for treatment of neurodegenerative disease using post-biotics: Breakthroughs and bottlenecks in clinical translation.

Recent studies have indicated the significant involvement of the gut microbiome in both human physiology and pathology. Additionally, therapeutic interventions based on microbiome approaches have been employed to enhance overall health and address various diseases including aging and neurodegenerative disease (ND). Researchers have explored potential links between these areas, investigating the potential pathogenic or therapeutic effects of intestinal microbiota in diseases. This article provides a summary of established interactions between the gut microbiome and ND. Post-biotic is believed to mediate its neuroprotection by elevating the level of dopamine and reducing the level of α-synuclein in substantia nigra, protecting the loss of dopaminergic neurons, reducing the aggregation of NFT, reducing the deposition of amyloid ß peptide plagues and ameliorating motor deficits. Moreover, mediates its neuroprotective activity by inhibiting the inflammatory response (decreasing the expression of TNFα, iNOS expression, free radical formation, overexpression of HIF-1α), apoptosis (i.e. active caspase-3, TNF-α, maintains the level of Bax/Bcl-2 ratio) and promoting BDNF secretion. It is also reported to have good antioxidant activity. This review offers an overview of the latest findings from both preclinical and clinical trials concerning the use of post-biotics in ND.

Wnt signalling pathways as mediators of neuroprotective mechanisms: therapeutic implications in stroke.

A stroke is a complicated neurological illness that occurs when there is a disruption in the blood flow to the brain. This disruption results in the damage of neurons, which then leads to functional abnormalities. The Wnt signalling pathway, which is already well-known for its important function in development and tissue homeostasis, has recently been recognised as a critical factor in the pathophysiology of stroke. Recent studies have shown the Wnt pathway's roles in stroke-related events. The complex-interactions between the Wnt pathway and stroke emphasising the pathway's contributions to neuro-protection and synaptic plasticity. The Wnt pathway's influence on neuro-genesis and synaptic plasticity underscores its potential for driving stroke recovery and rehabilitation strategies. The current review discusses about the Wnt signalling pathway in brain pathophysiology and stroke with special emphasis on the various pathways involved in the positive and negative modulation of Wnt pathway namely Phosphoinositide 3-kinase (PI3-K), Glycogen synthase kinase-3ß (GSK-3ß), Mitogen-activated protein kinase (MAPK) and nuclear factor erythroid 2-related factor 2 (Nrf2) pathway.

Pesticides: An alarming detrimental to health and environment.

Pesticides are chemical substances of natural or synthetic origin that are used to eradicate pests and insects. These are indispensable in the agricultural processes for better crop production. Pesticide use aims to promote crop yield and protect the crops from diseases and damage. Pesticides must be handled carefully and disposed of appropriately because they are dangerous to people and other species by default. Environmental pollution occurs when pesticide contamination spreads away from the intended plants. Older pesticides such as lindane and dichlorodiphenyltrichloroethane (DDT) may remain in water and soil for a longer time. These accumulate in various parts of the food chain and cause damage to the ecosystem. Biological techniques in the management of pest control such as importation, augmentation, and conservation, and the accompanying procedures are more efficient, less expensive, and ecologically sound than other ways. This review mainly focuses on the consequences on the targeted and non-targeted organisms including the health and well-being of humans by the use of pesticides and their toxicity. The side effects that occur when a pesticide's LD50 exceeds the accepted limit through oral or skin penetration due to their binding to various receptors such as estrogen receptors, GABA, EGFR, and others. These pesticide classes include carbamates, pyrethroids, organochlorides, organophosphorus, and others. The current study seeks to highlight the urgent requirement for a novel agricultural concept that includes a major reduction in the use of chemical pesticides.

Targeting cardiovascular risk factors with eugenol: an anti-inflammatory perspective.

