Publications by authors named "Xiuyan Yang"

101 Publications

Effects of Salvianolic acid B on RNA expression and co-expression network of lncRNAs in brown adipose tissue of obese mice.

J Ethnopharmacol 2021 Jun 3:114289. Epub 2021 Jun 3.

Traditional Chinese Medicine School, Beijing University of Chinese Medicine, Beijing, China. Electronic address:

Ethnopharmacological Relevance: Salvianolic acid B (SalB) is a polyphenolic compound in Salvia miltiorrhiza Bunge ("Danshen"), which has been largely used in Traditional Chinese Medicine for the treatment of metabolic syndrome, obesity, diabetes, among others.

Aim Of Study: This study was to investigate the effects of Salvianolic acid B (SalB) on mRNA, lncRNA and circRNA's expression profile in brown adipose tissue (BAT) of obese mice.

Materials And Methods: High-fat-diet induced obese C57BL/6J mice were treated with SalB (100 mg/kg/day) for 8 weeks. Then, BAT was harvested for RNA-Seq analysis. Differentially expressed mRNAs, lncRNAs and circRNAs were analyzed using the Illumina Hiseq 4000. Following this procedure, bioinformatic tools including Gene ontology (GO), KEGG pathway and lncRNA-mRNA co-network analysis were utilized. Finally, RT-qPCR was performed to validate the differentially expressed RNAs.

Results: Compared with control group, 2532 mRNAs, 774 lncRNAs and 25 circRNAs were differentially expressed in SalB group. Additionally, 40 upregulated and 109 downregulated gene-related pathways were identified in the SalB group. Among them, metabolic pathways showed the highest enrichment coefficient in upregulated genes. Moreover, 54 up-regulated and 626 down-regulated coding mRNAs associated with lncRNA-Hsd11b1 and lncRNA-Vmp1.

Conclusions: SalB may play an anti-obesity role by adjusting the expression of mRNAs correlated with inflammatory response and energy metabolism through regulating the expression of lncRNA-Hsd11b1. The findings of this research provide new directions to study the mechanisms of SalB, and would open therapeutic avenues for the treatment of obesity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jep.2021.114289DOI Listing
June 2021

Integrative analysis of transcriptome and proteome revealed nectary and nectar traits in the plant-pollinator interaction of Nitraria tangutorum Bobrov.

BMC Plant Biol 2021 May 22;21(1):230. Epub 2021 May 22.

Key Laboratory of Forest Genetics and Biotechnology of Ministry of Education of China, Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, 159 Longpan Rd, Xuanwu, Nanjing, 210037, China.

Background: Nitraria tangutorum is an important desert shrub that shows resistance to drought, salt and wind erosion stresses. It is a central ecological species in its area. Here, we have studied how N. tangutorum has adapted to achieve a successful reproduction strategy.

Results: We found that N. tangutorum is mainly pollinated by insects of the Hymenoptera, Diptera and Coleoptera orders. Nitraria tangutorum has very small flowers, with the nectary composed of secretive epidermal cells from which nectar is secreted, located within the inner petals. In addition, analyzing the transcriptome of four successive flower developmental stages revealed that mainly differentially expressed genes associated with flower and nectary development, nectar biosynthesis and secretion, flavonoid biosynthesis, plant hormone signal transduction and plant-pathogen interaction show dynamic expression. From the nectar, we could identify seven important proteins, of which the L-ascorbate oxidase protein was first found in plant nectar. Based on the physiological functions of these proteins, we predict that floral nectar proteins of N. tangutorum play an important role in defending against microbial infestation and scavenging active oxygen.

Conclusions: This study revealed that N. tangutorum is an insect-pollinated plant and its nectary is composed of secretive epidermal cells that specialized into secretive trichomes. We identified a large number of differentially expressed genes controlling flower and nectary development, nectar biosynthesis and secretion, flavonoid biosynthesis, plant hormone signal transduction and plant-pathogen interaction. We suggest that proteins present in N. tangutorum nectar may have both an antibacterial and oxygen scavenging effect. These results provide a scientific basis for exploring how the reproductive system of N. tangutorum and other arid-desert plants functions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12870-021-03002-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140516PMC
May 2021

Advances and Insights of APC-Asef Inhibitors for Metastatic Colorectal Cancer Therapy.

Front Mol Biosci 2021 22;8:662579. Epub 2021 Apr 22.

Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

In Colorectal cancer (CRC), adenomatous polyposis coli (APC) directly interacts with the Rho guanine nucleotide exchange factor 4 (Asef) and releases its GEF activity. Activated Asef promotes the aberrant migration and invasion of CRC cell through a CDC42-mediated pathway. Knockdown of either APC or Asef significantly decreases the migration of CRC cells. Therefore, disrupting the APC-Asef interaction is a promising strategy for the treatment of invasive CRC. With the growth of structural information, APC-Asef inhibitors have been designed, providing hope for CRC therapy. Here, we will review the APC-Asef interaction in cancer biology, the structural complex of APC-Asef, two generations of peptide inhibitors of APC-Asef, and small molecule inhibitors of APC-Asef, focusing on research articles over the past 30 years. We posit that these advances in the discovery of APC-Asef inhibitors establish the protein-protein interaction (PPI) as targetable and provide a framework for other PPI programs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmolb.2021.662579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100458PMC
April 2021

IP-assisted CSN-COP1 competition regulates a CRL4-ETV5 proteolytic checkpoint to safeguard glucose-induced insulin secretion.

Nat Commun 2021 04 28;12(1):2461. Epub 2021 Apr 28.

School of Life Sciences, Department of Biology, Southern University of Science and Technology, Shenzhen, Guangdong, China.

