Impact of Hypoxia-Inducible Factor-1α on Host Immune Metabolism and Tissue Damage During Mycobacterium bovis Infection.

HIF-1α is a pivotal regulator of metabolic and inflammatory responses. This study investigated the role of HIF-1α in M. bovis infection and its effects on host immune metabolism and tissue damage. We evaluated the expression of immunometabolism markers and MMPs infected with M. bovis, and following HIF-1α inhibition in vitro. To understand the implications of HIF-1α inhibition on disease progression, mice at different infection stages were treated with the HIF-1α inhibitor, YC-1. Our results revealed an upregulation of the HIF-1α in macrophages post-M. bovis infection, facilitating enhanced M1 macrophage polarization. The blockade of HIF-1α moderated these responses but escalated MMP activity, hindering bacterial control. Consistent with our in vitro results, early-stage treatment of mice with YC-1 aggravated pathological alterations and tissue damage, while late-stage HIF-1α inhibition proved beneficial in managing the disease. Overall, our findings underscored the nuanced role of HIF-1α across varying phases of M. bovis infection.

Selenium nanoparticles enhance mucosal immunity against Mycobacterium bovis infection.

Selenium nanoparticles (SeNPs) enhance the immune response as adjuvants, increasing the efficacy of viral vaccines, including those for COVID-19. However, the efficiency of mucosal SeNPs in boosting vaccine-induced protective immunity against tuberculosis remains unclear. Therefore, this study aims to investigate whether the combination of SeNPs with the AH antigen (Ag85A-HspX) can boost respiratory mucosal immunity and thereby enhance the protective effects against tuberculosis. We synthesized SeNPs and assessed their impact on the immune response and protection against Mycobacterium bovis (M. bovis) as a mucosal adjuvant in mice, administered intranasally at a dose of 20 µg. SeNPs outperformed polyinosinic-polycytidylic acid (Poly IC) in stimulating the maturation of bone marrow-derived dendritic cells (BMDCs), which enhanced antigen presentation. SeNPs significantly activated and proliferated tissue-resident memory T cells (TRMs) and effector CD4+ T cells in the lungs. The vaccines elicited specific antibody responses in the respiratory tract and stimulated systemic Th1 and Th17 immune responses. Immunization with AH and SeNPs led to higher levels of mucosal secretory IgA in bronchoalveolar lavage fluid (BALF) and secretory IL-17 in splenocytes. Moreover, SeNPs immunized mice showed reduced M. bovis infection loads and inflammatory lesions in the lungs post-challenge. Notably, immunization with AH and SeNPs significantly reduced bacterial load in the lungs, achieving the lowest levels compared to all other tested groups. This study calls for pre-clinical investigation of AHB-SeNPs as an anti-bovine tuberculosis vaccine and for exploring its human vaccine potential, which is anticipated to aid in the development of innovative vaccines or adjuvants.

Multicomponent Pathogen-Mimicking Nanoparticles Induce Intestinal Immune Responses against Paratuberculosis.

Given the worldwide problem posed by enteric pathogens, the discovery of safe and efficient intestinal adjuvants combined with novel antigen delivery techniques is essential to the design of mucosal vaccines. In this work, we designed poly (lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs) to codeliver all-trans retinoic acid (atRA), novel antigens, and CpG. To address the insolubility of the intestinal adjuvant atRA, we utilized PLGA to encapsulate atRA and form a "nanocapsid" with polydopamine. By leveraging polydopamine, we adsorbed the water-soluble antigens and the TLR9 agonist CpG onto the NPs' surface, resulting in the pathogen-mimicking PLPCa NPs. In this study, the novel fusion protein (HBf), consisting of the Mycobacterium avium subspecies paratuberculosis antigens HBHA, Ag85B, and Bfra, was coloaded onto the NPs. In vitro, PLPCa NPs were shown to promote the activation and maturation of bone marrow-derived dendritic cells. Additionally, we found that PLPCa NPs created an immune-rich microenvironment at the injection site following intramuscular administration. From the results, the PLPCa NPs induced strong IgA levels in the gut in addition to enhancing powerful systemic immune responses. Consequently, significant declines in the bacterial burden and inflammatory score were noted in PLPCa NPs-treated mice. In summary, PLPCa can serve as a novel and safe vaccine delivery platform against gut pathogens, such as paratuberculosis, capable of activating both systemic and intestinal immunity.

