Sulphonated Formononetin Induces Angiogenesis through Vascular Endothelial Growth Factor/cAMP Response Element-Binding Protein/Early Growth Response 3/Vascular Cell Adhesion Molecule 1 and Wnt/ß-Catenin Signaling Pathway.

BACKGROUND: Sodium formononetin-3'-sulphonate (Sul-F) is a derivative of the isoflavone formononetin. In this study, we investigated whether Sul-F can regulate angiogenesis and the potential mechanism in vitro. METHODS: We examined the effects of Sul-F on cell proliferation, cell invasion, and tube formation in the human umbilical vein endothelial cell line (HUVEC). To better understand the mechanism involved, we investigated effects of the following compounds: cAMP response element-binding protein (CREB) inhibitor 2-naphthol-AS-E-phosphate (KG-501), early growth response 3 (Egr-3) siRNA, vascular endothelial growth factor (VEGF) antagonist soluble VEGF receptor 1 (sFlt-1), VEGF receptor 2 blocker SU-1498, Wnt5a antagonist WIF-1 recombinant protein (WIF-1), and inhibitor of Wnt/ß-catenin recombinant Dickkopf-1 protein (DKK-1). HUVEC proliferation was tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). A scratch adhesion test was used to assess cell invasion ability. Matrigel tube formation assay was performed to test capillary tube formation ability. Activation of the VEGF/CREB/Egr-3/Vascular cell adhesion molecule 1 (VCAM-1) pathway in HUVEC was tested by Western blot analysis. RESULTS: Our results suggest that Sul-F induced angiogenesis in vitro by enhancing cell proliferation, invasion, and tube formation. The increase in proliferation and tube formation by Sul-F was counteracted by DKK-1, WIF-1, SU1498, KG-501, sFlt-1, and Egr-3 siRNA. CONCLUSIONS: These results may suggest that Sul-F induces angiogenesis in vitro via a programed Wnt/ß-catenin pathway and VEGF/CREB/Egr-3/VCAM-1 signaling axis.

Masson pine pollen aqueous extract ameliorates cadmium-induced kidney damage in rats.

Introduction: Cadmium (Cd) is a hazardous environmental pollutant present in soil, water, and food. Accumulation of Cd in organisms can cause systematic injury and damage to the kidney. The Masson pine pollen aqueous extract (MPPAE) has attracted increasing attention due to its antioxidant activity and ability to enhance immunity. Methods: In this study, we investigated the potential of MPPAE to protect against Cd-induced kidney damage in rats and the underlying mechanism. The transcriptome and metabolome of rats with Cd-induced kidney damage, following treatment with MPPAE, were explored. Results: The concentrations of superoxide dismutase (SOD) and malondialdehyde (MDA) were both significantly altered after treatment with MPPAE. Furthermore, sequencing and analysis of the transcriptome and metabolome of rats with Cd-induced kidney damage, following treatment with MPPAE, revealed differential expression of numerous genes and metabolites compared with the untreated control rats. These differentially expressed genes (DEGs) included detoxification-related genes such as cytochrome P450 and the transporter. The differentially expressed metabolites (DEMs) included 4-hydroxybenzoic acid, L-ascorbate, and ciliatine. Conjoint transcriptome and metabolome analysis showed that several DEGs were correlated with DEMs. Conclusion: These preliminary findings indicate the potential of MPPAE for the treatment of toxic metal poisoning.

PCC0208025 (BMS202), a small molecule inhibitor of PD-L1, produces an antitumor effect in B16-F10 melanoma-bearing mice.

The increased PD-L1 expression induces poorer prognosis in melanoma. The small molecule inhibitors of PD-1/PD-L1 pathways have been an encouraging drug development strategy because of good affinity and oral bioavailability without immunogenicity and immunotoxicities of PD-1/PD-L1 antibodies. In this study, we studied the effects of PCC0208025 (BMS202), a small molecule inhibitor of PD-L1, on PD-1/PD-L1 binding and the cytokines secretion in human CD3+ cells in vitro. We also investigated the antitumor and immunomodulatory activity of PCC0208025 and the pharmacokinetics properties in B16-F10 melanoma-bearing mice. The results showed that PCC0208025 inhibited the PD-1/PD-L1 proteins binding, and rescued PD-L1-mediated inhibition of IFN-γ production in human CD3+ T cells in vitro. Furthermore, in B16-F10 melanoma-bearing mice, PCC0208025 presented the antitumor effects, enhanced IFN-γ levels in plasma, increased the frequency of CD3+CD8+ T and CD8+IFN-γ+ T and the ratios of CD8+/Treg, and deceased the CD4+CD25+CD127low/- (Treg) number in tumor. Pharmacokinetics study found that PCC0208025 was absorbed and distributed into the tumors with much higher concentrations than those of the blockade against PD-1/PD-L1 binding. Our work suggests that PCC0208025 exhibited anti-tumor effects through inhibiting Treg expansion and increasing cytotoxic activity of tumor-infiltrating CD8+ T cells by the blockade of PD-1/PD-L1 binding, which may provide the pharmacological basis to develop small molecule inhibitors of PD-1/PD-L1 binding for PCC0208025 as a lead compound.

