Gynura Segetum Research Articles

Anticoagulant therapy likely increases risk of bleeding in Gynura segetum-induced hepatic sinus obstruction syndrome.

This study aimed to analyze the clinical characteristics of Gynura segetum (Tusanqi)-induced hepatic sinusoidal obstruction syndrome (HSOS) and the benefits and risks of anticoagulant therapy for Tusanqi-induced HSOS. This was a retrospective analysis of 49 patients with Tusanqi-induced HSOS who were treated with anticoagulation or standard therapy between July 2006 and December 2022. Clinical manifestations included abdominal pain (n = 47) and peritoneal or pleural effusion (n = 46); 2 patients died. Nineteen patients requested standard medical treatment, while 30 were treated with anticoagulants. HSOS resolved within 6 months in 22 patients but did not resolve in 27 patients. The resolution rate was higher in the anticoagulant than standard treatment group (P = .037). Logistic regression analysis revealed that a history of chronic liver disease or treatment increased the risk of poor outcomes. Bleeding complications occurred in 6 patients in the anticoagulant treatment group. Early diagnosis and anticoagulant treatment are beneficial for rapid recovery after Tusanqi-induced HSOS. However, anticoagulant treatment is associated with the risk of multisite bleeding.

Phytochemical compounds extraction from Orthosiphon aristatus, Andrographis paniculata, Gynura segetum using hydrothermal method: experimental kinetics and modeling

Orthosiphon aristatus (O. aristatus), Andrographis paniculata (A. paniculata), and Gynura segetum (G. segetum) leaves were subjected as raw material to obtain phytochemical compounds using sub-critical water extraction (SWE) technique. In a semi-batch process, the extraction was performed for ∼150 min extraction time at 120 – 160°C and 3 – 10 MPa. The Fourier-transform infrared spectroscopy (FT–IR) spectrum depicted that the phenolic and flavonoid compounds were liberated from each medicinal plant leaves in the aforementioned-temperature range. The second-order kinetic and Weibull models also may properly represent and describe the extraction kinetics curves of each sample at these operating conditions (120 – 160°C and 3 – 10 MPa). The amounts of phenolic and flavonoid compounds could approach 284.73 mg of GAE/g of dried sample (140°C, 3 MPa) and 232.89 mg of CE/g of dried sample (140°C, 3 MPa), respectively.

Transjugular Intrahepatic Portosystemic Shunt Benefits for Hepatic Sinusoidal Obstruction Syndrome Associated with Consumption of Gynura Segetum: a Propensity Score-Matched Analysis.

Pyrrolidine alkaloids-related hepatic sinusoidal obstruction syndrome (PA-HSOS) is associated with a high mortality rate without standardized therapy. The efficacy of transjugular intrahepatic portosystemic shunts (TIPS) remains controversial. The study aimed to explore the risk factors influencing the clinical response in patients with PA-HSOS related to Gynura segetum (GS) to assess the disease prognosis at an early stage and to evaluate the efficacy of TIPS in these patients. This study retrospectively enrolled patients diagnosed with PA-HSOS between January 2014 and June 2021 with a clear history of exposure to GS. Univariate and multivariate logistic regression analyses were used to evaluate the risk factors influencing the clinical response in patients with PA-HSOS. Propensity score matched (PSM) was performed to compensate for differences in baseline characteristics between patients with and without TIPS. The primary outcome was the clinical response defined as the disappearance of ascites with normal total bilirubin levels and/or a reduction of elevated transaminase levels < 50% within 2weeks. A total of 67 patients were identified in our cohort with a clinical response rate of 58.2%. Of these, thirteen patients were assigned to the TIPS group and 54 to the conservative treatment group. Logistic regression analysis revealed that TIPS treatment (P = 0.047), serum globulin levels (P = 0.043), and prothrombin time (P = 0.001) were independent factors influencing clinical response. After PSM, there was a higher long-term survival rate of patients (92.3% vs. 51.3%, P = 0.021) and a shorter hospital stay (P = 0.043), but a high trend in hospital costs (P = 0.070) in the TIPS group. The 6-month survival probability in patients undergoing TIPS therapy was more than ninefold higher than in patients without receiving that treatment [hazard ratio (95% CI) = 9.304 (4.250, 13.262), P < 0.05]. TIPS therapy may be an effective treatment option for patients with GS-related PA-HSOS.

