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1.
FASEB J ; : fj201901232RR, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31689372

RESUMO

Cytokines and chemokines play diverse roles in different organ systems. Family with sequence similarity 19, member A1-5 (FAM19A1-A5; also known as TAFA1-5) is a group of conserved chemokine-like proteins enriched in the CNS of mice and humans. Their functions are only beginning to emerge. Here, we show that the expression of Fam19a1-a5 in different mouse brain regions are induced or suppressed by unfed and refed states. The striking nutritional regulation of Fam19a family members in the brain suggests a potential central role in regulating metabolism. Using a knockout (KO) mouse model, we show that loss of FAM19A1 results in sexually dimorphic phenotypes. In male mice, FAM19A1 deficiency alters food intake patterns during the light and dark cycle. Fam19a1 KO mice are hyperactive, and locomotor hyperactivity is more pronounced in female KO mice. Behavior tests indicate that Fam19a1 KO female mice have reduced anxiety and sensitivity to pain. Spatial learning and exploration, however, is preserved in Fam19a1 KO mice. Altered behaviors are associated with elevated norepinephrine and dopamine turnover in the striatum. Our results establish an in vivo function of FAM19A1 and highlight central roles for this family of neurokines in modulating animal physiology and behavior.-Lei, X., Liu, L., Terrillion, C. E., Karuppagounder, S. S., Cisternas, P., Lay, M., Martinelli, D. C., Aja, S., Dong, X., Pletnikov, M. V., Wong, G. W. FAM19A1, a brain-enriched and metabolically responsive neurokine, regulates food intake patterns and mouse behaviors.

2.
FASEB J ; : fj201901279R, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31689374

RESUMO

Interorgan communication mediated by secreted proteins plays a pivotal role in metabolic homeostasis, yet the function of many circulating secretory proteins remains unknown. Here, we describe the function of protease-associated domain-containing 1 (PRADC1), an enigmatic secretory protein widely expressed in humans and mice. In metabolically active tissues (liver, muscle, fat, heart, and kidney), we showed that Pradc1 expression is significantly suppressed by refeeding and reduced in kidney and brown fat in the context of obesity. PRADC1 is dispensable for whole-body metabolism when mice are fed a low-fat diet. However, in obesity induced by high-fat feeding, PRADC1-deficient female mice have reduced weight gain and adiposity despite similar caloric intake. Decreased fat mass is attributed, in part, to increased metabolic rate, physical activity, and energy expenditure in these animals. Reduced adiposity in PRADC1-deficient mice, however, does not improve systemic glucose and lipid metabolism, insulin sensitivity, liver steatosis, or adipose inflammation. Thus, in PRADC1-deficient animals, decreased fat mass and enhanced physical activity are insufficient to confer a healthy metabolic phenotype in the context of an obesogenic diet. Our results shed light on the physiologic function of PRADC1 and the complex regulation of metabolic health.-Rodriguez, S., Stewart, A. N., Lei, X., Cao, X., Little, H. C., Fong, V., Sarver, D. C., Wong, G. W. PRADC1: a novel metabolic-responsive secretory protein that modulates physical activity and adiposity.

3.
Photodiagnosis Photodyn Ther ; : 101589, 2019 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-31689509

RESUMO

Chromoblastomycosis (CBM) is a prevalent implantation fungal infection. Patients with CBM show chronic granulomatous hyperplasia with ulcers and exudation. It may cause incapacity for labor in some severe clinical forms and it is often refractory to antifungal therapies. There is no optimal treatment until now. Here we report a case of a 71-year-old male farmer with refractory CBM who was successfully treated with 5-aminolevulinic acid-based photodynamic therapy (ALA-PDT) and Itraconazole in 2 months. Clinical cure achieved with no obvious side effects and the course shortened.

