Na3K6(CO3)3(NO3)2X·6H2O (X = NO3, Cl, Br): Exploring High-Performance UV Birefringent Crystals Induced by Coplanar π-Conjugated CO3 and NO3 Groups.

Planar π-conjugated groups, like CO3, NO3, and BO3 triangles, are ideal functional units for designing birefringent materials due to their large optical anisotropy and wide band gap. The key point for designing birefringent crystals is to select appropriate functional building blocks (FBBs) and the proper arrangement mode. It is well known that the substitution strategy has proven to be a promising and accessible approach. In this work, alkali metals were chosen to regulate and control two different π-conjugated groups, CO3 and NO3, to build new compounds with large birefringence. Subsequently, three new compounds, Na3K6(CO3)3(NO3)2X·6H2O (X = NO3, Cl, Br), were successfully synthesized using the hydrothermal method. The aliovalent substitution between the [NO3]- anionic group and halogen anions [Cl]-/[Br]- has been achieved in these compounds. Na3K6(CO3)3(NO3)2X·6H2O feature the well-coplanar CO3 and NO3 groups in their crystal structure. This coplanar arrangement mode may effectively enhance the anisotropic polarizability of Na3K6(CO3)3(NO3)2X·6H2O. And their experimental birefringence can reach 0.094-0.131 at 546 nm. Diffuse reflectance spectra demonstrate that these compounds exhibit short ultraviolet (UV) absorption edges of ∼235 nm. Meanwhile, Na3K6(CO3)3(NO3)2X·6H2O also have an easily grown capacity under facile conditions. This work not only reports three new potential UV birefringent crystals but also provides a strategy to make the π-conjugated MO3 group coplanar.

Robust Finite-Time Stability for Uncertain Discrete-Time Stochastic Nonlinear Systems with Time-Varying Delay.

The main concern of this paper is finite-time stability (FTS) for uncertain discrete-time stochastic nonlinear systems (DSNSs) with time-varying delay (TVD) and multiplicative noise. First, a Lyapunov-Krasovskii function (LKF) is constructed, using the forward difference, and less conservative stability criteria are obtained. By solving a series of linear matrix inequalities (LMIs), some sufficient conditions for FTS of the stochastic system are found. Moreover, FTS is presented for a stochastic nominal system. Lastly, the validity and improvement of the proposed methods are shown with two simulation examples.

Emperipolesis mediated by CD8+ T cells correlates with biliary epithelia cell injury in primary biliary cholangitis.

Primary biliary cholangitis (PBC) is an autoimmune disease characterized by chronic destruction of the bile ducts. A major unanswered question regarding the pathogenesis of PBC is the precise mechanisms of small bile duct injury. Emperipolesis is one of cell-in-cell structures that is a potential histological hallmark associated with chronic hepatitis B. This study aimed to clarify the pathogenesis and characteristics of emperipolesis in PBC liver injury. Sixty-six PBC patients, diagnosed by liver biopsy combined with laboratory test, were divided into early-stage PBC (stages I and II, n = 39) and late-stage PBC (stages III and IV, n = 27). Emperipolesis was measured in liver sections stained with haematoxylin-eosin. The expressions of CK19, CD3, CD4, CD8, CD20, Ki67 and apoptosis of BECs were evaluated by immunohistochemistry or immunofluorescence double labelling. Emperipolesis was observed in 62.1% of patients with PBC, and BECs were predominantly host cells. The number of infiltrating CD3+ and CD8+ T cells correlated with the advancement of emperipolesis (R2  = 0.318, P < .001; R2  = 0.060, P < .05). The cell numbers of TUNEL-positive BECs and double staining for CK19 and Ki67 showed a significant positive correlation with emperipolesis degree (R2  = 0.236, P < .001; R2  = 0.267, P < .001). We conclude that emperipolesis mediated by CD8+ T cells appears to be relevant to apoptosis of BEC and thus may aggravate the further injury of interlobular bile ducts.

Kinetic Resolution of P-Chiral Phosphindole Oxides through Rhodium-Catalyzed Asymmetric Arylation.