COP1 and COP9 signalosome (CSN) are the substrate receptor and deneddylase of CRL4 E3 ligase, respectively. How they functionally interact remains unclear. Here, we uncover COP1-CSN antagonism during glucose-induced insulin secretion. Heterozygous Csn2 mice with partially disrupted binding of IP, a CSN cofactor, display congenital hyperinsulinism and insulin resistance. This is due to increased Cul4 neddylation, CRL4 E3 assembly, and ubiquitylation of ETV5, an obesity-associated transcriptional suppressor of insulin secretion. Hyperglycemia reciprocally regulates CRL4-CSN versus CRL4 assembly to promote ETV5 degradation. Excessive ETV5 degradation is a hallmark of Csn2, high-fat diet-treated, and ob/ob mice. The CRL neddylation inhibitor Pevonedistat/MLN4924 stabilizes ETV5 and remediates the hyperinsulinemia and obesity/diabetes phenotypes of these mice. These observations were extended to human islets and EndoC-βH1 cells. Thus, a CRL4-ETV5 proteolytic checkpoint licensing GSIS is safeguarded by IP-assisted CSN-COP1 competition. Deregulation of the IP-CSN-CRL4-ETV5 axis underlies hyperinsulinemia and can be intervened to reduce obesity and diabetic risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-22941-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080631PMC
April 2021

MiR319-targeted OsTCP21 and OsGAmyb regulate tillering and grain yield in rice.

J Integr Plant Biol 2021 Apr 10. Epub 2021 Apr 10.

Key Laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), College of Agricultural Sciences, Guizhou University, Guiyang, 550025, China.

Multiple genes and microRNAs (miRNAs) improve grain yield by promoting tillering. MiR319s are known to regulate several aspects of plant development; however, whether miR319s are essential for tillering regulation remains unclear. Here, we report that miR319 is highly expressed in the basal part of rice plant at different development stages. The miR319 knockdown line Short Tandem Target Mimic 319 (STTM319) showed higher tiller bud length in seedlings under low nitrogen (N) condition and higher tiller bud number under high N condition compared with the miR319a-overexpression line. Through targets prediction, we identified OsTCP21 and OsGAmyb as downstream targets of miR319. Moreover, OsTCP21 and OsGAmyb overexpression lines and STTM319 had increased tiller bud length and biomass, whereas both were decreased in OsTCP21 and OsGAmyb knockout lines and OE319a. These data suggest that miR319 regulates rice tiller bud development and tillering through targeting OsTCP21 and OsGAmyb. Notably, the tiller number and grain yield increased in STTM319 and overexpression lines of OsTCP21 and OsGAmyb but decreased in OE319a and knockout lines of OsTCP21 and OsGAmyb. Taken together, our findings indicate that miR319s negatively affect tiller number and grain yield by targeting OsTCP21 and OsGAmyb, revealing a novel function for miR319 in rice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jipb.13097DOI Listing
April 2021

Population pharmacokinetics and individual analysis of daptomycin in kidney transplant recipients.

Eur J Pharm Sci 2021 Jul 24;162:105818. Epub 2021 Mar 24.

State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Key Laboratory for Drug Evaluation and Clinical Research of Zhejiang Province, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. Electronic address:

Background: Little is known about the population pharmacokinetics (PPK) of daptomycin in kidney transplant patients. The present study established a pharmacokinetic model for daptomycin in kidney transplant patients in China and examinee the important factors affecting the pharmacokinetic parameters of daptomycin.

Methods: The study population included 49 kidney transplant patients with 537 daptomycin concentrations. The PPK model of daptomycin was developed using a nonlinear mixed-effects model, a two-compartment structural model, and a mixed residual error model. The stability and predictive ability of the final model were evaluated based on bootstrapping, visual prediction checks and normalized prediction distribution errors.

Results: Glomerular filtration rate (GFR) and total body weight significantly affected clearance, and body weight influenced the central volume of distribution. The average clearance of the population was 0.316 L/h, the central volume of distribution was 6.04 L, the intercompartmental clearance was 2.31 L/h, and the peripheral volume of distribution was 2.46 L. Based on the established model and the target of area under curve (AUC)/minimum inhibition concentration (MIC) ≥666, we developed a recommended dose regimen for kidney transplant patients according to their renal function and weight. The daily doses were 4.0±0.31, 4.7±0.36, 5.1±0.40, 5.5±0.43, 5.8±0.45, and 6.1±0.48 mg/kg when the GFRs were 15, 30, 45, 60, 75, and 90 ml/min/1.73 m, respectively.

Conclusion: This study provides a reference for individualized daptomycin administration in kidney transplant recipients, and it is a valuable resource for improving the treatment effect and reducing the toxic effects of daptomycin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejps.2021.105818DOI Listing
July 2021

Application of a dissolved oxygen control strategy to increase the expression of Streptococcus suis glutamate dehydrogenase in Escherichia coli.

World J Microbiol Biotechnol 2021 Mar 12;37(4):60. Epub 2021 Mar 12.

Shandong Research Center of High Cell Density Fermentation and Efficient Expression Technology, Shandong Lvdu Bio-Science and Technology Co., Ltd., Shandong Binzhou Animal Science and Veterinary Medicine Academy, Binzhou, 256600, China.

The accumulation of acetate in Escherichia coli inhibits cell growth and desired protein synthesis, and cell density and protein expression are increased by reduction of acetate excretion. Dissolved oxygen (DO) is an important parameter for acetate synthesis, and the accumulation of acetate is inversely correlated to DO level. In this study, the effect of DO levels on glutamate dehydrogenase (GDH) expression was investigated, and then different DO control strategies were tested for effects on GDH expression. DO control strategy IV (50% 0-9 h, 30% 9-18 h) provided the highest cell density (15.43 g/L) and GDH concentration (3.42 g/L), values 1.59- and 1.99-times higher than those achieved at 10% DO. The accumulation of acetate was 2.24 g/L with DO control strategy IV, a decrease of 40.74% relative to that achieved for growth at 10% DO. Additionally, under DO control strategy IV, there was lower expression of PoxB, a key enzyme for acetate synthesis, at both the transcriptional and translational level. At the same time, higher transcription and protein expression levels were observed for a glyoxylate shunt gene (aceA), an acetate uptake gene (acs), gluconeogensis and anaplerotic pathways genes (pckA, ppsA, ppc, and sfcA), and a TCA cycle gene (gltA). The flux of acetate with DO strategy IV was 8.4%, a decrease of 62.33% compared with the flux at 10% DO. This decrease represents both lower flux for acetate synthesis and increased flux of reused acetate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11274-021-03025-2DOI Listing
March 2021

CIPK11: a calcineurin B-like protein-interacting protein kinase from Nitraria tangutorum, confers tolerance to salt and drought in Arabidopsis.