4.
Med Sci Monit ; 25: 7813-7825, 2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31625533

RESUMO

BACKGROUND The aim of this study was to investigate the protective mechanism of neurovascular unit of Buyang Huanwu decoction (BYHWD) in an Alzheimer's disease (AD) cell model via RAGE/LRP1 pathway and find a reliable target for Alzheimer's disease treatment. MATERIAL AND METHODS Rat brain microvessel endothelial cells (BMECs) were cultured in 10% FBS and 1% penicillin/streptomycin. The AD model was established by administration of 24 µmol/L amyloid-ß peptides 25~35. Different concentrations of BYHWD (0.1 mg/mL, 1 mg/mL, and 10 mg/mL) were added as the drug intervention. The morphology of the cells was observed by light microscopy and the ultrastructure of the cells was observed by microscopy. The inflammatory factors IL-1ß, IL-6, TNF-alpha, and Aß25-35 were detected by ELISA. Flow cytometry was used to assess the apoptosis rate. The expressions of RAGE, LRP1, ICAM-1, VCAM-1, Apo J, Apo E, and NF-kappaBp65 were detected by Western blotting. RESULTS The structure of cells in BYHWDM and BYHWDH gradually recovered with increasing dose. BYHWD decreased the apoptotic rate of BMECs induced by Aß25-35. The cells treated with different concentrations of BYHWD had significant difference in terms of anti-apoptotic effect. The therapeutic effect of BYHWD on AD was via the RAGE/LRP1 and NF-kappaBp65 pathways. CONCLUSIONS BYHWD regulates Aß metabolism via the RAGE/LRP1 pathway, inhibits vascular endothelial inflammation induced by ICAM-1 and VCAM-1 via the NF-kappaBP65 pathway, and promotes morphological changes induced by Aß-induced brain microvascular endothelial cell damage.

5.
J BUON ; 24(4): 1555-1561, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31646808

RESUMO

PURPOSE: The main purpose of this study was to investigate the selective anticancer effects of Kaempferol against MFE-280 endometrial carcinoma cells along with evaluating its effects on apoptotic pathway, cell cycle phase distribution, cell invasion, cell migration and m-TOR/PI3K/Akt signalling pathway. METHODS: Cell viability of MFE-280 endometrial carcinoma cells was assessed by MTS [(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium)] assay. Apoptosis was determined by acridine orange (AO)/ ethidium bromide (EB) double staining. Cell cycle analysis was determined by flow cytometry, while Boyden chamber assay was performed to study the effects of Kaempferol on cell migration and cell invasion, respectively. The effects of Kaempferol on the protein expression of m-TOR/PI3K/Akt signalling pathway were analysed by Western blot assay. RESULTS: Kaempferol exerted considerable and selective anticancer effects on MFE-280 endometrial carcinoma cells with IC50 of 10 µM. The anticancer effects were found to be due to activation of mitochondrial-mediated apoptotic pathway and G2/M phase cell cycle arrest. Furthermore, the results also revealed that Kaempferol significantly inhibited cell migration and cell invasion trend of these cancer cells. Our results also showed that, in comparison to the untreated cells, Kaempferol-treated cells exhibited a dose-dependent downregulation of p-mTOR, p-PI3K and p-AKT proteins. However, mTOR, PI3K and Akt expression levels remained more or less unaltered. CONCLUSIONS: In conclusion, the present study indicates that Kaempferol could exert anticancer effects in MFE-280 endometrial carcinoma cells selectively and that these effects were mediated via apoptosis induction, cell cycle arrest and inhibition of m-TOR/PI3K/Akt signalling pathway.