Noncirrhotic portal hypertension misdiagnosed as liver cirrhosis: A rare case

Noncirrhotic portal hypertension misdiagnosed as liver cirrhosis: A rare case

Serum metabolomics strategy for investigating the hepatotoxicity induced by different exposure times and doses of Gynura segetum (Lour.) Merr. in rats based on GC-MS.

Gynura segetum (Lour.) Merr. (GS), has been widely used in Chinese folk medicine and can promote circulation, relieve pain and remove stasis. In recent years, the hepatotoxicity caused by GS has been reported, however its mechanism is not fully elucidated. Metabolomic techniques are powerful means to explore the toxicological mechanism and therapeutic effects of traditional Chinese medicine. The purpose of this study was to establish a serum metabolomics method based on Gas Chromatography-Mass Spectrometry (GC-MS) to explore the hepatotoxicity mechanism of different exposure times and doses of GS in rats. Sprague Dawley (SD) rats were administered daily with distilled water, 7.5 g kg-1 GS, or 15 g kg-1 GS by intragastrical gavage for either 10 or 21 days. The methods adopted included enzyme-linked immunosorbent assay (ELISA), Hematoxylin and Eosin (H&E) staining and GC-MS-based serum metabolomics. Serum biochemistry analysis showed that the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglycerides (TG), total bilirubin (TBIL) and total bile acid (TBA) significantly (P < 0.05) increased while the levels of albumin (ALB) and high-density lipoprotein (HDL) significantly (P < 0.05) decreased in GS-treated groups, compared with the control group. Interestingly, the ALT, AST, TG and ALB levels changed in a time- and dose-dependent manner. The results of H&E staining showed the degree of liver damage after administration of GS gradually deepened with the extension of administration time and the increase of the dose. According to the results of metabolomics analysis, 26 differential metabolites were identified, which were involved in 8 metabolic pathways including phenylalanine metabolism, glyoxylic acid and dicarboxylic acid metabolism and so on. Meanwhile, the number of differential metabolites in different GS-treated groups was associated with GS exposure time and dose. Therefore, we concluded that GS might induce hepatotoxicity depending on the exposure time and dose.

Effects of bicyclol on hepatic sinusoidal obstruction syndrome induced by Gynura segetum.

The intake of Gynura segetum, a traditional Chinese medicine, may be induce hepatic sinusoidal obstruction syndrome (HSOS). It has a high mortality rate based on the severity of the disease and the absence of therapeutic effectiveness. Therefore, the current study was designed to investigate the effects of bicyclol on HSOS induced by Gynura segetum and the potential molecular mechanisms. Gynura segetum (30 g/kg) was administered for 4 weeks in the model group, while the bicyclol pretreatment group received bicyclol (200 mg/kg) administration. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), cholesterol (CHO), triglyceride (TG), and liver histological assays were detected to assess HSOS. The gene expressions of cytochrome P450 (CYP450) isozymes were quantified by real-time PCR. Moreover, hepatocellular apoptosis was detected using the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, then apoptosis and autophagy-related markers were determined using Western blot. As a result, bicyclol pretreatment is notably protected against Gynura segetum-induced HSOS, as observed by reducing serum ALT levels, inhibiting the reduction in CHO and TG levels, and alleviating the histopathological changes. Bicyclol pretreatment inhibited the changes in mRNA levels of CYP450 isozymes (including the increase in CYP2a5 and decrease in CYP2b10, 2c29, 2c37, 3a11, and 7b1). In addition, the upregulation of Bcl-2 and the downregulation of LC3-II/LC3-I proteins expression in HSOS were inhibited with bicyclol pretreatment. Bicyclol exerted a protective effect against HSOS induced by Gynura segetum, which could be attributed to the regulated expressions of CYP450 isozymes and alleviated the downregulation of autophagy.

Investigation of Gynura segetum root extract (GSrE) induced hepatotoxicity based on metabolomic signatures and microbial community profiling in rats.

