Synthesis and Biological Evaluation of Octahydroquinazolinones as Phospholipase A2, and Protease Inhibitors: Experimental and Theoretical Exploration.

Phospholipase A2 (PLA2) promotes inflammation via lipid mediators and releases arachidonic acid (AA), and these enzymes have been found to be elevated in a variety of diseases, including rheumatoid arthritis, sepsis, and atherosclerosis. The mobilization of AA by PLA2 and subsequent synthesis of prostaglandins are regarded as critical events in inflammation. Inflammatory processes may be treated with drugs that inhibit PLA2, thereby blocking the COX and LOX pathways in the AA cascade. To address this issue, we report herein an efficient method for the synthesis of a series of octahydroquinazolinone compounds (4a-h) in the presence of the catalyst Pd-HPW/SiO2 and their phospholipase A2, as well as protease inhibitory activities. Among eight compounds, two of them exhibited overwhelming results against PLA2 and protease. By using FT-IR, Raman, NMR, and mass spectroscopy, two novel compounds were thoroughly studied. After carefully examining the SAR of the investigated compounds against these enzymes, it was found that compounds (4a, 4b) containing both electron-donating and electron-withdrawing groups on the phenyl ring exhibited higher activity than compounds with only one of these groups. DFT studies were employed to study the electronic nature and reactivity properties of the molecules by optimizing at the BLYP/cc-pVDZ. Natural bond orbitals helped to study the various electron delocalizations in the molecules, and the frontier molecular orbitals helped with the reactivity and stability parameters. The nature and extent of the expressed biological activity of the molecule were studied using molecular docking with human non-pancreatic secretory phospholipase A2 (hnps-PLA2) (PDB ID: 1DB4) and protease K (PDB ID: 2PWB). The drug-ability of the molecule has been tested using ADMET, and pharmacodynamics data have been extracted. Both the compounds qualify for ADME properties and follow Lipinski's rule of five.

Ex Vivo Antiplatelet and Thrombolytic Activity of Bioactive Fractions from the New-Fangled Stem Buds of Ficus religiosa L. with Simultaneous GC-MS Examination.

Different parts of Ficus religiosa are the common components of various traditional formulations for the treatment of several blood disorders. The new-fangled stem buds' powder was extracted with 80% ethanol and successively fractionated by chloroform and methanol. Chloroform and methanol fractions of Ficus religiosa (CFFR and MFFR) were tested for antiplatelet, antithrombotic, thrombolytic, and antioxidant activity in ex vivo mode. The MFFR was particularly investigated for GC-MS and toxicity. The antiplatelet activity of the CFFR, MFFR, and standard drug aspirin at 50 µg/mL was 54.32%, 86.61%, and 87.57%, and a significant delay in clot formation was noted. CFFR at different concentrations did not show a significant effect on the delay of clot formation, antiplatelet, and free radical scavenging activity. The most possible marker compounds for antiplatelet and antioxidant activity identified by GC-MS in the MFFR are salicylate derivatives aromatic compounds such as benzeneacetaldehyde (7), phenylmalonic acid (13), and Salicylic acid (14), as well as Benzamides derivatives such as carbobenzyloxy-dl-norvaline (17), 3-acetoxy-2(1H)-pyridone (16), and 3-benzylhexahydropyrrolo [1,2-a] pyrazine-1,4-dione (35). A toxicity study of MFFR did not show any physical indications of toxicity and mortality up to 1500 mg/kg body weight and nontoxic up to 1000 mg/kg, which is promising for the treatment of atherothrombotic diseases.

Highlights on the Development, Related Patents, and Prospects of Lenacapavir: The First-in-Class HIV-1 Capsid Inhibitor for the Treatment of Multi-Drug-Resistant HIV-1 Infection.

The multidrug-resistant (MDR) human immunodeficiency virus 1 (HIV-1) infection is an unmet medical need. HIV-1 capsid plays an important role at different stages of the HIV-1 replication cycle and is an attractive drug target for developing therapies against MDR HIV-1 infection. Lenacapavir (LEN) is the first-in-class HIV-1 capsid inhibitor approved by the USFDA, EMA, and Health Canada for treating MDR HIV-1 infection. This article highlights the development, pharmaceutical aspects, clinical studies, patent literature, and future directions on LEN-based therapies. The literature for this review was collected from PubMed, authentic websites (USFDA, EMA, Health Canada, Gilead, and NIH), and the free patent database (Espacenet, USPTO, and Patent scope). LEN has been developed by Gilead and is marketed as Sunlenca (tablet and subcutaneous injection). The long-acting and patient-compliant LEN demonstrated a low level of drug-related mutations, is active against MDR HIV-1 infection, and does not reveal cross-resistance to other anti-HIV drugs. LEN is also an excellent drug for patients having difficult or limited access to healthcare facilities. The literature has established additive/synergistic effects of combining LEN with rilpivirine, cabotegravir, islatravir, bictegravir, and tenofovir. HIV-1 infection may be accompanied by opportunistic infections such as tuberculosis (TB). The associated diseases make HIV treatment complex and warrant drug interaction studies (drug-drug, drug-food, and drug-disease interaction). Many inventions on different aspects of LEN have been claimed in patent literature. However, there is a great scope for developing more inventions related to the drug combination of LEN with anti-HIV/anti-TB drugs in a single dosage form, new formulations, and methods of treating HIV and TB co-infection. Additional research may provide more LEN-based treatments with favorable pharmacokinetic parameters for MDR HIV-1 infections and associated opportunistic infections such as TB.

A Comprehensive Computational Investigation into the Conserved Virulent Proteins of Shigella species Unveils Potential Small-Interfering RNA Candidates as a New Therapeutic Strategy against Shigellosis.

Shigella species account for the second-leading cause of deaths due to diarrheal diseases among children of less than 5 years of age. The emergence of multi-drug-resistant Shigella isolates and the lack of availability of Shigella vaccines have led to the pertinence in the efforts made for the development of new therapeutic strategies against shigellosis. Consequently, designing small-interfering RNA (siRNA) candidates against such infectious agents represents a novel approach to propose new therapeutic candidates to curb the rampant rise of anti-microbial resistance in such pathogens. In this study, we analyzed 264 conserved sequences from 15 different conserved virulence genes of Shigella sp., through extensive rational validation using a plethora of first-generation and second-generation computational algorithms for siRNA designing. Fifty-eight siRNA candidates were obtained by using the first-generation algorithms, out of which only 38 siRNA candidates complied with the second-generation rules of siRNA designing. Further computational validation showed that 16 siRNA candidates were found to have a substantial functional efficiency, out of which 11 siRNA candidates were found to be non-immunogenic. Finally, three siRNA candidates exhibited a sterically feasible three-dimensional structure as exhibited by parameters of nucleic acid geometry such as: the probability of wrong sugar puckers, bad backbone confirmations, bad bonds, and bad angles being within the accepted threshold for stable tertiary structure. Although the findings of our study require further wet-lab validation and optimization for therapeutic use in the treatment of shigellosis, the computationally validated siRNA candidates are expected to suppress the expression of the virulence genes, namely: IpgD (siRNA 9) and OspB (siRNA 15 and siRNA 17) and thus act as a prospective tool in the RNA interference (RNAi) pathway. However, the findings of our study require further wet-lab validation and optimization for regular therapeutic use for treatment of shigellosis.

Nigella sativa L. and COVID-19: A Glance at The Anti-COVID-19 Chemical Constituents, Clinical Trials, Inventions, and Patent Literature.

COVID-19 has had an impact on human quality of life and economics. Scientists have been identifying remedies for its prevention and treatment from all possible sources, including plants. Nigella sativa L. (NS) is an important medicinal plant of Islamic value. This review highlights the anti-COVID-19 potential, clinical trials, inventions, and patent literature related to NS and its major chemical constituents, like thymoquinone. The literature was collected from different databases, including Pubmed, Espacenet, and Patentscope. The literature supports the efficacy of NS, NS oil (NSO), and its chemical constituents against COVID-19. The clinical data imply that NS and NSO can prevent and treat COVID-19 patients with a faster recovery rate. Several inventions comprising NS and NSO have been claimed in patent applications to prevent/treat COVID-19. The patent literature cites NS as an immunomodulator, antioxidant, anti-inflammatory, a source of anti-SARS-CoV-2 compounds, and a plant having protective effects on the lungs. The available facts indicate that NS, NSO, and its various compositions have all the attributes to be used as a promising remedy to prevent, manage, and treat COVID-19 among high-risk people as well as for the therapy of COVID-19 patients of all age groups as a monotherapy or a combination therapy. Many compositions of NS in combination with countless medicinal herbs and medicines are still unexplored. Accordingly, the authors foresee a bright scope in developing NS-based anti-COVID-19 composition for clinical use in the future.