Tris-(2,3-Dibromopropyl) Isocyanurate, a New Emerging Pollutant, Impairs Cognition and Provokes Depression-Like Behaviors in Adult Rats.

Tris-(2,3-dibromopropyl) isocyanurate (TDBP-TAZTO), an emerging brominated flame retardant, possesses the characteristics of candidate persistent organic pollutants and has displayed toxicity to fish and rodents. TDBP-TAZTO can pass through the blood brain barrier and accumulate in brain. However, the neurotoxicity of TDBP-TAZTO has not yet studied in rodents. We hypothesize that TDBP-TAZTO could induce the neurotoxicity in rat hippocampal neurons. The male adult rats were exposed to TDBP-TAZTO of 5 and 50 mg/kg by gavage, daily for 6 months. TDBP-TAZTO resulted in cognitive impairment and depression-like behaviors, which may be related with TDBP-TAZTO-induced hypothalamic-pituitary-adrenal axis hyperactivation, upregulation of inflammatory and oxidative stress markers, overexpression of pro-apoptotic proteins, downexpression of neurogenesis-related proteins in hippocampus, and hippocampal neurons damage in DG, CA1 and CA3 areas. Our findings suggested that TDBP-TAZTO induces significant hippocampal neurotoxicity, which provokes cognitive impairment and depression-like behaviors in adult rats. Therefore, this research will contribute to evaluate the neurotoxic effects of TDBP-TAZTO in human.

Tris-(2,3-dibromopropyl) isocyanurate induces depression-like behaviors and neurotoxicity by oxidative damage and cell apoptosis in vitro and in vivo.

Tris-(2,3-dibromopropyl) isocyanurate (TDBP-TAZTO), an emerging brominated flame retardant, possesses the characteristics of candidate persistent organic pollutants and has displayed toxicity to fish and rodents. TDBP-TAZTO can pass through the blood-brain barrier and accumulate in the brain. TDBP-TAZTO might also induce neuronal cell toxicity. However, the neurotoxicity and mechanisms of TDBP-TAZTO have not yet been studied. We hypothesize that TDBP-TAZTO could induce neurotoxicity in mouse hippocampal neurons and SH-SY5Y cells. The mice were exposed to TDBP-TAZTO of 5 and 50 mg/kg by gavage, daily for 30 days. TDBP-TAZTO resulted in depression-like behaviors, which may be related with TDBP-TAZTO-induced upregulation of oxidative stress markers and overexpression of pro-apoptotic proteins in hippocampus. Furthermore, TDBP-TAZTO treatment for 48 hr (12.5, 25 and 50 µM) damaged SH-SY5Y cells, and led to cell apoptosis and oxidative stress in concentration-dependent manner. Our findings suggested that cell apoptosis and oxidative stress are important mechanisms in neurotoxicity induced by TDBP-TAZTO.

The optimal timing of continuous renal replacement therapy for patients with sepsis-induced acute kidney injury.

PURPOSE: High mortality in the intensive care unit (ICU) is probably associated with sepsis-induced acute kidney injury (AKI). The aim of this study is to explore which stage of AKI may be the optimal timing for continuous renal replacement therapy (CRRT). METHODS: A retrospective analysis of 160 critically ill patients with septic AKI, treated with or without CRRT was performed in Binzhou medical college affiliated hospital ICU. The parameters including 28-days mortality rate, renal recovery, ventilation time and ICU stay between CRRT group and control group were assessed. RESULTS: Renal recovery, defined as independence from dialysis at discharge, was documented for 64/76 (84.2 %) of the surviving patients (48.1 % of total subjects included in the study). The mortality rate increased proportionally with acute kidney injury Network stages in CRRT subgroups (P = 0.001) and control groups (P = 0.029). CRRT initiation at stage 2 of AKI significantly reduced the 28-day mortality (P = 0.048) and increased the 28-day survival rate (P = 0.036) compared with those in control group. In addition, the ICU stay and ventilation time were shorter in CRRT group than that of control group in stage 2 of AKI. CONCLUSION: The stage 2 AKI might be the optimal timing for performing CRRT.