Inflammation is a multifaceted biological reaction to a wide range of stimuli, and it has been linked to the onset and progression of chronic diseases such as heart disease, cancer, and diabetes. Inflammatory markers found in the blood, including C-reactive protein, serum amyloid A, fibrinogen, plasma viscosity, erythrocyte sedimentation rate, interleukin-6, and soluble adhesion molecules (like intercellular adhesion molecule-1 and vascular cell adhesion molecule-1), are risk factors for cardiovascular diseases such as coronary heart disease, stroke, and peripheral arterial disease. These markers play a crucial role in understanding and assessing cardiovascular health. Due to this complicated relationship between inflammation and cardiovascular disease, anti-inflammatory agents of natural origin have been the subject of many preclinical and clinical studies in recent years. Eugenol is a natural phenolic compound found in clove oil, nutmeg oil, cinnamon oil, and bay leaf oil, as well as other essential oils. Eugenol has been shown to have anti-inflammatory properties in many forms of experimental inflammation. It may scavenge free radicals, which contribute to inflammation and tissue damage. Various studies also suggest that eugenol can limit the production of inflammatory mediators such as prostaglandins, cytokines, and chemokines. Animal models of arthritis, colitis, and lung damage, as well as human clinical studies, have shown that eugenol has phenomenal anti-inflammatory properties. These properties suggest that eugenol may be able to reduce the risk of cardiovascular diseases.

Targeting inflammatory signaling in obsessive compulsive disorder: a promising approach.

Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder. Approximately, around 2% to 3% percent of the general population experience symptoms of OCD over the course of their lifetime. OCD can lead to economic burden, poor quality of life, and disability. The characteristic features exhibited generally in OCD are continuous intrusive thoughts and periodic ritualized behaviours. Variations in genes, pathological function of Cortico-Striato-Thalamo-Cortical (CSTC) circuits and dysregulation in the synaptic conduction have been the major factors involved in the pathological progression of OCD. However, the basic mechanisms still largely unknown. Current therapies for OCD largely target monoaminergic neurotransmitters (NTs) in specific dopaminergic and serotonergic circuits. However, such therapies have limited efficacy and tolerability. Drug resistance has been one of the important reasons reported to critically influence the effectiveness of the available drugs. Inflammation has been a crucial factor which is believed to have a significant importance in OCD progression. A significant number of proinflammatory cytokines have been reportedly amplified in patients with OCD. Mechanisms of drug treatment involve attenuation of the symptoms via modulation of inflammatory signalling pathways, modification in brain structure, and synaptic plasticity. Hence, targeting inflammatory signaling may be considered as a suitable approach in the treatment of OCD. The present review focuses mainly on the significant findings from the animal and human studies conducted in this area, that targets inflammatory signaling in neurological conditions. In addition, it also focusses on the therapeutic approaches that target OCD via modification of the inflammatory signaling pathways.

Glycosylation: A new signaling paradigm for the neurovascular diseases.

A wide range of life-threatening conditions with complicated pathogenesis involves neurovascular disorders encompassing Neurovascular unit (NVU) damage. The pathophysiology of NVU is characterized by several features including tissue hypoxia, stimulation of inflammatory and angiogenic processes, and the initiation of intricate molecular interactions, collectively leading to an elevation in blood-brain barrier permeability, atherosclerosis and ultimately, neurovascular diseases. The presence of compelling data about the significant involvement of the glycosylation in the development of diseases has sparked a discussion on whether the abnormal glycosylation may serve as a causal factor for neurovascular disorders, rather than being just recruited as a secondary player in regulating the critical events during the development processes like embryo growth and angiogenesis. An essential tool for both developing new anti-ischemic therapies and understanding the processes of ischemic brain damage is undertaking pre-clinical studies of neurovascular disorders. Together with the post-translational modification of proteins, the modulation of glycosylation and its enzymes implicates itself in several abnormal activities which are known to accelerate neuronal vasculopathy. Despite the failure of the majority of glycosylation-based preclinical and clinical studies over the past years, there is a significant probability to provide neuroprotection utilizing modern and advanced approaches to target abnormal glycosylation activity at embryonic stages as well. This article focuses on a variety of experimental evidence to postulate the interconnection between glycosylation and vascular disorders along with possible treatment options.

Mechanistic Implications of GSK and CREB Crosstalk in Ischemia Injury.

