Antiparkinson potential of khellin on rotenone-induced Parkinson's disease in a zebrafish model: targeting MAO, inflammatory, and oxidative stress markers with molecular docking, MD simulations, and histopathology evidence.

In this study, the antiparkinson effect of khellin (KL) on rotenone-induced Parkinson's disease (PD) was examined in zebrafish. Initially, In silico evaluations, such as drug likeness and ADME/T analysis, confirmed the pharmacological viability of KL. Molecular docking and molecular dynamics (MD) analysis revealed stable binding interactions between KL and monamine oxidase B (MAO-B). Molecular docking results for KL and pioglitazone (CCl) revealed binding energies of -6.5 and -10.4 kcal/mol, respectively. Later, molecular dynamics (MD) studies were performed to assess the stability of these complexes, which yielded binding energies of -36.04 ± 55.21 and -56.2 ± 80.63 kJ/mol for KL and CCl, respectively. These results suggest that KL exhibits considerable binding affinity for MAO-B. In In vitro studies, according to the DPPH free radical scavenging assay, KL exhibited significant antioxidant effects, indicating that it can promote redox balance with an IC50 value of 22.68 ± 0.5 µg/ml. In vivo studies and evaluation of locomotor activity, social interaction, histopathology and biochemical parameters were conducted in KL-treated zebrafish to measure SOD and GSH antioxidant activity, the oxidative stress marker malondialdehyde (MDA), the inflammatory marker myeloperoxidase (MPO) and MAO-B. However, while the locomotor and social interaction abilities of the rotenone-treated zebrafish were significantly reduced, KL treatment significantly improved locomotor activity (p < 0.001) and social interaction (p < 0.001). KL alleviated PD symptoms, as indicated by significant increases in SOD (p < 0.01), GSH (p < 0.001), MDA (p < 0.001), MAO-B (p < 0.001) and MPO (p < 0.001) in rotenone-induced PD fish (p<0.001) significantly reduced activities. Histopathological studies revealed that rotenone-induced brain hyperintensity and abnormal cellularity of the periventricular gray matter in the optic tectum were significantly reduced by KL treatment. This study provides a strong basis for developing KL as a new candidate for the treatment of Parkinson's disease, with the prospect of improved safety profiles and efficacy.

JAK2/STAT3 as a new potential target to manage neurodegenerative diseases: An interactive review.

Neurodegenerative diseases (NDDs) are a collection of incapacitating disorders in which neuroinflammation and neuronal apoptosis are major pathological consequences due to oxidative stress. Neuroinflammation manifests in the impacted cerebral areas as a result of pro-inflammatory cytokines stimulating the Janus Kinase2 (JAK2)/Signal Transducers and Activators of Transcription3 (STAT3) pathway via neuronal cells. The pro-inflammatory cytokines bind to their respective receptor in the neuronal cells and allow activation of JAK2. Activated JAK2 phosphorylates tyrosines on the intracellular domains of the receptor which recruit the STAT3 transcription factor. The neuroinflammation issues are exacerbated by the active JAK2/STAT3 signaling pathway in conjunction with additional transcription factors like nuclear factor kappa B (NF-κB), and the mammalian target of rapamycin (mTOR). Neuronal apoptosis is a natural process made worse by persistent neuroinflammation and immunological responses via caspase-3 activation. The dysregulation of micro-RNA (miR) expression has been observed in the consequences of neuroinflammation and neuronal apoptosis. Neuroinflammation and neuronal apoptosis-associated gene amplification may be caused by dysregulated miR-mediated aberrant phosphorylation of JAK2/STAT3 signaling pathway components. Therefore, JAK2/STAT3 is an attractive therapeutic target for NDDs. Numerous synthetic and natural small molecules as JAK2/STAT3 inhibitors have therapeutic advances against a wide range of diseases, and many are now in human clinical studies. This review explored the interactive role of the JAK2/STAT3 signaling system with key pathological factors during the reinforcement of NDDs. Also, the clinical trial data provides reasoning evidence about the possible use of JAK2/STAT3 inhibitors to abate neuroinflammation and neuronal apoptosis in NDDs.

