Hepatocyte Aquaporin 8-mediated Water Transport Facilitates Bile Dilution and Prevents Gallstone Formation in Mice.

BACKGROUND AND AIMS: Although water channel aquaporin-8 (AQP8) has been implicated in hepatic bile formation and liver diseases associated with abnormal bile flow in human and animal studies, direct evidence of its involvement in bile secretion is still lacking. This study aimed to determine the role of AQP8 in bile secretion and gallstone formation. METHODS: We generated various transgenic knock-in and knockout mouse models and assessed liver AQP8 expression by immunostaining and immunoblotting, hepatic bile secretion by cannulation of the common bile duct, cholesterol gallstone formation by feeding a high-fat lithogenic diet, and identified regulatory small molecules by screening the organic fractions of cholagogic Chinese herbs and biochemical characterization. RESULTS: We identified a novel expression pattern of AQP8 protein in the canalicular membrane of approximately 50% of the liver lobules. AQP8-deficient mice exhibited impaired hepatic bile formation, characterized by the secretion of concentrated bile with a lower flow rate and higher levels of bile lipids than that of wild-type littermates. AQP8-/- mice showed accelerated gallstone formation, which was rescued by AAV-mediated hepatic expression of AQP8 or AQP1. Moreover, we identified a small molecule, scutellarin, that upregulates hepatocyte AQP8 expression in vitro and in vivo. In AQP8+/+ mice, scutellarin significantly increased bile flow, decreased bile lipid concentrations, and prevented gallstone formation compared to AQP8-/- mice. Molecular studies revealed that scutellarin promoted the ubiquitination and degradation of HIF-1α, a transcriptional negative regulator of AQP8, by disrupting its interactions with HSP90. CONCLUSIONS: AQP8 plays a crucial role in facilitating water transport and bile dilution during hepatic bile formation, thereby mitigating gallstone formation in mice. Small-molecule intervention validated hepatocyte AQP8 as a promising drug target for gallstone therapy. IMPACT AND IMPLICATIONS: The incidence of gallstone disease is high, and current drug treatments for gallstones are very limited, necessitating the identification of novel drug targets for developing new drugs with universal applicability. To our knowledge, this is the first study to provide direct evidence that hepatic water channel AQP8 plays a key role in bile dilution and gallstone formation. Modulation of hepatic water transport may provide a universal therapeutic strategy for all types of gallstone diseases.

METTL3 depletion contributes to tumour progression and drug resistance via N6 methyladenosine-dependent mechanism in HR+HER2-breast cancer.

BACKGROUND: Chemotherapy is an important strategy for the treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+HER2-) breast cancer (BC), but this subtype has a low response rate to chemotherapy. Growing evidence indicates that N6-methyladenosine (m6A) is the most common RNA modification in eukaryotic cells and that methyltransferase-like 3 (METTL3) participates in tumour progression in several cancer types. Therefore, exploring the function of METTL3 in HR+HER2- BC initiation and development is still important. METHODS: mRNA and protein expression levels were analysed by quantitative real-time polymerase chain reaction and western blotting, respectively. Cell proliferation was detected by CCK-8 and colony formation assays. Cell cycle progression was assessed by flow cytometry. Cell migration and invasion were analysed by wound healing assays and transwell assays, respectively, and apoptosis was analysed by TUNEL assays. Finally, m6A modification was analysed by methylated RNA immunoprecipitation. RESULTS: Chemotherapy-induced downregulation of the m6A modification is regulated by METTL3 depletion in HR+HER2- BC. METTL3 knockdown in MCF-7/T47D cells decreased the drug sensitivity of HR+HER2- BC cells by promoting tumour proliferation and migration and inhibiting apoptosis. Mechanistically, CDKN1A is a downstream target of METTL3 that activates the AKT pathway and promotes epithelial-mesenchymal transformation (EMT). Moreover, a decrease in BAX expression was observed when m6A modification was inhibited with METTL3 knockdown, and apoptosis was inhibited by the reduction of caspase-3/-9/-8. CONCLUSION: METTL3 depletion promotes the proliferation and migration and decreases the drug sensitivity of HR+HER2- BC via regulation of the CDKN1A/EMT and m6A-BAX/caspase-9/-3/-8 signalling pathways, which suggests METTL3 played a tumour-suppressor role and it could be a potential biomarker for predicting the prognosis of patients with HR+HER2- BC.

