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Context The Xihuang pill (XHP) is a traditional Chinese medicine formulation that has been historically used in the prevention and treatment of proliferative breast diseases. However, there is a lack of guidelines that offer recommendations for its clinical use.Objective The task force from the Chinese Guangdong Pharmaceutical Association aims to develop evidence-based guidelines for XHP to prevent and treat proliferative breast diseases.Methods We searched six Chinese and English electronic databases, including the China National Knowledge Infrastructure, the Chinese Scientific Journal Database, the Wanfang Medical Database, PubMed, and Embase, up to November 1, 2022. Publications (case reports, clinical observation, clinical trials, reviews) on using XHP to treat proliferative breast diseases were manually searched. The search terms were Xihuang pill, hyperplasia of the mammary gland, breast lump, and mastalgia. The writing team developed recommendations based on the best available evidence.Results Treatment should be customized based on syndrome identification. We recommend using XHP for the prevention and treatment of breast hyperplasia disease when a patient presents the following syndromes: concurrent blood stasis syndrome, concurrent phlegm-stasis syndrome, and concurrent liver fire syndrome. Safety indicators, including blood analysis and liver and kidney function monitoring, should be performed regularly during treatment.Conclusions Current clinical evidence suggests that XHP can be used as a standalone treatment or in conjunction with other medications to prevent and manage breast hyperplasia diseases. More randomized controlled studies are warranted to establish high-quality evidence of its use.

This study investigates the effect of a novel negative temperature early-strength agent (NEA) in enhancing concrete performance under varying curing temperatures, with a discussion on the underlying mechanism through analysis of hydration products and microstructure.The results indicate NEA markedly accelerates early cement hydration, reduces setting time, and enhances compressive strength. Moreover, the efficacy of NEA is more pronounced at lower temperatures. With an optimal dosage of 3 %, the incorporation of NEA leads to a remarkable 285.9 % increase in compressive strength at 28 days under −5°C curing temperature. Despite accelerating cement hydration can induce increased chemical shrinkage, NEA effectively mitigates early freezing expansion under negative temperature and significantly diminishes chloride ion permeability. Higher temperatures facilitate early cement hydration but also compromise long-term hydration continuity. Consequently, the highest hydration degree and loweast porosity are observed at 28 days under 5°C curing temperature. NEA's air-entraining component introduces numerous superfine pores into the paste, augmenting early pore volume while optimizing pore structure. As the early-strength component fosters hydration, these pores undergo further filling and refinement, ultimately reducing the total pore volume at 28 days. This study provides insights into optimizing concrete performance in cold environments.

Abstract Amyotrophic lateral sclerosis (ALS) is a devastating fatal neurodegenerative disease with no cure. Receptor-interacting protein kinase 1 (RIPK1) has been proposed to mediate pathogenesis of ALS. Primidone has been identified as an old drug that can also inhibit RIPK1 kinase. We conducted a drug-repurposing biomarker study of primidone as a RIPK1 inhibitor using SOD1G93A mice and ALS patients. SOD1G93A mice treated with primidone showed significant delay of symptomatic onset and improved motor performance. One-hundred-sixty-two ALS participants dosed daily with primidone (62.5 mg) completed 24-week follow-up. A significant reduction was showed in serum levels of RIPK1 and IL-8, which were significantly higher in ALS patients than that of healthy controls (P

Abstract Background Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent form of chronic liver disease, with a global prevalence of 25% worldwide, but a consensus treatment is still lacking. Previous studies have shown that Jian-Pi Huo-Xue granules (JPHX) can reduce hepatic steatosis in ultrasound images, but lacked quantitative observation in imagined liver fat content. This study aimed to refine the efficacy and safety assessment of JPHX for NAFLD with magnetic resonance imaging-proton density fat fraction (MRI-PDFF) as the primary outcome. Methods This is a randomized, double-blind, placebo-controlled clinical trial. The trial will enrol 84 NAFLD participants who will be equally randomized to receive either JPHX or a placebo for 24 weeks. Follow-up will be performed 12 weeks after the intervention. The primary outcome will be the change from baseline to week 24 in MRI-PDFF. Secondary outcomes will be the body weight, body mass index (BMI), waist circumference, waist-to-hip ratio (WHR), serum liver function, blood lipids and glucose-related indicators, quality of life measurement health survey, and traditional Chinese medicine (TCM) syndrome scale. Outcomes will be monitored at baseline, 12 weeks and 24 weeks after enrolment. Adverse events occurring in this trial will be managed and recorded promptly. Discussion We designed a clinical trial for the treatment of NAFLD using JPHX, a TCM formulation that has been shown to have a positive effect on hepatic steatosis in a previous self-controlled trial. This trial will use a more recognized and quantitative imaging approach to demonstrate the efficacy of JPHX in the treatment of NAFLD and observe its safety to provide clinical evidence for its translational applications. Trial registration Chinese Clinical Trial Registry ChiCTR2100046132 . Registered on 4 May 2021.

