CircTHBS1 promotes trophoblast cell migration and invasion and inhibits trophoblast apoptosis by regulating miR-136-3p/IGF2R axis.

The precise molecular mechanism behind fetal growth restriction (FGR) is still unclear, although there is a strong connection between placental dysfunction, inadequate trophoblast invasion, and its etiology and pathogenesis. As a new type of non-coding RNA, circRNA has been shown to play a crucial role in the development of FGR. This investigation identified the downregulation of hsa_circ_0034533 (circTHBS1) in FGR placentas through high-sequencing analysis and confirmed this finding in 25 clinical placenta samples using qRT-PCR. Subsequent in vitro functional assays demonstrated that silencing circTHBS1 inhibited trophoblast proliferation, migration, invasion, and epithelial mesenchymal transition (EMT) progression and promoted apoptosis. Furthermore, when circTHBS1 was overexpressed, cell function experiments showed the opposite result. Analysis using fluorescence in situ hybridization revealed that circTHBS1 was primarily found in the cytoplasmic region. Through bioinformatics analysis, we anticipated the involvement of miR-136-3p and IGF2R in downstream processes, which was subsequently validated through qRT-PCR and dual-luciferase assays. Moreover, the inhibition of miR-136-3p or the overexpression of IGF2R partially reinstated proliferation, migration, and invasion abilities following the silencing of circTHBS1. In summary, the circTHBS1/miR-136-3p/IGF2R axis plays a crucial role in the progression and development of FGR, offering potential avenues for the exploration of biological indicators and treatment targets.

Dysfunction of ZNF554 promotes ROS-induced apoptosis and autophagy in Fetal Growth Restriction via the p62-Keap1-Nrf2 pathway.

Fetal growth restriction (FGR) is one of the most common complications of an abnormal pregnancy. Placental dysplasia has been established as a significant contributing factor to FGR. Zinc finger protein 554 (ZNF554) is a member of the Krüppel-associated box domain zinc finger protein subfamily, primarily expressed in the placenta and essential for maintaining normal pregnancy outcomes. However, its precise role in FGR remains uncertain. In this study, we confirmed that ZNF554 was low expressed in the placenta of the FGR pregnancy. To further elucidate the impact of ZNF554 on trophoblasts, we conducted experiments using siRNA and overexpression plasmids on HTR8/SVneo and JEG3 cells. Our findings revealed that silencing ZNF554 increased apoptosis and inhibited migration and invasion, while overexpression reduced apoptosis and promoted migration and invasion. Notably, ZNF554 knockdown decreased cellular antioxidant capacity and elevated the production of reactive oxygen species (ROS). Conversely, ZNF554 activated the nuclear factor E2-related factor 2 (NRF2) signaling pathway, exerting its antioxidant effects. Additionally, ZNF554 knockdown promoted cellular autophagy by suppressing P62 and enhancing LC3-II/LC3-I expression. Importantly, the antioxidant N-acetylcysteine (NAC) partially mitigated the impact of ZNF554 knockdown on mitochondrial ROS in trophoblast cells and subsequent effects on cellular autophagy and apoptosis. In conclusion, our results suggest that ZNF554 plays a pivotal role in modulating trophoblast cell invasion and may serve as a prognostic marker and potential therapeutic target for FGR.

Effects of High Pharmaceutical Concentrations in Domestic Wastewater on Membrane Bioreactor Treatment Systems: Performance and Microbial Community.

