Publications by authors named "Yin Guo"

196 Publications

Vasohibin-1 rescues erectile function through up-regulation of angiogenic factors in the diabetic mice.

Sci Rep 2021 Jan 13;11(1):1114. Epub 2021 Jan 13.

National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, 27, Inhang-Ro, Jung-Gu, Incheon, 22332, Republic of Korea.

Neovascularization of the erectile tissue emerges as a beneficial curative approach to treat erectile dysfunction (ED). Here we for the first time report the unexpected role of vasohibin-1 (VASH1), mainly known as an anti-angiogenic factor, in restoring erectile function in diabetic mice. A diabetic patient has lower cavernous VASH1 expression than in the potent man. VASH1 was mainly expressed in endothelial cells. There were significant decreases in cavernous endothelial cell and pericyte contents in VASH1 knockout mice compared with those in wild-type mice, which resulted in impairments in erectile function. Intracavernous injection of VASH1 protein successfully restored erectile function in the diabetic mice (~ 90% of control values). VASH1 protein reinstated endothelial cells, pericytes, and endothelial cell-cell junction proteins and induced phosphorylation of eNOS (Ser1177) in the diabetic mice. The induction of angiogenic factors, such as angiopoietin-1 and vascular endothelial growth factor, is responsible for cavernous angiogenesis and the restoration of erectile function mediated by VASH1. Altogether, these findings suggest that VASH1 is proangiogenic in diabetic penis and is a new potential target for diabetic ED.
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http://dx.doi.org/10.1038/s41598-020-80925-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807034PMC
January 2021

A Method to Isolate Pericytes From the Mouse Urinary Bladder for the Study of Diabetic Bladder Dysfunction.

Int Neurourol J 2020 Dec 31;24(4):332-340. Epub 2020 Dec 31.

National Research Center for Sexual Medicine and Department of Urology, Inha University College of Medicine, Incheon, Korea.

Purpose: Pericytes surround the endothelial cells in microvessels and play a distinct role in controlling vascular permeability and maturation. The loss of pericyte function is known to be associated with diabetic retinopathy and erectile dysfunction. This study aimed to establish a technique for the isolation of pericytes from the mouse urinary bladder and an in vitro model that mimics in vivo diabetic bladder dysfunction.

Methods: To avoid contamination with epithelial cells, the urothelial layer was meticulously removed from the underlying submucosa and detrusor muscle layer. The tissues were cut into multiple pieces, and the fragmented tissues were settled by gravity into collagen I-coated culture plates. The cells were cultured under normal-glucose (5 mmol/L) or high-glucose (30 mmol/L) conditions, and tube formation, cell proliferation, and TUNEL assays were performed. We also performed hydroethidine staining to measure superoxide anion production.

Results: We successfully isolated high-purity pericytes from the mouse urinary bladder. The cells were positively stained for platelet-derived growth factor receptor-β and NG2 and negatively stained for smooth muscle cell markers (desmin and myosin) and an endothelial cell marker (CD31). The number of tubes formed and the number of proliferating cells were significantly lower when the pericytes were exposed to high-glucose conditions compared with normal-glucose conditions. In addition, there were significant increases in superoxide anion production and the number of apoptotic cells when the pericytes were cultured under high-glucose conditions.

Conclusion: To the best of our knowledge, this is the first study to isolate and culture pericytes from the mouse urinary bladder. Our model would be a useful tool for screening the efficacy of therapeutic candidates targeting pericyte function in diabetic bladder dysfunction and exploring the functional role of specific targets at the cellular level.
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http://dx.doi.org/10.5213/inj.2040172.086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788335PMC
December 2020

Determination and Comparison of Short-Chain Fatty Acids in Serum and Colon Content Samples: Alzheimer's Disease Rat as a Case Study.

Molecules 2020 Dec 4;25(23). Epub 2020 Dec 4.

Shenzhen Key Laboratory of Drug Quality Standard Research, Shenzhen Institute for Drug Control, Shenzhen 518057, China.

Short-chain fatty acids (SCFAs) are the main microbial fermentation products from dietary fibers in the colon, and it has been speculated that they play a key role in keeping healthy in the whole-body. However, differences in SCFAs concentration in the serum and colon samples had attracted little attention. In this study, we have optimized the extract and analysis methods for the determination of ten SCFAs in both serum and colon content samples. Methanol and acetonitrile were chosen for extraction of SCFAs from serum and colon content samples, respectively. Biological samples were collected from Alzheimer's disease rats treated by extract of (Turcz.) Baill (SC-extract) were taken as research objects. The results showed that, the relative peak intensities of SCFAs in the colon content from all groups were quite similar, and the trend was identical in the serum samples. Compared with the values in humans, the ratio of ten SCFAs in rat's colon was similar, while the percent of acetate in rat's serum was significantly higher. For therapy of Alzheimer's disease (AD), SC-extract decreased the concentration of butyrate, 3-Methyvalerate, and caproate in the serum samples towards the trend of normal rats. This study may help our understanding of how SCFAs are transported across colonic epithelium in healthy and diseased organisms.
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http://dx.doi.org/10.3390/molecules25235739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729479PMC
December 2020

Discovery of Pamiparib (BGB-290), a Potent and Selective Poly (ADP-ribose) Polymerase (PARP) Inhibitor in Clinical Development.

J Med Chem 2020 12 2;63(24):15541-15563. Epub 2020 Dec 2.

Poly (ADP-ribose) polymerase (PARP) plays a significant role in DNA repair responses; therefore, this enzyme is targeted by PARP inhibitors in cancer therapy. Here we have developed a number of fused tetra- or pentacyclic dihydrodiazepinoindolone derivatives with excellent PARP enzymatic and cellular PARylation inhibition activities. These efforts led to the identification of pamiparib (BGB-290, ), which displays excellent PARP-1 and PARP-2 inhibition with IC of 1.3 and 0.9 nM, respectively. In a cellular PARylation assay, this compound inhibits PARP activity with IC = 0.2 nM. Cocrystal of pamiparib shows similar binding sites with PARP with other PARP inhibitors, but pamiparib is not a P-gp substrate and shows excellent drug metabolism and pharmacokinetics (DMPK) properties with significant brain penetration (17-19%, mice). The compound is currently being investigated in phase III clinical trials as a maintenance therapy in platinum-sensitive ovarian cancer and gastric cancer.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01346DOI Listing
December 2020

Transcriptional profiling of mouse cavernous pericytes under high-glucose conditions: Implications for diabetic angiopathy.

Investig Clin Urol 2021 Jan 24;62(1):100-110. Epub 2020 Nov 24.

Department of Urology, Yantai Yuhuangding Hospital Affiliated to Medical College of Qingdao University, Yantai, Shandong, China.

Purpose: Penile erection requires integrative interactions between vascular endothelial cells, pericytes, smooth muscle cells, and autonomic nerves. Furthermore, the importance of the role played by pericytes in the pathogenesis of angiopathy has only recently been appreciated. However, global gene expression in pericytes in diabetes mellitus-induced erectile dysfunction (DMED) remains unclear. We aimed to identify potential target genes related to DMED in mouse cavernous pericytes (MCPs).

