Design,synthesis and biological evaluation of nitric oxide releasing derivatives of dapagliflozin as potential anti-diabetic and anti-thrombotic agents

The cardiovascular complications were highly prevalent in type 2 diabetes mellitus (T2DM), even at the early stage of T2DM or the state of intensive glycemic control. Therefore, there is an urgent need for the intervention of cardiovascular complications in T2DM. Herein, the new hybrids of NO donor and SGLT2 inhibitor were design to achieve dual effects of anti-hyperglycemic and anti-thrombosis. As expected, the preferred hybrid 2 exhibited moderate SGLT2 inhibitory effects and anti-platelet aggregation activities, and its anti-platelet effect mediated by NO was also confirmed in the presence of NO scavenger. Moreover, compound 2 revealed significantly hypoglycemic effects and excretion of urinary glucose during an oral glucose tolerance test in mice. Potent and multifunctional hybrid, such as compound 2, is expected as a potential candidate for the intervention of cardiovascular complications in T2DM.     

β‐carotene suppresses Porphyromonas gingivalis lipopolysaccharide‐mediated cytokine production in THP‐1 monocytes cultured with high glucose condition

Periodontitis is associated with development of diabetes mellitus. Although lipopolysaccharide (LPS) of Porphyromonas gingivalis (Pg), a major pathogen of periodontitis, may lead the progression of diabetes complications, the precise mechanisms are unclear. We, therefore, investigated the effects of β‐carotene on production of Pg LPS‐induced inflammatory cytokines in human monocytes cultured high glucose (HG) condition. THP‐1 cells were cultured under 5.5 mM or 25 mM glucose conditions, and cells were stimulated with Pg LPS. To investigate the productivity of TNF‐α, IL‐6, and MCP‐1, cell supernatants were collected for ELISA. To examine the effects of NF‐kB signals on cytokine production, Bay11‐7082 was used. HG enhanced Pg LPS‐induced production of TNF‐α, IL‐6, and MCP‐1 via NF‐kB signals in THP‐1. β‐carotene suppressed the enhancement of the Pg LPS‐induced cytokine production in THP‐1 via NF‐κB inactivation. Our results suggest that β‐carotene might be a potential anti‐inflammatory nutrient for circulating Pg LPS‐mediated cytokine production in diabetic patients with periodontitis.     

Failure of neutralizing gp120 monoclonal antibodies to prevent HIV infection of choriocarcinoma-derived trophoblasts

Although placental trophoblasts, the only fetal cells in direct contact with infectious maternal blood, can be infected with HIV, the precise cause for the low transmission rate of virus across the placental barrier is unknown. One of the most common conjectures is that maternal anti-HIV antibodies (Abs) contribute to the protection of the fetus. This hypothesis has been tested in vitro by infecting the CD4-negative placental trophoblast line, BeWo, with HIV-1_IIIB in the presence of serial dilutions of neutralizing monoclonal Abs against the V3 loop (No. 694) or CD4-binding conformational domain (No. 588). The results, based on measurement of p24 production from virus-exposed cells, reveal that the titers of Abs, adequate in preventing the infection of control MT-4 T lymphocytes, were less effective in protecting trophoblasts. Furthermore, PCR analysis of HIV DNA formed after a single round of infection has shown no significant decrease in the number of viral copies in Ab-protected BeWo cells. An anti-HIV serum from a pregnant woman did also have no effect. Although our in vitro observations do not necessarily apply to the in vivo situation, the results suggest that the humoral immune response sustained by neutralizing Abs may be able to protect T lymphocytes, but not placental trophoblasts. The findings are consistent with recent clinical studies demonstrating a lack of correlation between the presence of neutralizing anti-HIV Abs in pregnant women and HIV transmission in utero.     

Trypanosoma lewisi: termination of pregnancy in the infected rat

Trypanosoma lewisi has previously been described as a nonpathogenic parasite of the rat, but these experiments demonstrate that both embryonal and maternal death may occur in the pregnant rat after infection with this parasite.Rats infected early in the first week of pregnancy resorbed their young with little apparent difficulty, and exhibited parasitemia curves typical of nonpregnant infected females of similar age.Rats infected late in the first week of pregnancy experienced greater difficulty resorbing the young, with half of the females dying shortly before parturition. The parasitemia counts were also similar to those of nonpregnant infected rats.The majority of rats infected during the midterm of pregnancy died at the time of parturition, without giving birth to their young. The number of parasites in these animals was abnormally high compared to nonpregnant infected females. Unusually large numbers of dividing trypanosomes were present in the placentae of these animals, many of them containing 8–16 nuclei and kinetoplasts.Animals infected during the last week of pregnancy gave birth to litters of normal size with little apparent difficulty, and had extremely low parasite counts.The hematocrits of all groups of infected animals showed a decrease at the time of peak parasitemia, and the hematocrits of all groups of pregnant rats showed a decrease at the time of birth, except for those infected when day 2 pregnant. These animals completely resorbed their young. The weight losses of rats infected on day 2 and day 6 of pregnancy reflected a termination of pregnancy.     

