Activation of CTU2 expression by LXR promotes the development of hepatocellular carcinoma.

Cytosolic thiouridylase 2 (CTU2) is an enzyme modifying transfer RNAs post-transcriptionally, which has been implicated in breast cancer and melanoma development. And we found CTU2 participated in hepatocellular carcinoma (HCC) progression here. HepG2 cells as well as xenograft nude mice model were employed to investigate the role of CTU2 in HCC development in vitro and in vivo respectively. Further, we defined CTU2 as a Liver X receptor (LXR) targeted gene, with a typical LXR element in the CTU2 promoter. CTU2 expression was activated by LXR agonist and depressed by LXR knockout. Interestingly, we also found CTU2 took part in lipogenesis by directly enhancing the synthesis of lipogenic proteins, which provided a novel mechanism for LXR regulating lipid synthesis. Meanwhile, lipogenesis was active during cell proliferation, particularly in tumor cells. Reduction of CTU2 expression was related to reduced tumor burden and synergized anti-tumor effect of LXR ligands by inducing tumor cell apoptosis and inhibiting cell proliferation. Taken together, our study identified CTU2 as an LXR target gene. Inhibition of CTU2 expression could enhance the anti-tumor effect of LXR ligand in HCC, identifying CTU2 as a promising target for HCC treatment and providing a novel strategy for the application of LXR agonists in anti-tumor effect.

Inhibition of high-fat diet-induced obesity via reduction of ER-resident protein Nogo occurs through multiple mechanisms.

Obesity is a risk factor for insulin resistance, type 2 diabetes, and cardiovascular diseases. Reticulon-4 (Nogo) is an endoplasmic reticulum-resident protein with unclear functions in obesity. Herein, we investigated the effect of Nogo on obesity and associated metabolic disorders. Human serum samples were collected to explore the relationship between circulating Nogo-B and body mass index value. Nogo-deficient and WT littermate control mice were fed normal chow or high-fat diet (HFD) for 14 weeks, and HFD-induced obese C57BL/6J mice were injected scrambled or Nogo siRNA for 2 weeks. We found that in human and mouse serum, Nogo-B was positively correlated to body mass index/bodyweight and lipid profiles. Reduced Nogo (by genetic deletion or siRNA transfection) protected mice against HFD-induced obesity and related metabolic disorders. We demonstrate that Nogo deficiency reversed HFD-induced whitening of brown adipose tissue, thereby increasing thermogenesis. It also ameliorated lipid accumulation in tissues by activating the adiponectin-adiponectin receptor 1-AMP-activated kinase α signaling axis. Finally, Nogo deficiency potently reduced HFD-induced serum proinflammatory cytokines and infiltration of macrophages into metabolic organs, which is related to enhanced NF-κB p65 degradation via the lysosome pathway. Collectively, our study suggests that reduced levels of Nogo protect mice against HFD-induced obesity by increasing thermogenesis and energy metabolism while inhibiting NF-κB-mediated inflammation. Our results indicate that inhibition of Nogo may be a potential strategy for obesity treatment.

Predicting Infectious Complications after Percutaneous Thermal Ablation of Liver Malignancies: A 12-year Single-Center Experience.

Background Infectious complications after percutaneous thermal ablation are seldom discussed, but better understanding of risk factors and early prediction is critical. Purpose To estimate the incidence of infectious complications after percutaneous thermal ablation of liver malignancies and to develop prediction models. Materials and Methods This single-center retrospective study reviewed the data of 3167 patients who underwent 7545 percutaneous US-guided thermal ablation procedures of liver malignancies between January 2010 and January 2022. All procedures with infectious complications were included as the case group. For each case, one treatment date-matched control subject without infection was randomly selected following a nested case-control design. Independent factors of overall and hepatobiliary infection were investigated with multivariable logistic regression. Results A total of 80 patients (median age, 59 years; IQR, 51-68 years; 64 men, 16 women) developed infectious complications after 80 ablation procedures; the incidence was 1.1% (80 of 7545 procedures). Of those with infection, 18% (14 of 80 patients) were severe, and 10% (eight of 80 patients) died as a result. Independent risk factors for overall infectious complication included prior biliary intervention (odds ratio [OR], 18.6; 95% CI: 4, 86; P < .001), prior transarterial chemoembolization (TACE) (OR, 2.4; 95% CI: 1.0, 5.8; P = .045), and the largest tumor size (OR, 1.9; 95% CI: 1.3, 2.8; P = .002); on this basis, subcapsular location was an additional risk factor of hepatobiliary infection. Prediction models for overall and hepatobiliary infection had an area under the receiver operating characteristics curve (AUC) of 0.77 and 0.82, respectively, both of which showed better AUC compared with the models, including prior biliary intervention alone (AUC = 0.63 and 0.65, respectively; P = .01 and P = .005, respectively). Conclusion Infectious complications after percutaneous thermal ablation of liver malignancies were uncommon but potentially fatal. Independent predictors were prior biliary intervention, prior transarterial chemoembolization, and the largest tumor size. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Ben-Arie and Sosna in this issue.

