如意珍宝丸对偏头痛大鼠下行痛觉调节通道的影响

目的:研究藏药如意珍宝丸对硝酸甘油致偏头痛模型大鼠下行痛觉调制通道中心区域中脑导水管内神经生长因子(Nerve Growth Factor,NGF)、酪氨酸激酶A(Tyrosine Kinase A,TrkA)、瞬时感受器电位香草酸受体1(Transient Receptor Potential Vanilloid Receptor 1,TRPV1)的表达影响,探究该药干预神经源炎性痛敏性偏头痛的作用机制。方法:以颈部皮下注射硝酸甘油方法复制大鼠偏头痛模型,以如意珍宝丸为药物实验组,琥珀酸舒马普坦为阳性对照组,采用ELISA和Real-Time PCR法检测外周血清及中脑组织NGF、TrkA、TRPV1蛋白及基因表达水平,观察藏药如意珍宝丸对硝酸甘油致偏头痛模型大鼠下行痛觉调制系统的影响。结果:与空白组比较,模型组血清NGF、TrkA、TRPV1蛋白表达显著上升(P0.05);中脑NGF、TrkA、TRPV1基因表达差异性升高(P0.05)。与模型组比较,如意珍宝丸预防组可降低NGF、TRPV1蛋白表达(P0.05);如意珍宝丸观察组能使NGF、TrkA蛋白表达和NGF、TrkA、TRPV1 mRNA表达均降低(P0.05或P0.01)。结论:NGF、TrkA共同参与了下行疼痛调控中TRPV1介导的偏头痛发生;藏药如意珍宝丸可降低NGF、TrkA对TRPV1的上调作用,起到抑制神经源炎性痛敏性偏头痛的作用。     

IGF-1R pathway activation as putative biomarker for linsitinib therapy to revert tamoxifen resistance in ER-positive breast cancer

Preclinical studies indicate that activated IGF-1R can drive endocrine resistance in ER-positive (ER+) breast cancer, but its clinical relevance is unknown. We studied the effect of IGF-1R signaling on tamoxifen benefit in patients and we searched for approaches to overcome IGF-1R-mediated tamoxifen failure in cell lines. Primary tumor blocks from postmenopausal ER+ breast cancer patients randomized between adjuvant tamoxifen versus nil were recollected. Immunohistochemistry for IGF-1R, p-IGF-1R/InsR, p-ERα(Ser118), p-ERα(Ser167) and PI3K/MAPK pathway proteins was performed. Multivariate Cox models were employed to assess tamoxifen efficacy. The association between p-IGF-1R/InsR and PI3K/MAPK pathway activation in MCF-7 and T47D cells was analyzed with Western blots. Cell proliferation experiments were performed under various growth-stimulating and -inhibiting conditions. Patients with ER+, IGF-1R-positive breast cancer without p-IGF-1R/InsR staining (n = 242) had tamoxifen benefit (HR 0.41, p = 0.0038), while the results for p-IGF-1R/InsR-positive patients (n = 125) were not significant (HR 0.95, p = 0.3). High p-ERα(Ser118) or p-ERα(Ser167) expression was associated with less tamoxifen benefit. In MCF-7 cells, IGF-1R stimulation increased phosphorylation of PI3K/MAPK proteins and ERα(Ser167) regardless of IGF-1R overexpression. This could be abrogated by the dual IGF-1R/InsR inhibitor linsitinib, but not by the IGF-IR-selective antibody 1H7. In MCF-7 and T47D cells, stimulation of the IGF-1R/InsR pathway resulted in cell proliferation regardless of tamoxifen. Abrogation of cell growth was regained by addition of linsitinib. In conclusion, p-IGF-1R/InsR positivity in ER+ breast cancer is associated with reduced benefit from adjuvant tamoxifen in postmenopausal patients. In cell lines, stimulation rather than overexpression of IGF-1R is driving tamoxifen resistance to be abrogated by linsitinib.     

Clinical Features and Survival of Single Hormone Receptor–Positive Breast Cancer: A Population-Based Study of 531,605 Patients

