Sonic hedgehog signalling pathway contributes in age-related disorders and Alzheimer's disease.

Alzheimer's disease (AD) is caused by the aging process and manifested by cognitive deficits and progressive memory loss. During aging, several conditions, including hypertension, diabetes, and cholesterol, have been identified as potential causes of AD by affecting Sonic hedgehog (Shh) signalling. In addition to being essential for cell differentiation and proliferation, Shh signalling is involved in tissue repair and the prevention of neurodegeneration. Neurogenesis is dependent on Shh signalling; inhibition of this pathway results in neurodegeneration. Several protein-protein interactions that are involved in Shh signalling are implicated in the pathophysiology of AD like overexpression of the protein nexin-1 inhibits the Shh pathway in AD. A protein called Growth Arrest Specific-1 works with another protein called cysteine dioxygenase (CDO) to boost Shh signalling. CDO is involved in the development of the central nervous system (CNS). Shh signalling strengthened the blood brain barrier and therefore prevent the entry of amyloid beta and other toxins to the brain from periphery. Further, several traditional remedies used for AD and dementia, including Epigallocatechin gallate, yokukansan, Lycium barbarum polysaccharides, salvianolic acid, and baicalin, are known to stimulate the Shh pathway. In this review, we elaborated that the Shh signalling exerts a substantial influence on the pathogenesis of AD. In this article, we have tried to explore the various possible connections between the Shh signalling and various known pathologies of AD.

2D-QSAR, molecular docking and MD simulation based virtual screening of the herbal molecules against Alzheimer's disorder: an approach to predict CNS activity.

Acetylcholinesterase (AChE) is one of the key enzyme targets that have been used clinically for the management of Alzheimer's Disorder (AD). Numerous reports in the literature predict and demonstrate in-vitro, and in-silico anticholinergic activity of herbal molecules, however, majority of them failed to find clinical application. To address these issues, we developed a 2D-QSAR model that could efficiently predict the AChE inhibitory activity of herbal molecules along with predicting their potential to cross the blood-brain-barrier (BBB) to exert their beneficial effects during AD. Virtual screening of the herbal molecules was performed and amentoflavone, asiaticoside, astaxanthin, bahouside, biapigenin, glycyrrhizin, hyperforin, hypericin, and tocopherol were predicted as the most promising herbal molecules for inhibiting AChE. Results were validated through molecular docking, atomistic molecular dynamics simulations and Molecular mechanics-Poisson Boltzmann surface area (MM-PBSA) studies against human AChE (PDB ID: 4EY7). To determine whether or not these molecules can cross BBB to inhibit AChE within the central nervous system (CNS) for being beneficial for the management of AD, we determined a CNS Multi-parameter Optimization (MPO) score, which was found in the range of 1 to 3.76. Overall, the best results were observed for amentoflavone and our results demonstrated a PIC50 value of 7.377 nM, molecular docking score of -11.5 kcal/mol, and CNS MPO score of 3.76. In conclusion, we successfully developed a reliable and efficient 2D-QSAR model and predicted amentoflavone to be the most promising molecule that could inhibit human AChE enzyme within the CNS and could prove beneficial for the management of AD.Communicated by Ramaswamy H. Sarma.

Biomarkers: Role and Scope in Neurological Disorders.

Neurological disorders pose a great threat to social health and are a major cause for mortality and morbidity. Effective drug development complemented with the improved drug therapy has made considerable progress towards easing symptoms associated with neurological illnesses, yet poor diagnosis and imprecise understanding of these disorders has led to imperfect treatment options. The scenario is complicated by the inability to extrapolate results of cell culture studies and transgenic models to clinical applications which has stagnated the process of improving drug therapy. In this context, the development of biomarkers has been viewed as beneficial to easing various pathological complications. A biomarker is measured and evaluated in order to gauge the physiological process or a pathological progression of a disease and such a marker can also indicate the clinical or pharmacological response to a therapeutic intervention. The development and identification of biomarkers for neurological disorders involves several issues including the complexity of the brain, unresolved discrepant data from experimental and clinical studies, poor clinical diagnostics, lack of functional endpoints, and high cost and complexity of techniques yet research in the area of biomarkers is highly desired. The present work describes existing biomarkers for various neurological disorders, provides support for the idea that biomarker development may ease our understanding underlying pathophysiology of these disorders and help to design and explore therapeutic targets for effective intervention.