Ischemia-reperfusion (IR) injury is a damage to an organ when the blood supply is less than the demand required for normal functioning, leading to exacerbation of cellular dysfunction and death. IR injury occurs in different organs like the kidney, liver, heart, brain, etc., and may not only involve the ischemic organ but also cause systemic damage to distant organs. Oxygen-glucose deprivation in cells causes oxidative stress, calcium overloading, inflammation, and apoptosis. CREB is an essential integrator of the body's various physiological systems, and it is widely accepted that dysfunction of CREB signaling is involved in many diseases, including ischemia-reperfusion injury. The activation of CREB can provide life to a cell and increase the cell's survival after ischemia. Hence, GSK/CREB signaling pathway can provide significant protection to cells of different organs after ischemia and emerges as a futuristic strategy for managing ischemia-reperfusion injury. Different signaling pathways such as MAPK/ERK, TLR4/MyD88, RISK, Nrf2, and NF-κB, get altered during IR injury by the modulation of GSK-3 and CREB (cyclic AMP response element (CRE)-binding protein). GSK-3 (protein kinase B) and CREB are the downstream targets for fulfilling the roles of various signaling pathways. Calcium overloading during ischemia increases the expression of calcium-calmodulin-dependent protein kinase (CaMK), which subsequently activates CREB-mediated transcription, thus promoting the survival of cells. Furthermore, this review highlights the crosstalk between GSK-3 and CREB, promoting survival and rendering the cells resistant to subsequent severe ischemia.

Therapeutic targeting of angiopoietins in tumor angiogenesis and cancer development.

The formation and progression of tumors in humans are linked to the abnormal development of new blood vessels known as neo-angiogenesis. Angiogenesis is a broad word that encompasses endothelial cell migration, proliferation, tube formation, and intussusception, as well as peri-EC recruitment and extracellular matrix formation. Tumor angiogenesis is regulated by angiogenic factors, out of which some of the most potent angiogenic factors such as vascular endothelial growth factor and Angiopoietins (ANGs) in the body are produced by macrophages and other immune cells within the tumor microenvironment. ANGs have a distinct function in tumor angiogenesis and behavior. ANG1, ANG 2, ANG 3, and ANG 4 are the family members of ANG out of which ANG2 has been extensively investigated owing to its unique role in modifying angiogenesis and its tight association with tumor progression, growth, and invasion/metastasis, which makes it an excellent candidate for therapeutic intervention in human malignancies. ANG modulators have demonstrated encouraging outcomes in the treatment of tumor development, either alone or in conjunction with VEGF inhibitors. Future development of more ANG modulators targeting other ANGs is needed. The implication of ANG1, ANG3, and ANG4 as probable therapeutic targets for anti-angiogenesis treatment in tumor development should be also evaluated. The article has described the role of ANG in tumor angiogenesis as well as tumor growth and the treatment strategies modulating ANGs in tumor angiogenesis as demonstrated in clinical studies. The pharmacological modulation of ANGs and ANG-regulated pathways that are responsible for tumor angiogenesis and cancer development should be evaluated for the development of future molecular therapies.

Discussing pathologic mechanisms of Diabetic retinopathy & therapeutic potentials of curcumin and ß-glucogallin in the management of Diabetic retinopathy.

Diabetic retinopathy (DR) is a form of retinal microangiopathy that occurs as a result of long-term Diabetes mellitus (DM). Patients with Diabetes mellitus typically suffer from DR as a progression of the disease that may be due to initiation and dysregulation of pathways like the polyol, hexosamine, the AGE/RAGE, and the PKC pathway, which all have negative impacts on eye health and vision. In this review, various databases, including PubMed, Google Scholar, Web of Science, and Science Direct, were scoured for data relevant to the aforementioned title. The three most common therapies for DR today are retinal photocoagulation, anti-vascular endothelial growth factor (VEGF) therapy, and vitrectomy, however, there are a number of drawbacks and limits to these methods. So, it is of critical importance and profound interest to discover treatments that may successfully address the pathogenesis of DR. Curcumin and ß-glucogallin are the two potent compounds of natural origin that are already being used in various nutraceutical formulations for several ailments. They have been shown potent antiapoptotic, anti-inflammatory, antioxidant, anticancer, and pro-vascular function benefits in animal experiments. Their parent plant species have been used for generations by practitioners of traditional herbal medicine for the treatment and prevention of various eye ailments. In this review, we will discuss about pathophysiology of Diabetic retinopathy and the therapeutic potentials of curcumin and ß-glucogallin one of the principal compounds from Curcuma longa and Emblica officinalis in Diabetic retinopathy.

