Summary Infection of hepatitis B virus ( HBV ) occurs in ~10% of infants of HBV ‐infected mothers with positive hepatitis B e antigen ( HB eAg) after immunoprophylaxis. We aimed to evaluate the safety and efficacy of telbivudine used during late pregnancy for preventing mother‐to‐child transmission of HBV . We conducted a multicenter prospective cohort study in 5 hospitals from 2012 to 2014, which enrolled HBV ‐infected singleton pregnant women with positive HB eAg. By their choice, women were divided into therapy (telbivudine 600 mg/day, from gestation 28‐32 weeks to 3‐4 weeks postpartum) and control (no antiviral agent) groups. Infants received passive‐active immunoprophylaxis and follow‐up at the age of 7‐14 months. Totally, 328 pregnant women were included: 149 in the telbivudine group and 179 in the control group. Baseline HBV DNA levels were similar in the 2 groups (7.43 vs 7.37 log 10 IU /mL, P = .711). At delivery, HBV DNA levels in the telbivudine and control groups were 3.80 and 7.26 log 10 IU /mL, respectively ( P < .0001). Of the infants, 128 (85.9%) in the telbivudine group and 156 (87.2%) in the control group were followed up. No infant in the telbivudine group had chronic infection, while 2 (1.28%) infants in the control group did ( P = .503). Three (2.34%) infants in the telbivudine group, but none in the control group, had severe congenital or developmental abnormalities ( P = .090). The data indicate that telbivudine may block perinatal HBV transmission. However, larger studies are required to clarify whether anti‐ HBV therapy in pregnancy is associated with severe adverse effects in the foetuses and infants.
To investigate the anti-inflammatory effect and the possible mechanisms of an agonist of cannabinoid (CB) receptors, WIN55-212-2 (WIN55), in mice with experimental colitis, so as to supply experimental evidence for its clinical use in future.
Acute pancreatitis (AP), especially severe acute pancreatitis often causes extra-pancreatic complications, such as acute gastrointestinal mucosal lesion (AGML) which is accompanied by a considerably high mortality, yet the pathogenesis of AP-induced AGML is still not fully understood. In this report, we investigated the alterations of serum components and gastric endocrine and exocrine functions in rats with experimental acute pancreatitis, and studied the possible contributions of these alterations in the pathogenesis of AGML. In addition, we explored the intervention effects of cannabinoid receptor agonist HU210 and antagonist AM251 on isolated and serum-perfused rat stomach. Our results showed that the AGML occurred after 5 h of AP replication, and the body homeostasis was disturbed in AP rat, with increased levels of pancreatic enzymes, lipopolysaccharide (LPS), proinflammtory cytokines and chemokines in the blood, and an imbalance of the gastric secretion function. Perfusing the isolated rat stomach with the AP rat serum caused morphological changes in the stomach, accompanied with a significant increment of pepsin and [H+] release, and increased gastrin and decreased somatostatin secretion. HU210 reversed the AP-serum-induced rat pathological alterations, including the reversal of transformation of the gastric morphology to certain degree. The results from this study prove that the inflammatory responses and the imbalance of the gastric secretion during the development of AP are responsible for the pathogenesis of AGML, and suggest the therapeutic potential of HU210 for AGML associated with acute pancreatitis.
To investigate the effects of angelicanaphtha on proliferation, cell cycle, apoptosis, and collagen synthesis of human umbilical vein endothelial cells (HUVEC).HUVEC was cultured and passaged in Dulbecco's modified Eagle's medium (DMEM) and treated with angelicanaphtha 1 mg/ L, 4 mg/L, and 16 mg/L at 1, 3, 5, and 7 day respectively. The proliferation was measured with MTT method. The cell cycle and apoptosis were analyzed with flow cytometry and collagen synthesis was determined with radioimmunoassay.The proliferation of the HUVEC was accelerated by angelicanaphtha < or =4 mg/L and inhibited by angelicanaphtha at 16 mg/L (P < 0.05). Lower concentration (< or = 4 mg/L) of Angelicanaphtha decreased cells in G0/G1 phase and increased significantly cells in S phase and inhibited the apoptosis (P < 0.05). However, angelicanaphtha at 16 mg/L increased cells in G0/G1 phase and decreased cells in S phase and induced the apoptosis (P < 0.05). The collagen synthesis of HUVEC was inhibited by angelicanaphtha in concentration-dependent manner (P < 0.05 or 0.01).The proliferation effects of angelicanaphtha on HUVEC had dualistic regulation of increase by lower-concentration and inhibition by higher-concentration. Collagen synthesis of HUVEC was inhibited by angelicanaphtha in concentration-dependent manner.
