Deficiency of betaine-homocysteine methyltransferase activates glucose-6-phosphate dehydrogenase (G6PD) by decreasing arginine methylation of G6PD in hepatocellular carcinogenesis.

Betaine-homocysteine methyltransferase (BHMT) regulates protein methylation and is correlated with tumorigenesis; however, the effects and regulation of BHMT in hepatocarcinogenesis remain largely unexplored. Here, we determined the clinical significance of BHMT in the occurrence and progression of hepatocellular carcinoma (HCC) using tissue samples from 198 patients. BHMT was to be frequently found (86.6%) expressed at relatively low levels in HCC tissues and was positively correlated with the overall survival of patients with HCC. Bhmt overexpression effectively suppressed several malignant phenotypes in hepatoma cells in vitro and in vivo, whereas complete knockout of Bhmt (Bhmt-/-) produced the opposite effect. We combined proteomics, metabolomics, and molecular biological strategies and detected that Bhmt-/- promoted hepatocarcinogenesis and tumor progression by enhancing the activity of glucose-6-phosphate dehydrogenase (G6PD) and PPP metabolism in DEN-induced HCC mouse and subcutaneous tumor-bearing models. In contrast, restoration of Bhmt with an AAV8-Bhmt injection or pharmacological inhibition of G6PD attenuated hepatocarcinogenesis. Additionally, coimmunoprecipitation identified monomethylated modifications of the G6PD, and BHMT regulated the methylation of G6PD. Protein sequence analysis, generation and application of specific antibodies, and site-directed mutagenesis indicated G6PD methylation at the arginine residue 246. Furthermore, we established bidirectionally regulated BHMT cellular models combined with methylation-deficient G6PD mutants to demonstrate that BHMT potentiated arginine methylation of G6PD, thereby inhibiting G6PD activity, which in turn suppressed hepatocarcinogenesis. Taken together, this study reveals a new methylation-regulatory mechanism in hepatocarcinogenesis owing to BHMT deficiency, suggesting a potential therapeutic strategy for HCC treatment.

Enhanced protein-metabolite correlation analysis: To investigate the association between Staphylococcus aureus mastitis and metabolic immune pathways.

Mastitis is a disease characterized by congestion, swelling, and inflammation of the mammary gland and usually caused by infection with pathogenic microorganisms. Furthermore, the development of mastitis is closely linked to the exogenous pathway of the gastrointestinal tract. However, the regulatory mechanisms governing the gut-metabolism-mammary axis remain incompletely understood. The present study revealed alterations in the gut microbiota of mastitis rats characterized by an increased abundance of the Proteobacteria phylum. Plasma analysis revealed significantly higher levels of L-isoleucine and cholic acid along with 7-ketodeoxycholic acid. Mammary tissue showed elevated levels of arachidonic acid metabolites and norlithocholic acid. Proteomic analysis showed increased levels of IFIH1, Tnfaip8l2, IRGM, and IRF5 in mastitis rats, which suggests that mastitis triggers an inflammatory response and immune stress. Follistatin (Fst) and progesterone receptor (Pgr) were significantly downregulated, raising the risk of breast cancer. Extracellular matrix (ECM) receptors and focal adhesion signaling pathways were downregulated, while blood-milk barrier integrity was disrupted. Analysis of protein-metabolic network regulation revealed that necroptosis, protein digestion and absorption, and arachidonic acid metabolism were the principal regulatory pathways involved in the development of mastitis. In short, the onset of mastitis leads to changes in the microbiota and alterations in the metabolic profiles of various biological samples, including colonic contents, plasma, and mammary tissue. Key manifestations include disturbances in bile acid metabolism, amino acid metabolism, and arachidonic acid metabolism. At the same time, the integrity of the blood-milk barrier is compromised while inflammation is promoted, thereby reducing cell adhesion in the mammary glands. These findings contribute to a more comprehensive understanding of the metabolic status of mastitis and provide new insights into its impact on the immune system.