Epigenetics and Gut Microbiota Crosstalk: A potential Factor in Pathogenesis of Cardiovascular Disorders.

Cardiovascular diseases (CVD) are the leading cause of mortality, morbidity, and "sudden death" globally. Environmental and lifestyle factors play important roles in CVD susceptibility, but the link between environmental factors and genetics is not fully established. Epigenetic influence during CVDs is becoming more evident as its direct involvement has been reported. The discovery of epigenetic mechanisms, such as DNA methylation and histone modification, suggested that external factors could alter gene expression to modulate human health. These external factors also influence our gut microbiota (GM), which participates in multiple metabolic processes in our body. Evidence suggests a high association of GM with CVDs. Although the exact mechanism remains unclear, the influence of GM over the epigenetic mechanisms could be one potential pathway in CVD etiology. Both epigenetics and GM are dynamic processes and vary with age and environment. Changes in the composition of GM have been found to underlie the pathogenesis of metabolic diseases via modulating epigenetic changes in the form of DNA methylation, histone modifications, and regulation of non-coding RNAs. Several metabolites produced by the GM, including short-chain fatty acids, folates, biotin, and trimethylamine-N-oxide, have the potential to regulate epigenetics, apart from playing a vital role in normal physiological processes. The role of GM and epigenetics in CVDs are promising areas of research, and important insights in the field of early diagnosis and therapeutic approaches might appear soon.

Molecular Insights to the Wnt Signaling During Alzheimer's Disorder: a Potential Target for Therapeutic Interventions.

In the adult brain, Wnt signaling is crucial for neurogenesis, and it also regulates neuronal development, neuronal maturation, neuronal differential, and proliferation. Impaired Wnt signaling pathways are associated with enhanced levels of amyloid-ß, reduced ß-catenin levels, and increased expression of GSK-3ß enzyme, suggesting its direct association with the pathogenesis of Alzheimer's disorder (AD). These findings are consolidated by reports where activation of Wnt signaling by genetic factors and pharmacological intervention has improved the cognitive functions in animals and restored neurogenesis in the adult brain. Various natural and synthetic molecules have been identified that modulate Wnt signaling in the adult brain and promote neurogenesis and alleviate behavioral dysfunction. These molecules include lithium, valproic acid, ethosuximide, selenomethionine, curcumin, andrographolide, xanthoceraside, huperzine A, pyridostigmine, ginkgolide-B, ricinine, cannabidiol, and resveratrol. These molecules are associated with the DKK1 and GSK-3ß inhibition and ß-catenin stabilization along with their effects on neurogenesis, neuronal proliferation, and differentiation in the hippocampus through modulation of Wnt signaling and thereby could prove beneficial in the management of AD pathogenesis. Although modulation of the Wnt signaling seems to suggest to be promising in the management of AD, unfortunately, most of the literature available for the association of Wnt signaling and AD pathogenesis is either from preclinical studies or post-mortem brain. Therefore, it will be interesting to understand the role of Wnt signaling in AD patients, and a rigorous investigation could provide us with a better understanding of AD pathogenesis and the identification of novel targets for therapeutic interventions.

Exploring the Role of Autophagy Dysfunction in Neurodegenerative Disorders.

Autophagy is a catabolic pathway by which misfolded proteins or damaged organelles are engulfed by autophagosomes and then transported to lysosomes for degradation. Recently, a great improvement has been done to explain the molecular mechanisms and roles of autophagy in several important cellular metabolic processes. Besides being a vital clearance pathway or a cell survival pathway in response to different stresses, autophagy dysfunction, either upregulated or down-regulated, has been suggested to be linked with numerous neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis. Impairment at different stages of autophagy results in the formation of large protein aggregates and damaged organelles, which leads to the onset and progression of different neurodegenerative disorders. This article elucidates the recent progress about the role of autophagy in neurodegenerative disorders and explains how autophagy dysfunction is linked with the pathogenesis of such disorders as well as the novel potential autophagy-associated therapies for treating them.

Elucidating the Possible Role of FoxO in Depression.

