A rare case of Gynura-segetum-related hepatic sinus obstruction syndrome complicated with alcoholic liver disease.

Hepatic sinus obstruction syndrome (HSOS) is easy to be misdiagnosed or missed, and there is no unified and effective treatment for it. A patient was considered to have Budd-Chiari syndrome. He underwent a transjugular liver biopsy, and pathological examination revealed HSOS without liver cirrhosis. After the failure of anticoagulation therapy, he successfully received a transjugular intrahepatic portosystemic shunt (TIPS). After discharge, he was followed-up for four years with a good prognosis. G. segetum-induced HSOS can be easily overlooked, especially in patients with underlying liver diseases. When medical therapy fails, TIPS can control ascites and portal hypertension, and the long-term prognosis is optimistic.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

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

BACKGROUND: To evaluate the efficacy and safety of transjugular intrahepatic portosystemic shunt (TIPS) on hepatic sinusoidal obstruction syndrome (HSOS) associated with consumption of Gynura segetum (GS). METHODS: We 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. RESULTS: TIPS 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. CONCLUSION: TIPS may offer a potentially useful treatment for the GS-related HSOS.

Risk factors for hepatic veno-occlusive disease caused by Gynura segetum: a retrospective study.

BACKGROUND: Hepatic veno-occlusive disease (HVOD) caused by Gynura segetum has been increasingly reported in China in recent years. The aim of this retrospective study was to identify independent prognostic markers for survival in patients with Gynura segetum-induced HVOD and to evaluate the effect of anticoagulants and transjugular intrahepatic portosystemic shunt (TIPS) on survival rate. METHODS: Clinical data including symptoms, signs, imaging characteristics, laboratory test results, results of liver tissue biopsies, type of treatment during follow-up and clinical outcomes were collected. Univariate, multivariate and time-dependent Cox regression analyses were performed. RESULTS: Survival rates were 91% (95% confidence interval [CI], 82-95%), 64% (95% CI, 53-69%) and 57% (95% CI, 51-65%) at 1, 3 and 60 months, respectively. Total bilirubin, albumin and hepatic encephalopathy were independent prognostic markers of survival. Anticoagulants were administered to 76% of the patients. Among 75 patients treated with anticoagulants, 49 patients (65.3%) were cured, whereas 26 patients (34.7%) died; the cure rate in anticoagulant-treated patients was higher than that of those not treated with anticoagulants (χ2 = 9.129, P = 0.004). Cure rate of the anticoagulation + TIPS treatment group was 64.3%, which was also higher than that of the non-anticoagulation group; however, this was not significantly different (χ2 = 3.938, P = 0.096). CONCLUSIONS: The presence of hepatic encephalopathy, serum bilirubin and albumin levels were major prognostic factors for Gynura segetum-induced HVOD. Anticoagulation therapy significantly increased the cure rate; however, TIPS treatment did not have a beneficial effect on the cure rate.

4,5,4'-Trihydroxychalcone, 8,8'-(ethene-1,2-diyl)-dinaphtalene-1,4,5-triol and rutin from Gynura segetum inhibit phagocytosis, lymphocyte proliferation, cytokine release and nitric oxide production from phagocytic cells.

BACKGROUND: Gynura segetum is used traditionally to treat various ailments related to the immune system, which include cancer, inflammation, rheumatism, diabetes, hypertension, and viral infections but little studies have been carried out to validate their ethnopharmacological aspects. In this study the immunosuppressive effects of G. segetum and its constituents were investigated. METHODS: Isolation of compounds from G. segetum leaves was conducted using vacuum liquid chromatography (VLC) and column chromatography (CC). Two new compounds, namely 4,5,4'-trihydroxychalcone and 8,8'-(ethene-1,2-diyl)-dinaphtalene-1,4,5-triol, together with stigmasterol and ß-sitosterol were isolated from G. segetum methanol extract and their structures were determined spectroscopically. The presence of gallic acid and rutin in the extract was determined quantitatively by a validated HPLC method. G. segetum methanol extract and its constituents were investigated for their effects on chemotaxis, phagocytosis, ß2 integrin (CD18) expression, and reactive oxygen species (ROS) of polymorphonuclear leukocytes (PMNs), lymphocytes proliferation, cytokine release and nitric oxide (NO) production of phagocytes. RESULTS: All the samples significantly inhibited all the innate immune responses tested except CD 18 expression on surface of leukocytes. Among the samples, 8,8'-(ethene-1,2-diyl)-dinaphtalene-1,4,5-triol exhibited the strongest inhibitory on chemotaxis, phagocytosis, ROS and NO production. The compound exhibited exceptionally strong inhibitions on ROS and chemotaxis activities with IC50 values lower than the positive controls, aspirin and ibuprofen, respectively. 4,5,4'-Trihydroxychalcone revealed the strongest immunosuppressive activity on proliferation of lymphocytes (IC50 value of 1.52 µM) and on release of IL-1ß (IC50 value of 6.69 µM). Meanwhile rutin was the most potent sample against release of TNF-α from monocytes (IC50, 16.96 µM). CONCLUSION: The extract showed strong immunosuppressive effects on various components of the immune system and these activities were possibly contributed mainly by 4,5,4'-trihydroxychalcone, 8,8'-(ethene-1,2-diyl)-dinaphtalene-1,4,5-triol and rutin.