Efficacy of natural products on premature ovarian failure: a systematic review and meta-analysis of preclinical studies.

OBJECTIVE: This study aims to investigate the effects of natural products on animal models of premature ovarian failure (POF). METHODS: We conducted comprehensive literature searches and identified relevant studies that examined the protective effects of natural products on experimental POF. We extracted quantitative data on various aspects such as follicular development, ovarian function, physical indicators, oxidative stress markers, inflammatory factors, and protein changes. The data was analyzed using random-effects meta-analyses, calculating pooled standardized mean differences and 95% confidence intervals. Heterogeneity was assessed using the I2 statistic, and bias was estimated using the SYRCLE tool. RESULTS: Among the 879 reviewed records, 25 articles met our inclusion criteria. These findings demonstrate that treatment with different phytochemicals and marine natural products (flavonoids, phenols, peptides, and alkaloids, etc.) significantly improved various aspects of ovarian function compared to control groups. The treatment led to an increase in follicle count at different stages, elevated levels of key hormones, and a decrease in atretic follicles and hormone levels associated with POF. This therapy also reduced oxidative stress (specifically polyphenols, resveratrol) and apoptotic cell death (particularly flavonoids, chrysin) in ovarian granulosa cells, although it showed no significant impact on inflammatory responses. The certainty of evidence supporting these findings ranged from low to moderate. CONCLUSIONS: Phytochemicals and marine natural product therapy (explicitly flavonoids, phenols, peptides, and alkaloids) has shown potential in enhancing folliculogenesis and improving ovarian function in animal models of POF. These findings provide promising strategies to protect ovarian reserve and reproductive health. Targeting oxidative stress and apoptosis pathways may be the underlying mechanism.

Experimental treatment efficacy of dmrFABP5 on prostate cancer singly or in combination with drugs in use.

Enzalutamide is a drug used to treat prostate cancer (PC) and docetaxel is a drug for chemotherapeutic treatment of diverse cancer types, including PC. The effectiveness of these drugs in treating castration-resistant prostate cancer (CRPC) is poor and therefore CRPC is still largely incurable. However, the bio-inhibitor of fatty acid-binding protein 5 (FABP5), dmrFABP5, which is a mutant form of FABP5 incapable of binding to fatty acids, has been shown recently to be able to suppress the tumorigenicity and metastasis of cultured CRPC cells. The present study investigated the possible synergistic effect of dmrFABP5 combined with either enzalutamide or docetaxel on suppressing the tumorigenic properties of PC cells, including cell viability, migration, invasion and colony proliferation in soft agar. A highly significant synergistic inhibitory effect on these properties was observed when dmrFABP5 was used in combination with enzalutamide on androgen-responsive PC 22RV1 cells. Moreover, a highly significant synergistic inhibitory effect was also observed when dmrFABP5 was combined with docetaxel, and added to 22RV1 cells and to the highly malignant, androgen-receptor (AR)-negative Du145 cells. DmrFABP5 alone failed to produce any suppressive effect when added to the FABP5-negative cell line LNCaP, although enzalutamide could significantly suppress LNCaP cells when used as a single agent. These synergistic inhibitory effects of dmrFABP5 were produced by interrupting the FABP5-related signal transduction pathway in PC cells. Thus, dmrFABP5 appears to be not only a potential single therapeutic agent, but it may also be used in combination with existing drugs to suppress both AR-positive and AR-negative PC.

Leveraging an immune cell signature to improve the survival and immunotherapy response of lung adenocarcinoma.

