Nicotinate-curcumin improves NASH by inhibiting the AKR1B10/ACCα-mediated triglyceride synthesis.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a prevalent chronic liver condition. However, the potential therapeutic benefits and underlying mechanism of nicotinate-curcumin (NC) in the treatment of NASH remain uncertain. METHODS: A rat model of NASH induced by a high-fat and high-fructose diet was treated with nicotinate-curcumin (NC, 20, 40 mg·kg- 1), curcumin (Cur, 40 mg·kg- 1) and metformin (Met, 50 mg·kg- 1) for a duration of 4 weeks. The interaction between NASH, Cur and Aldo-Keto reductase family 1 member B10 (AKR1B10) was filter and analyzed using network pharmacology. The interaction of Cur, NC and AKR1B10 was analyzed using molecular docking techniques, and the binding energy of Cur and NC with AKR1B10 was compared. HepG2 cells were induced by Ox-LDL (25 µg·ml- 1, 24 h) in high glucose medium. NC (20µM, 40µM), Cur (40µM) Met (150µM) and epalrestat (Epa, 75µM) were administered individually. The activities of ALT, AST, ALP and the levels of LDL, HDL, TG, TC and FFA in serum were quantified using a chemiluminescence assay. Based on the changes in the above indicators, score according to NAS standards. The activities of Acetyl-CoA and Malonyl-CoA were measured using an ELISA assay. And the expression and cellular localization of AKR1B10 and Acetyl-CoA carboxylase (ACCα) in HepG2 cells were detected by Western blotting and immunofluorescence. RESULTS: The results of the animal experiments demonstrated that NASH rat model induced by a high-fat and high-fructose diet exhibited pronounced dysfunction in liver function and lipid metabolism. Additionally, there was a significant increase in serum levels of FFA and TG, as well as elevated expression of AKR1B10 and ACCα, and heightened activity of Acetyl-CoA and Malonyl-CoA in liver tissue. The administration of NC showed to enhance liver function in rats with NASH, leading to reductions in ALT, AST and ALP levels, and decrease in blood lipid and significant inhibition of FFA and TG synthesis in the liver. Network pharmacological analysis identified AKR1B10 and ACCα as potential targets for NASH treatment. Molecular docking studies revealed that both Cur and NC are capable of binding to AKR1B10, with NC exhibiting a stronger binding energy to AKR1B10. Western blot analysis demonstrated an upregulation in the expression of AKR1B10 and ACCα in the liver tissue of NASH rats, accompanied by elevated Acetyl-CoA and Malonyl-CoA activity, and increased levels of FFA and TG. The results of the HepG2 cell experiments induced by Ox-LDL suggest that NC significantly inhibited the expression and co-localization of AKR1B10 and ACCα, while also reduced levels of TC and LDL-C and increased level of HDL-C. These effects are accompanied by a decrease in the activities of ACCα and Malonyl-CoA, and levels of FFA and TG. Furthermore, the impact of NC appears to be more pronounced compared to Cur. CONCLUSION: NC could effectively treat NASH and improve liver function and lipid metabolism disorder. The mechanism of NC is related to the inhibition of AKR1B10/ACCα pathway and FFA/TG synthesis of liver.

Mal-deficiency impairs the tolerogenicity of dendritic cell of patients with allergic rhinitis.

The tolerogenic dendritic cell dysfunction is associated with the pathogenesis of immune diseases. Microbial stimulus is required in the maintenance of immune functions. This study aims to elucidate the role of Mal signal in the maintenance of DEC205+ DC (decDC) immune tolerogenic function. In this study, peripheral DCs were collected from allergic rhinitis (AR) patients and healthy control (HC) subjects to assess the functional status of decDCs. An AR murine model was developed to test the role of Mal signals in the maintenance of decDCs' functions. We observed that AR decDCs (decDCs obtained from AR patients) were incompetent in the induction of type 1 regulatory T cells (Tr1 cells). AR decDCs expressed less IL-10 than that in HC decDCs. IL-10 mRNA decayed spontaneously in AR decDCs. Tat-activating regulatory DNA-binding protein-43 (TDP43) protected IL-10 mRNA from decay. AR decDCs expressed lower levels of Mal than that in HC decDCs. Mal depletion resulted in IL-10 mRNA decay in HC decDCs. Reconstitution of Mal in AR decDCs restored the capacity of inducing Tr1 cells and attenuated experimental AR in mice. In conclusion, Mal plays a critical role in the maintenance of decDC's immune tolerogenic function. The absence or insufficient Mal signal impairs decDC's tolerogenic property. Reconstitution of Mal in AR decDCs can restore the immune tolerogenic capacity, which may have translational potential in the treatment of AR and other allergic diseases.

Restoration of immune suppressor function of regulatory B cells collected from patients with allergic rhinitis with Chinese medical formula Yupingfeng San.