In recent years, many reports focus on the hepatotoxicity of Gynura segetum root extract (GSrE), but the interaction between GSrE and the gut microbiota is still unclear. This study investigated the mechanism of GSrE-induced hepatotoxicity of different doses and exposure durations by combining metabolomics and gut microbiota analysis. SD rats were divided into 3 groups: blank, low-dose (7.5 g/kg), and high-dose (15 g/kg) groups. Urine and feces samples were collected on day 0, day 10, and day 21. Metabolomics based on gas chromatography-mass spectrometry (GC-MS) was carried out to identify metabolites and metabolic pathways. 16S rDNA gene sequencing was applied to investigate the composition of gut microbiota before and after GSrE-induced hepatotoxicity. Finally, a correlation analysis of metabolites and gut microbiota was performed. Differential metabolites in urine and feces involved amino acids, carbohydrates, lipids, organic acids, and short chain fatty acids. Among them, L-valine, L-proline, DL-arabinose, pentanoic acid, D-allose, and D-glucose in urine and D-lactic acid and glycerol in fecal metabolites depended on the exposure of time and dose. In addition, 16S rDNA sequencing analysis revealed that GSrE-induced hepatotoxicity significantly altered the composition of gut microbiota, namely, f_Muribaculaceae_Unclassified, Lactobacillus, Bacteroides, Lachnospiraceae_NK4A136_group, f_Ruminococcaceae_Unclassified, Prevotellaceae_Ga6A1_group, and Escherichia-Shigella. The correlation analysis between gut microbiota and differential metabolites showed the crosstalk between the gut microbiota and metabolism in host involving energy, lipid, and amino acid metabolisms. In summary, our findings revealed that peripheral metabolism and gut microbiota disorders were time- and dose-related and the correlation between gut microbiota and metabolites in GSrE-induced hepatotoxicity.

Retrospective analysis of the efficacy and safety of rivaroxaban in the treatment of hepatic sinus obstruction syndrome caused by Gynura segetum

Background and Objective: Pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome (PA-HSOS) is a rare disease with no specific treatment. Anticoagulants, antithrombotics, and microcirculation therapy can alleviate the progression of PA-HSOS. The application of rivaroxaban in patients with PA-HSOS has not yet been reported. The aim of this study was to analyze the efficacy and safety of rivaroxaban in the treatment of PAHSOS caused by Gynura segetum. Methods: A retrospective analysis was conducted using the clinical data of patients with PA-HSOS in the acute/subacute phase caused by the administration of Gynura segetum. The patients were divided into warfarin and rivaroxaban groups according to the anticoagulant therapy they received. The related biochemical indicators were monitored during hospitalization. Liver ultrasound, liver elastography, and related biochemical indicators were reviewed every two weeks or one month after discharge. The patients were followed until 1 year after complete remission or death. The efficacy and safety of rivaroxaban was compared with that of warfarin according to the patients’ hepatic venous recanalization rates and the occurrence of bleeding events. Results: The study included 20 patients, with 10 in the warfarin group and 10 in the rivaroxaban group. The results show that the average anticoagulant course in the rivaroxaban group was significantly shorter than that in the warfarin group (P = 0.007). With treatment, the remission rates of the rivaroxaban and warfarin groups reached 90%. There was no significant difference in the incidence of adverse reactions or bleeding events between the t wo groups (P ＞ 0.05). Conclusions: Compared with warfarin, rivaroxaban, a new oral anticoagulant, is convenient and safe for clinical use. It has a significant effect on PA-HSOS and a low risk of bleeding. This provides a new anticoagulant treatment for PA-HSOS.

Clinical Features and CT Imaging Analysis of Hepatic Sinuscase-Syndrome and Budd-Chiari Syndrome.

ObjectiveThis study aimed to analyze the clinical features and computed tomography (CT) manifestations of hepatic sinusoidal obstruction syndrome (HSOS) induced by Gynura segetum, a Chinese herbal medicine, so as to improve the clinical understanding and diagnosis of the disease.MethodsRelevant clinical and laboratory parameters and CT imaging data of 20 patients with HSOS confirmed by liver biopsy were retrospectively analyzed and compared with 16 patients with Budd-Chiari syndrome (BCS).ResultsLevels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and glutamyl transpeptidase increased significantly (p < 0.05) in HSOS patients compared to the BCS patients, while the albumin level and prothrombin time, which are indicators of liver synthesis function, decreased and prolonged significantly, respectively. All 20 patients with HSOS had manifestations of ascites and heterogeneous hypoattenuation on CT, including 18 cases (90%) with heterogeneous enhancement (characteristic map-like enhancement), 17 (85%) with hepatomegaly, 18 (90%) with gallbladder wall oedema, and 16 (80%) with stenosis of main hepatic veins and characteristic “clover-like” enhancement at the second porta hepatis.ConclusionBoth HSOS and BCS are post-sinusoidal portal hypertension, but have different etiologies and durations. Although they both cause liver congestion, the clinical manifestation of HSOS is acute liver injury. The CT manifestations are characterized by ascites, map-like enhancement and heterogeneous hypoattenuation of the liver parenchyma, and stenosis of the main hepatic veins. BCS is often found in the stage of decompensated liver cirrhosis, resulting in liver shrinkage, splenomegaly, and ascites.

