Activation of the YY1-UGT2B7 Axis Promotes Mammary Estrogen Homeostasis Dysregulation and Exacerbates Breast Tumor Metastasis.

Metastasis is the most common pathway of cancer death. The lack of effective predictors of breast cancer metastasis is a pressing issue in clinical practice. Therefore, exploring the mechanism of breast cancer metastasis to uncover reliable predictors is very important for the clinical treatment of breast cancer patients. In this study, tandem mass tag quantitative proteomics technology was used to detect protein content in primary breast tumor tissue samples from patients with metastatic and nonmetastatic breast cancer at diagnosis. We found that the high expression of yin-yang 1(YY1) is strongly associated with poor prognosis in high-grade breast cancer. YY1 expression was detected in both clinical tumor tissue samples and tumor tissue samples from mammary-specific polyomavirus middle T antigen overexpression mouse model mice. We demonstrated that upregulation of YY1 expression was closely associated with breast cancer metastasis and that high YY1 expression could promote the migratory invasive ability of breast cancer cells. Mechanistically, YY1 directly binds to the UGT2B7 mRNA initiation sequence ATTCAT, thereby transcriptionally regulating the inhibition of UGT2B7 expression. UGT2B7 can regulate the development of breast cancer by regulating estrogen homeostasis in the breast, and the abnormal accumulation of estrogen, especially 4-OHE2, promotes the migration and invasion of breast cancer cells, ultimately causing the development of breast cancer metastasis. In conclusion, YY1 can regulate the UGT2B7-estrogen metabolic axis and induce disturbances in estrogen metabolism in breast tumors, ultimately leading to breast cancer metastasis. Disturbances in estrogen metabolism in the breast tissue may be an important risk factor for breast tumor progression and metastasis SIGNIFICANCE STATEMENT: In this study, we propose for the first time a regulatory relationship between YY1 and the UGT2B7/estrogen metabolism axis and explore the molecular mechanism. Our study shows that the YY1/UGT2B7/estrogen axis plays an important role in the development and metastasis of breast cancer. This study further elucidates the potential mechanisms of YY1-mediated breast cancer metastasis and the possibility and promise of YY1 as a predictor of cancer metastasis.

Benzothiazole derivatives as histone deacetylase inhibitors for the treatment of autosomal dominant polycystic kidney disease.

Recent evidence suggests that histone deacetylases (HDACs) are important regulators of autosomal dominant polycystic kidney disease (ADPKD). In the present study, a series of benzothiazole-bearing compounds were designed and synthesized as potential HDAC inhibitors. Given the multiple participation of HDACs in ADPKD cyst progression, we embarked on a targeted screen using HeLa nuclear extracts to identify potent pan-HDAC inhibitors. Compound 26 emerged as the most efficacious candidate. Subsequent pharmacological characterization showed that compound 26 effectively inhibits several HDACs, notably HDAC1, HDAC2, and HDAC6 (IC50 < 150 nM), displaying a particularly high sensitivity towards HDAC6 (IC50 = 11 nM). The selected compound significantly prevented cyst formation and expansion in an in vitro cyst model and was efficacious in reducing cyst growth in both an embryonic kidney cyst model and an in vivo ADPKD mouse model. Our results provided compelling evidence that compound 26 represents a new HDAC inhibitor for the treatment of ADPKD.

Development and validation of a point-of-care nursing mobile tool to guide the diagnosis of malnutrition in hospitalized adult patients: a multicenter, prospective cohort study.

Malnutrition is a prevalent and severe issue in hospitalized patients with chronic diseases. However, malnutrition screening is often overlooked or inaccurate due to lack of awareness and experience among health care providers. This study aimed to develop and validate a novel digital smartphone-based self-administered tool that uses facial features, especially the ocular area, as indicators of malnutrition in inpatient patients with chronic diseases. Facial photographs and malnutrition screening scales were collected from 619 patients in four different hospitals. A machine learning model based on back propagation neural network was trained, validated, and tested using these data. The model showed a significant correlation (p < 0.05) and a high accuracy (area under the curve 0.834-0.927) in different patient groups. The point-of-care mobile tool can be used to screen malnutrition with good accuracy and accessibility, showing its potential for screening malnutrition in patients with chronic diseases.