Abstract Wood-based hydrogel with a unique anisotropic structure is an attractive soft material, but the presence of rigid crystalline cellulose in natural wood makes the hydrogel less flexible. In this study, an all-wood hydrogel was constructed by cross-linking cellulose fibers, polyvinyl alcohol (PVA) chains, and lignin molecules through the Hofmeister effect. The all-wood hydrogel shows a high tensile strength of 36.5 MPa and a strain up to ~ 438% in the longitudinal direction, which is much higher than its tensile strength (~ 2.6 MPa) and strain (~ 198%) in the radial direction, respectively. The high mechanical strength of all-wood hydrogels is mainly attributed to the strong hydrogen bonding, physical entanglement, and van der Waals forces between lignin molecules, cellulose nanofibers, and PVA chains. Thanks to its excellent flexibility, good conductivity, and sensitivity, the all-wood hydrogel can accurately distinguish diverse macroscale or subtle human movements, including finger flexion, pulse, and swallowing behavior. In particular, when “An Qi” was called four times within 15 s, two variations of the pronunciation could be identified. With recyclable, biodegradable, and adjustable mechanical properties, the all-wood hydrogel is a multifunctional soft material with promising applications, such as human motion monitoring, tissue engineering, and robotics materials.

Abstract Background Hyperlipidemia has become a common chronic disease worldwide in recent years. Studies have shown that hyperlipidemia patients, especially those with a high level of serum low-density lipoprotein cholesterol (LDL-C), have a significantly higher prevalence of atherosclerosis, leading to coronary heart disease. Previous basic experiments and clinical studies have shown that Qushi Huayu granules (QSHY) reduce blood lipids in patients with non-alcoholic fatty liver disease (NAFLD) accompanied by hyperlipidemia. However, the clinical efficacy of QSHY in patients with hyperlipidemia is still lacking. This study aims to investigate the effect and safety of QSHY for hyperlipidemia. Methods This is a randomized, double-blind, placebo-controlled trial. A total of 210 participants will be enrolled and randomized into the QSHY or placebo granules groups in equal proportions, who will receive treatment for 24 weeks. The primary outcome will be the change in LDL-C from baseline to week 12. Secondary outcomes will be changes in other serum lipids markers, life quality measuring health surveys, and traditional Chinese medicine (TCM) pattern scale. All related tests will be measured at baseline, week 12, and week 24 after enrollment. Adverse events and the safety of intervention will be monitored and evaluated. Discussion We designed a clinical trial of hyperlipidemia management with QSHY, a TCM prescription. The results of this trial will present the efficacy and safety of QSHY in patients with hyperlipidemia. Trial registration Chinese Clinical Trial Registry ChiCTR2000034125 . Registered on June 25, 2019

Background: Liver fibrosis is a dysregulated wound-healing process in response to diverse liver injuries, and an effective drug therapy is not yet available. Genistein, which is one of the most active natural flavonoids mainly derived from soybean products (e.g., Cordyceps sinensis mycelium), exhibits various biological effects, including hepatoprotective and anti-inflammatory properties. However, the anti-hepatic fibrosis mechanisms of genistein are poorly understood. The aim of our research is to explore the effect and the possible mechanism of genistein against liver fibrosis. Materials and methods: Cell counting kit-8, EdU, and flow cytometry assays were applied to evaluate the effects of genistein on cell viability, proliferation, and cell cycle arrest in human hepatic stellate cell (HSC) line LX2 cells. HSC activation was induced by transforming growth factor-β1 in LX2 cells and liver fibrosis model was established by the intraperitoneal injection of dimethylnitrosamine (DMN) in rats to assess the anti-fibrosis effects of genistein in vivo and in vitro models. HSC activation was assessed by qRT-PCR, Western blot, immunohistochemistry, and immunofluorescent assay. Liver injury and collagen deposition were evaluated by histopathological assay, serum biochemistry, and hepatic hydroxyproline content assays. The mRNA expressions of matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and inflammation related-factors were assessed by qRT-PCR assay. Furthermore, the functional properties of macrophage in the liver were assessed by immunohistochemistry assay. The expression levels of the JAK2/STAT3/SOCS3 signaling pathway related-protein were assessed by Western blot analysis. Results: Genistein significantly inhibited cell viability and proliferation and induced cell cycle arrest at G0/G1 phase in LX2 cells, respectively. Furthermore, oral administration of genistein significantly ameliorated liver injury and the collagen deposition in rats with DMN-induced fibrosis model. Genistein suppressed the expression levels of HSC activation marker α-smooth muscle actin and collagen type I alpha 1 in vivo and in vitro. Genistein significantly decreased the mRNA expression levels of extracellular matrix degradation genes MMP2/9 and TIMP1 in rats. Genistein alleviated the mRNA expression levels of IL-1β, IL-6, TNF-α, and MCP-1 and regulated the protein expressions of CD68, CD163, and CD206 in the liver. Moreover, genistein attenuated the expressions of p-JAK2/JAK2, p-STAT3/STAT3, and SOCS3 protein both in vivo and in vitro. Conclusion: Taken together, our results showed that genistein could be improved liver fibrosis both in vivo and in vitro, probably through regulating the functional properties of macrophage and inhibiting the JAK2/STAT3/SOCS3 signaling pathway.