Cytotoxic diterpenoid dimer containing an intricately caged core from Euphorbia fischeriana.

Bislangduoids A and B, a novel class of dimeric diterpenoids based on ent-abietanes tethered by C-17-C-15' bridge, were identified as trace components from a traditional Chinese medicine Euphorbia fischeriana (Langdu). Bislangduoid A features a highly oxidized scaffold incorporating a cage-like pentacyclic core. Their structures were elucidated by extensive spectroscopic techniques, electronic circular dichroism, and NMR calculations. The biosynthetic pathway for the dimeric skeleton and the unique caged moiety via Michael and acetal-formation reactions was proposed. Bislangduoid A showed pronounced cytotoxicity against HepG2 cells through the mitochondria-dependent apoptosis pathway.

Physical modelling of energy losses at surcharged three-way junction manholes in drainage system.

Motivated by the observation that vortex flow structure was evident in the energy loss at the surcharged junction manhole due to changes of hydraulic and geometrical parameters, a physical model was used to calculate energy loss coefficients and investigate the relationship between flow structure and energy loss at the surcharged three-way junction manhole. The effects of the flow discharge ratio, the connected angle between two inflow pipes, the manhole geometry, and the downstream water depth on the energy loss were analyzed based on the quantified energy loss coefficients and the identified flow structure. Moreover, two empirical formulae for head loss coefficients were validated by the experimental data. Results indicate that the effect of flow discharge ratio and connected angle are significant, while the effect of downstream water depth is not obvious. With the increase of the lateral inflow discharge, the flow velocity distribution and vortex structure are both enhanced. It is also found that a circular manhole can reduce local energy loss when compared to a square manhole. In addition, the tested empirical formulae can reproduce the trend of total head loss coefficient.

The development of novel cytochrome P450 2J2 (CYP2J2) inhibitor and the underlying interaction between inhibitor and CYP2J2.

Human Cytochrome P450 2J2 (CYP2J2) as an important metabolic enzyme, plays a crucial role in metabolism of polyunsaturated fatty acids (PUFAs). Elevated levels of CYP2J2 have been associated with various types of cancer, and therefore it serves as a potential drug target. Herein, using a high-throughput screening approach based on enzymic activity of CYP2J2, we rapidly and effectively identified a novel natural inhibitor (Piperine, 9a) with IC50 value of 0.44 µM from 108 common herbal medicines. Next, a series of its derivatives were designed and synthesised based on the underlying interactions of Piperine with CYP2J2. As expected, the much stronger inhibitors 9k and 9l were developed and their inhibition activities increased about 10 folds than Piperine with the IC50 values of 40 and 50 nM, respectively. Additionally, the inhibition kinetics illustrated the competitive inhibition types of 9k and 9l towards CYP2J2, and Ki were calculated to be 0.11 and 0.074 µM, respectively. Furthermore, the detailed interaction mechanism towards CYP2J2 was explicated by docking and molecular dynamics, and our results revealed the residue Thr114 and Thr 315 of CYP2J2 were the critical sites of action, moreover the spatial distance between the carbon atom of ligand methylene and Fe atom of iron porphyrin coenzyme was the vital interaction factor towards human CYP2J2.

[Correlation between circulating tumor cells and clinicopathological features of early breast cancer].

OBJECTIVE: To investigate the correlation between the number of peripheral blood circulating tumor cells (CTCs) and clinicopathological features of early breast cancer. 
 Methods: The clinical and pathological data from 100 patients with early breast cancer treated by a breast cancer treatment team in the Department of Breast Surgery, Second Xiangya Hospital, Central South University, were collected from January 2017 to December 2018. For these patients, their peripheral blood CTCs were detected, enumerated and typed by CanpatrolTM CTC assay.
 Results: The positive rate of CTCs was 90% in peripheral blood of patients with early breast cancer, and the majority of molecular phenotypes was hybrid CTCs (55.6%). The positive rate of CTCs was only related to the pathological type of tumor (P<0.05), but not to other clinicopathological features. No correlation between clinicopathological features and the total number of CTCs, the number of epithelial CTCs or the number of hybrid CTCs was found. However, the number of mesenchymal CTCs was significantly correlated with the expression of hormone receptors and Ki-67 (r=0.200, P<0.05), and there was a significant correlation between the proportion of mesenchymal CTCs and the expression level of Ki-67 (r=0.213, P<0.05).
 Conclusion: The number of CTCs is not correlated with all clinicopathological features, but patients with negative hormone receptor and high expression of Ki-67 probably have more hybrid CTCs.

