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NSCLC is the first cause of cancer-related deaths in China and threatens life expectancy of the people. Novel drugs and treatment strategies are urgently required. Capsaicin is noticed as a potential new drug for lots of tumors due to its anti-proliferative effect on cancer cells. Our study evaluated the roles of capsaicin in NSCLC cells (A549 and NCI-H23) and further explored its underlying mechanisms. Effect of capsaicin treatment on cell viability was determined by MTT assay and IC50 values for A549 and NCI-H23 cells were ascertained. The iron kit detected the total iron levels and the ferric divalent ions levels in A549 and NCI-H23 cells. GSH kit was used to detect the expression of GSH in A549 and NCI-H23 cells. Additionally, mRNA and protein levels of SLC7A11 and GPX4 were analyzed by real-time PCR and western blot analysis. Through MTT assay, we found that 200 μM capsaicin in cultured A549 cells for 48 h could reach the IC50 value, and the condition was 100 μM and 48 h for NCI-H23 cells. Capsaicin increased total iron levels and ferrous ion levels in A549 and NCI-H23 cells in contrast with the control group, whereas the levels of GSH was reduced in contrast with the control group. Besides, mRNA and protein levels of SLC7A11 and GPX4 were decreased significantly in A549 and NCI-H23 cells treated with capsaicin in contrast with the control group. Our study indicated that capsaicin inhibited the proliferation of A549 and NCI-H23 cells and induced ferroptosis by inactivating SLC7A11/GPX4 signaling. Capsaicin could be used as a potential anticancer agent in the treatment of NSCLC. [ABSTRACT FROM AUTHOR]

Background: N7-methylguanosine (m7G) is one of the most common RNA posttranscriptional modifications; however, its potential role in hepatocellular carcinoma (HCC) remains unknown. We developed a prediction signature based on m7G-related long noncoding RNAs (lncRNAs) to predict HCC prognosis and provide a reference for immunotherapy and chemotherapy. Methods: RNA-seq data from The Cancer Genome Atlas (TCGA) database and relevant clinical data were used. Univariate and multivariate Cox regression analyses were conducted to identify m7G-related lncRNAs with prognostic value to build a predictive signature. We evaluated the prognostic value and clinical relevance of this signature and explored the correlation between the predictive signature and the chemotherapy treatment response of HCC. Moreover, an in vitro study to validate the function of CASC19 was performed. Results: Six m7G-related lncRNAs were identified to create a signature. This signature was considered an independent risk factor for the prognosis of patients with HCC. TIDE analyses showed that the high-risk group might be more sensitive to immunotherapy. ssGSEA indicated that the predictive signature was strongly related to the immune activities of HCC. HCC in high-risk patients was more sensitive to the common chemotherapy drugs bleomycin, doxorubicin, gemcitabine, and lenalidomide. In vitro knockdown of CASC19 inhibited the proliferation, migration and invasion of HCC cells. Conclusion: We established a 6 m7G-related lncRNA signature that may assist in predicting the prognosis and response to chemotherapy and immunotherapy of HCC. [ABSTRACT FROM AUTHOR]