The Structural and Electronic Engineering of Molybdenum Disulfide Nanosheets as Carbon-Free Sulfur Hosts for Boosting Energy Density and Cycling Life of Lithium-Sulfur Batteries.

The compact sulfur cathodes with high sulfur content and high sulfur loading are crucial to promise high energy density of lithium-sulfur (Li-S) batteries. However, some daunting problems, such as low sulfur utilization efficiency, serious polysulfides shuttling, and poor rate performance, are usually accompanied during practical deployment. The sulfur hosts play key roles. Herein, the carbon-free sulfur host composed of vanadium-doped molybdenum disulfide (VMS) nanosheets is reported. Benefiting from the basal plane activation of molybdenum disulfide and structural advantage of VMS, high stacking density of sulfur cathode is allowed for high areal and volumetric capacities of the electrodes together with the effective suppression of polysulfides shuttling and the expedited redox kinetics of sulfur species during cycling. The resultant electrode with high sulfur content of 89 wt.% and high sulfur loading of 7.2 mg cm-2 achieves high gravimetric capacity of 900.9 mAh g-1 , the areal capacity of 6.48 mAh cm-2 , and volumetric capacity of 940 mAh cm-3 at 0.5 C. The electrochemical performance can rival with the state-of-the-art those in the reported Li-S batteries. This work provides methodology guidance for the development of the cathode materials to achieve high-energy-density and long-life Li-S batteries.

Mitochondrial damage-induced abnormal glucose metabolism with ageing in the hippocampus of APP/PS1 mice.

INTRODUCTION: Accumulation of ß-amyloid (Aß) in neurons of patients with Alzheimer's disease (AD) inhibits the activity of key enzymes in mitochondrial metabolic pathways, triggering mitochondrial dysfunction, which plays an important role in the onset and development of AD. Mitophagy is a process whereby dysfunctional or damaged mitochondria are removed from the cell. Aberrant mitochondrial metabolism may hinder mitophagy, promote autophagosome accumulation, and lead to neuronal death. OBJECTIVES: The aim of this experiment is to explore the mechanism of neuronal mitochondria damage in the hippocampus of different age APP/PS1 double transgenic AD mice, and to explore the related metabolites and metabolic pathways for further understanding of the pathogenesis, so as to provide new ideas and strategies for the treatment of AD. METHODS: In this study, 24 APP/PS1(APPswe/PSEN1dE9) mice were divided into 3, 6, 9, and 12-month-old groups, and 6-month-old wild-type C57BL/6 mice were as controls. The Morris water maze test was used to evaluate learning and memory. Levels of Aß were detected by immunohistochemistry. Electron microscopy was used to observe mitochondrial damage and autophagosome accumulation. Western blot was for measuring LC3, P62, PINK1, Parkin, Miro1, and Tom 20 protein expression levels. Gas chromatography coupled with mass spectrometry was used to screen differentially abundant metabolites. RESULTS: The results showed that with the increase of age in APP/PS1 mice, cognitive impairment, hippocampal neuron mitochondrial damage, and autophagosome accumulation all increased. Furthermore, enhanced mitophagy and impaired mitochondrial clearance leading to metabolic abnormalities were observed with ageing in APP/PS1 mouse hippocampus. Especially, abnormal accumulation of succinic acid and citric acid in the Krebs cycle was observed. CONCLUSION: This study investigated the abnormal glucose metabolism associated with age-related damage to mitochondria in the hippocampus of APP/PS1 mice. These findings provide new insights into the pathogenesis of AD.