An alternative peptone preparation using Hermetia illucens (Black soldier fly) hydrolysis: process optimization and performance evaluation.

Background: Hermetia illucens (HI), commonly known as the black soldier fly, has been recognized for its prowess in resource utilization and environmental protection because of its ability to transform organic waste into animal feed for livestock, poultry, and aquaculture. However, the potential of the black soldier fly's high protein content for more than cheap feedstock is still largely unexplored. Methods: This study innovatively explores the potential of H. illucens larvae (HIL) protein as a peptone substitute for microbial culture media. Four commercial proteases (alkaline protease, trypsin, trypsase, and papain) were explored to hydrolyze the defatted HIL, and the experimental conditions were optimized via response surface methodology experimental design. The hydrolysate of the defatted HIL was subsequently vacuum freeze-dried and deployed as a growth medium for three bacterial strains (Staphylococcus aureus, Bacillus subtilis, and Escherichia coli) to determine the growth kinetics between the HIL peptone and commercial peptone. Results: The optimal conditions were 1.70% w/w complex enzyme (alkaline protease: trypsin at 1:1 ratio) at pH 7.0 and 54 °C for a duration of 4 h. Under these conditions, the hydrolysis of defatted HIL yielded 19.25% ±0.49%. A growth kinetic analysis showed no significant difference in growth parameters (µmax, Xmax, and λ) between the HIL peptone and commercial peptone, demonstrating that the HIL hydrolysate could serve as an effective, low-cost alternative to commercial peptone. This study introduces an innovative approach to HIL protein resource utilization, broadening its application beyond its current use in animal feed.

Modulation of the RAC1/MAPK/ERK signalling pathway by farnesyl diphosphate synthase regulates granulosa cells proliferation in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a complex gynaecological endocrine disease that occurs in women of childbearing age. The pathogenesis of PCOS is still unclear and further exploration is needed. Here, proteomic analysis indicated that the expression of farnesyl diphosphate synthase (FDPS) protein in ovarian tissue of PCOS mice was significantly decreased. The purpose of this study is to investigate the relationship between potential biomarkers of PCOS and granulosa cells (GCs) function. The mechanisms by which FDPS affected the proliferation of granulosa cells were also explored both in vitro and in vivo. We found that knockdown of FDPS inhibited the proliferation of KGN (human ovarian granulosa cell line), while overexpression of FDPS had the opposite effect. FDPS activated Rac1 (Rac Family Small GTPase 1) activity and regulated MAPK/ERK signalling pathway, which affecting the proliferation of KGN cells significantly. In addition, treatment with the adeno-associated virus (AAV)-FDPS reverses the dehydroepiandrosterone (DHEA)-induced PCOS-phenotype in mice. Our data indicated that FDPS could regulate the proliferation of ovarian GCs by modulating MAPK/ERK (mitogen-activated protein kinase/extracellular regulated protein kinases) pathway via activating Rac1 activity. These findings suggest that FDPS could be of great value for the regulation of ovarian granulosa cell function and the treatment of PCOS.

Long-Residence Time Peptide Antagonist for the Vasopressin V2 Receptor to Treat Autosomal Dominant Polycystic Kidney Disease.