Herb-induced liver injury: Systematic review and meta-analysis.

BACKGROUNDThe use of herbal supplements and alternative medicines has been increasing in the last decades. Despite popular belief that the consumption of natural products is harmless, herbs might cause injury to various organs, particularly to the liver, which is responsible for their metabolism in the form of herb-induced liver injury (HILI).AIMTo identify herbal products associated with HILI and describe the type of lesion associated with each product.METHODSStudies were retrieved using Medical Subject Headings Descriptors combined with Boolean operators. Searches were run on the electronic databases Scopus, Web of Science, MEDLINE, BIREME, LILACS, Cochrane Library for Systematic Reviews, SciELO, Embase, and Opengray.eu. Languages were restricted to English, Spanish, and Portuguese. There was no date of publication restrictions. The reference lists of the studies retrieved were searched manually. To access causality, the Maria and Victorino System of Causality Assessment in Drug Induced Liver Injury was used. Simple descriptive analysis were used to summarize the results.RESULTSThe search strategy retrieved 5918 references. In the final analysis, 446 references were included, with a total of 936 cases reported. We found 79 types of herbs or herbal compounds related to HILI. He-Shou-Wu, Green tea extract, Herbalife, kava kava, Greater celandine, multiple herbs, germander, hydroxycut, skullcap, kratom, Gynura segetum, garcinia cambogia, ma huang, chaparral, senna, and aloe vera were the most common supplements with HILI reported. Most of these patients had complete clinical recovery (82.8%). However, liver transplantation was necessary for 6.6% of these cases. Also, chronic liver disease and death were observed in 1.5% and 10.4% of the cases, respectively.CONCLUSIONHILI is normally associated with a good prognosis, once the implied product is withdrawn. Nevertheless, it is paramount to raise awareness in the medical and non-medical community of the risks of the indiscriminate use of herbal products.

FORMULATION OF GEL FROM GYNURA SEGETUM EXTRACT AND ITS ACTIVITY ON BURN WOUND HEALING

Objective: The aims of this study were to formulate gel from Gynura segetum (GS) extract and evaluate its burn-healing activity.&#x0D; Methods: GS extract was formulated using carbomer and carboxymethylcellulose (CMC) as a stabilizer with various concentrations. Furthermore, the gel of GS extract was evaluated, including organoleptic, pH and viscosity. A burn-healing evaluation was conducted by making a wound with a hot plate on male Wistar rats, and 600 mg of the gel was applied. Subsequently, the presence of erythema and width contraction of the burns were observed for 15 d.&#x0D; Results: The result showed that the formulation containing 1 % of carbomer and 1.2 % of GS extract has the best physical stability. The gel also increased the rate of the healing process with decreased burn wound contraction (5.67 mm after 15 d) and the erythema than the control (8.50 mm after 15 d). The significance value was less than 0.05, indicating that the rate of the healing process was significantly different between the GS extract gel and the control.&#x0D; Conclusion: This finding demonstrated that the gel of GS extract can significantly improve the burns wound healing process and may also be safely used for topical preparation.

Transjugular intrahepatic portosystemic shunt for hepatic sinusoidal obstruction syndrome associated with consumption of Gynura segetum

