Mushroom-derived bioactive compounds potentially serve as the inhibitors of SARS-CoV-2 main protease: An in silico approach

Background and aim Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has now become the world pandemic. There is a race to develop suitable drugs and vaccines for the disease. The anti-HIV protease drugs are currently repurposed for the potential treatment of COVID-19. The drugs were primarily screened against the SARS-CoV-2 main protease. With an urgent need for safe and effective drugs to treat the virus, we have explored natural products isolated from edible and medicinal mushrooms that have been reported to possess anti-HIV protease. Experimental procedures We have examined 36 compounds for their potential to be SARS-CoV-2 main protease inhibitors using molecular docking study. Moreover, drug-likeness properties including absorption, distribution, metabolism, excretion and toxicity were evaluated by in silico ADMET analysis. Results Our AutoDock study showed that 25 of 36 candidate compounds have the potential to inhibit the main viral protease based on their binding affinity against the enzyme’s active site when compared to the standard drugs. Interestingly, ADMET analysis and toxicity prediction revealed that 6 out of 25 compounds are the best drug-like property candidates, including colossolactone VIII, colossolactone E, colossolactone G, ergosterol, heliantriol F and velutin. Conclusion Our study highlights the potential of existing mushroom-derived natural compounds for further investigation and possibly can be used to fight against SARS-CoV-2 infection. Taxonomy (classification by evise) Disease, Infectious Disease, Respiratory System Disease, Covid-19, Traditional Medicine, Traditional Herbal Medicine, Phamaceutical Analysis

Neuroprotective Effects against Glutamate-Induced HT-22 Hippocampal Cell Damage and Caenorhabditis elegans Lifespan/Healthspan Enhancing Activity of Auricularia polytricha Mushroom Extracts.

Oxidative stress is associated with several diseases, particularly neurodegenerative diseases, commonly found in the elderly. The attenuation of oxidative status is one of the alternatives for neuroprotection and anti-aging. Auricularia polytricha (AP), an edible mushroom, contains many therapeutic properties, including antioxidant properties. Herein, we report the effects of AP extracts on antioxidant, neuroprotective, and anti-aging activities. The neuroprotective effect of AP extracts against glutamate-induced HT-22 neuronal damage was determined by evaluating the cytotoxicity, intracellular reactive oxygen species (ROS) accumulation, and expression of antioxidant enzyme genes. Lifespan and healthspan assays were performed to examine the effects of AP extracts from Caenorhabditis elegans. We found that ethanolic extract (APE) attenuated glutamate-induced HT-22 cytotoxicity and increased the expression of antioxidant enzyme genes. Moreover, APE promoted in the longevity and health of the C. elegans. Chemical analysis of the extracts revealed that APE contains the highest quantity of flavonoids and a reasonable percentage of phenols. The lipophilic compounds in APE were identified by gas chromatography/mass spectrometry (GC/MS), revealing that APE mainly contains linoleic acid. Interestingly, linoleic acid suppressed neuronal toxicity and ROS accumulation from glutamate induction. These results indicate that AP could be an exciting natural source that may potentially serves as neuroprotective and anti-aging agents

Polygonumins A, a newly isolated compound from the stem of Polygonum minus Huds with potential medicinal activities

Polygonumins A, a new compound, was isolated from the stem of Polygonum minus. Based on NMR results, the compound’s structure is identical to that of vanicoside A, comprising four phenylpropanoid ester units and a sucrose unit. The structure diferences were located at C-3″″′. The cytotoxic activity of polygonumins A was evaluated on several cancer cell lines by a cell viability assay using tetrazolium dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The compound showed the highest antiproliferative (p<0.05) activities against K562 (Human Leukaemia Cell Line), MCF7 (Human breast adenocarcinoma cell line), and HCT116 (Colorectal cancer cells) cells. Cytotoxic studies against V79–4 cells were carried out and showed that polygonumins A was toxic at 50µg/ml, suggesting that this compound may be used as an anticancer drug without afecting normal cells. Polygonumins A also showed promising activity as an HIV-1 protease inhibitor with 56% relative inhibition. Molecular docking results indicated that the compound possesses high binding afnity towards the HIV protease over the low binding free energy range of -10.5 to -11.3kcal/mol. P. minus is used in Malaysian traditional medicine for the treatment of tumour cells. This is the frst report on the use of P. minus as an HIV-1 protease inhibitor

