Ge Lin

The Chinese University of Hong Kong | CUHK · School of Biomedical Sciences

In September 2022, the 3rd International Workshop on pyrrolizidine alkaloids (PAs) and related phytotoxins was held on-line, entitled ʼToxins in botanical drugs and plant-derived food and feed – from science to regulationʼ. The workshop focused on new findings about the occurrence, exposure, toxicity, and risk assessment of PAs. In addition, new sc...

Background: Currently, the mechanism(s) underlying corticogenesis is still under characterization. Methods: We curated the most comprehensive single-cell RNA-seq (scRNA-seq) datasets from mouse and human fetal cortexes for data analysis and confirmed the findings with co-immunostaining experiments. Results: By analyzing the developmental trajectori...

Pyrrolizidine alkaloids (PAs) are phytotoxins distributed in ∼6000 plant species. PA-contaminated/containing foodstuffs/herbs/supplements pose a potential threat to human health. Various regulatory authorities established different PA margins of exposure assuming an equal hepatotoxic potency of structurally diverse PAs, although they exhibit differ...

Background Pyrrolizidine alkaloids (PA) of retronecine-type and otonecine-type are phytotoxins present in ~6000 plant species and known to act as human toxins via metabolic activation to form pyrrole-protein adducts (PPA) leading to hepatotoxicity. To investigate PA absorption and disposition in the body, our group recently conducted toxicokinetic...

1,2-Unsaturated pyrrolizidine alkaloids (PAs) are carcinogenic phytochemicals. We previously determined that carcinogenic PAs and PA N-oxides commonly form a set of four (±)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-DNA adducts, namely, DHP-dG-3, DHP-dG-4, DHP-dA-3, and DHP-dA-4. This set of DHP-DNA adducts has been implicated as a...

Pyrrolizidine alkaloids (PAs) are widely distributed natural toxins and have been extensively studied for their hepatotoxicity. However, PA-induced pulmonary toxicity remains less studied regarding the initiating mechanism and treatment approaches. Our previous study demonstrated the formation of pyrrole–hemoglobin adducts after PA exposure in vivo...

The aberrant regulation of PD‐L1 in tumor cells remains poorly understood. Here, the authors systematically investigate the endosomal trafficking of plasma membrane PD‐L1 in tumor cells. They show that plasma membrane PD‐L1 is continuously internalized, and then trafficked from early endosomes to multivesicular bodies/late endosomes, recycling endo...

Pyrrolizidine alkaloids (PAs) have been found in over 6000 plants worldwide and represent the most common hepatotoxic phytotoxins. Catalyzed by hepatic cytochrome P450 enzymes, PAs are metabolized into reactive pyrrolic metabolites, which can alkylate cellular proteins and DNA to form pyrrole-protein adducts and pyrrole-DNA adducts, leading to cyto...

Background Misusage of pyrrolizidine alkaloid (PA)-containing plants or unaware intake of PA-contaminated foodstuffs causes thousands of PA poisoning cases in humans. PA intoxication is accompanied by oxidative stress and subsequent extensive hepatocellular damage. Our previous study has demonstrated that 18β-glycyrrhetinic acid (GA), a bioactive c...

Nesfatin-1 is an anorectic peptide expressed in both peripheral tissues and brain areas involved in the regulation of feeding, emotion and emesis. The aim of the present study is to characterize the distribution of NUCB2/nesfatin-1 in Suncus murinus and to investigate the actions of nesfatin-1 to affect gastrointestinal contractility, emesis, food...

Misuse of pyrrolizidine alkaloid (PA)-containing plants or consumption of PA-contaminated foodstuffs causes numerous poisoning cases in humans yearly, while effective therapeutic strategies are still limited. PA-induced liver injury was initiated by cytochrome P450 (CYP)-mediated metabolic activation and subsequent formation of adducts with cellula...

Pyrrolizidine alkaloids (PAs) are phytotoxins widely present in various natural products and foodstuffs. The present study aims to investigate the effects of fasting on PA-induced hepatotoxicity and the underlying biochemical mechanisms. The results of hepatotoxic study showed that 15-h overnight fasting significantly exacerbated the hepatotoxicity...

Background and aims There has been no reliable severity system based on the prognosis to guide therapeutic strategies for patients with pyrrolizidine alkaloid (PA)-induced hepatic sinusoidal obstruction syndrome (HSOS). We aimed to create a novel Drum Tower Severity Scoring (DTSS) system for these patients to guide therapy. Methods 172 Patients wi...