Despite pharmaceuticals being widely detected in water-bodies worldwide, what remain unclear are the effects of high pharmaceutical concentrations on the treatment efficiency of biological wastewater treatment processes, such as membrane bioreactor (MBR) systems. This study investigated the efficiency of MBR technology in the treatment of synthetic wastewater containing a mixture of five typical pharmaceuticals (ofloxacin, sulfamethoxazole, sulfamethylthiadiazole, carbamazepine and naproxen) with a total concentration of 500 µg/L. Both the control MBR (MBRc) without pharmaceutical dosing and the MBR operated with high influent pharmaceutical concentrations (MBRe) were operated under room temperature with the same hydraulic retention time of 11 h and the same sludge retention time of 30 d. The removal efficiency rates of total nitrogen and total phosphorus were 83.2% vs. 90.1% and 72.6% vs. 57.8% in the MBRc vs. MBRe systems, and both MBRs achieved >98% removal of organics for a 180-day period. The floc size decreased, and membrane fouling became more severe in the MBRe system. Microbial diversity increased in the MBRe system and the relative abundances of functional microbe differed between the two MBRs. Furthermore, the total relative abundances of genes involved in glycolysis, assimilating nitrate reduction and nitrification processes increased in the MBRe system, which could account for the higher organics and nitrogen removal performance. This work provides insights for MBR operation in wastewater treatment with high pharmaceutical concentrations.

LncRNA DANCR deficiency promotes high glucose-induced endothelial to mesenchymal transition in cardiac microvascular cells via the FoxO1/DDAH1/ADMA signaling pathway.

Cardiac fibrosis is the main pathological basis of diabetic cardiomyopathy (DCM), and endothelial-to-meschenymal transition (EndMT) is a key driver to cardiac fibrosis and plays an important role in the pathogenesis of DCM. Asymmetric dimethylarginine (ADMA), a crucial pathologic factor in diabetes mellitus, is involved in organ fibrosis. This study aims to evaluate underlying mechanisms of ADMA in DCM especially for EndMT under diabetic conditions. A diabetic rat model was induced by streptozotocin (STZ) injection, and human cardiac microvascular endothelial cells (HCMECs) were stimulated with high glucose to induce EndMT. Subsequently, the role of ADMA in EndMT was detected either by exogenous ADMA or by over-expressing dimethylarginine dimethylaminohydrolase 1 (DDAH1, degradation enzyme for ADMA) before high glucose stimulation. Furthermore, the relationships among forkhead box protein O1 (FoxO1), DDAH1 and ADMA were evaluated by FoxO1 over-expression or FoxO1 siRNA. Finally, we examined the roles of LncRNA DANCR in FoxO1/DDAH1/ADMA pathway and EndMT of HCMECs. Here, we found that EndMT in HCMECs was induced by high glucose, as evidenced by down-regulated expression of CD31 and up-regulated expression of FSP-1 and collagen Ⅰ. Importantly, ADMA induced EndMT in HCMECs, and over-expressing DDAH1 protected from developing EndMT by high glucose. Furthermore, we demonstrated that over-expression of FoxO1-ADA with mutant phosphorylation sites of T24A, S256D, and S316A induced EndMT of HCMECs by down-regulating of DDAH1 and elevating ADMA, and that EndMT of HCMECs induced by high glucose was reversed by FoxO1 siRNA. We also found that LncRNA DANCR siRNA induced EndMT of HCMECs, activated FoxO1, and inhibited DDAH1 expression. Moreover, over-expression of LncRNA DANCR could markedly attenuated high glucose-mediated EndMT of HCMECs by inhibiting the activation of FoxO1 and increasing the expression of DDAH1. Collectively, our results indicate that LncRNA DANCR deficiency promotes high glucose-induced EndMT in HCMECs by regulating FoxO1/DDAH1/ADMA pathway.

Connexin 43 Promotes Neurogenesis via Regulating Aquaporin-4 after Cerebral Ischemia.