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

PURPOSE: 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. METHODS: 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 2 weeks. RESULTS: 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]. CONCLUSIONS: TIPS therapy may be an effective treatment option for patients with GS-related PA-HSOS.

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

Objective: This 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. Methods: Relevant 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). Results: Levels 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. Conclusion: Both 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.

Gynura segetum-induced liver injury leading to acute liver failure: a case report and literature review.

BACKGROUND: Gynura segetum (GS) is widely used in medical care and in community settings in China as the herbal remedy. It is widely thought to have antiphlogistic properties and pain relief in traditional Chinese medicine. It has been reported that GS can cause chronic drug-induced liver injury (DILI), manifested as hepatic sinusoid obstruction syndrome (HOSO). But case reports of acute DILI developing acute liver failure (ALF) due to GS are extremely rare. CASE PRESENTATION: We report a case of a 63-year-old female patient with hepatolithiasis for more than 6 years. There were no deterioration of liver function and no history of viral liver disease, autoimmune liver disease, blood transfusion or surgical allergy before operation. ALF and grade II liver encephalopathy occurred after partial hepatectomy. To follow up the medical history, the patient has been taking GS (Tusanqi) for a year and a half. The causality assessment was done by the updated Roussel Uclaf Causality Assessment Method, and the possibility of DILI caused by GS as highly probable for the score was 6 points. Excluding other causes, a diagnosis of DILI-associated ALF was established. After symptomatic support and artificial liver support system (ALSS) treatment, the clinical symptoms and signs of the patients were significantly improved. After discharge, the liver function of the patients returned to normal. CONCLUSIONS: Based on this rare case of severe liver injury, we recommend that timely prevention, identification, and appropriate management of DILI is essential for patients with a history of taking GS and other hepatotoxic drugs, and careful monitoring of liver function for patients with DILI could avoid ALF as far as possible.

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.

Development of a Drum Tower Severity Scoring (DTSS) system for pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome.

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 with PA-HSOS who received supportive care and anticoagulation therapy in Nanjing Drum Tower Hospital from January 2008 to December 2020 were enrolled and analyzed retrospectively. These patients were randomized into a training or validation set in a 3:1 ratio. Next, we established and validated the newly developed DTSS system. RESULTS: Analysis identified a predictive formula: logit (P) = 0.004 × aspartate aminotransferase (AST, U/L) + 0.019 × total bilirubin (TB, µmol/L) - 0.571 × fibrinogen (FIB, g/L) - 0.093 × peak portal vein velocity (PVV, cm/s) + 1.122. Next, we quantified the above variables to establish the DTSS system. For the training set, the area under the ROC curve (AUC) (n = 127) was 0.787 [95% confidence interval (CI) 0.706-0.868; p < 0.001]. With a lower cut-off value of 6.5, the sensitivity and negative predictive value for predicting no response to supportive care and anticoagulation therapy were 94.7% and 88.0%, respectively. When applying a high cut-off value of 10.5, the specificity was 92.9% and the positive predictive value was 78.3%. For the validation set, the system performed stable with an AUC of 0.808. CONCLUSIONS: The DTSS system can predict the outcome of supportive care and anticoagulation in PA-HSOS patients with satisfactory accuracy by evaluating severity, and may have potential significance for guiding therapy.

Hepatic sinusoidal obstruction syndrome caused by the ingestion of Gynura segetum in a patient with alcoholic cirrhosis: a case report.

Hepatic sinusoidal obstruction syndrome (HSOS) is a rare hepatic vascular disorder characterized by intrahepatic congestion, liver injury, and post-sinusoidal portal hypertension, and it is frequently associated with hematopoietic stem cell transplantation. In this study, we observed a case of HSOS associated with the ingestion of Gynura segetum, a pyrrolizidine alkaloid (PA)-containing Chinese herb, in a patient with alcoholic cirrhosis. The patient was a 43-year-old man with chief complaints of physical asthenia and a loss of appetite for more than a month. The diagnosis of HSOS combined with alcoholic cirrhosis was confirmed via the histopathological examination of liver tissues. With proper supportive and symptomatic care and anticoagulation therapy using low-molecular-weight heparin, the patient's condition was stabilized. Because of its nonspecific symptoms in the early stage and a lack of information about PA consumption, PA-induced HSOS (PA-HSOS) has been long neglected, especially in patients with underlying liver diseases. Early identification and intervention are critical for optimizing outcomes. Further efforts are needed to supervise the use of PA-containing herbal medicines and identify accurate biomarkers for PA-HSOS.

Risk factors of poor prognosis in patients with pyrrolidine alkaloid-induced hepatic sinusoidal obstruction syndrome after transjugular intrahepatic portosystemic shunt.

AIMS: Transjugular intrahepatic portosystemic shunt (TIPS) is an effective method in treating patients with severe hepatic sinusoidal obstruction syndrome induced by pyrrolidine alkaloids (PA-HSOS). However, some patients still have poor postoperative prognosis. So, we aim to evaluate the predictors associated with poor outcomes in PA-HSOS patients receiving TIPS. METHODS: Patients who were diagnosed as PA-HSOS and received TIPS in our hospital between January 2013 and April 2019 were reviewed retrospectively. Baseline information and clinical data were collected. The hazard ratios (HRs) of factors associated with poor prognosis were analyzed by Cox proportional hazard analysis. The Kaplan-Meier method was used to analyze and compare the cumulative incidence of the poor results and survival rate of patients. RESULTS: During a median of 19.25-month follow-up, death occurred in 17 patients. We found that prothrombin time at baseline with an adjusted HR 1.110 (95% confidence interval 1.014-1.216, p = 0.024) and serum total bilirubin of 9 mg/dl 5 days after TIPS with an adjusted HR 1.114 (95% confidence interval 1.042-1.190, p = 0.001) were independent risk factors for death. The 1-year and 5-year survival rate were 86.2% and 82.1%, respectively. The 1-year survival rate in patients with prothrombin time > 17.85 s at baseline and serum total bilirubin > 9 mg/dl at 5 days after TIPS was significantly lower than that of patients below the corresponding threshold, respectively. CONCLUSIONS: Prolonged prothrombin time at baseline and increased serum total bilirubin levels 5 days after TIPS are independent risk factors for predicting death after TIPS treatment in PA-HSOS 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.

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

OBJECTIVE: Hepatic 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. METHODS: This 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. RESULTS: Sixty-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. CONCLUSION: HVOD 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.

Phosphocreatine attenuates Gynura segetum-induced hepatocyte apoptosis via a SIRT3-SOD2-mitochondrial reactive oxygen species pathway.

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 sirtuin 3 (SIRT3), acetylated superoxide dismutase 2 (Ac-SOD2), SOD2, and apoptosis were detected by Western blotting. Mito-TEMPO and cell lines of viral vector-mediated overexpression of SIRT3 and SIRT3H248Y were used to further verify the mechanism of GS-induced apoptosis. GS-induced liver injury mice models were built by GS through intragastric administration and interfered by PCr through intraperitoneal injection. A total of 30 C57BL/6J mice were assigned to 5 groups and treated with either saline, PCr (100 mg/kg), GS (30 g/kg), or PCr (50 or 100 mg/kg)+GS (30 g/kg). Liver hematoxylin and eosin (HE) staining, immunohistochemical analysis, and blood biochemical evaluation were performed. Results: GS induced hepatocyte apoptosis and elevated levels of mitochondrial ROS in L-02 cells. The expression of SIRT3 was decreased. Downregulation of SIRT3 was associated with increased levels of Ac-SOD2, which is the inactivated enzymatic form of SOD2. Conversely, when overexpressing SIRT3 in GS-treated cells, SOD2 activity was restored, and mitochondrial ROS levels and hepatocyte apoptosis declined. Upon administration of PCr to GS-treated cells, they exhibited a significant upregulation of SIRT3 and were protected against apoptosis. In animal experiments, serum ALT level and mitochondrial ROS of the mice treated with GS and 50 mg/kg PCr were significantly attenuated compared with only GS treated. The changes in SIRT3 expression were also consistent with the in vitro results. In addition, immunohistochemical analysis of the mouse liver showed that Ac-SOD2 was decreased in the PCr and GS co-treated group compared with GS treated group. Conclusion: GS caused liver injury by dysregulating mitochondrial ROS generation via a SIRT3-SOD2 pathway. PCr is a potential agent to treat GS-induced liver injury by mitochondrial protection.