Pyrrolizidine alkaloids (PAs) are the most common plant-derived toxins with emerging evidence to contaminate soil, water, nearby plants and derived food products. Outbreaks of human poisoning cases, due to the ingestion of PA-contaminated food, have been reported in various countries including Ethiopia. This study first investigated the contaminati...

This paper reports on the major contributions and results of the 2nd International Workshop of Pyrrolizidine Alkaloids held in September 2020 in Kaiserslautern, Germany. Pyrrolizidine alkaloids are among the most relevant plant toxins contaminating food, feed, and medicinal products of plant origin. Hundreds of PA congeners with widespread occurren...

Pyrrolizidine alkaloids (PAs) with 1,2-unsaturated necine base are hepatotoxic phytotoxins. Acute PA intoxication is initiated by the formation of adducts between PA-derived reactive pyrrolic metabolites with cellular proteins. The present study aimed to investigate the correlation between the formation of hepatic pyrrole–protein adducts and occurr...

Pyrrolizidine alkaloids (PAs) have been found in over 6000 plants worldwide and represent the most common hepatotoxic phytotoxins. Currently, a definitive diagnostic method for PA-induced liver injury (PA-ILI) is lacking. In the present study, using a newly developed analytical method, we identified four pyrrole-amino acid adducts (PAAAs), namely p...

Pyrrolizidine alkaloids (PAs) are the most common phytotoxins with documented human hepatotoxicity. PAs require metabolic activation by cytochromes P450 to generate toxic intermediates which bind to proteins and form protein adducts, thereby causing cytotoxicity. This study investigated the role of the gut–liver axis in PA intoxication and the unde...

Pyrrolizidine alkaloids (PAs) are among the most common phytotoxins with emerging evidence to contaminate soil, water, and nearby plants. Humans are frequently exposed to PA-contaminated food products or PA-containing herbal remedies. The reactive metabolites of PAs rapidly alkylate DNA to form pyrrole-DNA adducts (PDAs) and seed a population of mu...

Pyrrolizidine alkaloids (PAs) and PA N-oxides are common phytotoxins produced by over 6000 plant species. Humans are frequently exposed to PAs via ingestion of PA-containing herbal products or PA-contaminated foods. PAs require metabolic activation to form pyrrole–protein adducts and pyrrole-DNA adducts which lead to cytotoxicity and genotoxicity....

Background Pyrrolizidine alkaloids (PAs) are common phytotoxins. PA intoxication is reported to cause severe acute liver damage, typically known as hepatic sinusoidal obstruction syndrome (HSOS), but it remains obscure whether the acute liver damage may progress into chronic liver disease characterized by hepatic fibrosis. Purpose This study aims...

Background and aims: Mutational signature analyses are effective tool for identifying cancer etiology. Humans are frequently exposed to pyrrolizidine alkaloids (PAs), the most common carcinogenic phytotoxins widely distributed in herbal remedies and foods. However, due to the lack of human epidemiological data, PAs are classified as group II hepat...

Multidrug resistance (MDR) mediated by ATP binding cassette subfamily B member 1 (ABCB1) is significantly hindering effective cancer chemotherapy. However, currently, no ABCB1-inhibitory drugs have been approved to treat MDR cancer clinically, mainly due to the inhibitor specificity, toxicity, and drug interactions. Here, we reported that three pol...

Pyrrolizidine alkaloids (PAs) are common phytotoxins with both hepatotoxicity and pneumotoxicity. Hepatic cytochrome P450 enzymes are known to bioactivate PAs into reactive metabolites, which can interact with proteins to form pyrrole-protein adducts and cause intrahepatic cytotoxicity. However, the metabolic and initiation biochemical mechanisms u...

Pyrrolizidine alkaloids (PAs) are common phytotoxins. We performed the first comprehensive investigation on PA contamination in Chinese honeys. LC-MS analysis revealed that 58% of 255 honey samples purchased from 17 regions across Mainland China and Taiwan contained PAs with total content ranging over 0.2–281.1 μg/kg. Monocrotaline (from Crotalaria...