Highly efficient kinetic resolution of P-chiral phosphindole oxides via rhodium-catalyzed asymmetric arylation under mild conditions is described. Selectivity factors of up to 569 were achieved by employing chiral diene* as a ligand. The transformation of the enantiopure benzophosphole derivative into a useful P-chiral bisphosphine ligand is also demonstrated.

Rhodium-Catalyzed Asymmetric Addition to 4- or 5-Carbonyl-cycloenones through Dynamic Kinetic Resolution: Enantioselective Synthesis of (-)-Cannabidiol.

The reaction of 4/5-carbonyl-cycloalkenone 1 or its achiral isomer 1' with organoboronic acid 2 in the presence of a chiral diene (S,S)-Fc-tfb-rhodium catalyst gave disubstituted trans-cycloalkanone 3 with high diastereo- and enantioselectivity. This highly efficient dynamic kinetic resolution is achieved by fast racemization of 1 through the formation of a dienolate followed by kinetic resolution with the chiral catalyst. The utility is demonstrated by the synthesis of key intermediates en route to (-)-cannabidiol.

Advanced navigation technology enables endobronchial brachytherapy for peripheral lung cancer: An old technique plays a new role.

PURPOSE: To investigate the feasibility of super-selectively endobronchial brachytherapy in the treatment of peripheral lung cancer guided by advanced navigation technology. METHODS AND MATERIALS: Six patients with peripheral lung tumors successfully underwent treatment with super-selectively endobronchial brachytherapy guided by advanced navigation technology following pathway planning and were subsequently followed up to assess survival and treatment-related toxicities. RESULTS: The endobronchial applicators were successfully placed inside the tumors of all patients using advanced navigation techniques according to the pretreatment plan, and brachytherapy was delivered at curative doses after evaluation using radiotherapy planning software. None of the patients showed local progression of the treated lesions during the follow-up for a duration ranging from 11 months to 35 months, with a median follow-up time of 23 months. The patient with the longest follow-up, nearly 3 years, exhibited a stable condition. After undergoing endobronchial brachytherapy, patients predominantly experienced localized fibrosis as indicated. No significant alterations in cardiopulmonary function were detected during the follow-up, and no other adverse effects were found. CONCLUSIONS: The use of endobronchial brachytherapy for the curative treatment of peripheral lung cancers is feasible. Furthermore, the development of novel bronchial navigation techniques has the potential to broaden the application of endobronchial brachytherapy.

Activation of peroxisome proliferator activated receptor alpha ameliorates ethanol mediated liver fibrosis in mice.

BACKGROUND: Peroxisome proliferator activated receptor alpha (PPARα) ameliorates ethanol induced hepatic steatohepatitis. However, its role in alcoholic liver fibrosis has not been fully clarified. The aim of this study was to elucidate the effect and the molecular basis of PPARα in ethanol induced liver fibrosis in mice. METHODS: C57BL/6J mice were fed with 4% ethanol-containing Lieber-DeCarli liquid diet for eight weeks, and intraperitoneal injected with 5% carbon tetrachloride (CCl4) for the last four weeks to induce alcoholic liver fibrosis. PPARα agonist WY14643 was administered to mice during the last couple of weeks. The effects of PPARα induction on liver histology, activation of hepatic stellate cells (HSCs), as well as hepatic expression of inflammatory and fibrogenic factors were assessed. RESULTS: The ethanol plus CCl4 treated mice exhibited progressive liver injury including piecemeal necrosis of hepatocytes, severe inflammatory cells infiltration and bridging fibrosis. This was accompanied by down-regulated hepatic expression of PPARα and the protective cytokines adiponectin, heme oxygenase-1 and interleukin-10. Additionally, up-regulation of the proinflammatory cytokine tumor necrosis factor-alpha, as well as the profibrogenic genes osteopontin, transforming growth factor-beta 1, visfatin, phosphatidylinositol 3-kinase, matrix metalloproteinase-2 (MMP-2) and MMP-9 was observed. WY14643 treatment restored expression of cytokines altered by ethanol plus CCl4 treatment and concomitantly ameliorated the liver injury. CONCLUSIONS: The present study provides evidence for the protective role of PPARα induction in ameliorating ethanol mediated fibrosis through mediation of inflammatory and fibrogenic factors.

