Effects of different oil fractions and tannic acid concentrations on konjac glucomannan-stabilized emulsions.

Polysaccharide-stabilized emulsions have received extensive attention, but emulsifying activity of polysaccharides is poor. In this study, konjac glucomannan (KGM) and tannic acid (TA) complex (KGM-TA) was prepared via non-covalent binding to increase the polysaccharide interfacial stability. The emulsifying stabilities of KGM-TA complex-stabilized emulsions were analyzed under different TA concentrations and oil fractions. The results indicated that hydrogen bonds and hydrophobic bonds were the main binding forces for KGM-TA complex, which were closely related to TA concentrations. The interfacial tension of KGM-TA complex decreased from 20.0 mN/m to 13.4 mN/m with TA concentration increasing from 0 % to 0.3 %, indicating that TA improved the interfacial activity of KGM. Meanwhile, the contact angle of KGM-TA complex was closer to 90° with the increasing TA concentrations. The emulsifying stability of KGM-TA complex-stabilized emulsions increased in an oil mass fraction-dependent manner, reaching the maximum at 75 % oil mass fraction. Moreover, the droplet sizes of KGM-TA complex-stabilized high-internal-phase emulsions (HIPEs) decreased from 82.7 µm to 44.7 µm with TA concentration increasing from 0 to 0.3 %. Therefore, high TA concentrations were conducive to the improvement of the emulsifying stability of KGM-TA complex-stabilized HIPEs. High oil mass fraction promoted the interfacial contact of adjacent droplets, thus enhancing the non-covalent binding of KGM molecules at the interfaces with TA as bridges. Additionally, the high TA concentrations increased the gel network density in the aqueous phase, thus enhancing the emulsifying stability of emulsions. Our findings reveal the mechanisms by which polysaccharide-polyphenol complex stabilized HIPEs. Therefore, this study provides theoretical basis and references for the developments of polysaccharide emulsifier with high emulsifying capability and high-stability emulsions.

Effects and plasma proteomic analysis of GLP-1RA versus CPA/EE, in combination with metformin, on overweight PCOS women: a randomized controlled trial.

PURPOSE: Polycystic ovary syndrome (PCOS) is characterized by reproductive dysfunctions and metabolic disorders. This study aims to compare the therapeutic effectiveness of glucagon-like peptide-1 receptor agonist (GLP-1RA) + Metformin (Met) versus cyproterone acetate/ethinylestradiol (CPA/EE) + Met in overweight PCOS women and identify potential proteomic biomarkers of disease risk in women with PCOS. METHODS: In this prospective, open-label randomized controlled trial, we recruited 60 overweight PCOS women into two groups at a 1:1 ratio to receive CPA/EE (2 mg/day: 2 mg cyproterone acetate and 35-µg ethinylestradiol,) +Met (1500 mg/day) or GLP-1 RA (liraglutide, 1.2-1.8 mg/day) +Met (1500 mg/day) for 12 weeks. The clinical effectiveness and adverse effects were evaluated, followed by plasma proteomic analysis and verification of critical biomarkers by ELISA. RESULTS: Eighty(80%) patients completed the study. Both interventions improved menstrual cycle, polycystic ovaries, LH(luteinizing hormone) and HbA1c(hemoglobin A1c) levels after the 12-week treatment. GLP-1RA + Met was more effective than CPA/EE + Met in reducing body weight, BMI (Body Mass Index), and waist circumference, FBG(fasting blood glucose), AUCI(area under curve of insulin),TC (Total Cholesterol), IL-6(Interleukin-6) and improving insulin sensitivity, and ovulation in overweight women with PCOS, with acceptable short-term side effects. CPA/EE + Met was more effective in improving hyperandrogenemia, including T(total testosterone), LH, LH/FSH(Luteinizing hormone/follicle-stimulating hormone), SHBG(sex hormone-binding globulin) and FAI (free androgen index). By contract, GLP-1RA+Met group only improved LH. Plasma proteomic analysis revealed that the interventions altered proteins involved in reactive oxygen species detoxification (PRDX6, GSTO1, GSTP1, GSTM2), platelet degranulation (FN1), and the immune response (SERPINB9). CONCLUSIONS: Both CPA/EE+Met and GLP-1RA + Met treatment improved reproductive functions in overweight PCOS women. GLP-1RA + Met was more effective than CPA/EE + Met in reducing body weight, BMI, and waist, and improving metabolism, and ovulation in overweight women with PCOS, with acceptable short-term side effects. CPA/EE + Met was more effective in reducing hyperandrogenemia. The novel plasma biomarkers PRDX6, FN1, and SERPINB9, might be indicators and targets for PCOS treatment. TRIAL REGISTRATION CLINICALTIALS. GOV TRIAL NO: NCT03151005. Registered 12 May, 2017, https://clinicaltrials.gov/ct2/show/NCT03151005 .

ncRNADrug: a database for validated and predicted ncRNAs associated with drug resistance and targeted by drugs.

Drug resistance is a major barrier in cancer treatment and anticancer drug development. Growing evidence indicates that non-coding RNAs (ncRNAs), especially microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), play pivotal roles in cancer progression, therapy, and drug resistance. Furthermore, ncRNAs have been proven to be promising novel therapeutic targets for cancer treatment. Reversing dysregulated ncRNAs by drugs holds significant potential as an effective therapeutic strategy for overcoming drug resistance. Therefore, we developed ncRNADrug, an integrated and comprehensive resource that records manually curated and computationally predicted ncRNAs associated with drug resistance, ncRNAs targeted by drugs, as well as potential drug combinations for the treatment of resistant cancer. Currently, ncRNADrug collects 29 551 experimentally validated entries involving 9195 ncRNAs (2248 miRNAs, 4145 lncRNAs and 2802 circRNAs) associated with the drug resistance of 266 drugs, and 32 969 entries involving 10 480 ncRNAs (4338 miRNAs, 6087 lncRNAs and 55 circRNAs) targeted by 965 drugs. In addition, ncRNADrug also contains associations between ncRNAs and drugs predicted from ncRNA expression profiles by differential expression analysis. Altogether, ncRNADrug surpasses the existing related databases in both data volume and functionality. It will be a useful resource for drug development and cancer treatment. ncRNADrug is available at http://www.jianglab.cn/ncRNADrug.

DDX5 Functions as a Tumor Suppressor in Tongue Cancer.

DEAD-box polypeptide 5 (DDX5), a DEAD-box RNA helicase, is a multifunctional protein that plays important roles in many physiological and pathological processes. Contrary to its documented oncogenic role in a wide array of cancers, we herein demonstrate that DDX5 serves as a tumor suppressor in tongue cancer. The high expression of DDX5 is correlated with better prognosis for clinical tongue cancer patients. DDX5 downregulates the genes associated with tongue cancer progression. The knockdown of DDX5 promotes, while the overexpression of DDX5 inhibits, tongue cancer proliferation, development, and cisplatin resistance. Furthermore, the expression of DDX5 in tongue cancer is associated with immune cell infiltration in the tumor microenvironment. Specifically, the expression of DDX5 is associated with the reduced infiltration of M2 macrophages and increased infiltration of T cell clusters, which may contribute to anticancer effects in the tumor microenvironment. In this study, we establish DDX5 as a valuable prognostic biomarker and an important tumor suppressor in tongue cancer.

Molecular Engineering Design of Enhanced Donor-Acceptor Therapeutic Reagent for Efficient Image-Guided Photodynamic Therapy.