Herbs and dietary supplement-induced liver injury (HILI) is the leading cause of drug-induced liver injury in China. Among different hepatotoxic herbs, the pyrrolizidine alkaloid (PA)-producing herb Gynura japonica contributes significantly to HILI by inducing hepatic sinusoidal obstruction syndrome (HSOS), a liver disorder characterized by hepatom...

Pyrrolizidine alkaloids (PAs) are naturally occurring hepatotoxins widely present in hundreds of plant species and also known to contaminate many foodstuffs, such as grain, honey, and tea. The formation of pyrrole–protein adducts via metabolic activation of PAs has been suggested as a primary trigger initiating hepatotoxicity. The present study for...

Many pyrrolizidine alkaloids (PAs), an important class of natural products, are hepatotoxic and carcinogenic. Increased attention has been paid to PA poisoning cases worldwide. Generally, most PAs themselves are not toxic. However, reactive intermediates formed from PAs by metabolic oxidation have been linked to toxicity and carcinogenesis. PAs the...

Ethnopharmacological relevance Cyclophosphamide (CTX) is a first line chemotherapeutic agent, but often limited for its unstable therapeutic effect and serious side effects. Ginsenosides could facilitate the anti-tumor efficiency of CTX, including benefiting therapeutic effect and decreasing side effects. Aim of the study To investigate the potent...

Pyrrolizidine alkaloids (PAs) are extensively distributed in plants and are known to damage hepatic sinusoidal endothelial cells (HSECs) via metabolic activation mediated by hepatic cytochrome P450 enzymes (CYPs), particularly the CYP3A4 isozyme. Different PAs have distinct toxic potencies and their toxic effects on HSECs are difficult to be determ...

Background In Alzheimer's diseases, beta-amyloid may act as prion-like protein and migrate from the gastrointestinal tract towards the brain. Soy flavonoids have been identified as neuroprotective against cognitive loss in human. Diet with soy flavonoids may be used to slow down the progression of Alzheimer's diseases. Methods and results We perfo...

The hepatotoxic pyrrolizidine alkaloids (PAs) are metabolically activated in the liver to form reactive dehydro-PAs, which generate pyrrole-protein adducts leading to hepatotoxicity. Monocrotaline, but not other PAs, is also pneumotoxic, supposedly due to the migration of the liver-generated corresponding dehydro-PA into the lung to form pyrrole-pr...

Pyrrolizidine alkaloids (PAs) are toxic and carcinogenic phytochemicals widespread in the world. Metabolic formation of dehydro‐PAs and 6,7‐dihydro‐7‐hydroxy‐1‐hydroxymethyl‐5 H ‐pyrrolizine (DHP) has long been considered the principle metabolic activation pathway. We determined that a set of DHP‐DNA adducts are generally formed from the metabolism...

Pyrrolizidine alkaloids (PAs) are most common phytotoxins. Apart from their extensively reported hepatotoxicity, few PAs, such as MCT, are also reported to cause lung injury. However, whether different PAs commonly lead to pneumotoxicity remains largely unknown whether different PAs. PAs require metabolic activation to exert toxicity. Hepatic cytoc...

Among naturally occurring plant constituents, the 1,2-unsaturated pyrrolizidine alkaloids (in the following termed ‘PAs’) play a distinct role because of the large number of congeners occurring in nature and the pronounced toxicity of some congeners. Several PAs are hepatotoxic in humans, experimental and farm animals and were shown to be potent he...

Pyrrolizidine alkaloids (PAs) are carcinogenic phytochemicals, inducing liver tumors in experimental rodents. We previously determined that (±)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP), 7-glutathione-DHP, 7-cysteine-DHP, 7-N-acetylcysteine-DHP, and 1-CHO-DHP are DNA reactive pyrrolic metabolites potentially associated with PA-indu...

Background: Ginsenosides has been reported to facilitate the chemotherapy of cyclophosphamide (CTX), but the underlying mechanism is still elusive. Here, ICR mice bearing subcutaneous 4T1 tumor (mouse mammary carcinoma cells) were used to investigate the enhanced chemotherapeutic effects and underlying the mechanism of concurrent administration of...

Ethnopharmacological relevance: Pyrrolizidine alkaloids (PAs) are a group of phytotoxins widely present in about 3% of flowering plants. Many PA-containing herbal plants can cause liver injury. Our previous studies demonstrated that PA N-oxides are also hepatotoxic, with toxic potency much lower than the corresponding PAs, due to significant diffe...