Adverse Effect of Nonalcoholic Fatty Liver Disease on the Therapeutic Response in Patients with Chronic Hepatitis B.

Background and Aims: The impact of nonalcoholic fatty liver disease (NAFLD) on the treatment outcome of chronic hepatitis B (CHB) is undefined and deserves an in-depth investigation. Methods: Histologically-proven CHB receiving first-line antiviral regimens as initial therapy was enrolled and grouped by the concurrence of NAFLD, and followed up at six monthly intervals. Therapeutic response related data were recorded and compared at multiple time points. Kaplan-Meier and Cox regression analyses were utilized to estimate the impact of NAFLD on complete virological response (CVR). Results: We enrolled 267 patients (CHB: 164; CHB with NAFLD: 103) with comparable follow-up durations. They were also comparable in baseline HBV DNA levels and HBeAg positivity. Patients with concomitant NAFLD showed less significant decline in HBV DNA, qHBsAg, pgRNA, and liver enzyme levels over time; moreover, their cumulative incidences of CVR were significantly lower and that of low-level viremia (LLV) were significantly higher at 6, 12, 18, 24 months. First CVR of CHB was delayed with the presence NAFLD (11.0 vs. 7.0 months, p<0.001) and further prolonged with higher grade of liver steatosis (Grade 2-3 vs. 1: 13.0 vs. 9.0 months). On multivariate analysis, HBeAg positivity (HR: 0.650, p=0.036), grade of steatosis (G2 [HR: 0.447, p=0.004]; G3 [HR: 0.085, p=0.002]) and HBV DNA (log10 IU/mL) (HR: 0.687, p<0.001) were significantly associated with delayed CVR, whereas grade of necroinflammation (HR: 1. 758, p<0.001) accelerated the CVR. Conclusions: In CHB patients receiving initial antiviral therapy, NAFLD was associated with higher levels of HBV DNA, pgRNA, and liver enzymes, and higher incidence of LLV and delayed CVR.

Comparative study of purgative pharmacological effects and mechanisms of Moringa oleifera leaves and Rhei Radix et Rhizoma / 中国中药杂志

Moringa oleifera leaves are known for their "Virechana"(purgative) effect in Ayurvedic medicine in India. This study compared the purgative effects and mechanisms of M. oleifera leaves with the reference Rhei Radix et Rhizoma to establish a foundation for the further application of M. oleifera leaves in traditional Chinese medicine(TCM). Using network pharmacology and molecular docking methods, this study identified the material basis, common targets, and signaling pathways through which Rhei Radix et Rhizoma and M. oleifera leaves exerted their purgative pharmacological effects. A low-fiber diet-induced constipation mouse model was established to measure fecal parameters and small intestinal propulsion rate, and histological changes in the colon were observed using HE staining. Relative expression levels of relevant genes and target proteins were assessed using RT-qPCR and immunohistochemistry, respectively. The results showed that mapping the targets of Rhei Radix et Rhizoma and M. oleifera leaves onto the biological process network of constipation revealed close proximity, indicating that they may exert their therapeutic effects on constipation through similar biological processes. Molecular docking results indicated that compounds such as sennoside C and isoquercitrin could target serine/threonine protein kinases(AKT1) and mitogen-activated protein kinase 3(MAPK3), thereby affecting MAPK and calcium signaling pathways to promote defecation. Animal experiments demonstrated that both M. oleifera leaves and Rhei Radix et Rhizoma increased the number of fecal pellets and water content in constipated mice, improved small intestine motility, colon mucosal thickness, and muscle layer thickness, upregulated the gene expression levels of AKT1 and MAPK3 in the colon, and downregulated the expression of AQP3 protein. These findings suggest that M. oleifera leaves and Rhei Radix et Rhizoma share similarities in their therapeutic efficacy and mechanisms for treating constipation. Using Rhei Radix et Rhizoma as a reference can provide a better understanding of the characteristics of the "Virechana"(purgative) effect of M. oleifera leaves in TCM.