Background: Necroptosis is a necrotic programmed cell death with potent immunogenicity. Due to the dual effects of necroptosis on tumor growth, metastasis and immunosuppression, we evaluated the prognostic value of necroptosis-related genes (NRGs) in hepatocellular carcinoma (HCC). Methods: We first analyzed RNA sequencing and clinical HCC patient data obtained to develop an NRG prognostic signature based on the TCGA dataset. Differentially expressed NRGs were further evaluated by GO and KEGG pathway analyses. Next, we conducted univariate and multivariate Cox regression analyses to build a prognostic model. We also used the dataset obtained from the International Cancer Genome Consortium (ICGC) database to verify the signature. The Tumor Immune Dysfunction and Exclusion (TIDE) algorithm was used to investigate the immunotherapy response. Furthermore, we investigated the relationship between the prediction signature and chemotherapy treatment response in HCC. Results: We first identified 36 differentially expressed genes out of 159 NRGs in hepatocellular carcinoma. Enrichment analysis showed that they were mainly enriched in the necroptosis pathway. Four NRGs were screened by Cox regression analysis to establish a prognostic model. The survival analysis revealed that the overall survival of patients with high-risk scores was significantly shorter than that of patients with low-risk scores. The nomogram demonstrated satisfactory discrimination and calibration. The calibration curves validated a fine concordance between the nomogram prediction and actual observation. The efficacy of the necroptosis-related signature was also validated by an independent dataset and immunohistochemistry experiments. TIDE analysis revealed that patients in the high-risk group were possibly more susceptible to immunotherapy. Furthermore, high-risk patients were found to be more sensitive to conventional chemotherapeutic medicines such as bleomycin, bortezomib, and imatinib. Conclusion: We identified 4 necroptosis-related genes and established a prognostic risk model that could potentially predict prognosis and response to chemotherapy and immunotherapy in HCC patients in the future. [ABSTRACT FROM AUTHOR]

Background: To observe the sequence of chondrocyte degeneration and matrix degradation in the superficial surface cartilage of the tibial plateau in guinea pigs with spontaneous knee osteoarthritis (OA).Methods: Sixty guinea pigs were euthanized at the ages of 8 months (n = 20),10 months (n = 20) and 12 months (n = 20) respectively. The degree of degeneration of the tibial plateau cartilage was evaluated by Osteoarthritis Research Society International (OARSI) score. The levels of Aggrecan,CollagenX,MMP-13 and Caspase-3 in the chondrocytes were detected by immunohistochemistry (IHC). The serum concentration of CTX-II was measured and compared. Western blot analysis was used to detect the levels of Aggrecan,CollagenX,MMP-13 and Caspase-3 in the cartilage tissue.Results: The OARSI scores both in 8-month-old group and 10-month-old group were lower than that in the 12-month-old group. The levels of Aggrecan in articular chondrocyte were higher both in 8-month-old group and 10-month-old group than that in 12-month-old group. The level of Collagen X increased with the age of guinea pigs. And the levels of MMP-13 and caspase-3 both in 10-month-old group and 12-month-old group were higher than those in 8-month-old group. The concentration of CTX-II in serum increased significantly in 12 months old group.Conclusion: The superficial chondrocytes of the tibial plateau first appeared to be hypertrophic and then apoptotic, and the matrix was further degraded when spontaneous knee osteoarthritis occurred in guinea pigs. Changes in the physiological state of chondrocytes are the initiating factors in the pathogenesis of knee OA. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common neurodegenerative disease, which is associated with extracellular deposition of amyloid-β proteins (Aβ). It has been reported that triptolide (TP), an immunosuppressive and anti-inflammatory agent extracted from a Chinese herb Tripterygium wilfordii, shows potential neuroprotective effects pertinent to AD. However, the clinical use of TP for AD could be hampered due to its high toxicity, instability, poor water solubility, and nonspecific biodistribution after administration. In this paper, we reported a kind of multiple-coated PLGA nanoparticle with the entrapment of TP and surface coated by chitosan hydrochloride, Tween-80, PEG20000, and borneol/mentholum eutectic mixture (MC-PLGA-TP-NP) as a novel nasal brain targeting preparation for the first time. The obtained MC-PLGA-TP-NP was 147.5 ± 20.7 nm with PDI of 0.263 ± 0.075 , zeta potential of 14.62 ± 2.47 mV, and the entrapment efficiency and loading efficiency of 93.14 % ± 4.75 % and 1.17 ± 0.08 % , respectively. In comparison of TP, MC-PLGA-TP-NP showed sustained-release profile and better transcellular permeability to Caco-2 cells in vitro. In addition, our data showed that MC-PLGA-TP-NP remarkably reduced the cytotoxicity, attenuated the oxidative stress, and inhibited the increase of the intracellular Ca2+ influx in differentiated PC12 cells induced by Aβ1-42. Therefore, it can be concluded that MC-PLGA-TP-NP is a promising preparation of TP, which exerts a better neuroprotective activity in the AD cellular model. [ABSTRACT FROM AUTHOR]

