CXCR5+ CD4+ T follicular helper cells participate in the pathogenesis of primary biliary cirrhosis.

UNLABELLED: There is increasing interest in the role of T follicular helper (Tfh) cells in autoimmunity from the perspective of both their role in breach of tolerance and their effects on the natural history of disease progression. Indeed, the critical role of Tfh cells in autoimmunity is further highlighted based on their location in the germinal center (GC), a pathogenic hot spot for development of autoreactivity. To address the role of Tfh cells in primary biliary cirrhosis (PBC), we comprehensively evaluated the immunobiology of CXCR5(+) CD4(+) Tfh cells in 69 patients with PBC, including a nested subgroup of 16 autoimmune hepatitis (AIH) and 20 healthy controls (HC), followed for 1 year. We report herein several key observations. First, there was an increased frequency of circulating Tfh cells in patients with PBC compared to AIH (P < 0.05) and HC (P < 0.01). Second, the function of circulating Tfh cells from PBC patients, including interleukin (IL)-21 production (P < 0.05), the ability to promote B-cell maturation, and autoantibody production, were greater than HC. Third, the frequency of these cells was significantly decreased in ursodeoxycholic acid (UDCA) responders compared to UDCA-treated nonresponders, in both cross-sectional (P = 0.023) and longitudinal studies (P = 0.036), respectively. Indeed, similar increases of Tfh cells were noted in liver and spleen. CONCLUSION: These results significantly extend our understanding of lymphoid subpopulations in PBC and their relative role in disease expression. Our data also provide a novel biomarker for evaluation of the effectiveness of new therapeutic approaches.

Upregulation of OX40 ligand on monocytes contributes to early virological control in patients with chronic hepatitis C.

Dysfunctional hepatitis C virus (HCV) specific CD4(+) T cells are known to contribute to inadequate adaptive immunity in chronic hepatitis C (CHC), although the underlying mechanisms remain largely undefined. In this study, OX40 ligand (OX40L) expression was investigated in 41 treatment-naïve CHC patients, 20 sustained virological responders and 36 healthy subjects. We observed that OX40L expression was significantly upregulated in peripheral monocytes in CHC patients compared with sustained virological responders and healthy subjects. OX40L upregulation correlated significantly with plasma viral load rather than serum alanine aminotransaminase levels. Furthermore, longitudinal analyses indicated that upregulated OX40L expression on monocytes is closely associated with rapid or early virological responses in patients receiving pegylated IFN-α/ribavirin treatment. In vitro, HCV core antigen strongly stimulated monocyte expression of OX40L and blockade of TLR2 signaling significantly downregulated OX40L expression. More importantly, elevated OX40L expression was also shown to be closely associated with elevation of the HCV-specific CD4(+) T-cell response and in vitro blockade of OX40L expressed on monocytes led to impaired CD4(+) T-cell function. These findings, therefore, implicate OX40L expression can be used as a marker to evaluate antiviral treatment efficacy and extend the notion that enhancement of OX40L expression could be a good way for immunotherapy in CHC patients.

Interleukin-21 mediates hepatitis B virus-associated liver cirrhosis by activating hepatic stellate cells.

AIM: Interleukin-21 (IL-21) is involved in effective primary hepatic immune response against hepatitis B virus (HBV) and profibrotic function. However, the role of IL-21 in HBV-associated liver cirrhosis is poorly understood. This study aimed to investigate the role of IL-21 in HBV-associated liver cirrhosis and possible mechanisms. METHODS: The study subjects included 10 healthy controls and 30 patients with HBV-associated liver cirrhosis that categorized into three subgroups based on Child-Pugh score (A, 13; B, 10; C, 7). The frequencies of IL-21(+) CD4(+) T cells were detected by flow cytometry, and the level of IL-21 in plasma was measured by enzyme-linked immunoassay. The distribution of IL-21(+) cells in situ in liver was observed by immunohistochemistry. In addition, the in vitro expression of α-smooth muscle actin (α-SMA), apoptosis and proliferation markers of LX-2 cells were examined by flow cytometry and Cell Counting Kit-8 kit. Finally, the collagen levels in the supernatant were measured by chemiluminescence. RESULTS: Increased peripheral number of IL-21(+) CD4(+) cells, elevated plasma level of IL-21 and IL-21(+) cell accumulation in liver were observed in patients with HBV-associated liver cirrhosis. In vitro administration of IL-21 was accompanied with increased expression of α-SMA, inhibited LX-2 cells apoptosis and upregulated collagen production by LX-2 cells. CONCLUSION: IL-21 may contribute to the fibrogenesis of HBV-associated liver cirrhosis by activating the hepatic stellate cells. Therefore, neutralization of IL-21 could be a favorable new therapeutic strategy for liver cirrhosis treatment.