The greatest barrier to the further development and clinical application of tumor image-guided photodynamic therapy (PDT), is the inconsistency between the fluorescence intensity and singlet oxygen generation yield of the photosensitizer under light excitation. Herein, a novel donor-acceptor (D-A) system is designed from the point of molecular selection by wrapping a classical porphyrin molecule (5,10,15,20-tetraphenylphorphyrin, H2 TPP) as an acceptor into conjugated polymer (Poly[N,N'-bis(4-butylpheny)-N,N'-bis(phenyl)benzidine], ADS254BE) as a donor through fluorescence resonance energy transfer (FRET) mechanism, which exhibits bright red emission centered at 650 nm (quantum yield, 0.12), relatively large Stoke shift of 276 nm, enhanced singlet oxygen generation rate of 0.73, and excellent photostability. The investigations on distribution and killing effect of nanomaterials in cancer cells reveal that ADS254BE/H2 TPP NPs can accumulate in the cytoplasm for imaging while simultaneously producing a large amount of singlet oxygen to remarkably kill cancer cells, which can be used for real-time image-guided PDT. In the xenograft tumor model, real-time imaging and long-term tracing in tumor tissue with ADS254BE/H2 TPP NPs disclose that the growth of lung cancer in mice can be effectively inhibited during in situ imaging. From the standpoint of molecular engineering design, this work provides a feasible strategy for novel D-A systems to improve the development of image-guided PDT.

Single-cell transcriptome sequencing-based analysis: probing the mechanisms of glycoprotein NMB regulation of epithelial cells involved in silicosis.

Chronic exposure to silica can lead to silicosis, one of the most serious occupational lung diseases worldwide, for which there is a lack of effective therapeutic drugs and tools. Epithelial mesenchymal transition plays an important role in several diseases; however, data on the specific mechanisms in silicosis models are scarce. We elucidated the pathogenesis of pulmonary fibrosis via single-cell transcriptome sequencing and constructed an experimental silicosis mouse model to explore the specific molecular mechanisms affecting epithelial mesenchymal transition at the single-cell level. Notably, as silicosis progressed, glycoprotein non-metastatic melanoma protein B (GPNMB) exerted a sustained amplification effect on alveolar type II epithelial cells, inducing epithelial-to-mesenchymal transition by accelerating cell proliferation and migration and increasing mesenchymal markers, ultimately leading to persistent pulmonary pathological changes. GPNMB participates in the epithelial-mesenchymal transition in distant lung epithelial cells by releasing extracellular vesicles to accelerate silicosis. These vesicles are involved in abnormal changes in the composition of the extracellular matrix and collagen structure. Our results suggest that GPNMB is a potential target for fibrosis prevention.

Discovery of berberine analogs as potent and highly selective p300/CBP HAT inhibitors.

The protein p300 is a positive regulator of cancer progression and is related to many human pathological conditions. To find effective p300/CBP HAT inhibitors, we screened an internal compound library and identified berberine as a lead compound. Next, we designed, synthesized, and screened a series of novel berberine analogs, and discovered that analog 5d was a potent and highly selective p300/CBP HAT inhibitor with IC50 values of 0.070 µM and 1.755 µM for p300 and CBP, respectively. Western blotting further proved that 5d specifically decreased H3K18Ac and interfere with the function of histone acetyltransferase. Although 5d had only a moderate inhibitory effect on the MDA-MB-231 cell line, 5d suppressed the growth of 4T1 tumor growth in mice with a tumor weight inhibition ratio (TWI) of 39.7%. Further, liposomes-encapsulated 5d increased its inhibition of tumor growth to 57.8 % TWI. In addition, 5d has no obvious toxicity to the main organ of mice and the pharmacokinetic study confirmed that 5d has good absorption properties in vivo.

scDR: Predicting Drug Response at Single-Cell Resolution.

Heterogeneity exists inter- and intratumorally, which might lead to different drug responses. Therefore, it is extremely important to clarify the drug response at single-cell resolution. Here, we propose a precise single-cell drug response (scDR) prediction method for single-cell RNA sequencing (scRNA-seq) data. We calculated a drug-response score (DRS) for each cell by integrating drug-response genes (DRGs) and gene expression in scRNA-seq data. Then, scDR was validated through internal and external transcriptomics data from bulk RNA-seq and scRNA-seq of cell lines or patient tissues. In addition, scDR could be used to predict prognoses for BLCA, PAAD, and STAD tumor samples. Next, comparison with the existing method using 53,502 cells from 198 cancer cell lines showed the higher accuracy of scDR. Finally, we identified an intrinsic resistant cell subgroup in melanoma, and explored the possible mechanisms, such as cell cycle activation, by applying scDR to time series scRNA-seq data of dabrafenib treatment. Altogether, scDR was a credible method for drug response prediction at single-cell resolution, and helpful in drug resistant mechanism exploration.

Macrophage-derived GPNMB trapped by fibrotic extracellular matrix promotes pulmonary fibrosis.

Pulmonary fibrosis (PF) is a form of progressive lung disease characterized by chronic inflammation and excessive extracellular matrix (ECM) deposition. However, the protein changes in fibrotic ECM during PF and their contribution to fibrosis progression are unclear. Here we show that changes in expression of ECM components and ECM remodeling had occurred in silica-instilled mice. The macrophage-derived glycoprotein nonmetastatic melanoma protein B (GPNMB) captured by fibrotic ECM may activate resident normal fibroblasts around the fibrotic foci. Functional experiments demonstrated the activation of fibroblasts in fibrotic ECM, which was alleviated by GPNMB-neutralizing antibodies or macrophage deletion in the ECM of silica-instilled mice. Moreover, the Serpinb2 expression level was increased in fibroblasts in fibrotic ECM, and the expression of CD44 was increased in silica-instilled mice. In conclusion, macrophage-derived GPNMB is trapped by fibrotic ECM during transport and may activate fibroblasts via the CD44/Serpinb2 pathway, thus leading to the further development of fibrosis.

Pleiomorphism plurihormonal Pit-1-positive macroadenoma with central hyperthyroidism: a rare case report and literature review.

BACKGROUND: Thyrotropin-secreting pituitary neuroendocrine tumors (PitNETs) are rare pituitary adenomas that are occasionally accompanied by hypersecretion of other anterior pituitary hormones, such as growth hormone (GH) and prolactin (PRL). The clinical, biochemical, and pathological characteristics may represent diverse circumstances. CASE PRESENTATION: In this report, a 33-year-old female diagnosed with a TSH PitNET co-secreting GH presented no obvious clinical symptoms. The main characteristics were elevated thyroid-stimulating hormone (TSH), free tri-iodothyronine (FT3), and free thyroxine (FT4) levels accompanied by slightly elevated GH and insulin-like growth factor-1 (IGF-1) levels. Magnetic resonance imaging (MRI) detected a pituitary macroadenoma (18 × 16 × 16 mm) with cavernous sinus and suprasellar invasion. Immunohistochemistry revealed diffuse positivity for TSH, strong immunoreactivity for GH, and sporadic positivity for PRL. The electron microscope and double immunofluorescence staining confirmed a plurimorphous plurihormonal adenoma producing TSH, GH, and PRL. After preoperative somatostatin receptor ligand (SRL) treatment and transsphenoidal surgery, the patient achieved temporary clinical and biochemical remission. However, 3 months after surgery, the patient was suspected of having Hashimoto's thyroiditis due to higher thyroglobulin antibody (TGAb), thyroid peroxidase antibody (TPOAb), and thyroid receptor antibody (TRAb) and an enlarged thyroid nodule. During follow-up, thyroid function and TSH slowly transformed from transient hyperthyroidism to hypothyroidism. They were maintained in the normal range by L-T4. CONCLUSION: In the TSH PitNET, the positive immunohistochemistry for TSH, GH, and PRL translated into hormonal overproduction with TSH and GH.

Long non-coding RNA ENST00000469812 promotes Enterovirus type 71 replication via targeting the miR-4443/NUPR1 axis in rhabdomyosarcoma cells.