Anti-fibrosis Mechanism of Buyang Huanwutang： A Review / 中国实验方剂学杂志

Fibrosis can occur in nearly all organs of the body and is an outcome of many chronic diseases. As inflammation leads to necrosis of parenchymal cells， excessive proliferation of fibroblasts and overproduction of extracellular matrix （ECM） occur in tissues and organs， which may cause structural damage and loss of function of organs in the case of continuous progression. Chinese medicine has definite effect on fibrosis and prescriptions with effects of replenishing Qi and activating blood， such as Buyang Huanwutang， are frequently used in clinical settings. Clinical research and experiments show that Buyang Huanwutang can delay the progression of fibrosis in multiple organs such as lung， heart， liver， and kidney by improving organ function， reducing ECM deposition， anti-oxidative stress， anti-inflammatory response， regulating the imbalance of matrix metalloproteinases （MMPs）/tissue inhibitors of metalloproteinases （TIMPs）， and modulating transforming growth factor-β （TGF-β）/Smad pathway. According to traditional Chinese medicine， healthy Qi deficiency is the internal cause of fibrosis， and blood stasis is an important pathological factor in the formation of fibrosis. Moreover， deficiency and stasis exist in the whole process of fibrosis and the changes of microenvironment of fibrotic organs and tissues accord with the pathological manifestations of Qi deficiency and blood stasis. This article reviews the anti-fibrosis mechanism of Buyang Huanwutang in multiple organs， which provides a science-based explanation for the treatment of fibrosis by Buyang Huanwutang and lays a foundation for further clinical research.

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.

A Single-Domain Antibody-Based Anti-PSMA Recombinant Immunotoxin Exhibits Specificity and Efficacy for Prostate Cancer Therapy.

Prostate cancer (PCa) is the second most common cancer in men, causing more than 300,000 deaths every year worldwide. Due to their superior cell-killing ability and the relative simplicity of their preparation, immunotoxin molecules have great potential in the clinical treatment of cancer, and several such molecules have been approved for clinical application. In this study, we adopted a relatively simple strategy based on a single-domain antibody (sdAb) and an improved Pseudomonas exotoxin A (PE) toxin (PE24X7) to prepare a safer immunotoxin against prostate-specific membrane antigen (PSMA) for PCa treatment. The designed anti-PSMA immunotoxin, JVM-PE24X7, was conveniently prepared in its soluble form in an Escherichia coli (E. coli) system, avoiding the complex renaturation process needed for immunotoxin preparation by the conventional strategy. The product was very stable and showed a very strong ability to bind the PSMA receptor. Cytotoxicity assays showed that this molecule at a very low concentration could kill PSMA-positive PCa cells, with an EC50 value (concentration at which the cell viability decreased by 50%) of 15.3 pM against PSMA-positive LNCaP cells. Moreover, this molecule showed very good killing selectivity between PSMA-positive and PSMA-negative cells, with a selection ratio of more than 300-fold. Animal studies showed that this molecule at a very low dosage (5 × 0.5 mg/kg once every three days) completely inhibited the growth of PCa tumors, and the maximum tolerable dose (MTD) was more than 15 mg/kg, indicating its very potent tumor-treatment ability and a wide therapeutic window. Use of the new PE toxin, PE24X7, as the effector moiety significantly reduced off-target toxicity and improved the therapeutic window of the immunotoxin. The above results demonstrate that the designed anti-PSMA immunotoxin, JVM-PE24X7, has good application value for the treatment of PCa.

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.

CD14+ monocytes and CD163+ macrophages correlate with the severity of liver fibrosis in patients with chronic hepatitis C.