Background: Immune cells play a critical role in the prognosis of cancer. However, the function of different immune cell types in lung adenocarcinoma (LUAD) and the development of a prognostic signature based on immune cell types have not been comprehensively investigated. Methods: We collected and included a total of 2499 LUAD patients and performed calculations to determine the penetration level of 24 immune cells. This examination was conducted using the macro-gene-based approach provided by ImmuCellAI. We performed a meta-analysis using Lasso-Cox analysis to establish the immune cell pair score (ICPS). We conducted a survival analysis to measure differences in survival across ICPS-risk groups. Wilcox test was used to measure the difference in expression level. Spearman correlation analysis was used for the relevance assessment. Results: We collected a total of 24 immune cell types to construct cell pairs. Utilizing 17 immune cell pairs, we constructed and validated the ICPS, which plays a critical role in stratifying survival and dynamically monitoring the effectiveness of immunotherapy. Additionally, we identified several candidate drugs that target ICPS. Conclusions: The ICPS shows promise as a valuable tool for identifying suitable candidates for immunotherapy among patients. Our comprehensive assessment of immune cell interactions in LUAD contributes to a deeper understanding of infiltration patterns and functions, thereby guiding the development of more efficacious immunotherapy strategies.

Mechanisms of Bushen Tiaoxue Granules against controlled ovarian hyperstimulation-induced abnormal morphology of endometrium based on network pharmacology.

Bushen Tiaoxue Granules (BTG) is an empirical Chinese herbal formula that has been used for the treatment of subfertility. The protective effect of BTG on controlled ovarian hyperstimulation (COH)-induced impaired endometrial receptivity has been reported in our previous study. This study aims to explore the mechanisms of BTG on ameliorating abnormal morphology of endometrium based on network pharmacology. Active compounds of BTG were identified via the traditional Chinese medicine systems pharmacology and UPLC-MS technology. The SwissTargetPrediction platform and HERB database were used to screen out the putative targets of BTG. Potential targets of endometrial dysfunction caused by COH were obtained from three GEO databases. Through the STRING database, the protein-protein interaction was carried out according to the cross-common targets of diseases and drugs. GO terms and KEGG pathways enrichment analyses were conducted via the Metascape database. AutoDock Vina was used for docking validation of the affinity between active compounds and potential targets. Finally, in vivo experiments were used to verify the potential mechanisms derived from network pharmacology study. A total of 141 effective ingredients were obtained from TCMSP and nine of which were verified in UPLC-MS. Six genes were selected through the intersection of 534 disease related genes and 165 drug potential targets. Enrichment analyses showed that BTG might reverse endometrial dysfunction by regulating adherens junction and arachidonic acid metabolism. Hematoxylin-eosin staining revealed that BTG ameliorated the loose and edematous status of endometrial epithelium caused by COH. The protein expression of FOXO1A, ß-Catenin and COX-2 was decreased in the COH group, and was up-regulated by BTG. BTG significantly alleviates the edema of endometrial epithelium caused by COH. The mechanisms may be related to adheren junctions and activation of arachidonic acid metabolism. The potential active compounds quercetin, taxifolin, kaempferol, eriodictyol, and isorhamnetin identified from the BTG exhibit marginal cytotoxicity. Both high and low concentrations of kaempferol, eriodictyol, and taxifolin are capable of effectively ameliorating impaired hESC cellular activity.

FABP5 can substitute for androgen receptor in malignant progression of prostate cancer cells.

Fatty acid­binding protein 5 (FABP5) and androgen receptor (AR) are critical promoters of prostate cancer. In the present study, the effects of knocking out the FABP5 or AR genes on malignant characteristics of prostate cancer cells were investigated, and changes in the expression of certain key proteins in the FABP5 (or AR)­peroxisome proliferator activated receptor­Î³ (PPARγ)­vascular endothelial growth factor (VEGF) signaling pathway were monitored. The results obtained showed that FABP5­ or AR­knockout (KO) led to a marked suppression of the malignant characteristics of the cells, in part, through disrupting this signaling pathway. Moreover, FABP5 and AR are able to interact with each other to regulate this pathway, with FABP5 controlling the dominant AR splicing variant 7 (ARV7), and AR, in return, regulates the expression of FABP5. Comparisons of the RNA profiles revealed the existence of numerous differentially expressed genes (DEGs) comparing between the parental and the FABP5­ or AR­KO cells. The six most abundant changes in DEGs were found to be attributable to the transition from androgen­responsive to androgen­unresponsive, castration­resistant prostate cancer (CRPC) cells. These findings have provided novel insights into the complex molecular pathogenesis of CRPC cells, and have demonstrated that interactions between FABP5 and AR contribute to the transition of prostate cancer cells to an androgen­independent state. Moreover, gene enrichment analysis revealed that the most highly enriched biological processes associated with the DEGs included those responsive to fatty acids, cholesterol and sterol biosynthesis, as well as to lipid and fatty acid transportation. Since these pathways regulated by FABP5 or AR may be crucial in terms of transducing signals for cancer cell progression, targeting FABP5, AR and their associated pathways, rather than AR alone, may provide a new avenue for the development of therapeutic strategies geared towards suppressing the malignant progression to CRPC cells.