Forkhead box-O (FoxO) transcriptional factors perform essential functions in several physiological and biological processes. Recent studies have shown that FoxO is implicated in the pathophysiology of depression. Changes in the upstream mediators of FoxOs including brain-derived neurotrophic factor (BDNF) and protein kinase B have been associated with depressive disorder and the antidepressant agents are known to alter the phosphorylation of FoxOs. Moreover, FoxOs might be regulated by serotonin or noradrenaline signaling and the hypothalamic-pituitary-adrenal (HPA)-axis,both of them are associated with the development of the depressive disorder. FoxO also regulates neural morphology, synaptogenesis, and neurogenesis in the hippocampus, which accounts for the pathogenesis of the depressive disorder. The current article underlined the potential functions of FoxOs in the etiology of depressive disorder and formulate few essential proposals for further investigation. The review also proposes that FoxO and its signal pathway might establish possible therapeutic mediators for the management of depressive disorder.

Reckoning γ-Glutamyl-S-allylcysteine as a potential main protease (mpro) inhibitor of novel SARS-CoV-2 virus identified using docking and molecular dynamics simulation.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2 or COVID-19), outbreak was first reported in December 2019 in the Wuhan, China. COVID-19 managed to spread worldwide and so far more than 9.1 million cases and more than 4.7 lakh death has been reported globally. Children, pregnant women, elderly population, immunocompromised patients, and patients with conditions like asthma, diabetes, etc. are highly vulnerable to COVID infection. Currently, there is no treatment available for COVID-19 infection. Traditional medicinal plants have provided bioactive molecules in the past that are efficiently used during conditions like cancer, malaria, microbial infections, immune-compromised states, etc. AYUSH India has recommended the use of Curcuma longa, Allium sativum, Ocimum tenuiflorum, and Withania somnifera for immune-boosting during SARS-CoV-2 infection. In the present study, we investigated the potential of 63-major bioactive molecules of these plants against SARS-CoV-2 main protease (Mpro) through docking studies and compared the results with known inhibitor 11a. Our results proposed cuscohygrine, γ-Glutamyl-S-allylcysteine, anahygrine, and S-allylcystein as the potent inhibitors against Mpro identified using molecular docking and molecular simulation dynamics. Interestingly, these molecules are from A. sativum, and W. somnifera, which are known for their antimicrobial and immunomodulatory potential. None of the proposed molecules have earlier been reported as antiviral molecules. Our results predict very strong potential of these four-molecules against SARS-CoV-2 Mpro, especially γ-glutamyl-S-allylcysteine, as all four form hydrogen bonding with Glu166 that is a crucial residue for the formation of the biologically active dimeric form of Mpro. Therefore, we strongly recommend further research on these biomolecules against SARS-CoV-2.

Gut Microbiota Composition and Epigenetic Molecular Changes Connected to the Pathogenesis of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder, and its pathogenesis is not fully known. Although there are several hypotheses, such as neuroinflammation, tau hyperphosphorylation, amyloid-ß plaques, neurofibrillary tangles, and oxidative stress, none of them completely explain the origin and progression of AD. Emerging evidence suggests that gut microbiota and epigenetics can directly influence the pathogenesis of AD via their effects on multiple pathways, including neuroinflammation, oxidative stress, and amyloid protein. Various gut microbes such as Actinobacteria, Bacteroidetes, E. coli, Firmicutes, Proteobacteria, Tenericutes, and Verrucomicrobia are known to play a crucial role in the pathogenesis of AD. These microbes and their metabolites modulate various physiological processes that contribute to AD pathogenesis, such as neuroinflammation and other inflammatory processes, amyloid deposition, cytokine storm syndrome, altered BDNF and NMDA signaling, impairing neurodevelopmental processes. Likewise, epigenetic markers associated with AD mainly include histone modifications and DNA methylation, which are under the direct control of a variety of enzymes, such as acetylases and methylases. The activity of these enzymes is dependent upon the metabolites generated by the host's gut microbiome, suggesting the significance of epigenetics in AD pathogenesis. It is interesting to know that both gut microbiota and epigenetics are dynamic processes and show a high degree of variation according to diet, stressors, and environmental factors. The bidirectional relation between the gut microbiota and epigenetics suggests that they might work in synchrony to modulate AD representation, its pathogenesis, and progression. They both also provide numerous targets for early diagnostic biomarkers and for the development of AD therapeutics. This review discusses the gut microbiota and epigenetics connection in the pathogenesis of AD and aims to highlight vast opportunities for diagnosis and therapeutics of AD.

Stressed mitochondria: A target to intrude alzheimer's disease.