Paradoxical effects of JZL184, an inhibitor of monoacylglycerol lipase, on bone remodelling in healthy and cancer-bearing mice

Background Cancer-associated bone disease is a serious complication in bone sarcomas and metastatic carcinomas of breast and prostate origin. Monoacylglycerol lipase (MAGL) is an enzyme of the endocannabinoid system, and is responsible for the degradation of the most abundant endocannabinoid in bone, 2-arachidonoyl glycerol (2AG). Methods The effects of the verified MAGL inhibitor on bone remodelling were assessed in healthy mice and in mouse models of bone disease caused by prostate and breast cancers and osteosarcoma. Findings JZL184 reduced osteolytic bone metastasis in mouse models of breast and prostate cancers, and inhibited skeletal tumour growth, metastasis and the formation of ectopic bone in models of osteosarcoma. Additionally, JZL184 suppressed cachexia and prolonged survival in mice injected with metastatic osteosarcoma and osteotropic cancer cells. Functional and histological analysis revealed that the osteoprotective action of JZL184 in cancer models is predominately due to inhibition of tumour growth and metastasis. In the absence of cancer, however, exposure to JZL184 exerts a paradoxical reduction of bone volume via an effect that is mediated by both Cnr1 and Cnr2 cannabinoid receptors. Interpretation MAGL inhibitors such as JZL184, or its novel analogues, may be of value in the treatment of bone disease caused by primary bone cancer and bone metastasis, however, activation of the skeletal endocannabinoid system may limit their usefulness as osteoprotective agents

Anti-HIV-1 protease activity of the crude extracts and isolated compounds from Auricularia polytricha

© 2019 The Author(s). Background: Acquired immunodeficiency syndrome (AIDS) is caused by the Human immunodeficiency virus type-1 (HIV-1). HIV-1 protease (HIV-1 PR) is an essential enzyme for the HIV replication, and therefore, it is an important target for antiretroviral drugs development, particularly from natural products. Auricularia polytricha (AP) is an edible mushroom with several important therapeutic properties. These properties will be investigated as HIV-1 PR inhibitors. Methods: The sequential hexane (APH), ethanol (APE) and water (APW) extracts from AP were screened for inhibitory activity against HIV-1 PR. The extract that consistently showed the strong HIV-1 PR inhibition was further investigated for its phytochemical constituents. The compounds were purified by column chromatography. The isolated compounds were structurally elucidated using 1D and 2D NMR, HRMS, FTIR, and GC/MS techniques. Each compound was screened against HIV-1 PR to determine its inhibitory activity and to provide an explanation for the activity found in the extract. Results: Hexane crude extract of AP (APH) exhibited significant inhibition on HIV-1 PR activity. Four major compounds isolated from APH fraction were identified to be two triacylglycerols, linoleic acid and ergosterol. Moreover, all four compounds showed significant inhibition of HIV-1 PR activity. Conclusion: The findings from this study suggest that AP is a good source of fatty esters, fatty acids and ergosterol. These natural products exhibit anti-HIV-1 properties by blocking HIV-1 PR. These important biological results warrant further development of AP as an alternative antiretroviral drug

Neuroprotective Effects of Extracts from Tiger Milk Mushroom Lignosus rhinocerus Against Glutamate-Induced Toxicity in HT22 Hippocampal Neuronal Cells and Neurodegenerative Diseases in Caenorhabditis elegans