Background: The activation of HIF-1α/CXCR4 pathway in liver sinusoidal endothelial cells (LSECs) could downregulate CXCR7, leading to the capillarization of LSECs to promote hepatic fibrosis. However, the mechanism between CXCR4 and CXCR7 is still undefined. The aim is to investigate the role of PDGF-BB in the dedifferentiation of LSECs and hepatic stellate cells (HSCs) activation. Methods: The activation of HIF-1α/CXCR4 pathway in two kinds of liver fibrosis models were observed. The effects of HIF-1α, CXCR4, PDGF-BB on the dedifferentiation of LSECs were investigated by using the inhibitors of HIF-1α, CXCR4 or PDGFR-β separately or transfecting with a CXCR4 knockdown lentiviral vector. In addition, the relationship between LSECs and HSCs was demonstrated by co-culture of LSECs and HSCs using the transwell chamber. Results: CXCR4 upregulation and CXCR7 downregulation were accompanied by LSECs capillarization and HSCs activation both in CCl4-induced and BDL-induced fibrotic liver. In vitro, downregulation of HIF-1α significantly descreased CXCR4 and CD31 expression, and enhanced the expressions of CXCR7, CD44 and LYVE1. Downregulation of CXCR4 in LSECs significantly downregulated PDGF-BB, PDGFR-β and CD31, and enhanced CXCR7, CD44 and LYVE1 expression, while the expression of HIF-1α did not change significantly. STI571, a PDGF receptor inhibitor, could significantly downregulate PDGFR-β and increase the expression of CXCR7 to inhibit the dedifferentiation of LSECs. In addition, alleviateion the dedifferentiation of LSECs could decrease the expression of PDGFR-β of HSCs, then inhibiting the activation of HSCs. Conclusions: This study revealed that HIF-1α/CXCR4/PDGF-BB/CXCR7 axis promoted the dedifferentiation of LSECs, consequently triggering HSCs activation and liver fibrosis.

Introduction and Objectives: Liver fibrosis is a common pathological change in many chronic liver diseases. Activation of hepatic stellate cells (HSCs) is the core event in liver fibrosis. This study aimed to investigate the role of testicular orphan receptor 4 (TR4) in the activation of HSCs. Materials and Methods: In vivo, bile duct ligation (BDL)-induced rat liver fibrosis model was established, and the expressions of TR4 and α-smooth muscle actin (α-SMA) in liver tissues were detected. In vitro, TR4 knockdown and overexpression in JS-1 cells using lentiviral vectors were constructed, and the expressions of TR4, α-SMA, Col-I, and TGF-β1/smads and retinoid X receptor (RXR) pathway-related genes were detected. Results: TR4 was highly expressed in BDL-induced fibrotic liver, accompanied by increased expression of α-SMA. Knockdown of TR4 significantly inhibited the expressions of α-SMA, Col-I, p-TβRI, and p-Smad2/3, and up-regulated the expression of RXRα in HSCs in vitro. In contrast, TR4 overexpression significantly increased the expressions of α-SMA, Col-I, p-TβRI, and p-Smad2/3, and inhibited the expression of RXRα. Conclusions: TR4 may promote the activation of HSCs by up-regulating TβR I/Smad2/3 signaling pathway and down-regulating RXRα signaling, thereby promoting the progression of liver fibrosis. Our findings may provide a new therapeutic target against hepatic fibrosis.

Renal fibrosis, characterized by the destruction of renal tubules and interstitial capillaries and the accumulation of extracellular matrix proteins, is a common outcome of chronic renal diseases and has a wide spectrum of etiologies. Fibrosis can affect any organ and has similar pathological mechanisms. Fuzheng Huayu formula (FZHY), as the approved anti-liver fibrosis medicine in China, also can inhibit the kidney fibrosis induced by HgCl2 or unilateral ureteral obstruction. However, little is known about the mechanisms underlying the beneficial effects of FZHY on renal fibrosis. This study aimed to identify the mechanisms of FZHY acts on renal fibrosis through network pharmacological analysis and in vivo experiments. Data from online databases were mined and screened to predict the target related genes of FZHY acts on renal fibrosis. The STRING and Cytoscape were used to construct the protein-protein interaction (PPI) networks for FZHY and CKD target proteins. Mouse models with CKD induced by Aristolochic Acid I (AAI) were used to validate the effects of FZHY on renal fibrosis and their underlying mechanisms by detecting kidney function, renal fibrosis, and related intersection genes. A total of 129 FZHY–CKD crossover proteins were filtered and constructed into a protein–protein interaction network complex and designated as the potential targets of FZHY. One of the highest-scoring genes, FOS, and its related signaling pathways were more activated in CKD. The results demonstrated that FZHY can exert an anti-renal fibrosis effect by improving the levels of serum creatinine and blood urea nitrogen and alleviating excessive collagen deposition in kidney tissue, FZHY also could reduce the levels of TNF-α, IL-1β, and IL-6 and inhibit the expression of MAPK/FOS signal molecules. Our study findings provide insights into predicting the effects of FZHY on CKD through network pharmacology. FZHY can protect the kidney from inflammatory injury caused by AAI and can antagonize inflammatory factor-stimulated MAPK/FOS activation in fibrotic kidneys. These effects constitute the mechanisms of FZHY for renal fibrosis.