Plumbagin Alleviates Intracerebroventricular-Quinolinic Acid Induced Depression-like Behavior and Memory Deficits in Wistar Rats.

Plumbagin, a hydroxy-1,4-naphthoquinone, confers neuroprotection via antioxidant and anti-inflammatory properties. The present study aimed to assess the effect of plumbagin on behavioral and memory deficits induced by intrahippocampal administration of Quinolinic acid (QA) in male Wistar rats and reveal the associated mechanisms. QA (300 nM/4 µL in Normal saline) was administered i.c.v. in the hippocampus. QA administration caused depression-like behavior (forced swim test and tail suspension tests), anxiety-like behavior (open field test and elevated plus maze), and elevated anhedonia behavior (sucrose preference test). Furthermore, oxidative-nitrosative stress (increased nitrite content and lipid peroxidation with reduction of GSH), inflammation (increased IL-1ß), cholinergic dysfunction, and mitochondrial complex (I, II, and IV) dysfunction were observed in the hippocampus region of QA-treated rats as compared to normal controls. Plumbagin (10 and 20 mg/kg; p.o.) treatment for 21 days significantly ameliorated behavioral and memory deficits in QA-administered rats. Moreover, plumbagin treatment restored the GSH level and reduced the MDA and nitrite level in the hippocampus. Furthermore, QA-induced cholinergic dysfunction and mitochondrial impairment were found to be ameliorated by plumbagin treatment. In conclusion, our results suggested that plumbagin offers a neuroprotective potential that could serve as a promising pharmacological approach to mitigate neurobehavioral changes associated with neurodegeneration.

Potential Antioxidant Activity of Apigenin in the Obviating Stress-Mediated Depressive Symptoms of Experimental Mice.

This study aimed to examine the antidepressant properties of apigenin in an experimental mouse model of chronic mild stress (CMS). Three weeks following CMS, albino mice of either sex were tested for their antidepressant effects using the tail suspension test (TST) and the sucrose preference test. The percentage preference for sucrose solution and the amount of time spent immobile in the TST were calculated. The brain malondialdehyde (MDA) levels, catalase activity, and reduced glutathione levels were checked to determine the antioxidant potential of treatments. When compared to the control, animals treated with apigenin during the CMS periods showed significantly shorter TST immobility times. Apigenin administration raised the percentage preference for sucrose solution in a dose-dependent manner, which put it on par with the widely used antidepressant imipramine. Animals treated with apigenin displayed a significantly (p ˂ 0.05) greater spontaneous locomotor count (281) when compared to the vehicle-treated group (245). Apigenin was also highly effective in significantly (p ˂ 0.01) lowering plasma corticosterone levels (17 vs. 28 µg/mL) and nitrite (19 vs. 33 µg/mL) produced by CMS in comparison to the control group. During CMS, a high dose (50 mg/kg) of apigenin was given, which greatly increased the reduced glutathione level while significantly decreasing the brain's MDA and catalase activity when compared to the control group. As a result, we infer that high doses of apigenin may have potential antidepressant effects in animal models via various mechanisms.

New Thiazole Acetic Acid Derivatives: A Study to Screen Cardiovascular Activity Using Isolated Rat Hearts and Blood Vessels.

