Publications by authors named "Difei Wang"

60 Publications

The Kinocilia of Cochlear Hair Cells: Structures, Functions, and Diseases.

Authors:
Difei Wang Jun Zhou

Front Cell Dev Biol 2021 5;9:715037. Epub 2021 Aug 5.

State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China.

Primary cilia are evolutionarily conserved and highly specialized organelles that protrude from cell membranes. Mutations in genes encoding ciliary proteins can cause structural and functional ciliary defects and consequently multiple diseases, collectively termed ciliopathies. The mammalian auditory system is responsible for perceiving external sound stimuli that are ultimately processed in the brain through a series of physical and biochemical reactions. Here we review the structure and function of the specialized primary cilia of hair cells, termed kinocilia, found in the mammalian auditory system. We also discuss areas that might prove amenable for therapeutic management of auditory ciliopathies.
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http://dx.doi.org/10.3389/fcell.2021.715037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374625PMC
August 2021

Clinical Implications of Inter- and Intra-Tumor Heterogeneity of Immune Cell Markers in Lung Cancer.

J Natl Cancer Inst 2021 Aug 17. Epub 2021 Aug 17.

Integrative Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD, USA.

Background: Immune cell transcriptome signatures have been widely used to study the lung tumor microenvironment (TME). However, it is unclear to what extent the immune cell composition in the lung TME varies across histological and molecular subtypes (inter-tumor heterogeneity or Inter-TH) and within tumors (intratumor heterogeneity or ITH), and whether ITH has any prognostic relevance.

Methods: Using RNA sequencing in 269 tumor samples from 160 lung cancer patients we quantified the Inter-TH of immune gene expression and immune cell abundance and evaluated the association of median immune cell abundance with clinical/pathological features and overall survival. In 39 tumors with 132 multi-region samples, we also analyzed the ITH of immune cell abundance in relation to overall survival using a variance-weighted multivariate Cox model not biased by the number of samples per tumor.

Results: Substantial Inter-TH of 14 immune cell types was observed even within the same histological and molecular subtypes, but early-stage tumors had higher lymphocyte infiltration across all tumor types. In multi-region samples, an unbiased estimate of low ITH of overall immune cell composition (hazard ratio [HR] = 0.40, 95% confidence interval [CI] = 0.21 to 0.78; P = .007), dendritic cells (HR = 0.24, 95% CI = 0.096 to 0.58; P = .002) and macrophages (HR = 0.50, 95% CI = 0.30 to 0.84; P = .009) was strongly associated with poor survival. The ITH of three markers, including CD163 and CD68 (macrophages) and CCL13 (dendritic cells), was enough to characterize the ITH of the corresponding immune cell abundances and its association with overall survival.

Conclusion: This study suggests that lack of immune cell diversity may facilitate tumor evasion and progression. ITH inferred from CCL13, CD163 and CD68 could be used as a prognostic tool in clinical practice.
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http://dx.doi.org/10.1093/jnci/djab157DOI Listing
August 2021

A lacto-ovo-vegetarian dietary pattern is protective against sarcopenic obesity: A cross-sectional study of elderly Chinese people.

Nutrition 2021 Jun 7;91-92:111386. Epub 2021 Jun 7.

Department of Gerontology and Geriatrics, Shengjing Hospital of China Medical University. Electronic address:

Objectives: The purpose of this study was to investigate the correlation between dietary patterns and the risk of sarcopenic obesity (SO) in community-dwelling elderly people.

Methods: SO was defined as the coexistence of sarcopenia and obesity. Participants with low skeletal muscle index, low muscle strength, or low physical performance were diagnosed with sarcopenia, whereas obesity was defined as waist circumference ≥85 cm in men and ≥80 cm in women. Dietary patterns were determined by principal component analysis. Multinomial logistic regression analysis was used to evaluate the relationship between dietary patterns and SO.

Results: Among 3795 Chinese participants, 112 (3.0%) were diagnosed with SO. After adjustment for confounding variables, lacto-ovo-vegetarian dietary pattern was negatively associated with risk of SO. The odds ratio for SO was 0.79 (95% confidence interval, 0.65-0.97; P = 0.027) for the lacto-ovo-vegetarian dietary pattern, whereas meat-fish and junk food dietary patterns were not associated with the risk of SO.

Conclusions: We suggest that older people should have a balanced daily diet such as a lacto-ovo-vegetarian dietary pattern to prevent the occurrence and progression of SO.
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http://dx.doi.org/10.1016/j.nut.2021.111386DOI Listing
June 2021

Nr4a1 promotes cell adhesion and fusion by regulating Zeb1 transcript levels in myoblasts.

Biochem Biophys Res Commun 2021 06 8;556:127-133. Epub 2021 Apr 8.

Department of Gerontology, ShengJing Hospital of China Medical University, Shenyang, Liaoning, 110004, China. Electronic address:

Nuclear receptor subfamily 4 group A member 1 (NR4A1) acts as a myogenic factor in muscle development and regeneration; however, it remains unclear how Nr4a1 regulates myoblast physiology. In this study, report a role for Nr4a1-mediated regulation of cell adhesion in myoblast and muscle tissue. Nr4a1-overexpression myoblast, Nr4a1-konckdown myoblast and mice gastrocnemius muscle following an injection with an adenovirus vector expression Nr4a1 (Nr4a1-AAV) were used to observe the changes in cell adhesion. Nr4a1 was found to enhance cell-cell contact and adhesion molecule expression in myoblasts. In contrast, the deletion of Nr4a1 expression inhibited junction and adhesion between myoblasts. Moreover, Nr4a1 increased myoblast adhesion via directly binding to an upstream site of zinc finger E-box binding homeobox 1 (Zeb1), which is required for myogenesis in myoblasts. In mice, Zeb1 induced increased cadherin and integrin expression in the gastrocnemius muscle following an injection with an adenovirus vector expressing Nr4a1(Nr4a1-AAV). These data indicate that Nr4a1 regulates myoblast adhesion via Zeb1 expression.
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http://dx.doi.org/10.1016/j.bbrc.2021.03.153DOI Listing
June 2021

Whole genome sequencing of skull-base chordoma reveals genomic alterations associated with recurrence and chordoma-specific survival.

Nat Commun 2021 02 3;12(1):757. Epub 2021 Feb 3.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD, USA.

Chordoma is a rare bone tumor with an unknown etiology and high recurrence rate. Here we conduct whole genome sequencing of 80 skull-base chordomas and identify PBRM1, a SWI/SNF (SWItch/Sucrose Non-Fermentable) complex subunit gene, as a significantly mutated driver gene. Genomic alterations in PBRM1 (12.5%) and homozygous deletions of the CDKN2A/2B locus are the most prevalent events. The combination of PBRM1 alterations and the chromosome 22q deletion, which involves another SWI/SNF gene (SMARCB1), shows strong associations with poor chordoma-specific survival (Hazard ratio [HR] = 10.55, 95% confidence interval [CI] = 2.81-39.64, p = 0.001) and recurrence-free survival (HR = 4.30, 95% CI = 2.34-7.91, p = 2.77 × 10). Despite the low mutation rate, extensive somatic copy number alterations frequently occur, most of which are clonal and showed highly concordant profiles between paired primary and recurrence/metastasis samples, indicating their importance in chordoma initiation. In this work, our findings provide important biological and clinical insights into skull-base chordoma.
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http://dx.doi.org/10.1038/s41467-021-21026-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859411PMC
February 2021

Utility of image-guided external ventriculostomy: analysis of contemporary practice in the United Kingdom and Ireland.

J Neurosurg 2021 01 29:1-9. Epub 2021 Jan 29.

9Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, United Kingdom.

Objective: Freehand external ventricular drain (EVD) insertion is associated with a high rate of catheter misplacement. Image-guided EVD placement with neuronavigation or ultrasound has been proposed as a safer, more accurate alternative with potential to facilitate proper placement and reduce catheter malfunction risk. This study aimed to determine the impact of image-guided EVD placement on catheter tip position and drain functionality.

Methods: This study is a secondary analysis of a data set from a prospective, multicenter study. Data were collated for EVD placements undertaken in the United Kingdom and Ireland from November 2014 to April 2015. In total, 21 large tertiary care academic medical centers were included.

Results: Over the study period, 632 EVDs were inserted and 65.9% had tips lying free-floating in the CSF. Only 19.6% of insertions took place under image guidance. The use of image guidance did not significantly improve the position of the catheter tip on postoperative imaging, even when stratified by ventricular size. There was also no association between navigation use and drain blockage.

Conclusions: Image-guided EVD placement was not associated with an increased likelihood of achieving optimal catheter position or with a lower rate of catheter blockage. Educational efforts should aim to enhance surgeons' ability to apply the technique correctly in cases of disturbed cerebral anatomy or small ventricles to reduce procedural risks and facilitate effective catheter positioning.
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http://dx.doi.org/10.3171/2020.8.JNS20321DOI Listing
January 2021

Identification of New Subpopulations in Native Americans and Mestizos From Peru.

Front Microbiol 2020 14;11:601839. Epub 2020 Dec 14.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, United States.

Region-specific subpopulations have been identified. It is proposed that the hspAmerind subpopulation is being displaced from the Americans by an hpEurope population following the conquest. Our study aimed to describe the genomes and methylomes of isolates from distinct Peruvian communities: 23 strains collected from three groups of Native Americans (Asháninkas [ASHA, = 9], Shimaas [SHIM, = 5] from Amazonas, and Punos from the Andean highlands [PUNO, = 9]) and 9 modern mestizos from Lima (LIM). Closed genomes and DNA modification calls were obtained using SMRT/PacBio sequencing. We performed evolutionary analyses and evaluated genomic/epigenomic differences among strain groups. We also evaluated human genome-wide data from 74 individuals from the selected Native communities (including the 23 strains donors) to compare host and bacterial backgrounds. There were varying degrees of hspAmerind ancestry in all strains, ranging from 7% in LIM to 99% in SHIM. We identified three subpopulations corresponding to each of the Native groups and a novel hspEuropePeru which evolved in the modern mestizos. The divergence of the indigenous strains recapitulated the genetic structure of Native Americans. Phylogenetic profiling showed that Orthogroups in the indigenous strains seem to have evolved differentially toward epigenomic regulation and chromosome maintenance, whereas OGs in the modern mestizo (LIM) seem to have evolved toward virulence and adherence. The prevalence of / genotype was similar across populations ( = 0.32): 89% in ASHA, 67% in PUNO, 56% in LIM and 40% in SHIM. Both and sequences showed that LIM strains were genetically differentiated ( < 0.001) as compared to indigenous strains. We identified 642 R-M systems with 39% of the associated genes located in the core genome. We found 692 methylation motifs, including 254 population-specific sequences not previously described. In Peru, hspAmerind is not extinct, with traces found even in a heavily admixed mestizo population. Notably, our study identified three new hspAmerind subpopulations, one per Native group; and a new subpopulation among mestizos that we named hspEuropePeru. This subpopulation seems to have more virulence-related elements than hspAmerind. Purifying selection driven by variable host immune response may have shaped the evolution of Peruvian subpopulations, potentially impacting disease outcomes.
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http://dx.doi.org/10.3389/fmicb.2020.601839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767971PMC
December 2020

DNA Methylation in Prostate Tumor Tissue Is Associated with Gleason Score.

Genes (Basel) 2020 12 24;12(1). Epub 2020 Dec 24.

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20850, USA.

Increasing evidence suggests a role of epigenetic mechanisms at chromosome 8q24, an important cancer genetic susceptibility region, in prostate cancer. We investigated whether DNA methylation at 8q24 (six CpG sites from exon 3 to the 3' UTR) in prostate tumor was associated with tumor aggressiveness (based on Gleason score, GS), and we incorporated RNA expression data to investigate the function. We accessed radical prostatectomy tissue for 50 Caucasian and 50 African American prostate cancer patients at the University of Maryland Medical Center, selecting an equal number of GS 6 and GS 7 cases per group. DNA methylation was lower in tumor than paired normal prostate tissue for all six CpG sites (median difference: -14.74 to -0.20 percentage points), and we observed similar results for two nearby sites in The Cancer Genome Atlas ( < 0.0001). We observed significantly lower methylation for more aggressive (GS 7) than less aggressive (GS 6) tumors for three exon 3 sites (for CpG 212 (chr8:128753145), GS 6 median = 89.7%; GS 7 median = 85.8%; -value = 9.4 × 10). DNA methylation was not associated with expression, but was inversely associated with expression after multiple comparison adjustment (-value = 0.04). Findings suggest that prostate tumor exon 3 hypomethylation is associated with increased aggressiveness.
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http://dx.doi.org/10.3390/genes12010012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823928PMC
December 2020

Integrative molecular characterisation of gallbladder cancer reveals micro-environment-associated subtypes.

J Hepatol 2021 May 1;74(5):1132-1144. Epub 2020 Dec 1.

Division of Cancer Epidemiology and Genetics, NIH, Rockville, MD, USA. Electronic address:

Background & Aims: Gallbladder cancer (GBC) is the most common type of biliary tract cancer, but the molecular mechanisms involved in gallbladder carcinogenesis remain poorly understood. In this study, we applied integrative genomics approaches to characterise GBC and explore molecular subtypes associated with patient survival.

Methods: We profiled the mutational landscape of GBC tumours (whole-exome sequencing on 92, targeted sequencing on 98, in total 190 patients). In a subset (n = 45), we interrogated the matched transcriptomes, DNA methylomes, and somatic copy number alterations. We explored molecular subtypes identified through clustering tumours by genes whose expression was associated with survival in 47 tumours and validated subtypes on 34 publicly available GBC cases.

Results: Exome analysis revealed TP53 was the most mutated gene. The overall mutation rate was low (median 0.82 Mut/Mb). APOBEC-mediated mutational signatures were more common in tumours with higher mutational burden. Aflatoxin-related signatures tended to be highly clonal (present in ≥50% of cancer cells). Transcriptome-wide survival association analysis revealed a 95-gene signature that stratified all GBC patients into 3 subtypes that suggested an association with overall survival post-resection. The 2 poor-survival subtypes were associated with adverse clinicopathologic features (advanced stage, pN1, pM1), immunosuppressive micro-environments (myeloid-derived suppressor cell accumulation, extensive desmoplasia, hypoxia) and T cell dysfunction, whereas the good-survival subtype showed the opposite features.

Conclusion: These data suggest that the tumour micro-environment and immune profiles could play an important role in gallbladder carcinogenesis and should be evaluated in future clinical studies, along with mutational profiles.

Lay Summary: Gallbladder cancer is highly fatal, and its causes are poorly understood. We evaluated gallbladder tumours to see if there were differences between tumours in genetic information such as DNA and RNA. We found evidence of aflatoxin exposure in these tumours, and immune cells surrounding the tumours were associated with survival.
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http://dx.doi.org/10.1016/j.jhep.2020.11.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058239PMC
May 2021

Risk Factors for Sarcopenia in the Elderly with Type 2 Diabetes Mellitus and the Effect of Metformin.

J Diabetes Res 2020 7;2020:3950404. Epub 2020 Oct 7.

Department of Geriatrics, Shengjing Hospital of China Medical University, Shenyang 110004, China.

Aims: Sarcopenia is a common condition in older individuals, especially in the elderly with type 2 diabetes mellitus (T2DM). The aim of the present study was to examine the risk factors for sarcopenia in elderly individuals with T2DM and the effects of metformin.

Methods: A total of 1732 elderly with T2DM were recruited to this cross-sectional observational study, and we analyzed the data using logistic regression analyses. Skeletal muscle mass, grip strength, and usual gait speed were measured to diagnose sarcopenia according to the criteria of the Asian Working Group for Sarcopenia, combined with expert consensus on sarcopenia in China.

Results: The overall prevalence of sarcopenia was 10.37% of the participants. In the multivariate analysis, sex, age, educational level, and BMI were risk factors for sarcopenia, with women more likely to develop sarcopenia relative to men (OR = 2.539, 95% CI = 1.475-4.371; < 0.05). We observed that sarcopenia increased with age and decreased with increasing BMI and educational level ( < 0.05). Participants who took metformin alone or combined with other drugs exhibited a lower risk for sarcopenia than those who took no medication (OR = 0.510, 95% CI = 0.288-0.904 and OR = 0.398, 95% CI = 0.225-0.702, respectively; < 0.05).

Conclusions: We showed that being female and at an older age, lower educational level, and lower BMI were risk factors for sarcopenia in elderly T2DM and that metformin acted as a protective agent against sarcopenia in these patients.
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http://dx.doi.org/10.1155/2020/3950404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563046PMC
October 2020

Age-related DNA methylation in paired normal and tumour breast tissue in Chinese breast cancer patients.

Epigenetics 2021 Jun 24;16(6):677-691. Epub 2020 Sep 24.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD, USA.

Age-related DNA methylation is a potential mechanism contributing to breast cancer development. Studies of primarily Caucasian women have identified many CpG sites of age-related methylation in non-diseased breast tissue possibly driving cancer development over time. There is a paucity of studies involving Asian women whose ages at breast cancer onset are usually younger than Caucasians. We identified the 181 most consistent age-related methylation events in non-diseased breast tissue across published studies. Age-related methylation events were measured in adjacent normal and breast tumour tissue in an exclusively Asian population at the previously identified age-related methylation sites. Age-related methylation was found in 118 probes in adjacent normal breast tissue. Methylation of 99% of these sites was increased with age and predominantly located on CpG islands in promoter regions. To ascertain biological relevance to breast cancer, we focused on the 37 sites with overall higher methylation in tumour compared to adjacent normal samples. Some sites positively related to age, including and , inversely correlated with gene expression. Several others have known involvement in suppression of carcinogenesis including and , suggesting that perturbation of epigenetic regulation at these sites due to ageing may contribute to the progression of carcinogenesis. This study highlights an age-related methylation landscape in non-tumour tissue, consistent not just across studies, but also across different populations. We present candidate age-related methylation sites warranting further investigation as potential epigenetic drivers of breast cancer. They may serve as potential targets of site-specific demethylation intervention strategies for the prevention of age-related breast cancer.
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http://dx.doi.org/10.1080/15592294.2020.1819661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143246PMC
June 2021

Hypoxia-inducible Factor 2α Exerts Neuroprotective Effects by Promoting Angiogenesis via the VEGF/Notch Pathway after Intracerebral Hemorrhage Injury in Rats.

Neuroscience 2020 11 28;448:206-218. Epub 2020 Jul 28.

Department of Pathophysiology, Chongqing Medical University, Chongqing 400016, China; Institute of Neuroscience, Chongqing Medical University, Chongqing 400016, China. Electronic address:

Angiogenesis after intracerebral hemorrhage (ICH) injury can effectively alleviate brain damage and improve neurological function. Hypoxia-inducible factor 2α (HIF-2α) is an important angiogenic regulator and exhibits protective effects in several neurological diseases; however, its role in ICH has not yet been reported. Hence, in the present study, we explored whether HIF-2α reduces ICH injury by promoting angiogenesis. In addition, we explored the role of the vascular endothelial growth factor (VEGF)/Notch pathway in HIF-2α-mediated angiogenesis. We injected 50 μL of autologous blood taken from the femoral artery into the right striatum of healthy male adult Sprague-Dawley rats to create an autologous-blood-induced rat model of ICH. Lentiviral vectors were injected to both overexpress and knock down HIF-2α expression. VEGF receptor 2 (VEGFR2) and Notch-specific inhibitors were injected intraperitoneally to block VEGFR2- and Notch-mediated signaling after lentiviral injections. Our data showed that HIF-2α overexpression reduced neurological-damage scores and brain-water content, suggesting it had a protective effect on ICH injury. In addition, overexpression of HIF-2α promoted angiogenesis, increased focal cerebral blood flow (CBF), and reduced neuronal damage, whereas HIF-2α knockdown resulted in the opposite effects. Furthermore, we found that HIF-2α-mediated angiogenesis was blocked by a Notch-specific inhibitor. Likewise, the HIF-2α-mediated increase in phospho-VEGFR-2, cleaved-Notch1 and Notch1 expression was reversed via a VEGFR2-specific inhibitor. Taken together, our results indicate that HIF-2α promotes angiogenesis via the VEGF/Notch pathway to attenuate ICH injury. Moreover, our findings may contribute to the development of a novel strategy for alleviating ICH injury via HIF-2α-mediated upregulation of angiogenesis.
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http://dx.doi.org/10.1016/j.neuroscience.2020.07.010DOI Listing
November 2020

Erratum: Measurement of the Combined Levels of Serum Uric Acid and Alanine Aminotransferase and the Risk of Metabolic Syndrome in a Population Aged 60 Years or More in Northeastern China.

Med Sci Monit 2020 06 16;26:e926434. Epub 2020 Jun 16.

Department of Geriatrics, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, Huangshi, Hubei, China (mainland).

The authors informed the journal that several errors occurred in their manuscript and request the following to be corrected:  1. The affiliation for Jiabei Wang should be corrected from Department of Geriatric, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, Huangshi, Hubei, P.R. China to:  Department of Geriatric, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, Huangshi, Hubei, P.R. China Department of Geriatric, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, P.R. China 2. The affiliation for Difei Wang should be corrected from: Department of Geriatric, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, Huangshi, Hubei, P.R. China to: Department of Geriatric, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, P.R. China Reference: 1. Wang J, Wang Y, Chen F, Ma G, Wang D. Measurement of the Combined Levels of Serum Uric Acid and Alanine Aminotransferase and the Risk of Metabolic Syndrome in a Population Aged 60 Years or More in Northeastern China. Med Sci Monit, 2020; 26: e916459. doi: 10.12659/MSM.916459.
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http://dx.doi.org/10.12659/MSM.926434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318834PMC
June 2020

Calcipotriol and iBRD9 reduce obesity in Nur77 knockout mice by regulating the gut microbiota, improving intestinal mucosal barrier function.

Int J Obes (Lond) 2020 05 17;44(5):1052-1061. Epub 2020 Mar 17.

Department of Geriatric Endocrinology, The First Hospital of China Medical University, Shenyang, Liaoning, China.

Objective: The orphan nuclear receptor Nur77 is an important factor regulating metabolism. Nur77 knockout mice become obese with age, but the cause of obesity in these mice has not been fully ascertained. We attempted to explain the cause of obesity in Nur77 knockout mice from the perspective of the gut microbiota and to investigate the inhibitory effect of calcipotriol combined with BRD9 inhibitor (iBRD9) on obesity.

Methods: Eight-week-old wild-type mice and Nur77 knockout C57BL/6J mice were treated with calcipotriol combined with iBRD9 for 12 weeks. Mouse feces were collected and the gut microbiota was assessed by analyzing 16S rRNA gene sequences. The bacterial abundance difference was analyzed, and the intestinal mucosal tight junction protein, antimicrobial peptide, and inflammatory cytokine mRNA levels of the colon and serum LPS and inflammatory cytokine levels were measured.

Results: Calcipotriol combined with iBRD9 treatment reduced the body weight and body fat percentage in Nur77 knockout mice. In the gut microbiota of Nur77 knockout mice, the relative abundances of Lachnospiraceae and Prevotellaceae decreased, and Rikenellaceae increased; while Rikenellaceae decreased after treatment (p < 0.05). Correspondingly, the mRNA levels of intestinal mucosal tight junction proteins (occludin (Ocln), claudin3 (Cldn3)) in the colons of Nur77 knockout mice were significantly decreased, and they increased significantly after treatment (p < 0.001). The mRNA levels of inflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β)) were significantly increased in Nur77 knockout mice, and TNF-α and IL-6 levels were significantly decreased after treatment (p < 0.05, <0.01, or <0.001). The levels of serum LPS, TNF-α, and IL-1β in Nur77 knockout mice were significantly increased (p < 0.05). Serum LPS, TNF-α, and IL-6 levels were significantly decreased after treatment (p < 0.05 or <0.01).

Conclusions: Calcipotriol combined with iBRD9 can regulate the gut microbiota, improve intestinal mucosal barrier function, reduce LPS absorption into the blood, and alleviate obesity in Nur77 knockout mice.
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http://dx.doi.org/10.1038/s41366-020-0564-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188666PMC
May 2020

Assessment of Risk Factors for Fractures in Patients with Type 2 Diabetes over 60 Years Old: A Cross-Sectional Study from Northeast China.

J Diabetes Res 2020 27;2020:1508258. Epub 2020 Jan 27.

Department of Geriatrics, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China.

Aims: Previous evidence has demonstrated an increased fracture risk among the population with type 2 diabetes mellitus (T2DM). This study investigated the prevalence of bone fractures in elderly subjects (with and without type 2 diabetes) and identified any fracture risk factors, especially the risk factors for common known fractures in particular diabetic populations.

Methods: This cross-sectional study was conducted with community-dwelling people over 60 years old in nine communities from the city of Shenyang, which is the capital of Northeast China's Liaoning Province. A total of 3430 elderly adults (2201 females, mean ± standard deviation age 68.16 ± 6.1 years; 1229 males, 69.16 ± 6.7 years) were included. Our study measured the heel bone mineral density (BMD) and used the timed "up and go" (TUG) test and other indicators. In addition, we performed logistic regression analysis to explore the risk factors for fractures in the general population and the diabetic population and to analyze the differences.

Results: The results revealed that a total of 201 elderly persons (5.8%), with an average age of 70.05 ± 6.54 years, suffered from a history of fragility fractures, which affected more females (74.6%) than males ( = 0.001). The prevalence of fractures in the T2DM population was 7.3%, which was much higher than the 5.2% in non-T2DM population ( = 0.001). The prevalence of fractures in the T2DM population was 7.3%, which was much higher than the 5.2% in non-T2DM population ( = 0.001). The prevalence of fractures in the T2DM population was 7.3%, which was much higher than the 5.2% in non-T2DM population ( = 0.001). The prevalence of fractures in the T2DM population was 7.3%, which was much higher than the 5.2% in non-T2DM population (-score≤-2.5 (OR 1.750) were independent risk factors for fragility fractures in the non-T2DM population, but they were not risk factors in the T2DM population.

Conclusions: This study found that low BMD and slow TUG time were independent risk factors for fractures in non-T2DM patients, while no associations were found in the T2DM population. Patients with T2DM have a higher risk for fractures even when they have sufficient BMD and a short TUG time. TUG and BMD underestimated the risk for fractures in the T2DM population.
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http://dx.doi.org/10.1155/2020/1508258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007937PMC
December 2020

The effect of vitamin D on sarcopenia depends on the level of physical activity in older adults.

J Cachexia Sarcopenia Muscle 2020 06 5;11(3):678-689. Epub 2020 Feb 5.

Department of Geriatric Endocrinology, The First Hospital of China Medical University, Shenyang, China.

Objective: Sarcopenia in older adults is closely related to vitamin D deficiency and reduced levels of physical activity, but little has been reported on the interaction between physical activity and the positive effects of vitamin D. The purpose of this study was to explore the interactive effect of vitamin D and physical activity on muscle mass and function through animal experiments and population surveys.

Methods: Male 4-week-old C57BL/6J mice were fed different purified diets: a vitamin D-deficient diet (with increased calcium and phosphorus to prevent the effects of abnormal mineral levels on muscle) or a 1,25-dihydroxyvitamin D3 (1,25D)-supplemented diet. After 24 weeks on the assigned diets, the mice were immobilized. The level of skeletal muscle atrophy in the mice was determined by grip strength, gastrocnemius (GA) muscle mass and muscle fiber cross-sectional area (CSA); additionally, the protein expression levels of FOXO3a and the E3 ubiquitin ligases MuRF1 and MAFbx were detected. A cross-sectional study included data from 4139 older adults (64.9% women, 67.9 ± 6.7 years) as part of a survey in Shenyang, Northeast China. The associations of serum 25(OH)D3 and physical activity with timed up and go test (TUG) performance, handgrip strength, calf circumference, and body muscle mass were assessed by a linear regression analysis that was adjusted for covariates.

Results: In activity-limited mice, vitamin D deficiency accelerated the decrease in GA muscle weight, muscle fiber CSA, and grip strength and increased the protein expression of MuRF1, MAFbx, and FOXO3a (all P < 0.05). In addition, 1,25D supplementation may inhibit the grip-strength reduction induced by limited activity (P = 0.069). Serum 25(OH)D3 and physical activity were linearly related to TUG time (P < 0.001) and handgrip strength (P < 0.05) after adjustment for sex, age, body mass index (BMI), education level, smoking status, and serum calcium level. Serum 25(OH)D3 and physical activity had interactive effects on TUG (P < 0.001) and handgrip strength (P < 0.05) but not calf circumference or body muscle mass in older adults.

Conclusions: The effect of vitamin D on muscle strength and physical performance depends on physical activity level in the elderly. It is recommended that older adults strive to avoid both physical inactivity and vitamin D deficiency. Because physical inactivity and vitamin D deficiency may exacerbate muscle atrophy, the biological mechanism may involve synergistic effects of vitamin D and physical activity on the promotion of muscle protein ubiquitination and degradation.
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http://dx.doi.org/10.1002/jcsm.12545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296263PMC
June 2020

Measurement of the Combined Levels of Serum Uric Acid and Alanine Aminotransferase and the Risk of Metabolic Syndrome in a Population Aged 60 Years or More in Northeastern China.

Med Sci Monit 2020 Jan 20;26:e916459. Epub 2020 Jan 20.

Department of Geriatrics, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, Huangshi, Hubei, China (mainland).

BACKGROUND Serum uric acid (SUA) and alanine aminotransferase (ALT) levels are increased in patients with metabolic syndrome. This study aimed to investigate the association between the combined levels of SUA and ALT and the risk of metabolic syndrome in residents ≥60 years of age in Northeastern China. MATERIAL AND METHODS A population study included nine communities in Shenyang, Northeast China, and 3,998 participants (1,434 men and 2,564 women) who were ≥60 years old. SUA and ALT measurements (levels 1-3) and clinical parameters were recorded. Metabolic syndrome was diagnosed according to the criteria of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III). The association between the combined SUA and ALT levels and metabolic syndrome was determined by multivariate logistic regression analysis in tertiles that included Groups 1-9. RESULTS The prevalence of metabolic syndrome was 43.2% (men), and 61.9% (women), and the prevalence and odds ratio (OR) values increased with increasing SUA and ALT levels. The OR values of metabolic syndrome in the ALT Groups 2-3 were 1.329 (95% CI, 1.137-1.554) and 2.362 (95% CI, 2.006-2.781), and in the SUA Groups 2-3 the OR values were 1.718 (95% CI, 1.466-2.015) and 2.743 (95% CI, 2.310-3.256). The OR of the combined increase in SUA and ALT and metabolic syndrome in Groups 1-9 ranged from 1.494-5.889 (all, p<0.05). CONCLUSIONS Increased combined SUA and ALT was more significantly associated with metabolic syndrome than an increase in SUA or ALT alone.
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http://dx.doi.org/10.12659/MSM.916459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990664PMC
January 2020

Immune gene expression profiling reveals heterogeneity in luminal breast tumors.

Breast Cancer Res 2019 12 19;21(1):147. Epub 2019 Dec 19.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA.

Background: Heterogeneity of immune gene expression patterns of luminal breast cancer (BC), which is clinically heterogeneous and overall considered as low immunogenic, has not been well studied especially in non-European populations. Here, we aimed at characterizing the immune gene expression profile of luminal BC in an Asian population and associating it with patient characteristics and tumor genomic features.

Methods: We performed immune gene expression profiling of tumor and adjacent normal tissue in 92 luminal BC patients from Hong Kong using RNA-sequencing data and used unsupervised consensus clustering to stratify tumors. We then used luminal patients from The Cancer Genome Atlas (TCGA, N = 564) and a Korean breast cancer study (KBC, N = 112) as replication datasets.

Results: Based on the expression of 130 immune-related genes, luminal tumors were stratified into three distinct immune subtypes. Tumors in one subtype showed higher level of tumor-infiltrating lymphocytes (TILs), characterized by T cell gene activation, higher expression of immune checkpoint genes, higher nonsynonymous mutation burden, and higher APOBEC-signature mutations, compared with other luminal tumors. The high-TIL subtype was also associated with lower ESR1/ESR2 expression ratio and increasing body mass index. The comparison of the immune profile in tumor and matched normal tissue suggested a tumor-derived activation of specific immune responses, which was only seen in high-TIL patients. Tumors in a second subtype were characterized by increased expression of interferon-stimulated genes and enrichment for TP53 somatic mutations. The presence of three immune subtypes within luminal BC was replicated in TCGA and KBC, although the pattern was more similar in Asian populations. The germline APOBEC3B deletion polymorphism, which is prevalent in East Asian populations and was previously linked to immune activation, was not associated with immune subtypes in our study. This result does not support the hypothesis that the germline APOBEC3B deletion polymorphism is the driving force for immune activation in breast tumors in Asian populations.

Conclusion: Our findings suggest that immune gene expression and associated genomic features could be useful to further stratify luminal BC beyond the current luminal A/B classification and a subset of luminal BC patients may benefit from checkpoint immunotherapy, at least in Asian populations.
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http://dx.doi.org/10.1186/s13058-019-1218-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924001PMC
December 2019

Risk factors for depression in elderly diabetic patients and the effect of metformin on the condition.

BMC Public Health 2019 Aug 7;19(1):1063. Epub 2019 Aug 7.

Department of Geriatrics, the First Affiliated Hospital, China Medical University, Shenyang, 110001, China.

Background: At present, only a few studies have focused on the risk factors for depression in elderly diabetic patients, and there is little evidence for the effect of metformin in depressed elderly patients with diabetes than on its effect on blood glucose. The aim of the current work was to study the risk factors for depression in elderly diabetic patients and to ascertain the effects of metformin on the depressive state.

Methods: We initiated a 1:4 matched case-control study. The case group comprised 110 elderly diabetic patients with depression from nine communities in Shenyang in 2017. The control group comprised 440 non-depressed elderly diabetic patients from the same communities, which were matched by gender and age (± 2 years of age) with the case group. Depression was measured using the Geriatric Depression Scale-15, and we performed matched univariate and multivariate logistic regression analyses.

Results: In the multivariate analysis, overweight status, poor physical capabilities and low activity level, and the presence of more than two additional illnesses were risk factors for depression in elderly patients with diabetes. For these risk factors, the adjusted ORs (all P < 0.05) were as follows: an adjusted OR of 2.031 and 95% CI of 1.180-3.495; an adjusted OR of 2.342 and 95% CI of 1.465-3.743; and an adjusted OR of 5.350 and 95% CI of 2.222-12.883, respectively. Patients taking metformin had a lower risk of depression than those taking no medication, with an adjusted OR of 0.567 and 95% CI of 0.323-0.997 (P < 0.05).

Conclusions: Overweight status, poor physical capabilities and low activity level, and the presence of more than two additional illnesses were risk factors for depression in elderly diabetic patients, and metformin was a protective factor against depression in elderly diabetic patients.
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http://dx.doi.org/10.1186/s12889-019-7392-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686369PMC
August 2019

Specific higher levels of serum uric acid might have a protective effect on bone mineral density within a Chinese population over 60 years old: a cross-sectional study from northeast China.

Clin Interv Aging 2019 12;14:1065-1073. Epub 2019 Jun 12.

Department of Geriatrics, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, People's Republic of China.

Oxidative stress has been demonstrated to be a mechanism that leads to bone mass reduction, and according to many studies, serum uric acid (UA) is a strong endogenous antioxidant that can protect bone mineral density (BMD). To date, there have been no large-scale, cross-sectional studies based on the population in northeast China to assess the relationship between serum UA and BMD. Therefore, we examined the association between serum UA and BMD among a Chinese population older than 60 years old in northeast China. This research was a cross-sectional study of 3465 Chinese individuals over 60 years old in nine communities from the city of Shenyang, which is the capital of northeast China's Liaoning Province. Participants were stratified into three groups by serum UA or BMD levels, and then Pearson's correlation analysis and multiple regression analysis were used to study the relationship between serum UA and BMD. We found that participants with higher serum UA levels had significantly greater BMD and T-values compared to those of participants with lower serum UA levels. After adjusting for confounding factors, Pearson's correlation analysis and multiple regression analysis showed that higher serum UA levels remained associated with higher BMD levels (<0.05). In different models, the prevalence of osteoporosis (OP) among participants with higher serum UA levels was reduced by 23% to 26% (<0.05) compared to that in individuals with lower serum UA levels. In addition, serum UA levels were negatively correlated with estimated glomerular filtration rate (eGFR) and positively correlated with 25-hydroxy vitamin D [25-(OH)D] (<0.05). We concluded that higher serum UA levels are associated with greater BMD, and serum UA might have a protective effect on bone metabolism due to its antioxidant properties.
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http://dx.doi.org/10.2147/CIA.S186500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572710PMC
December 2019

Identification of Recent Trends in Research on Vitamin D: A Quantitative and Co-Word Analysis.

Med Sci Monit 2019 Jan 22;25:643-655. Epub 2019 Jan 22.

Department of Nutrition, The First Hospital of China Medical University, Shenyang, Liaoning, China (mainland).

BACKGROUND In recent years, many studies on vitamin D have been published. We combed these data for hot spot analyses and predicted future research topic trends. MATERIAL AND METHODS Articles (4625) concerning vitamin D published in the past 3 years were selected as a study sample. Bibliographic Items Co-occurrence Matrix Builder (BICOMB) software was used to screen high-frequency Medical Subject Headings (MeSH) terms and construct a MeSH terms-source article matrix and MeSH terms co-occurrence matrix. Then, Graphical Clustering Toolkit (gCLUTO) software was employed to analyze the matrix by double-clustering and visual analysis to detect the trends on the subject. RESULTS Ninety high-frequency major MeSH terms were obtained from 4625 articles and divided into 5 clusters, and we generated a visualized matrix and a mountain map. Strategic coordinates were established by the co-occurrence matrix of the MeSH terms based on the above classification, and the 5 clusters described above were further divided into 7 topics. We classified the vitamin D-related diseases into 12 categories and analyzed their distribution. CONCLUSIONS The analysis of strategic coordinates revealed that the epidemiological study of vitamin D deficiency and vitamin D-related diseases is a hot research topic. The use of vitamin D in the prevention and treatment of some diseases, especially diabetes, was found to have a significant potential future research value.
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http://dx.doi.org/10.12659/MSM.913026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350455PMC
January 2019

Phosphite Esters: Reagents for Exploring S-Nitrosothiol Chemistry.

Org Lett 2018 12 6;20(24):7860-7863. Epub 2018 Dec 6.

Department of Chemistry , Washington State University , Pullman , Washington 99163 , United States.