A previous study demonstrated the renal-protective effect of thalidomide (Thd) in diabetic nephropathy rats through the activation of the adenosine monophosphate-activated protein kinase (AMPK) and inhibition of the nuclear factor κB (NF-κB)/monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor (TGF)-β1/mothers against decapentaplegic homolog signaling pathways. The association between AMPK inactivation and high glucose (HG)-induced meningeal cell (MC) proliferation and extracellular matrix (ECM) accumulation via NF-κB and TGF-β1 signaling remains unknown. The aim of the current study was to demonstrate the effects of Thd on cell proliferation and ECM expression in HG-cultured MCs and the underlying mechanisms. HG-cultured human MCs were treated with Thd. Cell proliferation was measured by MTT assay and quantification of cell proliferation was based on the measurement of bromodeoxyuridine incorporation. The differences in TGF-β1, fibronectin and MCP-1 protein expression levels were detected via ELISA and western blot analysis. The AMPK signaling pathway was also examined by western blot analysis in MCs. Compound C, an AMPK inhibitor and AICAR (5-aminoimidazole-4-carboxamide 1β-D-ribofuranoside), an AMPK agonist, were used to analyze the functional role of AMPK in MCs. Cell proliferation was significantly decreased in HG-cultured MCs following treatment with high concentrations of Thd (100 and 200 µg/ml) for 24 h compared with the HG-cultured MC group. Thd suppressed the inflammatory processes in HG-induced MCs. These effects were partially mediated through the activation of AMPK and inhibition of the NF-κB/MCP-1 signaling pathways. Taken together, these results suggest that Thd may have therapeutic potential in diabetic renal injury via the AMPK signaling pathway. [ABSTRACT FROM AUTHOR]

Wide utilization of phthalates-containing products results in the significant exposure of humans to these compounds. Many adverse effects of phthalates have been documented in rodent models, but their effects in humans exposed to these chemicals remain unclear until more mechanistic studies on phthalate toxicities can be carried out. To provide new insights to predict the potential adverse effects of phthalates in humans, the recent study investigated the inhibition of representative phthalates di-n-octyl ortho-phthalate (DNOP) and diphenyl phthalate (DPhP) towards the important xenobiotic and endobiotic-metabolizing UDP-glucuronosyltransferases (UGTs). An in vitro UGTs incubation system was employed to study the inhibition of DNOP and DPhP towards UGT isoforms. DPhP and DNOP weakly inhibited the activities of UGT1A1, UGT1A7, and UGT1A8. 100 µM of DNOP inhibited the activities of UGT1A3, UGT1A9, and UGT2B7 by 41.8% (p < 0.01), 45.6% (p < 0.01), and 48.8% (p < 0.01), respectively. 100 µM of DPhP inhibited the activity of UGT1A3, UGT1A6, and UGT1A9 by 81.8 (p < 0.001), 49.1% (p < 0.05), and 76.4% (p < 0.001), respectively. In silico analysis was used to explain the stronger inhibition of DPhP than DNOP towards UGT1A3 activity. Kinetics studies were carried our to determine mechanism of inhibition of UGT1A3 by DPhP. Both Dixon and Lineweaver–Burk plots showed the competitive inhibition of DPhP towards UGT1A3. The inhibition kinetic parameter (K i ) was calculated to be 0.89 µM. Based on the [I]/Ki standard ([I]/Ki < 0.1, low possibility; 1>[I]/Ki > 0.1, medium possibility; [I]/Ki > 1, high possibility), these studies predicted in vivo drug–drug interaction might occur when the plasma concentration of DPhP was above 0.089 µM. Taken together, this study reveales the potential for adverse effects of phthalates DNOP and DPhP as a result of UGT inhibition. [ABSTRACT FROM AUTHOR]