Hand, foot, and mouth disease (HFMD) caused by Enterovirus type 71 (EV71) is a serious threat to children's health. However, the pathogenic mechanism of EV71 is still unclear. Long non-coding RNAs (lncRNAs), some of which bind to miRNA as competitive endogenous RNAs (ceRNA) and weaken the silencing effect on the mRNA of downstream target genes, play a key role in regulating the viral infection process. In this study, through experimental verification, we found miR-4443 to be downregulated in cells infected with EV71. Next, by predicting lncRNAs that potentially regulate miR-4443, we found that EV71 infection induced upregulation of lncRNA ENST00000469812 and then further downregulated miR-4443 expression by direct interaction. We also demonstrated that nuclear protein 1 (NUPR1) is one of the target genes of miR-4443 and is involved in the ENST00000469812/miR-4443/NUPR1 regulatory axis. Finally, the ENST00000469812/miR-4443/NUPR1 regulatory axis exhibited a positive effect on EV71 replication. Here, we lay a foundation for exploring the pathogenic mechanism of EV71 and identify potential targets for HFMD treatment.

CTpathway: a CrossTalk-based pathway enrichment analysis method for cancer research.

BACKGROUND: Pathway enrichment analysis (PEA) is a common method for exploring functions of hundreds of genes and identifying disease-risk pathways. Moreover, different pathways exert their functions through crosstalk. However, existing PEA methods do not sufficiently integrate essential pathway features, including pathway crosstalk, molecular interactions, and network topologies, resulting in many risk pathways that remain uninvestigated. METHODS: To overcome these limitations, we develop a new crosstalk-based PEA method, CTpathway, based on a global pathway crosstalk map (GPCM) with >440,000 edges by combing pathways from eight resources, transcription factor-gene regulations, and large-scale protein-protein interactions. Integrating gene differential expression and crosstalk effects in GPCM, we assign a risk score to genes in the GPCM and identify risk pathways enriched with the risk genes. RESULTS: Analysis of >8300 expression profiles covering ten cancer tissues and blood samples indicates that CTpathway outperforms the current state-of-the-art methods in identifying risk pathways with higher accuracy, reproducibility, and speed. CTpathway recapitulates known risk pathways and exclusively identifies several previously unreported critical pathways for individual cancer types. CTpathway also outperforms other methods in identifying risk pathways across all cancer stages, including early-stage cancer with a small number of differentially expressed genes. Moreover, the robust design of CTpathway enables researchers to analyze both bulk and single-cell RNA-seq profiles to predict both cancer tissue and cell type-specific risk pathways with higher accuracy. CONCLUSIONS: Collectively, CTpathway is a fast, accurate, and stable pathway enrichment analysis method for cancer research that can be used to identify cancer risk pathways. The CTpathway interactive web server can be accessed here http://www.jianglab.cn/CTpathway/ . The stand-alone program can be accessed here https://github.com/Bioccjw/CTpathway .

Clinical Characteristics and Associated Factors of Colonic Polyps in Acromegaly.

PURPOSE: To investigate the clinical characteristics and associated factors of colonic polyps in patients with acromegaly. METHODS: Clinical characteristics and colonoscopy findings of 86 acromegaly patients who received treatment were retrospectively reviewed, and colonoscopy findings and the correlation with growth hormone (GH)-secreting pituitary adenoma (GHPA) volume and hormonal/metabolic levels were analyzed. RESULTS: The prevalence of colonic polyps in acromegaly patients was 40.7% and increased significantly with advanced age, especially in those ≥50 years. Multiple polyps (62.8%) and colonic polyps in the left colon (54.2%) were detected more frequently. Compared to acromegaly patients without polyps, those with polyps displayed higher insulin-like growth factor-1 × upper limit of normal (IGF-1×ULN) levels (P=0.03). IGF-1 levels and GHPA volumes in patients with polyps showed increasing trends, although the differences were not significant. GH levels were higher in patients with polyps of diameter ≤5 mm than those with polyps of diameter >5 mm (P=0.031). The univariate and multivariate logistic regression analysis revealed that GHPA volumes (OR: 1.09, 95% CI: 1.01-1.20; P=0.039) and IGF-1×ULN Q2 levels (OR: 6.51, 95% CI: 1.20-44.60; P=0.038) were independent factors for predicting the risk of colonic polyp occurrence in acromegaly patients. A nomogram was prepared to evaluate the risk of colonic polyps in acromegaly patients. CONCLUSION: The acromegalic patients are a population with a high prevalence of colonic polyps. GHPA volumes and IGF-1×ULN levels may be predictors of colonic polyp occurrence.