Fuzheng Huayu recipe prevents nutritional fibrosing steatohepatitis in mice.

BACKGROUND: Fuzheng Huayu recipe (FZHY), a compound of Chinese herbal medicine, was reported to improve liver function and fibrosis in patients with hepatitis B virus infection. However, its effect on nutritional fibrosing steatohepatitis is unclear. We aimed to elucidate the role and molecular mechanism of FZHY on this disorder in mice. METHODS: C57BL/6 J mice were fed with methionine-choline deficient (MCD) diet for 8 weeks to induce fibrosing steatohepatitis. FZHY and/or heme oxygenase-1 (HO-1) chemical inducer (hemin) were administered to mice, respectively. The effect of FZHY was assessed by comparing the severity of hepatic injury, levels of hepatic lipid peroxides, activation of hepatic stellate cells (HSCs) and the expression of oxidative stress, inflammatory and fibrogenic related genes. RESULTS: Mice fed with MCD diet for 8 weeks showed severe hepatic injury including hepatic steatosis, necro-inflammation and fibrosis. Administration of FZHY or hemin significantly lowered serum levels of alanine aminotransferase, aspartate aminotransferase, reduced hepatic oxidative stress and ameliorated hepatic inflammation and fibrosis. An additive effect was observed in mice fed MCD supplemented with FZHY or/and hemin. These effects were associated with down-regulation of pro-oxidative stress gene cytochrome P450 2E1, up-regulation of anti-oxidative gene HO-1; suppression of pro-inflammation genes tumor necrosis factor alpha and interleukin-6; and inhibition of pro-fibrotic genes including α-smooth muscle actin, transforming growth factor beta 1, collagen type I (Col-1) and Col-3. CONCLUSIONS: Our study demonstrated the protective role of FZHY in ameliorating nutritional fibrosing steatohepatitis. The effect was mediated through regulating key genes related to oxidative stress, inflammation and fibrogenesis.

Synthesis of 1,4-benzoxazines via Y(OTf)3-catalyzed ring opening/annulation cascade reaction of benzoxazoles with propargylic alcohols.

A convenient Y(OTf)3-catalyzed cascade formal [4 + 2] cyclization approach for the formation of 1,4-benzoxazine scaffolds from benzoxazoles and propargyl alcohols through a ring-opening and regioselective ring-closure process has been developed. By using this mild and practical protocol, a broad range of aldehyde-containing 1,4-benzoxazine compounds were prepared in moderate to excellent yields with good functional group tolerance. Mechanistic studies indicated that an SN1 nucleophilic substitution of benzoxazole with a propargyl cation was involved in this transformation.

lncRNA MSC-AS1 Aggravates Diabetic Nephropathy by Regulating the miR-325/CCNG1 Axis.

BACKGROUND: Diabetic nephropathy (DN) is the most common microvascular complication of diabetes and has become the second leading cause of end-stage renal disease in the world. This study aims to clarify the regulatory mechanism of the lncRNA MSC-AS1/miR-325/cyclin G1 (CCNG1) axis in DN. METHODS: The regulatory mechanism of lncRNA MSC-AS1/miR-325/CCNG1 was evaluated by RT-qPCR, CCK-8 assay, flow cytometry assay, RNA pull-down assay, ELISA, and western blot assay. RESULTS: Upregulation of lncRNA MSC-AS1 was detected in DN patients and HRMC cells treated with high glucose (HG). Knockdown of lncRNA MSC-AS1 reduced the proliferation, fibrosis, and inflammation of HRMC cells induced by HG. In addition, lncRNA MSC-AS1 acts as a miR-325 sponge in the DN. CCNG1 is the direct target of miR-325, which can be positively regulated by lncRNA MSC-AS1 in DN. More importantly, downregulation of miR-325 and upregulation of CCNG1 can attenuate the protective effect of lncRNA MSC-AS1 knockdown on DN. CONCLUSION: lncRNA MSC-AS1 aggravates DN by downregulating miR-325 and upregulating CCNG1.