Materials And Methods: Mouse cavernous tissue was allowed to settle under gravity in collagen I-coated dishes, and sprouted cells were subcultivated for experiments. To imitate diabetic conditions, MCPs were treated with normal-glucose (NG, 5 mM) or high-glucose (HG, 30 mM) media for 3 days. Microarray technology was used to evaluate gene expression profiles, and RT-PCR was used to validate sequencing data. Histological examinations and Western blot were used to validate final selected target genes related to DMED.

Results: Decreased tube formation and increased apoptosis were detected in MCPs exposed to the HG condition. As shown by microarray analysis, the gene expression profiles of MCPs exposed to the NG or HG condition differed. A total of 2,523 genes with significantly altered expression were classified into 15 major gene categories. After further screening based on gene expression and RT-PCR and histologic results, we found that Hebp1 gene expression was significantly diminished under the HG condition and in DM mice.

Conclusions: This gene profiling study provides new potential targets responsible for diabetes in MCPs. Validation studies suggest that Hebp1 may be a suitable biomarker for DMED.
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http://dx.doi.org/10.4111/icu.20200272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801160PMC
January 2021

Gene expression profiling of mouse cavernous endothelial cells for diagnostic targets in diabetes-induced erectile dysfunction.

Investig Clin Urol 2021 Jan 9;62(1):90-99. Epub 2020 Nov 9.

Department of Urology, National Research Center for Sexual Medicine, Inha University School of Medicine, Incheon, Korea.

Purpose: To investigate potential target genes associated with the diabetic condition in mouse cavernous endothelial cells (MCECs) for the treatment of diabetes-induced erectile dysfunction (ED).

Materials And Methods: Mouse cavernous tissue was embedded into Matrigel, and sprouted cells were subcultivated for other studies. To mimic diabetic conditions, MCECs were exposed to normal-glucose (NG, 5 mmoL) or high-glucose (HG, 30 mmoL) conditions for 72 hours. An RNA-sequencing assay was performed to evaluate gene expression profiling, and RT-PCR was used to validate the sequencing data.

Results: We isolated MCECs exposed to the two glucose conditions. MCECs showed well-organized tubes and dynamic migration in the NG condition, whereas tube formation and migration were significantly decreased in the HG condition. RNA-sequencing analysis showed that MCECs had different gene profiles in the NG and HG conditions. Among the significantly changed genes, which we classified into 14 major gene categories, we identified that aging-related (9.22%) and angiogenesis-related (9.06%) genes were changed the most. Thirteen genes from the two gene categories showed consistent changes on the RNA-sequencing assay, and these findings were validated by RT-PCR.

Conclusions: Our gene expression profiling studies showed that , , , , , , , , , , , , and may play a critical role in diabetes-induced ED through aging and angiogenesis signaling. Additional research is necessary to help us understand the potential mechanisms by which these genes influence diabetes-induced ED.
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http://dx.doi.org/10.4111/icu.20200119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801162PMC
January 2021

Oral Administration of the p75 Neurotrophin Receptor Modulator, LM11A-31, Improves Erectile Function in a Mouse Model of Cavernous Nerve Injury.

J Sex Med 2021 01 24;18(1):17-28. Epub 2020 Nov 24.

National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Republic of Korea. Electronic address:

Background: Radical prostatectomy for prostate cancer can not only induce cavernous nerve injury (CNI), but also causes cavernous hypoxia and cavernous structural changes, which lead to a poor response to phosphodiesterase 5 inhibitors.

Aim: To investigate the therapeutic effect of oral administration of LM11A-31, a small molecule p75 neurotrophin receptor (p75) ligand and proNGF antagonist, in a mouse model of bilateral CNI, which mimics nerve injury-induced erectile dysfunction after radical prostatectomy.

Methods: 8-week-old male C57BL/6 mice were divided into sham operation and CNI groups. Each group was divided into 2 subgroups: phosphate-buffered saline and LM11A-31 (50 mg/kg/day) being administered once daily starting 3 days before CNI via oral gavage. 2 weeks after CNI, we measured erectile function by electrical stimulation of the bilateral cavernous nerve. The penis was harvested for histologic examination and Western blot analysis. The major pelvic ganglia was harvested and cultured for assays of ex vivo neurite outgrowth.

Outcomes: Intracavernous pressure, neurovascular regeneration in the penis, in vivo or ex vivo functional evaluation, and cell survival signaling were measured.

Results: Erectile function was decreased in the CNI group (44% of the sham operation group), while administration of LM11A-31 led to a significant improvement of erectile function (70% of the sham operation group) in association with increased neurovascular content, including cavernous endothelial cells, pericytes, and neuronal processes. Immunohistochemical and Western blot analyses showed significantly increased p75 expression in the dorsal nerve of CNI mice, which was attenuated by LM11A-31 treatment. Protein expression of active PI3K, AKT, and endothelial nitric oxide synthase was increased, and cell death and c-Jun N-terminal kinase signaling was significantly attenuated after LM11A-31 treatment. Furthermore, LM11A-31 promoted neurite sprouting in cultured major pelvic ganglia after lipopolysaccharide exposure.

Clinical Implications: LM11A-31 may be used as a strategy to treat erectile dysfunction after radical prostatectomy or in men with neurovascular diseases.

Strengths & Limitations: Unlike biological therapeutics, such as proteins, gene therapies, or stem cells, the clinical application of LM11A-31 would likely be relatively less complex and low cost. Our study has some limitations. Future studies will assess the optimal dosing and duration of the compound. Given its plasma half-life of approximately 1 hour, it is possible that dosing more than once per day will provide added efficacy.

Conclusion: Specific inhibition of the proNGF-p75 degenerative signaling via oral administration of LM11A-31 represents a novel therapeutic strategy for erectile dysfunction induced by nerve injury. Yin GN, Ock J, Limanjaya A, et al. Oral Administration of the p75 Neurotrophin Receptor Modulator, LM11A-31, Improves Erectile Function in a Mouse Model of Cavernous Nerve Injury. J Sex Med 2021;18:17-28.
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http://dx.doi.org/10.1016/j.jsxm.2020.10.015DOI Listing
January 2021

MicroRNA-disease association prediction by matrix tri-factorization.

BMC Genomics 2020 Nov 18;21(Suppl 10):617. Epub 2020 Nov 18.

School of Mathematics and Statistics, Xi'an Jiaotong University, Xianning West 28, Xi'an, China.

Background: Biological evidence has shown that microRNAs(miRNAs) are greatly implicated in various biological progresses involved in human diseases. The identification of miRNA-disease associations(MDAs) is beneficial to disease diagnosis as well as treatment. Due to the high costs of biological experiments, it attracts more and more attention to predict MDAs by computational approaches.

Results: In this work, we propose a novel model MTFMDA for miRNA-disease association prediction by matrix tri-factorization, based on the known miRNA-disease associations, two types of miRNA similarities, and two types of disease similarities. The main idea of MTFMDA is to factorize the miRNA-disease association matrix to three matrices, a feature matrix for miRNAs, a feature matrix for diseases, and a low-rank relationship matrix. Our model incorporates the Laplacian regularizers which force the feature matrices to preserve the similarities of miRNAs or diseases. A novel algorithm is proposed to solve the optimization problem.