The dysregulated intracellular cAMP in the kidneys drives cystogenesis and progression in autosomal dominant polycystic kidney disease (ADPKD). Mounting evidence supports that vasopressin V2 receptor (V2R) antagonism effectively reduces cAMP levels, validating this receptor as a therapeutic target. Tolvaptan, an FDA-approved V2R antagonist, shows limitations in its clinical efficacy for ADPKD treatment. Therefore, the pursuit of better-in-class V2R antagonists with an improved efficacy remains pressing. Herein, we synthesized a set of peptide V2R antagonists. Peptide 33 exhibited a high binding affinity for the V2R (Ki = 6.1 ± 1.5 nM) and an extended residence time of 20 ± 1 min, 2-fold that of tolvaptan. This prolonged interaction translated into sustained suppression of cAMP production in washout experiments. Furthermore, peptide 33 exhibited improved efficacies over tolvaptan in both ex vivo and in vivo models of ADPKD, underscoring its potential as a promising lead compound for the treatment of ADPKD.

Jujuboside A Attenuates Polycystic Ovary Syndrome Based on Estrogen Metabolism Through Activating AhR-mediated CYP1A2 Expression.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women. This study aimed to investigate the therapeutic effects and mechanism of Jujuboside A on PCOS using a dehydroepiandrosterone (DHEA)-induced PCOS mouse model. Estrogen and androgen homeostasis was evaluated in serum from both clinical samples and PCOS mice. The stages of the estrous cycle were determined based on vaginal cytology. The ovarian morphology was observed by stained with hematoxylin and eosin. Moreover, we analyzed protein expression of cytochrome P450 1A1 (CYP1A1), cytochrome P450 1A2 (CYP1A2) and aryl hydrocarbon receptor (AhR) in ovary and KGN cells. Molecular docking, immunofluorescence, and luciferase assay were performed to confirm the activation of AhR by Jujuboside A. Jujuboside A effectively alleviated the disturbance of estrogen homeostasis and restored ovarian function, leading to an improvement in the occurrence and progression of PCOS. Furthermore, the protective effect of JuA against PCOS was dependent on increased CYP1A2 levels regulated by AhR. Our findings suggest that Jujuboside A improves estrogen disorders and may be a potential therapeutic agent for the treatment of PCOS.

16α-OHE1 alleviates hypoxia-induced inflammation and myocardial damage via the activation of ß2-Adrenergic receptor.

OBJECTIVE: Myocardial injuries resulting from hypoxia are a significant concern, and this study aimed to explore potential protective strategies against such damage. Specifically, we sought to investigate the cardioprotective effects of 16α-hydroxyestrone (16α-OHE1). METHODS: Male Sprague‒Dawley (SD) rats were subjected to hypoxic conditions simulating high-altitude exposure at 6000 m in a low-pressure chamber for 7 days. Before and during hypoxic exposure, estradiol (E2) and various doses of 16α-OHE1 were administered for 14 days. Heart weight/body weight (HW/BW), myocardial structure, Myocardial injury indicators and inflammatory infiltration in rats were measured. H9C2 cells cultured under 5% O2 conditions received E2 and varying doses of 16α-OHE1; Cell viability, apoptosis, inflammatory infiltration, and Myocardial injury indicators were determined. Expression levels of ß2AR were determined in rat hearts and H9C2 cells. The ß2AR inhibitor, ICI 118,551, was employed to investigate ß2AR's role in 16α-OHE1's cardioprotective effects. RESULTS: Hypoxia led to substantial myocardial damage, evident in increased heart HW, CK-MB, cTnT, ANP, BNP, structural myocardial changes, inflammatory infiltration, and apoptosis. Pre-treatment with E2 and 16α-OHE1 significantly mitigated these adverse changes. Importantly, the protective effects of E2 and 16α-OHE1 were associated with the upregulation of ß2AR expression in both rat hearts and H9C2 cells. However, inhibition of ß2AR by ICI 118,551 in H9C2 cells nullified the protective effect of 16α-OHE1 on myocardium. CONCLUSION: Our findings suggest that 16α-OHE1 can effectively reduce hypoxia-induced myocardial injury in rats through ß2ARs, indicating a promising avenue for cardioprotection.

Metformin: A promising clinical therapeutical approach for BPH treatment via inhibiting dysregulated steroid hormones-induced prostatic epithelial cells proliferation.