From Traditional Medicine to Advanced Therapeutics: The Renaissance of Phyto-nano Interventions in Psoriasis.

Psoriasis is an autoimmune systemic chronic inflammatory disease that exhibits characteristic detrimental effects on the skin, often leading to infections or comorbid conditions. The multifaceted nature of psoriasis has made it very challenging to treat, especially with current chemotherapy options. Therefore, it is essential to consider phytoconstituents as novel alternatives. However, despite demonstrating higher anti-inflammatory, anti-psoriasis, and immunomodulatory potential, their clinical usage is hindered due to their poor physicochemical properties. To address these drawbacks, nanoparticulate drug delivery systems have been developed, helping to achieve better permeation of phytoconstituents through topical administration. This has breathed new life into traditional systems of medicine, particularly in the context of treating psoriasis. In this current review, we present a detailed, comprehensive, and up-to-date analysis of the literature, which will contribute to affirming the clinical role of phyto-nano interventions against psoriasis.

In-Silico Investigation of Ginseng Phytoconstituents as Novel Therapeutics Against MAO-A.

BACKGROUND: Ginseng (Panax ginseng) is a herb of medicinal and nutritional importance. Ginseng has been used since ancient times for the treatment of numerous ailments as it has many therapeutic properties. Several phytoconstituents are present in Panax ginseng that possess a variety of beneficial pharmacological properties. OBJECTIVE: To explore the potential of phytoconstituents of Panax ginseng in the treatment of depression, a molecular modeling technique was utilized targeting monoamine oxidase-A (MAOA). METHODS: A total of sixty-one phytoconstituents of ginseng were drawn with the help of ChemBioDraw Ultra 12.0 software and PDBs for MAO-A enzyme were retrieved from the RCSB PDB database. The prepared ligands were screened for MAO-A properties using the software Molegro Virtual Docker (MVD 2010.4.1.0). All the prepared ligands were evaluated for drug-likeliness properties using Swiss ADME. RESULT: Among the docking studies of 60 Ginseng phytochemicals including one standard, 15 phytoconstituents with the highest dock score and better binding interactions were selected further for absorption, distribution, metabolism and excretion (ADME) studies. Stachyose (-227.287, 17 interactions), Raffinose (-222.157, 14 interactions), and Ginsenoside Rg1 (-216.593, 10 interactions) were found to possess better interactions as compared to Clorgyline taken as a standard drug. CONCLUSION: Stachyose was found to be the most potent inhibitor of MAO-A enzyme under investigation and can be a potential lead molecule for the development of newer phytochemical-based treatment of depression.

Are Proton Pump Inhibitors Contributing in Emerging New Hypertensive Population?

Balancing the therapeutic advantages of a medicine with its possible risks and side effects is an important part of medical practice and drug regulation. When a drug is designed to treat a particular disease or medical condition ends up causing additional risks or side effects that lead to the development of other serious health problems, it can have detrimental consequences for patients. This article explores the correlation between persistent proton pump inhibitor (PPI) use and hypertension, a common cardiovascular ailment. While PPIs are beneficial in treating various gastrointestinal problems, their availability without a prescription has resulted in self-medication and long-term use without medical monitoring. Recent findings have revealed a link between long-term PPI usage and increased cardiovascular risks, particularly hypertension. This study investigates the intricate mechanisms underlying PPI's effects, focusing on potential pathways contributing to hypertension, such as endothelial dysfunction, disruption of nitric oxide bioavailability, vitamin B deficiency, hypocalcemia, and hypomagnesemia. The discussion explains how long-term PPI use can disrupt normal endothelial function, vascular control, and mineral balance, eventually leading to hypertension. The article emphasizes the significance of using PPIs with caution and ongoing research to better understand the implications of these medications on cardiovascular health.