Hepatic fibrosis is a crucial pathological process involved in the development of chronic hepatitis C (CHC) and may progress to liver cirrhosis and hepatocellular carcinoma. Activated peripheral blood monocytes and intrahepatic macrophages further promote hepatic fibrogenesis by releasing proinflammatory and profibrogenic cytokines. The present study aimed to investigate the role of peripheral CD14+ monocytes and intrahepatic CD163+ macrophages in hepatitis C virus (HCV)-associated liver fibrosis and clarify whether serum soluble CD163 (sCD163) may serve as a fibrosis marker in patients with CHC. A total of 87 patients with CHC and 20 healthy controls were recruited. Serum sCD163 levels were measured by ELISA. Frequencies of peripheral CD14+ monocytes and inflammatory cytokines expressed by CD14+ monocytes were analyzed by flow cytometry. The degree of fibrosis in human liver biopsies was graded using the Metavir scoring system and patients were stratified into two groups based on those results (F<2 vs. F≥2). Hepatic expression of CD163 was examined by immunohistochemical staining. The diagnostic values of sCD163, aspartate aminotransferase to platelet ratio index (APRI), fibrosis 4 score (FIB-4) and the aspartate aminotransferase to alanine aminotransferase ratio (AAR) in significant fibrosis (F≥2) were evaluated and compared using receiver operating characteristic (ROC) curves. The results indicated that the serum sCD163 levels and the frequency of CD14+ monocytes were significantly higher in the patients than that in the controls and positively correlated with liver fibrosis. The level of serum sCD163 was consistent with hepatic CD163 expression in the liver sections from patients. The frequencies of interleukin (IL)-8- and tumor necrosis factor-α-expressing monocytes were increased and that of IL-10-expressing monocytes was decreased in the patients. The area under the ROC curve (AUROC) for sCD163, APRI, FIB-4 and AAR was 0.876, 0.785, 0.825 and 0.488, respectively, and the AUROC for sCD163 was significantly higher than those for APRI and AAR. In conclusion, sCD163 may serve as a novel marker for assessing the degree of liver fibrosis in HCV-infected patients.

Early invasive strategy for non-ST elevation acute coronary syndrome: a meta-analysis of randomized, controlled trials.

OBJECTIVE: Patients with non-ST elevation acute coronary syndrome (NSTE-ACS) benefit from coronary intervention, but the optimal timing for an invasive strategy is not well defined. This study aimed to determine whether an early invasive strategy (<12 hours) is superior to a delayed invasive strategy. METHODS: Twelve studies of nine randomized, controlled trials of 8586 patients were included. RESULTS: There were no significant differences in all-cause death (risk ratio [95% confidence interval]) (0.90, [0.77-1.06), re-myocardial infarction (re-MI) (0.95 [0.70-1.29]), major bleeding (0.97 [0.77-1.23]), and refractory ischemia (0.74 [0.53-1.05]) when we compared use of early and delayed invasive strategies. Furthermore, analysis of the effect of the chosen strategy on high-risk patients showed that the rate of composite death or re-MI was significantly decreased in patients with either a Global Registry of Acute Coronary Events (GRACE) risk score >140 or with elevated troponin levels (risk ratio 0.82 [0.72-0.92]; risk ratio 0.84 [0.76-0.93], respectively). CONCLUSIONS: This meta-analysis shows that an early angiographic strategy does not improve clinical outcome in patients with NSTE-ACS. An early invasive strategy might reduce the rate of composite death or re-MI in high-risk patients with GRACE risk scores >140 or elevated cardiac markers.

Capture of Iodine from Nuclear-Fuel-Reprocessing Off-Gas: Influence of Aging on a Reduced Silver Mordenite Adsorbent after Exposure to NO/NO2.

