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In engineering systems such as energy systems and electronic devices, thermal reliability analysis of the heat source component area is critical to ensure the proper functioning of these components. Previous methods, due to the high data dimensionality of the temperature field of the whole heat source area, face high computational cost when analyzing the reliability. To solve the problem of high computational cost, reliability analysis methods based on deep neural network surrogate models are receiving more and more attention. However, the uncertainty of deep neural networks is rarely considered in reliability problems, leading to unreasonable or imperfect reliability analysis. Therefore, we propose a reliability analysis method for heat source layout temperature field prediction, considering the uncertainty of deep neural network surrogate models. The method uses the information on the standard deviation of temperature field prediction provided by the model uncertainty to obtain the interval prediction of the temperature field. Then, the temperature field reliability interval of the layout area can be obtained by combining the temperature field interval prediction and Monte Carlo sampling. Further, we propose a strategy for selecting the heat source layout scheme based on the reliability interval in the late engineering design stage. Finally, the method's validity is verified using some examples, which provides an important reference basis for engineers. [ABSTRACT FROM AUTHOR]

The plastic deformation behavior of a CHN327 nickel-based superalloy under temperatures ranging from 600 °C to 700 °C and strain rates ranging from 0.001 to 0.1 s−1 was investigated using uniaxial high-temperature tensile tests. The stress–strain curves obtained by the tests showed that the maximum stress decreased as the temperature increased, while it increased as the strain rate increased. Based on the extensive data obtained in the experiment, three constitutive models (Hollomon, Swift, and the modified Voce equation) were employed to predict the constitutive relation. It was found that the modified Voce equation had the highest correlation coefficient and the best prediction accuracy. Thereafter, in order to predict the fracture of CHN327 during high-temperature tensile deformation, five ductile fracture criteria (Freudenthal, C&L, Brozzo, Ayada, and the R&T model), and the modified Voce equation obtained were incorporated into the finite element software (DEFORM). According to the results, except for the C&L and Brozzo models, all of the other ductile fracture criteria (DFCs) were suitable for predicting the damage distribution of the CHN327 alloy in tensile tests. For all of the DFCs considered, the R&T model provided the most accurate predictions, whose mean error was only 8.9%, far less than the values that other models predicted. [ABSTRACT FROM AUTHOR]

• The impact of environmental pollution on China's crime rate is investigated. • Local government official corruption is an important threshold variable. • Generalized method of moments and Dynamic threshold panel model are used for empirical test. • Environmental pollution can promote provincial crime rate. • The promotion effect increases as the level of local government official corruption increases. Environmental pollution and its effects have attracted increasing attention, but few studies have examined the impact of environmental pollution on the crime rate. This study adopted panel data of 30 provinces in China for the period 2005 to 2016 to examine the relationship between environmental pollution and the crime rate. In addition, a mediating effect model is used to study the mechanism through which environmental pollution influences the crime rate. This study considers the threshold effect of government official corruption on the link between environmental pollution and the crime rate. The generalized method of moments and a newly developed dynamic threshold panel model are employed to manage potential endogeneity problems. The estimation results indicate that environmental pollution significantly promotes China's crime rate. Environmental pollution can indirectly affect the crime rate through residents' health level, education level and inequality. The magnitude of the effect of environmental pollution on the crime rate will be greater after corruption reaches the threshold value. Regional heterogeneity analysis shows that a significant positive impact of environmental pollution on the crime rate exists in the eastern and western regions of China but not in the middle region. Based on the findings, we propose a series of policy implications to reduce criminal activities in China from the perspective of environmental pollution. [ABSTRACT FROM AUTHOR]

Electrospinning one-dimensional (1-D) semiconductor nanofibers have been regarded as one of the most promising building blocks for future nanoelectronics with high performance because they can exhibit a broad range of device functions. However, electronic devices based on electrospinning-driven nanofibers often suffer from poor performance and inferior quality. In current works, continuous and uniform high-quality indium oxide (In2O3) nanofibers were obtained by electrospinning. The surface morphology, crystallinity, optical, and electrical properties of the In2O3 nanofibers were investigated by X-ray diffraction, scanning electron microscopy, optical spectroscopy, and electrical measurements. It has been detected that the field-effect transistors (FETs) with optimized electrospinning time of 30 s demonstrated superior electrical performance, including a high field-effect mobility (μFE) of 9.1 cm2 ⋅ V−1 ⋅ s−1 and a large ION/IOFF of 107. The high- k Al2O3 dielectric layer has also been used to greatly reduce the operating voltage (from 30 to 3 V), significantly improve μFE (to 27.7 cm2 ⋅ V−1 ⋅ s−1), and strengthen stability over cycling. To prove the device’s potential in more complex logic circuit applications, a resistor-loaded inverter was further integrated, and the maximum voltage gain of 9.8 was demonstrated at an ultralow operating voltage of 3 V. The present findings have demonstrated that electrospinning can potentially be used as a straightforward and cost-effective means for the assembly of 1-D nanostructures for use in next-generation low-power devices. [ABSTRACT FROM AUTHOR]

Calcium hexaaluminate (CA6) based castables with low thermal conductivity and sufficient strength were conveniently prepared by foaming and incorporating alumina bubbles. The pores are derived from stabilizing the liquid foams by the surfactant (air‐entraining agent) and hollow structure of alumina bubbles. The thermal and physical properties of CA6 based castables depended on the approaches producing pores as well as their quantity, morphology, and distribution. CA6 based castables with the thermal conductivity of.384–.491 W/(m∙K) tested at 800°C and the cold crushing strength of 49.4–99.5 MPa after firing at 1 300°C, exhibited promising application prospects as insulation linings used for the skid post and beam in the reheating furnace. [ABSTRACT FROM AUTHOR]

• (1) This work proposes a new type of precast local high-performance concrete frame beam-column joint to enhance the seismic performance of the precast concrete frame structures. • (2) The load-bearing capacity, hysteresis characteristics, stiffness degradation, and energy dissipation capacity of the designed two joints were experimentally studied. • (3) A tri-linear skeleton curve model was established for joints using the experimental fitting method, which can better describe the stress and deformation characteristics of each stage. • (4) The Tri-linear restoring force model of the joint is established by the test fitting method, and it is in good agreement with the test results. To enhance the seismic performance of conventional precast concrete frame structures, this study introduces a novel precast high-performance concrete frame beam-column joint. We designed and conducted experiments on two full-scale precast concrete frame beam-column exterior joints, varying the presence of L-shaped steel reinforcement at the bottom of the beam-column joint. The findings reveal that the load-bearing capacity, hysteresis characteristics, stiffness degradation, and energy dissipation capacity of both joints significantly improve when using reactive powder concrete (RPC) poured into the joint connection area and L-shaped steel at the beam-column junction. A finite element model for these joints was further developed and validated based on the experimental data. Additionally, a parametric study was conducted to assess the impact of axial compression ratio and spacing of hoop bars in the joint area on joint behavior. Using an experimental fitting approach, a tri-linear skeleton curve model for the joints was established, offering a more precise representation of stress and deformation characteristics at each stage. The hysteretic curve generated from this restoring force model closely matches the experimental data, demonstrating the model's ability to accurately depict the hysteretic behavior of beam-column joints in precast RPC/RC composite frames. [ABSTRACT FROM AUTHOR]

The seismic performance index of prefabricated structures is generally obtained via experimental analysis. However, in experimental research, it is impossible that every influencing factor can be taken into account. Therefore, the finite element analysis method can be used as a supplementary method for experimental research to carry out parametric analysis of joints. Based on this test, a hysteretic model of steel bars is developed on the ABAQUS platform; meanwhile, the model is used to simulate the seismic analysis of the proposed local reinforced joints. The hysteresis curve obtained via simulation exhibits a high degree of coincidence with the experimental results. Based on the validated model, a detailed parameter analysis of prefabricated local reinforced concrete frame joints is carried out. The analysis results illustrate that the axial pressure ratio at the top of the column has a minimal impact on the joint's performance. Decreasing the stirrup ratio within the core region, enlarging the diameter of the PC steel bar, and increasing the concrete strength that is poured in the keyway and the core region can raise the cumulative energy consumption of the joints, thereby reducing the damage degree of other units and improving the maximum bearing capability of the joints. [ABSTRACT FROM AUTHOR]

Berberine, an isoquinoline alkaloid, has been reported to ameliorate various autoimmune diseases including rheumatoid arthritis by oral administration. However, its mechanism remains mysterious due to an extremely low bioavailability. The fact that berberine readily accumulates in the gut, the largest endocrine organ in the body, attracted us to explore its antiarthritic mechanism in view of the induction of intestinal immunosuppressive neuropeptides. In this study, berberine (200 mg kg-1, i.g.) was shown to ameliorate collagen-induced arthritis in rats, which was manifested by the reduction of clinical signs and joint destruction, as well as marked down-regulation of Th17 cell frequency and interleukin-17 level in blood. In contrast, an intravenous injection of berberine failed to affect arthritis in rats, implying that its anti-arthritic effect was gut-dependent. Further studies revealed that oral berberine selectively elevated the levels of cortistatin, of five gut-derived neuropeptides tested, in the intestines and sera of arthrititic rats. Antagonists of ghrelin/growth hormone secretagogue receptor 1 (a subtype of cortistatin receptor) almost completely abolished the ameliorative effect of berberine on arthritis and Th17 cell responses in rats. In vitro, berberine showed a moderate ability to promote the expression of cortistatin in nerve cells, which was strengthened when the nerve cells were cocultured with enteroendocrine cells to induce an autocrine/paracrine environment. In summary, oral berberine exerted anti-arthritic effect through inhibiting the Th17 cell response, which was closely associated with the induction of cortistatin generation from gut through augmenting autocrine/paracrine action between enteric nerve cells and endocrine cells. [ABSTRACT FROM AUTHOR]