Covalent Organic Frameworks for Separator Modification of Lithium-Sulfur Batteries.

Lithium-sulfur (Li-S) batteries are regarded as one of the promising energy storage systems. However, rapid capacity attenuation caused by shuttle effect of soluble polysulfides is major challenge in practical application. The separator modification is regarded as one countermeasure besides the construction of sulfur host materials. Covalent organic frameworks (COFs) are one type of outstanding candidates for suppressing shuttle effect of polysulfides. Herein, recent advances of COFs in the application as commercial separator modifiers are summarized. COFs serve as ionic sieves, the importance of porous size and surface environments in inhibiting soluble polysulfides shuttling and promoting lithium ions conduction is highlighted. The superiority of charge-neutral COFs, ionic COFs, and the composites of COFs with conductive materials for improving reversible capacity and cycling stability is demonstrated. Some new strategies for the design of COF-based separator modifiers are proposed to achieving high energy density. The review provides new perspectives for future development of high-performance Li-S batteries.

Health-related quality of life among ethnic minority residents in remote Western China: a cross-sectional study.

BACKGROUND: Paying attention to the health-related quality of life (HRQOL) of rural residents in poverty-stricken areas is an important part of China's poverty alleviation, but most studies on health-related quality of life have focused on rural residents, elderly individuals, and patients; evidence on the HRQOL of rural minority residents is limited. Thus, this study aimed to assess the HRQOL of rural Uighur residents in remote areas of Xinjiang, China, and determine its influencing factors to provide policy opinions for realizing a healthy China strategy. METHODS: A cross-sectional study was performed on 1019 Uighur residents in rural areas. The EQ-5D and self-administered questionnaires were used to assess HRQOL. We applied Tobit and binary logit regression models to analyse the factors influencing HRQOL among rural Uighur residents. RESULTS: The health utility index of the 1019 residents was - 0.197,1. The highest proportion of respondents reporting any problem was for mobility (57.5%), followed by usual activity (52.8%). Low levels of the five dimensions were related to age, smoking, sleep time, Daily intake of vegetables and fruit per capita. Gender, age, marital status, physical exercise, sleep duration, daily intake of cooking oil per capita, daily intake of fruit per capita, distance to the nearest medical institution, non-infectious chronic diseases (NCDs), self-rated health score, and participation in community activities were correlated with the health utility index of rural Uighur residents. CONCLUSIONS: HRQOL was lower for rural Uyghur residents than for the general population. Improving health behavioural lifestyles and reducing the incidence of poverty (return to poverty) due to illness are effective means of promoting the health in Uyghur residents. The region must fulfil the health poverty alleviation policy and focus on vulnerable groups and low-income residents to improve the health, ability, opportunity, and confidence of this population to live well.

Circular RNA Circ_0005962 Contributes to Lung Adenocarcinoma Cell Proliferation and Stem Cell Formation Through Sponging of miR-3611 and Modulating CYP24A1 Expression.

Recently, several studies have revealed that circular RNAs (circRNAs) play significant roles in various tumors, including lung adenocarcinoma (LUAD). Furthermore, it has been reported that circ_0005962 was upregulated in LUAD cells. Accordingly, this research is designed to investigate the mechanism of circ_0005962 on LUAD development. Circ_0005962, microRNA-3611 (miR-3611), and Cytochrome P450 family 24 subfamily A member 1 (CYP24A1) level were detected by real-time quantitative polymerase chain reaction (RT-qPCR). Cell proliferation ability, cell cycle progression, and sphere formation ability were detected using Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), Colony formation, flow cytometry, and sphere formation assay. Protein levels of proliferating cell nuclear antigen (PCNA), Ki67, NANOG, CD133, OCT4, and CYP24A1 were determined using Western blot assay. Using bioinformatics software (Starbase3.0 and TargetScan), the binding between miR-3611 and circ_0005962 or CYP24A1 was predicted and proved using RNA Immunoprecipitation (RIP) and RNA pull-down assays. A xenograft tumor model in vivo was used to analyze the biological role of circ_0005962 on LUAD cell growth. Increased circ_0005962 and CYP24A1, and reduced miR-3611 were observed in LUAD tissues and cell lines. Functional assays testified that circ_0005962 depletion might hinder LUAD cell proliferation and sphere formation capability, but induced cell apoptosis in vitro. Molecular mechanism experiments exhibited that circ_0005962 served as a miR-3611 sponge and mediated CYP24A1 content by absorbing miR-3611. Additionally, silencing of circ_0005962 inhibited tumor growth in xenograft modes. Together, circ_0005962 was overexpressed in LUAD, and its deficiency repressed LUAD progression via targeting the miR-3611/ CYP24A1 axis, providing a novel mechanism for understanding the development of LUAD.