6.
J Biol Chem ; 294(43): 15638-15649, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31439668

RESUMO

The highly conserved C1q/TNF-related protein (CTRP) family of secreted hormones has emerged as important regulators of insulin action and of sugar and fat metabolisms. Among these, the specific biological function of CTRP2 remains elusive. Here, we show that the expression of human CTRP2 is positively correlated with body mass index (BMI) and is up-regulated in obesity. We used a knockout (KO) mouse model to determine CTRP2 function and found that Ctrp2-KO mice have significantly elevated metabolic rates and energy expenditure leading to lower body weights and lower adiposity. CTRP2 deficiency up-regulated the expression of lipolytic enzymes and protein kinase A signaling, resulting in enhanced adipose tissue lipolysis. In cultured adipocytes, CTRP2 treatment suppressed triglyceride (TG) hydrolysis, and its deficiency enhanced agonist-induced lipolysis in vivo CTRP2-deficient mice also had altered hepatic and plasma lipid profiles. Liver size and hepatic TG content were significantly reduced, but plasma TG was elevated in KO mice. Both plasma and hepatic cholesterol levels, however, were reduced in KO mice. Loss of CTRP2 also enhanced hepatic TG secretion and contributed to impaired plasma lipid clearance following an oral lipid gavage. Liver metabolomic analysis revealed significant changes in diacylglycerols and phospholipids, suggesting that increased membrane remodeling may underlie the altered hepatic TG secretion we observed. Our results provide the first in vivo evidence that CTRP2 regulates lipid metabolism in adipose tissue and liver.

7.
Rev Sci Instrum ; 90(7): 075110, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31370503

RESUMO

Thickness is an important characteristic parameter of electrospun submicron of fiber mats and membranes. The thickness of the mats directly influences performance properties such as permeability and is necessary when determining volumetric parameters such as porosity. Typical electrospun mats are very thin (less than 1 mm) and highly compressive due to the small diameter fibers, both of which make accurate measurements difficult when using conventional methods. An accurate measure of the thickness is desired for characterizing and comparing membrane performances. In this work, a thickness measurement instrument using laser interferometry has been designed to measure electrospun fiber mat thickness. A small disk is used to apply a small (reproducible) force applied across a reasonably small area of the fiber mat. A traversing pin moves to contact the disk and completes an electrical circuit to stop movement and determine the location of the disk relative to a reference plane. The fiber mat thickness is determined by measuring the difference in locations of the disk with and without the fiber mat between the disk and the reference plane. The prototype is simple to operate and user-friendly. Precision and accuracy of the prototype are discussed.

8.
BMC Infect Dis ; 19(1): 595, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31288749

RESUMO

BACKGROUND: Noroviruses (NVs) are an important cause of acute gastroenteritis (AGE) worldwide. There are limited data on the prevalence and molecular characterization of NVs in children in Hohhot, China. METHODS: Between January 2012 and December 2017, 1863 stool samples were collected at Maternal and Child Health Hospital in Hohhot. All samples were screened for NVs by real-time reverse transcription polymerase chain reaction (real-time RT-PCR). RESULTS: NVs were detected in 24.15% of these inpatient cases, ranging from 12.78 to 32.92% in different years. NV was detected throughout the year, with a peak in winter. Based on sequence analysis of the partial VP1 gene, the 306 identified NV strains were divided into six genotypes: GII.3 (71.24%), GII.4 (23.53%), and GII.2, GII.5, GII.6, and GII.13 (total 5.23%). Based on further sequence analysis of the RNA-dependent RNA polymerase (RdRp), GII.P12/GII.3, GII.Pe/GII.4, and GII.P4/GII.4 were identified as predominant genotypes, accounting for 92.6% of genotyped strains. The median age of the children with NV infection was 8.0 (range 0-59) months. However, children infected with GII.3 were younger (median 7.0 months) than GII.4-positive patients (median 10.0 months). CONCLUSION: NV contributed greatly to AGE among hospitalized children in Hohhot in China. Continuous surveillance is important for understanding the local prevalence and characterization of NV.


Assuntos
Infecções por Caliciviridae/diagnóstico , Gastroenterite/diagnóstico , Norovirus/genética , Doença Aguda , Infecções por Caliciviridae/epidemiologia , Criança Hospitalizada , Pré-Escolar , China/epidemiologia , Fezes/virologia , Feminino , Gastroenterite/epidemiologia , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Norovirus/classificação , Norovirus/isolamento & purificação , Filogenia , Prevalência , RNA Viral/isolamento & purificação , RNA Viral/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Estações do Ano
9.
Artigo em Inglês | MEDLINE | ID: mdl-31362110

RESUMO

Hidradenitis Suppurativa (HS) is a distressing painful chronic inflammatory skin follicular condition. It is a challenge to achieve better therapeutic effect and lower recurrence rate. In this report, ALA-PDT combined with surgery for the treatment achieved ulcer healing, pain elimination, with no relapse during our follow-up.

