Psychological stress-induced hyperthermia (PSH) is a fundamental autonomic stress response observed in many mammalian species. Here we show a hypothalamomedullary, glutamatergic neural pathway for psychological stress signaling that drives the sympathetic thermogenesis in brown adipose tissue (BAT) that contributes to PSH. Using in vivo drug nanoinjections into rat brain and thermotelemetry, we demonstrate that the rostral medullary raphe region (rMR) and dorsomedial hypothalamus (DMH) mediate a psychosocial stress-induced thermogenesis in BAT and PSH. Functional neuroanatomy indicates that the DMH functions as a hub for stress signaling, with monosynaptic projections to the rMR for sympathetic outputs and to the paraventricular hypothalamic nucleus for neuroendocrine outputs. Optogenetic experiments showed that the DMH-rMR monosynaptic pathway drives BAT thermogenesis and cardiovascular responses. These findings make an important contribution to our understanding of the central autonomic circuitries linking stress coping with energy homeostasis-potentially underlying the etiology of psychogenic fever, a major psychosomatic symptom.
The vascular endothelial growth factor (VEGF) is an important regulator of angiogenesis and vascular permeability. VEGF overexpression has been associated with advanced stage and poor survival of several cancers. We evaluated the association of functional polymorphisms in the VEGF gene with breast cancer survival in a cohort of 1,193 breast cancer patients who were recruited as part of a population-based case-control study in Shanghai, China from 1996 to 1998 and followed for cancer recurrence and mortality between March 2000 and December 2002. Included in the study were three functional polymorphisms (CÀ460T, G+405C, and C+936T) in the VEGF gene. Carrying the À460C or +405G allele was associated with decreased overall survival. The age-adjusted hazard ratios (HR) were 1.5 [95% confidence interval (95% CI), 0.9-2.5] for À460CC genotype carriers and 1.6 (95% CI, 1.0-2.5) for +405GG genotype carriers compared with noncarriers. Further analyses showed that the À460T/+450C/+936C haplotype was related to increased survival (HR, 0.57; 95% CI, 0.4-0.9), whereas the À460C/+405G/+936T haplotype was associated with nonsignificantly decreased survival (HR, 2.1; 95% CI, À0.9 to 4.7). The C+936T polymorphism alone was not related to overall or disease-free survival. This study suggests that VEGF polymorphisms may be a significant genetic marker for breast cancer prognosis. (Cancer Res 2005; 65(12): 5015-9)
Vascular endothelial growth factor (VEGF) is a major angiogenic factor involved in a number of pathologic processes, including neovascularization, a crucial step in the development of solid malignancies. Using data and specimens collected in the Shanghai Breast Cancer Study, a population-based case-control study conducted in urban Shanghai, China from 1996 to 1998, we evaluated the association of VEGF gene polymorphisms with breast cancer risk. Included in this study were 1,093 cases and 1,184 agematched controls who had completed an in-person interview and donated a blood sample to the study. Polymorphisms in the promoter region (TÀ460C), 5 ¶ untranslated region (C+405G), and 3 ¶untranslated region (C936T) were genotyped using the Taqman allelic discrimination assay. No statistically significant case-control difference was found for the C+405G and TÀ460C polymorphisms. However, the C936T polymorphism was associated with a reduced risk of breast cancer. Compared with CC genotype carriers, women who had the TT genotype showed a decreased risk [odds ratio (OR), 0.65; 95% confidence interval (95% CI) 0.41-1.02], and the inverse association was restricted to premenopausal women (OR, 0.45; 95% CI, 0.25-0.79). Six common haplotypes were identified. Compared with the most common haplotype (À460T/405C/936C), the À460T/405G/936T haplotype was associated with a reduced risk of breast cancer (OR, 0.67; 95% CI, 0.43-1.04), particularly in premenopausal women (OR, 0.47; 95% CI, 0.27-0.81). Our study suggests that the VEGF C936T polymorphism might be a susceptibility factor for breast cancer among Chinese women. (Cancer Epidemiol Biomarkers Prev 2006;15(6):1148 -52 )
The mechanism by which psychological stress elicits various physiological responses is unknown. We discovered a central master neural pathway in rats that drives autonomic and behavioral stress responses by connecting the corticolimbic stress circuits to the hypothalamus. Psychosocial stress signals from emotion-related forebrain regions activated a VGLUT1-positive glutamatergic pathway from the dorsal peduncular cortex and dorsal tenia tecta (DP/DTT), an unexplored prefrontal cortical area, to the dorsomedial hypothalamus (DMH), a hypothalamic autonomic center. Genetic ablation and optogenetics revealed that the DP/DTT→DMH pathway drives thermogenic, hyperthermic, and cardiovascular sympathetic responses to psychosocial stress without contributing to basal homeostasis. This pathway also mediates avoidance behavior from psychosocial stressors. Given the variety of stress responses driven by the DP/DTT→DMH pathway, the DP/DTT can be a potential target for treating psychosomatic disorders.
Human luteal cells have been reported to express human leukocyte antigen-DR and lymphocyte functional antigen-3 on the cell surface, suggesting physiological interaction between luteal cells and T-lymphocytes through the menstrual cycle into early pregnancy. To elucidate the role of peripheral lymphocytes on corpus luteum differentiation, the effect of peripheral blood mononuclear cells (PBMC) on steroidogenesis by luteal cells was investigated. The production of Th-2 cytokines such as interleukin (IL)-4 and IL-10 by the co-cultured cells was also examined, and the effects of these cytokines on progesterone production by luteal cells were investigated. Corpora lutea were obtained from eight non-pregnant women in the luteal phase and five women in early pregnancy for luteal cell culture. PBMC were isolated from unrelated women in the follicular phase, secretory phase, and early pregnancy. After coculture with allogenic PBMC for 48 h, progesterone production was significantly enhanced by PBMC from the secretory phase and early pregnancy in the non-pregnant luteal cell culture. In the pregnant luteal cell culture, a significant increase in progesterone production was also observed by the co-culture with PBMC from women in early pregnancy, showing that PBMC have a luteotrophic effect. The stimulatory effects of PBMC were also observed in co-culture conditions which prevented direct cell-to-cell interaction with luteal cells, showing the minor influence of mixed lymphocyte reaction. By co-culture with PBMC, the production of IL-10, but not IL-4, was significantly augmented in luteal cell culture derived from non-pregnant women, whereas the production of both IL-4 and IL-10 was significantly enhanced in the luteal cell culture derived from pregnant women. Moreover, IL-4 and IL-10 promoted progesterone production by cultured luteal cells, especially in the luteal cell culture derived from corpora lutea of early pregnancy. These findings indicate that PBMC stimulate progesterone production by luteal cells and suggest the involvement of PBMC in corpus luteum function and differentiation probably via the Th-2-type lymphocytes.
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