NGBR is required to ameliorate type 2 diabetes in mice by enhancing insulin sensitivity.

The reduction of insulin resistance or improvement of insulin sensitivity is the most effective treatment for type 2 diabetes (T2D). We previously reported that Nogo-B receptor (NGBR), encoded by the NUS1 gene, is required for attenuating hepatic lipogenesis by blocking nuclear translocation of liver X receptor alpha, suggesting its important role in regulating hepatic lipid metabolism. Herein, we demonstrate that NGBR expression was decreased in the liver of obesity-associated T2D patients and db/db mice. NGBR knockout in mouse hepatocytes resulted in increased blood glucose, insulin resistance, and beta-cell loss. High-fat diet (HFD)/streptozotocin (STZ)-treated mice presented the T2D phenotype by showing increased nonesterified fatty acid (NEFA) and triglyceride (TG) in the liver and plasma and increased insulin resistance and beta-cell loss. AAV-mediated NGBR overexpression in the liver reduced NEFA and TG in the liver and circulation and improved liver functions. Consequently, HFD/STZ-treated mice with hepatic NGBR overexpression had increased insulin sensitivity and reduced beta-cell loss. Mechanistically, NGBR overexpression restored insulin signaling of AMPKα1-dependent phosphorylation of AKT and GSK3ß. NGBR overexpression also reduced expression of endoplasmic reticulum stress-associated genes in the liver and skeletal muscle to improve insulin sensitivity. Together, our results reveal that NGBR is required to ameliorate T2D in mice, providing new insight into the role of hepatic NGBR in insulin sensitivity and T2D treatment.

The Pathway of Sulfide Oxidation to Octasulfur Globules in the Cytoplasm of Aerobic Bacteria.

Sulfur-oxidizing bacteria can oxidize hydrogen sulfide (H2S) to produce sulfur globules. Although the process is common, the pathway is unclear. In recombinant Escherichia coli and wild-type Corynebacterium vitaeruminis DSM 20294 with sulfide:quinone oxidoreductase (SQR) but no enzymes to oxidize zero valence sulfur, SQR oxidized H2S into short-chain inorganic polysulfide (H2Sn, n ≥ 2) and organic polysulfide (RSnH, n ≥ 2), which reacted with each other to form long-chain GSnH (n ≥ 2) and H2Sn before producing octasulfur (S8), the main component of elemental sulfur. GSnH also reacted with glutathione (GSH) to form GSnG (n ≥ 2) and H2S; H2S was again oxidized by SQR. After GSH was depleted, SQR simply oxidized H2S to H2Sn, which spontaneously generated S8. S8 aggregated into sulfur globules in the cytoplasm. The results highlight the process of sulfide oxidation to S8 globules in the bacterial cytoplasm and demonstrate the potential of using heterotrophic bacteria with SQR to convert toxic H2S into relatively benign S8 globules. IMPORTANCE Our results provide evidence of H2S oxidation producing octasulfur globules via sulfide:quinone oxidoreductase (SQR) catalysis and spontaneous reactions in the bacterial cytoplasm. Since the process is an important event in geochemical cycling, a better understanding facilitates further studies and provides theoretical support for using heterotrophic bacteria with SQR to oxidize toxic H2S into sulfur globules for recovery.

Long non-coding RNA OGFRP1 regulates cell proliferation and ferroptosis by miR-299-3p/SLC38A1 axis in lung cancer.