10.
Photodiagnosis Photodyn Ther ; 27: 79-84, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31075320

RESUMO

OBJECTIVES: To investigate the effects of low-dose aminolevulinic acid photodynamic therapy (ALA-PDT) on photoaging in human dermal fibroblasts (HDFs) and to explore the mechanism of Nuclear factor erythroid 2-related factor 2(Nrf2)-mediated photorejuvenation in vitro. METHODS: A photoaging model was established through repeated exposure of HDFs to UVA. Total superoxide dismutase (SOD) expression was detected by a SOD activity assay. Nrf2 was knocked down through adenovirus infection, and successful knockdown was confirmed by Western blot analysis and quantitative polymerase chain reaction. RESULTS: Sustained exposure to UVA induced photoaging in HDFs. Total SOD activity was significantly increased by low-dose aminolevulinic acid (ALA)-PDT. Upon application of low doses of ALA-PDT to photoaging HDFs, Nrf2 was translocated to the nucleus; in addition, the expression of Nrf2, transforming growth factor-ß1 (TGF-ß1), type I and III collagen (COL1 and COL3), heme oxygenase 1 (HO-1), and p-ERK was increased, while the expression of matrix metalloproteinase 9 (MMP-9) was decreased. However, after Nrf2 was knocked down in HDFs, the expression of TGF-ß1, COL1, COL3, and HO-1 was significantly decreased, while the expression of MMP-9 was increased. CONCLUSION: This study revealed that low-dose ALA-PDT decreases UVA-mediated photoaging through an Nrf2-mediated antioxidant effect.

11.
Euro Surveill ; 24(21)2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31138362

RESUMO

After no reported human cases of highly pathogenic avian influenza (HPAI) H7N9 for over a year, a case with severe disease occurred in late March 2019. Among HPAI H7N9 viral sequences, those recovered from the case and from environmental samples of a poultry slaughtering stall near their home formed a distinct clade from 2017 viral sequences. Several mutations possibly associated to antigenic drift occurred in the haemagglutinin gene, potentially warranting update of H7N9 vaccine strains.

12.
Sci Rep ; 9(1): 7040, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31065079

RESUMO

Ginsenoside Rg1, a natural triterpenoid saponins compound isolated from the Panax species, has been found to possess neuroprotective properties in neurodegenerative diseases such as Alzheimer's disease (AD). However, its pharmacological mechanism on AD has not been studied. In this study, an ultra-performance liquid chromatography combined with quadrupole time of-flight mass spectrometry (UPLC-Q/TOF-MS) based non-targeted metabolomics strategy was performed to explore the mechanism of Ginsenoside Rg1 protecting against AD mice by characterizing metabolic biomarkers and regulation pathways changes. A total of nineteen potential metabolites in serum were discovered and identified to manifest the difference between wild-type mice and triple transgenic mice in control and model group, respectively. Fourteen potential metabolites involved in ten metabolic pathways such as linoleic acid metabolism, arachidonic acid metabolism, tryptophan metabolism and sphingolipid metabolism were affected by Rg1. From the ingenuity pathway analysis (IPA) platform, the relationship between gene, protein, metabolites alteration and protective activity of ginsenoside Rg1 in AD mice are deeply resolved, which refers to increased level of albumin, amino acid metabolism and molecular transport. In addition, quantitative analysis of key enzymes in the disturbed pathways by proteomics parallel reaction was employed to verify changed metabolic pathway under Ginsenoside Rg1. The UPLC-Q/TOF-MS based serum metabolomics method brings about new insights into the pharmacodynamic studies of Ginsenoside Rg1 on AD mice.