Abstract: A rapid and simple high-performance liquid chromatographic (HPLC) method has been developed and validated for determination of scopoletin in rat plasma using psoralen as internal standard. Chromatographic separation was achieved on a C18 column using methanol and distilled water (49:51, v/v) containing 0.05% (v/v) phosphoric acid as mobile phase. The UV detector was set at 345nm. The calibration curve was linear over the range of 0.165–9.90μg/ml with a correlation coefficient of 0.9994. The recovery for plasma samples of 0.165, 1.32 and 6.60μg/ml was 93.2%, 95.9% and 95.5%, respectively. The RSD of intra- and inter-day assay variations was less than 6.7%. This HPLC assay is a precise and reliable method for the analysis of scopoletin in pharmacokinetic studies. [Copyright &y& Elsevier]

Background and Purpose Experimental Approach Key Results Conclusion and Implications Silibinin is used to treat non‐alcohol fatty liver disease (NAFLD) despite having rapid liver metabolism. Therefore, we investigated the role of the intestine in silibinin mechanism of action.NAFLD mice model was established by feeding them with a high‐fat diet (HFD). Liver pathological were examined using H&E and oil red O staining. Tissue distribution of silibinin was detected by LC–MS/MS. SiRNA was employed for gene silencing and plasmid was used for gene overexpression. ChIP‐qPCR assay was performed to detect the levels of histone acetylation. Recombinant adeno‐associated virus 9‐short hairpin‐fibroblast growth factor (FGF)‐15 and ‐farnesoid X receptor (FXR; NR1H4) were used to knockdown expression of FGF‐15 and FXR.Oral silibinin significantly reversed NAFLD in mice, although liver concentration was insufficient for reduction of lipid accumulation in hepatocytes. Among endogenous factors capable of reversing NAFLD, the expression of Fgf‐15 was selectively up‐regulated by silibinin in ileum and colon of mice. When intestinal expression of Fgf‐15 was knocked down, protection of silibinin against lipid accumulation and injury of livers nearly disappeared. Silibinin could reduce activity of histone deacetylase 2 (HDAC2), enhance histone acetylation in the promoter region of FXR and consequently increase intestinal expression of FGF‐15/19.Oral silibinin selectively promotes expression of FGF‐15/19 in ileum by enhancing transcription of FXR via reduction of HDAC2 activity, and FGF‐15/19 enters into circulation to exert anti‐NAFLD action. As the site of action is the intestine this would explain the discrepancy between pharmacodynamics and pharmacokinetics of silibinin. [ABSTRACT FROM AUTHOR]

This paper presents a study on the durability testing of a concrete facility located within the North Bay Port region, which has been in service for 200 months. Based on the results of 20 sets of concrete samples, an improved Kolmogorov-Smirnov (K-S) test method and gross error discrimination method are proposed to analyze the random distribution functions of the apparent chloride diffusion coefficient (D app) and the apparent surface chloride concentration (C s), and further explore the time-varying characteristics of chloride ion transmission in concrete. The research shows that the improved K-S method presented in this paper can effectively reduce the probability of type II errors by selecting a rational sample size, which can also improve detection efficiency. When the sample size does not exceed 10, the 2 σ criterion proposed in this paper can effectively identify and eliminate gross errors. In general, D app and C s follow the log-normal distribution, while the time factor (m) follows a normal distribution parameter. The value of C s basically stabilized after exposure to 80 months, whereas D app tended to stabilize after exposure to 100 months. The value of m obtained through fitting short-term experimental data is typically overestimated, and its value decreases as the exposure time prolongs. Therefore, m should also be considered a time-varying parameter that decreases with time. The tested RC structure will begin to experience rebar corrosion after 48.5–60 years of exposure to the marine environment based on the probabilistic assessment. • The 2 σ criterion was introduced to identify and rectify significant errors. • The improved K-S method was developed to minimize the likelihood of type II errors. • Chloride profiles were extracted from 200 months aged harbor concrete structures. • Both D app and C s demonstrated a good fit with the log-normal distribution. [ABSTRACT FROM AUTHOR]

Subcortical brain regions play essential roles in the pathology of social anxiety disorder (SAD). While adolescence is the peak period of SAD, the relationships between altered development of the subcortical regions during this period and SAD are still unclear. This study investigated the age-dependent alterations in structural co-variance among subcortical regions and between subcortical and cortical regions, aiming to reflect aberrant coordination during development in the adolescent with SAD. High-resolution T1-weighted images were obtained from 76 adolescents with SAD and 67 healthy controls (HC), ranging from 11 to 17.9 years. Symptom severity was evaluated with the Social Anxiety Scale for Children (SASC) and the Depression Self Rating Scale for Children (DSRS-C). Structural co-variance and sliding age-window analyses were used to detect age-dependent group differences in inter-regional coordination patterns among subcortical regions and between subcortical and cortical regions. The volume of the striatum significantly correlated with SAD symptom severity. The SAD group exhibited significantly enhanced structural co-variance among key regions of the striatum (putamen and caudate). While the co-variance decreased with age in healthy adolescents, the co-variance in SAD adolescents stayed high, leading to more apparent group differences in middle adolescence. Moreover, the striatum's mean structural co-variance with cortical regions decreased with age in HC but increased with age in SAD. Adolescents with SAD suffer aberrant developmental coordination among the key regions of the striatum and between the striatum and cortical regions. The degree of incoordination is age-dependent, which may represent a neurodevelopmental trait of SAD. [ABSTRACT FROM AUTHOR]

Several aryl hydrocarbon receptor (AhR) agonists have been reported to promote the generation of regulatory T cells (Treg cells), and the action mechanisms need to be identified. In this study, we addressed the underlying mechanism of AhR activation to induce the generation of Treg cells in the view of cellular metabolism. Naïve CD4+ T cells were purified with mouse CD4+ CD62L+ T Cells Isolation Kits. The proportions of Treg cells were detected by flow cytometry. The value of oxygen consumption rate (OCR) of CD4+ T cells was detected by the Seahorse XFe 96 analyzer. The activation of fatty acid oxidation (FAO)‐related metabolic pathways was detected by Western blotting. Intracellular localization of Lkb1 was detected by immunofluorescence. The Strad‐Mo25‐Lkb1 complex formation and K63 chain ubiquitination modification of Lkb1 were detected by co‐immunoprecipitation. The binding of AhR to the Skp2 promoter was detected by constructing luciferase reporter gene. AhR or carnitine palmitoyltransferases 1 was knockdown in dextran sulphate sodium (DSS)‐induced colitis or collagen‐induced arthritis (CIA) mice by infecting mice with adeno‐associated virus via the tail vein injection. Compared to the control group, exogenous and endogenous AhR agonists 3,3′‐diindolylmethane (DIM) and 2‐(1′H‐indole‐3′‐carbonyl)‐thiazole‐4‐carboxylic acid methyl ester (ITE) were shown to preferentially upregulate the mRNA expression of FAO‐related enzymes and the value of OCR. Consistently, pharmacological or genetic inhibition of FAO markedly diminished the induction of DIM and ITE on the differentiation of Treg cells. DIM and ITE functioned mainly through activating the liver kinase B1 (Lkb1)‐AMPK pathway via promotion of Lkb1‐Strad‐Mo25 complex formation and Lkb1 K63 ubiquitination. DIM and ITE were also shown to upregulate the mRNA expression of Skp2, a ubiquitination‐related enzyme, and facilitate the binding of AhR to the xenobiotic responsive element of Skp2 promoter region by luciferase reporter gene assay. Furthermore, the contribution of Skp2/K63 ubiquitination/Lkb1/FAO axis was verified in (DSS)‐induced colitis or CIA mice. In summary, these findings indicate that AhR activation promotes Treg cell generation by enhancing Lkb1‐mediated FAO via the Skp2/K63‐ubiquitination pathway, and AhR agonists may be used as inducers of Treg cells to prevent and treat autoimmune diseases. [ABSTRACT FROM AUTHOR]

The aryl hydrocarbon receptor (AhR), discovered 46 years ago, is a transcript factor member of the basic helix-loop-helix Per-ARNT-SIM (bHLH-PAS) family deeply implicated in health and diseases, and is traditionally associated with the metabolism of xenobiotic ligands. Recently, multiple and structurally diverse ingredients including amino acid metabolites, polyphenols, flavonoids, polyhydroxyalkanoates, polychlorinated biphenyls, and, triarylmethanes have been evaluated as AhR potential ligands, and there is increasing attention on AhR as an appealing target in various cancers, autoimmune disorders, inflammatory bowel diseases, rheumatoid arthritis and multiple sclerosis. Herein, this review focuses on the recent advances of AhR, covering articles published between 2002 and 2022. It summarizes the structure of AhR, regulation of the AhR pathway, physiological role, and AhR ligands, highlighting the vast opportunities and challenges for targeting drug development of AhR. [Display omitted] • Summarizing the latest research progress of diverse structures of AhR ligands and biological functions of AhR. • Summarizing the AhR ligands is of great importance to accelerate the discovery of novel pharmacotherapeutic agents. • Presenting the development potential of AhR and guide for future target drug modification and design. [ABSTRACT FROM AUTHOR]