Conclusions: We evaluate our model by 5-fold cross validation by using known MDAs from HMDD V2.0 and show that our model could obtain the significantly highest AUCs among all the state-of-art methods. We further validate our method by applying it on colon and breast neoplasms in two different types of experiment settings. The new identified associated miRNAs for the two diseases could be verified by two other databases including dbDEMC and HMDD V3.0, which further shows the power of our proposed method.
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http://dx.doi.org/10.1186/s12864-020-07006-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677824PMC
November 2020

Progression of Myopic Maculopathy in Chinese Children with High Myopia: A Long Term Follow-Up Study.

Retina 2020 Nov 6. Epub 2020 Nov 6.

Clinical College of Ophthalmology, Tianjin Medical University, Tianjin, China.

Purpose: To investigate the progression of myopic maculopathy (MM) and associated factors in highly myopic Chinese children.

Methods: In this retrospective observational case series, biometric fundus features were morphometrically measured on photographs. Myopic maculopathy was defined as recommended by the Meta-analysis of Pathologic Myopia Study Group.

Results: The study included 274 children (mean age:11.7±2.5 years; mean refractive error:-7.66±1.87 diopters) with a mean follow-up of 4.9±1.2 years. MM progression was detected in 52 eyes (18.9%; 95% confidence interval [CI]:14.3%,23.7%). In multivariable analysis, MM progression was associated with a decrease in refractive error (odds ratio [OR]:0.72;95%CI:0.56,0.92;P<0.001) (i.e. higher myopization) and enlargement of parapapillary gamma zone (OR:7.68;95%CI:1.63,36.2;P=0.002). Incident peripapillary diffuse choroidal atrophy noted in 47 of 236 eyes (20.0%; 95%CI, 14.8%-25.2%), was correlated with a decrease in refractive error (OR:0.70;95%CI:0.54,0.92;P=0.009) (i.e., higher myopization) and greater gamma zone enlargement (OR:8.28;95%CI:1.33,51.7;P=0.02).

Conclusions: Myopia in schoolchildren may have a considerable risk of progressing to MM. Enlargement of parapapillary gamma zone was a main independent risk factor.
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http://dx.doi.org/10.1097/IAE.0000000000003018DOI Listing
November 2020

Advances in myopia research anatomical findings in highly myopic eyes.

Eye Vis (Lond) 2020 2;7:45. Epub 2020 Sep 2.

Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karis-University, Universitäts-Augenklinik, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.

Background: The goal of this review is to summarize structural and anatomical changes associated with high myopia.

Main Text: Axial elongation in myopic eyes is associated with retinal thinning and a reduced density of retinal pigment epithelium (RPE) cells in the equatorial region. Thickness of the retina and choriocapillaris and RPE cell density in the macula are independent of axial length. Choroidal and scleral thickness decrease with longer axial length in the posterior hemisphere of the eye, most marked at the posterior pole. In any eye region, thickness of Bruch's membrane (BM) is independent of axial length. BM opening, as the inner layer of the optic nerve head layers, is shifted in temporal direction in moderately elongated eyes (axial length <26.5 mm). It leads to an overhanging of BM into the intrapapillary compartment at the nasal optic disc side, and to an absence of BM at the temporal disc border. The lack of BM at the temporal disc side is the histological equivalent of parapapillary gamma zone. Gamma zone is defined as the parapapillary region without BM. In highly myopic eyes (axial length >26.5 mm), BM opening enlarges with longer axial length. It leads to a circular gamma zone. In a parallel manner, the peripapillary scleral flange and the lamina cribrosa get longer and thinner with longer axial length in highly myopic eyes. The elongated peripapillary scleral flange forms the equivalent of parapapillary delta zone, and the elongated lamina cribrosa is the equivalent of the myopic secondary macrodisc. The prevalence of BM defects in the macular region increases with longer axial length in highly myopic eyes. Scleral staphylomas are characterized by marked scleral thinning and spatially correlated BM defects, while thickness and density of the choriocapillaris, RPE and BM do not differ markedly between staphylomatous versus non-staphylomatous eyes in the respective regions.

Conclusions: High axial myopia is associated with a thinning of the sclera and choroid posteriorly and thinning of the retina and RPE density in the equatorial region, while BM thickness is independent of axial length. The histological changes may point towards BM having a role in the process of axial elongation.
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http://dx.doi.org/10.1186/s40662-020-00210-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465809PMC
September 2020

Pericyte-Derived Extracellular Vesicle-Mimetic Nanovesicles Restore Erectile Function by Enhancing Neurovascular Regeneration in a Mouse Model of Cavernous Nerve Injury.

J Sex Med 2020 11 24;17(11):2118-2128. Epub 2020 Aug 24.

Department of Urology and National Research Center for Sexual Medicine, Inha University School of Medicine, Incheon, Republic of Korea. Electronic address:

Background: Extracellular vesicle (EV)-mimetic nanovesicles (NVs) from embryonic stem cells have been observed to stimulate neurovascular regeneration in the streptozotocin-induced diabetic mouse. Pericytes play important roles in maintaining penile erection, yet no previous studies have explored the effects of pericyte-derived NVs (PC-NVs) in neurovascular regeneration in the context of erectile dysfunction.

Aim: To investigate the potential effect of PC-NVs in neurovascular regeneration.

Methods: PC-NVs were isolated from mouse cavernous pericytes, and neurovascular regeneration was evaluated in an in vitro study. Twelve-week-old C57BL/6J mice were used to prepare cavernous nerve injury model. Erectile function evaluation, histologic examination of the penis, and Western blots were assessed 2 weeks after model creation and PC-NVs treatment.

Outcomes: The main outcomes of this study are PC-NVs characterization, intracavernous pressure, neurovascular regeneration in the penis, and in vitro functional evaluation.

Results: The PC-NVs were extracted and characterized by cryotransmission electron microscopy and EV-positive (Alix, TSG101, CD81) and EV-negative (GM130) markers. In the in vivo studies, PC-NVs successfully improved erectile function in cavernous nerve injury mice (∼82% of control values). Immunofluorescence staining showed significant increases in pericytes, endothelial cell, and neuronal contents. In the in vitro studies, PC-NVs significantly increased mouse cavernous endothelial cells tube formation, Schwann cell migration, and dorsal root ganglion and major pelvic ganglion neurite sprouting. Finally, Western blot analysis revealed that PC-NVs upregulated cell survival signaling (Akt and eNOS) and induced the expression of neurotrophic factors (brain-derived neurotrophic factor, neurotrophin-3, and nerve growth factor).

Clinical Implications: PC-NVs may be used as a strategy to treat erectile dysfunction after radical prostatectomy or in men with neurovascular diseases.

Strengths & Limitations: We evaluated the effect of PC-NVs in vitro and in a mouse nerve injury model, cavernous nerve injury. Additional studies are necessary to determine the detailed mechanisms of neurovascular improvement. Further study is needed to test whether PC-NVs are also effective when given weeks or months after nerve injury.

Conclusion: PC-NVs significantly improved erectile function by enhancing neurovascular regeneration. Local treatment with PC-NVs may represent a promising therapeutic strategy for the treatment of neurovascular diseases. Yin GN, Park S-H, Ock J, et al. Pericyte-Derived Extracellular Vesicle-Mimetic Nanovesicles Restore Erectile Function by Enhancing Neurovascular Regeneration in a Mouse Model of Cavernous Nerve Injury. J Sex Med 2020;17:2118-2128.
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http://dx.doi.org/10.1016/j.jsxm.2020.07.083DOI Listing
November 2020

High-performance liquid chromatography-based fingerprint analysis with chemical pattern recognition for evaluation of Mahonia bealei (Fort.) Carr.

J Sep Sci 2020 Sep 9;43(18):3625-3635. Epub 2020 Aug 9.

State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, P. R. China.

A simple and efficient high-performance liquid chromatography method combined with chemical pattern recognition was established for quality evaluation of Mahonia bealei (Fort.) Carr. A common pattern of 30 characteristic peaks was applied for similarity analysis, hierarchical cluster analysis, principal component analysis, and partial least squares discriminant analysis in the 37 batches of M. bealei (Fort.) Carr. to discriminate wild M. bealei (Fort.) Carr., cultivated M. bealei (Fort.) Carr., and its substitutes. The results showed that partial least squares discriminant analysis was the most effective method for discrimination. Eight characteristics peaks with higher variable importance in projection values were selected for pattern recognition model. A permutation test and 26 batches of testing set samples were performed to validate the model that was successfully established. All of the training and testing set samples were correctly classified into three clusters (wild M. bealei (Fort.) Carr., cultivated M. bealei (Fort.) Carr., and its substitutes) based on the selected chemical markers. Moreover, 26 batches of unknown samples were used to predict the accuracy of the established model with a discrimination accuracy of 100%. The obtained results indicated that the method showed great potential application for accurate evaluation and prediction of the quality of M. bealei (Fort.) Carr.
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http://dx.doi.org/10.1002/jssc.201901219DOI Listing
September 2020

Neutralizing antibody to proNGF rescues erectile function by regulating the expression of neurotrophic and angiogenic factors in a mouse model of cavernous nerve injury.

Andrology 2021 01 10;9(1):329-341. Epub 2020 Sep 10.

National Research Center for Sexual Medicine and Department of Urology, Inha University College of Medicine, Incheon, Korea.

Background: Radical prostatectomy induces some degree of cavernous nerve injury (CNI) and causes denervation-induced pathologic changes in cavernous vasculature, regardless of the advances in surgical techniques and robotic procedures. The precursor for nerve growth factor (proNGF) is known to be involved in neuronal cell apoptosis and microvascular dysfunction through its receptor p75 .

Objectives: To determine the expression of proNGF/p75 and the efficacy of proNGF neutralizing antibody (anti-proNGF-Ab) in a mouse model of ED induced by CNI.

Materials And Methods: Age-matched 12-week-old C57BL/6 mice were distributed into three groups: sham group and bilateral CNI group treated with intracavernous injections of PBS (20 μL) or of anti-proNGF-Ab (20 µg in 20 μL of PBS) on days -3 and 0. Two weeks after treatment, erectile function was measured by electrical stimulation of cavernous nerve. Penis tissues from a separate group of animals were harvested for further analysis. We also determined the efficacy of anti-proNGF-Ab on neural preservation in major pelvic ganglion (MPG) ex vivo.

Results: We observed increased penile expression of proNGF and p75 after CNI. Intracavernous administration of anti-proNGF-Ab increased nNOS and neurofilament expression probably by enhancing the production of neurotrophic factors, such as neurotrophin-3, NGF, and brain-derived neurotrophic factor. Anti-proNGF-Ab preserved the integrity of cavernous sinusoids, such as pericytes, endothelial cells, and endothelial cell-to-cell junctions, possibly by controlling angiogenic factors (angiopoietin-1, angiopoietin-2, and vascular endothelial growth factor) and induced endogenous eNOS phosphorylation in CNI mice. And finally, treatment with anti-proNGF-Ab rescued erectile function in CNI mice. Anti-proNGF-Ab also enhanced neurite sprouting from MPG exposed to lipopolysaccharide.

Discussion And Conclusion: The preservation of damaged cavernous neurovasculature through inhibition of the proNGF/p75 pathway may be a novel strategy to treat radical prostatectomy-induced erectile dysfunction.
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http://dx.doi.org/10.1111/andr.12873DOI Listing
January 2021

Kiss2 but not kiss1 is involved in the regulation of social stress on the gonad development in yellowtail clownfish, Amphiprion clarkii.

Gen Comp Endocrinol 2020 11 17;298:113551. Epub 2020 Jul 17.

State Key Laboratory of Marine Resource Utilization in South China Sea, Hainan University, Haikou, 570228, China; Institute of Aquatic Economic Animals, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, China.

The yellowtail clownfish (Amphiprion clarkii) is a hermaphrodite fish, whose sex differentiation and gonad development are closely related to its social status. The kisspeptin/KissR system is regarded as a key factor mediating social stress on reproductive regulation. In order to understand the effects of social rank stress on the yellowtail clownfish gonadal differentiation, full-length cDNAs of two paralogous genes encoding kisspeptin (kiss1 and kiss2) and KissR (kissr2 and kissr3) were cloned and characterized. The results of real-time PCR showed that kiss1 was primarily expressed in the hypothalamus, and kiss2/kissr2 were abundantly expressed in the liver, while kissr3 was almost exclusively concentrated in the cerebellum and pituitary. Moreover, both Kiss1-10 and Kiss2-10 peptides could initiate downstream signaling pathways by interacting with cognate receptors expressed in eukaryotic cells. Among the three social status groups, the mRNA levels of kiss2 in the hypothalamus and pituitary as well as kissr2 in the pituitary were significantly higher in subordinate individuals (nonbreeders) than dominate individuals (females and males); while the mRNA levels of kissr3 in the hypothalamus and gonad were low in subordinate individuals. Furthermore, the plasma estradiol (E) and testosterone (T) levels were higher in subordinate than dominate individuals. This study shows that kiss2 is involved in the regulation of social stress on the gonad development in the yellowtail clownfish, but not kiss1.
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http://dx.doi.org/10.1016/j.ygcen.2020.113551DOI Listing
November 2020

Pamiparib is a potent and selective PARP inhibitor with unique potential for the treatment of brain tumor.

Neoplasia 2020 09 8;22(9):431-440. Epub 2020 Jul 8.