The occurrence of benign prostate hyperplasia (BPH) was related to disrupted sex steroid hormones, and metformin (Met) had a clinical response to sex steroid hormone-related gynaecological disease. However, whether Met exerts an antiproliferative effect on BPH via sex steroid hormones remains unclear. Here, our clinical study showed that along with prostatic epithelial cell (PEC) proliferation, sex steroid hormones were dysregulated in the serum and prostate of BPH patients. As the major contributor to dysregulated sex steroid hormones, elevated dihydrotestosterone (DHT) had a significant positive relationship with the clinical characteristics of BPH patients. Activation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) by Met restored dysregulated sex steroid hormone homeostasis and exerted antiproliferative effects against DHT-induced proliferation by inhibiting the formation of androgen receptor (AR)-mediated Yes-associated protein (YAP1)-TEA domain transcription factor (TEAD4) heterodimers. Met's anti-proliferative effects were blocked by AMPK inhibitor or YAP1 overexpression in DHT-cultured BPH-1 cells. Our findings indicated that Met would be a promising clinical therapeutic approach for BPH by inhibiting dysregulated steroid hormone-induced PEC proliferation.

ACSL1-Mediated Fatty Acid ß-Oxidation Enhances Metastasis and Proliferation in Endometrial Cancer.

BACKGROUND: Gynecological malignancies, such as endometrial cancer (EC) and uterine cancer are prevalent. Increased Acyl-CoA synthetase long-chain family member 1 (ACSL1) activity may contribute to aberrant lipid metabolism, which is a potential factor that contributes to the pathogenesis of endometrial cancer. This study aimed to elucidate the potential molecular mechanisms by which ACSL1 is involved in lipid metabolism in endometrial cancer, providing valuable insights for targeted therapeutic strategies. METHODS: Xenograft mouse models were used to assess the effect of ACSL1 on the regulation of endometrial cancer progression. ACSL1 protein levels were assessed via immunohistochemistry and immunoblotting analysis. To assess the migratory potential of Ishikawa cells, wound-healing and Transwell invasion assays were performed. Changes in lipids in serum samples from mice with endometrial cancer xenotransplants were examined in an untargeted lipidomic study that combined multivariate statistical methods with liquid chromatography‒mass spectrometry (LC/MS). RESULTS: Patient sample and tissue microarray data suggested that higher ACSL1 expression is strongly associated with the malignant progression of EC. Overexpression of ACSL1 enhances fatty acid ß-oxidation and 5'-adenylate triphosphate (ATP) generation in EC cells, promoting cell proliferation and migration. Lipidomic analysis revealed that significant changes were induced by ACSL1, including changes to 28 subclasses of lipids and a total of 24,332 distinct lipids that were detected in both positive and negative ion modes. Moreover, pathway analysis revealed the predominant association of these lipid modifications with the AMPK/CPT1C/ATP pathway and fatty acid ß-oxidation. CONCLUSIONS: This study indicates that ACSL1 regulates the AMPK/CPT1C/ATP pathway, which induces fatty acid ß-oxidation, promotes proliferation and migration, and then leads to the malignant progression of EC.

Analysis of the Molecular Mechanism of Xueshuantong in the Treatment of Wet Age-Related Macular Degeneration (AMD) Using GEO Datasets, Network Pharmacology, and Molecular Docking.