BackgroundTo evaluate the efficacy and safety of transjugular intrahepatic portosystemic shunt (TIPS) on hepatic sinusoidal obstruction syndrome (HSOS) associated with consumption of Gynura segetum (GS).MethodsWe retrospectively reviewed 9 consecutive patients with GS-related HSOS who were refractory to supportive treatment and underwent TIPS at our institution between January 2014 and September 2019. The patients were evaluated for safety and efficacy, including TIPS complications and changes in portosystemic pressure gradient (PPG), ascites, total bilirubin, liver size and portal vein diameter.ResultsTIPS procedures were performed successfully in the 9 patients, and no technically-related complications due to the TIPS procedure were recorded. The PPG was improved by TIPS in all patients (mean PPG before TIPS, 30.4 ± 5.2 vs. 13.0 ± 4.1 mm Hg post-TIPS, P = 0.008). One patient who was lost to follow-up, whereas the remaining 8 patients survived with a median follow-up period of 12 months (range 5–39 months). Although the total bilirubin was significantly increased 5–7 days after TIPS compared with that before the procedure (3.57 ± 1.58 vs. 4.82 ± 2.06 mg/dl, P = 0.017), it returned to baseline levels at 1-month follow-up (3.53 ± 2.72 vs. 4.82 ± 2.06 mg/dl, P = 0.401). The patients experienced complete resolution or noticeable reduction of ascites (P < 0.001), significant reduction of liver size (16.7 ± 2.2 vs. 13.7 ± 1.7 cm, P = 0.018), and significant enlargement of the portal trunk (10.7 ± 2.5 vs. 13.4 ± 2.4 mm, P = 0.017) after TIPS compared to the pre-TIPS state.ConclusionTIPS may offer a potentially useful treatment for the GS-related HSOS.

Gynura segetum induces hepatic sinusoidal obstruction syndrome in mice by impairing autophagy.

ABSTRACTPurpose:To investigate the underlying mechanism of hepatic sinusoidal obstruction syndrome (HSOS) induced by Gynura segetum by measuring autophagy in mouse models.Methods:The model group was administered G. segetum (30 g/kg/d) by gavage, while the normal control group was administered an equal volume of saline daily for five weeks. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hepatic histopathological examinations, and Masson staining were performed to evaluate liver injury. Liver intercellular adhesion molecule-1 (ICAM-1) and P-selectin were evaluated by immunohistochemistry. Hepatocellular apoptosis was assessed using the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. Protein expression levels of autophagy markers were measured using Western blot analysis.Results: Gynura segetum was found to significantly induce liver injury compared with control mice, as evidenced by the increase of serum transaminases, a decrease in triglyceride levels, and histopathological changes in mice. Gynura segetum remarkably induced hepatocellular apoptosis and upregulated the expressions of ICAM-1 and P-selectin and also downregulated the protein expression levels of LC3, Atg12 and cytoplasmic polyadenylation element binding protein.Conclusions:Our results suggested that G. segetum induced liver injury with HSOS, and it was partly due to its ability to impair the autophagy pathway.

Metabolomics Based Comparison on the Biomarkers between Panax Notoginseng and its Counterfeit Gynura Segetum in Rats

Background: Because of the similar appearance of Gynura segetum and panax notoginseng, the patients often mistakenly use Gynura segetum as Panax notoginseng, which causes serious liver damage. There is no comparative study on the metabolism of Gynura segetum and Panax notoginseng in the literature. This study was conducted to compare the difference between Panax notoginseng and its counterfeit Gynura segetum by using metabolomics method. Methods: In this paper, an ultra performance liquid chromatography coupled to quadrupole time-offlight mass spectrometric(UPLC-Q/TOF/MS) were used to detect the type of endogenous metabolites in urine and plasma of three groups (normal group, ethanol extract of panax notoginseng, decoction of Gynura segetum respectively, and different multivariate statistical analysis methods were established. Results: In this experiment, main urine biomarkers were L-glutamate, L-methionine, cytidine, and Ltyrosine in the Panax notoginseng group, which are phytosphingosine, creatine and sphinganine in the Gynura segetum group. The plasma biomarkers identified in the Panax notoginseng group were arachidonic acid, L-tyrosine, linoleic acid, alpha-linolenoyl ethanolamide and lysoPC (15:0), and in the Gynura segetum group are L-arginine, L-valine, arachidonic acid and LysoPC(18:2(9Z,12Z)). Conclusion: There are significant difference between Panax notoginseng and Gynura segetum in biomarkers from the perspective of metabolomics in the body.