BMC Plant Biol 2021 Mar 1;21(1):123. Epub 2021 Mar 1.

Key Laboratory of Forest Genetics & Biotechnology of Ministry of Education, Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing, 210037, China.

Background: The CIPKs are a group of plant-specific Ser/Thr protein kinases acting in response to calcium signaling, which plays an important role in the physiological and developmental adaptation of plants to adverse environments. However, the functions of halophyte-derived CIPKs are still poorly understood, that limits a potential application of CIPKs from halophytes for improving the tolerance of glycophytes to abiotic stresses.

Results: In this study, we characterized the NtCIPK11 gene from the halophyte Nitraria tangutorum and subsequently analyzed its role in salt and drought stress tolerance, using Arabidopsis as a transgenic model system. NtCIPK11 expression was upregulated in N. tangutorum root, stem and blade tissues after salt or drought treatment. Overexpressing NtCIPK11 in Arabidopsis improved seed germination on medium containing different levels of NaCl. Moreover, the transgenic plants grew more vigorously under salt stress and developed longer roots under salt or drought conditions than the WT plants. Furthermore, NtCIPK11 overexpression altered the transcription of genes encoding key enzymes involved in proline metabolism in Arabidopsis exposed to salinity, however, which genes showed a relatively weak expression in the transgenic Arabidopsis undergoing mannitol treatment, a situation that mimics drought stress. Besides, the proline significantly accumulated in NtCIPK11-overexpressing plants compared with WT under NaCl treatment, but that was not observed in the transgenic plants under drought stress caused by mannitol application.

Conclusions: We conclude that NtCIPK11 promotes plant growth and mitigates damage associated with salt stress by regulating the expression of genes controlling proline accumulation. These results extend our understanding on the function of halophyte-derived CIPK genes and suggest that NtCIPK11 can serve as a candidate gene for improving the salt and drought tolerance of glycophytes through genetic engineering.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12870-021-02878-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919098PMC
March 2021

Tissue tolerance mechanisms conferring salinity tolerance in a halophytic perennial species Nitraria sibirica Pall.

Tree Physiol 2020 Dec 26. Epub 2020 Dec 26.

Research Center of Saline and Alkali Land of National Forestry and Grassland Administration, Chinese Academy of Forestry, Beijing, 10091, China.

Plant salt tolerance relies on a coordinated functioning of different tissues and organs. Salinity tissue tolerance is one of the key traits that confers plant adaptation to saline environment. This trait implies maintenance low cytosolic Na+/K+ ratio in metabolically active cellular compartments. In this study, we used Nitraria sibirica Pall., a perennial woody halophytes species, to understand the mechanistic basis of its salinity tissue tolerance. The results showed that the growth of seedlings was stimulated by 100-200 mM NaCl treatment. The ions distribution analysis showed that the leaves acted as Na+ sink while plant root possess superior K+ retention. The excessive Na+ absorbed from soil was mainly transported to the shoot and eventually sequestrated into mesophyll vacuoles in the leaves. As a result, N. sibirica could keep optimal balance of K+/Na+ at a tissue- and cell-specific level under saline condition. To enable this, N. sibirica increased both vacuolar H+-ATPase and H+-PPase enzymes activities and up-regulated expressions of NsVHA, NsVP1 and NsNHX1 genes. Vacuolar Na+ sequestration in the leaf mesophyll mediated by NsVHA, NsVP1 and NsNHX1 reduced the Na+ concentration in cytosol and inhibited further K+ loss. Meanwhile, N.sibirica enhanced the TPK expression at the transcriptional level to promote K+ efflux from vacuole into cytoplasm, assisting in maintaining cytosolic K+ homeostasis. It is concluded that the tissue tolerance traits such as vacuolar Na+ sequestration and intracellular K+ homeostasis is critical to confer adaptation of N. sibirica to soil salinity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/treephys/tpaa174DOI Listing
December 2020

Transcriptome Sequencing Analysis of Peripheral Blood of Type 2 Diabetes Mellitus Patients With Thirst and Fatigue.

Front Endocrinol (Lausanne) 2020 9;11:558344. Epub 2020 Nov 9.

Traditional Chinese Medicine School, Beijing University of Chinese Medicine, Beijing, China.

The purpose of this study is to explore the differences in transcriptome expression profiles between healthy subjects and type 2 diabetes mellitus patients with thirst and fatigue (D-T2DM) and, in addition, to investigate the possible role of noncoding ribonucleic acids (RNAs) in the pathogenesis of D-T2DM. We constructed the expression profiles of RNAs by RNA sequencing in the peripheral blood of D-T2DM patients and healthy subjects and analyzed differentially expressed RNAs. Compared with healthy subjects, a total of 469 mRNAs, 776 long non-coding RNAs (lncRNAs), and 21 circular RNAs (circRNAs) were differentially expressed in D-T2DM patients. Furthermore, several genes associated with insulin resistance, inflammation, and mitochondrial dysfunction were identified within the differentially expressed mRNAs. Differentially expressed lncRNAs were primarily involved in biological processes associated with immune responses. In addition, differentially expressed circRNAs may target miRNAs associated with glucose metabolism and mitochondrial function. Our results may bring a new perspective on differential RNA expression involved in the pathogenesis of D-T2DM and promote the development of novel treatments for this disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fendo.2020.558344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680858PMC
May 2021

: A Calcineurin B-Like Protein-Interacting Protein Kinase From the Halophyte , Enhances Arabidopsis Salt Tolerance.

Front Plant Sci 2020 21;11:1112. Epub 2020 Aug 21.

Key Laboratory of Forestry Genetics & Biotechnology of Ministry of Education, Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing, China.

Calcineurin B-like protein-interacting protein kinases () play essential roles in plant abiotic stress response. In order to better understand salt tolerance, we cloned and analyzed the gene from the halophyte . Phylogenetic analysis shows that belongs to a sister clade with the gene and is thought to localize to the plasma membrane. shows the highest expression level in the root under normal growth conditions, whereas after NaCl treatment, the highest expression was found in the blade. -overexpressing Arabidopsis plants have a higher seed germination rate, longer root length, and displayed higher salt tolerance than wild type seedlings under salt stress conditions. Furthermore, overexpression might enhance the expression of genes related to K transportation after NaCl treatment. Thus, we conclude that increases transgenic plant salt tolerance and reduces damage associated with salt stress by promoting the expression of genes controlling ion homeostasis. Our results suggest that could serve as an ideal candidate gene to genetically engineer salt-tolerant plants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fpls.2020.01112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472804PMC
August 2020

Association between glutathione peroxidase-3 activity and carotid atherosclerosis in patients with type 2 diabetes mellitus.

Brain Behav 2020 10 29;10(10):e01773. Epub 2020 Aug 29.

Department of Neurology, Suzhou Ninth People's Hospital, Suzhou, China.

Background And Aims: Deficiency of glutathione peroxidase 3 (GPx3) has been recognized as an independent risk factor for cardiovascular events. However, little is known regarding the role of GPx3 in carotid atherosclerosis, which is ubiquitously observed in type 2 diabetes mellitus (T2DM). This study aimed to investigate the relationship between GPx3 activity and carotid atherosclerosis among patients with T2DM.

Methods: From January 2018 to December 2018, 245 consecutive patients with T2DM were enrolled in this observational study. Assessment of serum GPx3 activity was performed after admission. We also used carotid ultrasound to measure the mean carotid intima-media thickness (CIMT) and to assess the presence of carotid plaque.

Results: Of the 245 patients, the median serum GPx3 activity was 22.5 U/ml (interquartile range, 12.4-35.9 U/ml). Carotid plaque was observed in 113 (46.1%) patients, and mean CIMT was 0.8 ± 0.1 mm. Univariate analysis showed that age, smoking, previous coronary heart disease, carotid plaque, and level of mean CIMT and hypersensitive C-reactive protein were significantly associated with decreasing tertile of GPx3. Furthermore, after adjusting for all potential confounders by multivariable logistic regression analysis, PGx3 activity was significantly and independently associated with the mean CIMT (β = -.406, p = .002) and carotid plaque (first tertile of GPx3, odds ratio, 1.870, 95% confidence intervals, 1.124-3.669, p = .024).

Conclusions: This study demonstrated that serum GPx3 activity was inversely associated with mean CIMT and carotid plaque, suggesting that lower GPx3 activity may be an independent predictor for carotid atherosclerosis in T2DM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/brb3.1773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559603PMC
October 2020

Decreased Serum Retinoic Acid May Predict Poor Outcome in Ischemic Stroke Patients.

Neuropsychiatr Dis Treat 2020 10;16:1483-1491. Epub 2020 Jun 10.

Department of Neurology, Suzhou Ninth People's Hospital, Suzhou, Jiangsu 215200, People's Republic of China.

Background And Aims: Decreased serum retinoic acid (RA) levels have been shown to be linked with increased mortality in cardiovascular diseases. This study aimed to investigate the relationship between serum RA and 3-month functional outcome after ischemic stroke.

Methods: Between January 2019 and September 2019, we prospectively recruited ischemic stroke patients within 24 hrs of symptom onset. Serum RA levels were measured for all patients at admission. The primary outcome was defined as poor functional outcome (modified Rankin Scale 3-6) at 90 days. The secondary outcome was defined as early neurological deterioration (END), which is considered as an increase of ≥1 point in motor power or total National Institutes of Health Stroke Scale score of ≥2 points within 7 days.

Results: A total of 217 patients were included in the analysis. The median RA levels were 2.9 ng/mL. Ninety-four (43.3%) and 65 (30.0%) patients experienced 3-month poor outcome and END, respectively. After adjusted for potential confounders, decreased levels of serum RA were associated with a higher risk of poor outcome ( for trend = 0.001) and END ( for trend = 0.002). Adding RA quartile to the existing risk factors improved risk prediction for poor outcome [net reclassification improvement (NRI) = 42.6%, = 0.001; integrated discrimination improvement (IDI) = 5.7%, = 0.001] and END (NRI index = 45.4%, = 0.001; IDI = 4.3%; = 0.005).

Conclusion: Low serum RA levels at baseline were associated with poor prognosis at 90 days after ischemic stroke, suggesting that RA may be a potential prognostic biomarker for ischemic stroke.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/NDT.S254591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293911PMC
June 2020

Suramin and NF449 are IP5K inhibitors that disrupt inositol hexakisphosphate-mediated regulation of cullin-RING ligase and sensitize cancer cells to MLN4924/pevonedistat.

J Biol Chem 2020 07 3;295(30):10281-10292. Epub 2020 Jun 3.

Department of Biology, Southern University of Science and Technology, Shenzhen, Guangdong, China

Inositol hexakisphosphate (IP) is an abundant metabolite synthesized from inositol 1,3,4,5,6-pentakisphosphate (IP) by the single IP 2-kinase (IP5K). Genetic and biochemical studies have shown that IP usually functions as a structural cofactor in protein(s) mediating mRNA export, DNA repair, necroptosis, 3D genome organization, HIV infection, and cullin-RING ligase (CRL) deneddylation. However, it remains unknown whether pharmacological perturbation of cellular IP levels affects any of these processes. Here, we performed screening for small molecules that regulate human IP5K activity, revealing that the antiparasitic drug and polysulfonic compound suramin efficiently inhibits IP5K and The results from docking experiments and biochemical validations suggested that the suramin targets IP5K in a distinct bidentate manner by concurrently binding to the ATP- and IP-binding pockets, thereby inhibiting both IP phosphorylation and ATP hydrolysis. NF449, a suramin analog with additional sulfonate moieties, more potently inhibited IP5K. Both suramin and NF449 disrupted IP-dependent sequestration of CRL by the deneddylase COP9 signalosome, thereby affecting CRL activity cycle and component dynamics in an IP5K-dependent manner. Finally, nontoxic doses of suramin, NF449, or NF110 exacerbate the loss of cell viability elicited by the neddylation inhibitor and clinical trial drug MLN4924/pevonedistat, suggesting synergistic ef-fects. Suramin and its analogs provide structural templates for designing potent and specific IP5K inhibitors, which could be used in combination therapy along with MLN4924/pevonedistat. IP5K is a potential mechanistic target of suramin, accounting for suramin's therapeutic effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1074/jbc.RA120.014375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383383PMC
July 2020

Twelve-week study of moxa smoke: occupational exposure in female rats.