Extracellular vesicles from adipose stem cells ameliorate allergic rhinitis in mice by immunomodulatory.

Background: Human adipose tissue-derived stem cells (hADSCs) exert potent immunosuppressive effects in the allogeneic transplantation treatment. In mouse model of allergic rhinitis (AR), ADSCs partially ameliorated AR. However, no study has evaluated the potential therapeutic effects of hADSC-derived extracellular vesicles (hADSC-EVs) on AR. Methods: Female BALB/c mice were sensitized and challenged with ovalbumin (OVA) to induce AR. One day after the last nasal drop, each group received phosphate buffered saline (PBS) or hADSC-EVs treatment. Associated symptoms and biological changes were then assessed. Results: hADSC-EV treatment significantly alleviated nasal symptoms, and reduced inflammatory infiltration. Serum levels of OVA-specific IgE, interleukin (IL)-4 and interferon (IFN)-γ were all significantly reduced. The mRNA levels of IL-4 and IFN-γ in the spleen also changed accordingly. The T helper (Th)1/Th2 cell ratio increased. The treatment efficacy index of hADSC-EV was higher than that of all human-derived MSCs in published reports on MSC treatment of AR. ADSC-EVs exhibited a greater therapeutic index in most measures when compared to our previous treatment involving ADSCs. Conclusion: These results demonstrated that hADSC-EVs could ameliorate the symptoms of AR by modulating cytokine secretion and Th1/Th2 cell balance. hADSC-EVs could potentially be a viable therapeutic strategy for AR. Further animal studies are needed to elucidate the underlying mechanisms and to optimize potential clinical protocols.

Construction of a Nomogram to Predict Overall Survival in Patients with Early-Onset Hepatocellular Carcinoma: A Retrospective Cohort Study.

Hepatocellular carcinoma (HCC) is a widespread and impactful cancer which has pertinent implications worldwide. Although most cases of HCC are typically diagnosed in individuals aged ≥60 years, there has been a notable rise in the occurrence of HCC among younger patients. However, there is a scarcity of precise prognostic models available for predicting outcomes in these younger patients. A retrospective analysis was conducted to investigate early-onset hepatocellular carcinoma (EO-LIHC) using data from the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2018. The analysis included 1392 patients from the SEER database and our hospital. Among them, 1287 patients from the SEER database were assigned to the training cohort (n = 899) and validation cohort 1 (n = 388), while 105 patients from our hospital were assigned to validation cohort 2. A Cox regression analysis showed that age, sex, AFP, grade, stage, tumor size, surgery, and chemotherapy were independent risk factors. The nomogram developed in this study demonstrated its discriminatory ability to predict the 1-, 3-, and 5-year overall survival (OS) rates in EO-LIHC patients based on individual characteristics. Additionally, a web-based OS prediction model specifically tailored for EO-LIHC patients was created and validated. Overall, these advancements contribute to improved decision-making and personalized care for individuals with EO-LIHC.