Lung cancer is devastating cancer that ranks as the leading cause of cancer-related death. Long noncoding RNA (lncRNA) opioid growth factor receptor pseudogene 1 (OGFRP1) was recognized as an oncogene in many cancers. However, the molecular mechanism of OGFRP1 in lung cancer is still poorly understood. The expression of target RNAs and genes was detected by quantitative real-time PCR and western blot. The interaction between miR-299-3p and OGFRP1 or solute carrier family 38 member 1 (SLC38A1) was predicted by StarbaseV3.0 and verified by dual-luciferase reporter assay and Pearson's correlation coefficient. Besides, a transplantation model of human lung cancer in nude mice was established to evaluate the role of OGFRP1 in lung cancer. OGFRP1 and SLC38A1 were overexpressed, whereas miR-299-3p was lowly expressed in lung cancer tumors and cells. OGFRP1 knockdown suppressed cell proliferation and facilitated ferroptosis by promoting lipid peroxidation and iron accumulation in lung cancer. Besides, Furthermore, miR-299-3p inhibitor or SLC38A1 overexpression attenuated OGFRP1 depletion-induced suppression on cell proliferation and ferroptosis in lung cancer. Animal experiments indicated that OGFRP1 deficiency restrained tumor growth in vivo by regulating the miR-299-3p/SLC38A1 axis. OGFRP1 regulated cell proliferation and ferroptosis in lung cancer by inhibiting miR-299-3p to enhance SLC38A1 expression, providing a novel therapeutic strategy for lung cancer.

Hsa_circ_0020850 promotes the malignant behaviors of lung adenocarcinoma by regulating miR-326/BECN1 axis.

BACKGROUND: Circular RNAs (circRNAs) are a novel type of endogenous RNAs and play vital roles in lung adenocarcinoma. However, the function and underlying mechanism of circ_0020850 in lung adenocarcinoma remain unknown. METHODS: The levels of circ_0020850, microRNA-326 (miR-326), and Beclin1 (BECN1) were analyzed by real-time quantitative polymerase chain reaction and western blot analyses. The migration and invasion were determined by wound healing and transwell assays, respectively. Colony formation assay was used to assess cell proliferation ability. The angiogenic ability was analyzed by Matrigel angiogenesis assay. The apoptosis rate was calculated by flow cytometry assay. Dual-luciferase reporter, RNA immunoprecipitation (RIP), and RNA pull-down assays were conducted to confirm the interaction relationship among circ_0020850, miR-326, and BECN1. A xenograft mice model was established to assess the role of circ_0020850 in vivo. RESULTS: We found that circ_0020850 was obviously overexpressed in lung adenocarcinoma tissues and cells. Knockdown of circ_0020850 inhibited migration, invasion, proliferation, and angiogenesis but induced apoptosis in lung adenocarcinoma cells in vitro, as well as curbed tumor growth in vivo. MiR-326 was a target of circ_0020850, and knockdown of miR-326 abolished the suppression effect of circ_0020850 on the malignant behaviors of lung adenocarcinoma cells. Additionally, miR-326 could negatively regulate BECN1 expression, thereby regulating lung adenocarcinoma cell phenotypes. Importantly, circ_0020850 could directly bind to miR-326 and thus relieve miR-326-mediated inhibition on BECN1. CONCLUSION: Circ_0020850 promoted the malignant development of lung adenocarcinoma by regulating miR-326/BECN1 axis, indicating that circ_0020850 might serve as a promising target for the diagnosis and treatment of lung adenocarcinoma patients.

Circ_0007031 Silencing Inhibits Cell Proliferation and Induces Cell Apoptosis via Downregulating MELK at a miR-485-3p-Dependent Way in Colorectal Cancer.