Our previous studies have demonstrated that tetrandrine can induce the generation of regulatory T (Treg) cells in vitro and in vivo. But, the underlying mechanism of tetrandrine remains obscure. Naïve CD4+ T cells are isolated from the mesenteric lymph nodes of mice for the differentiation of Treg cells. Flow cytometry is used to detect the frequencies of Treg cells. Non‐targeted metabolomics analysis based on UHPLC‐QTOF/MS is performed to assess the intracellular metabolic profiles. ChIP‐PCR analysis is conducted to detect the level of H3K27ac at Foxp3 promoter and CNS regions. Tetrandrine treatment alters the metabolic profile of Treg cells, and pathway enrichment of differential metabolites mainly involves fatty acid oxidation (FAO). Tetrandrine promotes the mRNA expression of carnitine palmitoyl transferase‐1, and increases the level of acetyl coenzyme A (acetyl‐CoA) and the intracellular oxygen consumption rate. Either CPT1 inhibitor (etomoxir) or siRNA markedly diminishes the promotion of tetrandrine on Treg cell differentiation. Furthermore, tetrandrine enhances the acetylation of H3K27 in the promoter and CNS1 regions of Foxp3 through the acetyl‐CoA derived from FAO. In the mice with collagen‐induced arthritis, tetrandrine also induces Treg cell generation through FAO pathway. In addition, tetrandrine enhances the immunosuppressive function of Treg cells both in vitro and in vivo. The findings indicate that tetrandrine promotes Treg cell differentiation by enhancing FAO‐mediated Foxp3 acetylation, and the CPT1‐mediated FAO can serve as the target for the discovery of novel inducers of Treg cell generation. [ABSTRACT FROM AUTHOR]

Tripterygium wilfordii (TW) preparations have been utilized in China for treating rheumatoid arthritis and autoimmune diseases. However, their clinical use is limited due to reproductive toxicity, notably premature ovarian failure (POF). Our study aimed to investigate the effect and mechanism of bergenin in attenuating POF induced by triptolide in mice. POF was induced in female ICR mice via oral triptolide administration (50 μg/kg) for 60 days. Mice received bergenin (25, 50, 100 mg/kg, i.g.) or estradiol valerate (EV) (0.1 mg/kg, i.g.) daily, 1 h before triptolide treatment. In vitro , ovarian granulosa cells (OGCs) were exposed to triptolide (100 nM) and bergenin (1, 3, 10 μM). Antioxidant enzyme activity, protein expression, apoptosis rate, and reactive oxygen species (ROS) levels were assessed. The results showed that triptolide-treated mice exhibited evident atrophy, along with an increase in atretic follicles. Bergenin (50, 100 mg/kg) and EV (0.1 mg/kg), orally administered, exerted significant anti-POF effect. Bergenin and EV also decreased apoptosis in mouse ovaries. In vitro , bergenin (1, 3, 10 μM) attenuated triptolide-induced OGCs apoptosis by reducing levels of apoptosis-related proteins. Additionally, bergenin reduced oxidative stress through downregulation of antioxidant enzymes activity and overall ROS levels. Moreover, the combined use with Sh-Nrf2 resulted in a reduced protection of bergenin against triptolide-induced apoptosis of OGCs. Together, bergenin counteracts triptolide-caused POF in mice by inhibiting Nrf2-mediated oxidative stress and preventing OGC apoptosis. Combining bergenin with TW preparations may effectively reduce the risk of POF. [Display omitted] Bergenin can attenuate triptolide-induced premature ovarian failure in mice. Bergenin functions by inhibiting the apoptosis of ovarian granulosa cells (OGCs). Bergenin inhibits the apoptosis of OGCs through down-regulating oxidative stress. Bergenin down-regulates oxidative stress via activation of Nrf2. [ABSTRACT FROM AUTHOR]

For centuries, Shaoyao-Gancao-Fuzi decoction (SGFD) has been a reliable traditional Chinese medicine for treating rheumatoid arthritis (RA). Despite its long history of use, the specific active components and underlying mechanisms of its therapeutic effects have yet to be fully understood. The aim of this study was to investigate the active ingredients and therapeutic effects of SGFD on RA, and to further understand its underlying mechanism. The chemical constituents in SGFD extract and in rat serum after oral administration of SGFD were identified and evaluated using ultra-performance liquid chromatography quadrupole-time-flight mass spectrometry (UPLC-Q-TOF/MS) together with various data-processing methods, respectively. The efficacy of SGFD was assessed by using an adjuvant-induced arthritis (AIA) rat model and lipopolysaccharide-stimulated RAW 264.7 cell. Subsequently, cell metabolomic was conducted to clarify the potential biomarkers and pathways. ELISA, RT-qPCR, and WB were used to verify the anti-arthritis mechanism of SGFD. A total of 65 chemical constituents were identified in SGFD. 17 active components were distinguished in rat serum samples, of which 13 may be the main active ingredients for SGFD treatment of RA. The remarkable efficacy of SGFD in reducing the symptoms of RA is evident through its ability to alleviate the redness and swelling of the affected paws, as well as reduce the infiltration of inflammatory cells. Cell experiments revealed that rat serum of SGFD reduced IL-1 β , IL-6, and TNF- α secretion in RAW 264.7 cells. 27 potential biomarkers were identified through cell metabolomics analysis. The arachidonic acid (AA) metabolism signaling pathway was activated in RA, which could be reversed by rat serum of SGFD. SGFD effectively inhibited the expression and transformation of AA by downregulating the expression of key enzymes, including phospholipase A and cyclooxygenase. SGFD may ameliorate RA symptoms by regulating the AA-PGH 2 -PGE 2 /PGF 2α pathway. The main active components include songorine, fuziline, neoline, albiflorin, paeoniflorin, liquiritin, benzoylmesaconine, isoformononetin, liquiritigenin, isoliquiritigenin, formononetin, glycyrrhizic acid, and glycyrrhetinic acid. [Display omitted] • Serum pharmacochemistry and metabolomics were used to investigate SGFD treatment mechanisms for RA. • Identification of 13 pharmacodynamic components of SGFD for the treatment of RA. • SGFD ameliorates RA mainly through AA-PGH 2 -PGE 2 /PGF 2α pathway. [ABSTRACT FROM AUTHOR]

Norisoboldine (NOR), an alkaloid isolated from Radix Lindera, was previously reported to promote the differentiation of regulatory T cells (Treg cells), an important subtype of lymphocytes capable of controlling autoimmune diseases. The present study was performed to explore the mechanism of NOR in the view of cellular metabolism. A global metabolomic analysis indicated that NOR preferentially altered the fatty acid oxidation (FAO) pathway and elevated the content of related metabolites during Treg cell differentiation. The detection of oxygen consumption rate (OCR) and mRNA expression of FAO‐related enzymes demonstrated that NOR promoted FAO in the early stage of Treg cell differentiation. Consistently, pharmacological or genetic inhibition of FAO markedly diminished the induction of NOR on Treg cell differentiation. Furthermore, NOR was shown to elevate the level of acetyl‐CoA derived from FAO and acetylation of lysine 27 on histone 3 (H3K27) at the Foxp3 promoter and CNS2 regions. A knockdown of CPT1, the rate‐limiting enzyme of FAO, weakened the promotion of NOR on the development, acetyl‐CoA level, and acetylation of H3K27 of Treg cells in vitro and in the mice with collagen‐induced arthritis, and attenuated the anti‐arthritic effect of NOR. These findings demonstrate that NOR induces the development of Treg cells through promoting FAO, therefore, facilitating gene transcription of Foxp3 via acetyl‐CoA‐mediated H3K27 acetylation modification, and FAO might serve as a novel target to induce Treg cell development. [ABSTRACT FROM AUTHOR]

[Display omitted] • Arctigenin improves colitis in mice by promoting colonic mucosal healing. • Arctigenin promotes colonic mucosal healing by stimulating epithelial cell migration. • Arctigenin promotes colonic epithelial cell migration by enhancing focal adhesion assembly. • Arctigenin accelerates focal adhesion assembly by directly binding and activating FAK. • FAK activation is notably decreased in colon epithelial cells of UC patients. Colonic mucosal defect constitutes the major reason of recurrence and deterioration of ulcerative colitis (UC), and mucosal healing has become the therapeutic endpoint of UC. Unfortunately, specific promoter of mucosal healing is still absent. Our previous researches demonstrated that arctigenin could alleviate colitis symptoms in mice, but whether it has a positive impact on colonic mucosal healing remains unclear. This study explores whether and how arctigenin promotes mucosal healing. Orally administered arctigenin was shown to alleviate colitis in mice primarily by enhancing mucosal healing. In vitro , arctigenin was shown to promote the wound healing by accelerating colonic epithelial cell migration but not proliferation. Acceleration of the focal adhesion turnover, especially assembly, is crucial for arctigenin promoting the cell migration. Arctigenin was able to activate focal adhesion kinase (FAK) in colonic epithelial cells through directly binding with Tyr251 site of FAK, as evidenced by surface plasmon resonance assay and site-directed mutagenesis experiment. In the colonic epithelial cells of UC patients and colitis mice, FAK activation was significantly down-regulated compared with the controls. Arctigenin promoted colonic epithelial cell migration and mucosal healing in dextran sulphate sodium (DSS)-induced colitis mice dependent on activating FAK, as confirmed by combined use with FAK inhibitor. In summary, arctigenin can directly promote mucosal healing in colitis mice through facilitating focal adhesion turnover, especially assembly, and consequent migration of epithelial cells via targeting FAK. Arctigenin may be developed as a mucosal healing promoter, and FAK is a potential therapeutic target for UC and other mucosal defect-related diseases. [ABSTRACT FROM AUTHOR]