Backgroud and aims: Ductular reaction (DR) is a common pathological change and thought to have a key role in the pathogenesis and progression of liver fibrosis. Our previous study reported Gypenosides (GPs) ameliorated liver fibrosis, however, the anti-fibrotic mechanisms of GPs are still unclear.Methods: Liver fibrosis was induced in rats by carbon tetrachloride combining with 2-acerylaminofluorene (CCl4/2-AAF), and Mdr2 knockout (Mdr2−/−) mice to evaluate the anti-fibrotic role of GPs. In vitro, WB-F344 cells, a hepatic progenitor cells (HPCs) line, with or without Gli1 overexpressing lentiviral vectors, were induced by sodium butyrate (SB) to validate the mechanism of GPs and NPLC0393, the main ingredient of GPs.Results: Both in CCl4/2-AAF-treated rats and Mdr2−/− mice, GPs obviously reduced the deposition of collagen and hydroxyproline content, inhibited the activation of hepatic stellate cells and inflammatory cell infiltration. Notably, GPs reduced the expressions of Epcam, CK19, CK7, Dhh, Smo, Ptch2, Gli1 and Gli2. Furthermore, CK19+ cells co-expressed Gli1, while the number of CK19+/Gli1+ cells was decreased by GPs. In vitro, GPs and NPLC0393 inhibited the differentiation of WB-F344 cells toward a biliary phenotype. Mechanistically, GPs and NPLC0393 protected against DR by inhibiting hedgehog signaling, which was supported by the results that DR, triggered directly by Gli1 overexpressing lentiviral vector was blocked by administration with GPs or NPLC0393.Conclusion: GPs attenuated DR and liver fibrosis by inhibiting hedgehog signaling, which provided more evidences and a novel mechanism of anti-fibrotic effect of GPs.

Cholestatic liver disease (CLD) is a chronic liver disease characterized by ductular reaction, inflammation and fibrosis. As there are no effective chemical or biological drugs now, majority of CLD patients eventually require liver transplantation. Astragali radix (AR) is commonly used in the clinical treatment of cholestatic liver disease and its related liver fibrosis in traditional Chinese medicine, however its specific active constituents are not clear. Total astragalus saponins (ASTs) were considered to be the main active components of AR. The aim of this study is to investigate the improvement effects of the total astragalus saponins (ASTs) and its main constituents in cholestatic liver disease. The ASTs from AR was prepared by macroporous resin, the content of saponins was measured at 60.19 ± 1.68%. The ameliorative effects of ASTs (14, 28, 56 mg/kg) were evaluated by 3, 5-Diethoxycarbonyl-1, 4-dihydrocollidine (DDC)-induced CLD mouse model. The contents of hydroxyproline (Hyp), the mRNA and protein expression of cytokeratin 19 (CK19) and α-smooth muscle actin (α-SMA) in liver tissue were dose-dependently improved after treatment for ASTs. 45 astragalus saponins were identified in ASTs by UHPLC-Q-Exactive Orbitrap HRMS, including astragaloside I, astragaloside II, astragaloside III, astragaloside IV, isoastragaloside I, isoastragaloside II, cycloastragenol, etc. And, it was found that ductular reaction in sodium butyrate-induced WB-F344 cell model were obviously inhibited by these main constituents. Finally, the improvement effects of astragaloside I, astragaloside II, astragaloside IV and cycloastragenol (50 mg/kg) were evaluated in DDC-induced CLD mice model. The results showed that astragaloside I and cycloastragenol significantly improved mRNA and protein expression of CK19 and α-SMA in liver tissue. It suggested that astragaloside I and cycloastragenol could alleviate ductular reaction and liver fibrosis. In summary, this study revealed that ASTs could significantly inhibit ductular reaction and liver fibrosis, and astragaloside I and cycloastragenol were the key substances of ASTs for treating cholestatic liver disease.

Astragali Radix (AR) has been widely used in traditional Chinese medicine prescriptions for acute and chronic liver injury. However, little is known about the effects of AR on acetaminophen (APAP)-induced liver injury (ALI). In the current study, a network pharmacology–based approach was applied to characterize the action mechanism of AR on ALI. All compounds of AR were obtained from the corresponding databases, and active compounds were selected according to its oral bioavailability and drug-likeness index. The potential genes of AR were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), and the Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine (BATMAN-TCM) and PubChem, whereas the potential genes related to ALI were obtained from Online databases (GeneCards and Online Mendelian Inheritance in Man) and Gene Expression Omnibus profiles. The enriched processes, pathways, and target genes of the diseases were analyzed by referring to the Search Tool for the Retrieval of Interacting Genes/Proteins database. A network constructed through Cytoscape software was used to identify the target proteins that connected the compounds in AR with the differential genes of ALI. Subsequently, the potential underlying action mechanisms of AR on ALI predicted by the network pharmacology analyses were experimentally validated in APAP-induced liver injury in mice and HL7702 cells incubated with APAP. The compound-target network included 181 targets, whereas the potential genes related to ALI were 4,621. A total of 49 AR–ALI crossover proteins, corresponding to 49 genes, were filtered into a protein–protein interaction network complex and designated as the potential targets of AR on ALI. Among the genes, the three highest-scoring genes, MYC, MAPK8, and CXCL8 were highly associated with apoptosis in ALI. Then in vitro and in vivo experiments confirmed that AR exhibited its prominent therapeutic effects on ALI mainly via regulating hepatocyte apoptosis related to inhibiting the expressions of MYC (c-Myc), MAPK8 (JNK1), and CXCL8 (IL-8). In conclusion, our study suggested that the combination of network pharmacology prediction with experimental validation might offer a useful tool to characterize the molecular mechanism of AR on ALI.

Numerous clay bricks produced by the demolition of old buildings occupy large amounts of valuable land resources and cause serious environmental pollution in the process of transportation, landfill and storage. The objective of this work is to evaluate the feasibility of using waste clay bricks as fine aggregates (CBFA) to prepare sustainable plastering mortar meeting the requirements of GB/T 25181-2019. The effects of CBFA on fresh and hardened properties of plastering mortar have been studied by water requirement, water retention, consistency loss rate, setting time, compressive strength, tensile bonding strength and drying shrinkage. Furthermore, the microstructure of plastering mortar has also been studied to understand the mechanism of CBFA on plastering mortar. The results demonstrate that CBFA can improve water retention of plastering mortar at all dosages (30%, 40%, 50% and 60%), and enhance compressive strength as well as tensile bond strength at 30% dosage. In addition, CBFA can refine the pore diameter and optimize interfacial transition zone (between cement paste and CBFA) of plastering mortar. Nevertheless, CBFA can increase consistency loss rate, drying shrinkage and porosity, and shorten setting time of plastering mortar. In summary, the maximum amount of CBFA in the plastering mortar that can meet the standard requirements is 50% of the total amount of fine aggregates. The utilization of CBFA to prepare plastering mortar not only expands the application range of waste clay bricks and reduces the consumption of natural river sand, but also produces economical green plastering mortar and benefits the sustainable development of building materials.

Dynamics of a spherical particle and the suspending low-Reynolds-number fluid confined by a cubic cavity were studied numerically. We calculated the particle’s hydrodynamic mobilities along x-, y-, and z-directions at various locations in the cavity. The mobility is largest in the cavity center and decays as the particle becomes closer to no-slip walls. It was found that mobilities in the entire cubic cavity can be determined by a minimal set in a unit tetrahedron therein. Fluid vortices in the cavity induced by the particle motion were observed and analyzed. We also found that the particle can exhibit a drift motion perpendicular to the external force. Magnitude of the drift velocity normalized by the velocity along the direction of the external force depends on particle location and particle-to-cavity sizes ratio. This work forms the basis to understand more complex dynamics in microfluidic applications such as intracellular transport and encapsulation technologies.

Sparse-view scanning has great potential for realizing ultra-low-dose computed tomography (CT) examination. However, noise and artifacts in reconstructed images are big obstacles, which must be handled to maintain the diagnosis accuracy. Existing sparse-view CT reconstruction algorithms were usually designed for circular imaging geometry, whereas the helical imaging geometry is commonly adopted in the clinic. In this paper, we show that the sparse-view helical CT (SHCT) images contain not only noise and artifacts but also severe anatomical distortions. These troubles reduce the applicability of existing sparse-view CT reconstruction algorithms. To deal with this problem, we analyzed the three-dimensional (3D) anatomical structure sparsity in SHCT images. Based on the analyses, we proposed a tensor decomposition and anisotropic total variation regularization model (TDATV) for SHCT reconstruction. Specifically, the tensor decomposition works on nonlocal cube groups to exploit the anatomical structure redundancy; the anisotropic total variation works on the whole volume to exploit the structural piecewise-smooth. Finally, an alternating direction method of multipliers is developed to solve the TDATV model. To our knowledge, the paper presents the first work investigating the reconstruction of sparse-view helical CT. The TDATV model was validated through digital phantom, physical phantom, and clinical patient studies. The results reveal that SHCT could serve as a potential solution for reducing HCT radiation dose to ultra-low level by using the proposed TDATV model.

Context Our previous studies indicated that Yiguanjian decoction (YGJ) has an anti-hepatic-fibrosis effect and could regulate macrophage status. Objective To elucidate the mechanism of YGJ in regulating macrophages. Materials and methods Liver cirrhosis was induced by CCl4 for 12 weeks combined with 2-acetylaminofluorene (2-AAF) for the last 4 weeks in male Wistar rats. YGJ (3.56 mg/kg) orally administered in the last 4 weeks, and SORA (1 mg/kg) as control. In vitro, RAW264.7 cells were treated with lipopolysaccharides (LPSs) to induce macrophage polarization to the M1 phenotype, and they were co-cultured with WB-F344 cells and allocated to M group, YGJ group (2 μg/mL) and WIF-1 group (1 μg/mL) with untreated cells as control. The differentiation direction of WB-F344 cell line was observed in the presence or absence of YGJ. Pathology, fibrosis-related cytokines, macrophage polarization-related components, and Wnt signalling pathway components were detected. Results In vivo, the expression levels of α-SMA, Col (1), OV6, SOX9, EpCAM and M1 macrophage-related components (STAT1, IRF3, IRF5, IRF8, SOCS3) significantly decreased in the YGJ group compared with those in the 2-AAF/CCl4 group (p

