Detoxification and underlying mechanisms towards toxic alkaloids by Traditional Chinese Medicine processing: A comprehensive review.

BACKGROUND: Alkaloids have attracted enduring interest worldwide due to their remarkable therapeutic effects, including analgesic, anti-inflammatory, and anti-tumor properties, thus offering a rich source for lead compound design and new drug discovery. However, some of these alkaloids possess intrinsic toxicity. Processing (Paozhi) is a pre-treatment step before the application of herbal medicines in traditional Chinese medicine (TCM) clinics, which has been employed for centuries to mitigate the toxicity of alkaloid-rich TCMs. PURPOSE: To explore the toxicity phenotypes, chemical basis, mode of action, detoxification processing methods, and underlying mechanisms, we can gain crucial insights into the safe and rational use of these toxic alkaloid-rich herbs. Such insights have the great potential to offer new strategies for drug discovery and development, ultimately improving the quality of life for millions of people. METHODS: Literatures published or early accessed until December 31, 2023, were retrieved from databases including PubMed, Web of Science, and CNKI. The following keywords, such as "toxicity", "alkaloid", "detoxification", "processing", "traditional Chinese medicine", "medicinal plant", and "plant", were used in combination or separately for screening. RESULTS: Toxicity of alkaloids in TCM includes hepatotoxicity, nephrotoxicity, neurotoxicity, cardiotoxicity, and other forms of toxicity, primarily induced by pyrrolizidines, quinolizidines, isoquinolines, indoles, pyridines, terpenoids, and amines. Factors such as whether the toxic-alkaloid enriched part is limited or heat-sensitive, and whether toxic alkaloids are also therapeutic components, are critical for choosing appropriate detoxification processing methods. Mechanisms of alkaloid detoxification includes physical removal, chemical decomposition or transformation, as well as biological modifications. CONCLUSION: Through this exploration, we review toxic alkaloids and the mechanisms underlying their toxicity, discuss methods to reduce toxicity, and unravel the intricate mechanisms behind detoxification. These offers insights into the quality control of herbs containing toxic alkaloids, safe and rational use of alkaloid-rich TCMs in clinics, new strategies for drug discovery and development, and ultimately helping improve the quality of life for millions of people.

Cornus officinalis with high pressure wine steaming enhanced anti-hepatic fibrosis: Possible through SIRT3-AMPK axis.

Cornus officinalis, a medicinal and edible plant known for its liver-nourishing properties, has shown promise in inhibiting the activation of hepatic stellate cells (HSCs), crucial indicators of hepatic fibrosis, especially when processed by high pressure wine steaming (HPWS). Herein, this study aims to investigate the regulatory effects of cornus officinalis, both in its raw and HPWS forms, on inflammation and apoptosis in liver fibrosis and their underlying mechanisms. In vivo liver fibrosis models were established by subcutaneous injection of CCl4, while in vitro HSCs were exposed to transforming growth factor-ß (TGF-ß). These findings demonstrated that cornus officinalis with HPWS conspicuously ameliorated histopathological injury, reduced the release of proinflammatory factors, and decreased collagen deposition in CCl4-induced rats compared to its raw form. Utilizing ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometer (UHPLC-QTOF-MS) combined with network analysis, we identified that the pharmacological effects of the changed components of cornus officinalis before and after HPWS, primarily centered on the adenosine phosphate (AMP)-activated protein kinase (AMPK) pathway. Of note, cornus officinalis activated AMPK and Sirtuin 3 (SIRT3), promoting the apoptosis of activated HSCs through the caspase cascade by regulating caspase3, caspase6 and caspase9. siRNA experiments showed that cornus officinalis could regulate AMPK activity and its mediated-apoptosis through SIRT3. In conclusion, cornus officinalis exhibited the ability to reduce inflammation and apoptosis, with the SIRT3-AMPK signaling pathway identified as a potential mechanism underlying the synergistic effect of cornus officinalis with HPWS on anti-liver fibrosis.

TCMSSD: A comprehensive database focused on syndrome standardization.

BACKGROUD: Quantitative and standardized research on syndrome differentiation has always been at the forefront of modernizing Traditional Chinese Medicine (TCM) theory. However, the majority of existing databases primarily concentrate on the network pharmacology of herbal prescriptions, and there are limited databases specifically dedicated to TCM syndrome differentiation. PURPOSE: In response to this gap, we have developed the Traditional Chinese Medical Syndrome Standardization Database (TCMSSD, http://tcmssd.ratcm.cn). METHODS: TCMSSD is a comprehensive database that gathers data from various sources, including TCM literature such as TCM Syndrome Studies (Zhong Yi Zheng Hou Xue) and TCM Internal Medicine (Zhong Yi Nei Ke Xue) and various public databases such as TCMID and ETCM. In our study, we employ a deep learning approach to construct the knowledge graph and utilize the BM25 algorithm for syndrome prediction. RESULTS: The TCMSSD integrates the essence of TCM with the modern medical system, providing a comprehensive collection of information related to TCM. It includes 624 syndromes, 133,518 prescriptions, 8,073 diseases (including 1,843 TCM-specific diseases), 8,259 Chinese herbal medicines, 43,413 ingredients, 17,602 targets, and 8,182 drugs. By analyzing input data and comparing it with the patterns and characteristics recorded in the database, the syndrome prediction tool generates predictions based on established correlations and patterns. CONCLUSION: The TCMSSD fills the gap in existing databases by providing a comprehensive resource for quantitative and standardized research on TCM syndrome differentiation and laid the foundation for research on the biological basis of syndromes.