We aimed to test the effects of connexin43 (Cx43) on ischemic neurogenesis and examined whether it was dependent on aquaporin-4 (AQP4). We detected the expression of Cx43 and AQP4 in the ipsilateral subventricular zone (SVZ) and peri-infarct cortex after middle cerebral artery occlusion (MCAO). Also, we examined neurogenesis in the above regions via co-labeling of 5-bromo-2-deoxyuridine (BrdU)/neuronal nuclear antigen (NeuN) and BrdU/doublecortin (DCX). The effects of Cx43 and AQP4 were investigated by using two transgenic animals: heterozygous Cx43 (Cx43±) mice and AQP4 knockout (AQP4-/-) mice, and connexin mimetic peptide (CMP), a selective Cx43 blocker. We demonstrated AQP4 and Cx43 were co-expressed in the astrocytes after MCAO and the expression was highly increased in ipsilateral SVZ and peri-infarct cortex. Cx43± mice had larger infarction volumes and worse neurological function. Both BrdU/NeuN and BrdU/DCX co-labeled cells in the two regions were reduced in Cx43± and AQP4-/- mice compared to wild-type (WT) mice, suggesting Cx43 and AQP4 participated in neurogenesis of neural stem cells. Moreover, CMP decreased AQP4 expression and inhibited neurogenesis in WT mice, while the latter failed to be observed in AQP4-/- mice. Besides, higher levels of IL-1ß and TNF-α were detected in the SVZ and peri-infarct cortex of AQP4-/- and Cx43± mice than those in WT mice. In conclusion, our data suggest that Cx43 elicits neuroprotective effects after cerebral ischemia through promoting neurogenesis in the SVZ to regenerate the injured neurons, which is AQP4 dependent and associated with down-regulation of inflammatory cytokines IL-1ß and TNF-α.

Inflammatory score predicts early hematoma expansion and poor outcomes in patients with intracerebral hemorrhage.

BACKGROUND: This study aimed to develop a prediction score named inflammatory score based on proper integration of several inflammatory markers and investigate whether it was associated with hematoma expansion and poor outcomes in patients with intracerebral hemorrhage (ICH). METHODS: This study involved a consecutive series of spontaneous ICH patients of two cohorts admitted within 24 hours after symptom onset. Inflammatory score (0-9) was developed with the combination of neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, systemic immune-inflammation index, lactate dehydrogenase, and C-reactive protein. The authors investigated the association between inflammatory score and hematoma expansion and poor outcomes by using univariate and multivariate logistic regression analyses. The optimal cutoff point of inflammatory score was determined by receiver operating characteristic analysis in the development cohort and then validated. RESULTS: A total of 301 and 154 ICH patients were enrolled in the development and validation cohorts. Inflammatory score was significantly higher in patients with hematoma expansion and poor outcomes. The multivariate logistic regression analysis revealed inflammatory score was independently associated with hematoma expansion, secondary neurological deterioration within 48 hours, 30-day mortality, and 3-month poor modified Rankin scale (4-6). The diagnostic accuracy of inflammatory score exhibited by area under the curve showed numerically or statistically higher than most of the individual indicators. Moreover, inflammatory score greater than or equal to 5 was selected as the optimal cutoff point, which was further prospectively validated with high diagnostic accuracy. CONCLUSIONS: The inflammatory score is a reliable predictor for early hematoma expansion and short-term and long-term poor outcomes with good diagnostic accuracies in ICH patients.

Fecal microbiota from MRL/lpr mice exacerbates pristane-induced lupus.

BACKGROUND: The roles of gut microbiota in the pathogenesis of SLE have been receiving much attention during recent years. However, it remains unknown how fecal microbiota transplantation (FMT) and microbial metabolites affect immune responses and lupus progression. METHODS: We transferred fecal microbiota from MRL/lpr (Lpr) mice and MRL/Mpj (Mpj) mice or PBS to pristane-induced lupus mice and observed disease development. We also screened gut microbiota and metabolite spectrums of pristane-induced lupus mice with FMT via 16S rRNA sequencing, metagenomic sequencing, and metabolomics, followed by correlation analysis. RESULTS: FMT from MRL/lpr mice promoted the pathogenesis of pristane-induced lupus and affected immune cell profiles in the intestine, particularly the plasma cells. The structure and composition of microbial communities in the gut of the FMT-Lpr mice were different from those of the FMT-Mpj mice and FMT-PBS mice. The abundances of specific microbes such as prevotella taxa were predominantly elevated in the gut microbiome of the FMT-Lpr mice, which were positively associated with functional pathways such as cyanoamino acid metabolism. Differential metabolites such as valine and L-isoleucine were identified with varied abundances among the three groups. The abundance alterations of the prevotella taxa may affect the phenotypic changes such as proteinuria levels in the pristane-induced lupus mice. CONCLUSION: These findings further confirm that gut microbiota play an important role in the pathogenesis of lupus. Thus, altering the gut microbiome may provide a novel way to treat lupus.