Iodine radioisotopes released during nuclear fuel reprocessing must be removed from the off-gas stream before discharge. One promising material for iodine capture is reduced silver mordenite (Ag0Z). Nevertheless, the adsorbent's capacity will degrade, or age, over time when the material is exposed to other off-gas constituents. Though the overall impact of aging is known, the underlying physical and chemical processes are not. To examine these processes, Ag0Z samples were prepared and aged in 2% NO2 in dry air and in 1% NO in N2 gas streams at 150 °C for up to six months. Aged samples were then characterized using scanning electron microscopy, X-ray diffraction, Raman spectroscopy, and X-ray absorption spectroscopy. These techniques show that aging involves two overarching processes: (i) oxidation of the silver nanoparticles present in Ag0Z and (ii) migration of oxidized silver into the mordenite's inner network. Silver on the nanoparticle's surface is oxidized through adsorption of O2, NO, and NO2. Raman spectroscopy and X-ray absorption spectroscopy indicate that nitrates are the primary products of this adsorption. Most of these nitrates migrate into the interior of the mordenite and exchange at framework binding sites, returning silver to its unreduced state (AgZ). The remaining nitrates exist at a persistent concentration without aggregating into bulk-phase AgNO3. X-ray absorption spectroscopy results further indicate that iodine adsorption occurs on not just Ag0Z but also on AgZ and a portion of the nitrates in the system. AgZ adsorbs a sizable quantity of iodine early in the aging process, but its capacity drops rapidly over time. For well-aged samples, nitrates are responsible for up to 95% of mordenite's iodine capacity. These results have enhanced our understanding of the aging process in silver mordenite and are expected to guide the development of superior adsorbents for the capture of radioactive iodine from reprocessing off-gas.

Multicenter prospective study to validate a new transient elastography device for staging liver fibrosis in patients with chronic hepatitis B.

OBJECTIVES: To validate the operational and diagnostic performances of a new device for transient elastography (TE), FibroTouch, for liver fibrosis in patients with chronic hepatitis B (CHB). METHODS: In this prospective multicenter study, adult patients with CHB and valid liver pathological results were recruited to validate the operational and diagnostic performance of a TE device by FibroTouch for staging liver fibrosis. RESULTS: In total, 517 patients with histologically proven CHB were enrolled. All had achieved at least 10 successful liver stiffness measurements (LSM), resulting in a success rate of 99.1% and reliable evaluations of 95.2%. Altogether 412 patients were included to analyze the diagnostic performance of FibroTouch. The area under the receiver operating characteristic curve for the LSM was 0.846 (95% confidence interval [CI] 0.808-0.880) for fibrosis stage ≥ F1, 0.850 (95% CI 0.811-0.883) for ≥ F2, 0.908 (95% CI 0.876-0.934) for ≥ F3 and 0.874 (95% CI 0.836-0.903) for F4. The diagnostic accuracy of LSM was superior to that of gamma-glutamyl transpeptidase-to-platelet ratio (GPR), aminotransferase-to-platelet ratio index (APRI), or fibrosis index based on 4 factors (FIB-4) index in staging fibrosis F2-F4 (P = 0.007 to < 0.0001). Optimal LSM cut-off values for diagnosing fibrosis stage ≥ F1, ≥ F2, ≥ F3, and F4 were 5.5 kPa, 7.85 kPa, 10.0 kPa, and 12.7 kPa, respectively. CONCLUSION: FibroTouch has a high success rate and good reliability in staging liver fibrosis in patients with CHB.

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.

Serum N-glycan markers for diagnosing liver fibrosis induced by hepatitis B virus.