Abstract: The present study determined the anti-inflammatory activity of scopoletin in gout air pouch model and revealed the underlying mechanisms by in vitro assays. Monosodium urate (MSU) crystal-induced inflammation in mouse air pouch model, an experimental model for acute gout, was used to assess the efficacy of scopoletin. The neutrophil and mononuclear phagocyte numbers and MPO levels were increased significantly six hours after MSU crystal injection into the air pouch, whereas these changes were inhibited substantially upon scopoletin (100 and 200mg/kg, i.p.) treatment. To get insight into the underlying mechanisms, the in vitro studies were performed to investigate the effects of scopoletin on activation of macrophages and resultant production of inflammatory mediators. The secretions of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), prostaglandin E2 (PGE2) and nitric oxide (NO) were elevated in MSU crystal-stimulated RAW 264.7 cells, and scopoletin (30–300μM) suppressed the production of all mediators. Moreover, RT-PCR assay and western blot analysis indicated that scopoletin regulated the transcriptional level of these mediators via suppression of NF-κB activation and blockade of MAPK signal pathway. Thus, the results clearly indicated that scopoletin inhibited the monosodium urate crystal-induced inflammation both in vivo and in vitro. In combination with our previous findings that scopoletin shows hypouricemic, anti-angiogenesis and pro-apoptotic activities, this compound may be a potential agent for gout therapy and could serve as a structural base for developing new drugs. [Copyright &y& Elsevier]

1. Morin, a natural flavonol, is present in many plants. It has anti-inflammatory and immunomodulatory activities and is often used as an adjuvant treatment for arthritis. Diclofenac sodium is the first-choice drug in the treatment of rheumatoid arthritis. However, the herb-drug interaction (HDI) between morin and diclofenac sodium remains unclear. 2. The aim of the present research was to investigate whether and how morin affect the pharmacokinetic profile of diclofenac sodium. 3. The enzyme kinetic and pharmacokinetic studies showed that morin significantly accelerated the metabolism and reduced systemic exposure of diclofenac sodium. Interestingly, the effect of morin on the pharmacokinetic profile of diclofenac sodium was not in a dose-dependent manner. Therefore, the effect of morin on P-glycoprotein (P-gp) was further investigated. 4. The results implied that the influence mechanism of morin on the pharmacokinetic of diclofenac sodium might be related to CYP2C9 and P-gp. Attention should be paid to the risk of HDI between morin and diclofenac sodium in clinical practice. [ABSTRACT FROM AUTHOR]

Arctigenin, the major active constituent of Fructus Arctii, has been reported to inhibit the growth of various tumors and alleviate colitis. This study aimed to prove the protective effect of arctigenin on colitis-associated cancer (CAC) and explore its mechanisms. Orally administered arctigenin prevented the progression of colitis and protected against colon carcinogenesis in azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced CAC mice. Arctigenin downregulated NLRP3 inflammasome activation and fatty acid oxidation (FAO) metabolism in macrophages, as determined by untargeted metabolomics. Arctigenin also inhibited the expression of carnitine palmitoyltransferase 1 (CPT1), reduced the acetylation of α-tubulin, and disrupted NLRP3 complex formation, which in turn inactivated the NLRP3 inflammasome. Downregulation of the CPT1-FAO-acetyl-coenzyme A (acetyl-CoA)-acetylated α-tubulin pathway was observed to inhibit the effect of arctigenin on NLRP3 inflammasome assembly, as confirmed by CPT1 overexpression. Lastly, arctigenin was shown to inhibit NLRP3 inflammasome activation and improve CAC in mice, and the effect was significantly diminished by the overexpression of adeno-associated virus (AAV)9-CPT1. Taken together, these results show that the inhibition of NLRP3 inflammasome assembly in macrophages due to FAO downregulation contributes to the preventative effect of arctigenin against CAC. Our findings highlight the potential value of arctigenin to reduce the risk of CAC in patients with colitis. [ABSTRACT FROM AUTHOR]

In current work, InCaOx thin films with different Ca-doping concentrations were prepared via solution-processed method. A systematic investigation was conducted to reveal the variation in the physical properties of InCaOx thin films as a function of Ca-doping concentration by using various characteristic measurements. Results not only demonstrate that Ca-doping can change the optical properties, microstructure, and surface roughness of In2O3 thin films but also indicate that Ca-doping can effectively decrease oxygen vacancies in In2O3 thin films. By measuring the electrical properties of InCaOx/HfGdOx thin-film transistors (TFTs) at a low operating voltage of 5 V, it is noteworthy that Ca-doping can improve the deteriorated performance of In2O3/HfGdOx TFT caused by excessive oxygen vacancies. As Ca-doping concentration reaches 0.5%, InCaOx/HfGdOx TFT manifests superior performances, including a larger μFE of 15.1 cm2V−1s−1 and a higher ION/IOFF of 2.3 × 1/2 107. Furthermore, the stability of In2O3/HfGdOx TFTs under positive bias stress is improved after Ca-doping. Finally, an inverter with a high gain of 6.0 is assembled on the basis of InCaOx/HfGdOx TFT. More importantly, these excellent performances of InCaOx/HfGdOx TFTs are achieved at a low operating voltage, which marks a giant step toward the achievement of low cost and low power consumption electrical devices. [ABSTRACT FROM AUTHOR]

• Orifice flow noise appears in two reverse flows of vortex areas of the pipe. • The SPL of orifice flow noise increases over velocity logarithmically. • Smaller orifice leads to higher SPL, while orifice thickness causes faint influence. Based on the previous measurements data, the standard orifice flowmeters is one of the main noise sources in nature gas metering stations. In this paper, a theoretical method that combines the Large Eddy Simulations (LES) with the Ffowcs Williams Hawkings (FW-H) acoustic analogy theory has been used to analysis the Sound Pressure Level (SPL) distribution in standard orifice flowmeter. And then, a series of numerical simulations have been performed over a range of conditions, including medium velocity, aperture size, and orifice thickness. At last, a correlation formula of the maximum SPL and medium velocity has been presented by fitting the numerical results. It shows that the SPL increases over velocity logarithmically, and the maximum SPL is present at the upstream wall of orifice and in two reverse flows of vortex areas of the downstream pipe. Meanwhile, a smaller aperture size leads to higher SPL, while orifice thickness brings about faint influence. The SPL increases by about 8 dB by the decreasing of aperture per 20 mm. Finally, the data obtained from the fitting are verified by field data and is approved by the staff. The results provide effective guidance for practical operation of orifice flowmeter noise prevention and control. [ABSTRACT FROM AUTHOR]

In this work, HfGdOx gate dielectric thin films have been prepared via a nontoxic and environmental-friendly fully water-driven (WD) method. An in-depth investigation has been conducted to reveal the evolution of physical properties in the as-prepared HfGdOx thin films as a function of annealing temperature. Based on the measurements of electrical parameters of the HfGdOx thin films, it is observed that the 500 °C-annealed HfGdOx thin films have shown optimized properties, including a smooth surface, lower leakage current density, and a larger areal capacitance. To validate the feasibility of the HfGdOx gate dielectrics in thin-film transistors (TFTs), In2O3/HfGdOx TFTs have been constructed. The optimized In2O3/HfGdOx TFT exhibited excellent electrical performances, including high field-effect mobility of 11.2 cm2 V−1 s−1, a high ON-/OFF-state current ratio of 4.1 × 106, a small sub-threshold swing of 105.2 mV/decade, and a threshold voltage shift of 0.58 V after 7200-s bias stress, respectively. Finally, based on the In2O3/HfGdOx TFT, an inverter is assembled by connecting an external 3-MΩ resistor. High gain of 8.73 and excellent swing characteristics have been obtained. As a result, it can be inferred that fully WD In2O3/HfGdOx TFTs with high performance will pave the way for achieving low-power-consumption, low-cost, and large-area electronics. [ABSTRACT FROM AUTHOR]

1. Afatinib is an oral, selective tyrosine kinase inhibitor (TKI) primarily transported by P-glycoprotein (MDR1, gene code ABCB1) and breast cancer resistance protein (BCRP, gene code ABCG2). In the present study, the effects of ABCB1 and ABCG2 genetic polymorphisms on the pharmacokinetics of afatinib in healthy Chinese were investigated. 2. Blood samples from 24 healthy participants who received afatinib were used for genotyping ABCB1 (1236C>T, 2677G > T/A, 3435C>T) and ABCG2 (34G>A, 421C>A) polymorphisms. Subsequently, the association between afatinib plasma concentrations and target single-nucleotide polymorphisms (SNPs) was analyzed. 3. Among the five polymorphisms, plasma concentrations of afatinib in healthy subjects with ABCB1 1236CC–3435CC were remarkably higher than in other genotype subjects. No significant differences of afatinib exposure were found between the ABCG2 wild-type and heterozygous groups. 4. The ABCB1 genetic polymorphism influenced the plasma exposure of afatinib, and gene testing before drug administration may be useful for clinically individualized use of afatinib. Our data suggest the usefulness of afatinib pharmacogenetics in treatment optimization. [ABSTRACT FROM AUTHOR]