At present, the main treatment method for wet AMD is single anti-VEGF therapy, which can require multiple injections, is costly and may have poor efficacy. Studies and clinical experiments have shown that the oral Chinese medicine Xueshuantong combined with anti-VEGF therapy is more effective, and this study aims to explore the molecular mechanism. The TCMSP database was used to identify the main Xueshuantong components. The PubChem database and SWISS Target Prediction data were used to find the SMILES molecular formulas of compounds and corresponding target genes and disease-related genes were searched using the GEO, DisGeNET, and GeneCards databases. Venny was used to identify the intersecting wet AMD-related genes and Xueshuantong targets and Cytoscape software was used to construct direct links between the drug components and disease targets. Then, PPI networks were constructed using the STRING website. R software was used for GO and KEGG enrichment analyses. Cytoscape software was used for topological analyses, and AutoDock Vina v.1.1.2 software was used for molecular docking. 64 compounds corresponding to four drugs were found by the TCMSP database, 1001 total drug targets were found by the PubChem database, 607 wet AMD target genes were found by the GEO, DisGeNET, and GeneCards databases, and 87 Xueshuantong target genes for wet AMD were obtained. Then, by constructing the drug component and disease target network and PPI network, we found that the components closely interacted with VEGF, TNF, caspase 3, CXCL8, and AKT1, which suggested that the therapeutic effects might be related to the inhibition of neovascularization, inflammation, and AKT pathway. Then, GO enrichment analysis showed that the biological processes response to hypoxia, positive regulation of angiogenesis, and inflammatory response were enriched. KEGG enrichment results showed that the HIF-1 and pi3k-akt pathways may mediate the inhibition of wet AMD by Xueshuantong. Topological analysis results identified 10 key proteins, including VEGF, TNF, AKT1, and TLR4. The results of molecular docking also confirmed their strong binding to their respective compounds. In this study, it was confirmed that Xueshuantong could inhibit wet AMD by targeting VEGF, TNF, TLR4, and AKT1, multichannel HIF-1, and the PI3K-AKT pathway, which further proved the therapeutic effects of Xueshuantong combined with single anti-VEGF therapy on wet AMD and provided new insights into the study of novel molecular drug targets for the treatment of wet AMD.

Assessing the Redox Toxicity of 2D Nanosheets Based on Their Redox Effect on Cytochrome c in Microchannels.

2D nanosheets (NSs) have been widely used in drug-related applications. However, a comprehensive investigation into the cytotoxicity mechanism linked to the redox activity is lacking. In this study, with cytochrome c (Cyt c) as the model biospecies, the cytotoxicity of 2D NSs was evaluated systematically based on their redox effect with microfluidic techniques. The interface interaction, dissolution, and redox effect of 2D NSs on Cyt c were monitored with pulsed streaming potential (SP) measurement and capillary electrophoresis (CE). The relationship between the redox activity of 2D NSs and the function of Cyt c was evaluated in vitro with Hela cells. The results indicated that the dissolution and redox activity of 2D NSs can be simultaneously monitored with CE under weak interface interactions and at low sample volumes. Both WS2 NSs and MoS2 NSs can reduce Cyt c without significant dissolution, with reduction rates measured at 6.24 × 10-5 M for WS2 NSs and 3.76 × 10-5 M for MoS2 NSs. Furthermore, exposure to 2D NSs exhibited heightened reducibility, which prompted more pronounced alterations associated with Cyt c dysfunction, encompassing ATP synthesis, modifications in mitochondrial membrane potential, and increased reactive oxygen species production. These observations suggest a positive correlation between the redox activity of 2D NSs and their redox toxicity in Hela cells. These findings provide valuable insight into the redox properties of 2D NSs regarding cytotoxicity and offer the possibility to modify the 2D NSs to reduce their redox toxicity for clinical applications.

Antibacterial activity of a polysaccharide isolated from Artemisia argyi leaf against Staphylococcus aureus and mechanism investigation.

