GNAI1 and GNAI3 Reduce Colitis-Associated Tumorigenesis in Mice by Blocking IL6 Signaling and Down-regulating Expression of GNAI2.

BACKGROUND & AIMS: Interleukin 6 (IL6) and tumor necrosis factor contribute to the development of colitis-associated cancer (CAC). We investigated these signaling pathways and the involvement of G protein subunit alpha i1 (GNAI1), GNAI2, and GNAI3 in the development of CAC in mice and humans. METHODS: B6;129 wild-type (control) or mice with disruption of Gnai1, Gnai2, and/or Gnai3 or conditional disruption of Gnai2 in CD11c+ or epithelial cells were given dextran sulfate sodium (DSS) to induce colitis followed by azoxymethane (AOM) to induce carcinogenesis; some mice were given an antibody against IL6. Feces were collected from mice, and the compositions of microbiomes were analyzed by polymerase chain reactions. Dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs) isolated from spleen and colon tissues were analyzed by flow cytometry. We performed immunoprecipitation and immunoblot analyses of colon tumor tissues, MDSCs, and mouse embryonic fibroblasts to study the expression levels of GNAI1, GNAI2, and GNAI3 and the interactions of GNAI1 and GNAI3 with proteins in the IL6 signaling pathway. We analyzed the expression of Gnai2 messenger RNA by CD11c+ cells in the colonic lamina propria by PrimeFlow, expression of IL6 in DCs by flow cytometry, and secretion of cytokines in sera and colon tissues by enzyme-linked immunosorbent assay. We obtained colon tumor and matched nontumor tissues from 83 patients with colorectal cancer having surgery in China and 35 patients with CAC in the United States. Mouse and human colon tissues were analyzed by histology, immunoblot, immunohistochemistry, and/or RNA-sequencing analyses. RESULTS: GNAI1 and GNAI3 (GNAI1;3) double-knockout (DKO) mice developed more severe colitis after administration of DSS and significantly more colonic tumors than control mice after administration of AOM plus DSS. Development of increased tumors in DKO mice was not associated with changes in fecal microbiomes but was associated with activation of nuclear factor (NF) κB and signal transducer and activator of transcription (STAT) 3; increased levels of GNAI2, nitric oxide synthase 2, and IL6; increased numbers of CD4+ DCs and MDSCs; and decreased numbers of CD8+ DCs. IL6 was mainly produced by CD4+/CD11b+, but not CD8+, DCs in DKO mice. Injection of DKO mice with a blocking antibody against IL6 reduced the expansion of MDSCs and the number of tumors that developed after CAC induction. Incubation of MDSCs or mouse embryonic fibroblasts with IL6 induced activation of either NF-κB by a JAK2-TRAF6-TAK1-CHUK/IKKB signaling pathway or STAT3 by JAK2. This activation resulted in expression of GNAI2, IL6 signal transducer (IL6ST, also called GP130) and nitric oxide synthase 2, and expansion of MDSCs; the expression levels of these proteins and expansion of MDSCs were further increased by the absence of GNAI1;3 in cells and mice. Conditional disruption of Gnai2 in CD11c+ cells of DKO mice prevented activation of NF-κB and STAT3 and changes in numbers of DCs and MDSCs. Colon tumor tissues from patients with CAC had reduced levels of GNAI1 and GNAI3 and increased levels of GNAI2 compared with normal tissues. Further analysis of a public human colorectal tumor DNA microarray database (GSE39582) showed that low Gani1 and Gnai3 messenger RNA expression and high Gnai2 messenger RNA expression were significantly associated with decreased relapse-free survival. CONCLUSIONS: GNAI1;3 suppresses DSS-plus-AOM-induced colon tumor development in mice, whereas expression of GNAI2 in CD11c+ cells and IL6 in CD4+/CD11b+ DCs appears to promote these effects. Strategies to induce GNAI1;3, or block GNAI2 and IL6, might be developed for the prevention or therapy of CAC in patients.

Multifunctional Additive CdAc2 for Efficient Perovskite-Based Solar Cells.