The association of subjective sleep characteristics and plasma biomarkers of Alzheimer's disease pathology in older cognitively unimpaired adults with higher amyloid-ß burden.

We aimed to investigate the association of subjective sleep characteristics and plasma Alzheimer's disease (AD) biomarkers in older cognitively unimpaired adults with higher amyloid-ß (Aß) burden. Unimpaired cognition was determined by education-adjusted performance for the Mini-Mental State Examination and exclusion of dementia and mild cognitive impairment via standardized neuropsychological tests. We used Pittsburgh Sleep Quality Index (PSQI) to assess subjective sleep quality. The participants also underwent examination of plasma AD biomarkers and 18F-florbetapir PET scan. Correlation and multiple linear regression analyses were used to investigate the association between subjective sleep characteristics and AD biomarkers. A total of 335 participants were included and 114 were Aß-PET positive. Multivariable regression analysis showed sleep duration > 8 h and sleep disturbance were associated with Aß deposition in total participants. Two multiple linear regression models were applied and the results revealed in participants with Aß-PET (+), falling asleep at ≥ 22:00 to ≤ 23:00 was associated with higher levels of Aß42 and Aß42/40. Other associations with higher Aß42/40 and standard uptake value ratio contained sleep efficiency value, sleep efficiency ≥ 75%, no/mild daytime dysfunction and PSQI score ≤ 5. Higher p-Tau-181 level was associated with sleep latency > 30 min in Aß-PET (+) group and moderate/severe sleep disturbance in Aß-PET (-) group. Our data suggests sleep duration ≤ 8 h and no/mild sleep disturbance may be related to less Aß burden. In participants with Aß deposition, falling asleep at 22:00 to 23:00, higher sleep efficiency (at least ≥ 75%), no/mild daytime dysfunction, sleep latency ≤ 30 min, and good sleep quality may help improve AD pathology.

6-O-desulfated heparin attenuates myocardial ischemia/reperfusion injury in mice through the regulation of miR-199a-5p/klotho axis.

Heparin has been documented to reduce myocardial injury caused by ischemia/reperfusion (I/R), but its clinical application is limited due to its strong intrinsic anticoagulant property. Some desulfated derivatives of heparin display low anticoagulant activity and may have potential value as therapeutic agents for myocardial I/R injury. In this study, we observed that 6-O-desulfated heparin, a desulfated derivative of heparin, shortened the activated partial thromboplastin time and exhibited lower anticoagulant activity compared with heparin or 2-O-desulfated heparin (another desulfated derivative of heparin). Then, we explored whether 6-O-desulfated heparin could protect against myocardial I/R injury, and elucidated its possible mechanisms. Administration of 6-O-desulfated heparin significantly reduced creatine kinase activity, myocardial infarct size and cell apoptosis in mice subjected to 30 min of myocardial ischemia following 2 h of reperfusion, accompanied by a reverse in miR-199a-5p elevation, klotho downregulation and reactive oxygen species (ROS) accumulation. In cultured H9c2 cells, the mechanism of 6-O-desulfated heparin against myocardial I/R injury was further explored. Consistent with the results in vivo, 6-O-desulfated heparin significantly ameliorated hypoxia/reoxygenation-induced injury, upregulated klotho and decreased miR-199a-5p levels and ROS accumulation, and these effects were reversed by miR-199a-5p mimics. In conclusion, these results suggested that 6-O-desulfated heparin with lower anticoagulant activity attenuated myocardial I/R injury through miR-199a-5p/klotho and ROS signaling. Our study may also indicate that 6-O-desulfated heparin, as an excellent heparin derivative, is a potential therapeutic agent for myocardial I/R injury.