Colorectal cancer (CRC) is a malignant cancer with an increasing incidence. Circular RNA (circRNA) is recently found to participate in the regulation of CRC progression. However, the role of circ_0007031 in CRC malignant progression remains elusive. 50 CRC patients were implicated in this study. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the RNA expression of circ_0007031, microRNA-485-3p (miR-485-3p) and maternal embryonic leucine zipper kinase (MELK). Western blot analysis was conducted to determine protein expression. Cell viability and proliferation were demonstrated by cell counting kit-8 and 5-Ethynyl-29-deoxyuridine (EdU) assays, respectively. Cell cycle and apoptosis were investigated by flow cytometry analysis. The interaction among circ_0007031, miR-485-3p and MELK was predicted by online databases, and identified by dual-luciferase reporter assay. Mouse model assay was conducted to reveal the effect of circ_0007031 on tumor formation in vivo. Circ_0007031 and MELK expression were obviously increased, while miR-485-3p expression was decreased in CRC tissues and cells compared with normal colorectal tissues or cells. Circ_0007031 knockdown repressed proliferation, whereas induced cell arrest at G0/G1 phase and apoptosis. On the opposite, circ_0007031 overexpression promoted cell proliferation and induced cell arrest at S phase. Additionally, miR-485-3p inhibitors attenuated circ_0007031 silencing-mediated CRC cell malignancy. MiR-485-3p was unveiled to regulate CRC cell processes via targeting MELK. Circ_0007031 controlled MELK expression via interacting with miR-485-3p. Furthermore, circ_0007031 contributed to tumor formation in vivo. Circ_0007031 knockdown repressed CRC malignant progression by reducing MELK expression through associating with miR-485-3p, suggesting that circ_0007031 was a potential target for the therapy of CRC.

Self-Assembled Platinum Supramolecular Metallacycles Based on a Novel TADF Photosensitizer for Efficient Cancer Photochemotherapy.

Recently, supramolecular coordination complexes (SCCs) based on photosensitizers as bridging ligands have attracted great attention in cancer therapy owing to their synergistic effect between photodynamic therapy (PDT) and chemotherapy. Herein, a highly emissive supramolecular platinum triangle BTZPy-Pt based on a novel type of photosensitizer BTZPy with thermally activated delayed fluorescence (TADF) was fabricated. The BTZPy and BTZPy-Pt exhibited strong luminescence emission in the visible range with high quantum yields (quantum yields (QYs) for BTZPy and BTZPy-Pt were about 78 and 62% in ethanol solutions, respectively). Additionally, BTZPy had been proved to be an excellent photosensitizer with superior 1O2 generation capability (the 1O2 generation quantum yield reached up to ca. 95%) for PDT. By the combination of the excellent phototoxicity of BTZPy and the antitumor activity of the Pt center, the platinum triangle BTZPy-Pt demonstrated a highly efficient anticancer performance toward HeLa cells (IC50: 0.5 µg mL-1). This study not only provides a blueprint to fabricate new types of photosensitizers but also paves a way to design novel SCCs for efficient PDT.

Epidemiological and clinical analysis of the outbreak of dengue fever in Zhangshu City, Jiangxi Province, in 2019.

This study analyzed the epidemiological and clinical features of dengue fever in Zhangshu, Jiangxi Province, in 2019 and provided evidence for the diagnosis, treatment, prevention, and control of dengue fever. A total of 718 dengue fever patients in Zhangshu in 2019 were involved. ELISA and qRT-PCR were used for pathogenic detection of dengue virus. Multiple adjuvant therapies were applied, and the condition of patients after treatment was examined. Patients were between the ages of 0.75 and 92 years old, and all of them had a fever. A total of 519 cases had fatigue, and 413 cases had generalized myalgia and bone ache; 356 cases had dry mouth, 289 cases had bitter taste, and 167 cases felt dry and bitter taste; 279 cases had rash, and 93 cases had pruritus; 587 cases had decreased leukocyte, among which, 7 cases had leukocyte lower than 1 × 10 [9]/L; 380 cases had a low platelet count, and the platelet count of 29 cases was lower than 50 × 10 [9]/L; 488 cases had increased aspartic transaminase, and 460 cases had increased alanine aminotransferase; 5 cases had a severe disease. It proved that the majority of dengue fever sufferers were adults, with the main clinical features being fever and rash and the chief injured organs being the blood system, liver, heart, and gastrointestinal tract. Besides, over 40% of patients had dry and bitter taste, and 12 cases had alopecia after discharge. It indicates that the incidence of dengue fever in Zhangshu is closely related to the sudden population flow and imported cases.

Genome-Guided Discovery of Highly Oxygenated Aromatic Polyketides, Saccharothrixins D-M, from the Rare Marine Actinomycete Saccharothrix sp. D09.