Expanding annotation of chemical compounds in hawthorn fruits and their variations in thermal processing using integrated mass spectral similarity networking.

Chemical structural characterization of chemical compounds from hawthorn fruits and its thermal processed products was carried out in present study. By linking Global Natural Products Social (GNPS) Molecular Networking and MolNetEnhancer workflow, seventy-four chemical compounds in hawthorn fruits and its thermal processed products were tentatively identified. Three quercetagetin derivatives (quercetagetin-3-O-glucoside, quercetagetin-di-glucoside and its isomer), five quercetin or kaempferol derivatives (quercetin-acetylapiosyl-hexoside, quercetin-3-O-(6″-malonyl-hexoside), quercetin-3-O-(6″-malonyl-hexoside)-(1 â†’ 2)-O-hexoside, quercetin-3-O-(6″-malonyl-hexoside)-(1 â†’ 2)-O-deoxyhexoside, kaempferol-3-O-(6″-malonyl-hexoside)), six procyanidins including four (E)C-ethyl-procyanidins and two A-type procyanidins digallate, as well as 13 triterpenoids including ursolic aldehyde, triterpenoid glycosides, and triterpene acids were reported for the first time in hawthorn fruits. In addition, triterpenoids exhibited considerable thermal stability, while all of flavonoid glycosides, proanthocyanidins and 10 in 13 organic acids showed dramatic decrease after thermal processing.

Nanodrug rescues liver fibrosis via synergistic therapy with H2O2 depletion and Saikosaponin b1 sustained release.

Hypoxia and hydrogen peroxide (H2O2) accumulation form the profibrogenic liver environment, which involves fibrogenesis and chronic stimulation of hepatic stellate cells (HSCs). Catalase (CAT) is the major antioxidant enzyme that catalyzes H2O2 into oxygen and water, which loses its activity in different liver diseases, especially in liver fibrosis. Clinical specimens of cirrhosis patients and liver fibrotic mice are collected in this work, and results show that CAT decrease is closely correlated with hypoxia-induced transforminmg growth factor ß1 (TGF-ß1). A multifunctional nanosystem combining CAT-like MnO2 and anti-fibrosis Saikosaponin b1 (Ssb1) is subsequently constructed for antifibrotic therapy. MnO2 catalyzes the accumulated H2O2 into oxygen, thereby ameliorating the hypoxic and oxidative stress to prevent activation of HSCs, and assists to enhance the antifibrotic pharmaceutical effect of Ssb1. This work suggests that TGF-ß1 is responsible for the diminished CAT in liver fibrosis, and our designed MnO2@PLGA/Ssb1 nanosystem displays enhanced antifibrotic efficiency through removing excess H2O2 and hypoxic stress, which may be a promising therapeutic approach for liver fibrosis treatment.

The pathogenesis of organ fibrosis: Focus on necroptosis.

Fibrosis is a common process of tissue repair response to multiple injuries in all chronic progressive diseases, which features with excessive deposition of extracellular matrix. Fibrosis can occur in all organs and tends to be nonreversible with the progress of the disease. Different cells types in different organs are involved in the occurrence and development of fibrosis, that is, hepatic stellate cells, pancreatic stellate cells, fibroblasts and myofibroblasts. Various types of programmed cell death, including apoptosis, autophagy, ferroptosis and necroptosis, are closely related to organ fibrosis. Among these programmed cell death types, necroptosis, an emerging regulated cell death type, is regarded as a huge potential target to ameliorate organ fibrosis. In this review, we summarize the role of necroptosis signalling in organ fibrosis and collate the small molecule compounds targeting necroptosis. In addition, we discuss the potential challenges, opportunities and open questions in using necroptosis signalling as a potential target for antifibrotic therapies. LINKED ARTICLES: This article is part of a themed issue on Translational Advances in Fibrosis as a Therapeutic Target. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.22/issuetoc.

A deep clustering-based mass spectral data visualization strategy for anti-renal fibrotic lead compound identification from natural products.

Natural products have been a key source of drug lead discovery. However, their identification has long been a challenge even with the state-of-the-art analysis technologies like high-resolution mass spectrometry (MS) due to their complexity. Emerging in silico chemical structure prediction tools have provided time-saving and highly efficient approaches for identification of these complex samples. Nevertheless, the interpretation of these MS annotations into key supporting evidence towards specific questions is still a bottleneck in medicinal and biological fields. Here we present a deep clustering-based MS data visualization strategy (MCnebula), integrated with the influential open-source automatic MS annotation platform SIRIUS and in vivo and in vitro methods, to screen and validate potential lead compounds from natural products. MCnebula could provide multi-layer clustering profiles with chemical ontologies and comparative analysis of differential treatments. Plantaginis Semen (PS) is commonly used for treating kidney disease and usually stir-fried with salt water to enhance its anti-renal fibrosis effect, but the reason behind this remains unclear. Taking PS as an example, we comprehensively identified and compared the raw and processed PS extracts with SIRIUS-MCnebula, and screened potential anti-renal fibrotic lead compounds using weighted fold change analysis. Eighty-nine components were identified in PS with isoacteoside, calceolarioside B, 2'-acetylacteoside, and plantainoside D being screened and validated to treat renal fibrosis. The novel developed mass spectral data visualization strategy combined with biological function investigation and validation workflow could not only accelerate the discovery of lead compounds from medicinal natural products, but also shed new light on the traditional processing theory.