13.
FASEB J ; 33(7): 8666-8687, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31002535

RESUMO

We recently described myonectin (also known as erythroferrone) as a novel skeletal muscle-derived myokine with metabolic functions. Here, we use a genetic mouse model to determine myonectin's requirement for metabolic homeostasis. Female myonectin-deficient mice had larger gonadal fat pads and developed mild insulin resistance when fed a high-fat diet (HFD) and had reduced food intake during refeeding after an unfed period but were otherwise indistinguishable from wild-type littermates. Male mice lacking myonectin, however, had reduced physical activity when fed ad libitum and in the postprandial state but not during the unfed period. When stressed with an HFD, myonectin-knockout male mice had significantly elevated VLDL-triglyceride (TG) and strikingly impaired lipid clearance from circulation following an oral lipid load. Fat distribution between adipose and liver was also altered in myonectin-deficient male mice fed an HFD. Greater fat storage resulted in significantly enlarged adipocytes and was associated with increased postprandial lipoprotein lipase activity in adipose tissue. Parallel to this was a striking reduction in liver steatosis due to significantly reduced TG accumulation. Liver metabolite profiling revealed additional significant changes in bile acids and 1-carbon metabolism pathways. Combined, our data affirm the physiologic importance of myonectin in regulating local and systemic lipid metabolism.-Little, H. C., Rodriguez, S., Lei, X., Tan, S. Y., Stewart, A. N., Sahagun, A., Sarver, D. C., Wong, G. W. Myonectin deletion promotes adipose fat storage and reduces liver steatosis.

14.
Biomater Sci ; 7(4): 1543-1553, 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30681086

RESUMO

Among various polymeric gene delivery systems, peptide-based vectors demonstrate great potential owing to their unique structure and properties, including flexibility; however, there is insufficient molecular understanding of the role and properties of amino acids as building blocks in gene delivery. In this work, we constructed a series of histidine (H)-containing peptide-grafted dextran (D-RxHy) vectors via a simple two-step reaction of dextran with five RxHyC peptides: R7H3C, R5H3C, R5H5C, R3H5C, and R3H7C. The gel electrophoresis study unveiled the DNA-binding ability of H residues. While all D-RxHy vectors possess similarly low cytotoxicity, D-R3H7 exhibited the highest gene transfection efficiency. Interestingly, at the low nitrogen to phosphate (N/P) ratio of 2, D-R3H7 displayed a 6-8-fold higher luciferase expression compared to the gold standard branched PEI (25k). D-R3H7 and D-R5H5 demonstrated favorable cell uptake rates. A chloroquine-treated transfection assay confirmed the key effect of the high buffering capacity of H-rich D-R3H7 on its high gene transfection efficiency, especially at low N/P ratios. The present work unveiled that histidine is critical for both DNA condensation and the accurate control of endosomal escape. The tunable D-RxHy platform not only demonstrates promising potential for therapeutic purposes but can also be used as a tool to elucidate the molecular mechanism of polymer-based transfection.


Assuntos
Dextranos/farmacologia , Técnicas de Transferência de Genes , Peptídeos/farmacologia , Polímeros/farmacologia , Animais , Células COS , Sobrevivência Celular/efeitos dos fármacos , Cercopithecus aethiops , DNA Bacteriano/química , DNA Bacteriano/genética , Dextranos/química , Endossomos/efeitos dos fármacos , Vetores Genéticos/síntese química , Vetores Genéticos/química , Humanos , Células MCF-7 , Peptídeos/química , Plasmídeos/química , Plasmídeos/genética , Polímeros/química
15.
J Biol Chem ; 293(47): 18086-18098, 2018 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-30228187

RESUMO

Secreted proteins are important metabolic regulators in both healthy and disease states. Here, we sought to investigate the mechanism by which the secreted protein complement 1q-like-3 (C1ql3) regulates insulin secretion from pancreatic ß-cells, a key process affecting whole-body glucose metabolism. We found that C1ql3 predominantly inhibits exendin-4- and cAMP-stimulated insulin secretion from mouse and human islets. However, to a lesser extent, C1ql3 also reduced insulin secretion in response to KCl, the potassium channel blocker tolbutamide, and high glucose. Strikingly, C1ql3 did not affect insulin secretion stimulated by fatty acids, amino acids, or mitochondrial metabolites, either at low or submaximal glucose concentrations. Additionally, C1ql3 inhibited glucose-stimulated cAMP levels, and insulin secretion stimulated by exchange protein directly activated by cAMP-2 and protein kinase A. These results suggest that C1ql3 inhibits insulin secretion primarily by regulating cAMP signaling. The cell adhesion G protein-coupled receptor, brain angiogenesis inhibitor-3 (BAI3), is a C1ql3 receptor and is expressed in ß-cells and in mouse and human islets, but its function in ß-cells remained unknown. We found that siRNA-mediated Bai3 knockdown in INS1(832/13) cells increased glucose-stimulated insulin secretion. Furthermore, incubating the soluble C1ql3-binding fragment of the BAI3 protein completely blocked the inhibitory effects of C1ql3 on insulin secretion in response to cAMP. This suggests that BAI3 mediates the inhibitory effects of C1ql3 on insulin secretion from pancreatic ß-cells. These findings demonstrate a novel regulatory mechanism by which C1ql3/BAI3 signaling causes an impairment of insulin secretion from ß-cells, possibly contributing to the progression of type 2 diabetes in obesity.

16.
Photodiagnosis Photodyn Ther ; 24: 88-94, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30006320

RESUMO

AIM: To investigate the effects of ALA-PDT on biofilm structure, virulence factor secretion, and quorum sensing (QS) in Pseudomonas aeruginosa. MATERIALS AND METHODS: We used confocal laser scanning microscopy (CLSM), an XTT assay, scanning electron microscopy (SEM), a virulence factor assay and qRT-PCR in this study. RESULTS: The XTT assay showed that ALA-PDT significantly inhibited the growth of planktonic P. aeruginosa. CLSM and SEM showed that ALA-PDT destroyed both bacterial and biofilm structures. The virulence factor assay showed that pyocyanin and elastase secretion were significantly inhibited in the ALA-PDT groups. qRT-PCR assays demonstrated that ALA-PDT significantly reduced the mRNA expression of QS-related genes. CONCLUSION: ALA-PDT kills planktonic and viable biofilm-associated P. aeruginosa cells, destroys biofilm structures, reduces virulence factor secretion and affects QS system gene expression.

17.
Front Pharmacol ; 9: 467, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29875657

RESUMO

Mammary gland hyperplasia (MGH) is a pathological condition that affects the majority of women at the child-bearing stage. The hormone and endocrinal therapy are typically used to treat MGH. Nevertheless, there are still some certain side effects accompanied with the benefits, which negatively affect the life quality of patients. Therefore, plant-derived agents that are effective against MGH development and with fewer side effects should be developed. The aim of this study was to investigate the protective effects and underlying mechanism of total saponins of Phytolaccae (TSP) against MGH in vivo. The results showed that treatment with TSP could significantly correct the disorder of serum sex hormones levels in rats with MGH, and eliminate the formation of MGH. Moreover, TSP significantly protected estrogen and progesterone-induced MGH histological changes, inhibited the swelling of the nipple, and improved the organ coefficient of uterus in rats with MGH. Mechanistically, TSP treatment not only effectively suppressed the mRNA and protein expression of ERα and PR in mammary gland, but also simultaneously up-regulated ERß expression, and thus blocked sex hormones from interacting with their receptors. TSP treatment markedly suppressed mammary phosphorylation levels of ERK1/2, as well as reduced the mRNA and protein overexpression of VEGF and bFGF in mammary of rats. In addition, TSP treatment substantially down-regulated the expression of Bcl-2 and Ki-67, as well as elevated the expression of Bax. These findings indicated that TSP could potentially be used for effective treatment of MGH.

