Hydroalcoholic root extracts of Houttuynia cordata (Thunb.) standardized by UPLC-Q-TOF-MS/MS promotes apoptosis in human hepatocarcinoma cell HepG2 via GSK-3ß/ß-catenin/PDL-1 axis.

Houttuynia cordata (Thunb.), an important medicinal plant of Northeast India, Korea, and China, is used to treat various ailments and for anticancer research. Knowing its traditional practices, we are interested in the mode-of-action of HCT on HepG2 to co-relate the traditional practice with modern drug therapeutics. UPLC-Q-ToF-Ms analysis of HCT reveals identification of 14 metabolites. Network pharmacology analysis of the 14 compounds showed interaction with 232 different targets with their potential involvement in hepatocellular carcinoma. Whole extracts impart cytotoxicity on variety of cell lines including HepG2. There was a significant morphological alteration in treated HepG2 cells due to impairment of cytoskeletal components like ß and γ- tubulin. Arrest at G1-S checkpoint was clearly indicated downregulation of Cyclin D1. The root extracts actuated apoptosis in HepG2 as evident from altered mitochondrial membrane potential, Annexin V- FITC, BrdU-PI, AO/EtBr assays, and modulations of apoptotic protein expression but without ROS generation. Whole extracts caused abrogation of epithelial to mesenchymal transition with repression of Snail, N-Cadherin, Vimentin, MMP-9, and upregulation of Pan-Cadherin. Pathway analysis found GSK-3ß in Wnt/ß-Catenin signaling cascade to be involved through Hepatocellular carcinoma (hsa05225) pathway. The GSK-3ß/ß-Catenin/PDL-1 signaling was found to be inhibited with the downregulation of pathway components. This was further confirmed by application of EGF, an inducer of the GSK-3ß/ß-Catenin pathway that neutralized the effect of Houttuynia cordata (Thunb.) root extract on the said pathway. Network pharmacology analysis also confirms the synergy network with botanical-bioactive-target-disease which showed Kaempferol to have the highest degree of association with the said pathway.

Therapeutic importance of Cucurbitaceae: A medicinally important family.

ETHNOPHARMACOLOGICAL RELEVANCE: Medicinal plants of Cucurbitaceae family consist of several edible fruits and vegetables consumed worldwide since ancient times. The plants of this family have played an essential role in the ethnopharmacological as well as traditional medicinal system globally and their evidence is well established in several traditional literatures. Various plant parts have been used to treat several human ailments viz. Pandu (anemia), Pliharoga (splenomegaly), Sopha (inflammation), Gulma (tumor growth), Adhmana (indigestion. acidity), Garavisa (poisoning) etc. AIM OF THE REVIEW: This review article aims to systematically document and bridge scientific evidences with the ethnopharmacological, ethnoveterinary and folklore claims along with the therapeutic efficacy with mechanism of action found in different literature, books, and scientific articles belonging to the Cucurbitaceae family. MATERIALS AND METHODS: To construct the manuscript a comprehensive literature review was done based on the information collected from Ayurvedic Pharmacopoeia of India; books, research articles and databases such as ScienceDirect, Wiley Online Library, SciFinder, Scopus, Springer, Google Scholar, Web of Science, ACS Publications and PubMed. RESULTS: The plants of Cucurbitaceae family are rich in phytochemicals like terpenoids, glycosides, alkaloids, saponins, tannins, steroids, etc., responsible for the therapeutic effect. Various parts of these plants such as leaves, stems, flowers, fruits, seeds, roots etc. exhibit a plethora of pharmacological activity viz. hypolipidemic, antihyperglycemic, anticancer, antimicrobial, analgesic, anti-inflammatory, anti-stress and immunomodulatory activities. Also, in-vitro and in-vivo reports suggest strong inhibitory potential against α-glucosidase, α-amylase, lipase, carbonic anhydrase enzyme along with antioxidant, anti-inflammatory, antidiabetic, anti-tumor, antifungal, etc. Furthermore many reports suggest these plants are beneficial for nutritional, economical and ethnoveterinary uses. CONCLUSIONS: The current review enlightens the therapeutic potential of the gourd family, comprising of the geographical origins, morphology, phytochemistry, ethnopharmacology, ethnoveterinary, nutritional importance, therapeutic benefits, safety, efficacy and related aspects. The phytochemical and pharmacological potential indicated will popularize this family as a potential source of novel therapeutic agents and functional foods. This study will help to validate the therapeutic claims of several ethnomedicinal uses of this plant family. Furthermore the Cucurbitaceae family needs to be evaluated based on the combine approaches of chemoprofiling and bioexploration to develop the concept of food as medicine for the development of new generation therapeutics leading to the human wellness.