J Tradit Chin Med 2019 04;39(2):207-212

School of Chinese Medicine, The University of Hong Kong, Hong Kong 999077, China.

Objective: To assess the toxicity of moxa smoke in rats.

Methods: Forty-eight female Wister rats were randomly divided into 4 groups (n = 12/group) to simulate moxa smoke exposure in Chinese medicine clinics (CMCs): the control group, and three moxa-smoke exposed groups of PM10 mass concentrations 3-5, 7-9 and 27-30 mg/m3 , respectively. These concentrations were 1 × , 2-3 × , and 7-9 × fold the concentrations found in CMCs. Exposures continued for 12 weeks (200 min/d, 5 d/week).

Results: No deaths were noted. After the exposure, the body weights, ratios of organ weight to body weight, urinary parameters, hematological parameters, clinical chemistry parameters and microscopic examinations revealed no obvious toxicity.

Conclusion: Moxa smoke did not induce toxic effects in female rats in the study. These findings provide new evidence to the toxicity of moxa smoke.
View Article and Find Full Text PDF

Download full-text PDF

Source
April 2019

miRNA-mRNA Integrated Analysis Reveals Roles for miRNAs in a Typical Halophyte, , during Seed Germination under Salt Stress.

Plants (Basel) 2020 Mar 10;9(3). Epub 2020 Mar 10.

Research Center of Saline and Alkali Land of State Forestry and Grassland Administration, Beijing 100091, China.

MicroRNAs (miRNAs) are endogenous small RNAs that play a crucial role in plant growth, development, and environmental stress responses. is a typical halophyte that is widely distributed in saline-alkali desert regions. Under salt stress, can complete germination, a critical biological process in the life cycle of seed plants. To identify miRNAs and predict target mRNAs involved in seed germination during salt stress, nine small-RNA libraries were constructed and analyzed from seeds treated with various concentrations of NaCl. We also obtained transcriptome data under the same treatment conditions. Further analysis identified 88 conserved miRNAs representing 25 defined families and discovered 13 novel miRNAs from nine libraries. A co-expression analysis was performed on the same samples to identify putative miRNA-mRNA interactions that were responsive to salt stress. A comparative analysis of expression during germination under 273 (threshold) and 43 mM (optimal) NaCl treatments identified 13 differentially expressed miRNAs and 23 corresponding target mRNAs, while a comparison between 43 mM NaCl and non-salt-stress conditions uncovered one differentially expressed miRNA and one corresponding target mRNA. These results provide basic data for further study of molecular mechanisms involved in the germination of salt-stressed seeds, and also provide a reference for the improvement of salt tolerance during plant germination.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/plants9030351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154850PMC
March 2020

Chromatographic Fingerprint Analysis of Radix Hedysari Using Supercritical Fluid Chromatography Coupled with Diode Array Detector.

J Chromatogr Sci 2020 Apr;58(3):262-273

School of Pharmacy, Lanzhou University, 199 Donggangxi Road, Lanzhou 730000, P. R China.

A newly and rapid supercritical fluid chromatography method for the simultaneous determination of 11 active compounds in Radix Hedysari samples has been developed and validated. Optimum separation was achieved on a HSS SB C18 column with a gradient elution at a flow rate of 1.5 mL/min, back pressure of 11.03 Mpa and diode array detector at 260 nm. The results from the quantitative data showed that contents of these 11 active compounds were different from plant regions. Especially the contents of formononetin in the Minxian county are ~6-fold than in wild Radix Hedysari. The chromatographic fingerprint of Radix Hedysari was recorded under the same chromatographic condition. Data analytic procedure was performed to differentiate the 25 batches of Radix Hedysari samples. Data from chromatographic fingerprint were also analyzed using hierarchical cluster analysis. The results showed that 23 batches of Radix Hedysari samples had a high similarity (> 0.90) and overall 25 batches of sample were divided into two clusters. Moreover, according to the comparison contents of active compounds in each Radix Hedysari samples, the cultivated location of Radix Hedysari was successfully distinguished. This method presented good stability, repeatability and precision and would be a useful and reliable approach for the quality control of Radix Hedysari. Moreover, all target compounds were quantified by ultra-high performance liquid chromatography-time-of-flight mass spectrometry.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/chromsci/bmz088DOI Listing
April 2020

Subthreshold depression may exist on a spectrum with major depressive disorder: Evidence from gray matter volume and morphological brain network.

J Affect Disord 2020 04 27;266:243-251. Epub 2020 Jan 27.

Beijing Engineering Research Center of Radiographic Techniques and Equipment, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, China; School of Nuclear Science and Technology, University of Chinese Academy of Sciences, Beijing, China; CAS center for Excellence in Brain Science and Intelligence Technology, Shanghai, China. Electronic address:

Background: Subthreshold depression (StD) is a prevalent condition that may increase the risk of incident major depressive disorder (MDD). However, the relationship between StD and MDD remains unclear.

Methods: A total of 153 adult subjects, including 53 drug-naive MDD, 50 StD and 50 healthy control (HC) subjects, underwent a T1-weighted magnetic resonance imaging scan, and the gray matter volume (GMV) alterations among the three groups were quantitatively analyzed using voxel-based morphometry (VBM). Then, to capture the whole-brain connectivity characteristics, we constructed morphological brain networks (MBN) based on the similarity among brain regions of individual VBM images and compared the network connection strengths among the three groups.

Results: The StD and MDD subjects had similar patterns of GMV reductions in the orbitofrontal cortex and left temporal gyrus, although the magnitude of the reductions was smaller in StD subjects. Moreover, a total of 21 morphological connections were significantly different among the three groups. For the majority of the different connections (15/21), the connection strength of the StD group took an intermediate position between that of the MDD and HC groups.

Limitations: There is still a lack of a consistent definition of StD, and the age range of the subjects in this study was wide. Meanwhile the mechanisms and biological significance of the MBN remains to be clarified.

