RESUMEN

The primary catalyst for nonalcoholic fatty liver disease (NAFLD) is widely recognized as the induction of lipotoxicity in hepatocytes by an excess of fatty acids. In China, Penthorum chinense Pursh (PcP) is commonly employed as a functional food due to its known hepatoprotective properties. The present study aimed to investigate the influence of PcP extract on in vivo and in vitro models of NAFLD. We found that PcP extract can attenuate palmitic acid (PA)-induced lipotoxicity in HepG2 cells. PA was observed to trigger pyroptosis, as indicated by the increased expression of NLRP3 and GSDMD/N, activation of Caspase-1, and subsequent release of IL-1ß and IL-18. However, these changes were reversed after PcP was administered. Furthermore, the application of an NLRP3 agonist inhibited the protective effects of PcP on lipotoxicity, indicating that PcP decreased lipotoxicity by inhibiting the NLRP3/Caspase-1/GSDMD pathway. Ultimately, we established a rat model of NAFLD through the administration of a high-fat diet (HFD), followed by the oral delivery of PcP extracts. The results demonstrated that the administration of PcP extract effectively decreased dyslipidemia and hepatic steatosis, which coincided with a decrease in hepatic pyroptosis through modulation of the NLRP3/Caspase-1/GSDMD pathway in liver tissues. Overall, our findings provide insight into the mechanism by which PcP extracts alleviate hepatic steatosis, highlighting the potential significance of modulating the NLRP3/Caspase-1/GSDMD pathway in the context of pyroptosis.

RESUMEN

Aims: The aim of this study was to investigate the protective effect of HLJDD on septic rats and the underlying mechanisms. Materials and methods: Adult male Sprague-Dawley (SD) adult rats (150-180 g) were randomly divided into the following 5 groups (n = 7 per group): the Sham group, caecal ligation and puncture (CLP) group, HLJDD + CLP (Huang Lian Jie Du Decoction, HLJDD) group (1 g/mL/100 g), HLJDD + Rap + CLP (H. Rap) group (Rap: 3 mg/kg), and HLJDD+3-MA + CLP (H. 3-MA) group (3-MA: 30 mg/kg). Rapamycin (Rap) and 3-methyladenosine (3-MA) were used to activate and inhibit autophagy, respectively. HLJDD was purchased from Beijing Tong Ren Tang Guiyang Branch and verified by experts as a genuine product. We used CLP to establish an animal model of sepsis in the last four groups. Survival was analysed by the Kaplan‒Meier method. Then, we examined autophagy-related genes (Atgs) and proteins using real-time PCR and Western blotting, respectively. The microstructure of the ileum and the number of autophagosomes were observed by transmission electron microscopy (TEM). Analyses of HE-stained pathological ileum and inflammatory factor levels were examined to assess the extent of septic injury. The effect of HLJDD on the gut microbiota was analysed by 16S rRNA gene sequencing of faeces. Results: In this study, we identified the protective effects of HLJDD on mortality and inflammation in septic rats. Several key proteins, including LC3-II, Beclin-1 and p62, were examined and showed that HLJDD could effectively reverse the sepsis-induced decrease in autophagy. TEM was performed and the expression of Atgs was assessed to evaluate fluctuations in autophagy. Then, we examined the intestinal tight junction protein zona occludens (ZO-1), lipopolysaccharide (LPS) and inflammatory factors, and found that HLJDD effectively alleviated the increase in ZO-1 gene expression, the level of LPS and serum level of inflammatory factors caused by sepsis. These results were consistent with those obtained from pathological sectioning and TEM analysis. Moreover, autophagy activation effectively ameliorated sepsis, and autophagy inhibition exacerbated the systemic symptoms caused by infection. By examining the expression of key proteins upstream of the autophagy pathway, we found that HLJDD inhibited mTOR via the MAPK/PI3K signalling pathway to promote autophagy in septic rats. 16S rRNA sequencing revealed that HLJDD significantly affected the diversity and physiological function of the gut microbiota in septic rats. Conclusions: The results of this study indicate that autophagy activation is a potential mechanism underlying the protective effect of HLJDD on the intestine in septic rats.

RESUMEN

It is currently thought that excess fatty acid-induced lipotoxicity in hepatocytes is a critical initiator in the development of nonalcoholic fatty liver disease (NAFLD). Lipotoxicity can induce hepatocyte death; thus, reducing lipotoxicity is one of the most effective therapeutic methods to combat NAFLD. Abundant evidence has shown that hesperidin (HSP), a type of flavanone mainly found in citrus fruits, is able to ameliorate NAFLD, but the molecular mechanisms are unclear. We previously reported that pyroptosis contributed to NAFLD development and that inhibiting pyroptosis contributed to blunting the progression of NAFLD in rat models. Therefore, we questioned whether HSP could contribute to ameliorating NAFLD by modulating pyroptosis. In this study, a high-fat diet (HFD) induced dyslipidemia and hepatic lipotoxicity in rats, and HSP supplementation ameliorated dyslipidemia and insulin resistance. In addition, the HFD also caused pyroptosis in the liver and pancreas, while HSP supplementation ameliorated pyroptosis. In vitro, we found that HSP ameliorated palmitic acid-induced lipotoxicity and pyroptosis in HepG2 and INS-1E cells. In conclusion, we showed for the first time that HSP has a protective effect against liver and pancreas damage in terms of pyroptosis and provides a novel mechanism for the protective effects of HSP on NAFLD.

Asunto(s)

Dislipidemias , Hesperidina , Enfermedad del Hígado Graso no Alcohólico , Ratas , Animales , Piroptosis , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/etiología , Dieta Alta en Grasa/efectos adversos , Hesperidina/farmacología , Hígado , Hepatocitos

RESUMEN

Background: Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial lung disease, and it carries a poor prognosis due to a lack of efficient diagnosis methods and treatments. Epithelial-mesenchymal transition (EMT) plays a key role in IPF pathogenesis. Endoplasmic reticulum (ER) stress contributes to fibrosis via EMT-mediated pathways. Mesenchymal stem cell (MSC) transplantation is a promising treatment strategy for pulmonary fibrosis and ameliorates lung fibrosis in animal models via paracrine effects. However, the specific mechanisms underlying the effect of transplanted MSCs are not known. We previously reported that MSCs attenuate endothelial injury by modulating ER stress and endothelial-to-mesenchymal transition. The present study investigated whether modulation of ER stress- and EMT-related pathways plays essential roles in MSC-mediated alleviation of IPF. Methods and Results: We constructed a A549 cell model of transforming growth factor-ß1 (TGF-ß1)-induced fibrosis. TGF-ß1 was used to induce EMT in A549 cells, and MSC coculture decreased EMT, as indicated by increased E-cadherin levels and decreased vimentin levels. ER stress participated in TGF-ß1-induced EMT in A549 cells, and MSCs inhibited the expression of XBP-1s, XBP-1u, and BiP, which was upregulated by TGF-ß1. Inhibition of ER stress contributed to MSC-mediated amelioration of EMT in A549 cells, and modulation of the IRE1α-XBP1 branch of the ER stress pathway may have played an important role in this effect. MSC transplantation alleviated bleomycin (BLM)-induced pulmonary fibrosis in mice. MSC treatment decreased the expression of ER stress- and EMT-related genes and proteins, and the most obvious effect of MSC treatment was inhibition of the IRE1α/XBP1 pathway. Conclusions: The present study demonstrated that MSCs decrease EMT by modulating ER stress and that blockade of the IRE1α-XBP1 pathway may play a critical role in this effect. The current study provides novel insight for the application of MSCs for IPF treatment and elucidates the mechanism underlying the preventive effects of MSCs against pulmonary fibrosis.

RESUMEN

HBV-associated hepatitis B virus x protein (HBx) plays multiple roles in the development of hepatocellular carcinoma. In our prior study, we discovered that miR-187-5p expression was inhibited by HBx. To investigate the underlying molecular mechanism of HBx-mediated miR-187-5p downregulation in hepatocellular carcinoma cells, effects of HBx and miR-187-5p on hepatoma carcinoma cell were observed, as well as their interactions. Through in vitro and in vivo experiments, we demonstrated that overexpression of miR-187-5p inhibited proliferation, migration, and invasion. Simultaneously, we observed a dysregulation in the expression of miR-187-5p in liver cancer cell lines, which may be attributed to transcriptional inhibition through the E2F1/FoxP3 axis. Additionally, we noted that HBx protein is capable of enhancing the expression of E2F1, a transcription factor that promotes the expression of FoxP3. In conclusion, our results suggest that the inhibitory effect of HBx on miR-187-5p is mediated through the E2F1/FoxP3 axis. As shown in this work, HBx promotes hepatoma carcinoma cell proliferation, migration, and invasion through the E2F1/FoxP3/miR-187 axis. It provides a theoretical basis for finding therapeutic targets that will help clinic treatment for HCC.