Intestinal epithelial barrier dysfunction is deeply involved in the pathogenesis of inflammatory bowel diseases (IBD). Arctigenin, the main active constituent in Fructus Arctii (a traditional Chinese medicine), has previously been found to attenuate colitis induced by dextran sulfate sodium (DSS) in mice. The present study investigated whether and how arctigenin protects against the disruption of the intestinal epithelial barrier in IBD. Arctigenin maintained the intestinal epithelial barrier function of mice with DSS‐ and TNBS‐induced colitis. In Caco‐2 and HT‐29 cells, arctigenin lowered the monolayer permeability, increased TEER, reversed the abnormal expression of tight junction proteins, and restored the altered localization of F‐actin induced by TNF‐α and IL‐1β. The specific antagonist PHTPP or shRNA of ERβ largely weakened the protective effect of arctigenin on the epithelial barrier function of Caco‐2 and HT‐29 cells. Molecular docking demonstrated that arctigenin had high affinity for ERβ mainly through hydrogen bonds as well as hydrophobic effects, and the protective effect of arctigenin on the intestinal barrier function was largely diminished in ERβ‐mutated (ARG346 and/or GLU305) Caco‐2 cells. Moreover, arctigenin‐blocked TNF‐α induced increase of the monolayer permeability in Caco‐2 and HT‐29 cells and the activation of myosin light chain kinase (MLCK)/myosin light chain (MLC) pathway in an ERβ‐dependent manner. ERβ deletion in colons of mice with DSS‐induced colitis resulted in a significant attenuation of the protective effect of arctigenin on the barrier integrity and colon inflammation. Arctigenin maintained the integrity of the intestinal epithelial barrier under IBD by upregulating the expression of tight junction proteins through the ERβ‐MLCK/MLC pathway. [ABSTRACT FROM AUTHOR]

Bergenin, a plant polyphenol, has been reported to lower the blood glucose level and ameliorate kidney function in streptozotocin (STZ)-induced diabetic rats. Herein, its protective effect on diabetic nephropathy (DN) was explored in view of extracellular matrix (ECM) generation in glomerular mesangial cells. Glomerular mesangial cells were treated with high glucose, and Q-PCR as well as western blot were used to determine the expression of ECM. To establish the participation and role of mammalian target of rapamycin (mTOR) and nuclear factor erythroid-derived 2-related factor 2 (Nrf2) in ECM generation, a combination of l -leucine (activator of mTOR) and Nrf2 shRNA transfection were performed, respectively. Moreover, a DN model was established in mice using high-glucose/high-fat diet and STZ. Bergenin impeded the generation of TGF-β1 and ECM, decreased the levels of intracellular superoxide anion and hydrogen peroxide, and increased the activity of antioxidant enzymes in the glomerular mesangial cells (HBZY-1 and HRMC cells) treated with high glucose. The inhibition of ECM generation by bergenin was dependent on the down-regulation of oxidative stress as confirmed via a superoxide overexpression system. The activation of Nrf2 was required for bergenin to inhibit the oxidative stress and ECM generation. Moreover, bergenin was found to inhibit the phosphorylation of mTOR, which is located at the upstream of Nrf2. Bergenin did not interfere with the expression of Nrf2 mRNA and Keap1 (the classic degradation control factor of Nrf2), but markedly inhibited the protein expression of the β-TrcP, an effect which could be abolished by l -leucine. In DN model mice, l -leucine diminished the ability of bergenin to reduce the levels of superoxide anion, hydrogen peroxide and ECM, which contributed to the eradication of the ameliorative effect of bergenin on nephropathy. Bergenin can inhibit glucose-induced ECM production in glomerular mesangial cells through the down-regulation of oxidative stress via the mTOR/β-TrcP/Nrf2 pathway, and it might be a candidate drug for the prevention and treatment of DN. Image 1 • Bergenin impedes ECM generation in GMCs dependent on the inhibition of oxidative stress. • mTOR is located upstream of Nrf2 in high glucose-stimulated GMCs. • Bergenin impedes ECM generation and ameliorates DN via the mTOR/β-TrcP/Nrf2 pathway. • The anti-DN potency of bergenin is nearly equivalent to that of the same dose of metformin. [ABSTRACT FROM AUTHOR]

In this article, novel ZrAlOx gate dielectric films were fabricated by a simple, low-cost, and environmentally, eco-friendly, fully water-induced (WI) method for the first time. The microstructure, optical transmittance, surface topography, chemical compositions, and electrical properties of WI ZrAlOx films annealed at 300 °C–600 °C were characterized. Experimental results demonstrated that the 500 °C-annealed WI ZrAlOx film has a good amorphous state, high transmittance, very smooth surface morphology, large area capacitance, and low leakage current density. In order to verify the feasibility of the 500 °C-annealed ZrAlOx film as a dielectric in thin-film transistor (TFT) devices, In2O3/ZrAlOx TFTs were successfully fabricated. The optimized 270 °C-annealed TFT devices have shown excellent electrical characteristics at an extremely low operating voltage of 3 V, including a high $\mu _{{\text {FE}}}$ of 10.14 cm2V−1S−1, a high ${I}_{{\text {on}}}/{I}_{{\text {off}}}$ of ~ 106, a small subthreshold slope (SS) (100 mV dec−1), a low ${V}_{{\text {TH}}}$ (0.36 V), and a small ${N}_{S}^{{\text {max}}}$ ($2.15\times {10}^{{12}}$ cm−2), respectively. To further explore the potential application of In2O3/ZrAlOx TFTs in digital circuits, a resistor-loaded inverter has been constructed and presented good voltage transfer characteristics and high voltage gain. In addition, the dynamic behavior with full swing characteristics has been obtained at a low ${V}_{{\text {DD}}}$ of 2 V. These excellent parameters show their great potential for application in low cost, highly transparent, portable, and low-power consumption electronics. [ABSTRACT FROM AUTHOR]

In this paper, a nontoxic and environmentally friendly water-driven (WD) route to prepare InZnO thin films with various molar ratio of In and Zn has been reported. The formation mechanisms and physical properties of InZnO thin films as a function of element molar ratio are investigated by various characterization techniques. By comparing the performance of InZnO/SiO2 thin-film transistors (TFTs) at different element molar ratio, the results indicate that the molar ratio of 2:1 (In:Zn) is the optimal choice. Based on the optimal molar ratio, fully WD InZnO/HfOx TFT is fabricated and the excellent electrical properties are obtained at a low operating voltage of 5 V, including a higher field-effect mobility of 9.1 cm $^{{2}}\text{V}^{-{1}}\text{s}^{-{1}}$ , a larger ON-/OFF-state current ratio of ${1.5} \times {10}^{{7}}$ , a smaller subthreshold swing of 0.09 V/dec, and a smaller threshold voltage shift of 0.44 V after 5400-s bias stressing, separately. Finally, to further validate the feasibility of InZnO TFTs in complex logic circuits, an inverter is assembled based on the InZnO/HfOx TFT, exhibiting a high gain of 8.8. More importantly, the excellent properties of InZnO/HfOx TFT are achieved at a low-voltage stage, which stands for the great application prospects of WD TFTs in low-cost and excellent performance electronic devices. [ABSTRACT FROM AUTHOR]

Metal–oxide high- ${k}$ material is regarded as the promising building block for large area high-performance flexible electronic devices. Here, we report that dysprosium oxide (DyOx) films were successfully integrated as dielectrics into thin-film transistors (TFTs) for the first time. Solution-driven DyOx films behave high transmittance over 85% and imply the possible application in transparent devices. Measurements based on 500 °C annealing ZnSnO/DyOx TFTs have indicated the dramatic improvement in electrical performance after natural aging diffusion for 10 days, containing the increased saturation mobility value from 0.57 to 2.5 cm $^{{2}}\cdot \text{V}^{-{1}}\cdot \text{s}^{-{1}}$ and the lifted current ON/ OFF ratio from $7.8\times 10^{{4}}$ to $2.4\times 10^{{6}}$. It is worth mentioning that the mobility of aging samples with the lower annealing temperature of 420 °C even surpasses the aforementioned 500 °C annealing without aging TFTs. The variable-range-hopping (VRH) percolation model and coherent interface theory are used to explore electronic transport mechanism for amorphous and polycrystalline ZnSnO films, respectively. Finally, the resistor-loaded inverter has been fabricated and revealed the gain of 7.3 at the low voltage of 2.5 V, which even surpasses many In-based TFT devices. It can be concluded that the solution-based samples can proceed with 10 days aging treatment before encapsulation to obtain the stable electrical performance, which affords a simple and effective approach toward building low-temperature, low power consumption transparent electronic devices. [ABSTRACT FROM AUTHOR]

