Reimagining old drugs with new tricks: Mechanisms, strategies and notable success stories in drug repurposing for neurological diseases.

Recent evolution in drug repurposing has brought new anticipation, especially in the conflict against neurodegenerative diseases (NDDs). The traditional approach to developing novel drugs for these complex disorders is laborious, time-consuming, and often abortive. However, drug reprofiling which is the implementation of illuminating novel therapeutic applications of existing approved drugs, has shown potential as a promising strategy to accelerate the hunt for therapeutics. The advancement of computational approaches and artificial intelligence has expedited drug repurposing. These progressive technologies have enabled scientists to analyse extensive datasets and predict potential drug-disease interactions. By prospecting into the existing pharmacological knowledge, scientists can recognise potential therapeutic candidates for reprofiling, saving precious time and resources. Preclinical models have also played a pivotal role in this field, confirming the effectiveness and mechanisms of action of repurposed drugs. Several studies have occurred in recent years, including the discovery of available drugs that demonstrate significant protective effects in NDDs, relieve debilitating symptoms, or slow down the progression of the disease. These findings highlight the potential of repurposed drugs to change the landscape of NDD treatment. Here, we present an overview of recent developments and major advances in drug repurposing intending to provide an in-depth analysis of traditional drug discovery and the strategies, approaches and technologies that have contributed to drug repositioning. In addition, this chapter attempts to highlight successful case studies of drug repositioning in various therapeutic areas related to NDDs and explore the clinical trials, challenges and limitations faced by researchers in the field. Finally, the importance of drug repositioning in drug discovery and development and its potential to address discontented medical needs is also highlighted.

Influence of enzyme activity on domestic wastewater amelioration in a hybrid subsurface flow constructed wetland.

Wastewater treatment in a constructed wetland is achieved by the presence of plant species, the metabolism of microorganisms, and the enzyme activities. Three small-scale hybrid subsurface flow constructed wetlands (HSFCWs) planted with Arundo donax and one unplanted HSFCW were constructed near a water resource recovery facility at Guru Gobind Singh Indraprastha University. The purpose of the study was to determine the correlation between soil enzymatic activities and the removal of contaminants from domestic wastewater. Enzyme activity of phosphatase, protease, urease, and cellulase increased with an increase in temperature. A strong correlation between enzyme activities and TKN and surfactant removal was observed, whereas moderate correlation was observed with phosphate in planted HSFCW during the study. The correlation between COD removal and enzyme activities was low to moderate. In unplanted HSFCW, the correlation between enzyme activities and COD removal was negative, negligible to moderate to strong in the case of TKN, low to moderate in the case of phosphate, and negligible to low in the case of surfactants. The increased removal efficiency of the planted system compared with that of the unplanted system indicated a positive impact on enzyme activities with the growth of plants and their roots. PRACTITIONER POINTS: Protease, urease, and cellulase activities: Planted HSFCW exhibited higher protease, urease, and cellulase activities than unplanted, signifying enhanced breakdown. July displayed maximum enzyme activities, correlating with heightened biological breakdown in both systems. Fluctuations in enzyme activities reflected seasonal changes, influencing nutrient degradation rates. Planted HSFCW consistently showed higher enzymatic activities across protease, urease, and cellulase than unplanted.

Simulation and Computational Study of RING Domain Mutants of BRCA1 and Ube2k in AD/PD Pathophysiology.

Lysine-based post-translational modification (PTM) such as acylation, acetylation, deamination, methylation, SUMOylation, and ubiquitination has proven to be a major regulator of gene expression, chromatin structure, protein stability, protein-protein interaction, protein degradation, and cellular localization. However, besides all the PTMs, ubiquitination stands as the second most common PTM after phosphorylation that is involved in the etiology of neurodegenerative diseases (NDDs) namely, Alzheimer's disease (AD) and Parkinson's disease (PD). NDDs are characterized by the accumulation of misfolded protein aggregates in the brain that lead to disease-related gene mutation and irregular protein homeostasis. The ubiquitin-proteasome system (UPS) is in charge of degrading these misfolded proteins, which involve an interplay of E1, E2, E3, and deubiquitinase enzymes. Impaired UPS has been commonly observed in NDDs and E3 ligases are the key members of the UPS, thus, dysfunction of the same can accelerate the neurodegeneration process. Therefore, the aim of this study is firstly, to find E3 ligases that are common in both AD and PD through data mining. Secondly, to study the impact of mutation on its structure and function. The study deciphered 74 E3 ligases that were common in both AD and PD. Later, 10 hub genes were calculated of which protein-protein interaction, pathway enrichment, lysine site prediction, domain, and motif analysis were performed. The results predicted BRCA1, PML, and TRIM33 as the top three putative lysine-modified E3 ligases involved in AD and PD pathogenesis. However, based on structural characterization, BRCA1 was taken further to study RING domain mutation that inferred K32Y, K32L, K32C, K45V, K45Y, and K45G as potential mutants that alter the structural and functional ability of BRCA1 to interact with Ube2k, E2-conjugating enzyme. The most probable mutant observed after molecular dynamics simulation of 50 ns is K32L. Therefore, our study concludes BRCA1, a potential E3 ligase common in AD and PD, and RING domain mutation at sites K32 and K45 possibly disturbs its interaction with its E2, Ube2k.

Triaging between post-translational modification of cell cycle regulators and their therapeutics in neurodegenerative diseases.

Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, present challenges in healthcare because of their complicated etiologies and absence of healing remedies. Lately, the emerging role of post-translational modifications (PTMs), in the context of cell cycle regulators, has garnered big interest as a potential avenue for therapeutic intervention. The review explores the problematic panorama of PTMs on cell cycle regulators and their implications in neurodegenerative diseases. We delve into the dynamic phosphorylation, acetylation, ubiquitination, SUMOylation, Glycation, and Neddylation that modulate the key cell cycle regulators, consisting of cyclins, cyclin-dependent kinases (CDKs), and their inhibitors. The dysregulation of these PTMs is related to aberrant cell cycle in neurons, which is one of the factors involved in neurodegenerative pathologies. Moreover, the effect of exogenous activation of CDKs and CDK inhibitors through PTMs on the signaling cascade was studied in postmitotic conditions of NDDs. Furthermore, the therapeutic implications of CDK inhibitors and associated alteration in PTMs were discussed. Lastly, we explored the putative mechanism of PTMs to restore normal neuronal function that might reverse NDDs.

Marburg I Polymorphism (G511E) in Adults with Deep Vein Thrombosis.

The Marburg I polymorphism (G511E) in FSAP gene was listed as one of the risk factor for idiopathic DVT among the western population. The frequency of Marburg I polymorphism in India is presently not known. Fifty DVT cases and 50 healthy controls were tested for Marburg I polymorphism using ARMS-PCR technique. The thrombophilic risk factors (Protein C, Protein S, Antithrombin III, Factor V Leiden and antiphospholipid antibodies) were also determined. Marburg I polymorphism (heterozygous) was found in 2 patients (4%) but not in control subjects. These two cases did not have any other thrombophilia markers. Among the thrombophilic markers, heterozygous FVL mutation, PS, PC, AT deficiencies and antiphospholipid antibodies were seen in 10%, 10%, 6%, 6% and 8% of the patients respectively. The controls showed only the presence of antiphospholipid antibodies in 6% of subjects. Marburg I polymorphism among Indians DVT patients was determined for the first time. Its incidence was found in 4% of cases and not in controls. Although not statically significant this may be considered as one of the contributory risk factors for the development of DVT. A larger study is required for the validation of data.

Evaluation of the relative efficacy of autologous platelet-rich fibrin membrane in combination with ß-tricalcium phosphate (Septodont- resorbable tissue replacement)™ alloplast versus ß-TCP alloplast alone in the treatment of grade II furcation defects.

INTRODUCTION: Platelet-rich fibrin (PRF) is considered as the second-generation platelet concentrate, contains combined properties of fibrin, platelets, leukocytes, growth factors, and cytokines that make it as healing biomaterial with incredible potential for hard tissue and soft tissue regeneration. The present study was aimed to evaluate the effectiveness of PRF with ß-tricalcium phosphate (ß-TCP) graft (R. T. R) and compare it with ß-TCP allograft alone in the treatment of mandibular Grade II furcation defects. MATERIAL AND METHODS: A total of 20 mandibular Grade II furcation defects sites were assigned in the study and treated with either ß-TCP alone (Group I) or ß-TCP with PRF membrane (Group II). The clinical parameters analyzed were probing pocket depth (PPD), clinical attachment level (CAL), gingival recession (GR), horizontal defect depth (HDD), and vertical defect depth (VDD), recorded baseline and at 6 months reentry. RESULTS: At 6 months, both groups showed statistically significant results for all parameters from their baseline value, although intergroup changes were statistically insignificant. In Group I, gain in CAL was 2.80 ± 1.40 and in Group II it was 3.00 ± 1.44. Bone fill in Group I was VDD (3.50 ± 2.12) and HDD (3.70 ± 0.67), whereas Group II showed VDD (3.70 ± 1.57) and HDD (4.0 ± 0.88), respectively. PPD reduction was higher in Group I (3.50 ± 2.27) than Group II (2.80 ± 1.93). At reentry GR was established, Group I showed higher GR (0.70 ± 0.67) and Group II (0.40 ± 0.52). CONCLUSIONS: Significant improvement was found in both groups, but the combination of PRF with ß-TCP allograft led to more favorable improvement in the management of Grade II furcation defect except PPD.

Defluoridation of groundwater using brick powder as an adsorbent.

Defluoridation of groundwater using brick powder as an adsorbent was studied in batch process. Different parameters of adsorption, viz. effect of pH, effect of dose and contact time were selected and optimized for the study. Feasible optimum conditions were applied to two groundwater samples of high fluoride concentration to study the suitability of adsorbent in field conditions. Comparison of adsorption by brick powder was made with adsorption by commercially available activated charcoal. In the optimum condition of pH and dose of adsorbents, the percentage defluoridation from synthetic sample, increased from 29.8 to 54.4% for brick powder and from 47.6 to 80.4% for commercially available activated charcoal with increasing the contact time starting from 15 to 120 min. Fluoride removal was found to be 48.73 and 56.4% from groundwater samples having 3.14 and 1.21 mg l(-1) fluoride, respectively, under the optimized conditions. Presence of other ions in samples did not significantly affect the deflouridation efficiency of brick powder. The optimum pH range for brick powder was found to be 6.0-8.0 and adsorption equilibrium was found to be 60 min. These conditions make it very suitable for use in drinking water treatment. Deflouridation capacity of brick powder can be explained on the basis of the chemical interaction of fluoride with the metal oxides under suitable pH conditions. The adsorption process was found to follow first order rate mechanism as well as Freundlich isotherm.