The predictive value of Ki-67 before neoadjuvant chemotherapy for breast cancer: a systematic review and meta-analysis.

AIM: To review the predictive values of Ki-67 before neoadjuvant chemotherapy (NAC) for breast cancer patients. METHODS: PubMed and EMBASE were searched. Random-effect model meta-analysis was conducted using Revman software. RESULTS: High Ki-67 was associated with more pathological complete responses (pCRs) events (odds ratio: 3.10; 95% CI: 2.52-3.81; 53 studies, 10,848 patients) regardless of HR+, HER2+ and triple-negative breast cancer types, the definitions of pCR and cut-off points for Ki-67. Ki-67 could predict pCR in those who received anthracyclines plus taxanes, and anthracyclines only, and those from Asia and Europe. CONCLUSION: High Ki-67 before NAC was a predictor for pCR in neoadjuvant setting for breast cancer patients.

RKIP suppresses the proliferation and metastasis of breast cancer cell lines through up-regulation of miR-185 targeting HMGA2.

Raf-1 kinase inhibitor protein (RKIP) is a tumor and metastasis suppressor in cancer cells. MicroRNAs (miRNAs) have been suggested to play a vital role in tumor initiation and progression by negatively regulating oncogenes and tumor suppressors. Quite recently, studies have identified some miRNAs operating to promote or suppress tumor invasion or metastasis via regulating metastasis-related genes, providing potential therapeutic targets on anti-metastasis strategy. In this study, we found the expression of RKIP and miR-185 in breast cancer tissues was significantly lower than that of in normal breast tissues. Over-expression of RKIP up-regulated miR-185 expression, inhibited breast cancer cell growth and invasion, and inhibited miR-185 target gene High-mobility group AT-hook 2 (HMGA2). HMGA2 is encoded by HMGA2 gene, which encodes a protein that belongs to the non-histone chromosomal high-mobility group (HMG) protein family. Moreover, RKIP knockdown attenuated the inhibition of breast cancer cell invasion and the expression of HMGA2 by miR-185. Forced HMGA2 overexpression could partly restore the inhibitory effect of miR-185 on breast cancer cell growth and invasion. Our findings newly described RKIP/miR-185 to HMGA2 link and provided a potential mechanism for breast cancer cell growth and invasion. It may illustrate the potential therapeutic utility of signaling pathway signatures.

[Tempo-spatial Variations in Nitrogen and Phosphorus Loads in Jianli-Hankou Reach of the Middle Yangtze River During the Past 20 Years].

Ammonia nitrogen （NH4+-N） and total phosphorus （TP） were the major control pollutants in the Yangtze River Basin. Based on measured data from 2003 to 2020, the temporal and spatial variations in concentrations and fluxes of NH4+-N and TP in the Jianli to Hankou （JL-HK） reach of the Middle Yangtze River were studied, and the impacts of flow-sediment factors, tributary inflows, and others on variations in NH4+-N and TP fluxes were discussed. The results showed that： ① In recent years, NH4+-N and TP concentrations in the mainstream have declined significantly, with annual NH4+-N and TP concentrations at each monitoring station in 2020 averagely decreasing by 41% and 34% compared to those in 2003, respectively. Spatially, NH4+-N and TP concentrations decreased and then increased along the mainstream. NH4+-N and TP concentrations of tributary inflows, which include the Dongting Lake and Han River, were generally lower than that of the mainstream. The multi-year average values of NH4+-N and TP concentrations were both averaged at 0.12 mg·L-1 in the mainstream and were averaged at 0.11 mg·L-1 and 0.09 mg·L-1 in the tributary inflows. ② The flux differences between the upper and lower sections net of tributary confluences showed that NH4+-N and TP fluxes were lost in the Jianli to Luoshan （JL-LS） sub-reach and increased in the Luoshan to Hankou （LS-HK） sub-reach in most years. NH4+-N and TP fluxes decreased in the JL-LS sub-reach, which was related to the lower NH4+-N and TP concentrations in lateral inflows, such as Dongting Lake, and thus lowered the NH4+-N and TP concentrations in the mainstream. The LS-HK sub-reach showed the opposite trends, and the water and sediment loads increased in this sub-reach. Across the whole JL-HK reach, TP flux as well as water and sediment loads were recharged along the reach, whereas NH4+-N flux was reduced greatly, which could be attributed to the pollution abatement conducted in the Yangtze River Basin, which mainly focused on NH4+-N. ③ The correlation analysis results showed that NH4+-N fluxes had the strongest correlation with NH4+-N concentrations but not significantly correlated with discharges and sediment transport rates, indicating that NH4+-N was mainly controlled by point source pollution in the study reach. TP fluxes had higher correlations with discharges and sediment transport rates in high flow level periods, and the correlations between TP fluxes and TP concentrations were better in low flow level periods, reflecting that point source pollution contributed more to TP in dry seasons compared to flood seasons.