Department of In Vivo Pharmacology, BeiGene (Beijing) Co., Ltd., Beijing, PR China. Electronic address:

Pamiparib, an investigational Poly (ADP-ribose) polymerase (PARP) inhibitor in clinical development, demonstrates excellent selectivity for both PARP1 and PARP2, and superb anti-proliferation activities in tumor cell lines with BRCA1/2 mutations or HR pathway deficiency (HRD). Pamiparib has good bioavailability and is 16-fold more potent than olaparib in an efficacy study using BRCA1 mutated MDA-MB-436 breast cancer xenograft model. Pamiparib also shows strong anti-tumor synergy with temozolomide (TMZ), a DNA alkylating agent used to treat brain tumors. Compared to other PARP inhibitors, pamiparib demonstrated improved penetration across the blood brain barrier (BBB) in mice. Oral administration of pamiparib at a dose as low as 3 mg/kg is sufficient to abrogate PARylation in brain tumor tissues. In SCLC-derived, TMZ-resistant H209 intracranial xenograft model, combination of pamiparib with TMZ overcomes its resistance and shows significant tumor inhibitory effects and prolonged life span. Our data suggests that combination of pamiparib with TMZ has unique potential for treatment of brain tumors. Currently, the combination therapy of pamiparib with TMZ is evaluated in clinical trial [NCT03150862].
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http://dx.doi.org/10.1016/j.neo.2020.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350150PMC
September 2020

Integration of ATAC-seq and RNA-seq Unravels Chromatin Accessibility during Sex Reversal in Orange-Spotted Grouper ().

Int J Mol Sci 2020 Apr 17;21(8). Epub 2020 Apr 17.

State Key Laboratory of Biocontrol, Guangdong Province Key Laboratory for Improved Variety Reproduction of Aquatic Economic Animals, Institute of Aquatic Economic Animals, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China.

Chromatin structure plays a pivotal role in maintaining the precise regulation of gene expression. Accessible chromatin regions act as the binding sites of transcription factors (TFs) and cis-elements. Therefore, information from these open regions will enhance our understanding of the relationship between TF binding, chromatin status and the regulation of gene expression. We employed an assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and RNA-seq analyses in the gonads of protogynous hermaphroditic orange-spotted groupers during sex reversal to profile open chromatin regions and TF binding sites. We focused on several crucial TFs, including ZNF263, SPIB, and KLF9, and analyzed the networks of TF-target genes. We identified numerous transcripts exhibiting sex-preferred expression among their target genes, along with their associated open chromatin regions. We then investigated the expression patterns of sex-related genes as well as the mRNA localization of certain genes during sex reversal. We found a set of sex-related genes that-upon further study-might be identified as the sex-specific or cell-specific marker genes that trigger sex reversal. Moreover, we discovered the core genes (, , and ) of several pathways related to sex reversal that provide the guideposts for future study.
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http://dx.doi.org/10.3390/ijms21082800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215633PMC
April 2020

Beta-Hydroxysteroid Dehydrogenase Genes in Orange-Spotted Grouper (): Genome-Wide Identification and Expression Analysis During Sex Reversal.

Front Genet 2020 4;11:161. Epub 2020 Mar 4.

State Key Laboratory of Biocontrol, Guangdong Provincial Key Laboratory for Aquatic Economic Animals and Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), School of Life Sciences, Sun Yat-sen University, Guangzhou, China.

Beta-hydroxysteroid dehydrogenases (β-HSDs) are a group of steroidogenic enzymes that are involved in steroid biosynthesis and metabolism, and play a crucial role in mammalian physiology and development, including sex determination and differentiation. In the present study, a genome-wide analysis identified the numbers of β genes in orange-spotted grouper () (19), human () (22), mouse () (24), chicken () (16), xenopus () (24), coelacanth () (17), spotted gar () (14), zebrafish () (19), fugu () (19), tilapia () (19), medaka () (19), stickleback () (17) and common carp () (27) samples. A comparative analysis revealed that the number of β genes in teleost fish was no greater than in tetrapods due to gene loss followed by a teleost-specific whole-genome duplication event. Based on transcriptome data from grouper brain and gonad samples during sex reversal, six β genes had relatively high expression levels in the brain, indicating that these genes may be required for neurogenesis or the maintenance of specific biological processes in the brain. In the gonad, two and eight β genes were up- and downregulated, respectively, indicating their important roles in sex reversal. Our results demonstrated that β genes may be involved in the sex reversal of grouper by regulating the synthesis and metabolism of sex steroid hormones.
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http://dx.doi.org/10.3389/fgene.2020.00161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064643PMC
March 2020

Intracavernous delivery of Dickkopf3 gene or peptide rescues erectile function through enhanced cavernous angiogenesis in the diabetic mouse.

Andrology 2020 09 10;8(5):1387-1397. Epub 2020 Apr 10.

National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Korea.

Background: Severe peripheral angiopathy in patients with diabetes is a major contributing factor for low response rate to phosphodiesterase-5 inhibitors.

Objectives: To examine whether and how Dickkopf3 (DKK3), a secreted modulator of the Wnt pathway that known to be involved in endothelial cell repair and vascular progenitor cell migration, restores erectile function in diabetic mice.

Methods: Eight-week-old C57BL/6 mice received intraperitoneal injections of streptozotocin (50 mg/kg for 5 days). Eight weeks after the diabetes was induced, the efficacy of DKK3 was determined by three independent experiments: experiment 1 (DKK3 peptide [5 μg in 20 μL PBS]); experiment 2 (DKK3 plasmid DNA with electroporation [10, 40, or 100 μg in 20 μL PBS, respectively]); and experiment 3 (DKK3 adenovirus [1 × 10 , 1 × 10 , 1 × 10 virus particles per 20 μL, respectively]). Erectile function was measured by electrical stimulation of the cavernous nerve one week (for peptide) or two weeks (for genes) after treatment. The angiogenic activity of DKK3 was determined in diabetic penis in vivo and in primary cultured mouse cavernous endothelial cells (MCECs) in vitro.

Results: The cavernous expression of DKK3 protein was significantly lower in the diabetic mice than in controls. DKK3 peptide or adenovirus significantly improved erectile function in diabetic mice (70% of the control values). DKK3 adenovirus profoundly restored cavernous endothelial cell and pericyte contents and increased endothelial junction proteins in diabetic mice in vivo. DKK3 peptide induced upregulation of angiogenic factors (angiopoietin-1, vascular endothelial growth factor, and basic fibroblast growth factor) and accelerated tube formation in MCECs cultivated under the high-glucose condition in vitro.

Conclusion: DKK3 restored cavernous vascular integrity and improved erectile function in diabetic mice. Therapeutic cavernous angiogenesis by the use of DKK3 will be a promising therapeutic strategy to treat diabetic erectile dysfunction.
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http://dx.doi.org/10.1111/andr.12784DOI Listing
September 2020

and Anti-AChE and Antioxidative Effects of Extract: A Potential Candidate for Alzheimer's Disease.

Evid Based Complement Alternat Med 2020 20;2020:2804849. Epub 2020 Feb 20.

Shenzhen Key Laboratory of Drug Quality Standard Research, Shenzhen Institute for Drug Control, Shenzhen, China.