Characteristics of lactate metabolism phenotype in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a highly heterogeneous cancer, and more effective prognostic markers are needed. Lactic acid has been proved to be an important metabolite involved in cancer development, metastasis, and the tumor microenvironment, affecting the prognosis of patients. The role of lactic acid metabolism regulators (LAMRs) in HCC is still unclear. In this study, we analyzed the status of LAMRs, a gene list containing lactate from Molecular Signatures database, in HCC and consensus clustering was performed based on these LAMRs. Cluster B showed higher infiltrations of immune cells, higher TME scores, and a poorer prognosis. We further constructed a risk score based on DEGs using LASSO and COX regression analysis between two clusters, which could effectively predict the prognosis of TCGA-LIHC patients. The GSE14520 cohort confirmed the result. We also examined the correlation of risk scores with clinical characteristics, genetic mutations, drug sensitivity, immune checkpoint inhibitors(ICIs), and immunotherapy. In conclusion, our findings will facilitate a further understanding of the role of partial lactate metabolism related genes in HCC and suggest a new risk score to predict prognosis.

Exploration of the shared genetic biomarkers in Alzheimer's disease and chronic kidney disease using integrated bioinformatics analysis.

In order to investigate the potential link between Alzheimer's disease (AD) and chronic kidney disease (CKD), we conducted a comprehensive analysis using a bioinformatics approach. We downloaded AD and CKD datasets from the Gene Expression Omnibus database and analyzed differentially expressed genes and weighted gene co-expression networks to identify candidate genes for AD and CKD. We used a combination of the least absolute shrinkage and selection operator and random forest algorithms to select the shared genes. Subsequently, we shared genes and performed an immune infiltration analysis to investigate the association between different immune cell types and shared genes. Finally, we elucidated the relationship between the expression levels of the shared genes in disease samples and cells using single-cell analysis. Our analysis identified 150 candidate genes that may be primarily involved in immune inflammatory responses and energy metabolism pathways. We found that JunD Proto-Oncogene, ALF transcription elongation factor 1, and ZFP36 Ring Finger Protein Like 1 were the best co-diagnostic markers for AD and CKD based on the results of Least Absolute Shrinkage Selection Operator analysis and the random forest algorithm. Based on the results of immune infiltration analysis, macrophages and T-cells play a significant role in the progression of AD and CKD. Our scRNA-sequencing data showed that the 3 shared genes in AD were significantly expressed in astrocytes, excitatory neurons, oligodendrocytes, and MAIT cells. The 3 shared genes in CKD were significantly expressed in oligodendrocytes, neutrophils, fibroblasts, astrocytes, and T-cells. JunD Proto-Oncogene, ALF transcription elongation factor 1, and ZFP36 Ring Finger Protein Like 1 genes are the best diagnostic markers for AD and CKD.

Differentiating mass-forming intrahepatic cholangiocarcinoma from atypical hepatocellular carcinoma using Gd-EOB-DTPA-enhanced magnetic resonance imaging combined with serum markers in at-risk patients with hepatitis B virus.

