Multi-omics reveal disturbance of glucose homeostasis in pregnant rats exposed to short-chain perfluorobutanesulfonic acid.

Perfluorobutanesulfonic acid (PFBS), a short-chain alternative to perfluorooctanesulfonic acid (PFOS), is widely used in various products and is increasingly present in environmental media and human bodies. Recent epidemiological findings have raised concerns about its potential adverse health effects, although the specific toxic mechanism remains unclear. This study aimed to investigate the metabolic toxicity of gestational PFBS exposure in maternal rats. Pregnant Sprague Dawley (SD) rats were randomly assigned to three groups and administered either 3% starch gel (control), 5, or 50 mg/kg bw·d PFBS. Oral glucose tolerance tests (OGTT) and lipid profiles were measured, and integrated omics analysis (transcriptomics and non-targeted metabolomics) was employed to identify changes in genes and metabolites and their relationships with metabolic phenotypes. The results revealed that rats exposed to 50 mg/kg bw·d PFBS exhibited a significant decrease in 1-h glucose levels and the area under the curve (AUC) of OGTT compared with the starch group. Transcriptomics analysis indicated significant alterations in gene expression related to cytochrome P450 exogenous metabolism, glutathione metabolism, bile acid secretion, tumor pathways, and retinol metabolism. Differentially expressed metabolites (DEMs) were enriched in pathways such as pyruvate metabolism, the glucagon signaling pathway, central carbon metabolism in cancer, and the citric acid cycle. Co-enrichment analysis and pairwise correlation analysis among genes, metabolites, and outcomes identified several differentially expressed genes (DEGs), including Gstm1, Kit, Adcy1, Gck, Ppp1r3c, Ppp1r3d, and DEMs such as fumaric acid, L-lactic acid, 4-hydroxynonenal, and acetylvalerenolic acid. These DEGs and DEMs may play a role in the modulation of glucolipid metabolic pathways. In conclusion, our results suggest that gestational exposure to PFBS may induce molecular perturbations in glucose homeostasis. These findings provide insights into the potential mechanisms contributing to the heightened risk of abnormal glucose tolerance associated with PFBS exposure.

New steroidal saponins from the aerial parts of Paris polyphylla var. yunnanensis and their effects on blood coagulation.

Five new steroidal saponins, paripolins D-H (1-5), and 6 known compounds (6-11) were isolated from the aerial parts of Paris polyphylla var. yunnanensis. The structures of 1-5 were determined using spectroscopic analyses in conjunction with acid hydrolysis. It is for the first time to report the 12-hydroxysteroidal saponins from the genus Paris. The effect of all isolated compounds on blood coagulation was determined in vitro using the plasma recalcification time method. Compounds 1 and 2 showed potent procoagulant activity, and 5-11 exhibited significant anticoagulant activity.

PDIA6, which is regulated by TRPM2-AS/miR-424-5p axis, promotes endometrial cancer progression via TGF-beta pathway.

PDIA6 have been reported to be involved in a variety of cancers, however, the underlying role in endometrial cancer is still unclear. In this study, we aimed to study the function of PDIA6 in endometrial cancer. Firstly, we verified that PDIA6 was significantly upregulated in endometrial cancer, which was correlated with the progression of endometrial cancer patients. Furthermore, we identified PDIA6 significantly altered the ability of endometrial cancer cells to proliferate and metastasize. In addition, our result illustrated the oncogene effects of PDIA6 in promoting malignant biological behavior of endometrial cancer cells by regulating TGF-ß pathway and being modulated by TRPM2-AS/miR-424-5p axis for the first time. Taken together, this study suggested that PDIA6 may be a new candidate target for endometrial cancer therapy.

Progesterone receptor membrane component 2 is critical for human placental extravillous trophoblast invasion.