Alzheimer's disease (AD) is the inoperable, incapacitating, neuropsychiatric, and degenerative manifestation that drastically affects human life quality. The current medications target extra-neuronal senile plaques, oxidative stress, neuroinflammation, intraneuronal neurofibrillary tangles, cholinergic deficits, and excitotoxicity. Among novel pathways and targets, bioenergetic and resultant mitochondrial dysfunction has been recognized as essential factors that decide the neuronal fate and consequent neurodegeneration in AD. The crucial attributes of mitochondria, including bioenergesis, signaling, sensing, integrating, and transmitting biological signals contribute to optimum networking of neuronal dynamics and make them indispensable for cell survival. In AD, mitochondrial dysfunction and mitophagy are a preliminary and critical event that aggravates the pathological cascade. Stress is known to promote and exaggerate the neuropathological alteration during neurodegeneration and metabolic impairments, especially in the cortico-limbic system, besides adversely affecting the normal physiology and mitochondrial dynamics. Stress involves the allocation of energy resources for neuronal survival. Chronic and aggravated stress response leads to excessive release of glucocorticoids by activation of the hypothalamic-pituitaryadrenal (HPA) axis. By acting through their receptors, glucocorticoids influence adverse mitochondrial changes and alter mtDNA transcription, mtRNA expression, hippocampal mitochondrial network, and ultimately mitochondrial physiology. Chronic stress also affects mitochondrial dynamics by changing metabolic and neuro-endocrinal signalling, aggravating oxidative stress, provoking inflammatory mediators, altering tropic factors, influencing gene expression, and modifying epigenetic pathways. Thus, exploring chronic stress-induced glucocorticoid dysregulation and resultant bio-behavioral and psychosomatic mitochondrial alterations may be a feasible narrative to investigate and unravel the mysterious pathobiology of AD.

Phytochemicals from Plant Foods as Potential Source of Antiviral Agents: An Overview.

To date, the leading causes of mortality and morbidity worldwide include viral infections, such as Ebola, influenza virus, acquired immunodeficiency syndrome (AIDS), severe acute respiratory syndrome (SARS) and recently COVID-19 disease, caused by the SARS-CoV-2 virus. Currently, we can count on a narrow range of antiviral drugs, especially older generation ones like ribavirin and interferon which are effective against viruses in vitro but can often be ineffective in patients. In addition to these, we have antiviral agents for the treatment of herpes virus, influenza virus, HIV and hepatitis virus. Recently, drugs used in the past especially against ebolavirus, such as remdesivir and favipiravir, have been considered for the treatment of COVID-19 disease. However, even if these drugs represent important tools against viral diseases, they are certainly not sufficient to defend us from the multitude of viruses present in the environment. This represents a huge problem, especially considering the unprecedented global threat due to the advancement of COVID-19, which represents a potential risk to the health and life of millions of people. The demand, therefore, for new and effective antiviral drugs is very high. This review focuses on three fundamental points: (1) presents the main threats to human health, reviewing the most widespread viral diseases in the world, thus describing the scenario caused by the disease in question each time and evaluating the specific therapeutic remedies currently available. (2) It comprehensively describes main phytochemical classes, in particular from plant foods, with proven antiviral activities, the viruses potentially treated with the described phytochemicals. (3) Consideration of the various applications of drug delivery systems in order to improve the bioavailability of these compounds or extracts. A PRISMA flow diagram was used for the inclusion of the works. Taking into consideration the recent dramatic events caused by COVID-19 pandemic, the cry of alarm that denounces critical need for new antiviral drugs is extremely strong. For these reasons, a continuous systematic exploration of plant foods and their phytochemicals is necessary for the development of new antiviral agents capable of saving lives and improving their well-being.

Exploring Sonic Hedgehog Cell Signaling in Neurogenesis: Its Potential Role in Depressive Behavior.