Background: The precise differentiation of intrahepatic cholangiocarcinoma (ICC) from atypical hepatocellular carcinoma (HCC) is vital for treatment strategy and prognostic prediction. In clinical practice, nearly 40% of HCCs demonstrate atypical manifestations, particularly HCCs with rim arterial phase hyperenhancement (APHE), which is challenging to differentiate from mass-forming ICC. Thus, we aimed to develop a diagnostic regimen of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) contrast-enhanced magnetic resonance imaging (MRI) combined with serum tumor markers in differentiating mass-forming ICC from atypical HCC in at-risk patients with the hepatitis B virus (HBV). Methods: This study enrolled 129 patients with pathologically proven mass-forming ICCs (n=53) and atypical HCCs (n=76) who had undergone preoperative Gd-EOB-DTPA contrast-enhanced MRI. The clinical data and imaging findings were analyzed. Univariate and multivariate logistic analyses were performed to identify the independent predictors for differentiating mass-forming ICCs from atypical HCCs. The diagnostic performance was evaluated using receiver operating characteristic (ROC) curves, and DeLong test was used to compare the areas under curves of all independent predictors. Results: Univariate logistic regression analysis revealed normal alpha fetoprotein (AFP), elevated carbohydrate antigen 19-9 (CA19-9) level, elevated carcinoma embryonic antigen (CEA) level, central hyperintensity on T2-weighted imaging (T2WI), central hypointensity on T2WI, and targetoid sign on hepatobiliary phase (HBP) and targetoid restriction on diffusion-weighted imaging (DWI) were more likely to be significant predictors favoring mass-forming ICCs (all P values <0.05). In contrast, multifocal hyperintensity on T2WI and capsule sign were more frequently seen in patients with atypical HCC (all P values <0.05). Multivariate analysis revealed normal AFP, elevated CA19-9 level, targetoid sign on HBP, and targetoid restriction on DWI (all P=0.001) were independent predictors for differentiating mass-forming ICCs from atypical HCCs; DeLong test showed that the area under curve (AUC) increased to 0.949 when the above predictors were combined (all P values <0.05), and the sensitivity, specificity, and accuracy of the combined independent predictors were 88.7%, 93.4%, and 91.5%, respectively. Conclusions: A diagnostic regimen integrating tumor markers (AFP, CA19-9) and imaging biomarkers (targetoid restriction on DWI and/or targetoid sign on HBP) using Gd-EOB-DTPA-enhanced MRI could help to differentiate mass-forming ICCs from atypical HCCs and achieve high diagnostic performance of mass-forming ICCs in at-risk patients with the HBV. Keywords: Mass-forming intrahepatic cholangiocarcinoma (mass-forming ICC); atypical hepatocellular carcinoma (atypical HCC); magnetic resonance imaging (MRI); gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA); hepatobiliary phase (HBP).

Preparation of Rechargeable Antibacterial Polypropylene/N-Halamine Materials Based on Melt Blending and Surface Segregation.

Polypropylene (PP) has been widely used in health care and food packaging fields, however, it lacks antibacterial properties. Herein, we prepared the polymeric antibacterial agents (MPP-NDAM) by an in situ amidation reaction between 2,4-diamino-6-dialkylamino-1,3,5-triazine (NDAM) and maleic anhydride grafted polypropylene (MPP) using the melt grafting method. The effects of reaction time and monomer content on the grafting degree of N-halamine were investigated, and a grafting degree of 4.86 wt % was achieved under the optimal reaction conditions. PP/MPP-NDAM composites were further obtained by a melt blending process between PP and MPP-NDAM. With the adoption of surface segregation technology, the content of N-halamine structure on the surface of PP/MPP-NDAM composites was significantly increased. The antibacterial tests showed that the PP/MPP-NDAM composite could achieve 99.9% bactericidal activity against 1.0 × 107 CFU/mL of Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) within 10 and 5 min of contact, respectively. The antibacterial effect became more pronounced with the prolongation of chlorinated time, and it could achieve 99.9% bactericidal activity against E. coli within merely 1 min of contact.

Prognostic value of controlling nutritional status on clinical and survival outcomes in cancer patients treated with immunotherapy.

Cancer is a leading cause of death globally. Immunotherapy has shown promise in treating various types of cancer, but its effectiveness varies among patients. The Controlling Nutritional Status (CONUT) score has been linked to the prognosis of different cancers. However, its predictive value for immunotherapy outcomes is not well understood. Our research represents the pioneering meta-study to examine the prognostic value of the CONUT score on cancer patients treated with an immune checkpoint inhibitor (ICI). A comprehensive literature search was conducted using various databases including PubMed, the Cochrane Library, EMBASE, and Google Scholar. The study was conducted until July 28, 2023. This analysis encompassed a comprehensive evaluation of various clinical outcomes, namely overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). 663 patients from 8 studies were included in this study. It showed that cancer patients with high CONUT score had poorer OS (HR: 1.94, 95% CI, 1.52-2.47, p < 0.001) and PFS (HR: 2.22, 95% CI, 1.48-3.31, p < 0.001), as well as worse ORR (OR: 0.46, 95% CI, 0.25-0.85, p = 0.013) and DCR (HR: 0.29, 95% CI, 0.14-0.59, p = 0.001). The CONUT score can predict the prognosis of tumor patients treated with ICIs.