Changes in arterial blood vessels and VEGF and Ang-1 expression in pregnant and non-pregnant yak uterine caruncle.

We investigated the structural features of arterial blood vessels in yak uterine caruncle and the effects of the expression of vascular regulation-related factors on angiogenesis in pregnant and non-pregnant yak uterus. Three-dimensional specimens of the uterine artery of non-pregnant and pregnant yaks were produced to observe and measure the distribution characteristics and number of arterial vessels in the uterus and caruncle in the two periods. The uterine caruncle structure was observed and analysed by haematoxylin-eosin staining. The expression features of vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1) in the uterine caruncle were detected with immunohistochemistry, quantitative real-time PCR (qRT-PCR) and western blotting. The length and number of blood vessels in the caruncle were increased, the degree of curvature was decreased, and the folding was more complicated during pregnancy as compared with that during non-pregnancy. The immunohistochemical results demonstrated that VEGF and Ang-1 were mainly expressed strongly in the mucosal epithelial cytoplasm. The glandular lumen of the uterine gland, lymphocytes and the media and adventitia of blood vessels are widely distributed, and they are all positive. VEGF and Ang-1 mRNA and protein levels were highest in pregnancy, followed by that in the luteal phase and in the follicular phase, and three stages were significantly different (p < .05). These findings provide an anatomical reference and theoretical basis for improving the diagnosis and treatment of yak reproductive disorders and other diseases in high-altitude and low-oxygen environments.

Silencing of B7-H4 induces intracellular oxidative stress and inhibits cell viability of breast cancer cells via downregulating PRDX3.

Breast cancer (BC) is the most common malignancy in women worldwide, accounting for 15.5% of total cancer deaths. B7-H4 belongs to the B7 family members and plays an important role in the development of a variety of cancers, while Peroxiredoxin III (PRDX3) is an antioxidant protein found in mitochondria. Aberrant expression of B7-H4 or PRDX3 has been implicated in the tumorigenesis of various cancers. However, the functional roles of B7-H4 and PRDX3 in BC and the underlying mechanisms remain unclear. In this research, we found that silencing of B7-H4 by siRNA could lead to not only cell viability inhibition but also the downregulation of PRDX3 in MCF-7 and T47D cells. In order to reveal the roles of PRDX3 in the B7-H4 pathway, we firstly transfected siRNA specifically targeting PRDX3 into MCF-7 and T47D cells, and the results showed that silencing of PRDX3 also inhibited the viability of MCF-7 and T47D cells significantly, accompanied by the increase of reactive oxygen species (ROS) levels. Then we overexpressed the expression of PRDX3 by transfecting PRDX3 expression plasmids into B7-H4 knocking-down cells of MCF-7 and T47D. The results showed that compared with the control groups (MCF-7 or T47D/siNC+pcDNA3.1 vector), cell viabilities were significantly inhibited in RNAi groups (MCF-7 or T47D/siB7-H4+pcDNA3.1 vector), and mildly inhibited in revertant groups (MCF-7 or T47D/siB7-H4+pcDNA3.1 PRDX3), meanwhile, ROS levels significantly elevated in RNAi groups and had no significant changes in revertant groups. All these results indicate that silencing of B7-H4 increases intracellular ROS levels and affects cell viability by modulating the expression of PRDX3 in BC cells, which may provide a potential strategy and therapeutic target for the treatment of BC.

Lenalidomide bypasses CD28 co-stimulation to reinstate PD-1 immunotherapy by activating Notch signaling.