Geographic Distribution of HCV Genotypes and Efficacy of Direct-Acting Antivirals in Chronic HCV-Infected Patients in North and Northeast China: A Real-World Multicenter Study.

Objective: To assess the geographic distribution of HCV genotypes, effectiveness, and safety of DAA treatment for HCV-infected patients in North and Northeast China. Methods: The geographic distribution of HCV genotypes was analyzed in 2162 patients recruited from April 2018 to February 2021. Sustained virologic response rates at 12 (SVR12) or 24 (SVR24) weeks posttreatment and safety were analyzed in 405 patients who completed DAA treatment according to patient baseline characteristics and treatment. Results: Four genotypes and six subtypes were identified as follows: 1b (1187, 54.90%), 2a (790, 36.54%), 3a/b (134, 6.20%), 6a/n (44, 2.04%), mixed genotypes (2a-6a or 2a-3a) (7, 0.32%). Overall, 99.01% patients achieved SVR12, while 98.43% achieved SVR24. All patients treated with elbasvir/grazoprevir (EBR/GZR), sofosbuvir/velpatasvir ± ribavirin (SOF/VEL ± RBV), and SOF/ledipasvir (LDV) achieved SVR12 or SVR24; 92.86% SVR12 and 95.83% SVR24 were observed in patients using SOF + RBV. SVR12 was higher in noncirrhosis versus compensated cirrhosis patients (100% vs. 97.09%, p=0.022). No severe drug-related adverse event was observed. Conclusions: Genotypes 1b and 2a were dominant subtypes in North and Northeast China. The approved drug regimens EBR/GZR and SOF/LDV for subtype 1b and SOF/VEL for nongenotype 1b are the optimal effective and safety profile.

Identification and Validation of Novel Biomarkers for Hepatocellular Carcinoma, Liver Fibrosis/Cirrhosis and Chronic Hepatitis B via Transcriptome Sequencing Technology.

Purpose: The aim of this study was to identify and validate novel biomarkers for distinguishing among hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), liver fibrosis/liver cirrhosis (LF/LC) and chronic hepatitis B (CHB). Patients and Methods: Transcriptomic sequencing was conducted on the liver tissues of 5 patients with HCC, 5 patients with LF/LC, 5 patients with CHB, and 4 healthy controls. The expression levels of selected mRNAs and proteins were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemical (IHC) staining, and were verified in validation set (n=200) and testing set (n=400) via enzyme-linked immunosorbent assay (ELISA). Results: A total of 9 hub mRNAs were identified by short time-series expression miner and weighted gene co-expression network analysis. Of note, the results of qRT-PCR and IHC staining demonstrated that SHC adaptor protein 1 (SHC1), SLAM family member 8 (SLAMF8), and interleukin-32 (IL-32) exhibited gradually increasing trends in the four groups. Subsequent ELISA tests on the validation cohort indicated that the plasma levels of SHC1, SLAMF8 and IL-32 also gradually increased. Furthermore, a diagnostic model APFSSI (age, PLT, ferritin, SHC1, SLAMF8 and IL-32) was established to distinguish among CHB, LF/LC and HCC. The performance of APFSSI model for discriminating CHB from healthy subjects (AUC=0.966) was much greater compared to SHC1 (AUC=0.900), SLAMF8 (AUC=0.744) and IL-32 (AUC=0.821). When distinguishing LF/LC from CHB, APFSSI was the most outstanding diagnostic parameter (AUC=0.924), which was superior to SHC1, SLAMF8 and IL-32 (AUC=0.812, 0.684 and 0.741, respectively). Likewise, APFSSI model with the greatest AUC value displayed an excellent performance for differentiating between HCC and LF/LC than other variables (SHC1, SLAMF8 and IL-32) via ROC analysis. Finally, the results in the test set were consistent with those in the validation set. Conclusion: SHC1, SLAMF8 and IL-32 can differentiate among patients with HCC, LF/LC, CHB and healthy controls. More importantly, the APFSSI model greatly improves the diagnostic accuracy of HBV-associated liver diseases.