Abstract Aims Sinomenine, an anti-rheumatoid arthritis drug used in China for decades, is usually co-administered with cardiovascular (CV) drugs to reduce arthritis-related risk of cardiovascular diseases. This study was to investigate whether and how CV drugs affect the pharmacokinetic profile of sinomenine. Main methods In rat liver microsomes (RLMs), the key metabolic enzymes of sinomenine were identified by using specific inhibitors. The influences of CV drugs, including propranolol, verapamil, warfarin, atorvastatin, simvastatin, and lovastatin, on the metabolism of sinomenine were examined. Cocktail probe, RT-qPCR, and western blotting were performed to unveil the underlying mechanism of the drug-drug interaction. Key findings The key metabolic enzymes of sinomenine were identified to be CYP3A1/2 and CYP2D1 in RLMs. Among the CV drugs screened, simvastatin and lovastatin were shown to inhibit the liver metabolism of sinomenine with Ki values of 13.00 and 25.83 μM, respectively. Single administration of simvastatin or lovastatin in rats increased the AUC value of sinomenine to 1.40- or 1.50-fold, and decreased the CLz/F value to 68.19% or 65.44%, respectively. In contrast, multiple administrations of simvastatin, but not lovastatin, increased the CLz/F value of sinomenine to 1.38-fold and decreased the AUC value to 71.59%. Further studies showed that the long-term administration of simvastatin could up-regulate the expression of CYP3A1/2 to account for the effect. Significance This study demonstrated the potential effect of simvastatin and lovastatin on the metabolism of sinomenine for the first time. The findings provide guidelines for the co-administration of sinomenine with simvastatin or lovastatin in clinic. [ABSTRACT FROM AUTHOR]

Tetrandrine is an effective ingredient isolated from the roots of a frequently used medicinal plant Stephania tetrandra S. Moore. It has been used for the management of arthritis in China, but the precise mechanism remains unclear. In the present study, a metabolomics method based on the 1 H NMR was constituted to quantify the alterations of the endogenous metabolites in the urines of collagen-induced arthritis (CIA) rats treated with tetrandrine. Data showed that tetrandrine treatment could alleviate the ankle joint swelling and ameliorate histopathological changes in rats. The metabonomic analysis indicated that 23 potential biomarkers in urine were affiliated with CIA. They mainly participated in energy metabolism, amino acid metabolism, lipid metabolism and gut microbe metabolism. Moreover, our results implied that tetrandrine could reverse the pathological process of CIA through adjusting the unbalanced metabolic pathways. Thus, these metabolic pathways and potential biomarkers might be the potential therapeutic targets of tetrandrine, and these findings supplied new visions into the protective effect of tetrandrine against arthritis in rats. [ABSTRACT FROM AUTHOR]

F-box protein 11 (FBXO11) has both the E3 ubiquitin ligase activity and the methyltrasferase activity, and regulates metastasis, apoptosis and chemosensitivity in human cancer. However, the clinical significance and biological function of FBXO11 in gastric cancer (GC) are rarely known. Here, we demonstrated up-regulated expression of FBXO11 in GC tissues in comparison with that in tumor-adjacent tissues. Clinical analysis based on our specimens and the TCGA database revealed that FBXO11 overexpression was associated with large tumor size, lymph node metastasis and advanced TNM stage. Notably, GC patients with high FBXO11 expression showed a significant shorter overall survival. Cell proliferation and mobility were measured by CCK-8 and Transwell assays. FBXO11 silencing by transfection with two specific shRNAs attenuated proliferation, migration and invasion of MGC-803 cells. In accordance, FBXO11 overexpression promoted these cellular processes in SGC-7901 cells. Mechanistically, FBXO11 obviously facilitated epithelial-mesenchymal transition (EMT) process as suggested by immunoblotting and immunofluorescence data. Moreover, we found that FBXO11 promoted the activation of AKT pathway with increased phosphorylated AKT level in SGC-7901 cells. LY294002 and Wortmannin, phosphotidylinsitol-3-kinase (PI3K) inhibitors, blocked FBXO11 induced EMT, proliferation, migration and invasion of SGC-7901 cells. Phosphatase and tensin homolog (PTEN), which played a crucial role in regulating PI3K/AKT pathway, was negatively modulated by FBXO11 in GC cells. Taken together, our findings contribute to current understanding of the functions of FBXO11 and suggest a mechanism by which FBXO11 plays an oncogenic role in the development of GC possibly by inhibiting PTEN and subsequently promoting PI3K/AKT pathway activation. [ABSTRACT FROM AUTHOR]

A specific and sensitive LC–MS/MS method was established for the simultaneous determination of bergenin, protocatechuic acid and gallic acid, the main active constituents of Saxifraga stolonifera (L.) Meerb. herb, in rat plasma. After fully validated, the method was applied to the comparative pharmacokinetic studies of the three compounds orally administered alone and in combination in the S. stolonifera extract, respectively. The results showed that the pharmacokinetic parameters, including C max , T max , AUC, CL z /F, MRT 0-∞ , were significantly different for both bergenin and protocatechuic acid in the extract as compared to the corresponding compounds administered alone. However, the pharmacokinetic behavior of gallic acid in the extract did not differ from that administered alone. Further studies found that quercetin, coexisting in the herb extract, significantly decreased the glucuronidation of bergenin through inhibiting the activities of UGT1A1 and UGT1A3, and reduced the metabolism of protocatechuic acid by inhibiting the activity of catechol-O-methyltransferase. Quercetin and other flavonoids occurring in the S. stolonifera extract might increase the absorption and improve the bioavailability of bergenin and protocatechuic acid by slowing down the liver metabolism. The findings provide a good guidance for the development and clinical application of S. stolonifera . [ABSTRACT FROM AUTHOR]

Background: Previous studies have demonstrated that oral administration of curcumin exhibited an anti-arthritic effect despite its poor bioavailability. The present study aimed to explore whether the gut-brain axis is involved in the therapeutic effect of curcumin.Methods: The collagen-induced arthritis (CIA) rat model was induced by immunization with an emulsion of collagen II and complete Freund's adjuvant. Sympathetic and parasympathetic tones were measured by electrocardiographic recordings. Unilateral cervical vagotomy (VGX) was performed before the induction of CIA. The ChAT, AChE activities, and serum cytokine levels were determined by ELISA. The expression of the high-affinity choline transporter 1 (CHT1), ChAT, and vesicular acetylcholine transporter (VAChT) were determined by real-time PCR and immunohistochemical staining. The neuronal excitability of the vagus nerve was determined by whole-cell patch clamp recording.Results: Oral administration of curcumin restored the imbalance between the sympathetic and parasympathetic tones in CIA rats and increased ChAT activity and expression of ChAT and VAChT in the gut, brain, and synovium. Additionally, VGX eliminated the effects of curcumin on arthritis and ACh biosynthesis and transport. Electrophysiological data showed that curcumin markedly increased neuronal excitability of the vagus nerve. Furthermore, selective α7 nAChR antagonists abolished the effects of curcumin on CIA.Conclusions: Our results demonstrate that curcumin attenuates CIA through the "gut-brain axis" by modulating the function of the cholinergic system. These findings provide a novel approach for mechanistic studies of anti-arthritic compounds with low oral absorption and bioavailability. [ABSTRACT FROM AUTHOR]

Butyrate, given by oral administration or in drinking water, has been shown to improve experimental pulmonary fibrosis (PF) in mice despite of very low bioavailability. The pharmacokinetic-pharmacodynamics disconnection attracts us to explore its anti-PF mechanism in view of the intestinal expression of anti-PF factors. In bleomycin-induced PF in mice, rectal administration of butyrate (500 mg/kg) exhibited a significant anti-PF effect, with a maximum plasma concentration largely lower than the minimum effective concentration (1 mM) at which butyrate inhibited the expression of pro-inflammatory factors by lung epithelial cells and the production of extracellular matrix by lung fibroblasts. The rectal administration of butyrate significantly upregulated the mRNA expression of hepatocyte growth factor (HGF) in the colons of PF mice, but showed no significant effect on the mRNA expression of HGF in the small intestines, lungs and livers. In colon epithelial cells, the monocarboxylate transporter inhibitor α-cyano-4-hydroxycinnamic acid (CHC) abrogated butyrate-induced expression of HGF, indicating that butyrate functions through entering into cells. Butyrate showed no significant effect on the histone acetylation in the promoter region of HGF, suggesting that it promotes HGF expression not by directly affecting the histone deacetylation of HGF but by other pathways. GW9662, the inhibitor of PPARγ, significantly attenuated the effect of butyrate to promote the mRNA expression of HGF. Butyrate was able to enhance the acetylation of PPARγ, and a targeted mutation of lysine at the position 240 (K240) of PPARγ markedly diminished the induction of butyrate on HGF expression, suggesting that butyrate promoted HGF expression in colon epithelial cells by upregulating PPARγ K240 acetylation. In summary, rectal administration of butyrate promotes the expression of HGF in colonic epithelial cells through upregulating PPARγ acetylation via inhibition of HDAC activity. The findings of the present study provide a reasonable explanation for the anti-PF action mode of butyrate based on the 'lung-gut axis', and found that intestine-derived butyrate and HGF may be involved in the modulation of the occurrence and progression of PF. [ABSTRACT FROM AUTHOR]