PurposeTo investigate the prognosis of single hormone receptor–positive (HR⁺) breast cancer (estrogen receptor [ER] positive and progesterone receptor [PR] negative, and ER⁻PR⁺) compared to double HR⁺ (ER⁺PR⁺) and double HR⁻ (ER⁻PR⁻) tumors.MethodsWe included 531,605 cases of invasive breast cancer between 1990 and 2012 from the US Surveillance, Epidemiology, and End Results (SEER) database for study and classified cases into 4 phenotypes according to expression of ER and PR: ER⁺PR⁺, ER⁺PR⁻, ER⁻PR⁺, and ER⁻PR⁻.ResultsOverall, 66,091 ER⁺PR⁻ tumors and 9320 ER⁻PR⁺ tumors were identified. The clinical characteristics of the ER⁺PR⁻ group were similar to those of the double HR⁺ group, while those of the ER⁻PR⁺ and double HR⁻ groups were similar. Overall survival of patients with single HR⁺ tumors was intermediate between that of double HR⁺ and double HR⁻ tumors. However, we observed no differences in disease-specific survival between ER⁻PR⁺ and ER⁻PR⁻ patients. In multivariate analysis, outcomes were similar. Relative to the double HR⁺ patient group, risk of death in the ER⁺PR⁻ group was higher (hazard ratio, 1.422, 95% confidence interval, 1.394-1.452). However, risk of death was comparable between ER⁻PR⁺ and ER⁻PR⁻ patients (hazard ratio, 1.03; 95% confidence interval, 0.98-1.08). Multivariate Cox proportional analysis showed that survival times of patients in the younger age bracket (< 60 years), those positive for human epidermal growth factor receptor 2 (HER2), and patients with tumor stage I-III were longer in the ER⁻PR⁺ group.ConclusionDisease-specific survival of single HR⁺ tumor cases was longer than that of double HR⁻ tumors but poorer than double HR⁺ tumors. However, differences in disease-specific survival were not significant between the ER⁻PR⁺ and ER⁻PR⁻ groups.     

Host–microbiome interactions: the aryl hydrocarbon receptor as a critical node in tryptophan metabolites to brain signaling

ABSTRACT

Tryptophan (Trp) is not only a nutrient enhancer but also has systemic effects. Trp metabolites signaling through the well-known aryl hydrocarbon receptor (AhR) constitute the interface of microbiome-gut-brain axis. However, the pathway through which Trp metabolites affect central nervous system (CNS) function have not been fully elucidated. AhR participates in a broad variety of physiological and pathological processes that also highly relevant to intestinal homeostasis and CNS diseases. Via the AhR-dependent mechanism, Trp metabolites connect bidirectional signaling between the gut microbiome and the brain, mediated via immune, metabolic, and neural (vagal) signaling mechanisms, with downstream effects on behavior and CNS function. These findings shed light on the complex Trp regulation of microbiome-gut-brain axis and add another facet to our understanding that dietary Trp is expected to be a promising noninvasive approach for alleviating systemic diseases.     

PPARγ: the dominant regulator among PPARs in dry eye lacrimal gland and diabetic lacrimal gland

AIM: To determine whether lectin-like ox-LDL receptor (LOX-1) regulates adhesion molecules expression and neutrophil infiltration in A. fumigatus keratitis of C57BL/6 mice.METHODS: C57BL/6 mice were pretreated with a neutralizing antibody to LOX-1 (5 μg/5 μL) or control nonspecific IgG (5 μg/5 μL), LOX-1 inhibitor Poly-I (2 μg/5 μL) or PBS by subconjunctival injection. Fungal keratitis mouse models of C57BL/6 mice were established by scraping corneal central epithelium, smearing A. fumigatus on the corneal surface and covering the eye with contact lenses. The corneal response to infection was assessed via clinical score. The mRNA levels of the adhesion molecules ICAM-1, VCAM-1, P-selectin and E-selectin were tested in control and infected corneas by RT-PCR. The protein levels of ICAM-1 were evaluated by immunofluorescence (IF) and Western blot. Neutrophils were extracted from the abdominal cavity of C57BL/6 mice followed by pretreatment using antibody to LOX-1 (10 μg/mL) or control nonspecific IgG (10 μg/mL), the Poly-I (4 μg/mL) or PBS. The cells were then stimulated with A. fumigatus and tested mRNA and protein levels of LFA-1 using RT-PCR and Western blot. IF and myeloperoxidase (MPO) assays were used to assess neutrophil infiltration in mice corneas.RESULTS: Pretreatment of LOX-1 antibody or the Poly-I reduced the degree of inflammation of cornea and decreased the clinical fungal keratitis score compared with pretreatment of IgG or PBS. And these pretreatment also displayed an obvious decline in the mRNA levels of ICAM-1, VCAM-1, P-selectin, E-selectin and LFA-1 expression compared with control groups . Furthermore, pretreated with LOX-1 antibody or Poly-I, the protein levels of ICAM-1 and LFA-1 also decreased compared with control groups. Neutrophil infiltration in the cornea was significantly reduced after pretreatment of LOX-1 antibody or Poly-I compared with control groups by IF and MPO assays. CONCLUSION: These data provide evidence that inhibition of LOX-1 can decrease the expression of adhesion molecules and thus reduce neutrophil infiltration in A. fumigatus infected corneas of C57BL/6 mice.     

