Untargeted Metabolomics and Bioactivities Assessment of Xylaria ellisii, an Endophytic Fungus Isolated from the Leaf of the Plant Acorus calamus Linn.

Article

Author: Garg, Neha ; Rai, Sachchida Nand ; Singh, Santosh Kumar ; Rajak, Naina ; Singh, Anurag Kumar ; Prajapati, Chandrabhan

Introduction:Fungal endophytes have mutualistic associations with the plant's host, communicating through genetic and metabolic processes. As a result, they gain the ability to generate therapeutically effective metabolites and their derivatives.Methods:The current study aims to assess antioxidant potential along with the identification of robust metabolites within the crude extract of a potent endophytic fungus Xylaria ellisii isolated from leaf tissues of the Acorus calamus Linn plant.Four endophytic fungi were obtained from leaf tissues of Acorus calamus Linn., and identified morphologically and molecularly as distinct species. Each ethyl acetate extract of the isolated fungi exhibited a unique chemical profile in the HPTLC fingerprint at various wavelengths. The ethyl acetate (EA) extract from the fungal strain ACL-4 (Xylaria ellisii) demonstrated the strongest antioxidant activity among the four fungal endophytes examined, with an EC50 value of 292.64 ± 3.558 μg/mL. Remarkably, fungal endophyte ACL-4 extract exhibited superior antimicrobial activity at the less concentrations compared to ACL-ME extract of leaf crude.Results:The extract of ACL-ME-treated HEK 293T cells exhibited significant toxicity, with an IC50 value of 1481.74 ± 23.772 μg/mL, compared to fungal strain ACL-4-treated HEK 293T cells, which had an IC50 value greater than 2000 μg/mL. Consequently, the crude extract of ACL-4 and ACL-ME along with the standard drug methotrexate exhibited cytotoxic activity against cancer cell line MDA-MB-231 with IC50 concentrations of 146.65 ± 0.394 μg/mL, 528.46 ± 10.912 μg/mL, and 134.11 ± 3.446 μg/mL, respectively. A total of 2,255 compounds were detected through LC-HRMS-based metabolomics in the crude metabolites of Xylaria ellisii, with certain compounds identified in multiple instances. Among this repertoire, 62 robust bioactive compounds were identified through meticulous screening, guided by existing literature. Comparative HPTLC fingerprint analysis, along with antioxidant efficacy assays of ethyl acetate extracts of Xylaria ellisii derived from Acorus calamus leaves and Cassia fistula twigs revealed the host-specific production of bioactive chemicals.Conclusion:The top-scoring Keap1 inhibitors derived from Xylaria ellisii, including Pregabalin (-6.083 Kcal/mol), Ferulic acid (-5.434 Kcal/mol), (R)-Piperidine-2-carboxylic acid (-5.31 Kcal/mol), Genipin (-5.197 Kcal/mol), and Brivaracetam (-5.17 Kcal/mol), respectively were considered as Keap 1 inhibitors, potentially mitigate oxidative stress.

01 Jan 2025·Toxicology and Applied Pharmacology

Synthesis and evaluation of novel ethyl ferulate derivatives as potent Keap1 inhibitors to activate the Nrf2/ARE pathway in Parkinson's disease

Article

Author: Sajini, Deepak Vasudevan ; Sugumar, Deepa ; Ramachandran, Vadivelan ; Mathew, Jinu ; Rymbai, Emdormi ; Selvaraj, Divakar ; Arumugam, Suresh ; Chakkittukandiyil, Amritha

The Kelch-like ECH-associated protein 1/Nuclear factor erythroid 2 related factor 2/Antioxidant Response Elements (Keap1/Nrf2/ARE) pathway is essential for neuronal resilience against the complex pathogenesis of Parkinson's disease (PD). Activating this pathway by covalently modifying Keap1 cysteine residues is a promising strategy for regulating neuroprotective gene expression. Our study aimed to identify phytochemicals that could irreversibly inhibit Keap1. A preliminary docking analysis revealed that ethyl ferulate could covalently bind with Cys151 of Keap1 by Michael's addition reaction. Further, we designed several ethyl ferulate derivatives with improved lipophilicity and assessed their binding affinity with Keap1. The molecules with good binding scores were synthesized and structures were confirmed through ¹H NMR, ¹³C NMR, FT-IR, and mass spectroscopy. Neuroprotection screening was conducted in all-trans retinoic acid differentiated SH-SY5Y cells using rotenone as a disease-inducing agent. Pre-treatment with compounds C2 and C4 significantly mitigated rotenone toxicity. Additionally, C2 and C4 decreased rotenone-induced ROS production and mitochondrial membrane potential loss. C2 and C4 also induced Nrf2 nuclear translocation in SH-SY5Y cells and increased mRNA expression of heme oxygenase-1, an Nrf2-regulated antioxidant response element. In vivo, pretreatment with C2 (50, 100 mg/kg, p.o.) and C4 (50, 100 mg/kg, p.o.) protected against neurodegenerative phenotypes associated with rotenone (1.5 mg/kg, s.c.) induction in Wistar rats. Results indicate, C2 and C4 dose-dependently improved muscle rigidity, catalepsy, and cognitive deficits in rotenone-induced Wistar rats, and mitigated dopaminergic neurodegeneration in the substantia nigra. These findings highlight the potential of ethyl ferulate derivatives in modulating oxidative stress and neurodegeneration in PD via activation of Nrf2.

01 Nov 2024·International Immunopharmacology

Research progress on the role and inhibitors of Keap1 signaling pathway in inflammation

Review

Author: Naseem, Anam ; Li, Hua ; Yang, Bingyou ; Liu, Yan ; Ding, Chao ; Chen, Lixia ; Zhan, Chaochao ; Wu, Ying

Inflammation is a protective mechanism against endogenous and exogenous pathogens. It is a typical feature of numerous chronic diseases and their complications. Keap1 is an essential target in oxidative stress and inflammatory diseases. Among them, the Keap1-Nrf2-ARE pathway (including Keap1-Nrf2-HO-1) is the most significant pathway of Keap1 targets, which participates in the control of inflammation in multiple organs (including renal inflammation, lung inflammation, liver inflammation, neuroinflammation, etc.). Identifying new Keap1 inhibitors is crucial for new drug discovery. However, most drugs have specificity issues as they covalently bind to cysteine residues of Keap1, causing off-target effects. Therefore, direct inhibition of Keap1-Nrf2 PPIs is a new research idea. Through non-electrophilic and non-covalent binding, its inhibitors have better specificity and ability to activate Nrf2, and targeting therapy against Keap1-Nrf2 PPIs has become a new method for drug development in chronic diseases. This review summarizes the members and downstream genes of the Keap1-related pathway and their roles in inflammatory disease models. In addition, we summarize all the research progress of anti-inflammatory drugs targeting Keap1 from 2010 to 2024, mainly describing their biological functions, molecular mechanisms of action, and therapeutic roles in inflammatory diseases.

100 Deals associated with VVD-702

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Inflammatory Bowel Diseases	Preclinical	United States	Vividion Therapeutics, Inc.	01 Nov 2024
Colitis	Preclinical	United States	Vividion Therapeutics, Inc.	25 Jun 2021

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

VVD-702

Overview

Basic Info

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation