Highly-dispersed 2D NiFeP/CoP heterojunction trifunctional catalyst for efficient electrolysis of water and urea.

The electrocatalytic production of "green hydrogen", such as through the electrolysis of water or urea has been vigorously advocated to alleviate the energy crisis. However, their electrode reactions including oxygen evolution reaction (OER), urea oxidation reaction (UOR), and hydrogen evolution reaction (HER) all suffer from sluggish kinetics, which urgently need catalysts to accelerate the processes. Herein, we design and prepare an OER/UOR/HER trifunctional catalyst by transforming the homemade CoO nanorod into a two-dimensional (2D) ultrathin heterojunction nickel-iron-cobalt hybrid phosphides nanosheet (NiFeP/CoP) via a hydrothermal-phosphorization method. Consequently, a strong electronic interaction was found among the Ni2P/FeP4/CoP heterogeneous interfaces, which regulates the electronic structure. Besides the high mass transfer property of 2D nanosheet, Ni2P/FeP4/CoP displays improved OER/UOR/HER performance. At 10 mA cm-2, the OER overpotential reaches 274 mV in 1.0 M KOH, and the potential of UOR is only 1.389 V in 1.0 M KOH and 0.33 M urea. More strikingly, the two-electrode systems for electrolysis water and urea-assisted electrolysis water assembled by NiFeP/CoP could maintain long-term stability for 35 h and 12 h, respectively. This work may help to pave the way for upcoming research horizons of multifunctional electrocatalysts.

Group 1 innate lymphoid cell activation via recognition of NKG2D and liver resident macrophage MULT-1: Collaborated roles in triptolide induced hepatic immunotoxicity in mice.

Triptolide (TP) is the major bioactive component of traditional Chinese medicine Tripterygium wilfordii Hook. F., a traditional Chinese medicinal plant categorized within the Tripterygium genus of the Celastraceae family. It is recognized for its therapeutic potential in addressing a multitude of diseases. Nonetheless, TP is known to exhibit multi-organ toxicity, notably hepatotoxicity, which poses a significant concern for the well-being of patients undergoing treatment. The precise mechanisms responsible for TP-induced hepatotoxicity remain unresolved. In our previous investigation, it was determined that TP induces heightened hepatic responsiveness to exogenous lipopolysaccharide (LPS). Additionally, natural killer (NK) cells were identified as a crucial effector responsible for mediating hepatocellular damage in this context. However, associated activating receptors and the underlying mechanisms governing NK cell represented innate lymphoid cell (ILC) activation remained subjects of inquiry and were not yet investigated. Herein, activating receptor Killer cell lectin like receptor K1 (NKG2D) of group 1 ILCs was specifically upregulated in TP- and LPS-induced acute liver failure (ALF), and in vivo blockade of NKG2D significantly reduced group 1 ILC mediated cytotoxicity and mitigated TP- and LPS-induced ALF. NKG2D ligand UL16-binding protein-like transcript 1 (MULT-1) was found upregulated in liver resident macrophages (LRMs) after TP administration, and LRMs did exhibit NK cell activating effect. Furthermore, M1 polarization of LRMs cells was observed, along with an elevation in intracellular tumor necrosis factor (TNF)-α levels. In vivo neutralization of TNF-α significantly alleviated TP- and LPS-induced ALF. In conclusion, the collaborative role of group 1 ILCs and LRMs in mediating hepatotoxicity was confirmed in TP- and LPS-induced ALF. TP-induced MULT-1 expression in LRMs was the crucial mechanism in the activation of group 1 ILCs via MULT-1-NKG2D signal upon LPS stimulation, emphasizing the importance of infection control after TP administration.

Obeticholic acid protects against lithocholic acid-induced exogenous cell apoptosis during cholestatic liver injury.

AIMS: Lithocholic acid (LCA)-induced cholestasis was accompanied by the occurrence of apoptosis, which indicated that anti-apoptosis was a therapeutic strategy for primary biliary cholangitis (PBC). As an agonist of (Farnesoid X receptor) FXR, we supposed that the hepatoprotection of Obeticholic acid (OCA) against cholestatic liver injury is related to anti-apoptosis beside of the bile acids (BAs) regulation. Herein, we explored the non-metabolic regulating mechanism of OCA for resisting LCA-induced cholestatic liver injury via anti-apoptosis. MAIN METHODS: LCA-induced cholestatic liver injury mice were pretreated with OCA to evaluate its hepatoprotective effect and mechanism. Biochemical and pathological indicators were used to detect the protective effect of OCA on LCA-induced cholestatic liver injury. The bile acids (BAs) profile in serum was detected by LC-MS/MS. Hepatocyte BAs metabolism, apoptosis and inflammation related genes and proteins alteration were investigated by biochemical determination. KEY FINDINGS: OCA improved LCA-induced cholestasis and hepatic apoptosis in mice. The BA profile in serum was changed by OCA mainly manifested as a reduction of taurine-conjugated bile acids, which was due to the upregulation of FXR-related bile acid efflux transporters bile salt export pump (BSEP), multi-drug resistant associated protein 2 (MRP2), MRP3 and multi-drug resistance 3 (MDR3). Apoptosis related proteins cleaved caspase-3, cleaved caspase-8 and cleaved PARP were obviously reduced after OCA treatment. SIGNIFICANCE: OCA improved LCA-induced cholestatic liver injury via FXR-induced exogenous cell apoptosis, which will provide new evidence for the application of OCA to ameliorate PBC in clinical.

TP induces hepatic intolerance to FasL-mediated hepatocyte apoptosis by inhibiting XIAP.

Triptolide (TP) is extracted from the traditional Chinese medicine Tripterygium wilfordii Hook. F. (TWHF). Its severe toxic side effects, especially hepatotoxicity, have limited the clinical application of TP-related drugs. In this study, we investigated the mechanism of the hepatotoxic effects of TP from the perspective that TP inhibited the expression of the pro-survival protein X-linked inhibitor of apoptosis protein (XIAP) and enhanced FasL-mediated apoptosis of hepatocytes. TP and CD95/Fas antibody (Jo-2) were administered by gavage to C57BL/6 mice for 7 consecutive days. After co-administration of TP and Jo-2, mouse livers showed large areas of necrosis and apoptosis and significantly increased Caspase-3 activity. KEGG pathway enrichment analysis indicated that TP may cause the development of liver injury through the apoptotic signaling pathway. Proteinprotein interaction networks showed that XIAP played an essential role in this process. TP reduced the protein expression of XIAP after combination treatment with Jo-2/FasL in vivo/in vitro. TP and FasL co-stimulation significantly increased microRNA-137 (miR-137) levels in AML12 cells, while inhibition of miR-137 expression induced a rebound in XIAP protein expression. In conclusion, TP presensitizes hepatocytes and enhances the sensitivity of hepatocytes to the Fas/FasL pathway by inhibiting the protein expression of XIAP, leading to hepatocyte apoptosis.

Altered resting-state cerebellar-cerebral functional connectivity in patients with end-stage renal disease.

BACKGROUND: End-stage renal disease (ESRD) patients have functional and structural brain abnormalities. The cerebellum also showed varying degrees of damage. However, no studies on cerebellar-cerebral functional connectivity (FC) have been conducted in ESRD patients. This study aimed to investigate the changes in cerebellar-cerebral FC in ESRD patients and its relationship with neuropsychological and clinical indexes. METHODS: Resting-state functional magnetic resonance imaging and neuropsychological assessment were performed on 37 ESRD patients and 35 control subjects. Seed-based FC analysis was performed to investigate inter-group differences in cerebellar-cerebral FC. In addition, the relations of altered FC with the neuropsychological function and clinical indicators were analyzed in ERSD patients. RESULTS: ESRD patients exhibited alterations in cerebellar-cerebral FC involving the executive control network, default mode network, and affective-limbic network compared to control subjects (False discovery rate-corrected, p < 0.05). The altered cerebellar-cerebral FC was associated with the Montreal Cognitive Assessment Scale score (p < 0.05), and correlated with serum creatinine and uric acid levels within the ESRD group (p < 0.05). CONCLUSIONS: The study indicates that cerebellar-cerebral FC is involved in the neural substrates of cognitive impairment in ESRD patients. The findings may provide clinically relevant new neuroimaging biomarkers for the neuropathological mechanisms underlying cognitive impairment of ESRD.

Carbon dot-based nanomaterials: a promising future nano-platform for targeting tumor-associated macrophages.

The tumor microenvironment (TME) is the internal environment that tumors depend on for survival and development. Tumor-associated macrophages (TAMs), as an important part of the tumor microenvironment, which plays a crucial role in the occurrence, development, invasion and metastasis of various malignant tumors and has immunosuppressant ability. With the development of immunotherapy, eradicating cancer cells by activating the innate immune system has yielded encouraging results, however only a minority of patients show a lasting response. Therefore, in vivo imaging of dynamic TAMs is crucial in patient-tailored immunotherapy to identify patients who will benefit from immunotherapy, monitor efficacy after treatment, and identify alternative strategies for non-responders. Meanwhile, developing nanomedicines based on TAMs-related antitumor mechanisms to effectively inhibit tumor growth is expected to become a promising research field. Carbon dots (CDs), as an emerging member of the carbon material family, exhibit unexpected superiority in fluorescence imaging/sensing, such as near infrared imaging, photostability, biocompatibility and low toxicity. Their characteristics naturally integrate therapy and diagnosis, and when CDs are combined with targeted chemical/genetic/photodynamic/photothermal therapeutic moieties, they are good candidates for targeting TAMs. We concentrate our discussion on the current learn of TAMs and describe recent examples of macrophage modulation based on carbon dot-associated nanoparticles, emphasizing the advantages of their multifunctional platform and their potential for TAMs theranostics.

Synergistic Effect of N-NiMoO4 /Ni Heterogeneous Interface with Oxygen Vacancies in N-NiMoO4 /Ni/CNTs for Superior Overall Water Splitting.

The exploring of economical, high-efficiency, and stable bifunctional catalysts for hydrogen evolution and oxygen evolution reactions (HER/OER) is highly imperative for the development of electrolytic water. Herein, a 3D cross-linked carbon nanotube supported oxygen vacancy (Vo )-rich N-NiMoO4 /Ni heterostructure bifunctional water splitting catalyst (N-NiMoO4 /Ni/CNTs) is synthesized by hydrothermal-H2 calcination method. Physical characterization confirms that Vo -rich N-NiMoO4 /Ni nanoparticles with an average size of ≈19 nm are secondary aggregated on CNTs that form a hierarchical porous structure. The formation of Ni and NiMoO4 heterojunctions modify the electronic structure of N-NiMoO4 /Ni/CNTs. Benefiting from these properties, N-NiMoO4 /Ni/CNTs drives an impressive HER overpotential of only 46 mV and OER overpotential of 330 mV at 10 mA cm-2 , which also shows exceptional cycling stability, respectively. Furthermore, the as-assembled N-NiMoO4 /Ni/CNTs||N-NiMoO4 /Ni/CNTs electrolyzer reaches a cell voltage of 1.64 V at 10 mA cm-2 in alkaline solution. Operando Raman analysis reveals that surface reconstruction is essential for the improved catalytic activity. Density functional theory (DFT) calculations further demonstrate that the enhanced HER/OER performance should be attributed to the synergistic effect of Vo and heteostructure that improve the conductivity of N-NiMoO4 /Ni/CNTs and facilitatethe desorption of reaction intermediates.

Effect of recombinant human growth hormone plus vitamin D on development and lipid metabolism in children with growth hormone deficiency.

The combination of rhGH and vitamin D has been suggested as a potential therapeutic approach for children with GHD. This retrospective study aimed to investigate the impact of recombinant human growth hormone plus vitamin D on development and lipid metabolism in children with growth hormone deficiency. A total of 198 children treated in our hospital from December 2011 to December 2021 were recruited. The study assessed development-related indices, lipid metabolism indices, growth factor indices, thyroid indices, and adverse reactions. After treatment, the development-related indices of children in both groups improved (P < 0.05), but the experimental group showed significantly better HtSDS and annual height growth rate (P < 0.05). Moreover, the experimental group had lower levels of TG, T-CHO, and LDL-C versus the observation group (P < 0.05), while no significant difference was observed in HDL-C levels between the two groups before and after treatment (P > 0.05). Moreover, patients receiving recombinant human growth hormone plus vitamin D had significantly higher IGF-1 and IGFBP-3 levels than those receiving recombinant human growth hormone alone (P < 0.05). The T3, T4, and TSH levels of children in both groups increased after treatment (P < 0.05). The incidence of adverse events did not significantly differ between the two groups (P > 0.05). In conclusion, our findings suggest that recombinant human growth hormone plus vitamin D effectively improves the development and lipid metabolism of children with growth hormone deficiency. Additionally, it increases growth factor levels without compromising thyroid function or increasing the risk of adverse drug reactions.

Triptolide leads to hepatic intolerance to exogenous lipopolysaccharide and natural-killer-cell mediated hepatocellular damage by inhibiting MHC class I molecules.

BACKGROUND: Tripterygium wilfordii Hook. F (TWHF) is used as a traditional Chinese medicine, called thunder god vine, based on its efficacy for treating inflammatory diseases. However, its hepatotoxicity has limited its clinical application. Triptolide (TP) is the major active and toxic component of TWHF. Previous studies reported that a toxic pretreatment dose of TP leads to hepatic intolerance to exogenous lipopolysaccharide (LPS) stimulation, and to acute liver failure, in mice, but the immune mechanisms of TP-sensitised hepatocytes and the TP-induced excessive immune response to LPS stimulation are unknown. PURPOSE: To identify both the key immune cell population and mechanism involved in TP-induced hepatic intolerance of exogenous LPS. STUDY DESIGN: In vitro and in vivo experiments were conducted to investigate the inhibitory signal of natural killer (NK) cells maintained in hepatocytes, and the ability of TP to impair that signal. METHODS: Flow cytometry was performed to determine NK cell activity and hepatocyte histocompatibility complex (MHC) class I molecules expression; the severity of liver injury was determined based on blood chemistry values, and drug- or cell-mediated hepatocellular damage, by measuring lactate dehydrogenase (LDH) release. In vivo H-2Kb transduction was carried out using an adeno-associated viral vector. RESULTS: Interferon (IFN)-γ-mediated necroptosis occurred in C57BL/6N mice treated with 500 µg TP/kg and 0.1 mg LPS/kg to induce fulminant hepatitis. Primary hepatocytes pretreated with TP were more prone to necroptosis when exposed to recombinant murine IFN-γ. In mice administered TP and LPS, the intracellular IFN-γ levels of NK cells increased significantly. Subsequent study confirmed that NK cells were activated and resulted in potent hepatocellular toxicity. In vivo and in vitro TP administration significantly inhibited MHC class I molecules in murine hepatocytes. An in vitro analysis demonstrated the susceptibility of TP-pretreated hepatocytes to NK-cell-mediated cytotoxicity, an effect that was significantly attenuated by the induction of hepatocyte MHC-I molecules by IFN-α. In vivo induction or overexpression of hepatocyte MHC-I also protected mouse liver against TP and LPS-induced injury. CONCLUSION: The TP-induced inhibition of hepatocyte MHC-I molecules expression leads to hepatic intolerance to exogenous LPS and NK-cell mediated cytotoxicity against self-hepatocytes. These findings shed light on the toxicity of traditional Chinese medicines administered for their immunomodulatory effects.

Glycocholic acid aggravates liver fibrosis by promoting the up-regulation of connective tissue growth factor in hepatocytes.

AIMS: The precise role of bile acid in the progression of liver fibrosis has yet to be elucidated. In this study, common bile duct ligation was used as an in vivo mouse model for the evaluation of bile acids that promote liver connective tissue growth factor expression. MAIN METHODS: Primary rat and mice hepatocytes, as well as primary rat hepatic stellate and HepaRG cells were evaluated as in vitro models for promoting the expression of connective tissue growth factor by bile acids. KEY FINDINGS: Compared with taurochenodeoxycholic acid, glycochenodeoxycholic acid, and taurocholic acid, glycocholic acid (GCA) most strongly promoted the secretion of connective tissue growth factor in mouse primary hepatocytes, rat primary hepatocytes and HepaRGs. GCA did not directly promote the activation of hepatic stellate cells. The administration of GCA in mice with ligated bile ducts promotes the progression of liver fibrosis, which may promote the yes-associated protein of hepatocytes into the nucleus, resulting in the hepatocytes secreting more connective tissue growth factor for hepatic stellate cell activation. In conclusion, our data showed that GCA can induce the expression of connective tissue growth factor in hepatocytes by promoting the nuclear translocation of yes-associated protein, thereby activating hepatic stellate cells. SIGNIFICANCE: Our findings help to elucidate the contribution of GCA to the progression of hepatic fibrosis in cholestatic disease and aid the clinical monitoring of cholestatic liver fibrosis development.

Proteomics analysis reveals novel insights into the mechanism of hepatotoxicity induced by Tripterygium wilfordii multiglycoside in mice.

Tripterygium wilfordii multiglycoside (GTW), extracted and purified from the peeled roots of T. wilfordii Hook.f. (TwHF), is a well-known traditional Chinese medicine and applied to various autoimmune diseases clinically. However, it has been reported to cause severe liver injury. At present, the mechanism underlying GTW-induced hepatotoxicity remain poorly defined. Here, we evaluated the effects of GTW on mouse liver and elucidated the associated mechanisms via label-free proteomics combined with bioinformatics analysis. Male C57BL/6J mice were randomly divided into normal group, a low-dose GTW (70 mg/kg) group and a high-dose GTW (140 mg/kg) group. After 1-week administration, GTW dose-dependently induced hepatotoxicity. Further analysis showed that GTW could act on the intestinal immune network for IgA production pathway, which plays an important role in maintaining intestinal homeostasis and influences the crosstalk between gut and liver. Western blots confirmed that GTW could decrease pIgR protein expression in the liver and ileum, and, as a result, the secretion of IgA into gut lumen was reduced. Further validation showed that intestinal barrier integrity was impaired in GTW-treated mice, promoting bacteria transferring to the liver and triggering proinflammatory response. Our study demonstrated that gut-liver axis may play a vital part in the progression of GTW-induced hepatotoxicity, which provides guidance for basic research and clinical application of GTW.

[Overexpression of miRNA-130a-3p alleviates LPS-induced cardiomyocyte injury by regulating autophagy and apoptosis].

Objective: To investigate the effects of miRNA-130a-3p on autophagy and apoptosis induced by LPS in myocardial cells and its molecular mechanisms. Methods: H9C2 cells were divided into five groups: normal control group, LPS model group, miRNA negative control group miRNA-130a-3p mimics group(overexpression of miRNA-130a-3p) and miRNA-130a-3p mimics + LY294002 group(overexpression of miRNA-130a-3p + PI3K inhibitor). The LPS model group was induced by LPS at a final concentration of 10 µg/ml for 24 h. In the miRNA negative control group and miRNA-130a-3p mimics group, negative contro miRNA or miRNA-130a-3p mimics were transfected into H9C2 cells by lipo3000. After 24 h of culture, LPS was added into the medium for 24 hours. In the miRNA -130A-3P mimics + LY294002 group, miRNA -130A-3P mimics was transfected into H9C2 cells by using lipo3000, and LY294002 at a final concentration of 10 µmol/L was added to the culture medium for 24 h, followed by LPS at a concentration of 10 µg/ml for 24 h. The expression of miRNA-130a-3p mRNA in cells was detected by RT-qPCR. The CCK-8 assay was used to detect the cell viability. The contents of TNF-α, IL-6 and IL-1ß were detected by ELISA assay. The contents of SOD and LDH in cell culture medium were detected by colorimetry. Western blot was used to detect the protein expressions of p-PI3K, p-AKT, Bax, Bcl-2, cleaved-caspase-3, LC3 and p62. Results: The results showed that the levels of miRNA-130a-3p mRNA, p-PI3K protein and p-AKT protein in LPS model cells were significantly lower than those in normal control group(P<0.01), and the expressions of p-PI3K, p-AKT protein in miRNA-130a-3p mimics group were increased significantly compared with LPS group(P<0.01,P<0.05). Compared with normal control group, the cell viability was decreased significantly and the contents of TNF-α, IL-6, IL-1ß and LDH were increased significantly(P<0.01), the contents of SOD was decreased significantly in LPS group(P<0.01). The protein expression levels of Bax, cleaved-caspase-3 and p62 were increased significantly, while the expression level of Bcl-2 and LC3II/I ratio were decreased significantly in LPS group(P<0.01). miRNA-130a-3p mimics could increase the cell viability, decrease the contents of TNF-α, IL-6, IL-1ß and LDH(P<0.01,P<0.05), increase the contents of SOD(P<0.05), decrease the expressions of Bax, cleaved caspase-3, p62(P<0.01), promote the expression of Bcl-2(P<0.01) and increase the ratio of LC3II/I(P<0.05). Compared with miRNA-130a-3p mimics group, LY294002 reversed the effects of miRNA-130a-3p mimics on cells. Conclusion: Overexpression miRNA-130a-3p could partly promote autophagy and inhibit cell apoptosis by activating PI3K/AKT signaling pathway to alleviate LPS-induced myocardial injury.

Triptolide increases resistance to bile duct ligation-induced liver injury and fibrosis in mice by inhibiting RELB.

Cholestasis is a common, chronic liver disease that may cause fibrosis and cirrhosis. Tripterygium wilfordii Hook.f (TWHF) is a species in the Euonymus family that is commonly used as a source of medicine and food in Eastern and Southern China. Triptolide (TP) is an epoxy diterpene lactone of TWHF, as well as the main active ingredient in TWHF. Here, we used a mouse model of common bile duct ligation (BDL) cholestasis, along with cultured human intrahepatic biliary epithelial cells, to explore whether TP can relieve cholestasis. Compared with the control treatment, TP at a dose of 70 or 140 µg/kg reduced the serum levels of the liver enzymes alanine transaminase, aspartate aminotransferase, and alkaline phosphatase in mice; hematoxylin and eosin staining also showed that TP reduced necrosis in tissues. Both in vitro and in vivo analyses revealed that TP inhibited cholangiocyte proliferation by reducing the expression of RelB. Immunohistochemical staining of CK19 and Ki67, as well as measurement of Ck19 mRNA levels in hepatic tissue, revealed that TP inhibited the BDL-induced ductular reaction. Masson 3 and Sirius Red staining for hepatic hydroxyproline showed that TP alleviated BDL-induced hepatic fibrosis. Additionally, TP substantially inhibited BDL-induced hepatic inflammation. In summary, TP inhibited the BDL-induced ductular reaction by reducing the expression of RelB in cholangiocytes, thereby alleviating liver injury, fibrosis, and inflammation.

Gut Microbiota Dysbiosis in the Development and Progression of Gastric Cancer.

Objectives: This study aims to explore gut microbiota dysbiosis in the histological stages of gastric cancer (GC). Methods: Feces samples and clinical characteristics were collected from patients with different stages of GC, including 15 superficial gastritis (SG), 13 atrophic gastritis (AG), 8 gastric mucosal atypical hyperplasia (GMAH), and 15 advanced GC cases. The diversity and composition of gut microbiota among the four groups were determined by sequencing the V4 region of bacterial 16S rRNA genes. Results: Reduced gut microbial alpha diversity and altered dissimilarity of the microbial community structure were found among the four groups. In addition, 18 species, 6 species, 6 species, and 16 species of bacteria were enriched in the SG, AG, GMAH, and GC groups, respectively, using the linear discriminant analysis (LDA) effect size (LEfSe) analyses. Besides, we found that two new genera, Scardovia and Halomonas, are associated with GC and the metabolic pathways of Genetic information processing and Circulatory System were more abundant in the GC group compared with noncancer groups. Conclusions: We identified differences in microbial compositional changes across stages of GC. Six genera and two metabolic pathways were more abundant in the GC group than noncancer groups, suggesting that these findings may contribute to the therapy strategies in GC in the near feature.