Pyrrolizidine alkaloids (PAs) are among the most significant groups of phytotoxins present in more than 6000 plants in the world. Hepatotoxic retronecine-type PAs and their corresponding N-oxides usually co-exist in plants. Although PA-induced hepatotoxicity is known for a long time and has been extensively studied, the toxicity of PA N-oxide is ra...

Isorhynchophylline (IRN) has been demonstrated to have distinct anti-Alzheimer's disease (AD) activity in several animal models of AD. In this study, we aimed at evaluating the preventive effect of IRN on the cognitive deficits and amyloid pathology in TgCRND8 mice. Male TgCRND8 mice were administered with IRN (20 or 40 mg/kg) by oral gavage daily...

Purpose To investigate the mitochondria-related mechanism of Gynura segetum (GS)-induced apoptosis and the protective effect of phosphocreatine (PCr), a mitochondrial respiration regulator. Methods First, the mechanism was explored in human hepatocyte cell line. The mitochondrial oxidative stress was determined by fluorescence assay. The level of...

Pyrrolizidine alkaloids (PAs) are phytochemicals present in more than 6000 plant species worldwide; about half of the PAs are hepatotoxic, genotoxic, and carcinogenic. Because of their wide exposure and carcinogenicity, the International Programme on Chemical Safety (IPCS) concluded that PAs are a threat to human health and safety. We recently dete...

Pyrrolizidine alkaloids (PAs)are hepatotoxic and specifically damage hepatic sinusoidal endothelial cells (HSECs)via cytochrome P450 enzymes (CYPs)-mediated metabolic activation. Due to the lack of CYPs in HSECs, currently there is no suitable cell model for investigating PA-induced HSEC injury. This study aimed to establish a two-layer transwell c...

Pyrrolizidine alkaloids (PAs) are naturally occurring phytotoxins widely distributed in about 3% of flowering plants. The formation of PA-derived pyrrole-protein adducts is considered as a primary trigger initiating PA-induced hepatotoxicity. The present study aimed to (i) further validate our previous established derivatization method using acidif...

Berberine is a natural alkaloid that has antineoplastic effects. However, in hepatoma cells like HepG2, the expressions of uptake transporters are minimal but efflux transporters are relatively high. Hence, how berberine enters and reaches a cytocidal concentration remains to be elucidated. In the present study, we revealed the accumulation mechani...

Ten new sesquiterpene lactones, carlipsines A-J (1-10), and 12 known analogues (11-22) were isolated from the whole plant of Carpesium lipskyi. Their structures were elucidated by using 1D and 2D NMR and HRESIMS analyses, and their absolute configurations were confirmed by X-ray diffraction studies. All compounds were identified as germacranolides...

Isorhynchophylline (IRN) and rhynchophylline (RN), a pair of stereoisomers, are tetracyclic oxindole alkaloids isolated from Uncaria rhynchophylla , a commonly used Chinese medicinal herb. These two compounds have drawn extensive attention due to their potent neuroprotective effects with promising therapeutic potential for the treatment of Alzheime...

(±)-Cryptomeriolide, a pair of racemic bis- seco-abietane diterpenoids, were isolated from the bark of Cryptomeria fortunei. The separation of enantiomers was achieved by using chiral stationary phase HPLC. Their structures including the absolute configuration and conformations in solution and solid state were determined by extensive analysis of sp...

Pyrrolizidine alkaloids (PAs) are one of the most significant groups of hepatotoxic phytotoxins. It is well-studied that metabolic activation of PAs generates reactive pyrrolic metabolites that rapidly bind to cellular proteins to form pyrrole–protein adducts leading to hepatotoxicity. Pyrrole–protein adducts all contain an identical core pyrrole m...

Estrogen is well known to have a modulatory role on gastrointestinal tract, particularly through its interaction with nuclear estrogen receptors (ERs), alpha and beta (ERα/β). Recent functional studies also indicate that estrogen can activate a G-protein coupled estrogen receptor, GPR30, or GPER1. The present study was designed to identify either t...

Introduction Pyrrolizidine alkaloids (PAs) are widely present in plants, and about half of them had been reported to induce toxicity in different organs. The previous study has proved that PAs exert their toxicity by metabolic activation to form dehydro‐PAs (DHPAs), which interact with proteins to form pyrrole‐protein adducts leading to toxicity. M...