Integrated modelling of flow-sediment transport and power generation in the Three Gorges Reservoir.

Reservoirs play a crucial role in regulating runoff and generating energy. However, they also lead to significant sedimentation in the reservoir area. In this study, we propose an integrated model that combines a 1-D hydro- and sediment dynamic module with a power generation module. The model considers both suspended and bed load transports. This model is applied to the Three Gorges Reservoir (TGR) and evaluate its performance against corresponding measurements. The results demonstrate that:① the proposed model accurately reproduces the processes of flow and sediment transport, bed deformation, and power generation during the hydrological years of 2019 and 2020. The relative errors for average discharge and bed deformation volume are <6 % and 10 %, respectively. Moreover, the calculated total power (982 × 108-1115 × 108 kW·h) closely agree with the measured values (969 × 108-1118 × 108 kW·h); ② the inflows of small tributaries have a noticeable impact on the calculated water discharge in the TGR. This impact will lead to a 16 % increase in average discharge and alter the magnitudes and occurrence times of flood peaks; ③ the flocculation of fine sediment particles significantly affects sediment transport, particularly in the sub-reach close to the dam. This flocculation will result in a 37 %-57 % reduction in average suspended sediment discharge and a 63 %-93 % reduction in peak sediment discharge. This research provides a comprehensive tool for simulating flow and sediment transport as well as power generation, which can support the optimal regulation of the TGR.

Shikonin and chitosan-silver nanoparticles synergize against triple-negative breast cancer through RIPK3-triggered necroptotic immunogenic cell death.

Necroptotic immunogenic cell death (ICD) can activate the human immune system to treat the metastasis and recurrence of triple-negative breast cancer (TNBC). However, developing the necroptotic inducer and precisely delivering it to the tumor site is the key issue. Herein, we reported that the combination of shikonin (SHK) and chitosan silver nanoparticles (Chi-Ag NPs) effectively induced ICD by triggering necroptosis in 4T1 cells. Moreover, to address the lack of selectivity of drugs for in vivo application, we developed an MUC1 aptamer-targeted nanocomplex (MUC1@Chi-Ag@CPB@SHK, abbreviated as MUC1@ACS) for co-delivering SHK and Chi-Ag NPs. The accumulation of MUC1@ACS NPs at the tumor site showed a 6.02-fold increase compared to the free drug. Subsequently, upon reaching the tumor site, the acid-responsive release of SHK and Chi-Ag NPs from MUC1@ACS NPs cooperatively induced necroptosis in tumor cells by upregulating the expression of RIPK3, p-RIPK3, and tetrameric MLKL, thereby effectively triggering ICD. The sequential maturation of dendritic cells (DCs) subsequently enhanced the infiltration of CD8+ and CD4+ T cells in tumors, while inhibiting regulatory T cells (Treg cells), resulting in the effective treatment of primary and distal tumor growth and the inhibition of TNBC metastasis. This work highlights the importance of nanoparticles in mediating drug interactions during necroptotic ICD.

An unsupervised learning model based on CT radiomics features accurately predicts axillary lymph node metastasis in breast cancer patients: diagnostic study.

BACKGROUND: The accuracy of traditional clinical methods for assessing the metastatic status of axillary lymph nodes (ALNs) is unsatisfactory. In this study, the authors propose the use of radiomic technology and three-dimensional (3D) visualization technology to develop an unsupervised learning model for predicting axillary lymph node metastasis in patients with breast cancer (BC), aiming to provide a new method for clinical axillary lymph node assessment in patients with this disease. METHODS: In this study, we retrospectively analyzed the data of 350 patients with invasive BC who underwent lung-enhanced computed tomography (CT) and axillary lymph node dissection surgery at the Department of Breast Surgery of the Second Xiangya Hospital of Central South University. The authors used 3D visualization technology to create a 3D atlas of ALNs and identified the region of interest for the lymph nodes. Radiomic features were subsequently extracted and selected, and a prediction model for ALNs was constructed using the K-means unsupervised algorithm. To validate the model, the authors prospectively collected data from 128 BC patients who were clinically evaluated as negative at our center. RESULTS: Using 3D visualization technology, we extracted and selected a total of 36 CT radiomics features. The unsupervised learning model categorized 1737 unlabeled lymph nodes into two groups, and the analysis of the radiomic features between these groups indicated potential differences in lymph node status. Further validation with 1397 labeled lymph nodes demonstrated that the model had good predictive ability for axillary lymph node status, with an area under the curve of 0.847 (0.825-0.869). Additionally, the model's excellent predictive performance was confirmed in the 128 axillary clinical assessment negative cohort (cN0) and the 350 clinical assessment positive (cN+) cohort, for which the correct classification rates were 86.72 and 87.43%, respectively, which were significantly greater than those of clinical assessment methods. CONCLUSIONS: The authors created an unsupervised learning model that accurately predicts the status of ALNs. This approach offers a novel solution for the precise assessment of ALNs in patients with BC.

Hydrologic and geomorphic effects on the reduction of channel discharge capacity in the Middle Yangtze River.

A systematic increase in the occurrence of flood events has been noted in rivers worldwide. However, our understanding remains unclear of how the flood level is affected by the change in channel discharge capacity. Therefore, the reduction of channel discharge capacity was quantified in the Middle Yangtze River (MYR) based on extensive measured data. It is confirmed that the variation in channel discharge capacity is a superposition result of channel-morphology and channel-resistance changes, as well as the change in local base-level at the outlet. Then a series of numerical simulations were carried out to quantitatively identify the contribution of each factor to the reduction of channel discharge capacity in the MYR for the years of 2004 and 2020. Simulated results reveal that channel degradation increased the flow passage area, helping the channel to convey floods, with the effect being weakened along the reach; however, the decline in flood level under the same discharge was not observed, which was primarily attributed to the increases in channel resistance and local base-level at the outlet. These two factors accounted for 16-91 % and 9-84 % of the total impact at four hydrometric stations in the MYR. It should be noted that the dominant factor to influence the discharge capacity varied greatly at different stations, which depended on the degree of bed-material coarsening, the distance from the confluence of lakes, etc. At the stations immediately downstream of the dam, the contribution of the increased movable bed roughness usually played a more essential role; while at the stations close to the outlet with the confluence of large lakes, the increase in local base-level became the main factor that accounted for the rise of high-flood levels under the specified large discharge.

Correlation between the expression of CD24 on circulating tumor cells and prognosis in breast cancer.

OBJECTIVE: To investigate the expression of tumor stem cell marker CD24 in peripheral blood circulating tumor cells (CTCs) of breast cancer and the value of CTCs in predicting the prognosis of breast cancer patients. METHODS: Clinical data of 102 breast cancer patients from January 2015 to December 2019 were retrospectively collected. CTC test results, CD24 test results, tumor size, tumor stage, pathological type, molecular type, lymph node metastasis, survival time, and survival status of patients were collected. The correlation between the expression of CD24 in peripheral blood CTCs of breast cancer and the survival time of patients was analyzed. RESULTS: Epithelial-CTCs were closely related to estrogen receptor (ER) expression (P = 0.036) and TNM stage (P = 0.018). Mixed epithelial/mesenchymal-CTCs were closely related to lymph node metastasis in breast cancer patients (P = 0.026). There was no obvious correlation between mesenchymal-CTCs and clinical characteristics (P > 0.05). The positive expression rate of CD24 in CTCs was 58.82% (60/102). The number of CD24-positive CTCs was closely related to TNM stage (P = 0.002), lymph node metastasis (P = 0.020), and tumor size (P = 0.025). The cumulative survival rate of patients with CD24-positive CTCs > 1.5/5 ml (73%) was significantly worse than that of patients with CD24-positive CTCs ≤ 1.5/5 ml (88%) (P < 0.05). There was no significant difference in the cumulative survival rate between patients with mixed-CTCs > 2.5/5 ml (72%) and patients with mixed-CTCs ≤ 2.5/5 ml (87%) (P = 0.336). The cumulative survival rate of patients with CD24-positive mixed-CTCs > 0.5/5 ml (72%) was significantly lower than that of patients with CD24-positive mixed-CTCs ≤ 0.5/5 ml (92%) (P < 0.05). CONCLUSION: The positive expression of CD24 in CTC is closely related to TNM stage, lymph node metastasis, and tumor size in breast cancer patients. The positive expression of CD24 in CTCs, especially in mixed-CTCs, may be one of the prognostic indicators for patients with early and intermediate stage breast cancer.