Obeticholic acid aggravates liver injury by up-regulating the liver expression of osteopontin in obstructive cholestasis.

AIMS: Obeticholic acid (OCA) was approved for the treatment of primary biliary cholangitis (PBC) patients, as it can significantly improve the level of serum alkaline phosphatase. However, OCA-induced liver injury in PBC patients puts them at risk of acute chronic liver failure, thus limiting the clinical application of OCA. Osteopontin (OPN), an extracellular cell matrix molecule, is highly induced in many cholestatic liver diseases. Herein we explored whether liver injury exacerbation by OCA was related to OPN. MAIN METHODS: Bile duct ligation (BDL) mice were treated with OCA (40 mg/kg) to evaluate its effect on liver injury and OPN involvement. Enzyme-linked immunosorbent assay, western blot, immunohistochemistry, and other assays were used to detect OPN levels in serum and liver. Immunohistochemistry, and immunofluorescence, among other assays, were used to evaluate the extent of ductular reaction. The extent of fibrosis was also determined using various assays, such as immunohistochemistry, quantitative real-time PCR (qPCR), and hydroxyproline assays. KEY FINDINGS: OPN was overexpressed in the liver of BDL mice treated with OCA. OCA induced overexpression of OPN exacerbated ductular reaction, fibrosis, and liver inflammation, and reduced hepatocyte proliferation. SIGNIFICANCE: Upon liver injury, OCA upregulates the expression of OPN in the liver and accelerates disease progression. This mechanism helps explain the risk of liver damage associated with OCA.

Circular RNA circESPL1 knockdown alleviates lipopolysaccharide (LPS)-induced lung cell injury via sponging miR-326 to regulate MAPK14.

BACKGROUND: Infantile pneumonia (IP) is a common inflammatory disease, which brings a heavy burden to young children's health. Previous studies suggested that circular RNA (circRNA) hsa_circ_0026579 (also called circESPL1) was significantly upregulated in pneumonia patients, which was associated with the disease severity. This subject aimed to explore the functional effects and potential regulatory mechanism of circESPL1 on lipopolysaccharide (LPS)-induced lung cell injury. METHODS: WI-38 and MRC-5 cells were stimulated by LPS to mimic the inflammatory injury model. CircESPL1, microRNA-326 (miR-326), and Mitogen-Activated Protein Kinase 14 (MAPK14)levels were measured using real-time quantitative polymerase chain reaction (RT-qPCR). Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), and flow cytometry assays were performed to assess cell proliferation and apoptosis. Western blot analysis of B-cell lymphoma-2 (Bcl-2), Bcl-2 related X protein (Bax), C-caspase 3, and MAPK14 protein levels. Tumor necrosis factor-α (TNF-α), Interleukin-6 (IL-6), and IL-1ß levels were examined using an Enzyme-linked immunosorbent assay (ELISA). Using Starbase analysis, the binding between miR-326 and circESPL1 or MAPK14 was predicted, followed by confirmation using a dual-luciferase reporter and RNA Immunoprecipitation (RIP) assays. RESULTS: Increased circESPL1 and MAPK14, and reduced miR-326 were observed in serum samples from preeclampsia sufferers and LPS-treated lung cells (P < 0.05). Furthermore, circESPL1 deficiency overturned LPS-mediated cell proliferation, apoptosis, and inflammatory response in vitro (P < 0.05). In terms of molecular mechanisms, circESPL1 worked as a sponge of miR-326, and miR-326 absence reversed the protective role of circESPL1 silencing on LPS-triggered lung cell injury (P < 0.05). Also, miR-326 directly targeted MAPK14, and MAPK14 overexpression abolished miR-326-mediated impacts under LPS treatment (P < 0.05). CONCLUSION: CircESPL1 knockdown might attenuate LPS-caused lung cell injury by regulating the miR-326/ MAPK14 axis, providing useful insight for exploring a novel therapeutic approach for IP.