Immune dysregulation, such as defects in immune suppressor function, plays an important role in the pathogenesis of many immune disorders including allergic rhinitis (AR). Some Chinese traditional medical formulae have an immune regulatory function. This study aims to restore the immune suppressor function in regulatory B cells (Bregs) collected from AR patients with a Chinese medical formula, Yupingfeng San (YPFS). In this study, Bregs were isolated from blood samples collected from AR patients and healthy (HA) subjects. The capacity of Breg in suppressing effector T cell (Teff) proliferation was observed in an in vitro experiment to be used as an indicator of immune suppressor function of Breg. The effects of YPFS on promoting Bregs' immune suppressor functions were tested in a cell culture study. The results showed that the number of peripheral Breg in AR patients was not significantly different from that in HA subjects, while the immune suppressor function of AR Breg was compromised. Bcl2L12 expression was higher in AR Bregs than that in HA Bregs. A negative correlation was identified between expression of Bcl2L12 and IL-10 in AR Bregs. Exposure of AR Bregs to YPFS in the culture suppressed the expression of Bcl2L12 and improved their immune suppressor function. In conclusion, YPFS can restore the immune suppressor function of AR Bregs via inhibiting the expression of Bcl2L12. The data suggest that YPFS has the potential to be used in the improvement of immune dysfunction, such as AR.

B cell lymphoma-2-like protein-12 association with T-helper 2 inflammation in chronic rhinosinusitis with allergy.

BACKGROUND: T-helper 2 (Th2) polarization plays a critical role in the pathogenesis of chronic rhinosinusitis (CRS) with accompanying nasal allergy. Recent studies indicate that B cell lymphoma-2-like protein-12 (Bcl2L12) is associated with immune dysregulation. The purpose of this study was to elucidate the role of Bcl2L12 in the pathogenesis of Th2 polarization of CRS patients. METHODS: CRS patients with nasal allergy (CRSa) and without nasal allergy (CRSna) were recruited into this study. CD4+ T cells were isolated from the blood samples of human subjects. A variety of immunologic molecular strategies were used to assess Th2 polarization and Bcl2L12 expression. RESULTS: Twenty CRSa patients, 20 CRSna patients, and 20 healthy subjects were recruited into this study. High levels of immunoglobulin E (IgE), interleukin 4 (IL-4), IL-5, IL-13, and Bcl2L12 were detected in nasal extracts of CRSa patients, but not in CRSna patients. The levels of Bcl2L12 were positively correlated with Th2 cytokines. CD4+ T cells from CRSa patients were prone to differentiate into Th2 cells, in which Bcl2L12 was required. CONCLUSION: Bcl2L12 is positively correlated with Th2 cytokine levels in the nasal mucosa of CRSa patients. Bcl2L12 contributes to the Th2 polarization, which may be a novel therapeutic target in the treatment of CRSa.

Treatment choice by patients with obstructive sleep apnea: data from two centers in China.

BACKGROUND: Standard management has been recommended for obstructive sleep apnea (OSA) by several guidelines, but patient choice in the practical setting is unclear. METHODS: A survey nested in two prospective cohort studies of OSA (enrollment: 2001-2010) in China. The last interview was conducted between July 2014 and May 2015, using a comprehensive 10-point questionnaire administered in a face-to-face or telephone interview, and assessed (I) whether the participant had received any OSA treatment; (II) why he or she had decided for or against treatment; (III) what treatment was received; (IV) whether the participant used continuous positive airway pressure (CPAP) or OA daily; and (V) the perceived efficacy of therapy. RESULTS: A total of 4,097 subjects with a mean age of 45 years [37-55] responded to this survey, with a response rate of 79.4% (4,097/5,160); 2,779 subjects (67.8%) did not receive any treatment: 1,485 (53.4%) believed that their condition was not serious, despite severe OSA in 53.7% of the patients. A multivariate regression showed that the decision to receive treatment was associated with: age between 45-59 years [odds ratio (OR) 0.805, 95% CI: 0.691-0.936; P<0.001], female gender (OR 0.492, 95% CI: 0.383-0.631; P<0.001), severe OSA (OR 1.92, 95% CI: 1.01-3.64; P<0.001), hypertension (OR 1.414, 95% CI: 1.209-1.654; P<0.001) and diabetes (OR 1.760, 95% CI: 1.043-2.972; P=0.034). In subjects receiving treatment (n=1,318), 50.9% reported negative perceptions about the treatments. CONCLUSIONS: Nearly two thirds of Chinese patients choose not to receive treatment after OSA diagnosis, and nearly half are negative about their treatments for OSA. This requires clinical attention, and warrants further study in different geographic settings.

Ex Vivo Explant Cultures of Non-Small Cell Lung Carcinoma Enable Evaluation of Primary Tumor Responses to Anticancer Therapy.

To improve treatment outcomes in non-small cell lung cancer (NSCLC), preclinical models that can better predict individual patient response to novel therapies are urgently needed. Using freshly resected tumor tissue, we describe an optimized ex vivo explant culture model that enables concurrent evaluation of NSCLC response to therapy while maintaining the tumor microenvironment. We found that approximately 70% of primary NSCLC specimens were amenable to explant culture with tissue integrity intact for up to 72 hours. Variations in cisplatin sensitivity were noted with approximately 50% of cases responding ex vivo Notably, explant responses to cisplatin correlated significantly with patient survival (P = 0.006) irrespective of tumor stage. In explant tissue, cisplatin-resistant tumors excluded platinum ions from tumor areas in contrast to cisplatin-sensitive tumors. Intact TP53 did not predict cisplatin sensitivity, but a positive correlation was observed between cisplatin sensitivity and TP53 mutation status (P = 0.003). Treatment of NSCLC explants with the targeted agent TRAIL revealed differential sensitivity with the majority of tumors resistant to single-agent or cisplatin combination therapy. Overall, our results validated a rapid, reproducible, and low-cost platform for assessing drug responses in patient tumors ex vivo, thereby enabling preclinical testing of novel drugs and helping stratify patients using biomarker evaluation. Cancer Res; 77(8); 2029-39. ©2017 AACR.