Modelling of phosphorus and nonuniform sediment transport in the Middle Yangtze River with the effects of channel erosion , tributary confluence and anthropogenic emission.

Phosphorus (P) transport plays a crucial role in the aquatic ecology of natural rivers. However, our understanding still remains unclear that how P transport is affected in a river-lake connected system downstream of a dam. This system usually undergoes both severe channel degradation and complex exchange of flow-sediment-phosphorus between the mainstem and tributaries. In the current study, a method was proposed firstly to determine the individual contribution of different sources to P recover based on the calculation of phosphorus budget; then an integrated model was developed, covering the modules of flow, nonuniform sediment and phosphorus transport. The application of the proposed method in the 955-km-long Middle Yangtze River (MYR) shows that the type of P transportation was predominantly changed from particulate phosphorus to dissolved phosphorus after the operation of the Three Gorges Project (TGP), but a significant longitudinal recovery of total phosphorus (TP) flux was observed. The TP flux exporting from the MYR was mainly from the Upper Yangtze River (44%), and 12%, 18% and 26% of that were originated from channel erosion, tributary confluence and anthropogenic emission. Moreover, the effects were investigated of nonuniform sediment transport and bed-material coarsening on P transport in the MYR, based on the proposed integrated model. Obtained results show that the TP transport process in the MYR was more reasonable simulated using the nonuniform sediment mode, and it is also confirmed that the process of bed-material coarsening after the TGP operation would lead to the decrease of particulate phosphorus flux in the MYR.

MiR-24-3p/Dio3 axis is essential for BDE47 to induce local thyroid hormone disorder and neurotoxicity.

BDE47 (2,2,4,4-tetrabromodiphenyl ether) is a member of the most important congeners of polybrominated diphenyl ethers (PBDEs) and has been identified as a developmental, reproductive and nervous system toxicant and endocrine system disruptor due to its frequent detection in human tissue and environmental samples. Our preliminary work suggested that high- and low-level of bromodiphenyl ethers have different effects on neuronal cells with differential targets of actions on neural tissues. In this study, we presented the underlying mechanism of BDE47 neurotoxicity from the perspective of thyroid hormone (TH) metabolism using in vitro model of human SK-N-AS neuronal cells. BDE47 could induce local TH metabolism disorder in neuronal cells by inhibiting the expression of the main enzyme, human type III iodothyronine deiodinase (Dio3). Further elucidation revealed that BDE47 effectively up-regulating miR-24-3p, which binds to the 3'-UTR of Dio3 and inhibits its expression. In addition, BDE47 could also inhibit the deiodinase activity of Dio3. Collectively, our study demonstrates the molecular mechanism of BDE47 regulating Dio3-induced TH metabolism disorder through inducing miR-24-3p, providing new clues for the role of miRNAs in neurodevelopmental toxicity mediated by environmental pollutants.

BDE209-promoted Dio2 degradation in H4 glioma cells through the autophagy pathway, resulting in hypothyroidism and leading to neurotoxicity.