Conclusions: These results may support the hypothesis that depression is better expressed as a spectrum and that StD exists on a spectrum with MDD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jad.2020.01.135DOI Listing
April 2020

Structure-immunomodulatory activity relationships of Hedysarum polysaccharides extracted by a method involving a complex enzyme combined with ultrasonication.

Food Funct 2019 Feb;10(2):1146-1158

School of Pharmacy, Lanzhou University, Lanzhou, 730000, P. R. China.

A new, more effective and environmentally friendly method involving a complex enzyme combined with ultrasonication was employed to extract and isolate three novel polysaccharides (HPS-MCs: HPS-MC, HPS-MC (50%) and HPS-MC (80%)) of Radix Hedysari. Compared with polysaccharides obtained using a traditional extraction method (hot water extraction, HPS-R), the yields and total carbohydrate contents of HPS-MCs were significantly higher. HPS-MC (80%) exhibited relatively strong immunomodulatory activity and a concentration-dependent dose-response relationship under cyclophosphamide (CP)-induced immunosuppressive conditions in mice models. To more comprehensively investigate the relationships between structural characteristics and immunomodulatory activity, HPS-MC (80%) was fractionated into three major homogeneous polysaccharide fractions (HPS-MC (80%)s: HPS-MC (80%)-1, HPS-MC (80%)-2, and HPS-MC (80%)-3). These three homogeneous polysaccharides had different mass percentages of monosaccharides species (rhamnose, arabinose, mannose, glucose, and galactose) by gas chromatography (GC) and different molecular weights and chain conformations by high-performance gel permeation chromatography coupled with multi-angle laser light scattering (HPGPC-MALLS), and promoted macrophage and splenocyte proliferation to different degrees. These findings indicated that HPS-MC (80%) had a prominent potential immune response, especially HPS-MC (80%)-2 and HPS-MC (80%)-3, and might be suitable candidates for functional foods or potential novel immunomodulators.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c8fo02293cDOI Listing
February 2019

[Teaching method of the basic ability of acupuncture in training the manipulation skills in ].

Zhongguo Zhen Jiu 2018 Nov;38(11):1215-7

School of Acupuncture, Moxibustion and Tuina, Beijing University of CM, Beijing 100029.

Through checking the ancient books and the articles at the modern times and combining the disciplinary characteristics of techniques of acupuncture and moxibustion, the training of manipulation skills was discussed. It is proposed that during the teaching of the techniques of acupuncture and moxibustion, the most basic ability of needling technique should be trained in the first place. This ability includes the ability of spiritual cultivation, the ability of tactile perception and the specific training for the needling techniques. The ability of spiritual cultivation refers to the consciousness concentration to the patient when providing acupuncture, which may promotes and conducts to the affected area. The ability of tactile perception refers to the different feelings of different tissues under the hands before and after acupuncture, the perception to the different needling sensations corresponding to the chief complains of patients as well as the different body responses after acupuncture. In order to ensure the better learning results, the specific manipulations of needling techniques should be provided accordingly on the base of these basic training skills of acupuncture.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.13703/j.0255-2930.2018.11.020DOI Listing
November 2018

Calycosin stimulates the osteogenic differentiation of rat calvarial osteoblasts by activating the IGF1R/PI3K/Akt signaling pathway.

Cell Biol Int 2019 Mar 29;43(3):323-332. Epub 2019 Jan 29.

Institute of Orthopaedics, Lanzhou General Hospital, Lanzhou Command of CPLA, Lanzhou, 730050, Gansu Province, People's Republic of China.

Calycosin has been reported to have a strong osteogenic activity and a positive correlation with anti-osteoporosis effects. However, its precise mechanism of action remains unclear. Since insulin-like growth factor 1 receptor (IGF1R) signaling and phosphatidylinositol 3-kinase/Akt (PI3K/Akt) signaling have been shown to play a pivotal role in regulating osteogenesis, we hypothesized that the osteogenic activity of calycosin is mediated by these signaling pathways. Rat calvarial osteoblasts (ROBs) were cultured in osteogenic medium containing calycosin with or without GSK1904529A (GSK) or LY294002 (LY) (inhibitors of IGF1R and PI3K, respectively). The effects on cell proliferation, alkaline phosphatase (ALP) activity, calcified nodules, mRNA or protein expression of osteogenic genes [alkaline phosphatase (Alpl), collagen type I (Col1a1), runt-related transcription factor 2 (Runx2), Osterix, and bone morphogenetic protein 2 (Bmp2)], and phosphorylation of IGF1R and Akt were examined. The present results showed that calycosin enhanced cell proliferation, ALP activity and Alizarin Red-S staining in a dose-dependent manner in the range of 10 -10  M, while an inhibitory effect was observed at 10  M. Treatment at the optimal concentration (10  M, a physiologically achievable concentration) increased mRNA levels of osteogenic genes and phosphorylation of IGF1R and Akt. Furthermore, treatment with GSK or LY partly reversed the effects of calycosin on ROBs, as indicated by the decreases in calycosin-induced ALP activity, calcified nodules and osteogenic gene expression. These results suggest that the osteogenic effect of calycosin partly involves the IGF1R/PI3K/Akt signaling pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cbin.11102DOI Listing
March 2019

Combined immunosuppressive treatment (CIST) in lupus nephritis: a multicenter, randomized controlled study.

Clin Rheumatol 2019 Apr 28;38(4):1047-1054. Epub 2018 Nov 28.

Department of Rheumatology and Immunology, Xiangya Hospital Central South University, Changsha, China.

Objectives: The standard strategy for treating lupus nephritis comprises glucocorticoids together with either intravenous cyclophosphamide or oral mycophenolate mofetil, but the low remission rate is still a challenge in practice. This study was aimed to seek higher remission rate of lupus nephritis using a combined strategy.

Method: A 24-week trial was conducted in 17 rheumatology or nephrology centers in China. A total of 191 lupus nephritis patients were randomized to follow a combined immunosuppressive treatment (CIST) with intravenous cyclophosphamide, an oral immunosuppressive agent, namely mycophenolate mofetil, azathioprine or leflunomide, and hydroxychloroquine (n = 95), or receive intravenous cyclophosphamide alone (n = 96) for 24 weeks. Glucocorticoid was given to both groups. The primary end point was a complete remission with a most stringent standard as proteinuria < 150 mg per 24 h, normal urinary sediment, serum albumin, and renal function at 24 weeks. The secondary end point was treatment failure at 24 weeks.