Abuse of antibiotics has led to excessive amounts of antibiotic residues in food and environment, thus enhancing pathogenic bacterium resistance and threatening human health. Therefore, searching and developing safe and green antibiotic alternatives are necessary. In this study, an Artemisia argyi leaf polysaccharide (AALP) fraction was extracted and analyzed. Chemical composition analysis showed that the carbohydrate, uronic acid, protein, and polyphenol content in AALP were 68.3 % ± 4.13 %, 9.4 % ± 0.86 %, 1.79 % ± 0.27 %, and 0.16 % ± 0.035 %, respectively. Chromatographic results suggested that AALP contained rhamnose, arabinose, glucosamine, galactose, glucose, xylose, mannose, galacturonic acid, and glucuronic acid in a molar ratio of 9.26, 1.35, 1.18, 3.04, 48.51, 2.33, 31.26, 3.93, and 9.08; the weight average molecular weight, number average molecular weight, and polydispersity of AALP were 5.41 kDa, 4.63 kDa, and 1.168, respectively. Fourier transform infrared spectroscopy indicated that AALP constituted the polysaccharide-specific groups of CH, CO, and OH. Meanwhile, AALP showed a dose-dependent inhibitory effect on Staphylococcus aureus in the inhibition zone assay, and the minimal inhibitory concentration was 1.25 mg/mL. Furthermore, AALP disrupted the cell wall, depolarized the inner membrane potential, and inhibited the activities of succinate dehydrogenase and malate dehydrogenase in S. aureus.

Bibliometric analysis of the Vogt‒Koyanagi‒Harada disease literature.

PURPOSE: As an autoimmune disease, Vogt‒Koyanagi‒Harada disease (VKHD) is a main type of uveitis in many countries and regions, significantly impacting patient vision. At present, information regarding VKHD is still limited, and further research is needed. We conducted a bibliometric analysis to characterize the overall status, current trends, and current focus of VKHD research. METHOD: Literature published from 1975 to 2022 was obtained from the Web of Science core collection and analysed with the R-language packages Bibliometrix, VOSviewer, and CiteSpace software. RESULTS: A total of 1050 papers on VKHD were retrieved from 261 journals, and 16,084 references were obtained from the papers in the original search. The average annual number of published articles was approximately 21.9, and the number of publications rapidly increased after 2004. The journal Ocular Immunology and Inflammation published the most papers on VKHD, while the American Journal of Ophthalmology has the highest citation frequency. The leading countries were Japan, China (PRC), and the United States of America (USA). Yang PZ from Chongqing Medical University was the most prolific and cited author. The most frequently cited study discussed revision of VKHD diagnostic criteria. An analysis of the highest frequency keywords showed that most research focused on the treatment, diagnosis, and pathogenesis of VKHD and its relationship with other related diseases. At present, the most urgent research direction is in the relationship between COVID-19 or COVID-19 vaccines and VKHD and the corresponding mechanisms underlying it. CONCLUSION: Utilizing dynamic and visualization tools, bibliometrics provides a clear depiction of the research history, development trends, and research hotspots in VKHD It serves as a valuable tool for identifying research gaps and areas that necessitate further exploration. Our study revealed potential directions for future VKHD research, including investigating specific molecular mechanisms underlying the disease, exploring the clinical utility of optical coherence tomography angiography and other diagnostic techniques, and conducting clinical research on novel therapeutic drugs.

N6-methyladenosine methylation regulator RBM15 promotes the progression of diabetic nephropathy by regulating cell proliferation, inflammation, oxidative stress, and pyroptosis through activating the AGE-RAGE pathway.