Depression is the most prevalent form of neuropsychiatric disorder affecting all age groups globally. As per the estimation of the World Health Organization (WHO), depression will develop into the foremost reason for disability globally by the year 2030. The primary neurobiological mechanism implicated in depression remains ambiguous; however, dysregulation of molecular and signaling transductions results in depressive disorders. Several theories have been developed to explain the pathogenesis of depression, however, none of them completely explained all aspects of depressive-pathogenesis. In the current review, we aimed to explore the role of the sonic hedgehog (Shh) signaling pathway in the development of the depressive disorder and its potential as the therapeutic target. Shh signaling has a crucial function in neurogenesis and neural tube patterning during the development of the central nervous system (CNS). Shh signaling performs a basic function in embryogenesis and hippocampal neurogenesis. Moreover, antidepressants are also known to enhance neurogenesis in the hippocampus, which further suggests the potential of Shh signaling. Furthermore, there is decreased expression of a glioma-associated oncogene (Gli1) and Smoothened (Smo) in depression. Moreover, antidepressants also regulate brain-derived neurotrophic factor (BDNF) and wingless protein (Wnt) signaling, therefore, Shh may be implicated in the pathogenesis of the depressive disorder. Deregulation of Shh signaling in CNS results in neurological disorders such as depression.

CNS implications of COVID-19: a comprehensive review.

COVID-19 was first reported in December 2019 in the Wuhan city of China, and since then it has spread worldwide taking a heavy toll on human life and economy. COVID-19 infection is commonly associated with symptoms like coughing, fever, and shortness of breath, besides, the reports of muscle pain, anosmia, hyposmia, and loss of taste are becoming evident. Recent reports suggest the pathogenic invasion of the SARS-CoV-2 into the CNS, that could thereby result in devastating long term complications, primarily because some of these complications may go unnoticed for a long time. Evidence suggest that the virus could enter the CNS through angiotensin-converting enzyme-2 (ACE-2) receptor, neuronal transport, haematogenous route, and nasal route via olfactory bulb, cribriform plate, and propagates through trans-synaptic signalling, and shows retrograde movement into the CNS along nerve fiber. COVID-19 induces CNS inflammation and neurological degenerative damage through a diverse mechanism which includes ACE-2 receptor damage, cytokine-associated injury or cytokine storm syndrome, secondary hypoxia, demyelination, blood-brain barrier disruption, neurodegeneration, and neuroinflammation. Viral invasion into the CNS has been reported to show association with complications like Parkinsonism, Alzheimer's disorder, meningitis, encephalopathy, anosmia, hyposmia, anxiety, depression, psychiatric symptoms, seizures, stroke, etc. This review provides a detailed discussion of the CNS pathogenesis of COVID-19. Authors conclude that the COVID-19 cannot just be considered as a disorder of the pulmonary or peripheral system, rather it has a significant CNS involvement. Therefore, CNS aspects of the COVID-19 should be monitored very closely to prevent long term CNS complications, even after the patient has recovered from COVID-19.

Integrating Endocannabinoid Signalling In Depression.

Depression is a common mental disorder and is the leading cause of suicide globally. Because of the significant diversity in mental disorders, accurate diagnosis is difficult. Hence, the investigation of novel biomarkers is a key research perspective in psychotherapy to enable an individually tailored treatment approach. The prefrontal cortex (PFC) is a vital cortical region whose circuitry has been implicated in the development of depressive disorder. The endocannabinoid system (ECS) has garnered increasing attention because of its involvement in several diverse physiological brain processes including regulation of emotional, motivational and cognitive functions. The current review article explores the function of the key elements of the ECS as a biomarker in depressive disorder. The activity of endocannabinoids is thought to be moderated by the CB1 receptors in the central nervous system (CNS). Variations in the concentration of endocannabinoids and the binding affinity of CB1 receptors and their density have been identified in the PFC of persons with depression. Such discoveries support our theory that alteration in endocannabinoid function leads to the pathophysiological features of depressive disorders. Moreover, evidence from animal and human studies has revealed that dysfunction in endocannabinoid signalling can produce depression-like behaviours; therefore, improvement of endocannabinoid signalling may represent a new therapeutic approach for the management of depressive disorders.

Dysregulation of the Gut-Brain Axis, Dysbiosis and Influence of Numerous Factors on Gut Microbiota Associated Parkinson's Disease.