Proper extravillous trophoblast invasion is essential for normal placentation and pregnancy. However, the molecular mechanisms by which cytotrophoblasts differentiate into extravillous trophoblast are unclear. We discovered that in the first-trimester placenta, progesterone receptor membrane component 2 was highly expressed in syncytiotrophoblast but significantly lower in extravillous trophoblast and cytotrophoblasts, indicating a divergent role for progesterone receptor membrane component 2 in trophoblast functions. We aim to examine the role of progesterone receptor membrane component 2 in extravillous trophoblasts invasion mediated by both intracellular and extracellular signals. Progesterone receptor membrane component 2 knockdown and overexpression cells were established in HTR8/SVneo cells, a first-trimester extravillous trophoblast-derived cell model, by transfection with small-interfering RNA or progesterone receptor membrane component 2 plasmids, respectively. Progesterone receptor membrane component 2 knockdown led to cellular morphological changes , enhanced trophoblast proliferation,invasion, and promoted tube formation. These effects were mediated by the activation of hypoxia-inducible factor 1alpha and an increased expression of vascular endothelial growth factor A. The culture supernatant collected from progesterone receptor membrane component 2 knockdown cells did not significantly affect extravillous trophoblast invasion compared to the controls, indicating that extracellular signaling did not robustly regulate extravillous trophoblast invasion in this study. In conclusion, attenuation of progesterone receptor membrane component 2 plays a role in placentation by promoting cell proliferation, invasion, and angiogenesis in extravillous trophoblasts via activation of hypoxia-inducible factor 1 alpha signaling. We thus identified a new function of progesterone receptor membrane component 2 and provide insights on understanding the mechanisms of trophoblast invasion.

A Natural-Position X-Ray for Evaluating Cervical Vertebra Physiology Curvature Before and After Conservative Treatment.

BACKGROUND Abnormal physiological curvature is one of the symptoms of early cervical spondylosis. An X-ray taken with the patient standing in a natural position can best reflect the real cervical vertebra physiological curvature. The purpose of this research was to study the value of natural-position X-ray in evaluating cervical vertebra physiology curvature before and after conservative treatment. MATERIAL AND METHODS This study included 135 participants of different ages diagnosed with cervical disease and who received conservative treatment for more than 12 months. The natural- and regular-position X-rays were performed before and after treatment. The positive change of D value in Borden's measurement and C2~7 Cobb angle should be recognized as an improvement of cervical vertebra physiology curvature. RESULTS Before treatment, the C2~7 Cobb angle of the regular-position group was larger than that of natural-position group. After treatment, the C2~7 Cobb angle of the natural-position group was larger than that of the regular-position group, and the D value increased after treatment in both groups. The effective rate of cervical physiological curvature of the natural-position group was higher than that of the regular-position group. CONCLUSIONS Natural-position X-ray has greater accuracy in evaluating cervical vertebra physiology curvature before and after conservative treatment compared with regular-position X-ray.

Grayanane diterpenoids from Craibiodendron yunnanense with anti-inflammatory and antinociceptive activities.

Twenty-five grayanane diterpenoids including six undescribed compounds (craibiodenoside A-F), were isolated from the leaves of Craibiodendron yunnanense W. W. Smith. The structures of the isolated compounds were determined by 1D-NMR, 2D-NMR, and HR-ESI-MS spectrometric analyses. All compounds were evaluated for their anti-inflammatory activities by inhibiting the release of interleukin-6 (IL-6) in lipopolysaccharide (LPS)-induced RAW264.7 cells. The results demonstrated that three undescribed compounds craibiodenoside A, B, F, and three known compounds could inhibit the release of IL-6 significantly. In addition, the antinociceptive activities of compounds were assessed using acetic acid-induced writhing test. Craibiodenoside D, grayanoside D, and rhodojaponins VI exhibited notable antinociceptive activities. Specifically, rhodojaponins VI exhibited antinociceptive activity with the inhibition percentage of 87.6%.

BDNF promotes mouse follicular development and reverses ovarian aging by promoting cell proliferation.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) plays an important role in ovarian function including follicle development and oocyte maturation, and embryonic development. However, whether BDNF treatment can reimpose ovarian aging and impaired fertility remains elusive. In this study, we investigated the reproductive outcomes of BDNF treatment and potential mechanisms in aged mice. METHOD: "Aged" mice (35-37 weeks old, n = 68) were treated with recombinant human BDNF protein (rhBDNF, 1 µg/200 µL) through daily intraperitoneal (IP) injection for 10 days with/without ovulation induction. Reproductive age mice (8-10 weeks old, n = 28) were treated with ANA 12 (a selective BDNF receptor, TrkB antagonist) through daily IP injection for 5 days with/without ovulation induction. Ovarian function was assessed by ovarian weight, number of follicles, and sex hormone productions. Following induction of ovulation, the number of total oocytes or abnormal oocytes, and blastocyst formation were assessed. Reproductive functions of the mice were evaluated, including pregnancy rate, mating duration for conception, implantation sites, litter size, and weight of offspring. Finally, the molecular mechanism of the effects of BDNF on ovarian cell functions in mice were examined by Western blot and immunofluorescence. RESULTS: rhBDNF treatment increased the ovarian weight, number of follicles, number and quality of oocytes including increased blastocysts formation, blood estrogen levels, and pregnancy rate in 35-37-week-old mice. Conversely, BDNF receptor antagonist, ANA 12, treatment decreased the ovarian volume and number of antral follicles and increased the proportion of abnormal oocytes in 8-10-week-old mice. We further demonstrated that BDNF treatment promoted ovarian cell proliferation as well as activation of TrkB and cyclinD1-creb signalling. CONCLUSION: We demonstrated that ten consecutive days of daily IP injection of rhBDNF rescued ovarian function in aged mice. Our results further indicate that TrkB and cyclin D1-creb signaling may underlie the BDNF function in ovaries. Targeting BDNF-TrkB signaling is a potential novel therapeutic strategy to reverse ovarian aging.