Asunto(s)

Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroARNs , Humanos , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , MicroARNs/genética , MicroARNs/metabolismo , Línea Celular , Factores de Transcripción Forkhead/metabolismo , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral , Células Hep G2

RESUMEN

Nobiletin (NOB) is a naturally occurring compound, commonly found in citrus peel, that shows hepatoprotective and lipid-reducing effects. However, the lipid biomarkers and the potential improvement mechanisms have not been adequately explored. Therefore, we investigated the ameliorative effect and the molecular mechanism of NOB on NAFLD induced by a high-fat diet in mice. The results showed that supplementation with NOB over 12 weeks markedly improved glucose tolerance, serum lipid profiles, inflammatory factors, hepatic steatosis, and oxidative stress. These beneficial effects were mainly related to reduced levels of potential lipid biomarkers including free fatty acids, diacylglycerols, triacylglycerols, and cholesteryl esters according to hepatic lipidomic analysis. Twenty lipids, including DGs and phosphatidylcholines, were identified as potential lipid biomarkers. Furthermore, RT-qPCR and Western blot analysis indicated that NOB inhibited the expression of lipogenesis-related factors such as SREBP-1c, SCD-1, and FAS, and upregulated the expression of lipid oxidation (PPARα) and cholesterol conversion (LXRα, CYP7A1, and CYP27A1) genes as well as antioxidation-related factors (Nucl-Nrf2, NQO1, HO-1, and GCLC), indicating that NOB intake may reduce lipid biosynthesis and increase lipid consumption to improve hepatic steatosis and oxidative stress. This study is beneficial for understanding the ameliorative effects of NOB on NAFLD.

Asunto(s)

Enfermedad del Hígado Graso no Alcohólico , Animales , Ratones , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/genética , Hígado , Metabolismo de los Lípidos , Estrés Oxidativo , Ácidos Grasos no Esterificados/metabolismo , Biomarcadores/metabolismo , Dieta Alta en Grasa/efectos adversos , Ratones Endogámicos C57BL

RESUMEN

Lake Luoma is an important storage lake for the Eastern route of the South-to-North Water Diversion Project (NSBD), which has many functions including flood control and irrigation, drinking water supply, and ecological maintenance. In order to understand the succession patterns and driving factors of water quality in Lake Luoma, we used monthly monitoring data from 2009 to 2020 in combination with historical data from 1996 to 2008. The long-term succession patterns, seasonal dynamics, and spatial patterns of total nitrogen (TN), total phosphorus (TP), permanganate index, and ammonia nitrogen (NH+4-N) were examined, and the influence of meteorological and hydrological factors on water quality was explored through correlation analyses and generalized additive models. The results showed that it remained in the status of grade Ⅳ-inferior Ⅴ over the past 25 years. The concentration of TN, which was the main pollutant, changed significantly (1.06-3.49 mg·L-1), experiencing three stages of gradual decline (1996-2002), significant interannual fluctuation (2002-2015), and significant increase (2015-2020). Permanganate index decreased significantly (2.97-6.38 mg·L-1), whereas TP and NH+4-N concentration fluctuated slightly, ranging from 0.024-0.076 mg·L-1 and 0.11-0.69 mg·L-1, respectively. The concentration of TN and TP increased abnormally in the summer of 2017-2020, reaching 3.30 mg·L-1 and 0.14 mg·L-1 in August, respectively, which was approximately 1.5 and 2.4 times the annual average. In terms of seasonal dynamics, the seasonal variation in water quality between summer/autumn and winter/spring reversed after 2015, with water quality in summer/autumn being worse than that in winter and spring, indicating the exacerbation of eutrophication. The water quality in the southern area was obviously better than that in the northern area. The input of pollutants from the Yihe River and Middle Canal increased with water quantity since 2015, which drove the water quality deterioration through nutrients. Our results suggested that the water quality of Lake Luoma should be improved by strengthening exogenous pollution reduction, endogenous control, polder dismantling, and ecological restoration.

Asunto(s)

Contaminantes Ambientales , Contaminantes Químicos del Agua , Calidad del Agua , Lagos , Monitoreo del Ambiente/métodos , Inundaciones , Fósforo/análisis , Nitrógeno/análisis , Eutrofización , Contaminantes Químicos del Agua/análisis , Contaminantes Ambientales/análisis , China