Peginterferon alpha-based therapy for chronic hepatitis B focusing on HBsAg clearance or seroconversion: a meta-analysis of controlled clinical trials.

BACKGROUND: Interferon alpha (IFNα) therapy has been widely used in the treatment of chronic hepatitis B (CHB) for decades. Nucleos(t)ide analogues are also increasingly used to treat CHB recently. More and more studies are being carried out concerning the clearance or seroconversion of HBsAg, which is recognized as an ideal goal of CHB therapy. This study conducted a meta-analysis to estimate the effect of pegylated interferon alpha (peginterferon α, PEG-IFNα)-based therapy on HBsAg clearance or seroconversion in CHB. METHODS: All available controlled clinical trials, published from 2004 to 2010, with the following antiviral therapies for CHB patients: PEG-IFNα combined with lamivudine (LAM), PEG-IFNα only, conventional IFNα and LAM, with a course ≥24 weeks, were meta-analysed for HBsAg clearance and seroconversion. RESULTS: Fourteen trials (involving a total of 2,682 patients) were identified, including seven high-quality and seven low-quality studies. The analysis results of the different antiviral therapies on HBsAg clearance or seroconversion were as follows: 1. No significant difference in HBsAg clearance or seroconversion was observed between the combination therapy group and PEG-IFNα monotherapy group [odds ratio (OR) = 1.16, 95% confidence intervals (CI) (0.73-1.85), P = 0.54 and OR = 1.07, 95% CI (0.58-1.97), P = 0.82, respectively]; 2. HBsAg clearance and seroconversion rates in patients with combination therapy were markedly higher than in those with LAM monotherapy [OR = 9.41, 95% CI (1.18-74.94), P = 0.03, and OR = 12.37, 95% CI (1.60-95.44), P = 0.02, respectively]; 3. There was significant difference in HBsAg clearance between the PEG-IFNα group and IFNα monotherapy group [OR = 4.95, 95% CI (1.23-20.00), P = 0.02], but not in seroconversion [OR = 2.44, 95% CI (0.35-17.08), P = 0.37]; 4. PEG-IFNα was superior to LAM in HBsAg seroconversion [OR = 14.59, 95% CI (1.91-111.49), P = 0.01]. CONCLUSIONS: PEG-IFNα facilitated HBsAg clearance or seroconversion in CHB patients. PEG-IFNα-based therapy was more effective than LAM monotherapy in achieving HBsAg clearance or seroconversion for both HBeAg-positive and HBeAg-negative CHB patients. There was no significant difference in HBsAg clearance or seroconversion between PEG-IFNα/LAM combination therapy and PEG-IFNα monotherapy. PEG-IFNα was obviously superior to conventional IFNα in HBsAg clearance, but not in HBsAg seroconversion. Although PEG-IFNα produced significantly higher rates of HBsAg clearance and seroconversion, the absolute change in the proportion of HBsAg clearance and seroconversion was low (about 3-6%). Therefore, additional interventions are needed to improve the rate of positive outcomes.

Activation of peroxisome proliferator activated receptor alpha ameliorates ethanol induced steatohepatitis in mice.

BACKGROUND: Peroxisome proliferator activated receptor alpha (PPARα) regulates lipids metabolism and inhibits inflammatory response. However, the role of PPARα in alcoholic liver disease is largely unknown. We aim to elucidate the effect and the molecular basis of PPARα in ethanol induced hepatic injury in mice. RESULTS: C57BL/6J mice fed with 4% ethanol-containing Lieber-DeCarli liquid diet for 12 weeks exhibited hepatocyte steatosis, necrosis and inflammatory infiltration, accompanied with elevated serum alanine aminotransferase (ALT) and aspartic transaminase (AST) levels, decreased hepatic expression of PPARα, lipids oxidation promoting genes and anti-inflammatory factors, as well as enhanced hepatic expression of fatty acids synthesis promoting genes and pro-inflammatory cytokines. Induction of PPARα by PPARα agonist WY14643 treatment for 2 weeks ameliorated the severity of liver injury and restored expression of genes altered by ethanol treatment. However, administration of PPARα antagonist GW6471 for 2 weeks promoted the inflammatory response. CONCLUSIONS: The present study provided the evidence for the protective role of PPARα in ameliorating ethanol induced liver injury through modulation of the genes related to lipid metabolism and inflammatory response.