Interleukin-33 promotes disease progression in patients with primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is a progressive autoimmune liver disease that can cause a series of complications, including cirrhosis, liver failure and hepatocellular carcinoma. Interleukin-33 (IL-33) is expressed in various non-hematopoietic cells and a certain population of immune cells, and exerts its biological effects by binding to the specific receptor, suppression of tumorigenicity 2 (ST2). A soluble form of ST2 (sST2) has been postulated to act as a decoy receptor for IL-33. In this study, we aimed to investigate the role of IL-33 in the pathogenesis of PBC. The study included 20 healthy controls and 68 patients with PBC. We thus found the increased serum IL-33 levels in PBC patients. Its elevated levels were positively correlated with serum alkaline phosphatase levels (a key parameter for the definition of PBC) and with Child-Pugh scores, which were used to determine the prognosis of liver cirrhosis. Moreover, the serum concentrations of sST2 were significantly higher in PBC patients compared with healthy subjects, irrespective of the disease severity. Importantly, the cells that express IL-33 and/or myeloperoxidase (a marker for neutrophils) were accumulated in the livers of PBC patients, and their number increased with the severity of liver lesions. Lastly, in vitro chemotaxis assays revealed that IL-33 enhanced the migration of neutrophils. These data suggest that IL-33 may affect the progress of PBC by recruiting neutrophils to the liver. This expanded knowledge of IL-33 in PBC patients is important for developing therapeutic strategies (e.g., neutralization of IL-33), selecting optimal clinical management, and predicting prognosis.

Development of a new Cox model for predicting long-term survival in hepatitis cirrhosis patients underwent transjugular intrahepatic portosystemic shunts.

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) placement is a procedure that can effectively treat complications of portal hypertension, such as variceal bleeding and refractory ascites. However, there have been no specific studies on predicting long-term survival after TIPS placement. AIM: To establish a model to predict long-term survival in patients with hepatitis cirrhosis after TIPS. METHODS: A retrospective analysis was conducted on a cohort of 224 patients who underwent TIPS implantation. Through univariate and multivariate Cox regression analyses, various factors were examined for their ability to predict survival at 6 years after TIPS. Consequently, a composite score was formulated, encompassing the indication, shunt reasonability, portal venous pressure gradient (PPG) after TIPS, percentage decrease in portal venous pressure (PVP), indocyanine green retention rate at 15 min (ICGR15) and total bilirubin (Tbil) level. Furthermore, the performance of the newly developed Cox (NDC) model was evaluated in an internal validation cohort and compared with that of a series of existing models. RESULTS: The indication (variceal bleeding or ascites), shunt reasonability (reasonable or unreasonable), ICGR15, postoperative PPG, percentage of PVP decrease and Tbil were found to be independent factors affecting long-term survival after TIPS placement. The NDC model incorporated these parameters and successfully identified patients at high risk, exhibiting a notably elevated mortality rate following the TIPS procedure, as observed in both the training and validation cohorts. Additionally, in terms of predicting the long-term survival rate, the performance of the NDC model was significantly better than that of the other four models [Child-Pugh, model for end-stage liver disease (MELD), MELD-sodium and the Freiburg index of post-TIPS survival]. CONCLUSION: The NDC model can accurately predict long-term survival after the TIPS procedure in patients with hepatitis cirrhosis, help identify high-risk patients and guide follow-up management after TIPS implantation.

Pilot study of umbilical cord-derived mesenchymal stem cell transfusion in patients with primary biliary cirrhosis.

BACKGROUND AND AIM: Ursodeoxycholic acid (UDCA) treatment is an effective medical therapy for patients with primary biliary cirrhosis (PBC); however, 40% of PBC patients show an incomplete response to the UDCA therapy. This study aimed to investigate the safety and efficacy of umbilical cord-derived mesenchymal stem cell (UC-MSC) transfusion in PBC patients with an incomplete response to UDCA. METHODS: We conducted a single-arm trial that included seven PBC patients with a suboptimal response to UDCA treatment. UC-MSCs were first cultured, and then 0.5 × 10(6) cells/kg body weights were infused through a peripheral vein. UC-MSCs were given three times at 4-week intervals, and patients were followed up for 48 weeks. Primary outcomes were to evaluate the safety and feasibility of UC-MSC treatment, and secondary outcomes were to evaluate liver functions and patient's quality of life. RESULTS: No obvious side-effects were found in the patients treated with UC-MSCs. Symptoms such as fatigue and pruritus were obviously alleviated in most patients after UC-MSC treatment. There was a significant decrease in serum alkaline phosphatase and γ-glutamyltransferase levels at the end of the follow-up period as compared with baseline. No significant changes were observed in serum alanine aminotransferase, aspartate aminotransferase, total bilirubin, albumin, prothrombin time activity, international normalized ratio, or immunoglobulin M levels. The Mayo risk score, a prognostic index, was also stable during the treatment and follow-up period. CONCLUSIONS: UC-MSC transfusion is feasible and well tolerated in patients with PBC who respond only partially to UDCA treatment, thus representing a novel therapeutic approach for patients in this subgroup. A larger, randomized controlled cohort study is warranted to confirm the clinical efficacy of UC-MSC transfusion.