Role of epithelial sodium channel-related inflammation in human diseases.

The epithelial sodium channel (ENaC) is a heterotrimer and is widely distributed throughout the kidneys, blood vessels, lungs, colons, and many other organs. The basic role of the ENaC is to mediate the entry of Na+ into cells; the ENaC also has an important regulatory function in blood pressure, airway surface liquid (ASL), and endothelial cell function. Aldosterone, serum/glucocorticoid kinase 1 (SGK1), shear stress, and posttranslational modifications can regulate the activity of the ENaC; some ion channels also interact with the ENaC. In recent years, it has been found that the ENaC can lead to immune cell activation, endothelial cell dysfunction, aggravated inflammation involved in high salt-induced hypertension, cystic fibrosis, pseudohypoaldosteronism (PHA), and tumors; some inflammatory cytokines have been reported to have a regulatory role on the ENaC. The ENaC hyperfunction mediates the increase of intracellular Na+, and the elevated exchange of Na+ with Ca2+ leads to an intracellular calcium overload, which is an important mechanism for ENaC-related inflammation. Some of the research on the ENaC is controversial or unclear; we therefore reviewed the progress of studies on the role of ENaC-related inflammation in human diseases and their mechanisms.

Burden and attributable risk factors of ischemic stroke in China from 1990 to 2019: an analysis from the Global Burden of Disease Study 2019.

Background: The epidemiologic characteristics and attributable risk factors of ischemic stroke in China have changed over the past three decades. An up-to-date analysis on deaths, disability-adjusted life-years (DALYs), prevalence, incidence, and attributable risk factors of ischemic stroke for China is needed. This study aims to provide a comprehensive analysis of burden and attributable risk factors of ischemic stroke at national level in China by sex from 1990 to 2019. Methods: This is a secondary analysis of the Global Burden of Disease (GBD) study 2019. All data used in this study was derived from the 2019 GBD study. Deaths, DALYs, prevalence, incidence, and attributable risk factors of ischemic stroke in China by sex from 1990 to 2019 were analyzed. Results: From 1990 to 2019, the age-standardized deaths rate decreased by 3.3%, age-standardized DALYs rate decreased by 4%, age-standardized prevalence rate increased by 33.5%, and age-standardized incidence rate of ischemic stroke in China increased by 34.7%. In 2019, ambient particulate matter pollution became an important risk factor, whereas household air pollution from solid fuels was no longer a major risk factor for ischemic stroke in China. Burden of ischemic stroke was higher in China compared to other regions. Ambient particulate matter pollution among men, and diet high in sodium, smoking, household air pollution from solid fuels among women account for the increased deaths/DALYs due to ischemic stroke in China. Conclusion: Our study revealed that great changes have occurred in burden and attributable risk factors of ischemic stroke in China in the past three decades. Distinct sex-specific differences are observed in burden and attributable risk factors.

Uridine Inhibits Hepatocellular Carcinoma Cell Development by Inducing Ferroptosis.

Uridine is a key metabolite used as a substrate for the production of DNA, RNA, and glucose, and it is mainly synthesized in the liver. Currently, it is not known whether uridine levels are altered in the tumor microenvironment of patients with hepatocellular carcinoma (HCC) and whether uridine can be a target for tumor therapy. In this study, the detection of genes associated with de novo uridine synthesis, carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, dihydroorotase (CAD) (n = 115), and dihydroorotate dehydrogenase (DHODH) (n = 115) in HCC tissues through tissue microarrays revealed that the expression of CAD and DHODH was higher in tumor compared with paraneoplastic tissues. Next, we collected tumor tissues from surgically resected HCC patients and the corresponding adjacent non-tumor tissues (n = 46) for LC-MS/MS assays. The results showed that the median and interquartile ranges of uridine content in non-tumor and tumor tissues were 640.36 (504.45-807.43) and 484.22 (311.91-626.73) nmol/g, respectively. These results suggest that uridine metabolism is disturbed in HCC patients. To further investigate whether uridine can be used as a tumor-therapeutic target, a series of high concentrations of uridine were incubated with HCC cells in vitro and in vivo. It was observed that uridine dose-dependently inhibited the proliferation, invasion, and migration of HCC cells by activating the ferroptosis pathway. Overall, these results reveal for the first time the range of uridine content in human HCC tissues and suggest that uridine may be a new target for HCC therapy.