Cardiovascular diseases are one of the major causes of mortalities worldwide. In the present research, new synthetic derivatives of thiazole were studied using isolated hearts and blood vessels of rats. The heart and thoracic aorta were tested with six new synthesized thiazole acetic acid derivatives (SMVA-10, SMVA-35, SMVA-40, SMVA-41, SMVA-42 and SMVA-60), and the data obtained were statistically analyzed and compared. Isolated rat hearts were used to record the changes in developed tension and heart rate, while thoracic aortas were used to measure the contractile response, before and after treatments. Analysis of the results indicated a significant (p < 0.01) increase in developed tension with the addition of SMVA-35, SMVA-40, SMVA-41 and SMVA-42, which was augmented in the presence of adrenaline without affecting the heart rate. On the other hand, acetylcholine significantly decreased the developed tension, which was significantly reversed (p < 0.01) in the presence of compounds (SMVA-35 and SMVA-60). However, in the presence of SMVA-35 and SMVA-40, acetylcholine-induced bradycardia was significantly (p < 0.01) reduced. Furthermore, only SMVA-42 induced a dose-dependent contractile response in the isolated blood vessel, which was abolished in the presence of prazosin. Therefore, it can be concluded that some of the new synthesized thiazole derivatives exhibited promising results by raising the developed tension without changing the heart rate or blood vessel function, which could be helpful in failing heart conditions. However, more research is required to fully comprehend the function, mechanism and effectiveness of the compounds.

Nanodelivery of Dietary Polyphenols for Therapeutic Applications.

Advancement in nanotechnology has unleashed the therapeutic potentials of dietary polyphenols by enhancing bioavailability, improving biological half-life, and allowing site-specific drug delivery. In this review, through citation of relevant literature reports, we discuss the application of nano-pharmaceutical formulations, such as solid lipid nanoparticles, nano-emulsions, nano-crystals, nano-polymersomes, liposomes, ethosomes, phytosomes, and invasomes for dietary polyphenols. Following this, we highlight important studies concerning different combinations of nano formulations with dietary polyphenols (also known as nanophytopolyphenols). We also provide nano-formulation paradigms for enhancing the physicochemical properties of dietary polyphenols. Finally, we highlight the latest patents that were granted on nano-formulations of dietary polyphenols. Based on our review, we observe that nanosized delivery of herbal constituents, spices, and dietary supplements have the ability to improve biological processes and address issues connected with herbal treatments.

Insights into the Protective Effects of Thymoquinone against Toxicities Induced by Chemotherapeutic Agents.

The drugs used to treat cancer not only kill fast-growing cancer cells, but also kill or slow the growth of healthy cells, causing systemic toxicities that lead to altered functioning of normal cells. Most chemotherapeutic agents have serious toxicities associated with their use, necessitating extreme caution and attention. There is a growing interest in herbal remedies because of their pharmacological activities, minimal side effects, and low cost. Thymoquinone, a major component of the volatile oil of Nigella sativa Linn, also known as black cumin or black seeds, is commonly used in Middle Eastern countries as a condiment. It is also utilized for medicinal purposes and possesses antidiabetic, anti-cancer, anti-inflammatory, hepatoprotective, anti-microbial, immunomodulatory, and antioxidant properties. This review attempts to compile the published literature demonstrating thymoquinone's protective effect against chemotherapeutic drug-induced toxicities.

Identification of 3-((1-(Benzyl(2-hydroxy-2-phenylethyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamoyl)pyrazine-2-carboxylic Acid as a Potential Inhibitor of Non-Nucleosidase Reverse Transcriptase Inhibitors through InSilico Ligand- and Structure-Based Approaches.

Non-nucleosidase reverse transcriptase inhibitors (NNRTIs) are highly promising agents for use in highly effective antiretroviral therapy. We implemented a rational approach for the identification of promising NNRTIs based on the validated ligand- and structure-based approaches. In view of our state-of-the-art techniques in drug design and discovery utilizing multiple modeling approaches, we report here, for the first time, quantitative pharmacophore modeling (HypoGen), docking, and in-house database screening approaches in the identification of potential NNRTIs. The validated pharmacophore model with three hydrophobic groups, one aromatic ring group, and a hydrogen-bond acceptor explains the interactions at the active site by the inhibitors. The model was implemented in pharmacophore-based virtual screening (in-house and commercially available databases) and molecular docking for prioritizing the potential compounds as NNRTI. The identified leads are in good corroboration with binding affinities and interactions as compared to standard ligands. The model can be utilized for designing and identifying the potential leads in the area of NNRTIs.

An eco-friendly HPLC-UV method for the determination of risedronate in its bulk and tablet dosage form with application to content uniformity, dissolution and stability testing.

Risedronate is a nitrogen-containing bisphosphonate for the treatment and prevention of postmenopausal osteoporosis. The current work aims to develop a novel green HPLC-UV method for the rapid analysis of risedronate sodium in bulk and tablet formulation. The analyzed samples were separated on Waters Atlantis dC18 (150 mm × 3.9 mm; 5 µm) column using a green mobile phase consisting of potassium phosphate buffer pH 2.9 and potassium edetate buffer pH 9.5 in a ratio of 1:2, the final pH was adjusted to 6.8 with phosphoric acid, the mobile phase was pumped at a rate of 1.0 mL/min, with column temperature set at 30 °C, eluted samples were detected at 263 nm and the chromatographic run time was 3.0 min. The method was found to be linear over the concentration range of 14-140 µg/mL with a correlation coefficient (r2) of 0.9994. Accuracy and precision were evaluated from three QC samples (LQC, MQC and HQC) together with the five calibrators where the percentage accuracy was found to be 101.84%. Processed quality control samples of risedronate sodium were tested for stability at different conditions, short term, long term and freeze- thaw stability. The current method was further extended to study the content uniformity of Actonel® tablets following United States Pharmacopoeia (USP) guidelines. The proposed method was fully validated as per ICH guidelines.

Hepatoprotective activity of depsidone enriched Cladonia rangiferina extract against alcohol-induced hepatotoxicity targeting cytochrome P450 2E1 induced oxidative damage.

Alcoholic liver disease (ALD) is a broad-spectrum disorder, covering fatty liver, cirrhosis, alcoholic hepatitis and in extreme untreated condition hepatocellular carcinoma (HCC) may also develop. Cladonia rangiferina (CR) is a class of lichen having a broad spectrum of pharmacological activity. It is used like traditional natural sources in ancient times in India, China, Sri Lanka, etc. Folkloric record about CR has reported their use as an antimicrobial, antitumor, antioxidant, anti-inflammatory activities, etc. Hence, the present study was requested to ascertain the effect of the ethanolic extract of Cladonia rangiferina (CRE) on alcohol-induced hepatotoxicity. The animals were evaluated for the estimation of the liver in vivo biochemical antioxidant parameters. The liver tissues were further evaluated histopathologically and western blotting examination for localization of apoptotic gene expression that plays a pivotal role in hepatotoxicity. The results of this study reveal that CRE proves to be helpful in the treatment of alcohol-induced hepatotoxicity and oxidative stress. Results of different markers have shown that among all, CRE has demonstrated the best hepatoprotective activity. These observations say about the importance of the components of the extract. The ameliorative action of CRE in alcoholic liver damage may exist due to antioxidant, anti-inflammatory, and anti-apoptotic activities.

Comparative study of subchronic toxicities of mosquito repellents (coils, mats and liquids) on vital organs in Swiss albino mice.

The aim of the current study was to evaluate and compare the toxicities of different types of mosquito repellents i.e. coils, mats and liquid vapors in animal models. Different types of mosquito repellents including liquid vaporizers, coils and mats have been extensively used by the people to get protection from the mosquitoes and diseases associated with them. The active constituents of these repellents include; allethrins, pyrethrins, paraffin and various other derivatives, are well known for their toxicities. Exposure of albino mice to these repellents for 3 h per day over a period of 20 days produced significant toxicological effects on vital body organs including; liver, lungs, kidneys, brain and heart. The order of toxicity of different repellents on nervous and hepatic tissues was found to be: Coil > Liquid > Mat while in renal and cardiac tissues, the coil was again found to be the most toxic one, mat with medium toxicity whereas liquid as least toxic (Coil > Mat > liquid). Lungs tissues are almost equally affected by all the repellants. On the basis of current findings, it has been concluded that exposure to various types of mosquito repellents can be deleterious to health and can cause various health related issues by producing pathological changes in the vital organs.

Oxidative free radicals scavenging activity (in vitro and in vivo assay) of standardized fractions from the seeds of Argyreia speciosa (Ghav-patta) a traditional Indian medicine.

TRADITIONAL PERTINENCE: Argyreia speciosa Sweet (Linn.), belongs to the family convolvulaceae, a traditional Indian medicinal herb, has been used to treat acute/chronic ulcers, gonorrhea, rheumatoid arthritis and several nervous disorders having a long history. AIM OF THE STUDY: A broad spectrum approach of this work was to find out the antioxidant activity of Argyreia speciosa seeds, in vitro and in vivo antioxidant assay were performed. MATERIAL AND METHODS: Total phenolic content (TPC), reducing power (RP), antioxidant activity (AOA), O 2 · - (superoxide anion), DPPH (1,1-diphenyl-2-picrylhydrazyl) and ˙OH (hydroxyl) radicals scavenging activities, GSH (glutathione), CAT (catalase), SOD (superoxide dismutase) and LPO (lipid peroxidase) are the major parameters which were studied for determining in vitro and in vivo antioxidant property of seed extract & their six fractions obtained from A. speciosa. Carbon tetrachloride (CCl4) induced rat model was used to determine in vivo antioxidant assay of extract and its fractions. RESULTS: Butanol fraction (AS-BF) showed strong antioxidant property and protected oxidative DNA damage. AS-BF was found best as compared to all other fraction for determining antioxidant property of seeds with the reduction in lipid peroxide formation and increment in GSH, CAT and SOD. AS-BF showed the presence of phenolic compounds viz. gallic acid, chlorogenic acid, and ellagic acid. CONCLUSION: From these results, it was proved that A. speciosa seeds prevent tissue damage due to oxidative stress with strong antioxidant activity.

In vitro wound healing activity of 1-hydroxy-5,7-dimethoxy-2-naphthalene-carboxaldehyde (HDNC) and other isolates of Aegle marmelos L.: Enhances keratinocytes motility via Wnt/ß-catenin and RAS-ERK pathways.

Wound healing is a complex process in which injured skin and tissues repaired by interaction of a complex cascade of cellular events that generates resurfacing, reconstitution and restoration of the tensile strength of injured skin. It follows ß-catenin, extracellular signal regulated kinase (ERK) and Akt signaling pathways. Aegle marmelos L., generally known as bael is found to act as anti-inflammatory, antioxidant and anti-ulcer agent. Furthermore, studies have demonstrated that this Indian traditional medicinal plant, A. marmelos flower extract (AMF) was used for wound injury. Henceforth, the current study was investigated to ascertain the effect of its active constituents in vitro wound healing with mechanism involve in migration of cells and activation of ß-catenin in keratinocytes, inhibition of PGE2 in macrophages and production of collagen in fibroblasts. We have taken full thickness wound of rats and applied AMF for 2 weeks. Cutaneous wound healing activity was performed using HaCaT keratinocytes, Hs68 dermal fibroblasts and RAW264.7 macrophages to determine cell viability, nitric oxide production, collagen expression, cell migration and ß-catenin activation. Results shows that AMF treated rats demonstrated reduced wound size and epithelisation was improved, involved in keratinocytes migration by regulation of Akt signaling, beta-catenin and extracellular signal-regulated kinase (ERK) pathways. AMF and its active constituent's increased mRNA expression, inhibited nitric oxide, PGE2 release, mRNA expression of mediators in RAW 264.7 macrophages and enhances the motility of HaCaT keratinocytes in vitro wound healing of rats.

Antitumor activity of extract and isolated compounds from Drechslera rostrata and Eurotium tonophilum.

Total extracts of Drechslera rostrata and Eurotium tonophilum in addition of two isolated compounds from their cultures [di-2-ethylhexyl phthalate (H1) and 1,8-Dihydroxy-3-methoxy-6-methyl-anthraquinone (H2)] were tested for their antitumor activity using four human carcinoma cell lines. Antitumor activity was assessed by performing MTT assay to check the % cell viability. The % viability of HCT-116 (colon carcinoma), HeLa (cervical carcinoma), HEp-2 (larynx carcinoma) and HepG-2 (hepatocellular carcinoma) cells decreased after treatment with Drechslera rostrata and Eurotium tonophilum extracts, these effects were ranged from 059.0 ± â€¯0.1 to 217.0  ± â€¯0.3 µg/ml on all types of cancer cells. The best activity was recorded for Eurotium tonpholium extract (054.5 ±â€¯0.3, 059.0 ±â€¯0.5 and 059.0 ±â€¯0.1 for HEp-2, Hela, and HepG-2 respectively). The isolated compounds (H1&H2) were found to be responsible about the activities because they recorded the lowest IC50 on tested cell lines with range of 9.5-20.3 µg/ml. Vinblastine sulphate was used as a reference standard and showed in vitro anticancer activity. This study demonstrated that all extracts and isolated compounds have antitumor activity against HCT-116, HeLa, HEp-2 and HepG-2 cells.

Evaluation of Cucurbita maxima extract against scopolamine-induced amnesia in rats: implication of tumour necrosis factor alpha.

Cucurbita maxima (CM) seed oil is commonly used in Indian folk medicine to treat various ailments. We have investigated the effect of CM seed oil on memory impairment induced by scopolamine in rats. Male adult Wistar rats were administered scopolamine 1 mg/kg body weight, i.p. or 1.25 mg/kg body weight, s.c. to induce memory impairment. The nootropic agent piracetam 100 mg/kg body weight, i.p. and CM seed oil 100 and 200 mg/kg body weight, p.o. were administered daily for five consecutive days. The memory function was evaluated in the Morris water maze (MWM) test, the social recognition test (SRT), the elevated plus maze (EPM) test, and the pole climbing test (PCT). Acetylcholinesterase (AChE) activity and oxidative stress parameters were estimated in the cortex, hippocampus, and cerebellum of the brains after completion of the behavioural studies. The effects of scopolamine on the levels of the tumour necrosis factor alpha (TNF-α) transcript were also investigated. Scopolamine caused memory impairment in all the behavioural paradigms along with a significant increase in the AChE activity and oxidative stress in the brain. Scopolamine also caused a significant increase in the expression of TNF-α in the hippocampus. CM seed oil exhibited antiamnesic activity as indicated by a significant reduction in the latency time in the MWM test and decreased social interaction during trial 2 in the SRT. Further, treatment with CM seed oil significantly decreased the AChE activity and malondialdehyde levels and increased the glutathione level in brain regions. CM seed oil also significantly decreased the expression of TNF-α in the hippocampus. The effect of CM seed oil on behavioural and biochemical parameters was comparable to that observed in rats treated with piracetam. These results indicate that CM seed oil may exert antiamnesic activity which may be attributed to the inhibition of AChE and inflammation as well as its antioxidant activity in the brain.

Investigation of natural compounds as methyltransferase inhibitors against dengue virus: an in silico approach.

The global challenge posed by Dengue virus (DENV) infection persists, exacerbated by the absence of specific antiviral therapies. The viral methyltransferase (MTase) enzyme, crucial for viral RNA methylation and immune system evasion, has emerged as a promising drug target for combating Dengue fever. In this study, a comprehensive exploration of natural compounds derived from the COCONUT database was conducted, selecting 224 compounds based on their structural similarity to the native substrate of the MTase enzyme, S-adenosyl-L-methionine (SAM). Employing virtual screening techniques, four natural compounds (CNP0307160, CNP0082902, CNP0449158, and CNP0296775) with acceptable docking scores were selected for further re-docking after geometry optimization by the DFT method. Re-docking analyses unveiled significant interactions, including hydrogen bonds and hydrophobic interactions, between these selected ligands and the MTase protein. To gain deeper insights into the dynamic stability of these complexes, we conducted molecular dynamics simulations which showed lower RMSD values for CNP0307160, CNP0082902, and CNP0296775 when compared to the reference molecule. Furthermore, we assessed the structural and dynamic stability of the protein-ligand complexes through free binding energy calculations and Principal Component Analysis (PCA) of the simulation trajectories. In these analyses, the CNP0296775 compound exhibited promising results compared to the other three compounds. The cumulative findings of these investigations underscore the potential of CNP0296775 as a strong inhibitor of DENV MTase, thus offering a promising starting point for its further experimental validation and optimization.Communicated by Ramaswamy H. Sarma.