Psychiatric state of college students with a history of childhood sexual abuse.

BACKGROUND: Childhood sexual abuse (CSA) seriously influences children's psychological status. This study aimed to investigate the relationship between CSA and the psychiatric disorders. METHODS: An anonymous and retrospective questionnaire survey was carried out in 1307 college students (aged 18-25 years; 701 females, 606 males) to investigate the participants' CSA experience by means of a complete random sampling method. The Symptom Check-List-90 (SCL-90) test was used to study the victims' psychiatric aspects. RESULTS: 22.11% (155/701) of the female students and 14.69% (89/606) of the male students experienced physical and/or non-physical contact CSA before age 18, with a significant difference between female and male (P<0.05). And 11.43% (80/701) of the female students and 7.26% (44/606) of the male students experienced physical contact CSA (P<0.05). Most abusers were male and young people, and only a few of them used violence. 78.7% of the females experienced non-physical contact CSA from strangers, while 71.3% experienced physical contact CSA from acquaintances. 89.9% of the male victims knew the abusers before. Females were more likely than males to experience physical contact CSA from members of the family circles. The CSA incidence increased with age in females, while 54.7% of the male victims experienced CSA from 12 to 16 years. The students who experienced CSA had higher SCL-90 scores than those who did not in somatization, obsessive-compulsive, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism. The more serious the CSA experience was, the higher SCL-90 scores of the psychiatric disorders would be. CONCLUSIONS: CSA is not uncommon in adolescents. Girls are more likely to experience CSA than boys. About half of the abusers are the victims' close relatives, neighbors and teachers; most abusers were male. Personal experience of CSA may seriously affect the victims' psychological health.

[Childhood sexual abuses among 1307 adult students and analysis on results of Symptom Checklist-90 test].

OBJECTIVE: To survey the occurrence of childhood sexual abuses (CSA) among adult students and analyze the correlation between the sexual abuses and the results of Symptom Check-List-90 (SCL-90) test. METHODS: Questionnaire survey of 1307 adult students (701 female students, 606 male students) in a college about their personal experience on childhood sexual abuses. The surveys were conducted anonymously. And SCL-90 test was carried out at the same time. RESULTS: A total of 1307 students were surveyed. 18.67% of them (female students, 155, 22.11%; male students, 89, 14.69%) experienced non-physical contact sexual abuses and/or physical contact sexual abuses before the age of 18 years, among whom 124 students (female students, 81, 11.55%; male students, 44, 7.26%) experienced physical contact sexual abuses, including 35 (26 female; 9 male) who suffered attempted genital or anal sexual intercourse and 11 (8 female and 3 male) were forced for genital or anal sexual intercourse; 13.70% (female 15.66%; male 11.44%) said they experienced sexual abuses before the age of 16 years. Of the boys, experienced sexual abuse 54.7% from age 12 to age 16 years. And among the girls sexual abuses tended to increase with their growth (results of tendency test: chi(2) = 33.5, P < 0.001). The abusers were mostly males; only a small percentage of them used violence; for most female students who experienced non-physical contact sexual abuses, the abusers were strangers (78.7%), while 71.3% of physical contact abuses were from acquaintances, 12.5% of them were teachers, 17.5% were neighbors and 21.3% were relatives. Of the male victims, 89.9% said they knew the abusers before the abuses happened, 14.6% (13 out of 89) of them were teachers, and neighbors constituted another 21.3% (19 out of 89). Students who experienced childhood sexual abuses got higher scores than the students who didn't have such experience in the nine basic symptom factors of SCL-90 and higher than normal model of national young group notably. CONCLUSION: Childhood sexual abuse among students is not rare. The female students' incidence was obviously higher than that among the male students (chi(2) = 11.8, P = 0.001). About half of the abusers were the victims' close relatives, neighbors and teachers who live or study together with them. Personal experience of childhood sexual abuses may be one of the important factors influencing the victims' results of SCL-90 test.