BACKGROUND: Diabetic nephropathy (DN) is a major cause of end-stage renal disease throughout the world, and m6A modification plays a critical role in the progression of DN. We aimed to find m6A-related genes and their regulatory mechanisms in DN. METHODS: The expression levels of four important m6A-related genes (METTL16, RBM15, IGF2BP1, and ALKBH5) were detected by quantitative real-time PCR (RT-qPCR). RBM15 was chosen and its function was explored. The downstream pathway of RBM15 was screened by transcriptome sequencing. The levels of AGE, inflammation, and oxidative stress were determined with enzyme-linked immunosorbent assay, and the expression of AGE-RAGE pathway-related proteins were detected by Western blot (WB). Cell proliferation was assessed by Cell counting Kit-8 (CCK-8). The levels of pyroptosis-related proteins were evaluated by RT-qPCR or WB. RESULTS: METTL16 and RBM15 were up regulated in the mouse model of DN, in which RBM15 was more significant. Silencing RBM15 recovered cell proliferation, reduced the levels of inflammation factors, and inhibited cell pyroptosis in high glucose-induced HK-2 cells. Transcriptome sequencing suggested that the AGE-RAGE pathway might be downstream of RBM15. RBM15 knockdown reduced AGE level and the expression of AGE-RAGE pathway-related proteins. After silencing RBM15, we found that activating the AGE-RAGE pathway inhibited cell proliferation, increased the levels of inflammation factors, promoted oxidative stress, and induced cell pyroptosis in HK-2 cell model of DN. CONCLUSION: The m6A-related gene RBM15 inhibited cell proliferation, promoted inflammation, oxidative stress, and cell pyroptosis, thereby facilitating the progression of DN through the activation of the AGE-RAGE pathway.

N-3, a novel synthetic derivative of bifendate, inhibits metastasis of triple-negative breast cancer via decreasing p38-regulated FOXC1 protein stability.

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with high invasiveness, metastatic potential, and poor prognosis. Epithelial-mesenchymal transition (EMT) is pivotal in TNBC progression, becoming a promising target for TNBC treatment. Our study evaluated N-3, a novel synthetic bifendate derivative, which inhibited the EMT-associated migration and invasion of MDA-MB-231 and 4T1 TNBC cells. The results were consistent with the suppression of FOXC1 expression and transcriptional activity. Additional studies indicated that N-3 reduced the protein stability of FOXC1 by enhancing ubiquitination and degradation. Moreover, N-3 downregulated p-p38 expression and FOXC1 interaction, decreasing the stability of p38-regulated FOXC1. Further, N-3 blocked TNBC metastasis with an artificial lung metastasis model in vivo, related to FOXC1 suppression and EMT. These results highlight the potential of N-3 as a TNBC metastasis treatment. Therefore, FOXC1 regulation could be a novel targeted therapeutic strategy for TNBC metastasis.

Parametric maps of spatial two-tissue compartment model for prostate dynamic contrast enhanced MRI - comparison with the standard tofts model in the diagnosis of prostate cancer.

The spatial two-tissue compartment model (2TCM) was used to analyze prostate dynamic contrast enhanced (DCE) MRI data and compared with the standard Tofts model. A total of 29 patients with biopsy-confirmed prostate cancer were included in this IRB-approved study. MRI data were acquired on a Philips Achieva 3T-TX scanner. After T2-weighted and diffusion-weighted imaging, DCE data using 3D T1-FFE mDIXON sequence were acquired pre- and post-contrast media injection (0.1 mmol/kg Multihance) for 60 dynamic scans with temporal resolution of 8.3 s/image. The 2TCM has one fast ([Formula: see text] and [Formula: see text]) and one slow ([Formula: see text] and [Formula: see text]) exchanging compartment, compared with the standard Tofts model parameters (Ktrans and kep). On average, prostate cancer had significantly higher values (p < 0.01) than normal prostate tissue for all calculated parameters. There was a strong correlation (r = 0.94, p < 0.001) between Ktrans and [Formula: see text] for cancer, but weak correlation (r = 0.28, p < 0.05) between kep and [Formula: see text]. Average root-mean-square error (RMSE) in fits from the 2TCM was significantly smaller (p < 0.001) than the RMSE in fits from the Tofts model. Receiver operating characteristic (ROC) analysis showed that fast [Formula: see text] had the highest area under the curve (AUC) than any other individual parameter. The combined four parameters from the 2TCM had a considerably higher AUC value than the combined two parameters from the Tofts model. The 2TCM is useful for quantitative analysis of prostate DCE-MRI data and provides new information in the diagnosis of prostate cancer.

Regulation strategy, bioactivity, and physical property of plant and microbial polysaccharides based on molecular weight.