Polycrystalline perovskite films fabricated on flexible and textured substrates often are highly defective, leading to poor performance of perovskite devices. Finding substrate-tolerant perovskite fabrication strategies is therefore paramount. Herein, this study shows that adding a small amount of Cadmium Acetate (CdAc2 ) in the PbI2 precursor solution results in nano-hole array films and improves the diffusion of organic salts in PbI2 and promotes favorable crystal orientation and suppresses non-radiative recombination. Polycrystalline perovskite films on the flexible substrate with ultra-long carrier lifetimes exceeding 6 µs are achieved. Eventually, a power conversion efficiency (PCE) of 22.78% is obtained for single-junction flexible perovskite solar cells (FPSCs). Furthermore, it is found that the strategy is also applicable for textured tandem solar cells. A champion PCE of 29.25% (0.5003 cm2 ) is demonstrated for perovskite/silicon tandem solar cells (TSCs) with CdAc2 . Moreover, the un-encapsulated TSCs maintains 109.78% of its initial efficiency after 300 h operational at 45 °C in a  nitrogen atmosphere. This study provides a facile strategy for achieving high-efficiency perovskite-based solar cells.

[Effect of electroacupuncture on expression of heat shock protein 70 in mice with amyotrophic lateral sclerosis].

OBJECTIVE: To observe the effects of electroacupuncture (EA) on the body weight, disease progression and the expression of heat shock protein 70 (HSP70) in lumbar spinal cord of amyotrophic lateral sclerosis (ALS) mice, so as to explore the mechanism of EA on treating ALS. METHODS: Eighteen ALS transgenic SOD1G93A mice were randomly divided into model, EA and medication groups, with 6 mice in each group, and six C57BL/6J mice were used as the normal group. Mice in the EA group received EA at "Quchi"(LI11)-"Hegu"(LI4), "Zusanli"(ST36)- "Sanyinjiao"(SP6), 30 min/time, 5 times/week, for 8 weeks.Mice in the medication group were given riluzole solution (7.6 mg·kg-1·d-1) by gavage for 8 weeks. The body weight of the mice was recorded and the motor function of the hind limbs was evaluated by the neurological function scoring stan-dard of the ALS Therapeutic Development Institute. The expression of HSP70 in lumbar spinal cord was detected by Western blot and immunohistochemistry, respectively. RESULTS: Compared with the normal group, the body weight and the expression of HSP70 in the model group decreased significantly (P<0.05), while no significant difference in the body weight was found among other groups(P>0.05). After intervention and in comparison with the model group, the disease onset time and paralysis time of the EA group and the medication group were significantly delayed (P<0.05, P<0.01), the expression of HSP70 in the EA group and the medicine group was significantly increased (P<0.05, P<0.01).But there was no significant difference in the survival time among all groups(P＞0.05). The disease onset time of the EA group was shorter than that in the medication group (P<0.05). CONCLUSION: EA can increase the expression of HSP70 in lumbar spinal cord, thereby delaying the progression of ALS.

Wet cupping therapy for treatment of herpes zoster: a systematic review of randomized controlled trials.

BACKGROUND: Wet cupping is a traditional Chinese medicine therapy commonly used in treating herpes zoster in China, and clinical studies have shown that wet cupping may have beneficial effect on herpes zoster compared with Western medication. METHODS: We included randomized controlled trials (RCTs) on wet cupping for herpes zoster. We searched PubMed, the Cochrane Library (Issue 3, 2008), China Network Knowledge Infrastructure (CNKI), Chinese Scientific Journals Fulltext Database VIP, and Wan Fang Database. All searches ended in February 2009. Two authors extracted data and assessed the trials' quality independently. RevMan 5.0.18 software (The Cochrane Collaboration, The Nordic Cochrane Centre, Copenhagen, Denmark) was used for data analysis with effect estimate presented as relative risk (RR) and mean difference (MD) with a 95% confidence interval (CI). RESULTS: Eight RCTs involving 651 patients were included, and the methodological quality of trials was generally fair in terms of randomization, blinding, and intention-to-treat analysis. Meta-analyses showed wet cupping was superior to medication in the number of cured patients (RR 2.49, 95% CI 1.91 to 3.24, P < .00001), the number of patients with improved symptoms (RR 1.15, 95% CI 1.05 to 1.26, P = .003), and reducing the incidence rate of postherpetic neuralgia (RR 0.06, 95% CI 0.02 to 0.25, P = .0001). Wet cupping plus medication was significantly better than medication alone on number of cured patients (RR 1.93, 95% CI 1.23 to 3.04, P = .005) but demonstrated no difference in symptom improvement (RR 1.00, 95% CI 0.92 to 1.08, P = .98). There were no serious adverse effects related to wet cupping therapy in the included trials. CONCLUSION: Wet cupping appears to be effective in the treatment of herpes zoster. However, further large, rigorously designed