This paper reported the facile fabrication of drug delivery devices for zero-order sustained release by molecular crowding strategy of molecularly imprinting technology. Crowding-assisted molecularly imprinting polymers (MIPs) matrices were prepared by free-radical precipitation polymerization using aminoglutethimide (AG) as a model drug. The crowding effect was achieved by adding polystyrene as a macromolecular co-solute in pre-polymerization mixture. The MIP prepared under the non-MMC condition and the two corresponding non-imprinted particles were tested as controlled vehicles. The release profiles presented zero-order behaviors from two crowding-assisted polymers, the duration of approximately 18 h for the crowding-assisted MIP and 10 h for the crowding-assisted NIP, respectively while AG were all very rapid released from the other two controlled particles (85% occurring in the first hour). The BET surface area and pore volume of the crowding-assisted MIP were about ten times than those of the controlled MIP. The value of imprinting factor is 6.02 for the crowding-assisted MIP and 1.19 for the controlled MIP evaluated by the equilibrium adsorption experiment. Furthermore, the values of effective diffusivity ( D eff ) obtained from crowding-assisted MIP (10 −17 cm 2 /s) was about two orders of magnitude smaller than those from the controlled MIP, although the values of free drug diffusivity ( D ) were all found in the order of 10 −13 cm 2 /s. Compared with the commercial AG tablet, the MMC-assisted MIP gave a markedly high relative bioavailability of 266.3%, whereas the MMC-assisted NIP gave only 57.7%. The results indicated that the MMC condition can modulate the polymer networks approaciate to zero-order release of the drug and maintain the molecular memory pockets, even if under the poor polymerization conditions of MIPs preparation. [ABSTRACT FROM AUTHOR]

• TIM-3 plays an important role in LN. Overexpression of TIM-3 in CD4 + T cells and Tregs leads to Treg quantity and quality deficiency in MRL/lpr mice. • TIM-3 may regulates Tregs in LN through mainly through cytokine-cytokine receptor interaction, PI3K-Akt signaling pathway, T cell receptor signaling pathway, Th17 cell differentiation and Foxo signaling pathway. • TIM-3 might be a potential therapeutic target for the treatment of LN. Blockade of TIM-3 protecting from LN by expands the Tregs and enhances suppressive capacity of Tregs. T Cell Immunoglobulin and Mucin Containing Protein-3 (TIM-3) is an important immune checkpoint protein that is expressed in Tregs and affects their function. However, the expression and role of TIM-3 in modulating regulatory T cells (Tregs) in lupus nephritis (LN) are still unknown. In this study, we found that the percentage of TIM-3+ cells among spleen lymphocytes, CD4+ T cells and Tregs was higher in MRL/lpr mice than in MpJ mice. TIM-3high CD4+ T cells and TIM-3high Tregs were mainly responsible for the increase. The percentage of Tregs in TIM-3high CD4+ T cells was lower than that in TIM-3low CD4+ T cells, and the expression of CTLA-4 and IL-10 was lower in TIM-3high Tregs than in the TIM-3low Tregs in MRL/lpr mice. Blockade of TIM-3 in vivo significantly increased the Treg population and the expression of CTLA-4 and IL-10 in Tregs, thus relieving the LN symptoms and pathology in MRL/lpr mice. Additionally, bioinformatics analysis indicated that TIM-3 regulates Treg cells in LN mainly through cytokine–cytokine receptor interactions, the PI3K-Akt signaling pathway, the T cell receptor signaling pathway, Th17 cell differentiation and the FoxO signaling pathway. Together, our study has demonstrated that TIM-3 regulates Tregs in LN and that overexpression of TIM-3 in CD4+ T cells and Tregs leads to Treg quantity and quality deficiency in MRL/lpr mice. Blockade of TIM-3 protects against LN by expanding Tregs and enhancing their suppressive capacity. Finally, TIM-3 might be a potential therapeutic target for the treatment of LN. [ABSTRACT FROM AUTHOR]