BACKGROUND: Parkinson's disease (PD) has been one of the substantial social, medical concerns and, burdens of the present time. PD is a gradually devastating neurodegenerative disorder of the neurological function marked with α-synucleinopathy affecting numerous regions of the brain-gut axis, as well as the central, enteric, and autonomic nervous system. Its etiology is a widely disputed topic. OBJECTIVE: This review emphasizes to find out the correlation among the microbial composition and the observable disturbances in the metabolites of the microbial species and its impact on the immune response, which may have a concrete implication on the occurrence, persistence and, pathophysiology of PD via the gut-brain axis. METHODS: An in-depth research and the database was developed from the available peer-reviewed articles to date (March 2020) utilizing numerous search engines like PubMed, MEDLINE and, other internet sources. RESULTS: Progressively increasing shreds of evidence have proved the fact that dysbiosis in the gut microbiome plays a central role in many neurological disorders, such as PD. Indeed, a disordered microbiome-gut-brain axis in PD could be focused on gastrointestinal afflictions that manifest primarily several years prior to the diagnosis, authenticating a concept wherein the pathological pathway progresses from the intestine reaching the brain. CONCLUSION: The microbiota greatly affects the bidirectional interaction between the brain and the gut via synchronized neurological, immunological, and neuroendocrine mechanisms. It can be concluded that a multitude of factors discussed in this review steadily induce the onset of dysbacteriosis that may exacerbate the etiologic mechanism of Parkinson's disease.

Molecular insights into the therapeutic promise of targeting HMGB1 in depression.

Depression is a common psychiatric disorder, the exact pathogenesis of which is still elusive. Studies have proposed that immunity disproportion and enhancement in proinflammatory cytokines might be linked with the development of depression. HMGB1 (High-mobility group box (1) protein has obtained more interest as an essential factor in inherent immune reactions and a regulating factor in various inflammation-related diseases. HMGB1 is a ubiquitous chromatin protein and is constitutively expressed in nucleated mammalian cells. HMGB1 is released by glial cells and neurons upon inflammasome activation and act as a pro-inflammatory cytokine. HMGB1 is a late mediator of inflammation and has been indicated as a major mediator in various neuroinflammatory diseases. Microglia, which is the brain immune cell, is stimulated by HMGB1 and released inflammatory mediators and induces chronic neurodegeneration in the CNS (central nervous system). In the current review, we aimed to investigate the role of HMGB1 in the pathogenesis of depression. The studies found that HMGB1 functions as proinflammatory cytokines primarily via binding receptors like RAGE (receptor for advanced glycation end product), TLR2 and TLR4 (Toll-like receptor 2 and 4). Further, HMGB1 added to the preparing impacts of stress-pretreatment and assumed a major function in neurodegenerative conditions through moderating neuroinflammation. Studies demonstrated that neuroinflammation played a major role in the development of depression. The patients of depression generally exhibited an elevated amount of proinflammatory cytokines in the serum, microglia activation and neuronal deficit in the CNS.

Exploring the Various Aspects of Brain-Derived Neurotropic Factor (BDNF) in Diabetes Mellitus.

Brain-Derived Neurotrophic Factor (BDNF) serves as a modulator for neurotransmitters by participating in neuronal plasticity, essential for their growth and neuronal survival. It also shows a wide range of expression patterns in the systemic and peripheral tissues; thereby, its biological actions are not just limited to the CNS but may a vital role in peripheral disorders, such as Diabetes Mellitus (DM). Platelets serve as one of the major sources of BDNF, which regulates energy homeostasis and glucose metabolism by participating in the expression of specific pro-survival genes. It also prevents ß cell exhaustion, thus may prove to be a key factor for the management of DM. The current article reviews the intricate role of BDNF in Type 2 DM (T2DM) by involving platelet reactivity and its association with these selected inflammatory platelet activator mediators. Besides, certain adipocytokines, such as adiponectin and leptin, are also involved in the metabolism of glucose during diabetes, which has been clearly proven by recent experimental studies and thus relating BDNF with adipocytokines. It is also involved in the modulation of secretion of various neurotransmitters, peptides and hormones like gherin, leptin and insulin, suggesting its association with T2DM. Thus, based on various evidence, BDNF can be categorised as a potential biomarker in predicting the development of T2DM and may have a distinctive role in the management of this disorder.

Distinctive Evidence Involved in the Role of Endocannabinoid Signalling in Parkinson's Disease: A Perspective on Associated Therapeutic Interventions.

