MOLECULAR DOCKING STUDY OF NEUROPROTECTIVE PLANT-DERIVED BIOMOLECULES IN PARKINSON'S DISEASE

Objective: The objective of this study was to explore the therapeutic role of biomolecules in targeting the altered expression of Parkin in PD pathogenesis.Methods: We employed various in silico tools such as drug-likeness parameters, namely, Lipinski filter analysis, Muscle tool for phylogenetic analysis, Castp Server for active site prediction, molecular docking studies using AutoDock 4.2.1 and LIGPLOT1.4.5 were carried out.Results: Our results show that neuroprotective activity of Quercetin to be most effective and can provide their possible clinical relevance in PD. Further, initial screenings of the molecules were done based on Lipinski's rule of five. CastP server used to predict the ligand binding site suggests that this protein can be utilized as a potential drug target. Finally, we have found Quercetin to be most effective amongst four biomolecules in modulating Parkin based on minimum inhibition constant, Ki and highest negative free energy of binding with the maximum interacting surface area in a course of docking studies.Conclusion: This research could provide a potential therapeutic window for the treatment of PD

AN IN SILICO STUDY OF NARINGENIN-MEDIATED NEUROPROTECTION IN PARKINSON'S DISEASE

  Objective: Naringenin is a dietary biomolecule with broad spectrum of activities which protects neurons from various neurotoxic insults and improves cognition and motor function in neurodegenerative diseases. DJ-1 has both, ubiquitin E3 ligase as well as chaperonic activity, and loss of ubiquitin E3 ligase activity of DJ-1 has been found to be associated with familial Parkinson's disease (PD). Naringenin induced E3 ligase activity of DJ-1 which can have possible clinical relevance in PD.Methods: Various in silico parameters such as phylogenetic analysis, homology modeling, active site prediction, and molecular docking studies using AutoDock 4.2.1 and LIGPLOT1.4.5 were carried out.Results: Three-dimensional structure of DJ-1 was generated and Ramachandran plot was obtained for quality assessment. RAMPAGE displayed 99.5% of residues in the most favored regions. 0% residues in additionally allowed and 0.5% disallowed regions of DJ-1 protein. Further, initial screenings of the molecules were done based on Lipinski's rule of five. CastP server used to predict the ligand binding site suggests that this protein can be utilized as a potential drug target. Finally, we have found naringenin to be most effective among four biomolecules in modulating DJ-1 based on minimum inhibition constant, Ki, and highest negative free energy of binding with maximum interacting surface area in the course of docking studies.Conclusion: Our study suggests that based on different in silico parameters and molecular docking studies, naringenin can provide a new avenue for PD therapeutics

Biohydrogen: Opportunities and challenges as an alternative energy resource

As the energy demand is continuously rising with the increase in population, the use of fossil fuels is also increasing at the same rate. These fossil fuels release greenhouse gases (GHG) which are harmful to human health and our environmental health and these fuels are also expected to exhaust in the near future. This eventually has led to an emerging need to shift to a more reliable, sustainable, clean energy source. Biohydrogen as fuel is a potential alternative, as hydrogen has proved to be one such fuel which has the potential to replace fossil fuels. There is a need to produce it in a clean, sustainable way to compete with the fuels that are being used currently. The hydrogen which is produced biologically is known as biohydrogen. Microorganisms also play a huge role in the process of hydrogen generation by virtue of their natural mechanism. Hydrogen can be produced biologically using approaches like biophotolysis (direct and indirect), fermentation (dark and photo) and microbial electrolysis cell (MEC). Among all, dark fermentation seems to be the most efficient when compared to other procedures. The challenges currently being faced with this technology are the yield of hydrogen, the high cost of the reactor and system efficiency. This technology still needs a lot of research and improvement to replace fossil fuels entirely

New insights into molecular signaling pathways and current advancements in prostate cancer diagnostics & therapeutics