Early life exposure to low-dose perfluorooctane sulfonate disturbs gut barrier homeostasis and increases the risk of intestinal inflammation in offspring.

Perfluorooctane sulfonate (PFOS), one of the legacy per- and poly-fluoroalkyl substances (PFAS), is associated with multiple adverse health effects on children. However, much remains to be known about its potential impacts on intestinal immune homeostasis during early life. Our study found that PFOS exposure during pregnancy in rats significantly increased the maternal serum levels of interleukin-6 (IL-6) and zonulin, a gut permeability biomarker, and decreased gene expressions of Tight junction protein 1 (Tjp1) and Claudin-4 (Cldn4), the tight junction proteins, in maternal colons on gestation day 20 (GD20). Being exposed to PFOS during pregnancy and lactation in rats significantly decreased the body weight of pups and increased the offspring's serum levels of IL-6 and tumor necrosis factor-α (TNF-α) on postnatal day 14 (PND14), and induced a disrupted gut tight junction, manifested by decreased expressions of Tjp1 in pup's colons on PND14 and increased pup's serum concentrations of zonulin on PND28. By integrating high-throughput 16S rRNA sequencing and metabolomics, we demonstrated that early-life PFOS exposure altered the diversity and composition of gut microbiota that were correlated with the changed metabolites in serum. The altered blood metabolome was associated with increased proinflammatory cytokines in offspring. These changes and correlations were divergent at each developmental stage, and pathways underlying immune homeostasis imbalance were significantly enriched in the PFOS-exposed gut. Our findings provide new evidence for the developmental toxicity of PFOS and its underlying mechanism and explain in part the epidemiological observation of its immunotoxicity.

Effect of the systemic immune-inflammation index on postoperative complications and the long-term prognosis of patients with colorectal cancer: a retrospective cohort study.

Background: Colorectal cancer (CRC) is one of the most common malignant tumors of the digestive tract. Surgery is the main way to cure CRC, but the postoperative complication rate and recurrence rate remain high. The systemic immune-inflammation (SII) index reflects a patient's systemic inflammatory state and immune state. Postoperative recurrence and the occurrence of complications are closely related to the inflammatory state and immune state. Thus, the SII index may have some value in predicting postoperative complications and the long-term prognosis of CRC patients, but relevant studies are currently lacking. The present study sought to examine the effect of the SII index on the postoperative complications and long-term prognosis of patients with CRC. Methods: From January 2014 to January 2017, the data of 440 patients with CRC who had been admitted to the Affiliated Hospital of Guangdong Medical University were retrospectively collected, and the patients were equally divided into the high and the low SII groups according to their preoperative SII index levels. The postoperative complication rate and postoperative progression-free survival (PFS) and mortality between the 2 groups were compared. Results: Compared to the low SII group, the incidence of postoperative infection in the high SII group was significantly increased (15.45% vs. 9.09%, P=0.042), mortality was significantly increased at 5 years postoperatively (20.91% vs. 7.27%, P<0.001), and PFS was significantly shortened (P<0.001). The SII index had certain predictive value for postoperative infection in CRC patients, and the area under the curve (AUC) was 0.645 [95% confidence interval (CI): 0.559-0.731, P=0.001]. The SII index also had certain predictive value for the progression of CRC patients within 5 years of surgery, and the AUC was 0.670 (95% CI: 0.610-0.729, P<0.001). Additionally, the SII index had certain predictive value for death within 5 years of surgery in patients with CRC, and the AUC was 0.660 (95% CI: 0.593-0.726, P<0.001). CRC patients with postoperative infection had a significantly shorter PFS period than those who did not develop postoperative infection (P=0.029). Conclusions: The SII index has certain predictive value for the diagnosis of postoperative infectious complications and the long-term prognosis of CRC patients.