Structural features affect the bioactivity, physical property, and application of plant and microbial polysaccharides. However, an indistinct structure-function relationship limits the production, preparation, and utilization of plant and microbial polysaccharides. Molecular weight is an easily regulated structural feature that affects the bioactivity and physical property of plant and microbial polysaccharides, and plant and microbial polysaccharides with a specific molecular weight are important for exerting their bioactivity and physical property. Therefore, this review summarized the regulation strategies of molecular weight via metabolic regulation; physical, chemical, and enzymic degradations; and the influence of molecular weight on the bioactivity and physical property of plant and microbial polysaccharides. Moreover, further problems and suggestions must be paid attention to during regulation, and the molecular weight of plant and microbial polysaccharides must be analyzed. The present work will promote the production, preparation, utilization, and investigation of the structure-function relationship of plant and microbial polysaccharides based on their molecular weight.

16α-OHE1, a novel oestrogen metabolite, attenuates dysfunction of left ventricle contractility via regulation of autophagy after myocardial ischemia and reperfusion.

BACKGROUND: Myocardial ischemia-reperfusion (MI/R) can exacerbate the initial cardiac damage in the myocardial functional changes, including dysfunction of left ventricular contractility. Oestrogen has been proven to protect the cardiovascular system. However, whether the oestrogen or its metabolites play the main role in attenuating dysfunction of left ventricular contractility is unknown. METHODS AND RESULTS: This study used the LC-MS/MS to detect oestrogen and its metabolites in clinical serum samples (n = 62) with heart diseases. After correlation analysis with markers of myocardial injury including cTnI (P < 0.01), CK-MB (P < 0.05), and D-Dimer (P < 0.001), 16α-OHE1 was identified. The result from LC-MS/MS in female and ovariectomised (OVX) rat serum samples (n = 5) matched the findings in patients. In MI/R model of animal, the recovery of left ventricular developed pressure (LVDP), rate pressure product (RPP), dp/dtmax and dp/dtmin after MI/R in OVX or male group were worsened than those in female group. Also, the infarction area of OVX or male group was larger than that in females (n = 5, p < 0.01). Furthermore, LC3 II in the left ventricle of OVX and male group was lower than that in females (n = 5, p < 0.01) by immunofluorescence. In H9C2 cells, after the application of 16α-OHE1, the number of autophagosomes was further increased and other organelles improved in MI/R. Simultaneously, LC3 II, Beclin1, ATG5, and p-AMPK/AMPK were increased, and p-mTOR/mTOR was decreased (n = 3, p < 0.01) by Simple Western. CONCLUSION: 16α-OHE1 could attenuate left ventricle contractility dysfunction via autophagy regulation after MI/R, which also offered fresh perspectives on therapeutical treatment for attenuating MI/R injury.

Inhibition of the maize salt overly sensitive pathway by ZmSK3 and ZmSK4.

Soil salinity is a worldwide problem that adversely affects plant growth and crop productivity. The salt overly sensitive (SOS) pathway is evolutionarily conserved and essential for plant salt tolerance. In this study, we reveal how the maize shaggy/glycogen synthase kinase 3-like kinases ZmSK3 and ZmSK4, orthologs of brassinosteroid insensitive 2 in Arabidopsis thaliana, regulate the maize SOS pathway. ZmSK3 and ZmSK4 interact with and phosphorylate ZmSOS2, a core member of the maize SOS pathway. The mutants defective in ZmSK3 or ZmSK4 are hyposensitive to salt stress, with higher salt-induced activity of ZmSOS2 than that in the wild type. Furthermore, the Ca2+ sensors ZmSOS3 and ZmSOS3-like calcium binding protein 8 (ZmSCaBP8) activate ZmSOS2 to maintain Na+/K+ homeostasis under salt stress and may participate in the regulation of ZmSOS2 by ZmSK3 and ZmSK4. These findings discover the regulation of the maize SOS pathway and provide important gene targets for breeding salt-tolerant maize.