Prostate adenocarcinoma accounts for more than 20% of deaths among males due to cancer. It is the fifth-leading cancer diagnosed in males across the globe. The mortality rate is quite high due to prostate cancer. Despite the fact that advancements in diagnostics and therapeutics have been made, there is a lack of effective drugs. Metabolic pathways are altered due to the triggering of androgen receptor (AR) signaling pathways, and elevated levels of dihydrotestosterone are produced due to defects in AR signaling that accelerate the growth of prostate cancer cells. Further, PI3K/AKT/mTOR pathways interact with AR signaling pathway and act as precursors to promote prostate cancer. Prostate cancer therapy has been classified into luminal A, luminal B, and basal subtypes. Therapeutic drugs inhibiting dihydrotestosterone and PI3K have shown to give promising results to combat prostate cancer. Many second-generation Androgen receptor signaling antagonists are given either as single agent or with the combination of other drugs. In order to develop a cure for metastasized prostate cancer cells, Androgen deprivation therapy (ADT) is applied by using surgical or chemical methods. In many cases, Prostatectomy or local radiotherapy are used to control metastasized prostate cancer. However, it has been observed that after 1.5 years to 2 years of Prostatectomy or castration, there is reoccurrence of prostate cancer and high incidence of castration resistant prostate cancer is seen in population undergone ADT. It has been observed that Androgen derivation therapy combined with drugs like abiraterone acetate or docetaxel improve overall survival rate in metastatic hormone sensitive prostate cancer (mHSPC) patients. Scientific investigations have revealed that drugs inhibiting poly ADP Ribose polymerase (PARP) are showing promising results in clinical trials in the prostate cancer population with mCRPC and DNA repair abnormalities. Recently, RISUG adv (reversible inhibition of sperm under guidance) has shown significant results against prostate cancer cell lines and MTT assay has validated substantial effects of this drug against PC3 cell lines. Current review paper highlights the advancements in prostate cancer therapeutics and new drug molecules against prostate cancer. It will provide detailed insights on the signaling pathways which need to be targeted to combat metastasized prostate cancer and castration resistant prostate cancer

Inhibition of Mycobacterium tuberculosis MtrA response regulator by anticancer drugs via computational methods

Mycobacterium tuberculosis (MTB) causes TB disease and millions of deaths are reported every year. Drug resistance TB and its complex treatment is a big problem worldwide. The present  study aimed to design new and safer antitubercular compounds to tackle this serious threat. The unique drug target is the MtrAB Two-component regulatory system (2CRS) of mycobacteria. MtrAB system consists of MtrB sensor kinase (SK) and MtrA response regulator (RR). This system is essential in MTB and is involved in mycobacteria's proliferation. This important physiological process is operated by the phosphorylation of MtrB and then to MtrA. The phosphorylation mechanism triggers modulation in the expression of MtrA targets genes and helps perform appropriate function. This phenomenon depends on the active and inactive confirmation of MtrA, which involves a ligand (Metal ion complex e.g. Mg2+). In this study, anti-cancerous compounds were selected for the inhibition of MtrA. However, molecular docking exhibited binding affinity ranging from −10.8 to −4.7 kcal/mol, targeting the binding pocket of the selected Tuberculosis–MtrA protein (PDB ID: 5L8X). This energy difference between the native ligand and docked compounds showed that the six molecules: (Risperidone, 2-(benzofuran-2-yl)-6,7-dimethyl-4H-chromen-4-one, (2E)-1-(4-hydroxyphenyl)-3-(quinolin-4-yl)prop-2-en-1-one, Estradiol Cypionate, (2Z)-6-hydroxy-2-(3,4,5-trimethoxybenzylidene)-1-benzofuran-3(2H)-one, (2E)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-(3-hydroxyphenyl)prop-2-en-1-one) mentioned are more potent than the native ligand.These six molecules were first time reported as the inhibitor for MtrA of MtrAB Two-component regulatory system and can be utelize for further study

Cytokinin and abiotic stress tolerance -What has been accomplished and the way forward?