Current pharmacotherapy of Parkinson's disease (PD) is symptomatic and palliative, with levodopa/carbidopa therapy remaining the prime treatment, and nevertheless, being unable to modulate the progression of the neurodegeneration. No available treatment for PD can enhance the patient's life-quality by regressing this diseased state. Various studies have encouraged the enrichment of treatment possibilities by discovering the association of the effects of the endocannabinoid system (ECS) in PD. These reviews delineate the reported evidence from the literature on the neuromodulatory role of the endocannabinoid system and expression of cannabinoid receptors in symptomatology, cause, and treatment of PD progression, wherein cannabinoid (CB) signalling experiences alterations of biphasic pattern during PD progression. Published papers to date were searched via MEDLINE, PubMed, etc., using specific key words in the topic of our manuscript. Endocannabinoids regulate the basal ganglia neuronal circuit pathways, synaptic plasticity, and motor functions via communication with dopaminergic, glutamatergic, and GABAergic signalling systems bidirectionally in PD. Further, gripping preclinical and clinical studies demonstrate the context regarding the cannabinoid compounds, which is supported by various evidence (neuroprotection, suppression of excitotoxicity, oxidative stress, glial activation, and additional benefits) provided by cannabinoid-like compounds (much research addresses the direct regulation of cannabinoids with dopamine transmission and other signalling pathways in PD). More data related to endocannabinoids efficacy, safety, and pharmacokinetic profiles need to be explored, providing better insights into their potential to ameliorate or even regress PD.

Ubiquitination in rheumatoid arthritis.

Rheumatoid arthritis is a chronic, inflammatory joint disease leading to inflammation of synovial membrane that lines the joints. This inflammation further progresses and results in destruction of joints and surrounding cartilages. The underlying factors can be oxidative stress, pro-inflammatory mediators, imbalance and attenuation between various enzymes and proteins (like nuclear factor erythroid 2 related factor 2/Nrf2 and ubiquitin). Protein degradation pathways comprises of lysosomal, proteasomal pathway, and autophagosome (that are carried out in mammalian cells) are regulated through ubiquitin. Ubiquitin proteasomal system is dominating pathway for carrying out non-lysosomal proteolysis of intracellularly proteins. Fundamental processes including cell cycle progression, process of division, apoptosis, modulation of immune responses and cell trafficking are regulated by process of ubiquitination. Ubiquitin proteasomal pathway (UPP) includes ubiquitin moieties which are covalently attached to proteins and guides them proteasome for degradation. Misfolded, oxidized and damaged proteins which are responsible for critical processes, are major targets of degradation process. Any alteration in this system leads to dysregulated cellular homeostasis; progressively leading to numerous diseases including rheumatoid arthritis. Factors including TAK1, TRAF6 undergo are required for the progression of disease and thus contributes towards pathology of inflammatory disorders such as rheumatoid arthritis. This review will include all linked aspects which contribute its major role in rheumatoid arthritis.

Gene Therapy in the Management of Parkinson's Disease: Potential of GDNF as a Promising Therapeutic Strategy.

The limitations of conventional treatment therapies in Parkinson's disorder, a common neurodegenerative disorder, lead to the development of an alternative gene therapy approach. Multiple treatment options targeting dopaminergic neuronal regeneration, production of enzymes linked with dopamine synthesis, subthalamic nucleus neurons, regulation of astrocytes and microglial cells and potentiating neurotrophic factors, were established. Viral vector-based dopamine delivery, prodrug approaches, fetal ventral mesencephalon tissue transplantation and dopamine synthesizing enzyme encoding gene delivery are significant therapies evidently supported by numerous trials. The review primarily elaborates on the significant role of glial cell-line derived neurotrophic factor in alleviating motor symptoms and the loss of dopaminergic neurons in Parkinson's disease. Neuroprotective and neuroregenerative effects of GDNF were established via preclinical and clinical study outcomes. The binding of GDNF family ligands with associated receptors leads to the formation of a receptor-ligand complex activating Ret receptor of tyrosine kinase family, which is only expressed in dopaminergic neurons, playing an important role in Parkinson's disease, via its association with the essential protein encoded genes. Furthermore, the review establishes delivery aspects, like ventricular delivery of recombinant GDNF, intraparenchymal and intraputaminal delivery using infusion catheters. The review highlights problems and challenges of GDNF delivery, and essential measures to overcome them, like gene therapy combinations, optimization of delivery vectors, newer targeting devices, motor symptoms curbing focused ultrasound techniques, modifications in patient selection criteria and development of novel delivery strategies based on liposomes and encapsulated cells, to promote safe and effective delivery of neurotrophic factor and establishment of routine treatment therapy for patients.