BACKGROUND: Hepatitis B virus (HBV) infection is the primary cause of hepatitis with chronic HBV infection, which may develop into liver fibrosis, cirrhosis and hepatocellular carcinoma. Detection of early-stage fibrosis related to HBV infection is of great clinical significance to block the progression of liver lesion. Direct liver biopsy is regarded as the gold standard to detect and assess fibrosis; however, this method is invasive and prone to clinical sampling error. In order to address these issues, we attempted to find more convenient and effective serum markers for detecting HBV-induced early-stage liver fibrosis. AIM: To investigate serum N-glycan profiling related to HBV-induced liver fibrosis and verify multiparameter diagnostic models related to serum N-glycan changes. METHODS: N-glycan profiles from the sera of 432 HBV-infected patients with liver fibrosis were analyzed. Significant changed N-glycan levels (peaks) (P < 0.05) in different fibrosis stages were selected in the modeling group, and multiparameter diagnostic models were established based on changed N-glycan levels by logistic regression analysis. The receiver operating characteristic (ROC) curve analysis was performed to evaluate diagnostic efficacy of N-glycans models. These models were then compared with the aspartate aminotransferase to platelet ratio index (APRI) , fibrosis index based on the four factors (FIB-4), glutamyltranspeptidase platelet albumin index (S index), GlycoCirrho-test, and GlycoFibro-test. Furthermore, we combined multiparameter diagnostic models with alanine aminotransferase (ALT) and platelet (PLT) tests and compared their diagnostic power. In addition, the diagnostic accuracy of N-glycan models was also verified in the validation group of patients. RESULTS: Multiparameter diagnostic models constructed based on N-glycan peak 1, 3, 4 and 8 could distinguish between different stages of liver fibrosis. The area under ROC curves (AUROCs) of Model A and Model B were 0.890 and 0.752, respectively differentiating fibrosis F0-F1 from F2-F4, and F0-F2 from F3-F4, and surpassing other serum panels. However, AUROC (0.747) in Model C used for the diagnosis of F4 from F0-F3 was lower than AUROC (0.795) in FIB-4. In combination with ALT and PLT, the multiparameter models showed better diagnostic power (AUROC = 0.912, 0.829, 0.885, respectively) when compared with other models. In the validation group, the AUROCs of the three combined models (0.929, 0.858, and 0.867, respectively) were still satisfactory. We also applied the combined models to distinguish adjacent fibrosis stages of 432 patients (F0-F1/F2/F3/F4), and the AUROCs were 0.917, 0.720 and 0.785. CONCLUSION: Multiparameter models based on serum N-glycans are effective supplementary markers to distinguish between adjacent fibrosis stages of patients caused by HBV, especially in combination with ALT and PLT.

Beta-blocker exposure for short-term outcomes following non-cardiac surgery: A meta-analysis of observational studies.

BACKGROUND: It remains uncertain whether there is a benefit to perioperative beta-blocker use on outcomes after non-cardiac surgery. This meta-analysis aims to update the evidence regarding the associations between beta-blocker exposure and patient major short-term outcomes following non-cardiac surgery. METHODS: Pubmed, Embase, and the Cochrane Central Register from their inception to May 2019 were searched by two independent authors. Observational studies reporting associations between perioperative beta-blocker treatment and short-term outcomes including 30-day all-cause mortality (ACM), 30-day major adverse cardiovascular events (MACE) and 30-day stroke risk were selected for inclusion. Meta-analyses were carried out by using random effects models. RESULTS: Nineteen studies with a total of 1,711,766 participants were identified. Beta-blocker exposure was associated with reduced 30-day all-cause mortality (ACM) (RR 0.83, 95% CI 0.72 to 0.96). No evidence of publication bias was observed. Subgroup analyses revealed that significant 30-day survival benefits were observed in prospective, population-based studies, drug exposure period last till 1-2 months after surgery, patients having abdominal gastrointestinal surgery or having 3-4 cardiac risk factors. Beta-blocker exposure was associated with increased 30-day ACM among patients with no cardiac risk factors (RR 1.30, 95% CI 1.19 to 1.43). However, meta-analysis demonstrated a non-significant risk reduction in 30-day MACE (RR 1.03; 95% CI 0.85 to 1.25) or 30-day stroke risk (RR 0.86; 95% CI 0.44 to 1.68) with beta-blocker exposure. CONCLUSIONS: The results of the current meta-analysis indicate beta-blocker exposure may be a significant indicator for 30-day ACM, but not for 30-day MACE or 30-day stroke risk. The association between beta-blocker exposure and long-term outcomes deserves further investigation.

Therapeutic efficiency of bone marrow-derived mesenchymal stem cells for liver fibrosis: A systematic review of in vivo studies.