The reactions between S-nitrosothiols and phosphite esters, including P(OPh), P(OBn), and P(OEt), were studied. Two different conjugated adducts, thiophosphoramidates and phosphorothioates, were formed, depending on the structures of the S-nitrosothiol substrate (e.g., primary vs tertiary). These reactions proceeded under mild conditions, and the reaction mechanisms were studied using experiments and calculations.
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http://dx.doi.org/10.1021/acs.orglett.8b03393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465146PMC
December 2018

Effects of sodium-glucose cotransporter 2 inhibitors in addition to insulin therapy on cardiovascular risk factors in type 2 diabetes patients: A meta-analysis of randomized controlled trials.

J Diabetes Investig 2019 Mar 26;10(2):446-457. Epub 2018 Jul 26.

Department of Geriatric Endocrinology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China.

Aims/introduction: In the present meta-analysis, we aimed to determine the effects of sodium-glucose cotransporter 2 inhibitor (SGLT-2i) in addition to insulin therapy on cardiovascular risk factors in type 2 diabetes patients.

Materials And Methods: Randomized controlled trials were identified by searching the PubMed, Embase and Cochrane Library databases published before September 2017. The intervention group received SGLT-2i as add-on treatment to insulin therapy, and the control group received placebos in addition to insulin. We assessed pooled data, including weighted mean differences and 95% confidence intervals (CIs) using a random-effects model.

Results: A total of 10 randomized controlled trials (n = 5,159) were eligible. The weighted mean differences for systolic blood pressure and diastolic blood pressure were -3.17 mmHg (95% CI -4.53, -1.80, I = 0%) and -1.60 mmHg (95% CI -2.52, -0.69, I = 0%) in the intervention groups. Glycosylated hemoglobin, fasting plasma glucose, postprandial glucose and daily insulin were also lower in the intervention groups, with relative weighted mean differences of -0.49% (95% CI -0.71, -0.28%, I = 92%), -1.10 mmol/L (95% CI -1.69, -0.51 mmol/L, I = 84%), -3.63 mmol/L (95% CI -4.36, -2.89, I = 0%) and -5.42 IU/day (95% CI -8.12, -2.72, I = 93%). The transformations of uric acid and bodyweight were -26.16 μmol/L (95% CI -42.14, -10.17, I = 80%) and -2.13 kg (95% CI -2.66, -1.60, I = 83%). The relative risk of hypoglycemia was 1.09 (95% CI 1.02, 1.17, P < 0.01). The relative risks of urinary tract and genital infection were 1.29 (95% CI 1.03, 1.62, P = 0.03) and 5.25 (95% CI 3.55, 7.74, P < 0.01).

Conclusions: The results showed that in the intervention group, greater reductions were achieved for blood pressure, glucose control, uric acid and bodyweight. This treatment regimen might therefore provide beneficial effects on the occurrence and development of cardiovascular events.
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http://dx.doi.org/10.1111/jdi.12876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400156PMC
March 2019

The anteroposterior diameter of nodules in the risk assessment of papillary thyroid microcarcinoma.

Medicine (Baltimore) 2018 Mar;97(10):e9712

Department of Ultrasonic Diagnosis, The First Affiliated Hospital of China Medical University Department of Ultrasonic Diagnosis, Liaoning Province Cancer Hospital and Institute Department of Geriatrics, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China.

This study investigates the application of ultrasound, especially the anteroposterior diameter of nodules in the malignancy and metastasis risk assessment of papillary thyroid microcarcinoma through a retrospective analysis of 500 cases of thyroid nodule ultrasonography.We selected 500 patients with thyroid nodules (maximum nodule diameter ≤2.0 cm) that had been diagnosed clinically and graded TI-RADS 4c by ultrasonography and surgically treated. Among these, there were 258 cases of pathologically diagnosed papillary thyroid microcarcinoma, 72 cases of nodular goiter or adenoma, 137 cases of papillary thyroid carcinoma, 28 cases of acinar cell carcinoma, and 5 cases of undifferentiated carcinoma. In all cases, color Doppler ultrasonography had been performed preoperatively to determine the size and number of nodules, surrounding lymph node metastasis, and TI-RADS grading. Cases of papillary thyroid microcarcinoma diagnosed by pathology were selected as the study group, and cases of nodular goiter or adenoma as the control group. Each group was further subdivided based on the anteroposterior, vertical, and transverse nodule diameters. Intergroup statistical analysis was also performed. Receiver operating characteristic (ROC) curve analysis was conducted on the study and control groups based on the anteroposterior nodule diameters, and the optimal critical value for malignancy risk was determined. Thyroid nodules in the study group were divided into groups based on the presence or absence of lymph node metastasis. Based on the anteroposterior nodule diameter, ROC curve analysis was performed, and the optimal critical value for metastasis risk was determined.There were 500 cases of malignant nodules diagnosed by ultrasound. Among these, there were 428 cases of malignant nodules diagnosed by pathology. The coincidence rate of the ultrasound diagnosis with pathological diagnosis was 85.60%. While, interestingly, There was a significant statistical difference between the study and control groups based on the anteroposterior nodule diameter. When the anteroposterior nodule diameter was 0.7 cm, sensitivity of malignant diagnosis was 76.70% and specificity of that was 66.70%, and the Youden index was the highest. The lymph node metastasis rate for papillary thyroid microcarcinoma was 13.95%. Within this group, the lymph node metastasis rate for nodules ≥0.9 cm (anteroposterior diameter) was 38.46%. When the anteroposterior nodule diameter was equal to 0.9 cm, sensitivity of diagnosis was 83.30%, and specificity of that was 77.80%, and the Youden index was the highest.The anteroposterior diameter of thyroid nodules is more suitable for assessing their malignancy with 0.7 cm, which can be used as the critical value. Nodules ≥ 0.7 cm require surgical treatment, and those <0.7 cm can be observed. An anteroposterior diameter of 0.9 cm can be used as the critical value for assessing the metastasis risk of malignant thyroid nodules. During surgery, the dissection of central cervical lymph nodes is required for nodules ≥0.9 cm.
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http://dx.doi.org/10.1097/MD.0000000000009712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882459PMC
March 2018

Pycnogenol protects against diet-induced hepatic steatosis in apolipoprotein-E-deficient mice.

Am J Physiol Endocrinol Metab 2018 08 20;315(2):E218-E228. Epub 2018 Feb 20.

Department of Endocrinology and Metabolism, The Endocrine Institute and The Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Hospital of China Medical University , Shenyang , China.