RacGAP1 promotes the malignant progression of cervical cancer by regulating AP-1 via miR-192 and p-JNK.

Cervical cancer (CC) is the most frequently diagnosed genital tract cancer in females worldwide. Rac GTPase-activating protein 1 (RacGAP1) is one of the specific GTPase-activating proteins. As a novel tumor protooncogene, overexpression of RacGAP1 was related to the occurrence of various tumors, but its function in CC is still unclear. In this study, bioinformatics analyses showed that RacGAP1 might be a key candidate gene in the progression of CC. RacGAP1 was significantly overexpressed in CC tissues. High RacGAP1 expression was positively associated with poor prognosis. Downregulating RacGAP1 significantly inhibited the proliferation, migration, and invasion of CC cells, while overexpressing RacGAP1 had the opposite effects. Further research showed that miR-192, which plays as a tumor suppressor in CC, was identified as a downstream target of RacGAP1 in CC cells. miR-192 inhibition could partially rescue the decrease in cell proliferation, migration, and invasion caused by RacGAP1 downregulation. In opposite, miR-192 overexpression could decrease the promotion of malignant progression caused by RacGAP1 upregulation. Mechanism studies revealed that RacGAP1 could regulate the expression and phosphorylation of c-Jun, which was the component of AP-1, via miR-192 and p-JNK separately. These findings suggested that RacGAP1 promoted tumorigenicity, migration, and invasion of CC. Therefore, it represented a potential novel prognostic marker in CC and may probably be a therapeutic target.

The Effector Protein CgNLP1 of Colletotrichum gloeosporioides Affects Invasion and Disrupts Nuclear Localization of Necrosis-Induced Transcription Factor HbMYB8-Like to Suppress Plant Defense Signaling.

Fungi secrete numerous effectors to modulate host defense systems. Understanding the molecular mechanisms by which fungal effectors regulate plant defense is of great importance for the development of novel strategies for disease control. In this study, we identified necrosis- and ethylene-inducing protein 1 (Nep1)-like protein (NLP) effector gene, CgNLP1, which contributed to conidial germination, appressorium formation, invasive growth, and virulence of Colletotrichum gloeosporioides to the rubber tree. Transient expression of CgNLP1 in the leaves of Nicotiana benthamiana induced ethylene production in plants. Ectopic expression of CgNLP1 in Arabidopsis significantly enhanced the resistance to Botrytis cinerea and Alternaria brassicicola. An R2R3 type transcription factor HbMYB8-like of rubber tree was identified as the target of CgNLP1.HbMYB8-like, localized on the nucleus, and induced cell death in N. benthamiana. CgNLP1 disrupted nuclear accumulation of HbMYB8-like and suppressed HbMYB8-like induced cell death, which is mediated by the salicylic acid (SA) signal pathway. This study suggested a new strategy whereby C. gloeosporioides exploited the CgNLP1 effector to affect invasion and suppress a host defense regulator HbMYB8-like to facilitate infection.

Efficacy and safety of angiogenesis inhibitors in melanoma: a meta-analysis of seven randomized controlled trials.

Little is known about the efficacy and safety of angiogenesis inhibitor therapy in patients with melanoma. The objective of this study was to assess the possible benefits and harms of angiogenesis inhibitor therapy in patients with melanoma. Electronic databases of PubMed and Web of Science were searched from inception to January 2020. Randomized controlled trials (RCTs) that investigated the efficacy and safety of angiogenesis inhibitor therapy in patients with melanoma were included. Primary outcomes were overall survival (OS) and progression-free survival (PFS), reported as hazard ratios (HRs). Secondary outcomes were disease control, objective response, and adverse events, reported as odds ratios (ORs), and trial sequential analysis (TSA) was also performed. We identified seven trials with 3185 patients. There was no significant difference in OS [HR, 0.99; 95% confidence interval (CI), 0.90-1.09] or PFS (HR, 0.91; 95% CI, 0.83-1.00) between the treatment groups. No significant effect of angiogenesis inhibitor therapy was identified on disease control (OR, 1.23; 95% CI, 0.97-1.55) or objective response (OR, 1.27; 95% CI, 0.99-1.62). TSA showed that the sample size for analysis of disease control was sufficient. Additionally, angiogenesis inhibitor therapy increased risks of hypertension, neurological symptoms, and diarrhea. Angiogenesis inhibitor therapy makes no significant improvement in OS or PFS in patients with melanoma and even causes an increased risk of important adverse events. Therefore, angiogenesis inhibitor therapy is not recommended for the treatment of melanoma.