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

BACKGROUND AND AIM: 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. METHODS: 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. RESULTS: 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%). CONCLUSION: Gynura segetum related HSOS often presents as progressive hepatic congestion, portal hypertension and liver failure, and has a high mortality and misdiagnosis rate.

Urine and plasma metabolomics study on potential hepatoxic biomarkers identification in rats induced by Gynura segetum.

ETHNOPHARMACOLOGICAL RELEVANCE: Gynura segetum (GS) is an herbal medicine containing Pyrrolizidine Alkaloids (PAs) that causes hepatic sinusoidal obstruction syndrome (HSOS). AIM OF THE STUDY: To discover potential biomarkers and metabolic mechanisms involved in the hepatotoxicity induced by GS. METHODS: SD rats were randomly divided into 4 groups including Saline, the decoction of GS high, medium and low dosage at dosages of 3.75g • kg-1, 7.5g • kg-1 and 15g • kg-1. A metabolomics approach using Ultraperformance Liquid Chromatography -Quadrupole-Time-of-Flight / Mass Spectrometry (UPLC-Q-TOF/MS) was developed to perform the plasma and urinary metabolic profiling analysis, and identified differential metabolites by comparing the saline control group and decoction of GS groups. RESULTS: The herbal was presented dosage-dependent led to ingravescence of hepatotoxicity after the rats were consecutively given with the decoction of GS at varied dosages. A total of 18 differential metabolites of decoction of GS-induced hepatotoxicity were identified, while 10 of them including arginine, proline, glutamate, creatine, valine, linoleic acid, arachidonic acid, sphinganine, phytosphingosine, and citric acid could be discovered in urine and plasma, and primarily involved in Amino acid metabolism, Lipids metabolism and Energy metabolism. CONCLUSIONS: The results suggested that the differential metabolites of arginine, creatine, valine, glutamine and citric acid were verified as potential markers of GS-induced hepatotoxicity via the regulation of multiple metabolic pathways primarily involving in Amino acids metabolism and Energy metabolism.

Anti-inflammatory and antioxidant activities of the methanol extract of Gynura segetum leaf.

Gynura segetum, family Compositae, is a cultivated species and can be found growing in the tropical regions of Indonesia and Malaysia. The plant is known for its use for the treatment of cancer, inflammation, diabetes, hypertension and skin afflictions. In the current study, in vivo anti-inflammatory effect of the methanol extract G. segetum leaf and its antioxidant effect in vitro have been investigated for the first time. The in vitro antioxidant activities of the methanol extract were measured using common methods including total phenolic content; total flavonoid content; scavenging of 1,1-diphenyl-2-picrylhydrazyl (DPPH) and ß-carotene bleaching assays. The in vivo anti-inflammatory activities were tested using the cotton pellet implanted animal model. The measurement of pro-inflammatory cytokine (TNF-α and IL-1) levels in the blood samples of the rats was carried out by using ELISA kits. The inhibitory activity on cyclooxygenase (COX) enzyme of methanol extract was also evaluated. The methanol extract exhibited good antioxidant activity which is associated with their total phenolic and flavonoid contents. Methanol extract strongly inhibited the granuloma tissue formation in rats and the anti-inflammatory potential was mediated through the inhibition of pro-inflammatory cytokines and COX-2 enzyme activities. Taken together, the present study suggests that G. segetum's leaf is a natural source of antioxidants and has potential therapeutic benefits against chronic inflammation.