More than a half-century has passed since it was discovered that phytohormone cytokinin (CK) is essential to drive cytokinesis and proliferation in plant tissue culture. Thereafter, cytokinin has emerged as the primary regulator of the plant cell cycle and numerous developmental processes. Lately, a growing body of evidence suggests that cytokinin has a role in mitigating both abiotic and biotic stress. Cytokinin is essential to defend plants against excessive light exposure and a unique kind of abiotic stress generated by an altered photoperiod. Secondly, cytokinin also exhibits multi-stress resilience under changing environments. Furthermore, cytokinin homeostasis is also affected by several forms of stress. Therefore, the diverse roles of cytokinin in reaction to stress, as well as its interactions with other hormones, are discussed in detail. When it comes to agriculture, understanding the functioning processes of cytokinins under changing environmental conditions can assist in utilizing the phytohormone, to increase productivity. Through this review, we briefly describe the biological role of cytokinin in enhancing the performance of plants growth under abiotic challenges as well as the probable mechanisms underpinning cytokinin-induced stress tolerance. In addition, the article lays forth a strategy for using biotechnological tools to modify genes in the cytokinin pathway to engineer abiotic stress tolerance in plants. The information presented here will assist in better understanding the function of cytokinin in plants and their effective investigation in the cropping system

Alzheimer's disease-like perturbations in HIV-mediated neuronal dysfunctions: understanding mechanisms and developing therapeutic strategies

Excessive exposure to toxic substances or chemicals in the environment and various pathogens, including viruses and bacteria, is associated with the onset of numerous brain abnormalities. Among them, pathogens, specifically viruses, elicit persistent inflammation that plays a major role in Alzheimer's disease (AD) as well as dementia. AD is the most common brain disorder that affects thought, speech, memory and ability to execute daily routines. It is also manifested by progressive synaptic impairment and neurodegeneration, which eventually leads to dementia following the accumulation of Aβ and hyperphosphorylated Tau. Numerous factors contribute to the pathogenesis of AD, including neuroinflammation associated with pathogens, and specifically viruses. The human immunodeficiency virus (HIV) is often linked with HIV-associated neurocognitive disorders (HAND) following permeation through the blood-brain barrier (BBB) and induction of persistent neuroinflammation. Further, HIV infections also exhibited the ability to modulate numerous AD-associated factors such as BBB regulators, members of stress-related pathways as well as the amyloid and Tau pathways that lead to the formation of amyloid plaques or neurofibrillary tangles accumulation. Studies regarding the role of HIV in HAND and AD are still in infancy, and potential link or mechanism between both is not yet established. Thus, in the present article, we attempt to discuss various molecular mechanisms that contribute to the basic understanding of the role of HIV-associated neuroinflammation in AD and HAND. Further, using numerous growth factors and drugs, we also present possible therapeutic strategies to curb the neuroinflammatory changes and its associated sequels.Peer reviewe

Microfluidic Platforms to Unravel Mysteries of Alzheimer's Disease: How Far Have We Come?

Alzheimer’s disease (AD) is a significant health concern with enormous social and economic impact globally. The gradual deterioration of cognitive functions and irreversible neuronal losses are primary features of the disease. Even after decades of research, most therapeutic options are merely symptomatic, and drugs in clinical practice present numerous side effects. Lack of effective diagnostic techniques prevents the early prognosis of disease, resulting in a gradual deterioration in the quality of life. Furthermore, the mechanism of cognitive impairment and AD pathophysiology is poorly understood. Microfluidics exploits different microscale properties of fluids to mimic environments on microfluidic chip-like devices. These miniature multichambered devices can be used to grow cells and 3D tissues in vitro, analyze cell-to-cell communication, decipher the roles of neural cells such as microglia, and gain insights into AD pathophysiology. This review focuses on the applications and impact of microfluidics on AD research. We discuss the technical challenges and possible solutions provided by this new cutting-edge technique to understand disease-associated pathways and mechanisms