The effect of flexible low-dose GnRH antagonist on pregnancy outcome in the fresh embryo transfer cycle of IVF-ET: a randomized controlled trial.

OBJECTIVE: To explore the practicality and effectiveness of a flexible low-dose protocol in the fresh embryo transfer cycle: reducing the total amount of antagonist by increasing the interval between administrations of Cetrotide. METHODS: A total of 211 patients with normal ovarian reserve who accepted GnRH-ant protocol for IVF-ET were selected, and they were randomized to the flexible low-dose antagonist group (test group, n = 101) or the conventional dose antagonist group (control group, n = 110). The initial dose of Cetrotide in the test group was 0.25 mg every other day, and then the dose was adjusted to 0.25 mg every day based on the subsequent luteinizing hormone (LH) levels. The dosage of Cetrotide in the control group was 0.25 mg per day. The primary outcome was the clinical pregnancy rate. Secondary outcomes included the incidence of premature LH rise, total dosage of Cetrotide, number of oocytes retrieved, number of fertilized oocytes, number of high-quality embryos, biochemical pregnancy rate and ongoing pregnancy rate. RESULTS: There was no significant difference in the general condition of the two groups. There was no significant difference in the clinical pregnancy rate (51.49% vs. 48.18%, p = 0.632) or the incidence of premature LH rise (18.81% vs. 15.45%, p = 0.584) between the two groups. However, the amount of Cetrotide used in the test group was significantly lower than that in the conventional dose antagonist group (1.13 ± 0.41 vs. 1.61 ± 0.59 mg, p < 0.001). CONCLUSION: The flexible low-dose antagonist protocol and the conventional dose antagonist protocol were equally effective in people with a normal ovarian reserve in the fresh embryo transfer cycle of IVF-ET.

Transcriptomics integrated with metabolomics reveals the effect of Bisphenol F (BPF) exposure on intestinal inflammation.

As a viable alternative to Bisphenol A (BPA), Bisphenol F (BPF) has been detected in humans at comparable concentrations and detection frequencies. Emerging evidence reveals that BPF induces intestinal toxicity. However, less information is available concerning BPF and its potential effects on intestinal inflammation, which has been associated with numerous disorders. The results from the present study showed that BPF exposure triggered lipopolysaccharide (LPS)-induced explosion of pro-inflammatory cytokines interleukin-17A (IL-17A), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) and impairment of the intestinal epithelial barrier by downregulating the expression of tight junction proteins Zonula Occludens-1 (ZO-1) and Claudin-1 (CLDN1) in normal colonic epithelial cells (NCM460). A multi-omics analysis integrating the transcriptomics with metabolomics revealed an altered transcripts and metabolites profile following BPF exposure. Correlation analysis indicated that RAS Guanyl Releasing Protein 2 (RASGRP2) and Phospholipase A2 Group IVE (PLA2G4E) were positively associated with the increased serotonin which was positively associated with the stimulated IFN-γ in BPF-treated NCM460 cells. Pyrogallol, pyridoxine, and N-acetylputrescine were positively associated with IL-17A levels. Collectively, the integrative analyses demonstrated an orchestrated coordination between the inflammatory response, transcriptomic, and metabolomics changes. Data presented herein provide evidence for the possible roles of BPF in the pathogenesis of intestinal inflammation. These results illustrate the advantages of using integrative analyses of high throughput datasets for characterizing the effects and mechanisms of toxicants.

Relationship Between Smoking and Pressure Injury Risk: A Systematic Review and Meta-Analysis.