Despite the Tiger Milk Mushroom Lignosus rhinocerus (LR) having been used as a traditional medicine, little is known about the neuroprotective effects of LR extracts. This study aims to investigate the neuroprotective effect of three extracts of LR against glutamate-induced oxidative stress in mouse hippocampal (HT22) cells as well as to determine their effect in Caenorhabditis elegans. In vitro, we assessed the toxicity of three LR extracts (ethanol extract (LRE), cold-water extract (LRC) and hot-water extract (LRH)) and their protective activity by MTT assay, Annexin V-FITC/propidium iodide staining, Mitochondrial Membrane Potential (MMP) and intracellular ROS accumulation. Furthermore, we determined the expression of antioxidant genes (catalase (CAT), superoxide dismutase (SOD1 and SOD2) and glutathione peroxidase (GPx)) by qRT-PCR. In vivo, we investigated the neuroprotective effect of LRE, not only against an A&beta;-induced deficit in chemotaxis behavior (Alzheimer model) but also against PolyQ40 formation (model for Morbus Huntington) in transgenic C. elegans. Only LRE significantly reduced both apoptosis and intracellular ROS levels and significantly increased the expression of antioxidant genes after glutamate-induced oxidative stress in HT22 cells. In addition, LRE significantly improved the Chemotaxis Index (CI) in C. elegans and significantly decreased PolyQ40 aggregation. Altogether, the LRE exhibited neuroprotective properties both in vitro and in vivo

Extracts of the Tiger Milk Mushroom (<em>Lignosus rhinocerus</em>) Enhance Stress Resistance and Extend Lifespan in <em>Caenorhabditis elegans</em> via the DAF-16/FoxO Signaling Pathway

The tiger milk mushroom, Lignosus rhinocerus (LR), exhibits antioxidant properties, as shown in a few in vitro experiments. The aim of this research was to study whether three LR extracts exhibit antioxidant activities in Caenorhabditis elegans. In wild-type N2 nematodes, we determined the survival rate under oxidative stress caused by increased intracellular ROS concentrations. Transgenic strains, including TJ356, TJ375, CF1553, CL2166, and LD1, were used to detect the expression of DAF-16, HSP-16.2, SOD-3, GST-4, and SKN-1, respectively. Lifespan, lipofuscin, and pharyngeal pumping rates were assessed. Three LR extracts (ethanol, and cold and hot water) protected the worms from oxidative stress and decreased intracellular ROS. The extracts exhibited antioxidant properties through the DAF-16/FOXO pathway, leading to SOD-3 and HSP-16.2 modification. However, the expression of SKN-1 and GST-4 was not changed. All the extracts extended the lifespan. They also reduced lipofuscin (a marker for aging) and influenced the pharyngeal pumping rate (another marker for aging). The extracts did not cause dietary restriction. This novel study provides evidence of the functional antioxidant and anti-aging properties of LR. Further studies must confirm that they are suitable for use as antioxidant supplements

Ergosterol promotes neurite outgrowth, inhibits amyloid-beta synthesis, and extends longevity: In vitro neuroblastoma and in vivo Caenorhabditis elegans evidence