Shaoyao-Gancao-Fuzi decoction (SGFD), a well-known traditional Chinese medicine formula, was originally described in "Treatise on Febrile Diseases" and has been extensively used to dispel wind, eliminate dampness and treat paralysis. It is widely used for the treatment of rheumatoid arthritis in clinic. However, the effect of SGFD on the activity of cytochrome P450 enzymes (CYP450s) and the herb-drug interactions are rarely studied. The aim of this study was to investigate the effect of SGFD on the activity of CYP450s and evaluate the potential herb-drug interactions between SGFD and tofacitinib, commonly used disease-modifying antirheumatic drug in rheumatoid arthritis. The cocktail approach was employed to assess the effect of SGFD on the activity of CYP1A2, 3A4, 2A6, 2E1, and 2C9. The pharmacokinetic profile of oral administration of tofacitinib in rats after two weeks of treatment with SGFD was investigated. RT-qPCR and molecular docking were performed to unveil the underlying mechanism of the herb-drug interaction. SGFD had no effect on the activities of CYP2E1 and 2C9, had a weak effect on CYP2A6, and had activatory effect on CYP1A2. However, it had a dramatically inhibitory effect on the activity of CYP3A4. Simultaneously, the values of C max and AUC 0-∞ of tofacitinib were obviously increased after treatment with SGFD for 14 days. The mechanism study manifested that SGFD significantly reduced the gene transcription of CYP3A. Molecular docking work confirmed that the inhibitory activity of glycyrrhetinic acid, glycyrrhizic acid and liquiritin, the main ingredients of SGFD, occurred by occupying the active sites of CYP3A4 and by making favorable interactions with its key residues. The system exposure of tofacitinib was increased by SGFD. SGFD could affect the activity and gene expression of the key metabolic enzyme CYP3A. These findings give a clear understanding to predict herb-drug interaction of SGFD for safe clinical use in future. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] Madecassic acid (MA), a triterpene compound isolated from Centella Asiatica herbs, has previously been shown to attenuate colitis induced by DSS in mice. In the present study, we address whether and how MA ameliorates colitis-associated colorectal cancer (CAC), which accounts for a considerable proportion of colorectal cancer. CAC was induced by AOM/DSS in mice, and MA was administered orally once a day. To identify the source cells of IL-17 and the target cells for MA reducing the expression of IL-17 in the colons of CAC mice, single-cell suspensions were prepared from the colons of CAC mice and analyzed by flow cytometry. An adoptive transfer experiment was performed to verify the importance of the decreasing γδT17 cell population in the anti-CAC effect of MA. Oral administration of MA reduced the burden and incidence of tumors in the CAC mice. MA decreased the number of MDSCs in the colon tissues of CAC mice and ameliorated anti-tumor immune responses. MA could prevent the migration of MDSCs by inhibiting the activation of γδT17 cells and the expression of chemokines. The population of activated-γδT17 cells in the tumor microenvironment of CAC mice positively correlated with the number of MDSCs and tumors as well as tumor load. Moreover, the anti-CAC effect of MA was significantly counteracted by the adoptive transfer of γδT17 cells. MA alleviates CAC by blocking the recruitment of MDSCs to increase the population of anti-tumor immune cells in tumor microenvironment via inhibition of the activation of γδT17 cells. [ABSTRACT FROM AUTHOR]

Objective Norisoboldine (NOR), an isoquinoline alkaloid with very poor oral bioavailability, was previously proven to have a unique anti-arthritis activity in rats by inducing intestinal Treg cells. Herein, we explored its underlying mechanism in view of aryl hydrocarbon receptor (AhR). Methods The differentiation of regulatory T cells (Treg cells) and IL-17-producing T cells (Th17 cells) from naïve T cells was analyzed in vitro . The key role of AhR was ascertained using siRNA transfection. AhR agonistic effect was verified based on the activation of downstream signaling pathway and target genes. The correlation between AhR activation and Treg cell induction as well as pathological changes of joints was confirmed in collagen-induced arthritis (CIA) mouse model. Results NOR promoted intestinal Treg cell differentiation and function in an AhR-dependent manner. It acted as an AhR agonist, as evidenced by induction of CYP1A1 expression and activity, promotion of AhR/Hsp90 dissociation and AhR nuclear translocation, induction of XRE reporter activity, and facilitation of AhR/XRE binding. In CIA mice, NOR exerted substantial anti-arthritic effect through enhancing AhR activation in intestinal tissues and inducing intestinal Treg cell generation, which could be largely abolished by resveratrol (a antagonist of AhR). An adoptive transfer of Treg cells from NOR-treated mice could successfully alleviate arthritis symptoms in CIA mice. Conclusion Oral NOR induces the generation of intestinal Treg cells by the activation of AhR, and thereby exerts anti-arthritic effect. [ABSTRACT FROM AUTHOR]

Morin, a flavonoid isolated from Morus alba L. (Moraceae), possesses anti-inflammatory, antiangiogenic among other biological activities. This study investigated its effect on type II collageninduced arthritis (CIA) in rats and explored the underlying mechanisms in view of synovial angiogenesis. Morin administered po attenuated arthritic progression as indicated by reduction of arthritis scores and paw swelling. It also markedly reduced serum levels of the proinflammatory cytokines, tumor necrosis factor alpha (TNF-β) and interleukin-6 (IL-6), but increased the level of anti-inflammatory cytokine interleukin-10, and ameliorated histopathological changes of joints. Morin markedly inhibited expression of CD31, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor in synovial membrane tissues, and decreased serum levels of VEGF in CIA rats. In vitro, morin markedly inhibited VEGFinduced migration and tube formation in human umbilical vein endothelial cells. These results indicate that morin had antirheumatoid potential, and its mechanism might be associated with inhibition of synovial angiogenesis. [ABSTRACT FROM AUTHOR]

Endotoxin can stimulate inflammatory cytokine release from monocytes/macrophages and result in septic shock. Glycyrrhetinic acid (GA), the main bioactive component of licorice, possesses substantial anti-inflammatory activity. Here, we explored effect of 11-deoxy-18α-glycyrrhetinic acid-30-ethyl ester (DGAEE), a newly synthesized derivative of GA, on septic shock. DGAEE and its main metabolite 11-deoxy-18α-glycyrrhetinic acid (DGA) significantly alleviated septic shock as evidenced by improvements of survival rates, lung histopathological changes and wet/dry ratio in lipopolysaccharide (LPS)/D-galactosamine-stimulated mice, and decreased blood pressure in LPS/D-galactosamine-stimulated rats. The two compounds decreased serum levels of NO, TNF-α, IL-6, IL-1β, and increased the level of IL-10 more potently in mice. In LPS-stimulated RAW 264.7 cells, DGA but not DGAEE showed marked regulation of NO, TNF-α, IL-6 and IL-10 levels, suggesting that DGAEE display anti-shock effect by DGA rather than itself. Moreover, the neutralizing antibody against IL-10 markedly prohibited the inhibitory effect of DGA on the production of cytokines from RAW 264.7 cells, and AS101 (an inhibitor of IL-10 biosynthesis) almost completely reversed the anti-shock effect of DGA in mice. In addition, DGA did not affect activation of NF-κB-p65 and p38 MAPK as well as IκBα degradation, but moderately reduced activation of ERK and JNK, and markedly increased phosphorylation of GSK3β in LPS-stimulated RAW 264.7 cells. LY294002 (an inhibitor of GSK3β phosphorylation) and LiCl (an inhibitor of GSK3β activity) diminished and potentiated increase of IL-10 levels by DGA, respectively. In conclusion, DGAEE alleviates septic shock through DGA in an IL-10-dependent manner, and the mechanism is related to inactivation of GSK3β. [ABSTRACT FROM AUTHOR]

Arctigenin, the main effective constituent of Arctium lappa L. fruit, has previously been proven to dramatically attenuate dextran sulfate sodium (DSS)-induced colitis in mice, a frequently used animal model of inflammatory bowel disease (IBD). As Th1 and Th17 cells play a crucial role in the pathogenesis of IBD, the present study addressed whether and how arctigenin exerted anti-colitis efficacy by interfering with the differentiation and activation of Th1/Th17 cells. In vitro , arctigenin was shown to markedly inhibit the differentiation of Th17 cells from naïve T cells, and moderately inhibit the differentiation of Th1 cells, which was accompanied by lowered phosphorylation of STAT3 and STAT4, respectively. In contrast, arctigenin was lack of marked effect on the differentiation of either Th2 or regulatory T cells. Furthermore, arctigenin was shown to suppress the mammalian target of rapamycin complex 1 (mTORC1) pathway in T cells as demonstrated by down-regulated phosphorylation of the downstream target genes p70S6K and RPS6, and it functioned independent of two well-known upstream kinases PI3K/AKT and ERK. Arctigenin was also able to inhibit the activity of mTORC1 by dissociating raptor from mTOR. Interestingly, the inhibitory effect of arctigenin on T cell differentiation disappeared under a status of mTORC1 overactivation via knockdown of tuberous sclerosis complex 2 (TSC2, a negative regulator of mTORC1) or pretreatment of leucine (an agonist of mTOR). In DSS-induced mice, the inhibition of Th1/Th17 responses and anti-colitis effect of arctigenin were abrogated by leucine treatment. In conclusion, arctigenin ameliorates colitis through down-regulating the differentiation of Th1 and Th17 cells via mTORC1 pathway. [ABSTRACT FROM AUTHOR]