BACKGROUND: Smoking is a risk factor for many diseases. PURPOSE: This study explored the relationship between current or past smoking and pressure injury (PI) risk through a systematic review and meta-analysis. METHODS: The databases PubMed, Web of Science, and China National Knowledge Infrastructure were searched for the years between 2001 and 2020. Quality of evidence was estimated by the Newcastle-Ottawa Scale. The random effects model was applied to assess the odds ratios (OR) and 95% confidence intervals (CI); pooled adjusted OR and 95% CI, subgroup analysis, publication bias, sensitivity analyses, and meta-regression analysis were performed. RESULTS: Fifteen (15) studies (12 retrospective and 3 prospective) comprising data on 11 304 patients were eligible for inclusion in the review. The meta-analysis demonstrated that smoking increased the risk of PI (OR = 1.498; 95% CI, 1.058-2.122), and the pooled adjusted OR (1.969) and 95% CI (1.406-2.757) confirmed this finding. Publication bias was not detected by funnel plot, Begg's test (P = .322), or Egger's test (P = .666). Subgroup analyses yielded the same observations in both retrospective (OR = 1.607; 95% CI, 1.043-2.475) and prospective (OR = 1.218; 95% CI, 0.735-2.017) studies. The results were consistent across sensitivity analyses (OR = 1.07; 95% CI, 1.043- 2.475). Relevant heterogeneity moderators were not identified by meta-regression analysis with PI incidence (P = .466), years of patient data included (P = .637), mean patient age (P = .650), and diabetes mellitus diagnosis (P = .509). CONCLUSION: This study found that individuals who are current or formers smokers have an almost 1.5 times higher risk of PI development than do those who do not smoke.

Perfluoroalkyl Substance Exposure and the BDNF Pathway in the Placental Trophoblast.

Background: Per- and polyfluoroalkyl substances (PFAS) are persistent organic pollutants that have become globally ubiquitous in humans and the environment. In utero PFAS exposure is associated with neurodevelopmental effects; however, the mechanism is poorly understood. Brain-derived neurotrophic factor (BDNF) signaling is critical to fetal neurodevelopment during pregnancy and maintains important regulatory roles later in life. This study aims to characterize placental BDNF signaling and investigate whether PFAS exposure disrupts the signaling pathway in placental trophoblast cells. Methods: The expression and localization of BDNF receptors-p75NTR and TrkB-in first trimester and term human placentas and trophoblast cells were investigated by immunofluorescence staining. To assess the effects of PFAS exposure on the BDNF pathway, BeWo cells were treated with PFAS mixtures that mimicked blood levels in a highly exposed population and major PFAS compounds in the mixture at 0.01, 0.1, 1, and 10 µM concentrations. Changes in pro-BDNF levels and phosphorylation of TrkB receptors were examined by Western blot. Results: In first trimester human placentas, TrkB and p75NTR receptors were primarily localized to syncytiotrophoblast and cytotrophoblast cells. At term, TrkB and p75NTR receptors were primarily observed in the placental villous stroma. TrkB receptor staining in trophoblasts was reduced at term, while p75NTR receptor staining was negative. TrkB receptors were confined to the nuclear and perinuclear spaces, and phosphorylation occurred at the Tyr816 residue in BeWo cells. Exposure to PFOS, PFOA, PFBS, and the six-PFAS mixture did not significantly affect BDNF levels or activation (phosphorylation) of TrkB. Treating cells with 1 µM and 10 µM of PFNA resulted in increased TrkB phosphorylation compared to unexposed controls, but BDNF levels were unchanged. Conclusions: BDNF receptors are present in different regions of human placental villi, indicating diverse functions of BDNF signaling in placental development. Our findings suggest that the BDNF pathway in placental trophoblast cells is not disrupted by exposures to PFOS, PFOA, PFBS, and a PFAS mixture, but may be affected by PFNA exposures. Further investigation is needed on how PFAS affects other critical signaling pathways during fetal neurodevelopment.

Interactions between gut microbiota and metabolites modulate cytokine network imbalances in women with unexplained miscarriage.

A dysregulation of cytokine networks has been suggested to be involved in the pathogenesis of unexplained pregnancy loss. Gut microbiota affects host immune response and induces an imbalance in cytokine levels. However, how gut microbial dysbiosis disturbs cellular immune function in miscarriage remains inconclusive. Here we report that IL-2, IL-17A, IL-17F, TNF-α, and IFN-γ are significantly increased in serum of miscarriage patients. Fecal microbiome analyses indicate that microbial diversity and the relative abundances of Prevotella_1, Prevotellaceae_UCG_003 and Selenomonas_1 are significantly reduced in the cases. Correlation analyses indicate that some microbe-associated metabolites are positively associated with changes in levels of Th1/Th17 cytokines in the miscarriage group. Moreover, we identify that imidazolepropionic acid and 1,4-methylimidazoleacetic acid are associated with subsequent recurrent miscarriage. Our study highlights the network among gut microbiota, fecal metabolites and Th1/Th17-mediated immune response in miscarriage patients and explores the potential predictive values of two fecal metabolites for recurrent miscarriages.