Angucyclines and angucyclinones are aromatic polyketides with intriguing structures and therapeutic value. Genome mining of the rare marine actinomycete Saccharothrix sp. D09 led to the identification of a type II polyketide synthase biosynthetic gene cluster, sxn, which encodes several distinct subclasses of oxidoreductases, implying that this strain has the potential to produce novel polycyclic aromatic polyketides with unusual redox modifications. The "one strain-many compounds" (OSMAC) strategy and comparative metabolite analysis facilitated the discovery of 20 angucycline derivatives from the D09 strain, including six new highly oxygenated saccharothrixins D-I (1-6), four new glycosylated saccharothrixins J-M (7-10), and 10 known analogues (11-20). Their structures were elucidated based on detailed HRESIMS, NMR spectroscopic, and X-ray crystallographic analysis. With the help of gene disruption and heterologous expression, we proposed their plausible biosynthetic pathways. In addition, compounds 3, 4, and 8 showed antibacterial activity against Helicobacter pylori with MIC values ranging from 16 to 32 µg/mL. Compound 3 also revealed anti-inflammatory activity by inhibiting the production of NO with an IC50 value of 28 µM.

The combination of conventional ultrasound and shear-wave elastography in evaluating the segmental heterogeneity of liver fibrosis in biliary atresia patients after Kasai portoenterostomy.

OBJECTIVE: To retrospectively assess the value of the combination of conventional ultrasound and shear-wave elastography (SWE) in evaluating the segmental heterogeneity of liver fibrosis in biliary atresia (BA) patients after Kasai portoenterostomy. METHODS: A total of 35 BA patients with liver segmental deformation were enrolled. The segmental deformation was assessed by conventional ultrasound followed with SWE examinations for evaluating the liver stiffness. Liver biopsy was performed in 11 patients in the region of SWE measurement and liver fibrosis was assessed using the Metavir classification. Aminotransferase to platelet ratio index (APRI) was calculated for comparison. The correlations between serum biochemical tests with SWE values were evaluated. Spearman's rank coefficient test was performed to evaluate the correlation between variables. RESULTS: The SWE values of the biopsy segments had significant positive correlations with liver fibrosis severity (r = 0.828, p = 0.001), which was better than APRI (r = 0.366, p = 0.242). The levels of bilirubin and transaminase showed significant correlations with the SWE values at hypertrophic segments in all patients (r from 0.336 to 0.576, all p < 0.05). CONCLUSIONS: Awareness of the segmental heterogeneity of liver fibrosis evaluated by conventional ultrasound and SWE may assist in selecting an appropriate biopsy location and predicting postoperative surveillance for patients with BA.

Reduced Nogo expression inhibits diet-induced metabolic disorders by regulating ChREBP and insulin activity.

BACKGROUND & AIMS: Chronic overconsumption of a high-carbohydrate diet leads to steatosis and its associated metabolic disorder and, eventually, to non-alcoholic fatty liver disease. Carbohydrate-responsive element binding protein (ChREBP) and insulin regulate de novo lipogenesis from glucose. Herein, we studied the effect of reticulon-4 (Nogo) expression on diet-induced metabolic disorders in mice. METHODS: Nogo-deficient (Nogo-/-) and littermate control [wild-type (WT)] mice were fed a high-glucose or high-fructose diet (HGD/HFrD) to induce metabolic disorders. The effects of Nogo small interfering (si) RNA (siRNA) on HFrD-induced metabolic disorders were investigated in C57BL/6J mice. RESULTS: HGD/HFrD induced steatosis and its associated metabolic disorders in WT mice by activating ChREBP and impairing insulin sensitivity. They also activated Nogo-B expression, which in turn inhibited insulin activity. In response to HGD/HFrD feeding, Nogo deficiency enhanced insulin sensitivity and energy metabolism to reduce the expression of ChREBP and lipogenic molecules, activated AMP-activated catalytic subunit α, peroxisome proliferator activated receptor α and fibroblast growth factor 21, and reduced endoplasmic reticulum (ER) stress and inflammation, thereby blocking HGD/HFrD-induced hepatic lipid accumulation, insulin resistance and other metabolic disorders. Injection of Nogo siRNA protected C57BL/6J mice against HFrD-induced metabolic disorders by ameliorating insulin sensitivity, ChREBP activity, ER stress and inflammation. CONCLUSIONS: Our study identified Nogo as an important mediator of insulin sensitivity and ChREBP activity. Reduction of Nogo expression is a potential strategy for the treatment of high-carbohydrate diet-induced metabolic complications. LAY SUMMARY: Nogo deficiency blocks high-carbohydrate diet-induced glucose intolerance and insulin resistance, while increasing glucose/lipid utilisation and energy expenditure. Thus, reduction of Nogo expression protects against high-carbohydrate diet-induced body-weight gain, hepatic lipid accumulation and the associated metabolic disorders, indicating that approaches inhibiting Nogo expression can be applied for the treatment of diseases associated with metabolic disorders.