Aberrant expression of heparanase (Hpa) is associated with apoor prognosis in ovarian and cervical cancer patients. Inhibitors of Hpa can prevent the growth and metastasis of malignant tumor cells, and suramin may be such a compound that has strong anti-proliferative effects on several kinds of cancer cells. We have therefore tested whether the growth inhibiting effect of suramin on ovarian and cervical cancer cells is due to downregulation of Hpa expression.Suramin at 300-600 μg/ml significantly inhibited HO-8910 PM and HeLa cell growth at 24 h, in both a time-dependent and dose-dependent manner, with an IC50 of 320 μg/ml and 475 μg/ml, respectively. Suramin at 300 μg/ml significantly decreased the expression of Hpa mRNA (P < 0.005) and protein (P < 0.005) in both HO-8910 PM and HeLa cells at 48 h.The inhibitory effect of suramin on Hpa enzyme may be due to downregulating of its expression in cancer cells. These findings confirm the importance of Hpa in tumor growth and the potential clinical application of Hpa inhibitors in the treatment of ovarian and cervical cancer.
Abstract Clear cell renal cell carcinoma (ccRCC) is the most lethal form of kidney cancer. Small molecule VEGFR inhibitors are widely used but are not curative and various resistance mechanisms have been described. Previous studies have indicated cross-talk between the cAMP pathway and the MAPK pathway, and the elevation of cAMP levels by inhibition of Phosphodiesterase-4 (PDE4) activities can result in growth arrest and/or cell death. In this study we focused on the effects of PDE4 in ccRCC. We first analyzed the expression of PDE4 in human RCC cell lines and found PDE4D to be dominantly expressed. PDE4D CRISPR Knockout (KO) was then performed on Caki-1 RCC cells and normal renal proximal tubular epithelial cells as control. Cell proliferation, cell cycle cAMP, MAPK plus PI3K/AKT signaling pathways were additionally analyzed to define the effects of PDE4D inhibition. PDE4D KO Caki-1 cells showed decreased cell viability and a higher apoptosis rate compared with wild type controls. Increased intracellular cAMP levels in PDE4D KO resulted in downregulated MAPK but not PI3K/AKT signaling in Caki-1 tumor cells. In addition, PDE4D KO Caki-1 cells demonstrated higher sensitivity to VEGFR inhibitors. To conclude, we provide a new preclinical rationale for dual PDE4/VEGFR2 inhibition in patients with ccRCC. While the MAPK signaling pathway is activated in ccRCC, dual inhibitors may improve the anti-tumor effects in a patient subset with evidence of MAPK involvement. Future work involving in vivo models will be useful to better define efficacy of this dual strategy of anti-tumor activity. Citation Format: Minghua Cao, Karol Nawalaniec, Yueming Luo, Romana Moench, Li-Li Hsiao, Ana Maria Waaga-Gasser. Combined PDE4 and VEGFR2 inhibition as a new preclinical rationale in clear cell renal cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6386.
Introduction Intestinal inflammatory responses play a critical role in the pathogenesis of postoperative ileus (POI). As cannabinoid receptor-1 (CB1) is involved in inhibiting gastrointestinal (GI) motility and anti-inflammation, we aimed to explore its contribution to POI. Methods Experimental POI was induced in adult female CB1-deficient (CB1–/–) mice and wild-type littermates (C57BL/6N) by standardized small bowel manipulation. Twenty-four hours after surgery, GI transit was assessed by charcoal transport. FITC avidin, F4/80, and myeloperoxidase immunohistochemistry techniques were used to evaluate the inflammatory response in the muscularis of ileum and colon. Expressions of p38MAPK and its phosphorylated form (pp38) in the intestine were determined. Plasma levels of proinflammatory cytokines and chemokines were measured by ELISA as well. Results POI was characterized by decreased GI transit (p<0.01) and accompanied by a marked intestinal and systematic inflammatory response in wild-type and CB1–/– mice. Increased numbers of inflammatory cells, including macrophages, neutrophils, and mast cells were observed in the muscularis of ileum and colon (p<0.01, or p<0.05). Plasma levels of interleukin-6 (IL-6), cytokine-induced neutrophil chemoattractant-1 (CINC-1/KC), and monocyte chemoattractant protein-1 (MCP-1) were elevated (p<0.01, or p<0.05). Expression of p38 and pp38 increased in the intestine (p<0.01, or p<0.05). CB1–/– mice showed an increased inflammatory response during POI, especially the systemic inflammatory markers, such as IL-6, KC, CINC1, and pp38 expression were increased as compared to those in WT mice (p<0.05). Conclusions Intestinal motility was inhibited during POI. In this condition, inhibition of motility did not seem to be altered by the absence of CB1 receptors, however, an increased inflammatory response was observed in CB1–/– mice. Hence, CB1 receptor activation rather than inhibition may reduce the inflammatory response in POI, which has a remote potential to relate into reduced inhibition of intestinal motility during POI.
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