Achieving Self-Supported Hierarchical Cu(OH)2/Nickel-Cobalt Sulfide Electrode for Electrochemical Energy Storage.

Herein, nickel-cobalt sulfide (NCS) nanoflakes covering the surface of Cu(OH)2 nanorods were achieved by a facile two-step electrodeposition strategy. The effect of CH4N2S concentration on formation mechanism and electrochemical behavior is investigated and optimized. Thanks to the synergistic effect of the selected composite components, the Cu(OH)2/NCS composite electrode can deliver a high areal specific capacitance (Cs) of 7.80 F cm-2 at 2 mA cm-2 and sustain 5.74 F cm-2 at 40 mA cm-2. In addition, coulombic efficiency was up to 84.30% and cyclic stability remained 82.93% within 5000 cycles at 40 mA cm-2. This innovative work provides an effective strategy for the design and construction of hierarchical composite electrodes for the development of energy storage devices.

Efficient Photodegradation of Rhodamine B by Fiber-like Nitrogen-Doped TiO2/Ni(OH)2 Nanocomposite under Visible Light Irradiation.

N-TiO2/Ni(OH)2 nanofiber was successfully prepared by combining the electrospinning and solvothermal method. It has been found that under visible light irradiation, the as-obtained nanofiber exhibits excellent activity for the photodegradation of rhodamine B, and the average degradation rate reaches 3.1%/min-1. Further insight investigations reveal that such a high activity was mainly due to the heterostructure-induced increase in the charge transfer rate and separation efficiency.

Hierarchical Design of CuO/Nickel-Cobalt-Sulfide Electrode by a Facile Two-Step Potentiostatic Deposition.

Herein, a scalable electrodeposition strategy is proposed to achieve hierarchical CuO/nickel-cobalt-sulfide (NCS) electrodes using two-step potentiostatic deposition followed by high-temperature calcination. The introduction of CuO provides support for the further deposition of NSC to ensure a high load of active electrode materials, thus generating more abundant active electrochemical sites. Meanwhile, dense deposited NSC nanosheets are connected to each other to form many chambers. Such a hierarchical electrode prompts a smooth and orderly transmission channel for electron transport, and reserves space for possible volume expansion during the electrochemical test process. As a result, the CuO/NCS electrode exhibits superior specific capacitance (Cs) of 4.26 F cm-2 at 20 mA cm-2 and remarkable coulombic efficiency of 96.37%. Furthermore, the cycle stability of the CuO/NCS electrode remains at 83.05% within 5000 cycles. The multistep electrodeposition strategy provides a basis and reference for the rational design of hierarchical electrodes to be applied in the field of energy storage.

Facile Route to Achieve a Hierarchical CuO/Nickel-Cobalt-Sulfide Electrode for Energy Storage.

Herein, a novel self-supporting CuO/nickel-cobalt-sulfide (NCS) electrode was designed in a two-step electrodeposition technique followed by a calcination process. Three-dimensional copper foam (CF) was exploited as the current collector and spontaneous source for the in situ preparation of the CuO nanostructures, which ensured sufficient deposition space for the subsequent NCS layer, thus forming abundant electrochemical active sites. Such a hierarchical structure is conducive to providing a smooth path for promoting electronic transmission. Therefore, the optimized CuO/NCS electrode exhibits outstanding energy storage capability with extremely superior specific capacitance (Cs) of 7.08 F cm-2 at 4 mA cm-2 and coulombic efficiency of up to 94.83%, as well as excellent cycling stability with capacitance retention of 83.33% after 5000 cycles. The results presented in this work extend our horizons to fabricate novel hierarchical structured electrodes applied to energy storage devices.

Controllable Synthesis, Formation Mechanism, and Photocatalytic Activity of Tellurium with Various Nanostructures.