Citronellal as a Promising Candidate for Alzheimer's Disease Treatment: A Comprehensive Study on In Silico and In Vivo Anti-Acetylcholine Esterase Activity.

One of the primary therapeutic approaches for managing Alzheimer's disease (AD) involves the modulation of Acetylcholine esterase (AChE) activity to elevate acetylcholine (ACh) levels inside the brain. The current study employed computational chemistry approaches to evaluate the inhibitory effects of CTN on AChE. The docking results showed that Citronellal (CTN) and standard Donepezil (DON) have a binding affinity of -6.5 and -9.2 Kcal/mol, respectively, towards AChE. Further studies using molecular dynamics (MD) simulations were carried out on these two compounds. Binding free energy calculations and ligand-protein binding patterns suggested that CTN has a binding affinity of -12.2078. In contrast, DON has a much stronger binding relationship of -47.9969, indicating that the standard DON has a much higher binding affinity than CTN for AChE. In an in vivo study, Alzheimer-type dementia was induced in mice by scopolamine (1.5 mg/kg/day i.p) for 14 days. CTN was administered (25 and 50 mg/kg. i.p) along with scopolamine (SCO) administration. DON (0.5 mg/kg orally) was used as a reference drug. CTN administration significantly improved the mice's behavior as evaluated by the Morris water maze test, evident from decreased escape latency to 65.4%, and in the CPS test, apparent from reduced escape latency to 69.8% compared to the positive control mice. Moreover, CTN significantly increased the activities of antioxidant enzymes such as catalase and superoxide dismutase (SOD) compared to SCO. Furthermore, CTN administration significantly decreased SCO-induced elevated AChE levels in mice. These results were supported by histopathological and in silico molecular docking studies. CTN may be a potential antioxidant and neuroprotective supplement.

Unravelling the Molecular Mechanisms of a Quercetin Nanocrystal for Treating Potential Parkinson's Disease in a Rotenone Model: Supporting Evidence of Network Pharmacology and In Silico Data Analysis.

The prevalence of Parkinson's disease places a significant burden on society; therefore, there is an urgent need to develop more effective drugs. However, the development of these drugs is both expensive and risky. Quercetin (QUE) has potent pharmacological effects on neurodegenerative diseases, but its low solubility in water and poor bioavailability limit its use in pharmaceutical applications. In this study, Quercetin nanocrystals (QNC) were synthesized and compared to standard QUE. A network-pharmacology-based methodology was applied, including target prediction, network construction, a gene ontology (GO) analysis, a KEGG pathway enrichment analysis, and molecular docking. This study aimed to identify the targets of QUE relevant to the treatment of Parkinson's disease and investigate the associated pharmacological mechanisms. Most of the predicted targets are involved in dopamine uptake during synaptic transmission. QUE regulates the key targets DRD2 and DRD4, which significantly affect dopaminergic synapses. The molecular docking results showed that QUE had a better binding affinity than the standard drug l-Dopa. From these experiments, it can be concluded that QNC effectively reduced the adverse effects caused by rotenone-induced oxidative stress in biochemical, neurochemical, and histopathological alterations. Therefore, QNC can potentially treat Parkinson's disease, and its effectiveness should be assessed in future clinical trials.

Salazinic acid attenuates male sexual dysfunction and testicular oxidative damage in streptozotocin-induced diabetic albino rats.

