Dipeptidyl peptidase-4 (DPP4) inhibitor sitagliptin alleviates liver inflammation of diabetic mice by acting as a ROS scavenger and inhibiting the NFκB pathway.

As a common chronic metabolic disease, the development of diabetes mellitus (DM) may also be accompanied by liver damage and inflammatory disorders. Sitagliptin is an inhibitor of dipeptidyl peptidase-4 (DPP4, also known as CD26), which is clinically used for DM treatment. However, the mechanism of sitagliptin's efficiency in liver diseases is largely unknown. In this study, mice suffering from streptozotocin (STZ) exhibit elevated liver DPP4 expression and activity, as well as inflammatory and chronic liver injury phenotype, whereas specifically inhibiting the activity of DPP4 in mouse liver tissues and hepatocytes by sitagliptin contributes to decreased cytokines, oxidative stress, cell apoptosis, and inflammation in STZ-induced diabetic mice. Moreover, sitagliptin reduced TNFα or LPS-induced cellular reactive oxygen species (ROS) level, cell apoptosis, and protein expression in the NFκB signaling pathway in HepG2 cells or primary mouse hepatocytes. Altogether, our study confirms that sitagliptin may protect liver tissue by alleviating ROS production and NFκB signaling activation, providing a putative mechanism for preventing the development of diabetic liver disease.

Effects of IL-18 on the proliferation and steroidogenesis of bovine theca cells: Possible roles in the pathogenesis of polycystic ovary syndrome.

Interleukin 18 (IL-18) is a pleiotropic pro-inflammatory cytokine and is associated with arrested follicle development and anovulation which are the typical pathological changes of PCOS. Theca cells (TCs) have a key role in follicular growth and atresia. But whether IL-18 can directly affect ovarian TCs function is unknown. Therefore, the objective of this study was to determine the effect of IL-18 on proliferation and steroidogenesis of bovine TCs and to explore the biological effect of IL-18 on folliculogenesis. This work revealed that at 300-1000 pg/mL, IL-18 led to a time- and dose-dependently increase in cell proliferation (P < .05). IL-18 increased 17-hydroxyprogesterone (17OHP4) and androstenedione (A2) secretion with up-regulation of key steroidogenesis-related genes CYP11A1 and CYP17A1 (P < .05). Furthermore, our data demonstrated that the IL-18R protein is predominantly expressed in small-follicle (3-6 mm) TCs than large follicles (8-22 mm) by immunohistochemistry. We also found that the stimulation effects of IL-18 on TCs can be reversed with the addition of IL-18BP as early as at 4 hours of culture and reached the peak at 16 hours. We conclude that IL-18 appears to target TCs in bovine, and suggest an important role for this cytokine in ovarian function. Present findings further validate potential effects of IL-18 in the conditions associated with follicular dysplasia and excessive growth of ovarian TCs (such as PCOS). But additional research is needed to further understand the mechanism of action of IL-18 in theca cells as well as its precise role in folliculogenesis.

[Effects of Gui Zhi Fu Ling Jiao Nang on Hemorheology and Expression of Phenotypic Proteins in Uterine Smooth Muscle Cells in Rats with An Intrauterine Device].

Objective To observe the effect of Gui Zhi Fu Ling Jiao Nang (GZFLJN) on the expressions of alpha smooth muscle actin (α-SMA) and proliferating cell nuclear antigen (PCNA) in uterine vascular smooth muscle cells (VSMC) of rat models with an intrauterine device (IUD) and to determine the thromboxane B2 (TXB2) and 6-keto-prostaglandin F1α (6-keto-PGF1α) levels in peripheral blood. Methods Female Wistar rats were randomly divided into four groups:normal group (n=16,with normal breed without treatment),model group (n=18,drenching 0.9% normal saline after modeling of IUD),GZFLJN group (n=18),and aminocaproic acid tablets group (n=17). Immunohistochemical SP method was used to detect the expressions of α-SMA and PCNA in uterine VSMC.ELISA was served to detect the levels of TXB2 and 6-keto-PGF1α in peripheral blood. Results The positive rate of α-SMA were (50.89±9.41)%,(26.93±6.80)%,(48.92±6.80)%,and (34.63±7.26)%,respectively,in normal group,model group,GZFLJN group,and aminocaproic acid tablets group;obviously,it was significantly higher in normal group (t=14.43,P=0.00) and GZFLJN group (t=11.37,P=0.00) than that in model group and it was significantly lower in aminocaproic acid tablets group than in normal group (t=9.96,P=0.00) and GZFLJN group (t=8.23,P=0.00). The positive rate of PCNA were (25.66±7.24)%,(61.26±9.98)%,(28.36±9.17)%,and (50.23±8.71)%,respectively,in these four groups;obviously,it was significantly lower in the normal group (t=20.86,P=0.00) and GZFLJN group (t=19.12,P=0.00) than in model group and it was significantly higher in aminocaproic acid tablets group than in normal group (t=17.82,P=0.00) and GZFLJN group (t=16.05,P=0.00). Serum TXB2 level in these four groups were (445.86±24.43),(508.78±12.42),(448.11±9.63),and (498.11±13.63)ng/L;obviously,it was significantly higher in model group than in normal group (t=16.55,P=0.00) and aminocaproic acid tablets group (t=-4.12,P=0.00) and it was significantly lower in GZFLJN group than in model group (t=-15.23,P=0.00) and aminocaproic acid tablets group (t=-12.08,P=0.00). Serum 6-keto-PGF1α level in these four groups were (23.17±1.93),(18.09±0.93),(22.70±1.61),and (20.70±1.41)ng/L,respectively;obviously,it was significantly lower in model group than in normal group (t=-13.98,P=0.00) and aminocaproic acid tablets group (t=5.26,P=0.00) and it was significantly higher in GZFLJN group than in model group (t=11.43,P=0.00) and aminocaproic acid tablets group (t=8.76,P=0.00). Conclusion GZFLJN can regulate the expressions of α-SMA and PCNA of VSMC in the endometrium of IUD rats and the concentrations of TXB2 and 6-keto-PGF1α in the serum.

Bu Shen Yi Sui capsule promotes remyelination correlating with Sema3A/NRP-1, LIF/LIFR and Nkx6.2 in mice with experimental autoimmune encephalomyelitis.

ETHNOPHARMACOLOGICAL RELEVANCE: Bu Shen Yi Sui capsule (BSYSC), based on traditional Chinese formula Liu Wei Di Huang pill, is effective for the treatment of multiple sclerosis (MS) in clinical experience and trials. Our previous studies confirmed that BSYSC had the neuroprotective effect in MS and its animal model, experimental autoimmune encephalomyelitis (EAE); however, its mechanism of action was not clear. Thus, the effect of BSYSC on remyelination and the underlying mechanisms were investigated in the EAE mice. MATERIALS AND METHODS: The EAE model was established by injecting subcutaneously myelin oligodendrocyte protein (MOG) 35-55 in mice. Mice were treated with BSYSC (3.02 g/kg) or vehicle daily by oral gavage for 40 days. The body weight and clinical score of mice were evaluated. Brain was observed by magnetic resonance imaging. The inflammation infiltrate of brain and spinal cord was determined by hematoxylin-eosin staining, while the structure of myelin sheath was visualized by transmission electron microscopy on days 23 and 40 post immunization (dpi), respectively. The protein and mRNA levels of platelets-derived growth factor receptor (PDGFR) α and 2', 3'-cyclic nucleotide-3'-phosphodiesterase (CNPase) were measured by immunohistochemistry, western blot and quantitative real-time polymerase chain reaction. The protein expressions of semaphorins (Sema) 3A, Neuropilin (NRP) - 1, leukemia inhibitory factor (LIF), LIF receptor (LIFR) and Nkx6.2 were further investigated by western blot. RESULTS: BSYSC treatment improved the body weight and clinical score of EAE mice, alleviated inflammatory infiltration and nerve fiber injuries. It also protected the ultrastructural integrity of myelin sheath. BSYSC significantly increased expressions of PDGFRα and CNPase in mice with EAE on 40 dpi. Furthermore, BSYSC treatment increased the expressions of LIF, LIFR and Nkx6.2 and reduced Sema3A and NRP-1 in EAE mice on 40 dpi. CONCLUSIONS: The data demonstrated that BSYSC exhibited the neuroprotective effect against EAE by promoting oligodendrocyte progenitor cells (OPCs) proliferation and differentiation, thus facilitating remyelination. Sema3A/NRP-1, LIF/LIFR and Nkx6.2 are likely contributed to the effects of BSYSC on OPCs.

A randomized study comparing the side effects and hormonal status of triptorelin and leuprorelin following conservative laparoscopic surgery for ovarian endometriosis in Chinese women.

OBJECTIVES: Different gonadotropin-releasing-hormone agonist (GnRH-a) formulations with different potency and associated side effects, therefore, different compliance and persistence of therapy. This study was to evaluate the difference of hormonal profile and side effects due to hypoestrogenic status after treatment of leuprorelin and triptorelin in Chinese women with ovarian endometrioma after conservative surgical treatment. STUDY DESIGN: A total of 302 women underwent laparoscopic excision of ovarian endometriomas with rASRM III and IV were enrolled in the study.Subjects were randomized into two groups with use of a random table. Twenty two patients dropped out during the study. Thus 142 patients had three doses of i.m. leuprorelin (group A) and 138 patients had three doses of i.m. triptorelin(group B) at 4 weeks intervals after surgical treatment. Menopausal symptoms were evalutaed using a questionnaire and serum sex hormonal levels were also measured during the follow-up. RESULTS: At week 4 after the treatment, most of the patients in leuprorelin group have no obvious side effects. After 9 weeks, bone pain, hot flashes and sweating, and irregular bleeding were the main side effects and showed no difference between the groups. Anxiety, depression, vaginal dryness, headache, and acne rates were all significantly higher in triptorelin group than in leuprorelin group. A significant difference in FSH (p=0.003), LH (p=0.026) and E2 (p=0.002) levels between the groups were observed after 21 days of the GnRHa treatment. The FSH (p=0.021) and E2 (p=0.033) levels remained higher in the leuprorelin group than the triptorelin group after six weeks of treatment, but the difference of LH(p=0.917) level was no longer discernible. CONCLUSION: Leuprorelin in down-regulating the pituitary-ovarian function was more moderate, and the hormonal levels decrease progressively and gradually, therefore, with lower rate of menopausal symptoms. Leuprorelin acetate maybe better tolerated than triptorelin.