Impact of Traditional Chinese Medicine on Prognosis of Patients with Hepatocellular Carcinoma: A Retrospective Cohort Study.

BACKGROUND: In a previous study, we found that traditional Chinese medicine (TCM) alleviated the clinical symptoms and improved the quality of life (QoL) in patients with hepatocellular carcinoma (HCC). OBJECTIVES: A cohort was continuously followed up to determine the impact of the TCM adjuvant therapies on the prognosis of HCC after conventional treatments. METHODS: We did a retrospective monocentric cohort study including 175 eligible patients. The participants who received TCM adjuvant therapies were termed as TCM group. For the purpose of stratification analysis, the patients who received TCM adjuvant therapies over 3 months per year were further classified into the high frequency group, while the rest of the TCM users were classified into the low frequency group. Non-users were recorded as the control group. The primary outcome was overall survival (OS) and the secondary outcome was the mean progression-free survival (mPFS) primarily introduced in this study, referring to the time from initial diagnosis to the latest progression over the number of disease progressions. Analyses used Cox proportional hazards and Kaplan-Meier (K-M) methods, adjusted for stratification factors. RESULTS: Until June 30, 2021, 56 patients survived, 21 patients were lost to follow-up, and 98 patients died from the disease. Each disease progression of every individual was recorded, and most of the PFS was within 1 year. The baseline data of the allocated groups were balanced, the result revealed that TCM adjuvant therapies might have little influence on OS (P = .129). However, the 1, 3, and 5-year progression-free survival rates of the patients in TCM and control group were 68.75%, 37.50%; 25.00%, 8.33% and 8.33%, 2.08%, respectively, indicating TCM use significantly extended the mPFS, and decreased the risk of disease progression by a factor of 0.676 (P = .006). In the patients with BCLC stage B HCC, compared with controls, a 37-month median OS advantage in the high frequency group was noted (P = .045); and the high frequency of TCM use significantly suppressed disease progression (P = .001). CONCLUSIONS: The present study revealed that TCM adjuvant therapies could postpone disease progression in HCC. Furthermore, using TCM over 3 months per year might extend OS in patients with intermediate HCC.

Role of SIRT5 in the analgesic effectiveness of moxibustion at ST36 in mice with inflammatory pain.

Sirtuine5 (SIRT5) is an important molecule involved in the pathology of inflammatory diseases. To investigate the impact of SIRT5 on the analgesic effectiveness of moxibustion, we established a complete Freund's adjuvant- (CFA-) induced inflammatory pain in mice model. Moxibustion was applied at the Zusanli (ST36) acupoint in mice with inflammatory pain. The analgesic effectiveness was evaluated by thermal hyperalgesia and mechanical allodynia tests in the right paws after CFA injection. The expression of inflammatory cytokines, including the pro-inflammatory factors IL-1ß and TNF-α, and the anti-inflammatory factors IL-4 and TGF-ß expressions, was evaluated using by ELISA. Furthermore, SIRT5 was evaluated by immunofluorescence and western blotting. The results showed that, compared with the CFA group, both thermal and mechanical pain thresholds increased with moxibustion and the SIRT5 inhibitor MC3482 intervention at ST36. Additionally, compared to the CFA-induced group, the inflammatory mediators, including IL-1ß and TNF-α, decreased, while the anti-inflammatory cytokines IL-4 and TGF-ß increased with moxibustion and MC3482 ST36 acupoint injection. Western blot results showed a decreased expression of SIRT5 at the ST36 site with moxibustion and MC3482 injection, compared to the CFA-induced group. SIRT5 expression in the right paw of mice injected with moxibustion and MC3482 was higher than that in the CFA-induced group. This study revealed that SIRT5 expression is involved in moxibustion analgesia and may be a potential mediator in the regulation of analgesia.

Urban-rural difference in the lagged effects of PM2.5 and PM10 on COPD mortality in Chongqing, China.

BACKGROUND: It is true that Chronic obstructive pulmonary disease (COPD) will increase social burden, especially in developing countries. Urban-rural differences in the lagged effects of PM2.5 and PM10 on COPD mortality remain unclear, in Chongqing, China. METHODS: In this study, a distributed lag non-linear model (DLNMs) was established to describe the urban-rural differences in the lagged effects of PM2.5, PM10 and COPD mortality in Chongqing, using 312,917 deaths between 2015 and 2020. RESULTS: According to the DLNMs results, COPD mortality in Chongqing increases with increasing PM2.5 and PM10 concentrations, and the relative risk (RR) of the overall 7-day cumulative effect is higher in rural areas than in urban areas. High values of RR in urban areas occurred at the beginning of exposure (Lag 0 ~ Lag 1). High values of RR in rural areas occur mainly during Lag 1 to Lag 2 and Lag 6 to Lag 7. CONCLUSION: Exposure to PM2.5 and PM10 is associated with an increased risk of COPD mortality in Chongqing, China. COPD mortality in urban areas has a high risk of increase in the initial phase of PM2.5 and PM10 exposure. There is a stronger lagging effect at high concentrations of PM2.5 and PM10 exposure in rural areas, which may further exacerbate inequalities in levels of health and urbanization.

Association of polycythemia vera with non­cirrhotic portal hypertension in five patients: A case series.

Polycythemia vera (PV) and non-cirrhotic portal hypertension (NCPH) are relatively independent diseases, and few studies have linked them. However, in clinical settings, there may be a causal relationship. The aim of the present study was to analyze the clinical data of five patients with portal hypertension caused by PV and summarize the characteristics of PV with portal hypertension, to enhance the knowledge of this disease. The clinical data of five patients with PV and portal hypertension treated at Beijing You'an Hospital (Beijing, China) from January 2010 to March 2022 were retrospectively collected. The characteristics of these patients were then summarized and analyzed, including general information, laboratory tests, imaging and gastroscopy data. Overall, four patients were diagnosed with PV earlier compared with those with NCPH (ranging between days and years), whereas one patient was diagnosed with NCPH at the time of PV diagnosis. These four patients had blood cell elevations of 2-3 categories (red blood cells, white blood cells or platelets). The Child classification of liver functions in all five patients were found to be grades A-B. All five patients had splenomegaly, where three patients had portal vein thrombosis and cavernous degeneration. In addition, four patients had moderate or severe esophageal varices. In conclusion, to the best of our knowledge, this was the first case series of NCPH caused by PV. Among the patients, it was revealed that: i) NCPH caused by PV had milder liver function damage compared with cirrhosis-induced portal hypertension; ii) splenomegaly, ascites and esophageal varicose veins were prominent symptoms of NCPH caused by PV; iii) If PV is diagnosed, esophagogastroduodenoscopy should be performed as early as possible and regularly, where primary prevention measures for esophageal variceal hemorrhage are recommended; and iv) patients with PV with portal hypertension are at risk of thrombosis and bleeding, but it remains to be determined whether early antithrombotic therapy can reduce complications.

Spatial association between green space and COPD mortality: a township-level ecological study in Chongqing, China.

BACKGROUND: There are regional differences in the effect of green space on mortality of Chronic obstructive pulmonary disease (COPD). We conduct an ecological study, using the administrative divisions of Chongqing townships in China as the basic unit, to investigate the association between COPD mortality and green space based on data of 313,013 COPD deaths in Chongqing from 2012 to 2020. Green space is defined by Fractional vegetation cover (FVC), which is further calculated based on the normalised vegetation index (NDVI) from satellite remote sensing imagery maps. METHODS: After processing the data, the non-linear relationship between green space and COPD mortality is revealed by generalised additive models; the spatial differences between green space and COPD mortality is described by geographically weighted regression models; and finally, the interpretive power and interaction of each factor on the spatial distribution of COPD mortality is examined by a geographic probe. RESULTS: The results show that the FVC local regression coefficients ranged from - 0.0397 to 0.0478, 63.0% of the regions in Chongqing have a positive correlation between green space and COPD mortality while 37.0% of the regions mainly in the northeast and west have a negative correlation. The interpretive power of the FVC factor on the spatial distribution of COPD mortality is 0.08. CONCLUSIONS: Green space may be a potential risk factor for increased COPD mortality in some regions of Chongqing. This study is the first to reveal the relationship between COPD mortality and green space in Chongqing at the township scale, providing a basis for public health policy formulation in Chongqing.

Clinical analysis of patients with systemic lupus erythematosus complicated with liver failure.

The objective of this study is to analyze and summarize the characteristics of the clinical data of patients with systemic lupus erythematosus (SLE) complicated with liver failure, and to improve the cognition of the disease. The clinical data of patients with SLE complicated with liver failure hospitalized in Beijing Youan Hospital from January 2015 to December 2021 were collected retrospectively, including general information and laboratory examination data, and the clinical characteristics of the patients were summarized and analyzed. Twenty-one SLE patients with liver failure were analyzed. The diagnosis of liver involvement was earlier in 3 cases than that of SLE, and later in 2 cases. Eight patients were diagnosed with SLE and autoimmune hepatitis at the same time. The medical history is between 1 month and 30 years. This was the first case report of SLE complicated with liver failure. We found that: (1) among the 21 patients, organ cysts (liver and kidney cysts) were more common and the proportion of cholecystolithiasis and cholecystitis was higher than that in previous studies, but the proportion of renal function damage and joint involvement was lower. (2) The inflammatory reaction was more obvious in SLE patients with acute liver failure. The degree of liver function injury in SLE patients with autoimmune hepatitis was less than that in patients with other liver diseases. (3) The use of glucocorticoid in SLE patients with liver failure was worthy of further discussion. Key Points • Patients with SLE complicated with liver failure have a lower proportion of renal impairment and joint involvement. • The study firstly reported SLE patients with liver failure. • Glucocorticoids in the treatment of SLE patients with liver failure are worthy of further discussion.

Serum Interleukins as Potential Prognostic Biomarkers in HBV-Related Acute-on-Chronic Liver Failure.

Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is relatively common in China and has complex pathogenesis, difficult clinical treatment, and poor prognosis. Immune status is an important factor affecting ACLF prognosis. Interleukins are a family of secreted lymphocyte factors that interact with a host of cell types including immune cells. These signaling molecules play important roles in transmitting information; regulating immune cells; mediating the activation, proliferation, and differentiation of T and B cells; and modulating inflammatory responses. Many studies have investigated the correlation between interleukin expression and the prognosis of HBV-ACLF. This review focuses on the potential use of interleukins as prognostic biomarkers in HBV-ACLF. References were mainly identified through PubMed and CNKI search, including relevant studies published until December 2021. We have summarized reports of several promising diagnostic interleukin biomarkers that predict susceptibility to HBV-ACLF. The use of biomarkers to understand early prognosis can help devise different therapeutic measures and improve patient survival. Ongoing research on prognostic biomarkers of HBV-ACLF is promising, and future preclinical and clinical studies are warranted.

[Research progress on three-dimensional printed interbody fusion cage].

Spinal fusion is a standard operation for treating moderate and severe intervertebral disc diseases. In recent years, the proportion of three-dimensional printing interbody fusion cage in spinal fusion surgery has gradually increased. In this paper, the research progress of molding technology and materials used in three-dimensional printing interbody fusion cage at present is summarized. Then, according to structure layout, three-dimensional printing interbody fusion cages are classified into five types: solid-porous-solid (SPS) type, solid-porous-frame (SPF) type, frame-porous-frame (FPF) type, whole porous cage (WPC) type and others. The optimization process of three-dimensional printing interbody fusion cage and the advantages and disadvantages of each type are analyzed and summarized in depth. The clinical application of various types of 3D printed interbody fusion cage was introduced and summarized later. Lastly, combined with the latest research progress and achievements, the future research direction of three-dimensional printing interbody fusion cage in molding technology, application materials and coating materials is prospected in order to provide some reference for scholars engaged in interbody fusion cage research and application.

Effects of Chinese Medicine on Symptoms, Syndrome Evolution, and Lung Inflammation Absorption in COVID-19 Convalescent Patients during 84-Day Follow-up after Hospital Discharge: A Prospective Cohort and Nested Case-Control Study.

OBJECTIVE: To observe the changes of symptoms, Chinese medicine (CM) syndrome, and lung inflammation absorption during convalescence in patients with coronavirus disease 2019 (COVID-19) who had not totally recovered after hospital discharge and whether CM could promote the improvement process. METHODS: This study was designed as a prospective cohort and nested case-control study. A total of 96 eligible patients with COVID-19 in convalescence were enrolled from Beijing Youan Hospital and Beijing Huimin Hospital and followed up from the hospital discharged day. Patients were divided into the CM (64 cases) and the control groups (32 cases) based on the treatment with or without CM and followed up at 14, 28, 56, and 84 days after discharge. In the CM group, patients received the 28-day CM treatment according to two types of CM syndrome. Improvements in clinical symptoms, CM syndrome, and absorption of lung inflammation were observed. RESULTS: All the 96 patients completed the 84-day follow-up from January 21 to March 28, 2020. By the 84th day of follow-up, respiratory symptoms were less than 5%. There was no significant difference in the improvement rates of symptoms, including fatigue, sputum, cough, dry throat, thirst, and upset, between the two groups (P>0.05). Totally 82 patients (85.42%) showed complete lung inflammation absorption at the 84-day follow-up. On day 14, the CM group had a significantly higher absorption rate than the control group (P<0.05) and the relative risk of absorption for CM vs. control group was 3.029 (95% confidence interval: 1.026-8.940). The proportions of CM syndrome types changed with time prolonging: the proportion of the pathogen residue syndrome gradually decreased, and the proportion of both qi and yin deficiency syndrome gradually increased. CONCLUSIONS: Patients with COVID-19 in convalescence had symptoms and lung inflammation after hospital discharge and recovered with time prolonging. CM could improve lung inflammation for early recovery. The types of CM syndrome can be transformed with time prolonging. (Registration No. ChiCTR2000029430).

[Value of a new predictive model in evaluating short-term prognosis of patients with hepatitis B virus related acute-on-chronic liver failure].

OBJECTIVE: To establish a predictive model and investigate its value in evaluating short-term prognosis of patients with hepatitis B virus related acute-on-chronic liver failure (HBV-ACLF). METHODS: Patients with HBV-ACLF admitted to Tianjin Second People's Hospital and Beijing Youan Hospital, Capital Medical University from May 2015 to October 2018 were enrolled. The data of gender, age, laboratory markers at admission, model for end-stage liver disease (MELD) score and clinical complications were collected for analysis. According to the prognosis on 12-week, patients were divided into survival group and death group. Univariate analysis and binary Logistic regression analysis were used to test the risk factors for short-term prognosis of the patients with HBV-ACLF, and a prediction model was established. The accuracy of each index and the established model were verified by the receiver operating characteristic (ROC) curve. RESULTS: A total of 148 patients with HBV-ACLF were enrolled in the study, 91 cases survived while 57 cases died during the 12-week period. The age, total bilirubin (TBIL), neutrophil percentage (NEUT%), hepatitis B surface antigen (HBsAg), MELD score of death group were higher than those of survival group [age (years old): 50.00 (44.50, 55.00) vs. 43.00 (34.00, 53.00), TBIL (µmol/L): 310.30 (240.70, 405.70) vs. 266.40 (184.20, 360.20), NEUT%: (74.52±13.05)% vs. (66.64±12.35)%, lgHBsAg (kU/L): 3.72 (3.29, 3.92) vs. 2.97 (2.49, 3.78), MELD score: 24.27 (19.71, 27.40) vs. 21.88 (18.83, 24.38), all P < 0.05], while albumin (ALB), total cholesterol (CHO), prothrombin activity (PTA) and alpha-fetoprotein (AFP) were lower than those of survival group [ALB (g/L): 29.80 (27.05, 31.05) vs. 30.80 (28.00, 33.90), CHO (mmol/L): 1.98 (1.50, 2.38) vs. 2.49 (2.05, 3.01), PTA: (30.37±7.09)% vs. (32.94±6.03)%, AFP (µg/L): 21.54 (9.28, 51.54) vs. 66.16 (24.50, 152.80), all P < 0.05]. Logistic regression analysis showed that NEUT%, HBsAg and AFP were independent risk factors for short-term prognosis of patients with HBV-ACLF [odds ratio (OR) was 77.843, 1.439, 0.995, respectively, all P < 0.05]. According to the results of regression analysis, the NHA-ACLF model (NEUT%+HBsAg+AFP) was established. The formula was logit (NHA-ACLF) = -5.441+5.688×NEUT%+0.430×lgHBsAg-0.005×AFP. The area under the ROC curve (AUC) of the NHA-ACLF model for pred HBV-ACLF patients was 0.790, which was better than NEUT% (AUC = 0.696), lgHBsAg (AUC = 0.670), AFP (AUC = 0.703) and MELD score (AUC = 0.640). When the cut-off value of NHA-ACLF model score was 0.459, the sensitivity was 73.7%, and the specificity was 79.1%. CONCLUSIONS: NEUT%, HBsAg and AFP are independent predictive indicator for short-term prognosis in patients with HBV-ACLF. Compared with MELD score, the risk assessment model NHA-ACLF has a greater value in predicting the short-term prognosis of patients with HBV-ACLF.

Effect of Jinhua Qinggan granules on novel coronavirus pneumonia in patients.

OBJECTIVE: To evaluate the effectiveness and safety of Jinhua Qinggan granules in the treatment of patients with novel coronavirus pneumonia (COVID-19). METHODS: Eighty cases of COVID-19 diagnosed from January 24 to February 17, 2020 in Beijing YouAn Hospital Affiliated to Capital Medical University were retrospectively analyzed. All 80 patients received symptomatic and supportive treatment. Among them, 44 patients took Jinhua Qinggan granules (treatment group) within 24 h of admission, and the remaining 36 patients either did not take Jinhua Qinggan granules or took the granules for less than 2 d (control group). In this study, we compared the duration of viral nucleic acid detection and of pneumonia absorption improvement between the two groups. RESULTS: Among the 80 cases, 37 were male (46%) and 43 were female (54%) with age ranging from 15 to 86 years, with an average age of 51.19 years. The average duration of viral nucleic acid detection was (7 ± 4) d in the Jinhua Qinggan administration group and (10 ± 4) d for the control group (P = 0.010), following which, nucleic acid tests were negative. Of the two groups, 56.82% in the Jinhua Qinggan treatment group and 27.78% in the control group demonstrated negative nucleic acid tests within 7 d or less. The 7-day viral clearance rate was significantly higher in the Jinhua Qinggan group compared with the control group (P = 0.009). Furthermore, the pneumonia recovery time indicated by chest CT was (8 ± 4) d in the Jinhua Qinggan group, which was significantly shorter than the control group, at (10 ± 5) d (P = 0.021). No adverse reactions were found in the treatment group after taking this medicine. CONCLUSION: In patients with COVID-19, Jinhua Qinggan granules can effectively shorten the duration of nucleic acid detection and promote the absorption of pneumonia inflammatory exudate without obvious adverse reactions.

[Light and heat of moxibustion for knee osteoarthritis：a multi-center randomized controlled trial].

OBJECTIVE: To explore the clinical therapeutic effect of light and heat of moxibustion for knee osteoarthritis (KOA). METHODS: A total of 216 patients with KOA were randomized into a traditional moxibustion group (72 cases, 8 cases dropped off), a moxibustion light group (72 cases, 9 cases dropped off) and a moxibustion heat group (72 cases, 10 cases dropped off).The special light-heat separation moxibustion cup was applied, the patients in the traditional moxibustion group received the treatment of moxibustion, the patients in the moxibustion light group received the treatment of moxibustion light and the patients in the moxibustion heat group received the treatment of moxibustion heat. The acupoint selection of the three groups was Neixiyan (EX-LE 4), Dubi (ST 35) and Zusanli (ST 36), the treatment was given 20 min each time, 3 times a week, 4 weeks were required totally, and the follow-up surveys were made 4 and 8 weeks after treatment. The scores of Western Ontario and McMaster University osteoarthritis index (WOMAC) and visual analogue scale (VAS) were observed before treatment, after 2 and 4 weeks of treatment, 4 and 8 weeks after treatment. The therapeutic effects were evaluated according to the criterion of patient global assessment (PGA) after 4 weeks of treatment and 8 weeks after treatment. RESULTS: Compared with before treatment, the pain scores, stiffness scores, physical function scores and total scores of WOMAC were reduced after 2, 4 weeks of treatment and 4 weeks after treatment in the three groups (P<0.05). The pain scores, stiffness scores, physical function scores and total scores of WOMAC were reduced 8 weeks after treatment in the traditional moxibustion group and the moxibustion heat group (P<0.05). The stiffness score, physical function score and total score of WOMAC were reduced 8 weeks after treatment in the moxibustion light group (P<0.05). The pain score, physical function score and total score of WOMAC in the traditional moxibustion group after 4 weeks of treatment were lower than the moxibustion light group (P<0.05). Compared with before treatment, the VAS scores were reduced after 2, 4 weeks of treatment and 4 , 8 weeks after treatment in the three groups (P<0.05). The improvement rates in the traditional moxibustion group and the moxibustion heat group after 4 weeks of treatment and 8 weeks after treatment were superior to the moxibustion light group (P<0.05). CONCLUSION: The light and heat of moxibustion have therapeutic effect for KOA, and the therapeutic effect of moxibustion heat is superior to moxibustion light.

[Expert consensus statement on Hugan Tablets in clinical practice].

Hugan Tablets is a Chinese patent medicine,it has the function of anti-inflammation and reducing transaminase. Based on questionnaire investigation of doctors and a systematic review of research literature on Hugan Tablets,using international clinical practice guidelines' developing methods,with the best available evidence and fully combining expert experience,and following the principle of " evidence-based,consensus-based and experience-based",Expert consensus statement on Hugan Tablets in clinical practice was developed by more than 30 multidisciplinary experts from the nationwide,aimed at guiding and standardizing the rational use of Hugan Tablets by clinicians and to improve clinical efficacy and safety. The expert consensus adopts internationally recognized recommendation criteria for classification of evidence: GRADE. The formation of expert consensus adopts the nominal group technique. Six main considerations are quality of evidence,curative effect,safety,economical efficiency,patient acceptability and other factors. If there is sufficient evidence,a " recommendation" is formed,using GRADE grid voting rule. If there isn' t sufficient evidence,a " consensus opinion" is formed,using majority counting rule. Focus on the indication,usage and dosage,drug use in special population and safety of Hugan Tablets,two recommendations and eight consensus opinions were put forward. Through expert meetings and correspondence,a nationwide consultation and peer review was conducted. This consensus applies to clinicians in hospitals and grass-roots health services,to provide guidance and reference for the rational use of Hugan Tablets.

Extracellular histones are clinically associated with primary graft dysfunction in human liver transplantation.

Extracellular histones have been involved in numerous inflammatory conditions such as ischemia/reperfusion (I/R) injury, trauma, and infection. There is growing evidence of I/R injury associated with primary graft dysfunction (PGD) following organ transplantation. Here we investigated whether extracellular histones are clinically involved with PGD in human liver transplantation. In total 58 patients undergoing liver transplantation were studied. We collected blood samples from the recipients before and serially after transplantation (24 h, 72 h). We measured extracellular histones, myeloperoxidase (MPO), S100A8/A9, and multiple inflammatory cytokines. Additionally, we exposed human L02 hepatocytes or U937 monocytic cells to the recipient's sera overnight, and assessed cellular viability and cytokine production respectively. Lastly, we assessed the effect of histone-targeted interventions by administration of heparin or an anti-histone antibody. It showed that extracellular histones increased immediately after transplantation, peaked within 24 hours and remained at high levels up to 72 hours (all p < 0.01). Notably, extracellular histone levels were significantly higher in recipients with PGD (n = 9) than recipients without PGD (n = 49, p = 0.004). Extracellular histones correlated positively with MPO, S100A8/A9 and most detected cytokines. Ex vivo analysis demonstrated that the patients' sera after graft markedly induced L02 cell death and caused profound cytokine production in cultured U937 cells, which could be abrogated by heparin or an anti-histone antibody. Collectively, extracellular histones were increased significantly after liver transplantation, which may contribute to the occurrence of PGD through direct cytotoxicity and enhancement of systemic inflammation. Targeting extracellular histones may provide a promising approach for preventing PGD or other complications in clinical practice.

Correction: Extracellular histones are clinically associated with primary graft dysfunction in human liver transplantation.

[This corrects the article DOI: 10.1039/C9RA00425D.].

Qingchangligan formula alleviates acute liver injury by attenuating extracellular histone-associated inflammation.

Qingchangligan formula (QCLGF) is a traditional Chinese medicine that has exhibited remarkable clinical efficacy for patients with acute-on-chronic liver failure (ACLF). However, the hepatoprotective mechanisms of QCLGF are not completely understood. Extracellular histones were recently identified as the novel inflammatory mediators involved in the pathogenesis of acute liver injury. This study aimed to investigate whether QCLGF provides hepatoprotection by targeting extracellular histones. We showed that QCLGF significantly improved the survival rate of the ConA-treated mice, ameliorated hepatotoxicity, and markedly decreased the levels of extracellular histones and the associated cytokines. We further demonstrated that QCLGF attenuated systemic inflammation by inhibiting the mitogen-activated protein kinase (MAPK) signaling pathway. In addition, exogenous histones induced a significant HL-7702 cell damage, which could be prevented by administration of QCLGF. Lastly, we observed that extracellular histones and the associated cytokines were consistently lower in ACLF patients receiving conventional medical therapy plus QCLGF than in patients receiving only conventional medical therapy. Collectively, these results provide evidence that QCLGF has therapeutic potentials for treating ACLF, which may be due to its ability to interfere with extracellular histone-mediated cellular damage and systemic inflammation.

Qingchangligan formula attenuates the inflammatory response to protect the liver from acute failure induced by d-galactosamine/lipopolysaccharide in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: The Qingchangligan formula, a traditional Chinese medicine comprising five herbs, is useful for treatment of patients with liver failure; however, its protective and regulatory mechanisms remain elusive. AIM OF THE STUDY: To test the hypothesis that the Qingchangligan formula protects mice against acute liver failure by inhibiting liver inflammation. MATERIALS AND METHODS: Acute liver failure (ALF) was induced by intraperitoneal injection of D-GalN (700mg/kg) plus LPS (10µg/kg). The Qingchangligan formula was administered to mice in three doses of 50mg/kg (on day 1, day 2, and day 3) prior to D-GalN/LPS injection by intragastric administration. The mice in different groups were sacrificed at 6h after D-GalN/LPS injection, and liver samples and blood were collected for analysis. RESULTS: Administration of the Qingchangligan formula not only ameliorated liver injury, as evidenced by reduced transaminase levels and well-preserved liver architecture, but also decreased the lethality in ALF mice. Moreover, in the ALF model, pretreatment with the Qingchangligan formula alleviated liver inflammation and decreased hepatocyte apoptosis. Further demonstrating the protective effects of the Qingchangligan formula, we found that pretreatment with the Qingchangligan formula reduced the expression of inflammatory cytokines by decreasing the expression of components of the mitogen-activated protein kinase (MAPK) pathway and promoting autophagy in vitro and in vivo. CONCLUSIONS: Our findings demonstrated that the Qingchangligan formula exerts a protective effect against the pathophysiology of ALF, especially in regulating liver inflammation, and provide a rationale for using the Qingchangligan formula as a potential therapeutic strategy to ameliorate ALF.

Circulating histones are major mediators of systemic inflammation and cellular injury in patients with acute liver failure.

Acute liver failure (ALF) is a life-threatening systemic disorder. Here we investigated the impact of circulating histones, recently identified inflammatory mediators, on systemic inflammation and liver injury in murine models and patients with ALF. We analyzed histone levels in blood samples from 62 patients with ALF, 60 patients with chronic liver disease, and 30 healthy volunteers. We incubated patients' sera with human L02 hepatocytes and monocytic U937 cells to assess cellular damage and cytokine production. d-galactosamine plus lipopolysaccharide (GalN/LPS), concanavalin A (ConA), and acetaminophen (APAP) were given to C57BL/6N mice to induce liver injury, respectively, and the pathogenic role of circulating histones was studied. Besides, the protective effect of nonanticoagulant heparin, which can bind histones, was evaluated with in vivo and ex vivo investigations. We observed that circulating histones were significantly increased in patients with ALF, and correlated with disease severity and mortality. Significant systemic inflammation was also pronounced in ALF patients, which were associated with histone levels. ALF patients' sera induced significant L02 cell death and stimulated U937 cells to produce cytokines, which were abrogated by nonanticoagulant heparin. Furthermore, circulating histones were all released remarkably in GalN/LPS, ConA, and APAP-treated mice, and associated with high levels of inflammatory cytokines. Heparin reduced systemic inflammation and liver damage in mice, suggesting that it could interfere with histone-associated liver injury. Collectively, these findings demonstrate that circulating histones are critical mediators of systemic inflammation and cellular damage in ALF, which may be potentially translatable for clinical use.

Cancer of the Liver Italian Program score helps identify potential candidates for transarterial chemoembolization in patients with Barcelona Clinic Liver Cancer stage C.

BACKGROUND: The Barcelona Clinic Liver Cancer (BCLC) staging system for hepatocellular carcinoma (HCC) recommends transarterial chemoembolization (TACE) as the first line therapy for stage B patients and sorafenib treatment for stage C patients. However, stage C patients exhibit variations in terms of tumor burden, liver function, and extrahepatic metastasis, which could potentially affect disease outcome. Here, we assessed whether the Cancer of the Liver Italian Program (CLIP) scores can help identify stage C patients likely to benefit from TACE. METHODS: Out of 295 BCLC stage C HCC patients enrolled between January 2009 and December 2011, those with platelet counts >30 X 10(9) cells/L, total bilirubin <51 µmoL/L, and an unobstructed main portal vein were scheduled for TACE (n=195). The remaining patients received best supportive care (BSC, n=100). All the patients were followed up for symptoms, performance status, and Child-Pugh classification scores every 4 weeks until death or December 2013. The prognosis of each group was evaluated by using the log-rank test and Cox-Mantel test. RESULTS: The median overall survival (OS) was 6 months [95% confidence interval (CI): 4.64-7.36]. The OS was 9 months for the TACE group and 4 months for the BSC group. The TACE group had a longer OS than the BSC subgroup for CLIP scores 0-2 [13 months (95% CI: 8.55-17.45) vs 4 months (95% CI: 0.00-10.96), P=0.001]. No significant differences were found between the TACE and BSC groups for CLIP scores 3-5. The CLIP score and treatment methods were found to be independent prognostic factors. CONCLUSIONS: BCLC stage C HCC patients exhibit definite disease heterogeneity and can be reclassified by using the CLIP scoring system. Moreover, patients with CLIP scores 0-2 are likely to benefit from TACE. However, additional studies with long-term follow-up will be required to validate these findings.

Echinacoside ameliorates D-galactosamine plus lipopolysaccharide-induced acute liver injury in mice via inhibition of apoptosis and inflammation.

OBJECTIVE: This study aimed to investigate the protective effects of echinacoside, one of the phenylethanoids isolated from the stems of Cistanche salsa, a Chinese herbal medicine, on D-galactosamine (GalN) and lipopolysaccharide (LPS)-induced acute liver injury in mice. METHODS: We administered GalN (650 mg/kg) together with LPS (30 µg/kg) to mice by intraperitoneal injection to induce acute liver damage. Echinacoside (60 mg/kg) was given intraperitoneally to mice at 1 h prior to GalN/LPS exposure. Mice were sacrificed at different time points following GalN/LPS treatment, and the liver and blood samples were collected for future analysis. RESULTS: It showed that GalN/LPS treatment produced severe hepatic injury, evidenced by significantly elevated plasma alanine aminotransferase (ALT) levels and abnormal histological changes such as hepatocyte necrosis or apoptosis, hemorrhage, fatty degeneration, and neutrophil infiltration. Notably, pretreatment with echinacoside remarkably improved the survival rate of GalN/LPS-treated mice and attenuated acute hepatotoxicity, as demonstrated by decreased ALT levels and improved histological signs. Echinacoside shows both anti-apoptotic and anti-inflammatory properties, characterized by a substantial inhibition of hepatocyte apoptosis and a significant reduction in the inflammatory markers, including myeloperoxidase, extracellular nucleosomes, high-mobility group box 1, and inflammatory cytokines in the plasma of mice, which may be important mechanisms related to its protective effect. CONCLUSION: Our results suggest that echinacoside can provide a pronounced protection against GalN/LPS-induced acute liver injury in mice, which may complement the available strategies for management of acute liver damage in clinical settings.