Jinwei Tang modulates HDAC2 expression in a rat model of COPD.

The aim of the present study was to investigate the effect of a Traditional Chinese Herbal Medicine (TCHM), named Jinwei Tang on histone deacetylase 2 (HDAC2) and its role in the regulation of corticosteroid resistance in a rat model of chronic obstructive pulmonary disease (COPD). Male Wistar rats were divided into five groups (each n=10): COPD group, established by the intratracheal instillation of lipopolysaccharide and passive smoke exposure, and control, budesonide, theophylline + budesonide and Jinwei Tang + budesonide groups. Lung function was measured, lung tissue histopathology was examined and HDAC2 expression in the lung was assessed by immunohistochemistry. In addition, protein levels of interleukin-8 (IL-8), tumor necrosis factor (TNF)-α and HDAC2 in lung homogenate were quantified by ELISA. The rat COPD model exhibited alterations of the ratio of forced expiratory volume in 0.2 sec (FEV0.2) to the forced vital capacity, FEV0.2, dynamic compliance and airway resistance. HDAC2 expression was markedly reduced in the lung tissue of the COPD group compared with the control group, and treatment with Jinwei Tang + budesonide or theophylline + budesonide resulted in significant attenuation of the reduction of HDAC2 expression in the lungs (P<0.05). However, treatment with budesonide alone did not significantly alter HDAC2 expression. In the Jinwei Tang + budesonide and theophylline + budesonide groups, IL-8 and TNF-α expression was significantly decreased (P<0.05) and the HDAC2 level increased (P<0.05) compared with that in the COPD group. In conclusion, Jinwei Tang modulates airway inflammation and may enhance the anti-inflammatory effect of glucocorticoid through the upregulation of HADC2 expression in a rat model of COPD.

Comparison between herbal medicine and fluoxetine for depression: a systematic review of randomized controlled trials.

OBJECTIVE: To evaluate the effectiveness and safety of Chinese herbal medicine (CHM) versus fluoxetine on depression. DESIGN: A systematic review of randomized controlled trials (RCTs). METHODS: RCT with two parallel groups that compared CHM and fluoxetine on treatment of depression with reported decreased Hamilton Depression Scale (HAMD) and adverse events during treatment were included after searching through six electric-databases. The methodological quality of RCTs was assessed according to the Cochrane risk of bias tool. Meta-analysis was conducted using RevMan 5.3 software with pooled mean difference (MD) or risk ratio (RR) and their 95% confidence interval (CI) if no significant heterogeneity was detected. A SOF table was generated using GRADEPro software to evaluate the overall quality of the evidence. RESULTS: Twenty-six trials with 3294 participants were included in the review. Most of them had high risk of bias during conducting and reporting. The results achieved weak evidence which showed CHM had similar effect to fluoxetine (20mg/day) on relieving depression according to HAMD assessment (for primary depression: MD=-0.08, 95%CI -0.98-0.82; for secondary depression: MD=-0.36, 95%CI -1.55-0.83), but fewer incidences of adverse events than the drug (for primary depression: RR=0.31, 95%CI 0.17-0.59; for post-stroke depression: RR=0.04, 95%CI 0.00-0.25). No serious adverse event was found in neither CHM nor fluoxetine group. CONCLUSIONS: Due to the poor quality of included trials and the potential publication bias of this review, no confirmed conclusion could be draw to evaluate the effectiveness and safety of CHM for depression compared with fluoxetine.