Acetylcholinesterase (AChE) inhibition and antioxidants are two common strategies for the treatment in the early stage of Alzheimer's Disease (AD). In this study, extracts from nine traditional Chinese medical (TCM) herbs were tested for anti-AChE activity by Ellman's microplate assay and cytotoxicity by CCK-8. Based on its excellent AChE inhibition effect and its lowest cytotoxicity, (SC) extract was selected to do the mechanism research. SC extract protected pheochromocytoma (PC12) cells against HO-induced toxicity by improving the cell survival rate in a dose-dependent manner. And it also showed significant free radical (DPPH) scavenging activities, ferric reducing antioxidant power (FRAP), and 2,2'-Azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging. To confirm these results, the scopolamine-induced mice models were utilized in this study. Compared with the positive drug (piracetam), SC could also exhibit similar effects to alleviate the mice's cognitive deficits. Moreover, in the mice brain samples, the AChE activity and malondialdehyde (MDA) levels of SC-treatment group both showed a reverse as compared to model group. Taken together, these results all suggested that SC extract may be a potential therapeutic candidate for AD.
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http://dx.doi.org/10.1155/2020/2804849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053447PMC
February 2020

In vitro effects of androgen on testicular development by the AR-foxl3-rec8/fbxo47 axis in orange-spotted grouper (Epinephelus coioides).

Gen Comp Endocrinol 2020 06 11;292:113435. Epub 2020 Feb 11.

College of Marine Sciences, South China Agricultural University, Guangzhou 510642, Guangdong, People's Republic of China. Electronic address:

In orange-spotted grouper, androgen can promote the development of testis and spermatogenesis, but the effect of androgen on testis development is unclear. Forkhead box L 3 (Foxl3) is important in the development of fish testis. Rec8 and fbxo47 are involved in meiosis, which impacts spermatogenesis. The present study investigated the plausible role of testis development through the Foxl3 transcriptional regulation of rec8 and fbxo47. The results of tissue distribution showed that rec8 and fbxo47 are highly expressed in gonad. In addition, the highest expression of foxl3, rec8, and fbxo47 was in the testis and intersex compared with the other stages of gonadal development, suggesting that foxl3, rec8, and fbxo47 are important in testis development. In addition, by using dual-luciferase assays, we found that the androgen can increase foxl3 promoter activity and Foxl3 can upregulate rec8 and fbxo47 promoter activity. Furthermore, the addition of β-testosterone significantly increased foxl3, rec8, and fbxo47 promoter activity. Together, these results suggest that foxl3 plays a decisive role in testis development by regulating the expression of rec8 or fbxo47 and imply that AR-foxl3-rec8/fbxo47 affects the testis development pathway.
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http://dx.doi.org/10.1016/j.ygcen.2020.113435DOI Listing
June 2020

Transcriptome profiling of laser-captured germ cells and functional characterization of zbtb40 during 17alpha-methyltestosterone-induced spermatogenesis in orange-spotted grouper (Epinephelus coioides).

BMC Genomics 2020 Jan 23;21(1):73. Epub 2020 Jan 23.

State Key Laboratory of Biocontrol, Guangdong Province Key Laboratory for Improved Variety Reproduction of Aquatic Economic Animals, Institute of Aquatic Economic Animals, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China.

Background: Spermatogenesis is an intricate process regulated by a finely organized network. The orange-spotted grouper (Epinephelus coioides) is a protogynous hermaphroditic fish, but the regulatory mechanism of its spermatogenesis is not well-understood. In the present study, transcriptome sequencing of the male germ cells isolated from orange-spotted grouper was performed to explore the molecular mechanism underlying spermatogenesis.

Results: In this study, the orange-spotted grouper was induced to change sex from female to male by 17alpha-methyltestosterone (MT) implantation. During the spermatogenesis, male germ cells (spermatogonia, spermatocytes, spermatids, and spermatozoa) were isolated by laser capture microdissection. Transcriptomic analysis for the isolated cells was performed. A total of 244,984,338 clean reads were generated from four cDNA libraries. Real-time PCR results of 13 genes related to sex differentiation and hormone metabolism indicated that transcriptome data are reliable. RNA-seq data showed that the female-related genes and genes involved in hormone metabolism were highly expressed in spermatogonia and spermatozoa, suggesting that these genes participate in the spermatogenesis. Interestingly, the expression of zbtb family genes showed significantly changes in the RNA-seq data, and their expression patterns were further examined during spermatogenesis. The analysis of cellular localization of Eczbtb40 and the co-localization of Eczbtb40 and Eccyp17a1 in different gonadal stages suggested that Eczbtb40 might interact with Eccyp17a1 during spermatogenesis.

Conclusions: Our study, for the first time, investigated the transcriptome of the male germ cells from orange-spotted grouper, and identified functional genes, GO terms, and KEGG pathways involved in spermatogenesis. Furthermore, Eczbtb40 was first characterized and its role during spermatogenesis was predicted. These data will contribute to future studies on the molecular mechanism of spermatogenesis in teleosts.
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http://dx.doi.org/10.1186/s12864-020-6477-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6979330PMC
January 2020

Identification of Candidate Growth-Related SNPs and Genes Using GWAS in Brown-Marbled Grouper (Epinephelus fuscoguttatus).

Mar Biotechnol (NY) 2020 Apr 11;22(2):153-166. Epub 2020 Jan 11.

State Key Laboratory of Biocontrol, Institute of Aquatic Economic Animals and Guangdong Provincial Key Laboratory for Aquatic Economic Animals, Life Science School, Sun Yat-sen University, Guangzhou, 510275, People's Republic of China.

Brown-marbled grouper, Epinephelus fuscoguttatus, is not only an important commercial fish species, but also an important crossbreeding parent in grouper industry. Improvement of growth traits of this species contributes to the development of grouper breeding. Currently, the development of molecular marker associated with growth of brown-marbled grouper is rare. Thus, we performed the first genome-wide association study (GWAS) for five growth traits in 172 brown-marbled groupers with 43,688 SNPs detected by ddRAD-seq. We identified a total of 5 significant and 18 suggestive QTLs located in multiple chromosomes associated with growth traits. In the 20 kb window of the significant SNPs and suggestive SNPs, 5 and 14 potential candidate genes affecting growth were detected, respectively. Five potential candidate genes near the significantly associated SNPs were selected for expression analysis. Among of which, bmp2k, wasf1, and acyp2 involved in bone development, maintenance of mitochondrion structure, and metabolism were differentially expressed. Interestingly, the SNP 23:29601315 located in the intron of bmp2k was significantly associated with body weight, body length, body height, and body thickness and suggestively associated with total length. We verified the locus using another new group including 123 individuals. The results showed that individuals with CC genotype have better growth traits comparing other individuals. Our findings not only contribute to understanding the molecular mechanism of growth regulation, but also promote the advance of marker-assisted selection in brown-marbled grouper.
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http://dx.doi.org/10.1007/s10126-019-09940-8DOI Listing
April 2020

Antimicrobial activities of Asian ginseng, American ginseng, and notoginseng.

Phytother Res 2020 Jun 29;34(6):1226-1236. Epub 2019 Dec 29.

Institute of Crop Science, Chinese Academy of Agricultural Sciences, Beijing, China.

Asian ginseng (Panax ginseng C.A. Meyer), American ginseng (Panax quinquefolius) and notoginseng (Panax notoginseng) are the three most commonly used ginseng botanicals in the world. With the increasing interests on antimicrobial properties of plants, the antimicrobial activities of ginseng species have been investigated by a number of researchers worldwide. This overview interprets our present knowledge of the antimicrobial activities of the three ginseng species and some of their bioactive components against pathogenic bacteria (Pseudomonas aeruginosa, Helicobacter pylori, Staphylococcus aureus, Escherichia coli, Propionibacterium acnes, et al.) and fungi (Candida albicans, Fusarium oxysporum, et al). Ginsenosides, polysaccharides, essential oil, proteins, and panaxytriol are all might responsible for the antimicrobial activities of ginseng. The antimicrobial mechanisms of ginseng components could be summarized to the following points: (a) inhibit the microbial motility and quorum-sensing ability; (b) affect the formation of biofilms and destroy the mature biofilms, which can weaken the infection ability of the microbes; (c) perturb membrane lipid bilayers, thus causing the formation of pores, leakages of cell constituents and eventually cell death; (d) stimulate of the immune system and attenuate microbes induced apoptosis, inflammation, and DNA damages, which can protect or help the host fight against microbial infections; and (e) inhibit the efflux of antibiotics that can descend the drug resistance of the microbial. The collected information might facilitate and guide further studies needed to optimize the use of ginseng and their components to improve microbial food safety and prevent or treat animal and human infections.
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http://dx.doi.org/10.1002/ptr.6605DOI Listing
June 2020

Embryonic stem cell-derived extracellular vesicle-mimetic nanovesicles rescue erectile function by enhancing penile neurovascular regeneration in the streptozotocin-induced diabetic mouse.

Sci Rep 2019 12 27;9(1):20072. Epub 2019 Dec 27.

National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, 22332, Korea.

Extracellular vesicles (EVs) have attracted particular interest in various fields of biology and medicine. However, one of the major hurdles in the clinical application of EV-based therapy is their low production yield. We recently developed cell-derived EV-mimetic nanovesicles (NVs) by extruding cells serially through filters with diminishing pore sizes (10, 5, and 1 μm). Here, we demonstrate in diabetic mice that embryonic stem cell (ESC)-derived EV-mimetic NVs (ESC-NVs) completely restore erectile function (~96% of control values) through enhanced penile angiogenesis and neural regeneration in vivo, whereas ESC partially restores erectile function (~77% of control values). ESC-NVs promoted tube formation in primary cultured mouse cavernous endothelial cells and pericytes under high-glucose condition in vitro; and accelerated microvascular and neurite sprouting from aortic ring and major pelvic ganglion under high-glucose condition ex vivo, respectively. ESC-NVs enhanced the expression of angiogenic and neurotrophic factors (hepatocyte growth factor, angiopoietin-1, nerve growth factor, and neurotrophin-3), and activated cell survival and proliferative factors (Akt and ERK). Therefore, it will be a better strategy to use ESC-NVs than ESCs in patients with erectile dysfunction refractory to pharmacotherapy, although it remains to be solved for future clinical application of ESC.
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http://dx.doi.org/10.1038/s41598-019-54431-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934510PMC
December 2019

Integrative subspace clustering by common and specific decomposition for applications on cancer subtype identification.

BMC Med Genomics 2019 12 24;12(Suppl 9):191. Epub 2019 Dec 24.

School of Mathematics and Statistics, Xi'an Jiaotong University, Xianning West 28, Xi'an, China.

Background: Recent high throughput technologies have been applied for collecting heterogeneous biomedical omics datasets. Computational analysis of the multi-omics datasets could potentially reveal deep insights for a given disease. Most existing clustering methods by multi-omics data assume strong consistency among different sources of datasets, and thus may lose efficacy when the consistency is relatively weak. Furthermore, they could not identify the conflicting parts for each view, which might be important in applications such as cancer subtype identification.

Methods: In this work, we propose an integrative subspace clustering method (ISC) by common and specific decomposition to identify clustering structures with multi-omics datasets. The main idea of our ISC method is that the original representations for the samples in each view could be reconstructed by the concatenation of a common part and a view-specific part in orthogonal subspaces. The problem can be formulated as a matrix decomposition problem and solved efficiently by our proposed algorithm.

Results: The experiments on simulation and text datasets show that our method outperforms other state-of-art methods. Our method is further evaluated by identifying cancer types using a colorectal dataset. We finally apply our method to cancer subtype identification for five cancers using TCGA datasets, and the survival analysis shows that the subtypes we found are significantly better than other compared methods.

Conclusion: We conclude that our ISC model could not only discover the weak common information across views but also identify the view-specific information.
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http://dx.doi.org/10.1186/s12920-019-0633-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929329PMC
December 2019

Prostaglandin E1 protects cardiomyocytes against hypoxia-reperfusion induced injury via the miR-21-5p/FASLG axis.

Biosci Rep 2019 12;39(12)

Depatment of Pharmacy, The third Xiangya Hospital of Central South University, Changsha, Hunan, China.

Background: Prostaglandin-E1 (PGE1) is a potent vasodilator with anti-inflammatory and antiplatelet effects. However, the mechanism by which PGE1 contributes to the amelioration of cardiac injury remains unclear.

Methods: The present study was designed to investigate how PGE1 protects against hypoxia/reoxygenation (H/R)-induced injuries by regulating microRNA-21-5p (miR-21-5p) and fas ligand (FASLG). Rat H9C2 cells and isolated primary cardiomyocytes were cultured under hypoxic conditions for 6 h (6H, hypoxia for 6 h), and reoxygenated for periods of 6 (6R, reoxygenation for 6 h), 12, and 24 h, respectively. Cells from the 6H/6R group were treated with various doses of PGE1; after which, their levels of viability and apoptosis were detected.

Results: The 6H/6R treatment regimen induced the maximum level of H9C2 cell apoptosis, which was accompanied by the highest levels of Bcl-2-associated X protein (Bax) and cleaved-caspase-3 expression and the lowest level of B-cell lymphoma 2 (Bcl-2) expression. Treatment with PGE1 significantly diminished the cell cytotoxicity and apoptosis induced by the 6H/6R regimen, and also decreased expression of IL-2, IL-6, P-p65, TNF-α, and cleaved-caspase-3. In addition, we proved that PGE1 up-regulated miR-21-5p expression in rat cardiomyocytes exposed to conditions that produce H/R injury. FASLG was a direct target of miR-21-5p, and PGE1 reduced the ability of H/R-injured rat cardiomyocytes to undergo apoptosis by affecting the miR-21-5p/FASLG axis. In addition, we proved that PGE1 could protect primary cardiomyocytes against H/R-induced injuries.

Conclusions: These results indicate that PGE1 exerts cardioprotective effects in H9C2 cells during H/R by regulating the miR-21-5p/FASLG axis.
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http://dx.doi.org/10.1042/BSR20190597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923339PMC
December 2019

A dual-responsive biosensor for blood lead detection.

Anal Chim Acta 2020 Jan 25;1093:131-141. Epub 2019 Sep 25.

National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing, 210023, China. Electronic address:

Simple and accurate detection of trace heavy metals in blood is very important. A novel dual-responsive electrochemical/fluorescent biosensor based on magnetic hyperbranched polyamide with heparin modification (MHPAM-H) for blood lead detection has been successfully developed. Upon conjugated with blood lead ions, dual-biosensor could not only display electrochemical signal but also fluorescence signal owing to the enriched amino groups, cavity structure, and good fluorescence properties of HPAM. Blood biocompatibility, construction of the dual-responsive biosensor, electrochemical/fluorescent detection of lead ions in water phase and blood condition, selectivity and stability of the dual-responsive biosensor were investigated in detail. The proposed dual-responsive biosensor displays good linear relationship (1.5 pM- 4.8 × 10 pM for electrochemical detection and 0.5 pM-4.8 × 10 pM for fluorescent detection) with low detection limit (4.4 pM for electrochemical detection and 1.0 pM for fluorescent detection) for blood lead, providing potential application for blood lead detection in the future.
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http://dx.doi.org/10.1016/j.aca.2019.09.062DOI Listing
January 2020

Quality Evaluation of (Fort.) Carr. Using Supercritical Fluid Chromatography with Chemical Pattern Recognition.

Molecules 2019 Oct 13;24(20). Epub 2019 Oct 13.

Shenzhen Institute for Drug Control, Shenzhen 518057, China.

(Fort.) Carr. () plays an important role in the treatment of many diseases. In the present study, a comprehensive method combining supercritical fluid chromatography (SFC) fingerprints and chemical pattern recognition (CPR) for quality evaluation of was developed. Similarity analysis, hierarchical cluster analysis (HCA), principal component analysis (PCA) were applied to classify and evaluate the samples of wild , cultivated and its substitutes according to the peak area of 11 components but an accurate classification could not be achieved. PLS-DA was then adopted to select the characteristic variables based on variable importance in projection (VIP) values that responsible for accurate classification. Six characteristics peaks with higher VIP values (≥1) were selected for building the CPR model. Based on the six variables, three types of samples were accurately classified into three related clusters. The model was further validated by a testing set samples and predication set samples. The results indicated the model was successfully established and predictive ability was also verified satisfactory. The established model demonstrated that the developed SFC coupled with PLS-DA method showed a great potential application for quality assessment of .
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http://dx.doi.org/10.3390/molecules24203684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832872PMC
October 2019

Phosphorylated Hexa-Acyl Disaccharides Augment Host Resistance Against Common Nosocomial Pathogens.

Crit Care Med 2019 11;47(11):e930-e938

Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN.

Objectives: To determine whether synthetic phosphorylated hexa-acyl disaccharides provide antimicrobial protection in clinically relevant models of bacterial infection.

Design: Laboratory study.

Setting: University laboratory.

Subjects: BALB/c, C57BL/10J, and C57BL/10ScNJ mice.

Interventions: Mice were treated with lactated Ringer's (vehicle) solution, monophosphoryl lipid A, or phosphorylated hexa-acyl disaccharides at 48 and 24 hours prior to intraperitoneal Pseudomonas aeruginosa or IV Staphylococcus aureus infection. Leukocyte recruitment, cytokine production, and bacterial clearance were measured 6 hours after P. aeruginosa infection. In the systemic S. aureus infection model, one group of mice was monitored for 14-day survival and another for S. aureus tissue burden at 3 days postinfection. Duration of action for 3-deacyl 6-Acyl phosphorylated hexa-acyl disaccharide was determined at 3, 10, and 14 days using a model of intraperitoneal P. aeruginosa infection. Effect of 3-deacyl 6-Acyl phosphorylated hexa-acyl disaccharide on in vivo leukocyte phagocytosis and respiratory burst was examined. Leukocyte recruitment, cytokine production, and bacterial clearance were measured after P. aeruginosa infection in wild-type and toll-like receptor 4 knockout mice treated with 3-deacyl 6-Acyl phosphorylated hexa-acyl disaccharide or vehicle to assess receptor specificity.

Measurements And Main Results: During intraperitoneal P. aeruginosa infection, phosphorylated hexa-acyl disaccharides significantly attenuated infection-induced hypothermia, augmented leukocyte recruitment and bacterial clearance, and decreased cytokine production. At 3 days post S. aureus infection, bacterial burden in lungs, spleen, and kidneys was significantly decreased in mice treated with monophosphoryl lipid A or phosphorylated hexa-acyl disaccharides, which was associated with improved survival. Leukocyte phagocytosis and respiratory burst functions were enhanced after treatment with monophosphoryl lipid A or phosphorylated hexa-acyl disaccharides. A time course study showed that monophosphoryl lipid A- and 3-deacyl 6-Acyl phosphorylated hexa-acyl disaccharide-mediated protection against P. aeruginosa lasts for up to 10 days. Partial loss of augmented innate antimicrobial responses was observed in toll-like receptor 4 knockout mice treated with 3-deacyl 6-Acyl phosphorylated hexa-acyl disaccharide.

Conclusions: Phosphorylated hexa-acyl disaccharides significantly augment resistance against clinically relevant Gram-negative and Gram-positive infections via enhanced leukocyte recruitment, phagocytosis, and respiratory burst functions of innate leukocytes. Improved antimicrobial protection persists for up to 10 days and is partially mediated through toll-like receptor 4.
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http://dx.doi.org/10.1097/CCM.0000000000003967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791756PMC
November 2019

Prevalence and Associations of Fundus Tessellation Among Junior Students From Greater Beijing.

Invest Ophthalmol Vis Sci 2019 09;60(12):4033-4040

Department of Epidemiology and Biostatistics, School of Public Health, Capital Medical University, Beijing, China.

Purpose: To determine the prevalence of fundus tessellation and associations with ocular and systemic parameters among junior students from Greater Beijing.

Methods: The school-based study included 1443 individuals with a mean age of 12.4 ± 0.5 years (range: 9-16 years). All participants underwent a comprehensive ophthalmic examination and an interview. Fundus tessellation, defined as variation in the visibility of large choroidal vessels, was differentiated into three grades.

Results: The prevalence and degree of fundus tessellation were 688/1430 (48.1%; 95% confidence intervals [CI]: 45.5%, 50.7%) and 0.54 ± 0.61 (median, 0.00; range, 0-3), respectively. In multivariable regression analysis, a higher degree of fundus tessellation was associated with reduced subfoveal choroidal thickness (P < 0.001; beta, -0.02; odds ratio [OR], 0.98; 95% CI: 0.98, 0.99) and longer axial length (P < 0.001; beta, 0.23; OR, 1.25; 95% CI: 1.10, 1.43). Subfoveal choroidal thickness decreased from 299 ± 61 μm (95% CI: 293, 304) in eyes without fundus tessellation to 246 ± 57 μm (95% CI: 241, 251), 197 ± 43 μm (95% CI: 187, 207), and 131 ± 30 μm (95% CI: 93, 168) in eyes with grade 1, 2, and 3 fundus tessellation, respectively. A higher degree of peripapillary fundus tessellation was associated with reduced subfoveal choroidal thickness (P < 0.001; beta, -0.02; OR, 0.98; 95% CI: 0.98, 0.99) and younger age at myopia onset (P = 0.008; beta, 0.41; OR, 1.51; 95% CI: 1.11, 2.04).

Conclusions: The prevalence of fundus tessellation is relatively high in Chinese teenagers. As in adults, the degree of fundus tessellation is a surrogate for choroidal thickness in teenagers. Marked fundus tessellation indicates a leptochoroid and is associated with earlier myopia onset.
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http://dx.doi.org/10.1167/iovs.19-27382DOI Listing
September 2019