Male sexual dysfunctions such as infertility and impotence are recognized as the consequences of diabetes. Salazinic acid (Sa) is a depsidone found in lichen genera of Lobaria, Parmelia, and Usnea, which has prominent free radical and α-glucosidase inhibitory actions. The present study establishes the beneficial role of salazinic acid (Sa) to combat the deleterious effects of streptozotocin-induced diabetes on the male reproductive system of rats. In a dose-dependent manner, Sa significantly restored the reproductive organs weight, sperm characteristics, and testicular histoarchitecture in diabetic rats. Further, a significant recovery of insulin, follicle-stimulating hormone, luteinizing hormone and testosterone levels in serum was recorded in Sa-treated diabetic rats. The malondialdehyde levels were significantly lowered, and the activities of glutathione, superoxide dismutase, glutathione peroxidase and catalase, markedly elevated in the blood serum, as well as testicular tissue after Sa-supplementation. Sa also suppressed the protein expression levels of tumor necrosis factor-α in serum. The high dose of Sa showed significant improvement in glycemia and testicular protection, similar to sildenafil citrate. Moreover, the docking results showed that both Sa and sildenafil have a high affinity toward the target protein, PDE5 with binding affinity values found to be -9.5 and -9.2 kcal mol-1, respectively. Molecularly, both Sa and sildenafil share similar hydrogen bonding patterns with PDE5. Hence, our study clearly showed the protective role of Sa against diabetic-induced spermatogenic dysfunction in rats, possibly by competing with cGMP to bind to the catalytic domain of PDE5 and thereby controlling the oxidative impairment of testes.

Small molecules in the race of COVID-19 drug development.

COVID-19, caused by SARS-CoV-2, is spreading worldwide, regardless of different continents, increasing the death toll to almost five million, with more than 300 million reported cases. Researchers have been fighting the greatest threats to human civilization. This report provides a glimpse of ongoing small-molecule research on COVID-19 drugs to save millions of lives, which may provide researchers with a better understanding of rigorously investigated therapeutic agents. This report emphasizes the chemical structures and mechanisms of activity along with drug target information for several small molecules, including marketable drugs and agents under investigation.

Computational study for identifying promising therapeutic agents of hydroxychloroquine analogues against SARS-CoV-2.

Hydroxychloroquine (HCQ) and its derivatives have recently gained tremendous attention as a probable medicinal agent in the COVID-19 outbreak caused by SARS-CoV-2. An efficient agent to act directly in inhibiting the SARS-CoV-2 replication is yet to be achieved. Thus, the goal is to investigate the dynamic nature of HCQ derivatives against SARS-CoV-2 main protease and spike proteins. Molecular docking studies were also performed to understand their binding affinity in silico methods using the vital protein domains and enzymes involved in replicating and multiplying SARS-CoV-2, which were the main protease and spike protein. Molecular Dynamic simulations integrated with MM-PBSA calculations have identified In silico potential inhibitors ZINC05135012 and ZINC59378113 against the main protease with -185.171 ± 16.388, -130.759 ± 15.741 kJ/mol respectively, ZINC16638693 and ZINC59378113 against spike protein -141.425 ± 22.447, -129.149 ± 11.449 kJ/mol. Identified Hit molecules had demonstrated Drug Likeliness features, PASS values and ADMET predictions with no violations. Communicated by Ramaswamy H. Sarma.

In silico identification of potential inhibitors from Cinnamon against main protease and spike glycoprotein of SARS CoV-2.

Cinnamon has been utilized to remedy a lot of afflictions of humans. Literary works illustrate that it possesses numerous biological activities. Our research study is intended to recognize the phyto-derived antiviral substances from Cinnamon against COVID-19 main protease enzyme and to understand the in silico molecular basis of its activity. In the present study, 48 isolates compounds from Cinnamon retrieved from the PubMed database, are subjected to docking analysis. Docking study was performed using Autodock vina and PyRx software. Afterwards, admetSAR, as well as DruLiTo servers, were used to investigate drug-likeness prophecy. Our study shows that the nine phytochemicals of Cinnamon are very likely against the main protease enzyme of COVID-19. Further MD simulations could identify Tenufolin (TEN) and Pavetannin C1 (PAV) as hit compounds. Utilizing contemporary strategies, these phyto-compounds from a natural origin might establish a reliable medication or support lead identification. Identified hit compounds can be further taken for in vitro and in vivo studies to examine their effectiveness versus COVID-19.