Synthesis of disubstituted piperazine derivatives is accomplished by a one-pot ring opening and tri-component domino reaction. [ABSTRACT FROM AUTHOR]

The title compounds (III) are obtained by reaction of 2-aminothiadiazoles with cyanoacetate via a combination of [3+3] cycloaddition, reduction, and deamination reactions using diversity-oriented catalysis. [ABSTRACT FROM AUTHOR]

A novel KF-catalyzed tandem nucleophilic addition is developed for the synthesis of polysubstituted β-cyanopropan-1-ones. [ABSTRACT FROM AUTHOR]

SUMMARY Background: The current prognostic models for mortality and functional outcome after intracerebral hemorrhage (ICH) are not simple enough. To predict the outcome of ICH, a new simple model, ICH index (ICHI), was established and evaluated in this study. Methods: Medical records of all cases with ICH in our hospital from January 2008 to August 2009 were reviewed. Multiple linear regression analyses were used to assess the contributions of independent variables to hospital mortality after ICH. Results: Age, serum glucose, white blood cell counts (WBC), and Glasgow Coma Scale (GCS) score were found to be greatly associated with mortality. A formula of ICH index [ICHI = age (years)/10 + glucose (mmol/L) + WBC (109/L) - GCS score] was established. Furthermore, the receiver operating characteristic (ROC) analyses were performed to estimate the predictive value of the ICHI. The model showed an area under the ROC curve (AURC) of 0.923 (95% CI: 0.883-0.963, P < 0.001). The best cut-off value of ICHI for mortality was 18, which gave sensitivity, specificity, and Youden's index of 0.65, 0.95, and 0.60, respectively. The hospital mortality was extremely increased when 18 < ICHI < 28 (mortality 72.0%) and when ICHI ≥28 (mortality 100%), in contrast with overall mortality (21.6%). Conclusion: The ICHI can be a simple predictive model and complementary to other prognostic models. [ABSTRACT FROM AUTHOR]

We performed a two-stage genome-wide association study of IgA nephropathy (IgAN) in Han Chinese, with 1,434 affected individuals (cases) and 4,270 controls in the discovery phase and follow-up of the top 61 SNPs in an additional 2,703 cases and 3,464 controls. We identified associations at 17p13 (rs3803800, P = 9.40 × 10?11, OR = 1.21; rs4227, P = 4.31 × 10?10, OR = 1.23) and 8p23 (rs2738048, P = 3.18 × 10?14, OR = 0.79) that implicated the genes encoding tumor necrosis factor (TNFSF13) and ?-defensin (DEFA) as susceptibility genes. In addition, we found multiple associations in the major histocompatibility complex (MHC) region (rs660895, P = 4.13 × 10?20, OR = 1.34; rs1794275, P = 3.43 × 10?13, OR = 1.30; rs2523946, P = 1.74 × 10?11, OR = 1.21) and confirmed a previously reported association at 22q12 (rs12537, P = 1.17 × 10?11, OR = 0.78). We also found that rs660895 was associated with clinical subtypes of IgAN (P = 0.003), proteinuria (P = 0.025) and IgA levels (P = 0.047). Our findings show that IgAN is associated with variants near genes involved in innate immunity and inflammation. [ABSTRACT FROM AUTHOR]

Some new target products 5-aryl-4,5-dihydro-3-(5-methyl-1- p-tolyl-1 H-1,2,3-triazol-4-yl)-1-(4-phenylthiazol-2-yl)pyrazoles 5a-j have been synthesized by reaction of 2-bromo-1-phenylethanone and compounds 4a-j which were prepared from the combination of thiosemicarbazide and ( E)-3-aryl-1-(5-methyl-1- p-tolyl-1 H-1,2,3-triazol-4-yl)-prop-2-en-1-ones 3a-j. All the structures were established by MS, IR, CHN, and 1H NMR spectra data. Synthesis of structure diversity is applied. J. Heterocyclic Chem., (2011). [ABSTRACT FROM AUTHOR]