A correlation analysis of the serum hepcidin concentrations and viral loads in HCV-infected patients.

OBJECTIVE: To investigate the correlation between the serum hepcidin levels and the viral loads in hepatitis C virus (HCV) infected patients. METHODS: Sixty HCV-infected patients (the study group) and 50 healthy controls (the control group) were recruited as the study cohort. The liver function and inflammation-related parameters were compared, and the 60 HCV patients were divided into mild (G1-G2), moderate (G3), and severe (G4) groups according to each patient's inflammatory activity grade (G). The serum iron (SI), ferritin (SF), and transferrin (TRF), hepcidin levels were compared. The relationships between the HCV-RNA, HCV Ag, HCV Ab, albumin (ALB), total bilirubin (TBIL), aminotransferase (ALT), and aspartate aminotransferase (AST) levels and the hepcidin levels was analyzed. The SI, SF, IL-6, ALT, AST, and TBIL levels were significantly higher, and the hepcidin, TRF, and ALB levels were significantly lower in the study group than they were in the control group (P<0.05). The G4 patients' SI and SF levels were significantly higher than they were in the G3 and the G1-G2 groups (P<0.05). The TRF and hepcidin levels in the G1-G2 group were significantly higher than they were in the G3 and G4 groups (P<0.05). The HCV-RNA, HCV Ag, and HCV Ab levels were negatively correlated with the hepcidin levels (r=-0.7679, r=-0.9062, r=-0.6095, P<0.05), positively correlated with the serum ALB, TBIL, and ALT levels (r=0.9792, r=0.9759, r=0.8236, P<0.05), and not significantly correlated with the AST levels (r=-0.2803, P>0.05). CONCLUSION: The HCV patients' serum hepcidin levels showed an abnormal decrease, suggesting that HCV patients may have an iron metabolism disorder, which indicates that there is a possibility of evaluating the HCV patients' conditions by measuring the hepcidin levels and of improving HCV patients' prognoses by regulating the iron metabolism.

Traditional Chinese medicine Yiqi Huoxue recipe attenuates hepatic fibrosis via YAP/TAZ signaling.

BACKGROUND/AIMS: The Yiqi Huoxue (YQHX) recipe has been shown to attenuate liver fibrosis, but precise mechanisms have not yet been elucidated. Recently, Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) signaling has been implicated in liver fibrogenesis. This study investigated whether the YAP/TAZ signaling is involved in the therapeutic effect of YQHX on hepatic fibrosis. MATERIALS AND METHODS: Wistar rats were used to generate a model of carbon tetrachloride (CCl4)-induced liver fibrosis. Chronic hepatitis B (CHB) patients with liver fibrosis were enrolled and assigned to receive either nucleoside/nucleotide analogues (NAs) or NAs plus YQHX. Histology, immunohistochemistry, qRT-PCR, and western blotting were conducted to mechanistically assess the therapeutic effects of YQHX on liver fibrosis. RESULTS: YQHX markedly alleviated morphological alterations in CCl4-induced liver fibrosis and decreased markers of hepatic fibrosis in rats. Furthermore, YQHX significantly suppressed CCl4-meidated activation of the transforming growth factor-beta (TGF-ß)/Smad signaling pathway. Notably, CCl4 induced up-regulation of YAP, TAZ, and connective tissue growth factor (CTGF), which were significantly abrogated by YQHX. Consistent with the above major findings in rats, CHB patients treated with NAs plus YQHX had greater improvement in liver fibrosis than those given NAs alone (71.4% vs. 28.6%; P = 0.057). In addition, hepatic and plasma levels of YAP were significantly decreased after YQHX treatment in CHB patients with liver fibrosis. CONCLUSION: YAP/TAZ signaling plays a role, at least in part, in the anti-fibrotic activity of YQHX. The findings may help to better understand the mechanisms of YQHX in the treatment of liver fibrosis.