Decabromodiphenyl ether (BDE209), the homologue with the highest number of brominates in polybrominated diphenyl ethers (PBDEs), is one of the most widespread environmental persistent organic pollutants (POPs) due to its mass production and extensive application in recent decades. BDE209 is neurotoxic, possibly related to its interference with the thyroid hormone (TH) system. However, the underlying molecular mechanisms of BDE209-induced TH interference and neurobehavioral disorders remains unknown. Here, we explored how BDE209 manipulated the major enzyme, human type II iodothyronine deiodinase (Dio2), that is most important in regulating local cerebral TH equilibrium by neuroglial cells, using an in vitro model of human glioma H4 cells. Clonogenic cell survival assay and LC/MS/MS analysis showed that BDE209 could induce chronic neurotoxicity by inducing TH interference. Co-IP assay, RT-qPCR and confocal assay identified that BDE209 destroyed the stability of Dio2 without affecting its expression, and promoted its binding to p62, thereby enhancing its autophagic degradation, thus causing TH metabolism disorder and neurotoxicity. Furthermore, molecular docking studies predicted that BDE209 could effectively suppress Dio2 activity by competing with tetraiodothyronine (T4). Collectively, our study demonstrates that BDE209-induced Dio2 degradation and loss of its enzymatic activity in neuroglial cells are the fundamental pathogenic basis for BDE209-mediated cerebral TH disequilibrium and neurotoxicity, providing a target of interest for further investigation using glial/neuronal cell co-culture system and in vivo models.

The p23 co-chaperone is a succinate-activated COX-2 transcription factor in lung adenocarcinoma tumorigenesis.

P23, historically known as a heat shock protein 90 (HSP90) co-chaperone, exerts some of its critical functions in an HSP90-independent manner, particularly when it translocates into the nucleus. The molecular nature underlying how this HSP90-independent p23 function is achieved remains as a biological mystery. Here, we found that p23 is a previously unidentified transcription factor of COX-2, and its nuclear localization predicts the poor clinical outcomes. Intratumor succinate promotes p23 succinylation at K7, K33, and K79, which drives its nuclear translocation for COX-2 transcription and consequently fascinates tumor growth. We then identified M16 as a potent p23 succinylation inhibitor from 1.6 million compounds through a combined virtual and biological screening. M16 inhibited p23 succinylation and nuclear translocation, attenuated COX-2 transcription in a p23-dependent manner, and markedly suppressed tumor growth. Therefore, our study defines p23 as a succinate-activated transcription factor in tumor progression and provides a rationale for inhibiting p23 succinylation as an anticancer chemotherapy.

Association between diabetes status and breast cancer in US adults: findings from the US National Health and Nutrition Examination Survey.

Objectives: The aim of this study was to investigate the association between diabetes status and the risk of breast cancer among adult Americans, exploring the impact of BMI, age, and race on this relationship. Methods: A cross-sectional analysis of 8,249 individuals from the National Health and Nutrition Examination Survey (NHANES) was conducted. Diabetes was categorized as type 2 diabetes and prediabetes, with both conditions diagnosed according to the ADA 2014 guidelines. The association between diabetes status and breast cancer risk was explored using multiple logistic regression analysis. Results: Patients with diabetes had higher odds of breast cancer (OR: 1.51; 95% CI 1.00 to 2.28), Using the two-piecewise linear regression model, it was observed that there is a threshold effect in the risk of breast cancer occurrence at the age of 52 years. Specifically, the risk of breast cancer is relatively low before the age of 52 but increases significantly after this age. Conclusions: This study identified a significant association between diabetes status and breast cancer risk among adult Americans. We also found a threshold effect in breast cancer occurrence at the age of 52. Age was significantly associated with breast cancer risk in both Non-Hispanic White and Non-Hispanic Black individuals. These findings underscore the importance of diabetes management, maintaining a healthy BMI, and age-related risk considerations in reducing breast cancer risk.

Analysis on the Differences of Combination Effects of Science and Technology Innovation Policies.

Science and technology innovation (STI) policy is a strategic principle to guide the whole cause of STI. The study on STI policy and its effect is particularly important. Most of the existing studies on the effect of STI policy focus on the effect of a single policy, and the studies on the effect of policy combination and its differences need to be further enriched and improved. This study proposes a method combining system simulation experiment and analysis of variance (ANOVA) to study the differences of combination effects of STI policies. The results show that there are significant effect differences in the combination of STI policies as a whole, but when it comes to different combinations of STI policies, not all policy combinations have significant differences. This study not only points out whether there are significant differences in a certain effect among which combinations of STI policies but also points out whether there are significant differences in all effects among which combinations of STI policies at the same time. This study has theoretical and practical significance for realizing scientific policy-making and sustainable development.