Differential Diagnosis of Type 1 and Type 2 Papillary Renal Cell Carcinoma Based on Enhanced CT Radiomics Nomogram.

Objectives: To construct a contrast-enhanced CT-based radiomics nomogram that combines clinical factors and a radiomics signature to distinguish papillary renal cell carcinoma (pRCC) type 1 from pRCC type 2 tumours. Methods: A total of 131 patients with 60 in pRCC type 1 and 71 in pRCC type 2 were enrolled and divided into training set (n=91) and testing set (n=40). Patient demographics and enhanced CT imaging characteristics were evaluated to set up a clinical factors model. A radiomics signature was constructed and radiomics score (Rad-score) was calculated by extracting radiomics features from contrast-enhanced CT images in corticomedullary phase (CMP) and nephrographic phase (NP). A radiomics nomogram was then built by incorporating the Rad-score and significant clinical factors according to multivariate logistic regression analysis. The diagnostic performance of the clinical factors model, radiomics signature and radiomics nomogram was evaluated on both the training and testing sets. Results: Three validated features were extracted from the CT images and used to construct the radiomics signature. Boundary blurring as an independent risk factor for tumours was used to build clinical factors model. The AUC value of the radiomics nomogram, which was based on the selected clinical factors and Rad-score, were 0.855 and 0.831 in the training and testing sets, respectively. The decision curves of the radiomics nomogram and radiomics signature in the training set indicated an overall net benefit over the clinical factors model. Conclusion: Radiomics nomogram combining clinical factors and radiomics signature is a non-invasive prediction method with a good prediction for pRCC type 1 tumours and type 2 tumours preoperatively and has some significance in guiding clinicians selecting subsequent treatment plans.

Histone methyltransferase SUV39H2 regulates LSD1-dependent CDH1 expression and promotes epithelial mesenchymal transition of osteosarcoma.

OBJECTIVE: Osteosarcoma (OS) is a malignant tumor characterized by the direct production of bone or osteoid tissues by proliferating tumor cells. Suppressor of variegation 3-9 homolog 2 (SUV39H2) is implicated in the occurrence of OS. Therefore, we designed this study to investigate effects of SUV39H2 in OS meditated by the lysine specific demethylase-1/E-cadherin (LSD1/CDH1) axis. METHODS: Clinical OS tissues and paracancerous tissues were collected for analysis of SUV39H2, LSD1 and CDH1 expression, and Kaplan-Meier survival analysis was applied to test the relationship between SUV39H2 expression and overall survival. Loss- and gain-of-function assays were conducted to determine the roles of SUV39H2, LSD1 and CDH1 in OS epithelial mesenchymal transition (EMT) and migration in OS cells, with quantitation of relevant proteins by immunofluorescence. We confirmed the effects of modulating the SUV39H2/CDH1 axis in a mouse OS tumor model. RESULTS: SUV39H2 and LSD1 were highly expressed, while CDH1 was downregulated in OS tissues and cells. SUV39H2 expression correlated inversely with overall survival of patients with OS. SUV39H2 positively regulated LSD1 expression, while LSD1 negatively regulated CDH1 expression. SUV39H2 or LSD1 overexpression, or CDH1 silencing promoted migration and EMT, as indicated by reduced E-cadherin and dramatically upregulated Vimentin and N-cadherin of OS cells. SUV39H2 expedited the progression of OS, which was reversed by CDH1 repression in the setting of OS in vitro and in vivo. CONCLUSIONS: Collectively, our results demonstrate highly expressed SUV39H2 in OS elevates the expression of LSD1 to downregulate CDH1 expression, thereby aggravating OS, providing a potential therapeutic target for treatment of OS.