Telluriums (Te) with various nanostructures, including particles, wires, and sheets, are controllably synthesized by adjusting the content of polyvinylpyrrolidone (PVP) in a facile solvothermal reaction. Te nanostructures all have complete grain sizes with excellent crystallinity and mesopore structures. Further, the formation mechanisms of Te nanostructures are proposed to be that the primary nuclei of Te are released from the reduction of TeO32- using N2H4·H2O, and then grow into various nanostructures depending on the different content of PVP. These nanostructures of Te all exhibit the photocatalytic activities for the degradation of MB and H2 production under visible light irradiation, especially Te nanosheets, which have the highest efficiencies of degradation (99.8%) and mineralization (65.5%) at 120 min. In addition, compared with pure Te nanosheets, the rate of H2 production increases from 412 to 795 µmol∙h-1∙g-1 after the introduction of Pt, which increases the output by nearly two times. The above investigations indicate that Te with various nanostructures is a potential photocatalyst in the field of degradation of organic pollutants and H2 fuel cells.

Maltitol-Derived Sacrificial Agent for Enhancing the Compatibility between PCE and Cement Paste.

At present, it is known that when there is clay in concrete, polycarboxylates (PCE) will preferably adsorb in the clay, so that PCE cannot be fully combined with cement particles, which reduces the workability of the cement slurry. In this paper, a new type of maltitol-ammonium salt cationic (KN-lm) sacrificial agent (SA) has been successfully developed via a simple method, which makes PCE easier to bond with cement particles in the cement slurry containing clay. The effect of KN-lm on the fluidity of clay-containing cement paste is studied, and the experimental results show that KN-lm, as an efficient SA of cement slurry, makes PCE more compatible with clay-containing cement slurry, and increases the initial fluidity of cement slurry by about 19%. Further investigations of TOC, XRD, and zeta potential measurements reveal that a KN-lm ion is only preferably adsorbed into clay compared to PCE through electrostatic adsorption but without having any crystal structure change, thus resulting in good dispersion of cement particles. The addition of KN-lm plays an important role in hindering the hydration expansion of the clay by preferential electrostatic adsorption, which means PCE cannot easily insert into the interlayer of the clay.

Human umbilical cord mesenchymal stem cells improve liver function and ascites in decompensated liver cirrhosis patients.

Decompensated liver cirrhosis (LC), a life-threatening complication of chronic liver disease, is one of the major indications for liver transplantation. Recently, mesenchymal stem cell (MSC) transfusion has been shown to lead to the regression of liver fibrosis in mice and humans. This study examined the safety and efficacy of umbilical cord-derived MSC (UC-MSC) in patients with decompensated LC. A total of 45 chronic hepatitis B patients with decompensated LC, including 30 patients receiving UC-MSC transfusion, and 15 patients receiving saline as the control, were recruited; clinical parameters were detected during a 1-year follow-up period. No significant side-effects and complications were observed in either group. There was a significant reduction in the volume of ascites in patients treated with UC-MSC transfusion compared with controls (P < 0.05). UC-MSC therapy also significantly improved liver function, as indicated by the increase of serum albumin levels, decrease in total serum bilirubin levels, and decrease in the sodium model for end-stage liver disease scores. UC-MSC transfusion is clinically safe and could improve liver function and reduce ascites in patients with decompensated LC. UC-MSC transfusion, therefore, might present a novel therapeutic approach for patients with decompensated LC.

[Prospective controlled trial of safety of human umbilical cord derived-mesenchymal stem cell transplantation in patients with decompensated liver cirrhosis].

OBJECTIVE: To evaluate the safety of human umbilical cord derived-mesenchymal stem cell (UC-MSC) transplantation therapy in patients with decompensated liver cirrhosis. METHODS: UC-MSCs were transplanted intravenously into patients with decompensated liver cirrhosis. Serum levels of glucose (GLU), total cholesterol (TC), blood urea nitrogen (BUN), alpha fetoprotein (AFP), white blood cells (WBC), and prothrombin activity (PA) were detected at different time points after UC-MSCs transplantation. RESULTS: Most UC-MSC transplanted patients experienced an improvement in quality of life, to varying degrees. With the exception of low-grade fever in a few patients, side effects and oncogenic events were rare (treatment group: 1/38 vs. control group: 1/16; P more than 0.05). The UC-MSCs transplantation showed no effect on GLU, TC, BUN, AFP, WBC, or PA. CONCLUSION: UC-MSCs transplantation in patients with decompensated liver cirrhosis is safe and may improve the patient's quality of life.

Design and Construction of Cu(OH)2/Ni3S2 Composite Electrode on Cu Foam by Two-Step Electrodeposition.