Results: At week 24, both the rate of complete remission (39.5%) and total response (87.2%) was higher in the combined group, compared with CYC group (20.8% and 68.8%, p < 0.05). The cumulative probability of complete remission was also higher in the combined group (p = 0.013). In addition, the combined treatment was superior to routine CYC with less treatment failure (12.8% vs.31.2%, p < 0.001). No difference was found between the incidences of severe adverse events in the two arms: 3.2% (3/95 combined group) vs.4.2% (4/96 CYC group).

Conclusion: Treatment with a combined immunosuppressive agent is superior to routine CYC only therapy in lupus nephritis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10067-018-4368-8DOI Listing
April 2019

Design, synthesis, and biological evaluation of thieno[3,2-d]pyrimidine derivatives as potential simplified phosphatidylinositol 3-kinase alpha inhibitors.

Chem Biol Drug Des 2019 12 14;94(6):2013-2022. Epub 2019 Oct 14.

Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

A series of thieno[3,2-d]pyrimidine derivatives as phosphatidylinositol 3-kinase (PI3K) inhibitors was designed using the combination strategy. The synthesis and biological evaluation of the derivatives demonstrated their potent inhibition of PI3K, culminating in the discovery of 7 and 21. Determination of a co-crystal structure of 7 complexed with PI3Kα provided the structural basis for the high enzymatic activity. Furthermore, cellular investigation of compounds 7 and 21 revealed that they efficiently suppressed cancer cell lines proliferation through inhibition of intracellular PI3K/AKT/mammalian target of rapamycin pathway. The results provided potent simplified inhibitors of PI3K with a promising overall profile and a chemical series for further optimization to progress into vivo experiments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cbdd.13425DOI Listing
December 2019

Identification of a cellularly active SIRT6 allosteric activator.

Nat Chem Biol 2018 12 29;14(12):1118-1126. Epub 2018 Oct 29.

Key Laboratory of Cell Differentiation and Apoptosis, Ministry of Education, Department of Pathophysiology, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.

SIRT6, a member of the SIRT deacetylase family, is responsible for deacetylation of histone H3 N-acetyl-lysines 9 (H3K9ac) and 56 (H3K56ac). As a tumor suppressor, SIRT6 has frequently been found to have low expression in various cancers. Here, we report the identification of MDL-800, a selective SIRT6 activator. MDL-800 increased the deacetylase activity of SIRT6 by up to 22-fold via binding to an allosteric site; this interaction led to a global decrease in H3K9ac and H3K56ac levels in human hepatocellular carcinoma (HCC) cells. Consequently, MDL-800 inhibited the proliferation of HCC cells via SIRT6-driven cell-cycle arrest and was effective in a tumor xenograft model. Together, these data demonstrate that pharmacological activation of SIRT6 is a potential therapeutic approach for the treatment of HCC. MDL-800 is a first-in-class small-molecule cellular SIRT6 activator that can be used to physiologically and pathologically investigate the roles of SIRT6 deacetylation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41589-018-0150-0DOI Listing
December 2018

Disability and health-related quality of life in Chinese patients with rheumatoid arthritis: A cross-sectional study.

Int J Rheum Dis 2018 Sep;21(9):1709-1715

Department of Rheumatology and Immunology, The People's Hospital of Hebei Province, Shijiazhuang, China.

Aim: The objective of this study was to evaluate the impact of rheumatoid arthritis (RA) on physical function and health-related quality of life (HRQoL) in China.

Method: A cross-section survey was conducted in 21 general hospitals in China. Eight hundred and seven patients were recruited. Data on demographics, clinical data, physical function (Stanford Health Assessment Questionnaire Disability Index, HAQ-DI) and HRQoL (Study Short Form 36 Health Survey, SF-36) were collected on site.

Results: In our cohort, physical function was impaired in 77.6% of patients (HAQ-DI >0). The median (interquartile range, IQR) of HAQ-DI was 0.750 (0.125, 1.500). Rated by HAQ-DI 0-1, >1-2, and >2-3, percentage of patients with mild, moderate and severe disability was 61.0%, 25.4%, and 13.6%, respectively. Older age, long disease duration, presence of extra-articular manifestations, tender joint count (TJC), overall status (assessed by patient Global Visual Analogue Scale [G-VAS] and physician G-VAS) and lacking disease-modifying anti-rheumatic drugs were identified as predictive factors for worse physical function (P < .05). The composite scores of SF-36 in the observed patients were: physical component summary 40.4 (IQR 27.4, 60.3), and mental component summary 49.0 (IQR 33.6, 70.9). Impaired physical health may be predicted by low income, presence of extra-articular manifestations, TJC, patient G-VAS and high HAQ-DI. Predictors for suboptimal mental health were low income, physical labor, married status, increased swollen joint count (SJC), physician G-VAS and high HAQ-DI.

Conclusion: Rheumatoid arthritis has profound effects on physical function and HRQoL in Chinese patients. Patients with identified predictive factors for poor outcome should be closely monitored.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1756-185X.13345DOI Listing
September 2018

Active tuberculosis in patients with systemic lupus erythematosus from Southern China: a retrospective study.

Clin Rheumatol 2019 Feb 23;38(2):535-543. Epub 2018 Sep 23.

Department of Rheumatology, the First Affiliated Hospital of Sun Yat-sen University, No 58, Zhongshan Road 2, Guangzhou, 510080, Guangdong, China.