Pycnogenol (PYC), a combination of active flavonoids derived from French maritime pine bark, is a natural antioxidant that has various pharmacological activities. Here, we investigated the beneficial effect of PYC on diet-induced hepatic steatosis. Apolipoprotein E (ApoE)-deficient male mice were administered PYC at oral doses of 30 or 100 mg·kg·day for 2 wk in advance and were then fed a high-cholesterol and -fat diet (HCD) for 8 wk. Biochemical, immunohistochemical, and gene expression analyses were conducted to explore the effect of PYC on lipid metabolism in ApoE-deficient mice on a HCD. Short-term treatment with HCD in ApoE-deficient mice induced hepatic injuries, such as lipid metabolism disorder and hepatic histopathological changes. We found that PYC reduced body weight and the increase of serum lipids that had been caused by HCD. Supplementation of PYC significantly reduced lipid deposition in the liver, as shown by the lowered hepatic lipid content and histopathological lesions. We subsequently detected genes related to lipid metabolism and inflammatory cytokines. The study showed that PYC markedly suppressed the expression of genes related to hepatic lipogenesis, fatty acid uptake, and lipid storage while increasing the lipolytic gene, which thus reduced hepatic lipid content. Furthermore, PYC mainly reduced the expression of inflammatory cytokines and the infiltration of inflammatory cells, which were resistant to the development of hepatic steatosis. These results demonstrate that PYC protects against the occurrence and development of hepatic steatosis and may provide a new prophylactic approach for nonalcoholic fatty liver disease (NAFLD).
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http://dx.doi.org/10.1152/ajpendo.00009.2017DOI Listing
August 2018

PI3K/AKT/Afadin signaling pathway contributes to pathological vascularization in glioblastomas.

Oncol Lett 2018 Feb 21;15(2):1893-1899. Epub 2017 Nov 21.

Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing 400014, P.R. China.

Glioblastomas are brain tumors with extensive vascularization that are associated with tumor malignancy. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway is activated in endothelial cell tumors, although its exact function in glioblastoma neovascularization is poorly characterized. The present study identified that endothelial cells derived from human glioblastomas exhibit increased permeability and motility compared with normal brain vascular endothelial cells. Furthermore, the phosphorylation of AKT was significantly induced in glioblastoma-derived endothelial cells and glioblastoma vessels. To the best of our knowledge, the present study demonstrated for the first time that the cell-cell adhesion junction protein Afadin is phosphorylated and re-localized in glioblastoma-derived endothelial cells, and the phosphorylation and re-localization of Afadin is PI3K/AKT pathway-dependent. AKT-mediated phosphorylation and re-localization of Afadin may be critically involved in the modulation of brain endothelial permeability and migration. Therapies targeting the PI3K/AKT/Afadin pathway may therefore be beneficial for reducing the angiogenic potential of glioblastoma.
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http://dx.doi.org/10.3892/ol.2017.7461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5774428PMC
February 2018

Cyclic Acyl Disulfides and Acyl Selenylsulfides as the Precursors for Persulfides (RSSH), Selenylsulfides (RSeSH), and Hydrogen Sulfide (HS).

Org Lett 2018 02 18;20(3):852-855. Epub 2018 Jan 18.

Department of Chemistry, Washington State University , Pullman, Washington 99164, United States.

The reactions of three model compounds (1-3) for cyclic acyl disulfides and cyclic acyl selenylsulfides are studied. These compounds were found to be effective precursors for persulfides (RSSH) and selenylsulfides (RSeSH) upon reacting with nucleophilic species. They could also act as HS donors when interacting with cellular thiols. The most interesting discovery was the generation of RSeSH from compound 3 under mild conditions. Selenylsulfides (RSeSH) are expected to be important regulating molecules involved in Sec-related redox signaling. The method of producing RSeSH should allow researchers to better understand the chemical biology of RSeSH.
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http://dx.doi.org/10.1021/acs.orglett.7b04005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797492PMC
February 2018

A General Strategy for Development of Near-Infrared Fluorescent Probes for Bioimaging.

Angew Chem Int Ed Engl 2017 12 30;56(52):16611-16615. Epub 2017 Nov 30.

Department of Chemistry, Washington State University, Pullman, WA, 99164, USA.

Near-infrared (NIR) fluorescent dyes with favorable photophysical properties are highly useful for bioimaging, but such dyes are still rare. The development of a unique class of NIR dyes via modifying the rhodol scaffold with fused tetrahydroquinoxaline rings is described. These new dyes showed large Stokes shifts (>110 nm). Among them, WR3, WR4, WR5, and WR6 displayed high fluorescence quantum yields and excellent photostability in aqueous solutions. Moreover, their fluorescence properties were tunable by easy modifications on the phenolic hydroxy group. Based on WR6, two NIR fluorescent turn-on probes, WSP-NIR and SeSP-NIR, were devised for the detection of H S. The probe SeSP-NIR was applied in visualizing intracellular H S. These dyes are expected to be useful fluorophore scaffolds in the development of new NIR probes for bioimaging.
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http://dx.doi.org/10.1002/anie.201710688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773255PMC
December 2017

The impairment of glucose-stimulated insulin secretion in pancreatic β-cells caused by prolonged glucotoxicity and lipotoxicity is associated with elevated adaptive antioxidant response.

Food Chem Toxicol 2017 Feb 25;100:161-167. Epub 2016 Dec 25.

Program of Environmental Toxicology, School of Public Health, China Medical University No 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China. Electronic address:

Type 2 diabetes (T2D) is a progressive disease characterized by sustained hyperglycemia and is frequently accompanied by hyperlipidemia. Deterioration of β-cell function in T2D patients may be caused, in part, by long-term exposure to high concentrations of glucose and/or lipids. We developed systems to study how chronic glucotoxicity and lipotoxicity might be linked to the impairment of glucose-stimulated insulin secretion (GSIS) machinery in pancreatic β-cells. INS-1 (832/13) were exposed to glucose and/or palmitate for up to 10 weeks. Chronic high glucose and/or palmitate exposure resulted in impaired GSIS accompanied by a dramatic increase in oxidative stress, as determined by basal intracellular peroxide levels. In addition, the GSIS-associated reactive oxygen species (ROS) signals, assessed as glucose-stimulated peroxide accumulation positively correlated with GSIS in glucose- and/or palmitate-exposed cells, as well as glucose-stimulated reductions in GSH/GSSG ratios. Furthermore, the impairment of GSIS caused by chronic high glucose and/or palmitate exposures were attributed to the induction of adaptive antioxidant response and mitochondrial uncoupling, which negatively regulates glucose-derived ROS generation. Taken together, persistent glucotoxicity- and/or lipotoxicity-mediated oxidative stress and subsequent adaptive antioxidant response impair glucose-derived ROS signaling and GSIS in pancreatic β-cells.
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http://dx.doi.org/10.1016/j.fct.2016.12.016DOI Listing
February 2017
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