THU166 - Clinical characteristics and prognostic risk factors for patients with hepatic sinusodial obstruction syndrome caused by gynura segetum

THU166 - Clinical characteristics and prognostic risk factors for patients with hepatic sinusodial obstruction syndrome caused by gynura segetum

Clinical characteristics and outcomes of patients with hepatic veno-occlusive disease induced by Gynura segetum: A retrospective study

ObjectiveHepatic veno-occlusive disease (HVOD) has attracted increasing attention in recent years due to its relationship with ingestion of Gynura segetum. The mortality of severe HVOD remains high due to the lack of specific therapies. The aim of the study was to delineate the clinical characteristics and outcomes and explore the potential prognostic factors of HVOD. MethodsThis was a single-center retrospective study. Eighty-nine HVOD patients were screened from the First Affiliated Hospital of Zhejiang University with an ingestion history of G. segetum before developing symptoms from January 2009 to May 2018. The enrolled patients were divided into the survivor and death groups according to the clinical follow-up that ended on September 1, 2019. The demographic variables and clinical data of the patients were recorded. A binary logistic regression analysis and receiver operating characteristic curve were conducted to identify the prognostic factors and assess the prognostic value for predicting death, and a survival analysis was performed to evaluate the clinical outcomes. ResultsSixty-four patients were eligible for further analysis. Most patients showed abdominal distension and were positive for migrating dullness in the abdomen (P = 0.740 and P = 0.732, respectively). The patients who died had higher levels of model for end-stage liver disease score, and higher prothrombin time than those who survived (both P < 0.001). All HVOD patients in both the survival and death groups showed ascites with abnormal imaging presentations of the liver parenchyma and hepatic blood vessels. Unexpectedly, we found that hydrothorax was detected in 21 (65.63%) patients in the death group and 19 (59.38%) patients in the survivor group during hospitalization, which was rarely mentioned in previous studies. Furthermore, international normalized ratio (INR) and creatinine are found to be potential independent prognostic factors for predicting death. Six severe patients achieved clinical improvements and survived after liver transplantation. ConclusionHVOD can be induced by the ingestion of G. segetum, and INR combined with creatinine has prognostic value for predicting death. Liver transplantation may be an effective treatment option for severe HVOD patients.

Pulmonary toxicity is a common phenomenon of toxic pyrrolizidine alkaloids

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-protein adducts to induce pneumotoxicity. The present study investigated whether other PAs are also pneumotoxic. Metabolic activation of four representative hepatotoxic PAs, monocrotaline, retrorsine, riddelliine and clivorine, was investigated using rat liver or lung S9 incubation. All PAs produced pyrrole-protein adducts significantly in rat liver S9 but negligible in lung S9 fraction, revealing that liver is the key organ responsible for metabolic activation generating dehydro-PAs. Furthermore, these four PAs and another two PAs present in the alkaloid extract of Gynura segetum, a widely used PA-producing herb responsible for human PA poisonings in China, were orally administered to rats using the same hepatotoxic dose of 0.2 mmol/kg. All six PAs induced pneumotoxicity in rats within 48 h. The results demonstrated that pneumotoxicity could be a common phenomenon of PAs and the liver-derived dehydro-PAs might move to the lung and form pyrrole-protein adducts, leading to pulmonary toxicity.

Investigation on Pneumotoxicity Induced by Pyrrolizidine AlkaloidsInvestigation on Pneumotoxicity Induced by Pyrrolizidine Alkaloids

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 cytochrome P450s are proposed to be responsible for bioactivation of PAs to reactive dehydro‐PAs, which interact with proteins to form pyrrole‐protein adducts causing intrahepatic cytotoxicity. However, the mechanisms underlying pneumotoxicity of PAs, especially the site of metabolic activation of PAs, have not been delineated. Here we aimed to investigate pneumotoxicity of different types of PAs and also identify the contribution of hepatic P450s and extrahepatic P450s to metabolic bioactivation of PAs.Pulmonary toxicity of four representative PAs of both retronecine and otonecine types and Gynura Segetum (GS) alkaloid extract containing two retronecine type PAs, to mimic human PA poisoning, were investigated. Rats were orally administered with representative PAs and GS at 0.2 mmol/kg for 48 hours. Biochemical and histological examinations were applied to evaluate PA‐induced toxicity in liver and lung. The results showed that all PAs induced liver injury to varied levels. Significant lung lesions including pulmonary arterial hypertrophy, capillary congestion, endothelium damage, and abnormal proliferation of smooth muscle cells were found in all PA‐treated groups, demonstrating that both retronecine and otonecine types of PAs can cause pulmonary toxicity.Further to delineate the role of hepatic and extrahepatic CYPs in metabolic bioactivation of PAs, mice with conditional deletion of cytochrome P450 reductase (Cpr) gene and resultant dysfunctional P450s were used. After oral exposure to MCT (120 mg/kg), a well‐known pneumotoxic PA, metabolic activation and pneumotoxicity of MCT among wild‐type (WT), liver‐specific Cpr‐null (LCN), and extrahepatic Cpr‐knockdown (XhCL) mice were compared. The results demonstrated that comparing with WT mice, pyrrole‐protein adducts were significantly decreased (by &gt;60%) in the serum, liver and lungs in LCN mice but unchanged in XhCL mice. In addition, comparing with WT mice, MCT‐exposed LCN mice had significantly higher blood concentration of the intact MCT. Consistently, lung injury represented by vasculature damage was observed in WT and XhCL mice but not in LCN mice. All the data confirmed that hepatic CYPs, not extrahepatic CYPs, were responsible for metabolic activation of PAs.To conclude, the present study for the first time demonstrated that PAs can commonly induce lung injury, which is dependent on the metabolic activation mediated by functional hepatic CYPs.Support or Funding InformationThe present study was supported by General Research Fund (GRF Project No. 14160817) from Research Grants Council of Hong Kong Special Administrative Region.