生物信息学分析IGF-2R在乳腺癌中的作用机制

目的 确定IGF-2R基因对乳腺癌的调控作用,挖掘参与乳腺癌发生发展潜在的基因及通路。方法 利用“GEOquery”、“idmap2.0”、“limma”、“Clusterprolifer”等R包筛选乳腺肿瘤组织与正常组织的差异表达基因,并进行GO和KEGG分析。STRING、GEPIA和UALACN数据库绘制蛋白互作网络,分析IGF-2R基因与乳腺癌Hub基因的相关性,以及IGF2R表达水平与乳腺癌患者基本情况的相关性。结果 筛选得到128个上调差异表达基因,256个下调差异表达基因；IGF-2R基因与核心基因ASPM、RRM2相关性显著；IGF-2R基因表达水平在乳腺癌组织中显著降低(P<0.05)；IGF-2R表达水平与患者年龄(20-80岁)、临床分期(Ⅰ、Ⅱ、Ⅲ)、绝经情况和淋巴结转移密切相关(P<0.05)。IGF-2R基因的表达水平仅在Luminal型(LuminalA型、Luminal B-HER2阴性型)乳腺癌中显著降低(P<0.05)。结论IGF-2R通过与ASPM和RRM2正相关参与乳腺癌的调控作用,有望为乳腺癌的防治提供新的思路。     

Positive association between cerebral grey matter metabolism and dopamine D2/D3 receptor availability in healthy and schizophrenia subjects: An 18F-fluorodeoxyglucose and 18F-fallypride positron emission tomography study

Abstract

Objectives: Overlapping decreases in extrastriatal dopamine D₂/D₃-receptor availability and glucose metabolism have been reported in subjects with schizophrenia. It remains unknown whether these findings are physiologically related or coincidental.

Methods: To ascertain this, we used two consecutive ¹⁸F-fluorodeoxyglucose and ¹⁸F-fallypride positron emission tomography scans in 19 healthy and 25 unmedicated schizophrenia subjects. Matrices of correlations between ¹⁸F-fluorodeoxyglucose uptake and ¹⁸F-fallypride binding in voxels at the same xyz location and AFNI-generated regions of interest were evaluated in both diagnostic groups.

Results: ¹⁸F-fluorodeoxyglucose uptake and ¹⁸F-fallypride binding potential were predominantly positively correlated across the striatal and extrastriatal grey matter in both healthy and schizophrenia subjects. In comparison to healthy subjects, significantly weaker correlations in subjects with schizophrenia were confirmed in the right cingulate gyrus and thalamus, including the mediodorsal, lateral dorsal, anterior, and midline nuclei. Schizophrenia subjects showed decreased D₂/D₃-receptor availability in the hypothalamus, mamillary bodies, thalamus and several thalamic nuclei, and increased glucose uptake in three lobules of the cerebellar vermis.

Conclusions: Dopaminergic system may be involved in modulation of grey matter metabolism and neurometabolic coupling in both healthy human brain and psychopathology. Hyperdopaminergic state in untreated schizophrenia may at least partly account for the corresponding decreases in grey matter metabolism.     

针刺调控α7nAchR激活胆碱能抗炎通路的研究现状

胆碱能抗炎通路是一条神经免疫通路,主要依靠乙酰胆碱与巨噬细胞及其他细胞表面上的α7nAchR相结合抑制促炎因子的合成与释放,从而防止组织损伤。α7nAchR是胆碱能递质的主要受体,在胆碱能抗炎通路中起关键作用。针刺治疗有明确的抗炎作用,其作用机制可能与调控α7nAchR激活胆碱能抗炎通路有关。近年来虽然国内外学者对针刺抗炎机制进行了大量研究,然而针刺抗炎的作用机制目前仍不明确。该文从胆碱能抗炎通路概述、α7nAchR结构及功能、α7nAchR的分布、α7nAchR在胆碱能抗炎通路的作用、针刺调控α7nAchR激活胆碱能抗炎通路的机制等方面对针刺调控α7nAchR激活胆碱能抗炎通路进行分析总结,为今后探究针刺抗炎作用机制提供借鉴思路和科学依据。     

浅谈“七损八益”与三阴性乳腺癌雌激素受体、雄激素受体的表达

乳腺癌是我国女性发病率第一的恶性肿瘤[1],其中三阴性乳腺癌较其他类型乳腺癌相比,具有治疗棘手、预后更差的特点。"七损八益"是以阴阳损益之道来谈保身长全的理论思想。文章将结合"七损八益"的观点,从其损益转化的角度来讨论三阴性乳腺癌的治疗方法。其中以七损对应三阴性乳腺癌雌激素受体阴性,八益为应用雄激素受体治疗三阴性乳腺癌的手段。试以《内经》"七损八益"理论来探讨三阴性乳腺癌的关系,为研究治疗乳腺癌提供更多的思路。