Context Xiayuxue decoction (XYXD), a traditional Chinese medicine, is used for treating liver disease. However, the potential active constituents and mechanisms are still unclear. Objective To explore the main active fraction extracts, active ingredients and possible mechanisms of XYXD for anti-hepatic fibrosis. Materials and methods Different fractions including ethyl acetate fraction (EF) were prepared from XYXD. These fractions, especially EF, were used to evaluate cell viability, proliferation, cell cycle, cytotoxicity and activation in hepatic stellate cells (HSCs). Liver fibrosis model was established by CCl4 in C57BL/6 mice, and allocated to CCl4 group, XYXD group and EF group with normal mice as control. Further, mitochondrial apoptosis-related proteins of HSCs, destruction and angiogenesis of liver sinusoidal endothelial cells (LSECs) and active ingredients of EF were evaluated. Results The inhibition of proliferation, increase of S or/and G2/M phase population and suppression of α-SMA and COL-1 expression were obeserved in EF treated-JS1 and -LX2. Liver fibrosis-related indicators were improved by EF similar to XYXD in vivo. EF induced the apoptosis of HSCs in CCl4-induced fibrosis, and inhibited the expression of HSCs apoptosis pathway-related proteins (JNK and p38-MAPKs), and LSECs destruction and angiogenesis. Multiple ingredients (emodin, rhein, aloe-emodin, prunasin) in EF have shown inhibited the activation of JS1. Discussion and Conclusion EF was the main active fraction extracts of XYXD, and the underlying mechanisms might relate to induction of HSCs apoptosis. Emodin, rhein, aloe-emodin and prunasin were main active ingredients of EF, which provides a potential drug for the treatment of liver fibrosis.

Various isoforms of myocyte enhancer factor 2 (MEF2) have been shown to play a role in the activation of rat hepatic stellate cells (HSCs) in culture. The signals that regulate MEF2 in HSCs are unknown. In addition, whether MEF2s regulate the activation of human HSCs (H-HSCs) is unclear. Here, we studied the expression and function of MEF2s in H-HSCs. Our data showed that the levels of MEF2A, C, and D proteins were high in liver tissues from patients with cirrhosis and increased during culture-induced activation of primary H-HSCs. Exposure of H-HSCs to transforming growth factor beta 1 (TGF-β1) led to a significant increase in MEF2A and C protein levels and enhanced MEF2 activity. Interestingly, TGF-β1 did not further enhance MEF2D levels. Furthermore, TGF-β1 activated p38 mitogen-activated protein kinase (MAPK) and led to increased phosphorylation of MEF2C at its p38 recognition site. Inhibition of p38 MAPK inhibited both TGF-β1- and culture-induced activation of MEF2. The activity of collagen I reporter in H-HSCs was significantly reduced when MEF2A and MEF2C were blocked with overexpression of dominant negative MEF2 mutants. Salvianolic-acid B (SA-B), a water-soluble element of Salvia miltiorrhiza known to have anti-fibrosis effects, attenuated both basal and TGF-β1-induced increased levels of MEF2A and C mRNA and protein. In addition, SA-B inhibited MEF2 activity, which correlated with reduced expression of the HSC activation markers, α-smooth muscle actin (α-SMA), and collagen I. Administration of SA-B reduced MEF2A in vivo, which was accompanied by reduced levels of α-SMA in a model of dimethylnitrosamine-induced rat liver fibrosis. We concluded that the MEF2 transcription factor was stimulated by TGF-β1 in H-HSCs. Antagonizing TGF-β1-induced activation of the MEF2 signaling pathway may account in part for the anti-fibrosis effects of SA-B.

This study proposes a new method to distinguish between the different qualities of dry alfalfa. This method uses scanning electron microscopy (SEM) to obtain grayscale images, and. then, using an equalized histogram, the gray-level co-occurrence matrix (GLCM) extracts 14 texture features. The texture feature vector is processed by principal component analysis (PCA) and linear discriminant analysis (LDA) to reduce data redundancy and extract the best features. Finally, a back propagation neural network (BPNN) algorithm, an artificial neural network (ANN) and a least square support vector machine (LS-SVM) classification model are established to evaluate the classification effect. The results show that LDA is more effective in transforming the original data. In addition, LDA-based classification results are better than PCA-based classification results, and the recognition rate is 100% accurate. In contrast, the reliability and potential of extracting the main information based on LDA are shown. Based on these conclusions, it is possible to identify various types of alfalfa after different drying methods.

The present study was performed to evaluate the food safety of TT51-1, a new type of genetically modified rice that expresses the Cry1Ab/Ac protein (Bt toxin) and is highly resistant to most lepidopteran pests. Sixteen male and 16 female cynomolgus monkeys were randomly divided into four groups: conventional rice (non-genetically modified rice, non-GM rice), positive control, 17.5% genetically modified rice (GM rice) and 70% GM rice. Monkeys in the non-GM rice, positive control, and GM rice groups were fed on diets containing 70% non-GM rice, 17.5% GM rice or 70% GM rice, respectively, for 182 days, whereas animals in the positive group were intravenously injected with cyclophosphamide every other day for a total of four injections before the last treatment. Six months of treatment did not yield abnormal observations. Specifically, the following parameters did not significantly differ between the non-GM rice group and GM rice groups: body weight, food consumption, electrocardiogram, hematology, immuno-phenotyping of lymphocytes in the peripheral blood, mitogen-induced peripheral blood lymphocyte proliferation, splenocyte proliferation, KLH-T cell-dependent antibody response, organ weights and ratios, and histological appearance (p>0.05). Animals from the GM rice group differed from animals in the non-GM rice group (p