Gynura Segetum Related Hepatic Sinusoidal Obstruction Syndrome: A Liver Disease with High Mortality and Misdiagnosis Rate.

Gynura segetum (Tusanqi or Jusanqi) is widely used in China as a herbal remedy, however, it has often been associated with hepatic sinusoidal obstruction syndrome (HSOS). Its extent in inducing hepatotoxicity is not sufficiently understood. Hence, we aimed to identify the characteristic features of Gynura segetum associated HSOS. A total of 64 patients diagnosed with HSOS induced by gynura segetum were enrolled from eight Chinese tertiary care hospitals between 2008 and 2018. General information regarding diagnosis, disease history, suspected drug use, symptoms and signs, biochemical index, imaging data, liver histology, treatment methods, severity and prognosis were collected and analyzed. The mean age of the enrolled patients were 58.07±11.44 years. Male patients accounted for 64.1% of HSOS patients. The median latency period was 75 days. The number of patients with a definite diagnosis from the eight hospitals was 5 (7.81%), with a misdiagnosis rate of 92.18%. Hepatomegaly, splenomegaly, ascites and lower limbs edema were present in 89.1%, 76.6%, 81.3% and 43.8% of the patients, respectively. The imaging characteristic changes were liver parenchyma echo thickening, uneven density, and hepatic vein stenosis and occlusion. Liver biopsies had characteristic pathological changes. Except for ALT and D-Dimer, liver function and coagulation index at admission and before discharge were not significantly different (p>0.05). The 6-month mortality rate was 77.55%, with upper-gastrointestinal bleeding being the leading cause of death (42.11%). The second leading cause of death was a secondary infection (36.84%), while the third was hepatorenal syndrome (21.05%). Gynura segetum related HSOS often presents as progressive hepatic congestion, portal hypertension and liver failure, and has a high mortality and misdiagnosis rate.

Efficacy of transjugular intrahepatic portosystemic shunt in treatment of sinusoidal obstruction syndrome caused by gynura segetum

Objective To evaluate the safety and efficacy of transjugular intrahepatic portosystemic shunt (TIPS) in the treatment of sinusoidal obstruction syndrome (SOS) caused by gynura segetum. Methods The clinical data of 9 patients with SOS caused by gynura segetum (5 males and 4 females) who underwent TIPS were retrospectively analyzed from February 2017 to June 2018. The Child-Pugh scores were (9.5±1.3) and the MELD scores were (12.5±5.0). The success rates, complications and follow-up results were evaluated. Results TIPS was performed successfully in all the 9 patients. The portal venous pressure gradient dropped from (22.4±2.7) mmHg to (10.4±3.2) mmHg (P<0.05). There was no complication such as abdominal hemorrhage and biliary peritonitis. Nine patients were followed-up for 1~17months, mean 7.8±6.0 months. One month after treatment, the Child-Pugh scores were (7.1±1.8), compared with that of the preoperative scores, the difference was statistically significant (P<0.05). The MELD scores were (5.3±4.6), compared with that of the preoperative scores, the difference was also statistically significant (P<0.05). At the end point of the follow-up, color Doppler ultrasound and portal CTA showed that the TIPS shunt was patent and hepatic congestion was relieved in all the 9 patients. All patients were alive. Conclusion TIPS was a safe and efficacious treatment for SOS caused by gynura segetum. Key words: Portasystemic shunt, transjugular intrahepatic; Gynura segetum; Sinusoidal obstruction syndrome