Association of Serum Pyridoxal-5'-Phosphate, Pyridoxal, and PAr with Colorectal Cancer Risk: A Large-Scale Case-Control Study.

Previous epidemiological studies have focused on the association of dietary vitamin B6 or circulating pyridoxal-5'-phosphate (PLP) with colorectal cancer risk. This study aimed to investigate the vitamin B6 in relation to colorectal cancer risk combining the biomarkers of PLP, pyridoxal (PL) plus PLP, and PAr (the ratio of 4-pyridoxic acid over the sum of PLP and PL). A large-scale hospital-based case-control study was conducted in Guangdong Province, China, which included 1233 colorectal cancer cases and 1245 sex and age frequency-matched controls. Serum PLP, PL, and 4-pyridoxic acid (PA) were detected with ultra-high-performance liquid chromatography−tandem mass spectrometry. Unconditional logistic regression models were used to assess the odds ratios (ORs) and 95% confidence intervals (95% CIs). Serum PLP and the sum of PLP and PL were inversely associated with colorectal cancer risk, while PAr was positively associated with colorectal cancer risk. Comparing the highest with the lowest quartile, the adjusted OR (95% CI) was 0.26 (0.20−0.33, Ptrend < 0.001) for serum PLP, 0.51 (0.40−0.66, Ptrend < 0.001) for serum PLP plus PL, and 2.90 (2.25−3.75, Ptrend < 0.001) for PAr. Serum PLP and PAr had significantly stronger associations with colorectal cancer risk in the male group and smoking group. Our results supported the protective role of vitamin B6 in colorectal cancer risk among Chinese people. The positive association of PAr with colorectal cancer risk suggested the potential role of inflammation and oxidative stress in colorectal carcinogenesis.

Aquaporin-4 and Cognitive Disorders.

Aquaporin-4 (AQP4) is the most abundantly expressed aquaporin in the central nervous system (CNS) and is an integral part of the glymphatic system that cannot be ignored. The CNS has the glymphatic system instead of the conventional lymphatic system. The glymphatic system plays an essential role in the pathophysiological processes of many cognitive disorders. AQP4 shows noteworthy changes in various cognitive disorders and is part of the pathogenesis of these diseases. For this reason, AQP4 has attracted attention as a potential and promising target for regulating and even reversing cognitive dysfunction. This review will summarize the role of AQP4 in the pathophysiological processes of several cognitive disorders as reported in recent studies.

The stress hyperglycemia ratio predicts early hematoma expansion and poor outcomes in patients with spontaneous intracerebral hemorrhage.

BACKGROUND: Different from diabetic hyperglycemia, stress-induced hyperglycemia (SIH) can better reflect elevated blood glucose owing to intracerebral hemorrhage (ICH). However, studies about the outcome of ICH patients with SIH are still very limited. AIMS: This study aimed to investigate whether SIH measured by stress-induced hyperglycemia ratio (SHR) was associated with hematoma expansion and poor outcomes in patients with ICH. METHODS: A consecutive series of patients with spontaneous ICH from two clinical centers admitted within 24 h after symptom onset were enrolled for prospective analysis. SHR was defined as admission fasting blood glucose divided by estimated average glucose [1.59 × Hemoglobin A1c (%) - 2.59]. This study investigated the association between SHR and hematoma expansion, and short-term and long-term poor outcomes using univariate and multivariate logistic regression analyses. RESULTS: A total of 313 ICH patients were enrolled in the study. SHR was markedly higher in patients with hematoma expansion and poor outcomes (p < 0.001). The multivariate logistic regression analysis demonstrated SHR independently associated with hematoma expansion (p < 0.001) and poor outcomes, including secondary neurological deterioration within 48 h, 30-day mortality, and 3-month poor modified Rankin Scale (mRS 4-6) (p < 0.001), while the blood glucose only predicted 30-day mortality. Meanwhile, the diagnostic accuracy of SHR exhibited by area under the curve in receiver operating characteristic analysis was statistically equal to or higher than the well-known predictors. CONCLUSION: SHR is a reliable predictor for early hematoma expansion and poor outcomes in patients with ICH.