Exposure to perfluorobutane sulfonate and perfluorooctanesulfonic acid disrupts the production of angiogenesis factors and stress responses in human placental syncytiotrophoblast.

Poly- and per-fluoroalkyl substances (PFAS) have attracted widespread attention in recent years due to their bioaccumulation, toxicity, and ubiquitous nature. We and others have reported that maternal exposure to PFAS is associated with adverse birth outcomes due to altered placental functions. In this study, we investigated the effects of two major PFAS compounds, perfluorobutane sulfonate (PFBS) and perfluorooctanesulfonic acid (PFOS), on the regulation of the production of angiogenic factors and stress response in placental multinucleated syncytial BeWo cells using qRT-PCR and ELISA. Using this in vitro model, we showed that 1) PFOS or PFBS treatment did not seem to interrupt BeWo cell fusion through syncytins; 2) Exposure to PFOS at 10 µM decreased a potent angiogenic factor PlGF gene expression, which is implicated in preeclampsia; 3) Exposure to either PFOS or PFBS significantly decreased the production of CGB7 and hCG except hCG secretion in PFOS (10 nM) and PFBS (100 nM) treatment groups; 4) Exposure to PFOS (10 µM) increased the gene expression of the stress response molecules CRH while neither PFOS nor PFBS treatment affected a stress mitigation factor 11ß-HSD2 expression. Our results demonstrate that exposure to PFOS or PFBS impacts several key pathways involved in placental cell functions. PFOS seems more potent than PFBS. These novel findings provide a potential explanation for the adverse reproductive complications associated with prenatal exposure to PFOS or PFBS, including preeclampsia and contribute to our knowledge of the reproductive toxicity of PFAS, specifically PFOS and PFBS.

Perfluorobutane sulfonate exposure disrupted human placental cytotrophoblast cell proliferation and invasion involving in dysregulating preeclampsia related genes.

We reported that maternal PFBS, an emerging pollutant, exposure is positively associated with preeclampsia which can result from aberrant trophoblasts invasion and subsequent placental ischemia. In this study, we investigated the effects of PFBS on trophoblasts proliferation/invasion and signaling pathways. We exposed a human trophoblast line, HTR8/SVneo, to PFBS. Cell viability, proliferation, and cell cycle were evaluated by the MTS assay, Ki-67 staining, and flow cytometry, respectively. We assessed cell migration and invasion with live-cell imaging-based migration assay and matrigel invasion assay, respectively. Signaling pathways were examined by Western blot, RNA-seq, and qPCR. PFBS exposure interrupted cell proliferation and invasion in a dose-dependent manner. PFBS (100 µM) did not cause cell death but instead significant cell proliferation without cell cycle disruption. PFBS (10 and 100 µM) decreased cell migration and invasion, while PFBS (0.1 µM) significantly increased cell invasion but not migration. Further, RNA-seq analysis identified dysregulated HIF-1α target genes that are relevant to cell proliferation/invasion and preeclampsia, while Western Blot data showed the activation of HIF-1α, but not Notch, ERK1/2, (PI3K)AKT, and P38 pathways. PBFS exposure altered trophoblast cell proliferation/invasion which might be mediated by preeclampsia-related genes, suggesting a possible association between prenatal PFBS exposure and adverse placentation.

Two pairs of bisabolane sesquiterpenoid stereoisomers, bisacurone D-G, from the rhizome of Curcuma longa L.

Phytochemical investigation of an extract of the rhizome of Curcuma longa L., resulted in the identification of four undescribed bisabolane sesquiterpenoids, namely as bisacurone D-G (1-4). With the aid of comprehensive spectroscopic techniques (NMR, IR, UV, MS), the structures of all isolated compounds were elucidated and subsequently screened for both anti-inflammatory and cytotoxic biological activities, Compounds 1 and 2 showed moderate inhibitory activity toward LPS-induced NO production on RAW 264.7 macrophages.