Pyrrolizidine alkaloids (PAs) are naturally occurring heterocyclic compounds that can cause severe toxicities particularly in the liver. The reactive pyrroles formed by hepatic metabolic activation of toxic PAs can rapidly bind to intracellular proteins forming pyrrole‐protein adducts, which is deemed to be a major trigger initiating PA‐induced hep...

Humans and animals can be exposed to carcinogenic pyrrolizidine alkaloids (PAs) through consumption of plants commonly found in many parts of the world. Although the liver is the primary target organ for carcinogenic PAs, they have also induced lung tumors in rodents. Hepatic cytochrome P450 activity converts PAs into dehydro-PAs that can be hydrol...

The first phytochemical investigation of the fruits of Rhododendron websterianum resulted in the isolation of two new triterpenoids, 11-dehydroxytrisnormogrol acid (1), 11-dehydroxytrisnormogrol (2), and 21 known analogues. Their structures were determined by extensive analysis of spectroscopic and mass data, as well as by comparison with those in...

Pyrrolizidine alkaloids (PAs) are phytotoxins identified in over 6000 plant species worldwide. Approximately 600 toxic PAs and PA N-oxides have been identified in about 3% flowering plants. PAs can cause toxicities in different organs particularly in the liver. The metabolic activation of PAs is catalyzed by hepatic cytochrome P450 and generates re...

A toxicoproteomic study was performed on liver of rats treated with retrorsine (RTS), a representative hepatotoxic pyrrolizidine alkaloid at a toxic dose (140 mg/kg) known to cause severe acute hepatotoxicity. By comparing current data with our previous findings in mild liver lesions of rats treated with a lower dose of RTS, seven proteins and thre...

Pyrrolizidine alkaloids (PAs) are phytochemical constituents of more than 6000 plant species worldwide; approximately half of the PAs are hepatotoxic, genotoxic, and carcinogenic. Because of their wide exposure and carcinogenicity, the International Programme on Chemical Safety (IPCS) concluded that PAs are a threat to human health and safety. We r...

Pyrrolizidine alkaloids (PAs) are among the most hepatotoxic phytotoxins present in about 3% of the flowering plants. Ingestion of PAs causes hepatic sinusoidal obstruction syndrome (HSOS), characterized by primary sinusoidal endothelial cell damage. The hepatic cytochrome P450‐mediated metabolic activation of PAs leading to the formation of pyrrol...

The sustained release of drug at adequate and stable cytosolic drug concentrations is found to be a feasible scheme to circumvent the multidrug resistance effect and serves as a promising guideline for drug design to overcome drug resistance in cancer therapeutics. In article number 1700289, Quan Li and co-workers demonstrate the feasibility of usi...

The abilities of a drug delivery system to target and penetrate tumor masses are key factors in determining the system’s chemotherapeutic efficacy. Here, we explored the utility of an anti-carbonic anhydrase IX (anti-CA IX) antibody and CPP33 dual-ligand modified triptolide-loaded liposomes (dl-TPL-lip) to simultaneously enhance the tumor-specific...

Introduction. Nesfatin-1 is a recently discovered 82-amino acid peptide derived from nucleobindin2 (NUCB2). NUCB2/nesfatin-1 is widely distributed in brain areas involved in the regulation of feeding, emotion and emesis. Aims. In the present studies, we identified the amino acid sequence of nesfatin-1 in Suncus murinus (SM). We investigated the act...

Antibody-decorated liposomes can facilitate the precise delivery of chemotherapeutic drugs to the lung by targeting a recognition factor present on the surface of lung tumor cells. Carbonic anhydrase IX (CA IX) is an enzyme expressed on the surface of lung cancer cells with a restricted expression in normal lungs. Here, we explored the utility of a...

Pyrrolizidine alkaloids (PAs) are among the most potent phytotoxins widely distributed in plant species around the world. PA is one of the major causes responsible for the development of hepatic sinusoidal obstruction syndrome (HSOS) and exerts hepatotoxicity via metabolic activation to form the reactive metabolites, which bind with cellular protei...

It is discovered that sustained cytosolic drug release at a sufficient concentration is an effective mechanism to circumvent multidrug resistance and consequently enhance antitumor drug efficacy. It is showed that a simple way to enable this mechanism is to reach an intracellular kinetic balance of the drug movement between the drug released from t...