Aims: Alzheimer's disease (AD), the most common neurodegenerative disorder associated with aging, is characterized by amyloid-beta (A beta) plaques in the hippocampus. Ergosterol, a mushroom sterol, exhibits neuroprotective activities; however, the underlying mechanisms of ergosterol in promoting neurite outgrowth and preventing A beta associated aging have never been investigated. We aim to determine the beneficial activities of ergosterol in neuronal cells and Caenorhabditis elegans (C. elegans). Materials and methods: The neuritogenesis and molecular mechanisms of ergosterol were investigated in wildtype and A beta precursor protein (APP)-overexpressing Neuro2a cells. The anti-amyloidosis properties of ergosterol were determined by evaluating in vitro A beta production and the potential inhibition of A beta-producing enzymes. Additionally, AD-associated transgenic C. elegans was utilized to investigate the in vivo attenuating effects of ergosterol. Key findings: Ergosterol promoted neurite outgrowth in Neuro2a cells through the upregulation of the transmembrane protein Teneurin-4 (Ten-4) mRNA and protein expressions, phosphorylation of the extracellular signal-regulated kinases (ERKs), activity of cAMP response element (CRE), and growth-associated protein-43 (GAP-43). Furthermore, ergosterol enhanced neurite outgrowth in transgenic Neuro2A cells overexpressing either the wild-type APP (Neuro2a-APPwt) or the Swedish mutant APP (Neuro2a-APPswe) through the Ten-4/ ERK/CREB/GAP-43 signaling pathway. Interestingly, ergosterol inhibited A beta synthesis in Neuro2a-APPwt cells. In silico analysis indicated that ergosterol can interact with the catalytic sites of beta- and gamma-secretases. In A beta-overexpressing C. elegans, ergosterol decreased A beta accumulation, increased chemotaxis behavior, and prolonged lifespan. Significance: Ergosterol is a potential candidate compound that might benefit AD patients by promoting neurite outgrowth, inhibiting A beta synthesis, and enhancing longevity

Antioxidant and Anti-Skin Aging Potential of Selected Thai Plants: In Vitro Evaluation and In Silico Target Prediction

The skin is the largest organ that performs a variety of the body’s essential functions. Impairment of skin structure and functions during the aging process might severely impact our health and well-being. Extensive evidence suggests that reactive oxygen species play a fundamental role in skin aging through the activation of the related degradative enzymes. Here, the 16 Thai medicinal plant species were screened for their potential anti-skin aging properties. All extracts were investigated for total phenolic and flavonoid contents, antioxidant, anti-elastase, and anti-tyrosinase activities, as well as the binding ability of compounds with target enzymes by molecular docking. Among all the plants screened, the leaves of A. occidentale and G. zeylanicum exhibited strong antioxidants and inhibition against elastase and tyrosinase. Other potential plants include S. alata leaf and A. catechu fruit, with relatively high anti-elastase and anti-tyrosinase activities, respectively. These results are also consistent with docking studies of compounds derived from these plants. The inhibitory actions were found to be more highly positively correlated with phenolics than flavonoids. Taken together, our findings reveal some Thai plants, along with candidate compounds as natural sources of antioxidants and potent inhibitors of elastase and tyrosinase, could be developed as promising and effective agents for skin aging therapy

Protective Effect of <i>Aquilaria crassna</i> Leaf Extract against Benzo[a]pyrene-Induced Toxicity in Neuronal Cells and <i>Caenorhabditis elegans</i>: Possible Active Constituent Includes Clionasterol

Aquilaria crassna (AC) is a beneficial plant widely used to alleviate various health ailments. Nevertheless, the neuroprotection, antiaging, and xenobiotic detoxification against high benzo[a]pyrene induction have not been investigated. This study aimed to investigate the effects of ethanolic extract of AC leaves (ACEE) in vitro using SH-SY5Y cells and in vivo using Caenorhabditis elegans (C. elegans). Neuroprotective activities and cell cycle progression were studied using SH-SY5Y cells. Additionally, C. elegans was used to determine longevity, health span, and transcriptional analysis. Furthermore, ACEE possible active compounds were analyzed by gas chromatograph–mass spectrometry (GC-MS) analysis and the possible active compounds were evaluated using a molecular docking study. First, ACEE possessed neuroprotective effects by normalizing cell cycle progression via the regulation of AhR/CYP1A1/cyclin D1 pathway. Next, ACEE played a role in xenobiotic detoxification in high B[a]P-induced C. elegans by the amelioration of lifespan reduction, and body length and size decrease through the reduction in gene expression in hexokinase (hxk) and CYP35 pathway. Finally, phytochemicals of ACEE were identified and we uncovered that clionasterol was the possible active constituent in powerfully inhibiting both CYP1A1 and hexokinase II receptor. Essentially, ACEE was recognized as a potential alternative medicine to defend against high B[a]P effects on neurotoxicity and xenobiotic detoxification