To investigate the characteristics and associated factors for Mycobacterium tuberculosis (TB) infection in patients with systemic lupus erythematosus (SLE) from Southern China. A retrospective study of 1108 patients admitted to the First Affiliated Hospital of Sun Yat-Sen University from January 2007 to December 2017 was performed. Demographic and clinical characteristics, laboratory data, and radiographic manifestations were recorded. A total of 59 (5.3%) lupus patients with active TB were included. Pulmonary TB occurred in 41 (69.5%) patients. Single lobe involvement was showed in 14 (34.1%) patients. Multi-lobar involvement, including miliary TB (36.6%), was presented in 27 (65.8%) patients. Lower lobe involvement accounted for 31 (75.6%) of the cases. Extrapulmonary TB occurred in 18 (30.5%) patients. Nearly one-third (35.6%) of the patients developed disseminated TB. T-SPOT.TB assay was performed in 23 patients and positive in 18 patients (78.3%). Nineteen patients (32.2%) had co-infection with TB and other pathogens, most of which were bacterial-associated (52.6%). Lymphopenia was predominant in TB-infected patients, especially in those with disseminated TB. Multivariate logistic regression analysis found that lymphopenia [odds ratio (OR) = 2.19, 95% confidence interval (CI) 1.03-4.63, P = 0.04] and the accumulated doses of glucocorticoid (GC) (OR = 2.32, 95% CI 1.69-3.20, P < 0.001) were associated with TB. TB infection is a common comorbidity in patients with SLE. Manifestations of pulmonary computed tomography (CT) scan are relatively atypical. Co-infection with TB and other pathogens is not rare. Lymphopenia and the accumulated doses of GC are associated with TB infection in lupus patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10067-018-4303-zDOI Listing
February 2019

Long noncoding RNA LERFS negatively regulates rheumatoid synovial aggression and proliferation.

J Clin Invest 2018 10 10;128(10):4510-4524. Epub 2018 Sep 10.

Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.

Fibroblast-like synoviocytes (FLSs) are critical to synovial aggression and joint destruction in rheumatoid arthritis (RA). The role of long noncoding RNAs (lncRNAs) in RA is largely unknown. Here, we identified a lncRNA, LERFS (lowly expressed in rheumatoid fibroblast-like synoviocytes), that negatively regulates the migration, invasion, and proliferation of FLSs through interaction with heterogeneous nuclear ribonucleoprotein Q (hnRNP Q). Under healthy conditions, by binding to the mRNA of RhoA, Rac1, and CDC42 - the small GTPase proteins that control the motility and proliferation of FLSs - the LERFS-hnRNP Q complex decreased the stability or translation of target mRNAs and downregulated their protein levels. But in RA FLSs, decreased LERFS levels induced a reduction of the LERFS-hnRNP Q complex, which reduced the binding of hnRNP Q to target mRNA and therefore increased the stability or translation of target mRNA. These findings suggest that a decrease in synovial LERFS may contribute to synovial aggression and joint destruction in RA and that targeting the lncRNA LERFS may have therapeutic potential in patients with RA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI97965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159954PMC
October 2018

Glycogen Metabolism and Rheumatoid Arthritis: The Role of Glycogen Synthase 1 in Regulation of Synovial Inflammation Blocking AMP-Activated Protein Kinase Activation.

Front Immunol 2018 27;9:1714. Epub 2018 Jul 27.

Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.

Objective: To investigate the role of glycogen metabolism in regulating rheumatoid fibroblast-like synoviocyte (FLS)-mediated synovial inflammation and its underlying mechanism.

Methods: FLSs were separated from synovial tissues (STs) obtained from rheumatoid arthritis (RA) patients. Glycogen content was determined by periodic acid Schiff staining. Protein expression was analyzed by Western blot or immunohistochemistry. Gene expression of cytokines and matrix metalloproteinases (MMPs) was evaluated by quantitative real-time PCR. FLS proliferation was detected by EdU incorporation. Migration and invasion were measured by Boyden chamber assay.

Results: Glycogen levels and glycogen synthase 1 (GYS1) expression were significantly increased in the ST and FLSs of RA patients. TNF-α or hypoxia induced GYS1 expression and glycogen synthesis in RA FLSs. GYS1 knockdown by shRNA decreased the expression of IL-1β, IL-6, CCL-2, MMP-1, and MMP-9 and proliferation and migration by increasing AMP-activated protein kinase (AMPK) activity in RA FLS. AMPK inhibitor or knockdown AMPK could reverse the inhibitory effect of GYS1 knockdown on the inflammatory response in RA FLSs; however, an AMPK agonist blocked RA FLS activity. We further determined that hypoxia-inducible factor-1α mediates TNF-α- or hypoxia-induced GYS1 expression and glycogen levels. Local joint depletion of GYS1 or intraperitoneal administration with an AMPK agonist ameliorated the severity of arthritis in rats with collagen-induced arthritis.

Conclusion: Our data demonstrate that GYS1-mediated glycogen accumulation contributes to FLS-mediated synovial inflammation in RA by blocking AMPK activation. In our knowledge, this is a first study linking glycogen metabolism to chronic inflammation. Inhibition of GYS1 might be a novel therapeutic strategy for chronic inflammatory arthritis, including RA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2018.01714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072843PMC
September 2019

Rational Design and Structure Validation of a Novel Peptide Inhibitor of the Adenomatous-Polyposis-Coli (APC)-Rho-Guanine-Nucleotide-Exchange-Factor-4 (Asef) Interaction.

J Med Chem 2018 09 20;61(17):8017-8028. Epub 2018 Aug 20.

School of Pharmacy , Jinan University , 601 Huangpu Avenue West , Guangzhou 510632 , China.

In colorectal cancer, adenomatous polyposis coli (APC) interacts with Rho guanine-nucleotide-exchange factor 4 (Asef), thereby stimulating aberrant colorectal-cancer-cell migration. Consequently, the APC-Asef interaction represents a promising therapeutic target for mitigating colorectal-cancer migration. In this study, we adopted the rational-design strategy involving the introduction of intramolecular hydrogen bonds and optimization of the lipophilic substituents to improve the binding affinities of peptides, leading to the discovery of MAI-400, the best inhibitor of the APC-Asef interaction known to date ( K = 0.012 μM, IC = 0.25 μM). Comprehensive evaluation of MAI-400 by biochemical and biophysical assays revealed the formation and effect of an intramolecular hydrogen bond. A cell-based assay showed MAI-400 efficiently blocking the APC-Asef interaction in a dose-dependent manner. Therefore, our study provides a best-in-class inhibitor, MAI-400, based on the rational drug design and structural validation, that can effectively inhibit the APC-Asef interaction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.8b01112DOI Listing
September 2018