RESUMEN

Excessive free fatty acid- (FFA-) induced endothelial lipotoxicity is involved in the pathogenesis of atherosclerosis. Endoplasmic reticulum (ER) stress is mechanistically related to endothelial lipotoxicity. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is the major oxidatively modified low-density lipoprotein (OxLDL) receptor in endothelial cells and is highly abundant in atherosclerotic lesions. Curcumin reduces the LOX-1 expression; however, the mechanism underlying this effect remains unknown. In the current study, we explored whether curcumin ameliorates palmitic acid- (PA-) induced endothelial lipotoxicity and LOX-1 upregulation by reducing ER stress in human umbilical vein endothelial cells (HUVECs). We built endothelial lipotoxicity in vitro and found that LOX-1 was upregulated after PA stimulation, during which ER stress played an important role. Next, we observed that curcumin substantially alleviated PA-induced lipotoxicity by restoring cell viability, increasing angiogenesis, and decreasing lipid deposition. Furthermore, LOX-1 upregulation in HUVECs was blocked by curcumin, possibly via ER stress suppression. Overall, our findings demonstrated that curcumin alleviates endothelial lipotoxicity and LOX-1 upregulation, and ER stress inhibition may play a critical role in this effect.

Asunto(s)

Aterosclerosis/tratamiento farmacológico , Curcumina/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Ácido Palmítico/toxicidad , Receptores Depuradores de Clase E/metabolismo , Antiinflamatorios no Esteroideos/farmacología , Aterosclerosis/inducido químicamente , Aterosclerosis/metabolismo , Aterosclerosis/patología , Supervivencia Celular , Células Cultivadas , Inhibidores Enzimáticos/toxicidad , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos

RESUMEN

Clarifying the current situation of regional water pollutants and the relationship between pollutants and pollution sources is considered essential for managing the water environment. Water quality identification index (WQI), cluster analysis (CA), positive matrix factorization (PMF), and stable isotope analysis in R (SIAR) were employed to interpret a large and complex water quality data set of the Qinhuai River catchment generated during 2015 to 2019 to monitor of 11 parameters at 29 different sampling sites. WQI analysis indicated that water quality in Qinhuai River catchment is considered to have "moderate pollution," and an improving trend of water quality was observed at the interannual scale. TN was the most deteriorated of all pollution parameters. CA and PMF results on the spatial scale revealed that sampling sites located at downtown of Nanjing and Lishui District or Jangling University town were highly polluted due to the sewage from domestic sewage and business service sewage (28.88%) as well as industrial wastewater (27.43%), while sampling sites located at Hushu Street Administrative District, Ergan River, and Sangan River were slightly polluted by rural domestic wastewater and garbage (28.79%), and agricultural non-point source pollution (24.3%). The middle-lower reaches (Jiangning Development Zone and Moling Street) and middle reaches (Lukou Street Administrative District) were moderately polluted by industrial wastewater (27.25%), sewage from domestic wastewater and business service wastewater (31.62%) as well as inner sources (24.76%). The SIAR results showed that NO3--N was the main nitrogen form, and the NO3--N mainly originated from sewage (61%) and soil (34%) in the Yuntaishan River sub-catchment. These results will aid in the development of measures required to control water pollution in river catchments.

Asunto(s)

Ríos , Contaminantes Químicos del Agua , China , Monitoreo del Ambiente , Humanos , Urbanización , Contaminantes Químicos del Agua/análisis , Contaminación del Agua/análisis , Calidad del Agua

RESUMEN

Autophagy is a cell adaptive response that involves the process of microbial infections. Our previous study has indicated that Bombyx mori nucleopolyhedrovirus (BmNPV) infection triggers the complete autophagic process in BmN-SWU1 cells, which is beneficial to the viral infection. Autophagy-related (ATG) protein ATG13, as part of the ULK complex (a serine-threonine kinase complex composed of ULK1, ULK2, ATG13, ATG101, and FIP200), is the most upstream component of the autophagy pathway, and how it affects virus infections will improve our understanding of the interaction between the virus and the host. This study has determined that the overexpression of the BmAtg13 gene promotes the expression of viral genes and increases viral production in BmN-SWU1 cells, whereas knocking down the BmAtg13 gene suppresses BmNPV replication. Moreover, the BmAtg13 overexpression transgenic line contributed to viral replication and increased mortality rate of BmNPV infection. In contrast, the BmAtg13 knockout transgenic line reduced viral replication 96 h post-infection. Furthermore, BmATG13 directly interacted with viral protein BRO-B, forming a protein complex. Taken together, the findings of this study suggest that BmATG13 may be utilized by the BRO-B protein to promote BmNPV replication and proliferation, which, in turn, provides important insights into the mechanism that autophagy influences viral infection.

Asunto(s)

Proteínas de Insectos/metabolismo , Nucleopoliedrovirus/patogenicidad , Replicación Viral/fisiología , Animales , Proliferación Celular/genética , