The Mechanisms of Cucurbitacin E as a Neuroprotective and Memory-Enhancing Agent in a Cerebral Hypoperfusion Rat Model: Attenuation of Oxidative Stress, Inflammation, and Excitotoxicity

Impaired cerebral hemodynamic autoregulation, vasoconstriction, and cardiovascular and metabolic dysfunctions cause cerebral hypoperfusion (CH) that triggers pro-oxidative and inflammatory events. The sequences linked to ion-channelopathies and calcium and glutamatergic excitotoxicity mechanisms resulting in widespread brain damage and neurobehavioral deficits, including memory, neurological, and sensorimotor functions. The vasodilatory, anti-inflammatory, and antioxidant activities of cucurbitacin E (CuE) can alleviate CH-induced neurobehavioral impairments. In the present study, the neuroprotective effects of CuE were explored in a rat model of CH. Wistar rats were subjected to permanent bilateral common carotid artery occlusion to induce CH on day 1 and administered CuE (0.25, 0.5 mg/kg) and/or Bay-K8644 (calcium agonist, 0.5 mg/kg) for 28 days. CH caused impairment of neurological, sensorimotor, and memory functions that were ameliorated by CuE. CuE attenuated CH-triggered lipid peroxidation, 8-hydroxy-2′-deoxyguanosine, protein carbonyls, tumor necrosis factor-α, nuclear factor-kappaB, myeloperoxidase activity, inducible nitric oxide synthase, and matrix metalloproteinase-9 levels in brain resulting in a decrease in cell death biomarkers (lactate dehydrogenase and caspase-3). CuE decreased acetylcholinesterase activity, glutamate, and increased γ-aminobutyric acid levels in the brain. An increase in brain antioxidants was observed in CuE-treated rats subjected to CH. CuE has the potential to alleviate pathogenesis of CH and protect neurological, sensorimotor, and memory functions against CH.

Technology of obtaining a food additive from citrullus colocynthis and its hypoglycemic activity

The aim of the study is to develop a technology for obtaining a food additive for the extract of the pulp of bitter watermelon - Citrullus colocynthis, introduced in Uzbekistan as a hypoglycemic agent. Pharmacological studies have shown the presence of a hypoglycemic effect for aqueous and alcoholic extracts and 2-O-β-glucopyranosyl-cucurbitacin E in rats with alloxan diabetes mellitus. Cucurbitacins were isolated from the extract - cucurbitacin E, 2-O-β-glucopyranosyl-cucurbitacin E and other bioactive substances. The food supplement obtained from bitter watermelon (Citrullus colocynthis (family Cucurbitaceae)) according to the developed technology showed a higher hypoglycemic activity compared to the drug arfazetin.

The efficacy of natural bioactive compounds for the treatment of nasopharyngeal carcinoma

: The death toll associated with cancer worldwide is constantly on the increase. Efforts to combat and treat the different forms of this disease is also evolving. Nasopharyngeal carcinoma (NPC) is a lethal form of cancer which is prevalent in Southern China that is normally treated by using radiotherapy. Here we review products obtained from natural sources that have potential cytotoxic and apoptotic properties against NPC. These include grifolin, dihydroartemisinin, luteolin, honokiol, indole-3-carbinol, caffeic acid phenethyl ester, 6-O-angeloylenolin, cucurbitacin E, genistein, helenalin, celastrol, coronarin D, quercetin, trans-cinnamaldehyde, 5'-epimer episilvestrol, silvestrol, arnicolide D, brevilin A and baicalin hydrate. Ethyl acetate extracts of Wedelia chinensis and aqueous extracts of Ajuga bracteosa are also included although the bioactive compounds involved have yet to be identified. The known mechanism of action of these products are discussed. It is anticipated that one or more of these substances may provide the general population with alternative and cost effective ways to combat this fatal disease.

In Silico studies of Natural compounds that inhibit SARS-CoV-2 Nucleocapsid Nsp1/Nsp3 proteins mediated Viral Replication and Pathogenesis

Highly Transmissible and pathogenic coronavirus that emerged in late December of 2019 caused Severe acute respiratory syndrome (SARS-CoV-2), which challenged human health and public safety. Severity of the disease depends on the viral load and the type of mutation that occurred in the coronavirus. Nonstructural proteins like, Nsp1, Nsp3, Nsp12 and Nsp13 including other viral proteins plays important role during viral replication life cycle. Viral Replication initiated by hacking the host cellular mechanism either by synergy or by suppression using nucleocapsid proteins of the virus. Spike (S) protein of the SARS-CoV-2 uses angiotensin-converting enzyme II (ACE2) and TRMPSS as a cell entry. Once virus enters host cell, nucleocapsid proteins along with its genome is releases from endosomes into cytosol of the host cell. Ca2+/CaM (Calmodulin)/Calcineurin complex of the host cell plays important role during viral replication which is mediated by nucleocapsid proteins of the virus. Nsp1/Nsp3 nonstructural proteins triggers synergetic activity with CD147/CyPA/HSPG pathway and TRMP2/ADPr/Ca+2 mediated Ca2+/CaM (Calmodulin)/Calcineurin synthesis and free radicle generation in mitochondria leading to viral replication and severe chemokine activation pathways. Docking studies were carried out to inhibit Cyclophilin A and TRMP2 proteins as drug targets. Natural compounds like Withanolide A, Columbin, Cucurbitacin E, Boswellic acid along with Cyclosporines, Vitamin E and N-Acetyl cysteine (NAC) were selected as ligands to study docking studies. Withanolide A and Cyclosporines had shown good inhibition activity against Cyclophilin A, whereas Columbin, Boswellic acid, Cucurbitacin E, Vitamin E and N-Acetyl cysteine (NAC) had shown inhibitory activity against TRMP2. Thus, we suggest conducting further studies to conclude above pathways mechanism and inhibitory effect of natural compounds against the Nsp1/Nsp3 mediated pathways Invitro and In vivo.

Molecular Insights into the Interaction of Ursolic Acid and Cucurbitacin from Colocynth with Therapeutic Targets of Mycobacterium tuberculosis

Aims: Medicinal plants like Citrullus colocynthis are a potential choice to produce helpful novel antimycobacterial drugs. The existence of a range of natural products in the plants, especially Ursolic Acid (UA) and cucurbitacin E 2-0-β-d-glucopyranoside (CEG), with promising antibacterial activity against a variety of bacteria, prompted the need to check its actions against Mycobacterium tuberculosis (Mtb). Background: Mycobacterium tuberculosis (Mtb), an obligate human pathogen causes tuberculosis and is one of the major causes of death worldwide. A few combinations of drugs are currently accessible for treating TB patients, but these are inadequate to tackle worldwide TB cases. Objective: The molecular interactions between ursolic acid and cucurbitacin E with the eight potential Mtb target proteins were investigated with the objective of finding drug-like inhibitors. Methods: Avogadro v.1.2.0 and Openbabel v.2.4.1 were used for creating file formats required for docking analysis. Molecular docking was performed with eight different proteins essential for Mtb metabolism and survival. AutoDock v.4.2 and AutoDock vina v.1.1.2 were used for docking and Gromacs 5.1.4 was used for simulation studies. Results and Discussion: Among the two ligands used in this research, cucurbitacin E showed a better docking score relative to the drugs presently available for all the target proteins. Rifampicin showed the best binding affinity (among known inhibitors) i.e. -10.8 kcal/mol with C terminal caspase recruitment domain. Moreover, ursolic acid and cucurbitacin E showed uniform binding score (above -7.5 kcal/mol) with all the target proteins, acknowledged its availability as a potential multi-target drug. Conclusion: Ursolic acid can be useful in the creation of novel, multi-targeted and effective anti- TB medicines since it showed stable structure with FabH.