Adiponectin agonist ADP355 ameliorates doxorubicin-induced cardiotoxicity by decreasing cardiomyocyte apoptosis and oxidative stress.

Doxorubicin (DOX) is an anthracycline derivative and widely used as an anticancer drug. However, the severe cardiotoxicity of DOX limits its application. ADP355 is an adiponectin-based active peptide with anti-liver fibrosis and atherosclerosis properties. It remains unclear the effects and involved mechanisms of ADP355 in DOX-induced cardiotoxicity. C57BL/6J mice were intraperitoneally injected DOX once a week to induce heart failure while receiving ADP355 treatment daily for 4 weeks. At the end of experiment, blood and heart tissues were collected. We found that ADP355 markedly improved DOX-induced cardiac dysfunction and histopathological damage, and decreased serum creatine kinase, lactate dehydrogenase and hydroxybutyrate dehydrogenase levels. The anti-apoptotic activity of ADP355 was indicated by reduction in TUNEL-positive cells and cleaved caspase-3 expression, along with decreased BCL2-associated X protein/B cell lymphoma 2 (BAX/BCL2) levels in heart tissues. Additionally, ADP355 markedly increased DOX-decreased cell viability by reducing BAX/BCL2, but inhibited reactive oxygen species production in H9c2 cells. Mechanistically, ADP355 attenuated expression of DOX-reduced nuclear factor-erythroid 2-related factor 2 (Nrf2) and superoxide dismutase 2, as well as mRNA levels of Nrf2 downstream targets. Furthermore, ADP355 activated sirtuin 2 and its target genes. In conclusion, we demonstrate that ADP355 alleviates DOX-induced cardiotoxicity by inhibiting myocardial apoptosis and oxidative stress through Nrf2 and sirtuin 2 signaling pathways. These findings suggest that ADP355 can be a promising candidate for the treatment of cardiac dysfunction.

Combination of MEK1/2 inhibitor and LXR ligand synergistically inhibit atherosclerosis in LDLR deficient mice.

Combined LXR ligand (T0901317) and MEK1/2 inhibitor (U0126) not only reduces atherosclerosis in apoE deficient mice, but also blocks LXR ligand-induced fatty liver and hypertriglyceridemia. However, the atheroprotective function of combined T0901317 and U0126 should be further investigated in LDLR deficient (LDLR-/-) mice since deficiency of LDLR not apoE can occur to humans with a high frequency. Herein, we validated the effectiveness of this combinational therapy on the development of atherosclerosis in LDLR-/- mice to demonstrate its potential application in clinic. We found although T0901317 or U0126 alone reduced atherosclerotic plaques in en face and aortic root areas in HFD-fed LDLR-/- mice, their combination inhibited lesions in a synergistic manner. Combined U0126 and T0901317 had no effect on serum total cholesterol levels. T0901317 deceased HDL-cholesterol levels, which was restored by combined U0126. Meanwhile, U0126 alleviated T0901317-induced triglyceride accumulation, the major adverse effect of T0901317 which limits its clinical utility. Mechanistically, U0126 reduced fatty acid de novo synthesis by inhibiting hepatic fatty acid synthase (FASN) expression, thereby correcting T0901317-induced triglyceride overproduction. In conclusion, our study demonstrates that combination of MEK1/2 inhibitor and LXR ligand can synergistically reduce atherosclerosis in LDLR deficient mice without lipogenic side effects.