Although multiple drugs are accessible for recovering liver function in patients, none are considered efficient. Liver transplantation is the mainstay therapy for end-stage liver fibrosis. However, the worldwide shortage of healthy liver donors, organ rejection, complex surgery, and high costs are prompting researchers to develop novel approaches to deal with the overwhelming liver fibrosis cases. Mesenchymal stem cell (MSC) therapy is an emerging alternative method for treating patients with liver fibrosis. However, many aspects of this therapy remain unclear, such as the efficiency compared to conventional treatment, the ideal MSC sources, and the most effective way to use it. Because bone marrow (BM) is the largest source for MSCs, this paper used a systematic review approach to study the therapeutic efficiency of MSCs against liver fibrosis and related factors. We systematically searched multiple published articles to identify studies involving liver fibrosis and BM-MSC-based therapy. Analyzing the selected studies showed that compared with conventional treatment BM-MSC therapy may be more efficient for liver fibrosis in some cases. In contrast, the cotreatment presented a more efficient way. Nevertheless, BM-MSCs are lacking as a therapy for liver fibrosis; thus, this paper also reviews factors that affect BM-MSC efficiency, such as the implementation routes and strategies employed to enhance the potential in alleviating liver fibrosis. Ultimately, our review summarizes the recent advances in the BM-MSC therapy for liver fibrosis. It is grounded in recent developments underlying the efficiency of BM-MSCs as therapy, focusing on the preclinical in vivo experiments, and comparing to other treatments or sources and the strategies used to enhance its potential while mentioning the research gaps.

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.

Evaluation on Effectiveness and Safety of Chinese Herbs in Treatment of Sub-health: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: To evaluate the effectiveness and safety of Chinese herbs in the treatment of sub-health systematically. METHODS: Nine databases were systematically and extensively searched to collect randomized controlled trials (RCTs) about Chinese herbs in the treatment of sub-health. The outcomes included overall effective rate, main symptoms, quality of life, etc. Literature screening, data extraction and quality assessment were conducted according to Cochrane Handbook 5.1. Meta-analysis was conducted to the included literature with Review Manager Software. RESULTS: Seventy-two studies involving 9,296 patients with sub-health were included with 4,908 patients in experimental groups and 4,387 patients in control groups. The overall quality of included clinical research was not high. In the aspect of improving overall effective rate, relieving main symptoms, Pittsburgh sleep quality index (PSQI) score, Athens Insomnia Scale (AIS) score, Fatigue Scale-14 (FS-14), Cornell Medical Index (CMI) score and discontinuation rate, the effects of experimental groups were better than that of control groups. According to available research reports, adverse reactions in Chinese herb groups were mainly mild gastrointestinal symptoms, which did not affect the treatment. CONCLUSION: Chinese herbs have a curative effect in the treatment of sub-health. However, there are no clear criteria for diagnosis and curative effectiveness judgment globally, which would affect the accuracy of curative effect evaluation.

Evaluation on Effectiveness and Safety of Chinese Herbs in Treatment of Sub-health: A Systematic Review and Meta-Analysis of Randomized Controlled Trials / 中国结合医学杂志

OBJECTIVE@#To evaluate the effectiveness and safety of Chinese herbs in the treatment of sub-health systematically.@*METHODS@#Nine databases were systematically and extensively searched to collect randomized controlled trials (RCTs) about Chinese herbs in the treatment of sub-health. The outcomes included overall effective rate, main symptoms, quality of life, etc. Literature screening, data extraction and quality assessment were conducted according to Cochrane Handbook 5.1. Meta-analysis was conducted to the included literature with Review Manager Software.@*RESULTS@#Seventy-two studies involving 9,296 patients with sub-health were included with 4,908 patients in experimental groups and 4,387 patients in control groups. The overall quality of included clinical research was not high. In the aspect of improving overall effective rate, relieving main symptoms, Pittsburgh sleep quality index (PSQI) score, Athens Insomnia Scale (AIS) score, Fatigue Scale-14 (FS-14), Cornell Medical Index (CMI) score and discontinuation rate, the effects of experimental groups were better than that of control groups. According to available research reports, adverse reactions in Chinese herb groups were mainly mild gastrointestinal symptoms, which did not affect the treatment.@*CONCLUSION@#Chinese herbs have a curative effect in the treatment of sub-health. However, there are no clear criteria for diagnosis and curative effectiveness judgment globally, which would affect the accuracy of curative effect evaluation.