Educational level and colorectal cancer risk: the mediating roles of lifestyle and dietary factors.

OBJECTIVE: The association between the educational level and colorectal cancer risk was controversial in developed countries and evidence was limited in Chinese population. This study aimed to investigate the association between the educational level and colorectal cancer risk in Guangdong Province, China. METHODS: From July 2010 to April 2019, 2502 newly diagnosed colorectal cancer patients and 2538 sex- and age-matched controls were recruited in this case-control study. Multivariable logistic regression models were used to examine the association between the educational level and colorectal cancer risk. Path analysis was used to investigate whether behavioral risk factors potentially mediated the association between the educational level and colorectal cancer risk. RESULTS: Educational level was inversely associated with the colorectal cancer risk. People who graduated from the college or above had a lower risk of colorectal cancer than those from the primary school or below, with an adjusted odds ratio of 0.42 [95% confidence intervals (CI), 0.34-0.52]. The total, direct and indirect effects of the educational level for the colorectal cancer risk were statistically significant in the path diagram. Path analysis showed that lower red and processed meat intake and higher tea and coffee drinking among high educational participants contributed to the inverse association between the educational level and colorectal cancer risk. CONCLUSION: The findings suggested that the educational level was inversely associated with the colorectal cancer risk. The association might be mediated by red and processed meat intake, household and leisure-time activities, and tea and coffee drinking.

Peptide5 Attenuates rtPA Related Brain Microvascular Endothelial Cells Reperfusion Injury via the Wnt/ß-Catenin Signalling Pathway.

AIMS: Brain vascular endothelial cell dysfunction after rtPA treatment is a significant factor associated with poor prognosis, suggesting that alleviation of rtPA-related endothelial cell injury may represent a potential beneficial strategy along with rtPA thrombolysis. BACKGROUND: Thrombolysis with recombinant tissue plasminogen activator (rtPA) is beneficial for acute ischemic stroke but may increase the risk of Hemorrhagic Transformation (HT), which is considered ischemia-reperfusion injury. The underlying reason may contribute to brain endothelial injury and dysfunction related to rtPA against ischemic stroke. As previous studies have demonstrated that transiently blocked Cx43 using peptide5 (Cx43 mimetic peptide) during retinal ischemia reduced vascular leakage, it is necessary to know whether this might help decrease side effect of rtPA within the therapeutic time window. OBJECTIVE: This study aims to investigate the effects of peptide5 on rtPA-related cell injury during hypoxia/reoxygenation (H/R) within the therapeutic time window. METHODS: In this study, we established a cell hypoxia/reoxygenation H/R model in cultured primary Rat Brain Microvascular Endothelial Cells (RBMECs) and evaluated endothelial cell death and permeability after rtPA treatment with or without transient peptide5. In addition, we also investigated the potential signaling pathway to explore the underlying mechanisms preliminarily. RESULTS: The results showed that peptide5 inhibited rtPA-related endothelial cell death and permeability. It also slightly increased tight junction (ZO-1, occluding, claudin-5) and ß-catenin mRNA expression, demonstrating that peptide5 might attenuate endothelial cell injury by regulating the Wnt/ ß-catenin pathway. The following bioinformatic exploration from the GEO dataset GSE37239 was also consistent with our findings. CONCLUSION: This study showed that the application of peptide5 maintained cell viability and permeability associated with rtPA treatment, revealing a possible pathway that could be exploited to limit rtPA-related endothelial cell injury during ischemic stroke. Furthermore, the altered Wnt/ß- catenin signaling pathway demonstrated that signaling pathways associated with Cx43 might have potential applications in the future. This study may provide a new way to attenuate HT and assist the application of rtPA in ischemic stroke.

Involvement of miR-199a-3p/DDR1 in vascular endothelial cell senescence in diabetes.