Ultrastructure of the corpus luteum of antarctic seals during pregnancy

Summary The fine structure of granulosa lutein cells from three crabeater seals, Lobodon carcinophagus, and two leopard seals, Hydrurga leptonyx, has been studied from early through mid-pregnancy. Analysis of the arrangement and modifications of the cytoplasmic organelles and inclusions has revealed three types of lutein cells throughout the corpus. Type I cell typically possesses a central nucleus and cytoplasm containing very large amounts of smooth and/or fenestrated endoplasmic cisternae which frequently extend from the juxta-nuclear to the periphery of the cell. Type II cell contains a central or eccentric nucleus, moderate amounts of peripheral, smooth and fenestrated cisternae which often form large and concentric membranous whorls, numerous mitochondria and small lipid droplets. Frequently these cells show polarity in the arrangement of the cytoplasmic organelles and inclusions. Type III cell contains predominant large lipid droplets, many mitochondria, and small amounts of smooth and fenestrated cisternae. In light microscopy the type I cell is evenly granular, while the type III cell is highly vacuolated. Type II cells have both granular and vacuolated conditions. Ultrastructural features of type I and II cells suggest that they probably secrete most of the steroids, whereas the primary role of the type III cells appear to be lipid storage.This research was supported by National Science Foundation, Grant No. 1325 from the Office of Antarctic Biology.     

TNF-α induces vascular endothelial cells apoptosis through overexpressing pregnancy induced noncoding RNA in Kawasaki disease model

Kawasaki disease (KD) is an autoimmune disease in which the medium-sized blood vessels throughout the body become inflamed. The increased evidences showed that TNF-α was association with vascular inflammation in KD patients. However the detailed mechanism was still unclear. Recent studies indicated abnormal expressed long non-coding RNAs (LncRNAs) involved in many diseases. Thus the purpose of this study is to explore the role of lncRNAs in KD and find out the new target for KD treatment. In this study, firstly we verified the overexpressed TNF-α in KD patients, and found TNF-α was able to induce HUVECs apoptosis and inhibit HUVECs proliferation. After this we screened out pregnancy induced noncoding RNA (PINC) was significantly overexpression in TNF-α treated HUVECs. We also found PINC overexpressed in KD patients. For further study, we designed two siRNA of PINC. After silenced the expression of PINC in HUVECs, we found the Knockdown of PINC enhanced the viability of HUVECs treated with TNF-α, and increased the expression of anti-apoptotic and reduced the expression of apoptotic gene. These results suggest PINC involves in the process of TNF-α induces vascular endothelial cell apoptosis, it may become a new target for KD treatment.     

Effect of multiple stress factors (thermal,nutritional and pregnancy type) on adaptive capability of native ewes under semi-arid environment

This study was conducted to evaluate the effect of multiple stress factors (thermal, nutritional and pregnancy type) on two different native track breeds of ewes as reflected by their adaptive capability under semi-arid environment. The multiple stressor experiment was conducted in twenty-four ewes (12 Santa Inês and 12 Morada Nova ewes). Both heat stress and pregnancy stress was common to all four groups. However, the animals were divided into further two groups within each breed on the basis of nutrition regimen. According the groupings were: Group 1 (Six Santa Ines ewes; heat stress; nutrition at 0.5% of BW; single pregnancy); Group 2 (Six Santa Ines ewes; heat stress; nutrition at 1.5% BW; twin pregnancy); groups Group 3 (Six Morada Nova ewes; heat stress; nutrition at 0.5% of BW; single pregnancy); Group 4 (Six Morada Nova ewes; heat stress; nutrition at 1.5% BW; twin pregnancy). All the animals in the experiment were pregnant. Heat stress was induced by exposing all animals to summer heat stress in outside environment while the nutritional regimen followed was at 0.5% and 1.5% level of body weight (BW) respectively in each breed. The experiment was conducted in a completely randomized design with two breeds, two nutritional treatments and two pregnancy types, 10 repetitions for physiological parameters and six for blood parameters, with repeated measures over time. Physiological parameters (respiratory rate, pulse rate and rectal temperature) were measured with the animals at rest in the morning and afternoon, 0600-0700 and 1300–1400 h, respectively, every seven days. Blood samples were collected every 14 d for determination of serum glucose, triglycerides, cholesterol, urea and creatinine. We found interaction effect between breed and pregnancy type on respiratory rate and rectal temperature with greater values in Santa Inês ewes than Morada Nova ewes. However, there was no significant fixed effect of pregnancy type and supplementation level on physiological responses of breeds. Environmental factor (period of the day) had influenced the physiological responses of ewes during all gestational period. Santa Inês ewes had greater serum glucose concentration at 105 d and 120 d of gestation compared to the Morada Nova ewes. Morada Nova ewes had greater concentrations of triglycerides, urea at 120 d, 150 d and also greater cholesterol at 105 d, 135 d and 150 d of gestation compared with Santa Inês ewes. The present result indicates that thermal condition was most important factor that modified the physiological responses of ewes in a semi-arid tropical environment.     