Hepatic progenitor cells (HPCs) appear to play an important role in chronic liver injury. In this study, cirrhosis was induced in F-344 rats (n = 32) via subcutaneous injection of 50% carbon tetrachloride (CCl4) twice a week for 8 weeks. Then, 30% CCl4 was administered in conjunction with intragastric 2-acetylaminofluorine (2-AAF) for 4 weeks to induce activation of HPCs. WB-F344 cells were used to provide direct evidence for differentiation of HPCs to myofibroblasts. The results showed that after administration of 2-AAF, the hydroxyproline content and the expressions of α-SMA, Col I, Col IV, TGF-β1, CD68, TNF-α, CK19 and OV6 were significantly increased. OV6 and α-SMA were largely co-expressed in fibrous septum and the expressions of Wnt5b, frizzled2, frizzled3 and frizzled6 were markedly increased, while β-catenin expression was not statistically different among the different groups. Consistent with the above results, WB-F344 cells, treated with TGF-β1 in vitro, differentiated into myofibroblasts and α-SMA, Col I, Col IV, Wnt5b and frizzled2 expressions were significantly increased, while β-catenin expression was decreased. After blocking the non-canonical Wnt pathway via WIF-1, the Wnt5b level was down regulated, and α-SMA and F-actin expressions were significantly decreased in the WIF-1-treated cells. In conclusion, these results indicate that HPCs appear to differentiate into myofibroblasts and exhibit a profibrotic effect in progressive cirrhosis via activation of the non-canonical Wnt pathway. Blocking the non-canonical Wnt pathway can inhibit the differentiation of HPCs into myofibroblasts, suggesting that blocking this pathway and changing the fate of differentiated HPCs may be a potential treatment for cirrhosis.

Abstract Background The visual organ plays a crucial role in sensing environmental information. However, its mucosal surfaces are constantly exposed to selective pressures from aquatic or airborne pathogens and microbial communities. Although few studies have characterized the conjunctival-associated lymphoid tissue (CALT) in the ocular mucosa (OM) of birds and mammals, little is known regarding the evolutionary origins and functions of immune defense and microbiota homeostasis of the OM in the early vertebrates. Results Our study characterized the structure of the OM microbial ecosystem in rainbow trout (Oncorhynchus mykiss) and confirmed for the first time the presence of a diffuse mucosal-associated lymphoid tissue (MALT) in fish OM. Moreover, the microbial communities residing on the ocular mucosal surface contribute to shaping its immune environment. Interestingly, following IHNV infection, we observed robust immune responses, significant tissue damage, and microbial dysbiosis in the trout OM, particularly in the fornix conjunctiva (FC), which is characterized by the increase of pathobionts and a reduction of beneficial taxa in the relative abundance in OM. Critically, we identified a significant correlation between viral-induced immune responses and microbiome homeostasis in the OM, underscoring its key role in mucosal immunity and microbiota homeostasis. Conclusions Our findings suggest that immune defense and microbiota homeostasis in OM occurred concurrently in early vertebrate species, shedding light on the coevolution between microbiota and mucosal immunity. Video Abstract

The eye of vertebrates is constantly faced with numerous challenges from aquatic or airborne pathogens. As a crucial first line of defense, the ocular mucosa (OM) protects the visual organ from external threats in vertebrates such as birds and mammals. However, the understanding of ocular mucosal immunity in early vertebrates, such as teleost fish, remains limited, particularly concerning their resistance to bacterial infections. To gain insights into the pivotal role of the OM in antibacterial immunity among teleost fish, we developed a bacterial infection model using Flavobacterium columnare in rainbow trout (Oncorhynchus mykiss). Here the qPCR and immunofluorescence results showed that F. columnare could invade trout OM, suggesting that the OM could be a primary target and barrier for the bacteria. Moreover, immune-related genes (il-6, il-8, il-11, cxcl10, nod1, il1-b, igm, igt, etc.) were upregulated in the OM of trout following F. columnare infection, as confirmed by qPCR, which was further proved through RNA-seq. The results of transcriptome analyses showed that bacterial infection critically triggers a robust immune response, including innate, and adaptive immune-related signaling pathways such as Toll-like, NOD-like, and C-type lectin receptor signaling pathway and immune network for IgA production, which underscores the immune role of the OM in bacterial infection. Interestingly, a substantial reduction in the expression of genes associated with visual function was observed after infection, indicating that bacterial infection could impact ocular function. Overall, our findings have unveiled a robust mucosal immune response to bacterial infection in the teleost OM for the first time, providing valuable insights for future research into the mechanisms and functions of ocular mucosal immunity in early vertebrate species.

Abstract The air-filled organs (AOs) of vertebrates (lungs and swim bladders) have evolved unique functions (air-breathing or buoyancy control in water) to adapt to different environments. Thus far, immune responses to microbes in AOs have been described exclusively in the lungs of tetrapods. Similar to lungs, swim bladders (SBs) represent a mucosal surface, a feature that leads us to hypothesize a role for SB in immunity. In this study, we demonstrate that secretory IgT (sIgT) is the key SB immunoglobulin (Ig) responding to the viral challenge, and the only Ig involved in viral neutralization in that organ. In support of these findings, we found that the viral load of the SB from fish devoid of sIgT was much higher than that of control fish. Interestingly, similar to the lungs in mammals, the SB represents the mucosal surface in fish with the lowest content of microbiota. Moreover, sIgT is the main Ig class found coating their surface, suggesting a key role of this Ig in the homeostasis of the SB microbiota. In addition to the well-established role of SB in buoyancy control, our findings reveal a previously unrecognized function of teleost SB in adaptive mucosal immune responses upon pathogenic challenge, as well as a previously unidentified role of sIgT in antiviral defense. Overall, our findings indicate that despite the phylogenetic distance and physiological roles of teleost SB and mammalian lungs, they both have evolved analogous mucosal immune responses against microbes which likely originated independently through a process of convergent evolution.