18.
Mol Cell Proteomics ; 17(8): 1546-1563, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29735541

RESUMO

Exercise is known to confer major health benefits, but the underlying mechanisms are not well understood. The systemic effects of exercise on multi-organ systems are thought to be partly because of myokines/cytokines secreted by skeletal muscle. The extent to which exercise alters cytokine expression and secretion in different muscle fiber types has not been systematically examined. Here, we assessed changes in 66 mouse cytokines in serum, and in glycolytic (plantaris) and oxidative (soleus) muscles, in response to sprint, endurance, or chronic wheel running. Both acute and short-term exercise significantly altered a large fraction of cytokines in both serum and muscle, twenty-three of which are considered novel exercise-regulated myokines. Most of the secreted cytokine receptors profiled were also altered by physical activity, suggesting an exercise-regulated mechanism that modulates the generation of soluble receptors found in circulation. A greater overlap in cytokine profile was seen between endurance and chronic wheel running. Between fiber types, both acute and chronic exercise induced significantly more cytokine changes in oxidative compared with glycolytic muscle. Further, changes in a subset of circulating cytokines were not matched by their changes in muscle, but instead reflected altered expression in liver and adipose tissues. Last, exercise-induced changes in cytokine mRNA and protein were only minimally correlated in soleus and plantaris. In sum, our results indicate that exercise regulates many cytokines whose pleiotropic actions may be linked to positive health outcomes. These data provide a framework to further understand potential crosstalk between skeletal muscle and other organ compartments.

19.
J Am Heart Assoc ; 7(9)2018 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-29680823

RESUMO

BACKGROUND: Phospholipid transfer protein (PLTP) is one of the major modulators of lipoprotein metabolism and atherosclerosis development; however, little is known about the regulation of PLTP. The effect of hepatic prodomain of furin (profurin) expression on PLTP processing and function is investigated. METHODS AND RESULTS: We used adenovirus expressing profurin in mouse liver to evaluate PLTP activity, mass, and plasma lipid levels. We coexpressed PLTP and profurin in human hepatoma cell line cells and studied their interaction. We found profurin expression significantly reduced plasma lipids, plasma PLTP activity, and mass in all tested mouse models, compared with controls. Moreover, the expression of profurin dramatically reduced liver PLTP activity and protein level. We further explored the mechanism using in vivo and ex vivo approaches. We found that profurin can interact with intracellular PLTP and promote its ubiquitination and proteasomal degradation, resulting in less PLTP secretion from the hepatocytes. Furin does not cleave PLTP; instead, it forms a complex with PLTP, likely through its prodomain. CONCLUSIONS: Our study reveals that hepatic PLTP protein is targeted for proteasomal degradation by profurin expression, which could be a novel posttranslational mechanism underlying PLTP regulation.

20.
J Cereb Blood Flow Metab ; : 271678X18764083, 2018 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-29533123

RESUMO

The major pathophysiological process of vascular cognitive impairment (VCI) is chronic cerebral ischemia, which causes disintegration of the blood-brain barrier (BBB), neuronal death, and white matter injury. This study aims to test whether sulforaphane (Sfn), a natural activator of nuclear factor erythroid 2-related factor 2 (Nrf2), reduces the chronic ischemic injury and cognitive dysfunction after VCI. Experimental VCI was induced in rats by permanent occlusion of both common carotid arteries for six weeks. This procedure caused notable neuronal death in the cortex and hippocampal CA1, myelin loss in the corpus callosum and hippocampal fimbria, accumulation of myelin debris in the corpus callosum, and remarkable cognitive impairment. Sfn treatment alleviated these ischemic injuries and the cognitive dysfunction. Sfn-mediated neuroprotection was associated with enhanced activation of Nrf2 and upregulation of heme oxygenase 1. Sfn also reduced neuronal and endothelial death and maintained the integrity of BBB after oxygen-glucose deprivation in vitro in an Nrf2 dependent manner. Furthermore, Nrf2 knockdown in endothelial cells decreased claudin-5 protein expression with downregulated claudin-5 promoter activity, suggesting that claudin-5 might be a target gene of Nrf2. Our results demonstrate that Sfn provides robust neuroprotection against chronic brain ischemic injury and may be a promising agent for VCI treatment.

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