Co-administration of obeticholic acid and simvastatin protects against high-fat diet-induced non-alcoholic steatohepatitis in mice.

Non-alcoholic steatohepatitis (NASH) has no approved therapy. The farnesoid X nuclear receptor (FXR) agonist obeticholic acid (OCA) has shown promise as a drug for NASH, but can adversely affect plasma lipid profiles. Therefore, the present study aimed to investigate the effects and underlying mechanisms of OCA in combination with simvastatin (SIM) in a high-fat diet (HFD)-induced model of NASH. C57BL/6J mice were fed with a HFD for 16 weeks to establish the NASH model. The mice were randomly divided into the following five groups: HFD, HFD + OCA, HFD + SIM, HFD + OCA + SIM and control. After 16 weeks, the mice were sacrificed under anesthesia. The ratios of liver weight to body weight (Lw/Bw) and of abdominal adipose tissue weight to body weight were calculated. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol, triglycerides and low-density lipoprotein were measured. Liver sections were stained with hematoxylin and eosin. The protein levels of FXR, small heterodimeric partner (SHP) and cytochrome P450 family 7 subfamily A member 1 (CYP7A1) in the liver were detected by western blotting, while the mRNA levels of FXR, SHP, CYP7A1, bile salt export pump, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), sterol regulatory element binding protein-1 (SREBP1) and fatty acid synthase (FASN) were examined by reverse transcription-quantitative polymerase chain reaction. The administration of OCA with or without SIM reduced the liver inflammation score compared with those of the HFD and HFD + SIM groups, with no significant difference between the HFD + OCA and HFD + OCA + SIM groups. The steatosis score followed similar trends to the inflammation score. In HFD-fed mice, OCA combined with SIM prevented body weight gain compared with that in HFD and HFD + OCA groups, and reduced the Lw/Bw ratio compared with that in the HFD and HFD + SIM groups. In addition to preventing HFD-induced increases of ALT and AST, the combination of OCA and SIM reduced the mRNA levels of IL-6, TNF-α, SREBP1 and FASN. On the basis of these results, it may be concluded that the strategy of combining OCA with SIM represents an effective pharmacotherapy for NASH.

Hepatic Macrophage activation and the LPS pathway in patients with different degrees of severity and histopathological patterns of drug induced liver injury.

BACKGROUND: Inflammatory activation of hepatic macrophages plays a primary role in drug-induced liver injury (DILI). However, the exact mechanism underlying DILI remains unclear. METHODS: A total of 328 DILI patients and 80 healthy individuals were prospectively enrolled in this study. The DILI patients were categorized into subgroups based on either disease severity or histopathological patterns. Plasma soluble CD163 (sCD163) and hepatic CD163 were examined to determine hepatic macrophage activation, and CD8, CD20, and MUM-1 were assessed to determine cellular immunity using immunohistochemistry. The lipopolysaccharide (LPS) pathway proteins [e.g. LPS, soluble CD14 (sCD14), and LPS-binding protein (LBP)] were measured using enzyme-linked immunosorbent assay. RESULTS: Plasma sCD163 levels were nine-fold higher in DILI patients than in healthy controls at the baseline, but significantly decreased at the 4-week follow-up visit after treatment. The numbers of hepatic macrophages, B cells, and plasma cells were significantly higher in the liver tissues from DILI patients than those from healthy controls. Furthermore, the baseline levels of LPS pathway proteins in the DILI patients were significantly higher than those in the controls. Notably, these proteins significantly decreased at the 4-week follow-up visit but remained significantly higher than the levels for the controls. CONCLUSIONS: Hepatic inflammation in DILI involves the activation of hepatic macrophages and cellular immunity, in which the LPS pathway likely plays a role, at least in part. As such, this study has improved our understanding of the pathological mechanisms for DILI and may facilitate the development of better treatments for patients with DILI.