Endothelial cell dysfunction is a prominent feature of diabetic cardiovascular complications, and endothelial cell senescence is considered to be an important contributor to endothelial dysfunction. Discoidin domain receptor 1 (DDR1) has been reported to be involved in atherogenesis and cerebral ischemia/reperfusion injury. In this study, we aimed to explore the role of DDR1 in endothelial cell senescence under diabetic conditions and elucidate the underlying mechanisms. A diabetic rat model was established by a single intraperitoneal injection of streptozocin (STZ) (60 mg/kg), which showed an increase in senescence-associated ß-galactosidase (SA-ß-gal) staining signal of thoracic aortic endothelium, impaired vascular structure and function, accompanied by an up-regulation of DDR1. Next, we verified the role of DDR1 in endothelial senescence and the underlying mechanisms in high glucose-treated human umbilical vein endothelial cells (HUVECs). Consistent with the in vivo findings, high glucose induced endothelial senescence, impaired endothelial function and elevated DDR1 expression, accompanied by the elevation of senescence-related genes p53 and p21 expression, and these effects were reversed by DDR1 siRNA. DDR1 has been documented to be a potential target of miR-199a-3p. Here, we found that miR-199a-3p was down-regulated by high glucose in the aorta tissue and HUVECs, while miR-199a-3p mimic significantly suppressed increased endothelial senescence and elevated DDR1 induced by high glucose. In conclusion, our data demonstrated that miR-199a-3p/DDR1/p53/p21 signaling pathway was involved in endothelial senescence under diabetic conditions, and therapeutic targeting DDR1 would be exploited to inhibit endothelial senescence owing to high glucose exposure.

The deubiquitinating enzyme USP15 stabilizes ERα and promotes breast cancer progression.

Breast cancer has the highest incidence and mortality in women worldwide. There are 70% of breast cancers considered as estrogen receptor α (ERα) positive. Therefore, the ERα-targeted therapy has become one of the most effective solution for patients with breast cancer. Whereas a better understanding of ERα regulation is critical to shape evolutional treatments for breast cancer. By exploring the regulatory mechanisms of ERα at levels of post-translational modifications, we identified the deubiquitinase USP15 as a novel protector for preventing ERα degradation and a critical driver for breast cancer progression. Specifically, we demonstrated that USP15 promoted the proliferation of ERα+, but not ERα- breast cancer, in vivo and in vitro. Meanwhile, USP15 knockdown notably enhanced the antitumor activities of tamoxifen on breast cancer cells. Importantly, USP15 knockdown induced the downregulation of ERα protein via promoting its K48-linked ubiquitination, which is required for proliferative inhibition of breast cancer cells. These findings not only provide a novel treatment for overcoming resistance to endocrine therapy, but also represent a therapeutic strategy on ERα degradation by targeting USP15-ERα axis.

Iron intake with the risk of breast cancer among Chinese women: a case-control study.

OBJECTIVE: The current study evaluated the associations between different forms and sources of Fe and breast cancer risk in Southern Chinese women. DESIGN: Case-control study. We collected data on the consumption of Fe from different forms and food sources by using a validated FFQ. Multivariable logistic regression and restricted cubic spline (RCS) analysis was used to reveal potential associations between Fe intake and breast cancer risk. SETTING: A case-control study of women at three major hospitals in Guangzhou, China. PARTICIPANTS: From June 2007 to March 2019, 1591 breast cancer cases and 1622 age-matched controls were recruited. RESULTS: In quartile analyses, Fe from plants and Fe from white meat intake were inversely associated with breast cancer risk, with OR of 0·65 (95 % CI 0·47, 0·89, Ptrend = 0·006) and 0·76 (95 % CI 0·61, 0·96, Ptrend = 0·014), respectively, comparing the highest with the lowest quartile. No associations were observed between total dietary Fe, heme or non-heme Fe, Fe from meat or red meat and breast cancer risk. RCS analysis demonstrated J-shaped associations between total dietary Fe, non-heme Fe and breast cancer, and reverse L-shaped associations between heme Fe, Fe from meat and Fe from red meat and breast cancer. CONCLUSION: Fe from plants and white meat were inversely associated with breast cancer risk. Significant non-linear J-shaped associations were found between total dietary Fe, non-heme Fe and breast cancer risk, and reverse L-shaped associations were found between heme Fe, Fe from meat or red meat and breast cancer risk.