Simultaneously Enhancing the Flame Retardancy, Water Resistance, and Mechanical Properties of Flame-Retardant Polypropylene via a Linear Vinyl Polysiloxane-Coated Ammonium Polyphosphate.

It is challenging to improve the water resistance, flame retardancy, mechanical performance, and balance of halogen-free flame-retardant polypropylene (PP) composites. For this purpose, a linear vinyl polysiloxane (PD) was synthesized and then self-crosslinked under benzoyl peroxide to prepare surface-coated ammonium polyphosphate (APP@PD). Apparently, this linear vinyl polysiloxane self-crosslinking coating strategy was completely different from the commonly used sol-gel-coated APP with silane monomers. After coating, the water contact angles (WCA) of APP and APP@PD were 26.8° and 111.7°, respectively, showing high hydrophobicity. More importantly, PP/APP@PD/dipentaerythritol (DPER) showed a higher limiting oxygen index (LOI) and better UL-94 V-0 rate in comparison with PP/APP/DPER composites. After water immersion at 70 °C for 168 h, only PP/APP@PD/DPER kept the UL-94 V-0 rate and lowered the deterioration of the LOI, reflecting the better water-resistance property of APP@PD. Consistently, the cone calorimeter test results displayed a 26.2% and 16.7% reduction in peak heat release rate (PHRR) and total smoke production (TSP), respectively. Meanwhile, the time to peak smoke production rate (TPSPR) increased by 90.2%. The interfacial free energy (IFE) between APP@PD and PP was calculated to evaluate the interfacial interaction between PP and APP@PD. A reduction of 84.2% in the IFE between APP@PD and PP is responsible for the improvement in compatibility and the increase in flame retardancy, water resistance, and mechanical properties of the composites.

Targeted Deletion of Rictor in BMSCs Reduces the Biological Activity of K7M2 Cells and Mitigates OS-Induced Bone Destruction.

Bone marrow mesenchymal stem cells (BMSCs) are indispensable cells constituting the bone marrow microenvironment that are generally recognized as being involved in the development and progression of osteosarcoma (OS). To explore whether mTORC2 signaling inhibition in BMSCs suppressed OS growth and tumor-caused bone destruction, 3-month-old littermates genotyped Rictorflox/flox or Prx1-cre; Rictorflox/flox (with same gender) were injected with K7M2 cells in the proximal tibia. After 40 days, bone destruction was alleviated in Prx1-cre; Rictorflox/flox mice, as observed on X-ray and micro-CT. This was accompanied by decreased serum N-terminal propeptide of procollagen type I (PINP) levels and reduced tumor bone formation in vivo. Interactions between K7M2 and BMSCs were studied in vitro. Rictor-deficient BMSCs, which were cultured in tumor-conditioned medium (TCM), caused reduced bone proliferation and suppressed osteogenic differentiation. Moreover, compared with the control group, K7M2 cells cultured in BCM (culture medium extracted from Rictor-deficient BMSCs) displayed less proliferation, migration, and invasion, and attenuated osteogenic activity. Forty types of cytokines were then analyzed by mouse cytokine array and decreased levels CCL2/3/5 and interleukin-16 were detected in Rictor-deficient BMSCs. These results suggested that inhibition of mTORC2 (Rictor) signaling pathway in BMSCs exerted anti-OS effects through 2 mechanisms: (1) by suppressing the proliferation and osteogenic differentiation of BMSCs induced by OS to alleviate bone destruction; (2) by reducing the secretion of cytokines by BMSCs, which are closely related to OS cell growth, migration, invasion, and tumorigenic osteogenesis.