[Display omitted] • Neuropeptide CST can inhibit Th17 cell differentiation by attenuating glycolysis. • CST inhibits glycolysis of Th17 cells by down-regulating the expression of HK2. • CST attenuates glycolysis and inhibits Th17 cell differentiation by activating GHSR1 receptor. The neuropeptide cortistatin (CST) has been reported to attenuate Th17 cell response in multiple disease models, but the mechanism of action remains obscure. Here, we show that either overexpression or exogenous addition of CST obviously restricts Th17 cell differentiation. As metabolic reprogramming plays an important role in Th17 cell development, we explore whether CST inhibits Th17 cell differentiation by regulating glycolysis. The results show that CST substantially attenuates the glycolysis during Th17 differentiation and down-regulates the mRNA expression of myelocytomatosis oncogene (Myc) and hexokinase 2 (HK2), the glycolysis rate-limiting enzyme. Following the overexpression of Myc and HK2, the inhibitory effect of CST on Th17 differentiation nearly disappears, suggesting that Myc-HK2 pathway is deeply involved. Furthermore, growth hormone secretagogue receptor 1 (GHSR1) is identified as the key receptor subtype for CST attenuating glycolysis and Th17 cell differentiation by the combined uses of CST with various receptor subtype blockers. The knockdown of GHSR1 abrogates the inhibition of CST on Th17 differentiation and glycolysis. Finally, in the colitis mice induced by dextran sulfate sodium, an intraperitoneal injection of CST markedly inhibits Th17 cell response and down-regulates the expression of HK2 in the Th17 cells, which is reversed by the combined use of GHSR1 antagonist. These findings suggest that inhibition of glycolysis is the key pathway for CST attenuating Th17 cell response, and GHSR1, Myc and HK2 are potential therapeutic targets of Th17 cell-related diseases. [ABSTRACT FROM AUTHOR]

(E)-3-(4-chlorophenyl)-N-(7-hydroxy-6-methoxy-2-oxo-2H-chromen-3-yl) acrylamide (SC-III3), a newly synthesized derivative of scopoletin, was previously shown to reduce the viability of HepG2 cells and tumor growth of HepG2 xenograft mouse model. It induces the death of HepG2 cells by a way irrelevant to apoptosis and necrosis. To shed light on the cytotoxic mechanisms of SC-III3, the present study addresses whether and how it can induce autophagic cell death. When HepG2 cells were incubated with various concentrations of SC-III3, autophagic vacuoles could be observed by transmission electron microscopy and monodansylcadaverine staining. Increased expressions of LC3-II to LC3-I and Beclin-1, required for autophagosome formation, were accompanied. These characteristics integrally indicated that SC-III3 could initiate autophagy in HepG2 cells. N-acetyl- l -cysteine (NAC), a ROS scavenger, could reverse SC-III3-caused ROS accumulation, but it did not affect SC-III3-induced autophagy, suggesting that ROS was not involved in SC-III3-mediated autophagy in HepG2 cells. SC-III3 significantly depressed mitochondrial function, as evidenced by disruption of mitochondrial transmembrane potential and loss of the mitochondrial cristae structure, as well as decrease of Cox-I, Cox-III, Cox-IV, and ATP levels. The autophagy and activation of AMPK–TSC2–mTOR–p70s6k pathways induced by SC-III3 in HepG2 cells could be efficiently blocked by pre-treatments of compound C (an inhibitor of AMPK). Moreover, addition of extracellular ATP to the cell culture media could reverse SC-III3-caused activation of AMPK–TSC2–mTOR–p70s6k pathway, autophagy and cell viability decrease in HepG2 cells. Collectively, SC-III3 leads to autophagy through inducing mitochondrial dysfunction, depleting ATP, and activating AMPK–mTOR pathway, which thus reflects the cytotoxic effect of SC-III3 in HepG2 cells. [ABSTRACT FROM AUTHOR]

Sinomenine (SIN) has long been used as a therapeutic agent of rheumatoid arthritis (RA) in China. However, the discrepancy between low oral bioavailability and higher minimal effective concentration made its action mode mysterious. The present study aimed to gain insight into the mechanisms by which SIN suppressed collagen-induced arthritis (CIA) in rats in view of Th17 and regulatory T (Treg) cell balance. SIN was orally administered, and the clinical symptoms of CIA rats were monitored; inflammatory cytokines levels in serum were measured by ELISA; pharmacokinetic studies were performed in normal and CIA rats; Th17 and Treg cell frequencies were analyzed by flow cytometry. The data showed that SIN treatment resulted in a dramatic decrease of arthritis scores and paw volume of CIA rats, which was accompanied by down-regulation of IL-17A and up-regulation of IL-10 in rat serum. The frequency of Treg cells was increased and the frequency of Th17 cells was decreased in the gut lymphoid tissues of SIN-treated rats. Immunohistochemistry assay demonstrated that more α4β7-positive cells were detained in joint tissues after SIN treatment. Moreover, the anti-arthritis efficacy of SIN disappeared when it was given by intraperitoneal injection, further confirming the action of SIN was gut-dependent. In conclusion, SIN exerts anti-RA action probably through modulating the frequencies of Treg cells and Th17 cells in intestinal lymph nodes and yielding a trafficking of lymphocytes (especially Treg cells) from gut to joint. [ABSTRACT FROM AUTHOR]

Curcumin (CUR) has been proven to be clinically effective in rheumatoid arthritis (RA) therapy, but its low oral bioavailability eclipses existent evidence that attempts to explain the underlying mechanism. Small intestine, the only organ exposed to a relatively high concentration of CUR, is the main site that generates gut hormones which are involved in the pathogenesis of RA. This study aims at addressing the hypothesis that one or more gut hormones serve as an intermediary agent for the anti-arthritic action of CUR. The protein and mRNA levels of gut hormones in CUR-treated rats were analyzed by ELISA and RT-PCR. Somatostatin (SOM) depletor and receptor antagonist were used to verify the key role of SOM in CUR-mediated anti-arthritic effect. The mechanisms underlying CUR-induced upregulation of SOM levels were explored by cellular experiments and immunohistochemical staining. The data showed that oral administration of CUR (100 mg/kg) for consecutive two weeks in adjuvant-induced arthritis rats still exhibited an extremely low plasma exposure despite of a dramatic amelioration of arthritis symptoms. When injected intraperitoneally, CUR lost anti-arthritic effect in rats, suggesting that it functions in an intestine-dependent manner. CUR elevated SOM levels in intestines and sera, and SOM depletor and non-selective SOM receptor antagonist could abolish the inhibitory effect of CUR on arthritis. Immunohistochemical assay demonstrated that CUR markedly increased the number of SOM-positive cells in both duodenum and jejunum. In vitro experiments demonstrated that CUR could augment SOM secretion from intestinal endocrine cells, and this effect could be hampered by either MEK1/2 or Ca 2+ /calmodulin-dependent kinase II (CAMKII) inhibitor. In summary, oral administration of CUR exhibits anti-arthritic effect through augmenting SOM secretion from the endocrine cells in small intestines via cAMP/PKA and Ca 2+ /CaMKII signaling pathways. [ABSTRACT FROM AUTHOR]

A series of hybrids of scopoletin and substituted cinnamic acid were designed, synthesized and evaluated in vitro and in vivo against five human tumor cell lines [MCF-7, MDA-MB-231, A549, HCT-116, and HeLa] with doxorubicin as the positive control. Compounds 17a , 17b , 17c and 17g exhibited potent cytotoxic activity. Especially, compound 17b displayed broad spectrum activity with IC 50 values ranging from 0.249 μM to 0.684 μM. Moreover, in a preliminary pharmacological study, 17b not only remarkably induced cellular apoptosis, but also clearly induced A549 cells cycle arrest at S phase. In vivo study showed that 17b significantly suppressed tumor growth in a dose-dependent manner without causing the loss of the mean body weight of mice, which was superior to doxorubicin. These preliminary results indicate that 17b is an optimal anti-cancer leading compound and merit further structural modification. [ABSTRACT FROM AUTHOR]

Madecassoside, a triterpenoid saponin present in Centella asiatica herbs with extremely low bioavailability, possesses excellent anti-rheumatoid arthritis property after oral administration. Such a disconnection between poor pharmacokinetic property and undoubted bioactivity also exists in many other herbal medicines. However, there is no reasonable explanation for this phenomenon to date. Here we showed that orally administered madecassoside displayed marked therapeutic effect on collagen-induced arthritis (CIA) in rats, which was accompanied by a systemic downregulation of inflammatory cytokines and an upregulation of anti-inflammatory cytokine IL-10. In vitro assays demonstrated that neither madecassoside nor its main metabolite madecassic acid could directly interfere with the secretion of inflammatory cytokines and IL-10. Intraperitoneal injection of madecassoside or madecassic acid was absent of significant effects on CIA progression, which further excluded the possibility of systemic action and highlighted the indispensable role of intestinal tracts. Notably, madecassoside could dramatically enhance the secretion of IL-10 from the small intestine of CIA rats probably through increasing the number of Foxp3 + T lymphocytes in the lamina propria. In conclusion, madecassoside displays anti-arthritis property not by absorption into blood or by its metabolite, but through an intestine-dependent manner. The action can be mediated by, at least partially, the mobilization of IL-10 that originates from small intestines. [ABSTRACT FROM AUTHOR]