A Cu(OH)2/Ni3S2 composite has been designed and in situ constructed on Cu foam substrate by facile two-step electrodeposition. Cu(OH)2 is achieved on Cu foam by galvanostatic electrodeposition, and the subsequent coating of Ni3S2 is realized by cyclic voltammetric (CV) electrodeposition. The introduction of Cu(OH)2 provides skeleton support and a large specific surface area for the Ni3S2 electrodeposition. Benefiting from the selection of different components and preparation technology, the Cu(OH)2/Ni3S2 composite exhibits enhanced electrochemical properties with a high specific capacitance of 4.85 F cm-2 at 2 mA cm-2 and long-term cyclic stability at 80.84% (4000 cycles).

Engineering of Ni(OH)2 Modified Two-Dimensional ZnIn2S4 Heterostructure for Boosting Hydrogen Evolution under Visible Light Illumination.

Developing efficient catalysts to produce clean fuel by using solar energy has long been the goal to mitigate the issue of traditional fossil fuel scarcity. In this work, we design a heterostructure photocatalyst by employing two green components, Ni(OH)2 and ZnIn2S4, for efficient photocatalytic H2 evolution under the illumination of visible light. After optimization, the obtained photocatalyst exhibits an H2 evolution rate at 0.52 mL h-1 (5 mg) (i.e., 4640 µmol h-1 g-1) under visible light illumination. Further investigations reveal that such superior activity is originated from the efficient charge separation due to the two-dimensional (2D) structure of ZnIn2S4 and existing high-quality heterojunction.

In Situ Construction of ZnO/Ni2S3 Composite on Ni Foam by Combing Potentiostatic Deposition with Cyclic Voltammetric Electrodeposition.

The ZnO/Ni2S3 composite has been designed and in situ synthesized on Ni foam substrate by two steps of electrodeposition. ZnO was achieved on Ni foam by a traditional potentiostatic deposition, followed by cyclic voltammetric (CV) electrodeposition, to generate Ni2S3, where the introduction of ZnO provides abundant active sites for the subsequent Ni2S3 electrodeposition. The amount of deposit during CV electrodeposition can be adjusted by setting the number of sweep segment and scan rate, and the electrochemical characteristics of the products can be readily optimized. The synergistic effect between the ZnO as backbones and the deposited Ni2S3 as the shell enhances the electrochemical properties of the sample significantly, including a highly specific capacitance of 2.19 F cm-2 at 2 mA cm-2, good coulombic efficiency of 98%, and long-term cyclic stability at 82.35% (4000 cycles).

Tumour necrosis factor-alpha affects blood-brain barrier permeability and tight junction-associated occludin in acute liver failure.

BACKGROUND: Cerebral oedema leading to cerebral herniation is a major cause of death during acute liver failure (ALF), but the underlying mechanism is not clear. AIMS: We investigated the role of tumour necrosis factor (TNF)-alpha in changing the permeability of the blood-brain barrier (BBB) during ALF. METHODS: ALF animal models were generated by administering D-galactosamine (GalN) and lipopolysaccharide, or GalN and TNF-alpha. ALF induction was blocked by first administering anti-TNF-alpha-IgG or anti-TNF-alpha-R1. We investigated the BBB permeability with Evans blue staining, and the structure with electron microscopy. RESULTS: BBB permeability increased in ALF mice and correlated with elevated serum TNF-alpha levels. No vascular endothelial cell (EC) apoptosis was detected, but electron microscopy of cells from human and mouse ALF tissues revealed tight junction (TJ) disruptions and EC shrinkage, as well as increased vesicles and vacuoles. In addition, the expression of the TJ-associated protein occludin was significantly decreased in both ALF mice and patients, although the expression of occludin mRNA did not change. Changes in BBB permeability, brain tissue ultrastructure and occludin expression in ALF-induced mice could be prevented by prophylaxis treatment with either antibody to TNF-alpha-IgG or antibody to TNF-alpha-R1. CONCLUSIONS: Our results suggest that TNF-alpha plays a critical role in the development of brain oedema in ALF, and that both vasogenic and cytotoxic mechanisms may be involved. Increased BBB permeability may be because of the disruption of TJs, and loss of the TJ-associated protein occludin.

Underdogs make an alliance: The co-experience of rejection promotes cooperation.

Social rejection research has largely focused on the consequences of rejection when individuals experience rejection alone. Yet little is known about the reaction of those co-experiencing rejection. We tested the hypothesis that the co-experience of rejection increases cooperation between the co-experiencers. Three experiments provided supporting evidence for the hypothesis. The participants cooperated more when they co-experienced rejection than when they experienced rejection alone. The need to belong mediated the relationship between those co-experiencing rejection and cooperation. These findings shed light on the factors that initiate the formation of small groups, especially deviant ones.