Abstract Transformer models have made great progress in automatic speech recognition. However, it is challenging for streaming transformer models to make trade‐off between output latency and recognition accuracy. In this letter, it is aimed to propose a low‐latency transformer model with satisfactory recognition accuracy. First, a streaming transformer is designed and explain how it works streamingly. Second, the authors propose to use CTC during training to minimise the latency of transformer models. Finally, the authors also propose to utilise CTC as a backup during decoding to ensure that the low‐latency characteristic is maintained. The authors fairly compare our streaming transformer model to existing streaming models, particularly the transducer model, which is a popular low‐latency approach. The experiments show that, while having comparable output latency, the transformer model outperforms the transducer model by average relative character (or word) error rate reduction of 22.18%, 26.71% and 19.36% on HKUST, Switchboard and Call Home, respectively.

In conventional communication systems, the random access (RA) is a necessary procedure for a user equipment (UE) to establish wireless connection to the network before actual data transmission.Focusing on the massive IoT with large number of nodes, the fundamental characteristics and limitations of conventional grant-based RA were firstly discussed.Then, the grant-free RA, semi-grant-free RA and unsourced RA for massive IoT were addressed in details from multiple perspectives, including their system models, protocol frameworks, algorithm procedures, system performance, related pros and cons, as well as critical challenges and potential opportunities.Finally, some highlights on the related key techniques and common issues in random access for massive IoT were concluded.

The fish intestinal mucosa is among the main sites through which environmental microorganisms interact with the host. Therefore, this tissue not only constitutes the first line of defense against pathogenic microorganisms but also plays a crucial role in commensal colonization. The interaction between the mucosal immune system, commensal microbiota, and viral pathogens has been extensively described in the mammalian intestine. However, very few studies have characterized these interactions in early vertebrates such as teleosts. In this study, rainbow trout (Oncorhynchus mykiss) was infected with infectious hematopoietic necrosis virus (IHNV) via a recently developed immersion method to explore the effects of viral infection on gut immunity and microbial community structure. IHNV successfully invaded the gut mucosa of trout, resulting in severe tissue damage, inflammation, and an increase in gut mucus. Moreover, viral infection triggered a strong innate and adaptive immune response in the gut, and RNA−seq analysis indicated that both antiviral and antibacterial immune pathways were induced, suggesting that the viral infection was accompanied by secondary bacterial infection. Furthermore, 16S rRNA sequencing also revealed that IHNV infection induced severe dysbiosis, which was characterized by large increases in the abundance of Bacteroidetes and pathobiont proliferation. Moreover, the fish that survived viral infection exhibited a reversal of tissue damage and inflammation, and their microbiome was restored to its pre−infection state. Our findings thus demonstrated that the relationships between the microbiota and gut immune system are highly sensitive to the physiological changes triggered by viral infection. Therefore, opportunistic bacterial infection must also be considered when developing strategies to control viral infection.

Objective To observe the effect of different doses of ε-aminocaproic acid （EACA） on wound bleeding in infants undergoing cleft palate repair. Methods One hundred and twenty infants scheduled to undergo cleft palate repair， aged from 6 to 36 months， ASA status Ⅰ or Ⅱ， were randomly divided into the control （group C）， conventional-dose EACA （group E1） and low-dose EACA groups （group E2）， 40 cases in each group. Infants in groups E1 and E2 were administrated with a loading dose of EACA （40 mg/kg） for 20 min before incision， followed by continuous infusion of 30 mg/（kg·h） and 10 mg/（kg·h） in two groups， respectively. In group C， continuous infusion of normal saline was applied. Same anesthesia regimen was delivered for all patients among three groups. Wound bleeding scores during operation， before extubation and 24 h after operation， intraoperative blood loss， anesthesia time， operation time， and fibrinogen concentration before and 24 h after surgery， and the incidence of delayed haemorrhage， deep vein thrombosis and epilepsy were recorded. Results Compared with group C， the wound bleeding scores during operation and before extubation in group E1 and E2 were significantly lower， the amount of intraoperative blood loss was significantly less， and the fibrinogen concentration at postoperative 24 h was significantly increased （all P < 0.05）， while no significant statistical difference was observed between groups E1 and E2 （all P > 0.05）. There were no statistically significant differences in operation time， anesthesia time and the incidence of delayed hemorrhage among three groups （all P > 0.05）. No deep vein thrombosis or epilepsy occurred among three groups. Conclusion The application of EACA in infants with cleft palate repair can mitigate perioperative wound bleeding and lower the incidence of delayed hemorrhage. Low-dose EACA yields favorable hemostatic effect. These findings provide reference for drug use in clinical practice.