Yiqi Huoxue Recipe Improves Liver Regeneration in Rats after Partial Hepatectomy via JNK Pathway.

The liver is the only visceral organ that exhibits a remarkable capability of regenerating in response to partial hepatectomy (PH) or chemical injury. Improving liver regeneration (LR) ability is the basis for the favourable treatment outcome of patients after PH, which can serve as a potential indicator for postoperative survival. The present study aimed to investigate the protective effects of Yiqi Huoxue recipe (YQHX) on LR after PH in rats and further elucidate its underlying mechanism. A two-thirds PH rat model was used in this study. Wistar rats were randomly divided into four groups: sham-operated, PH, YQHX + PH, and Fuzheng Huayu decoction (FZHY) + PH groups. All rats were sacrificed under anesthesia at 24 and 72 h after surgery. The rates of LR were calculated, and the expression levels of cyclin D1 and c-jun were determined by immunohistochemical staining. The protein levels of p-JNK1/2, JNK1/2, p-c-jun, c-jun, Bax, and Bcl-2 were detected by Western blotting, while the mRNA levels of JNK1, JNK2, c-jun, Bax, and Bcl-2 were examined by real-time polymerase chain reaction (RT-PCR). At the corresponding time points, YQHX and FZHY administration dramatically induced the protein levels of p-JNK1/2 compared to the PH group (p < 0.05), while FZHY + PH group showed prominently increase in p-JNK1/2 protein levels compared to the YQHX + PH group (p < 0.05). A similar trend was observed for the expression levels of p-c-jun. Compared to the PH group, YQHX and FZHY markedly reduced the mRNA and protein expression levels of Bax at 24 h after PH, while those in the FZHY + PH group decreased more obviously (p < 0.05). Besides, in comparison with the PH group, YQHX and FZHY administration predominantly upregulated the mRNA and protein expression levels of Bcl-2 at 24 and 72 h after PH (p < 0.05). In conclusion, YQHX improves LR in rats after PH by inhibiting hepatocyte apoptosis via the JNK signaling pathway.

Glutamate-Cysteine Ligase Catalytic Subunit Attenuated Hepatitis C Virus-Related Liver Fibrosis and Suppressed Endoplasmic Reticulum Stress.

The study aimed to clarify the role and molecular mechanism of glutamate-cysteine ligase catalytic subunit (GCLC) in modulating Hepatitis C virus (HCV)-related liver fibrosis. Twenty patients with HCV-related liver fibrosis and 15 healthy controls were enrolled. Differentially expressed plasma mRNAs were detected by digital gene expression profile analysis and validated by qRT-PCR. Hepatic histopathology was observed by H&E and Masson stained liver sections. The mRNA and protein expression of GCLC, endoplasmic reticulum (ER) stress markers, and inflammatory and fibrogenic factors were detected in liver tissues from patients with HCV-related hepatic fibrosis and HCV core protein-expressing LX-2. The GCLC-overexpressing LX-2 were established by transfecting puc19-GCLC plasmid. Then, glutathione and reactive oxygen species (ROS) levels were measured respectively by spectrophotometric diagnostic kit and dihydrodichlorofluorescein diacetate kit. GCLC were dramatically down-regulated in HCV-related fibrotic livers and activated HSCs, which companied with up-regulation of ER stress-related genes, including inositol-requiring 1 (IRE1) and glucose-regulated protein 78 (GRP78). Also, the proinflammatory and profibrogenic gene, including nuclear factor kappa B (NF-κB), tumor necrosis factor α (TNFα), and transforming growth factor 1(TGFß1), was highly upregulated. Overexpression of GCLC in hepatic stellate cells could suppress α-SMA and collagen I expression, produce hepatic GSH and reduce ROS, and down-regulate IRE1, GRP78, NF-κB, TNF-α, and TGFß1 expression. GCLC was a negative regulatory factor in the development of HCV-related liver fibrosis and might be a potential therapeutic target for liver fibrosis.