The normal function of ovaries, along with the secretion of sex hormones, is among the most important endocrine factors that maintain the female sexual characteristics and promote follicular development and ovulation. Premature ovarian insufficiency (POI) is a common cause in the etiology of female infertility. It is defined as the loss of ovarian function before the age of 40. The characteristics of POI are menstrual disorders, including amenorrhea and delayed menstruation, accompanied by a raised gonadotrophin level and decreased estradiol level. Inflammatory aging is a new concept in the research field of aging. It refers to a chronic and low-degree proinflammatory state which occurs with increasing age. Inflammatory aging is closely associated with multiple diseases, as excessive inflammation can induce the inflammatory lesions in certain organs of the body. In recent years, studies have shown that inflammatory aging plays a significant role in the pathogenesis of POI. This paper begins with the pathogenesis of inflammatory aging and summarizes the relationship between inflammatory aging and premature ovarian insufficiency in a comprehensive way, as well as discussing the new diagnostic and therapeutic methods of POI.

SummaryBlood platelets contain angiopoietin-1, a growth factor essential for blood vessel development via stabilization of proliferating endothelial cells. It has recently been reported that angiopoietin-1 can act as a vascular stability factor (Nature Medicine 6:460, 2000). In investigating the normal tissue distribution of angiopoietin-1 from surgically-removed frozen specimens by RT-PCR, we found it consistently present in platelets and megakaryocytes, usually absent in relatively non-vascular tissue: breast, colon, lung, skin, kidney, thyroid, testicle, cervix and occasionally present in tissue enriched with vasculature: prostate, endometrium, ovary, under conditions in which mRNA stability was verified by the positive detection of internal control, actin mRNA. The consistent distribution in platelets and relatively absent distribution in non-vascular normal tissue suggested that the well-known role of platelets in maintaining vascular stability, may in part be due to platelet release of angiopoietin-1 following platelet activation. In this communication we report the incidence of Ang-1 in various normal tissues and demonstrate that thrombin-treated human platelets release angiopoietin-1 in vitro.

Angiogenesis is required for tumor growth and metastasis. It has recently been suggested that thrombin is a potent promoter of angiogenesis. We therefore examined the possibility that thrombin could be inducing the expression of angiopoietin-2 (Ang-2), necessary for remodeling. Human umbilical vein endothelial cells were incubated with or without thrombin (1 U/mL) for 1 to 24 hours and then examined for messenger RNA (mRNA) by Northern analysis. Enhanced mRNA expression (about 4-fold over baseline) was noted at 4 hours. Enhanced expression of Ang-2 mRNA was secondary to enhanced transcription (about 4-fold), with no effect on stabilization. Enhanced Ang-2 mRNA transcription was inhibited by H7 and PD98059, indicating the requirement of serine/threonine kinases as well as the mitogen-activated protein kinase pathway.

Thrombin-treated tumor cells induce a metastatic phenotype in experimental pulmonary murine metastasis. Thrombin binds to a unique protease-activated receptor (PAR-1) that requires N-terminal proteolytic cleavage for activation by its tethered end. A 14-mer thrombin receptor activation peptide (TRAP) of the tethered end induces the same cellular changes as thrombin. Four murine tumor cells (Lewis lung, CT26 colon CA, B16F10 melanoma, and CCL163 fibroblasts) contain PAR-1, as detected by reverse transcriptase-polymerase chain reaction (RT-PCR). B16F10 cells did not contain the two other thrombin receptors, PAR-3 and glycoprotein Ib. TRAP-treated B16F10 tumor cells enhance pulmonary metastasis 41- to 48-fold (n = 17). Thrombin-treated B16F10 cells transfected with full-length murine PAR-1 sense cDNA (S6, S7, S14, and S22) enhanced their adhesion to fibronectin 1.5- to 2.4-fold (n = 5, P < .04), whereas thrombin-treated wild-type cells do not. S6 (adhesion index, 1.5-fold) and S14 (index, 2.4-fold) when examined by RT-PCR and Northern analysis showed minimal expression of PAR-1 for S6 over wild-type and considerable expression for S14. Immunohistochemistry showed greater expression of PAR-1 for S14 compared with wild-type or empty-plasmid transfected cells. In vivo experiments with the thrombin-treated S14 transfectant showed a fivefold to sixfold increase in metastases compared with empty-plasmid transfected thrombin-treated naive cells or S6 cells (n = 20, P = .0001 to .02). Antisense had no effect on thrombin-stimulated tumor mass. Thus, PAR-1 ligation and expression enhances and regulates tumor metastasis.