Complications after breast reconstruction with alloplastic material in breast cancer patients submitted or not to post mastectomy radiotherapy

Background and purposeBreast reconstruction following mastectomy is a relevant element of breast cancer treatment. The purpose of this study was to evaluate the influence of radiotherapy (RT) on local complications in patients with breast cancer that had undergone breast reconstruction with alloplastic material.Materials and methodsRetrospective study of breast cancer patients submitted to mastectomy and breast reconstruction from 2009 to 2013. Clinical and treatment variables were correlated with early and late complications.Results251 patients were included; mean age was 49.7 (25 to 78) years. Reconstruction was immediate in 94% of the patients, with 88% performed with a temporary tissue expander. Postoperative radiotherapy (RT) was delivered to 167 patients (66.5%). Early complications were present in 26.3% of the patients. Irradiated patients presented 5.4% incidence of late complications versus 2.4% for non-irradiated patients (p = 0.327). Diabetes (OR = 3.41 95% CI: 1.23–9.45, p = 0.018) and high body mass index (BMI) (OR = 2.65; 95% CI: 1.60–4.37, p < 0.0001) were the main risk factors. The overall incidence of late complications was 4.4%, with predominance of severe capsular contracture (8/11). Arterial hypertension (OR = 4.78; 95% CI: 1.97–11.63, p = 0.001), BMI (OR = 0.170; 95% CI: 0.048–0.607, p = 0.006) and implant placement (OR = 3.55; 95% CI: 1.26–9.99, p = 0.016) were related to late complications.ConclusionsThe overall rate of complications was low in this population. Radiotherapy delivery translated into a higher but not statistically significant risk of late complications when compared with the non-irradiated patients. Already well-known clinical risk factors for complications after breast reconstruction were identified.     

甲状腺功能减退孕妇糖代谢、肾功能指标的变化及临床意义

目的:探究妊娠期甲状腺功能减退患者糖代谢及肾功能变化及临床意义。方法:选择2015年6月至2019年8月来我院就诊的甲状腺功能减退孕妇60例作为甲减组及同期健康孕妇60例作为对照组。比较两组患者甲状腺功能[促甲状腺激素(TSH)、游离三碘甲状腺原氨酸(FT_3)及游离甲状腺素(FT_4)]、糖代谢指标[空腹血糖水平(FBG)、糖化血红蛋白(HbA1C)、餐后2 h抽取肘静脉血测定餐后2 h葡萄糖水平(2hPG)、胰岛素抵抗指标(HOMA-IR)]及肾功能[血清肌酐(Cr)、血清尿酸(UA)、血尿素氮(BUN)],分析甲状腺功能与糖代谢及肾功能的关系,比较两组患者的妊娠结局。结果:甲减组孕妇的TSH、糖代谢、肾功能各指标水平较对照组显著升高,FT_4较对照组明显降低(P0.05)。TSH与糖代谢各指标均呈正相关(P0.05);FT_4与糖代谢各指标均呈负相关(P0.05),FT_3与Cr呈负相关(P0.05),TSH、FT_4与Cr、UA、BUN均无明显相关性(P0.05)。甲减组的不良妊娠结局率为20.00%,显著高于对照组(6.67%,P0.05)。结论:妊娠期甲状腺功能减退患者存在糖代谢紊乱、肾功能异常,可能导致不良妊娠结局。     

Focus: Rare Disease: Necrotizing Fasciitis: Association with Pregnancy-related Risk Factors Early in Life

Background: Pregnancy-related risk factors for necrotizing fasciitis are poorly understood. We investigated pregnancy-related characteristics associated with the long-term risk of developing necrotizing fasciitis, a rare life-threatening infectious disease. Methods: We analyzed a longitudinal cohort of 1,344,996 parous women in Quebec, Canada between 1989 and 2020. The main exposure measures included complications of pregnancy such as gestational diabetes, preterm delivery, metabolic disorder, and other maternal characteristics. We followed the women over time to identify future hospitalizations for necrotizing fasciitis up to three decades after delivery. We estimated adjusted hazard ratios (HR) and 95% confidence intervals (CI) for the association of pregnancy characteristics with risk of necrotizing fasciitis in time-varying Cox proportional hazards regression models. Results: A total of 420 women were hospitalized for necrotizing fasciitis during follow-up, including 83 (19.8%) with diabetes-related necrotizing fasciitis. The incidence of necrotizing fasciitis was elevated for women with gestational diabetes (2.9 per 100,000 person-years), preterm delivery (3.2 per 100,000 person-years), and metabolic disorders (5.4 per 100,000 person-years), compared with no pregnancy complication (1.1 per 100,000 person-years). Compared with no pregnancy complication, gestational diabetes was associated with 1.87 times the risk (95% CI 1.38-2.53), preterm delivery with 2.10 times the risk (95% CI 1.65-2.66), and metabolic disorder with 3.72 times the risk (95% CI 2.92-4.74) of developing necrotizing fasciitis over time. Pregnancy complications were more strongly associated with the risk of necrotizing fasciitis 5 years or more after delivery. Conclusions: Complications of pregnancy may be associated with the long-term risk of necrotizing fasciitis in women.