Programmed cell death protein 1 (PD-1) checkpoint blockade therapy requires the CD28 co-stimulatory receptor for CD8+ T cell expansion and cytotoxicity. However, CD28 expression is frequently lost in exhausted T cells and during immune senescence, limiting the clinical benefits of PD-1 immunotherapy in individuals with cancer. Here, using a cereblon knockin mouse model that regains in vivo T cell response to lenalidomide, an immunomodulatory imide drug, we show that lenalidomide reinstates the anti-tumor activity of CD28-deficient CD8+ T cells after PD-1 blockade. Lenalidomide redirects the CRL4Crbn ubiquitin ligase to degrade Ikzf1 and Ikzf3 in T cells and unleashes paracrine interleukin-2 (IL-2) and intracellular Notch signaling, which collectively bypass the CD28 requirement for activation of intratumoral CD8+ T cells and inhibition of tumor growth by PD-1 blockade. Our results suggest that PD-1 immunotherapy can benefit from a lenalidomide combination when treating solid tumors infiltrated with abundant CD28- T cells.

Identification of Key Genes and Pathways in Peripheral Blood Mononuclear Cells of Type 1 Diabetes Mellitus by Integrated Bioinformatics Analysis.

BACKGROUND: The onset and progression of type 1 diabetes mellitus (T1DM) is closely related to autoimmunity. Effective monitoring of the immune system and developing targeted therapies are frontier fields in T1DM treatment. Currently, the most available tissue that reflects the immune system is peripheral blood mononuclear cells (PBMCs). Thus, the aim of this study was to identify key PBMC biomarkers of T1DM. METHODS: Common differentially expressed genes (DEGs) were screened from the Gene Expression Omnibus (GEO) datasets GSE9006, GSE72377, and GSE55098, and PBMC mRNA expression in T1DM patients was compared with that in healthy participants by GEO2R. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and protein-protein interaction (PPI) network analyses of DEGs were performed using the Cytoscape, DAVID, and STRING databases. The vital hub genes were validated by reverse transcription-polymerase chain reaction using clinical samples. The disease-gene-drug interaction network was built using the Comparative Toxicogenomics Database (CTD) and Drug Gene Interaction Database (DGIdb). RESULTS: We found that various biological functions or pathways related to the immune system and glucose metabolism changed in PBMCs from T1DM patients. In the PPI network, the DEGs of module 1 were significantly enriched in processes including inflammatory and immune responses and in pathways of proteoglycans in cancer. Moreover, we focused on four vital hub genes, namely, chitinase-3-like protein 1 (CHI3L1), C-X-C motif chemokine ligand 1 (CXCL1), matrix metallopeptidase 9 (MMP9), and granzyme B (GZMB), and confirmed them in clinical PBMC samples. Furthermore, the disease-gene-drug interaction network revealed the potential of key genes as reference markers in T1DM. CONCLUSION: These results provide new insight into T1DM pathogenesis and novel biomarkers that could be widely representative reference indicators or potential therapeutic targets for clinical applications.

Plasma Diaphanous Related Formin 1 Levels Are Associated with Altered Glucose Metabolism and Insulin Resistance in Patients with Polycystic Ovary Syndrome: A Case Control Study.

BACKGROUND: Diaphanous related formin 1 (DIAPH1) is a novel component of advanced glycation end product (AGE) signal transduction that was recently found to participate in diabetes-related disorders, obesity, and androgen hormones. We investigated whether plasma DIAPH1 levels were a potential prognostic predictor for polycystic ovary syndrome (PCOS). METHODS: The levels of circulating plasma DIAPH1 and indicators of glucose, insulin, lipid metabolism, liver enzymes, kidney function, sex hormones, and inflammation were measured in 75 patients with PCOS and 77 healthy participants. All of the participants were divided into normal-weight (NW) and overweight/obese (OW) subgroups. Statistical analyses were performed with R studio. RESULTS: PCOS patients manifested hyperandrogenism, increased luteinizing hormone/follicle-stimulating hormone (LH/FSH), and accumulated body fat and insulin resistance. Plasma DIAPH1 levels were significantly decreased in women with PCOS compared to control participants, and DIAPH1 levels were distinctly reduced in OW PCOS compared to OW control subjects (P < 0.001). DIAPH1 levels correlated with fasting blood glucose (FBG), total cholesterol (TC), the homeostasis model assessment of ß-cell function (HOMA-ß), and LH/FSH in all participants (FBG: r = 0.351, P < 0.0001; TC: r = 0.178, P = 0.029; HOMA-ß: r = -0.211, P = 0.009; LH/FSH: r = -0.172, P = 0.040). Multivariate logistic regression analysis revealed that plasma DIAPH1 levels were an independent risk factor for PCOS. A model containing DIAPH1, BMI, FBG, and testosterone was constructed to predict the risk of PCOS, with a sensitivity of 92.0% and a specificity of 80.9%. A nomogram was constructed to facilitate clinical diagnosis. CONCLUSIONS: These findings suggest the association of plasma DIAPH1 with glucose metabolism, insulin resistance, and sex hormones and support DIAPH1 as a potential predictive factor for PCOS.

The methyl-CpG-binding domain 2 facilitates pulmonary fibrosis by orchestrating fibroblast to myofibroblast differentiation.

Although DNA methylation has been recognised in the pathogenesis of idiopathic pulmonary fibrosis (IPF), the exact mechanisms are yet to be fully addressed. Herein, we demonstrate that lungs originated from IPF patients and mice after bleomycin (BLM)-induced pulmonary fibrosis are characterised by altered DNA methylation along with overexpression in myofibroblasts of methyl-CpG-binding domain 2 (MBD2), a reader responsible for interpreting DNA methylome-encoded information. Specifically, depletion of Mbd2 in fibroblasts or myofibroblasts protected mice from BLM-induced pulmonary fibrosis coupled with a significant reduction of fibroblast differentiation. Mechanistically, transforming growth factor (TGF)-ß1 induced a positive feedback regulatory loop between TGF-ß receptor I (TßRI), Smad3 and Mbd2, and erythroid differentiation regulator 1 (Erdr1). TGF-ß1 induced fibroblasts to undergo a global DNA hypermethylation along with Mbd2 overexpression in a TßRI/Smad3 dependent manner, and Mbd2 selectively bound to the methylated CpG DNA within the Erdr1 promoter to repress its expression, through which it enhanced TGF-ß/Smad signalling to promote differentiation of fibroblast into myofibroblast and exacerbate pulmonary fibrosis. Therefore, enhancing Erdr1 expression strikingly reversed established pulmonary fibrosis. Collectively, our data support that strategies aimed at silencing Mbd2 or increasing Erdr1 could be viable therapeutic approaches for prevention and treatment of pulmonary fibrosis in clinical settings.

[Impact of anterior lobe thickness of the prostate on the clinical progression of benign prostatic hyperplasia].

OBJECTIVE: To investigate the correlation of the anterior lobe thickness of the prostate (ALTP) with bladder outlet obstruction (BOO), and evaluate the effect of ALTP on the clinical progression of BPH. METHODS: This retrospective study included 159 cases of BPH. We obtained the clinical indicators of the patients, including ALTP, prostate volume (PV), postvoid residual urine (PVR), maximum urinary flow rate (Qmax), BOO index (BOOI) and IPSS, and analyzed the correlations of ALTP with IPSS, PV, Qmax, age, PVR and BOOI. Using the ROC curve and cut-off point of ALTP, we compared the clinical indicators between the small and large ALTP groups, and analyzed the correlation between ALTP and the clinical progression of BPH. RESULTS: IPSS was not significantly correlated with ALTP (P > 0.05), nor was ALTP with PV and Qmax (P > 0.05). The area under the ROC curve was 0.742 (95% CI: 0.656－0.828) and the cut-off point of ALTP was 0.65 cm. Statistically significant differences were observed in PV, Qmax, IPSS and the rate of surgery between the small ALTP (<0.65 cm) and large ALTP (≥0.65 cm) groups (P < 0.05). CONCLUSION: ALTP is not proportional to PV or to IPSS. ALTP ≥ 0.65 cm increases the incidence of BOO, and may be a risk factor for the clinical progression of BPH.