Serum isoflavones and lignans and odds of breast cancer in pre- and postmenopausal Chinese women.

OBJECTIVE: Isoflavones and lignans are phytoestrogens present in plant-based foods, which have a potential preventive effect on breast carcinogenesis. The effects of phytoestrogens on breast cancer may differ according to the hormonal environment. This case-control study aimed to investigate the association between serum phytoestrogens and odds of breast cancer among Chinese pre- and postmenopausal women. METHODS: A total of 792 cases and 813 age-matched controls were included. Serum isoflavone (daidzein, genistein, glycitein, equol, and formononetin) and lignan (enterodiol and enterolactone) concentrations were measured using a liquid chromatography-tandem mass spectrometry method. RESULTS: Significant inverse associations were found between serum total soy isoflavone precursors, daidzein, genistein, formononetin, total lignans, enterodiol, enterolactone, and the odds of breast cancer in premenopausal but not postmenopausal women. For premenopausal women, the adjusted odds ratios (95% confidence intervals) for the highest versus the lowest serum concentration groups were 0.60 (0.41-0.87) for total soy isoflavones precursors, 0.64 (0.44-0.93) for daidzein, 0.62 (0.43-0.90) for genistein, 0.49 (0.35-0.68) for formononetin, 0.38 (0.25-0.57) for total lignans, 0.49 (0.33-0.73) for enterodiol, and 0.49 (0.33-0.74) for enterolactone. However, the interaction between serum phytoestrogens and menopausal status on odds of breast cancer was statistically significant only for daidzein. No significant association was found between serum equol or gycitein and the odds of breast cancer among either pre- or postmenopausal women. CONCLUSIONS: Higher levels of certain serum isoflavones and lignans were associated with reduced odds of breast cancer in premenopausal women, but the interaction was statistically significant only for daidzein.

Rapid electrochemical reduction of a typical chlorinated organophosphorus flame retardant on copper foam: degradation kinetics and mechanisms.

With the widespread use, chlorinated organophosphorus flame retardants (Cl-OPFRs) as a new emerging contaminant have been widely detected in water environments over the last few years. In this study, the degradation of a typical Cl-OPFR, TCEP (tris (2-chloroethyl) phosphate), by electrochemical reduction was investigated. It was found that copper (Cu) foam as the cathode showed more rapid and effective degradation for TCEP, compared to other cathodes. When TCEP was at the low concentrations (0.1 and 1 mg L-1), its degradation by Cu foam could reach above 95% within 20 min, and the maximum rate constant was 0.127 min-1. TCEP reduction was little influenced by the co-existing humic substance and anions, except Cl-. Compared with the reported oxidation methods, electrochemical reduction showed fast and stable degradation for TCEP. For other types of Cl-OPFRs, electrochemical reduction displayed a fast and effective removal for tris (1,3-dichloro-2-propyl) phosphate but lower removal for tris (2-cholroisopropyl) phosphate who possessed methyl units in the branched chains, influencing its reducibility. Based on the product analysis and Fukui function calculation, the bonds of TCEP molecule were found to be gradually broken, and the three oxygen-ethyl-chlorine arms were cleaved one by one. The products including C6H13Cl2O4P (MW = 249.99278 Da), C4H9Cl2O4P (MW = 221.96105 Da) and C4H10ClO4P (MW = 188.0002 Da) were detected at 60 min reaction, and those intermediates showed much lower toxicities than TCEP according to the previous report. The findings may provide a promising treatment for Cl-OPFRs removal from aqueous environments and help understand their reductive fate.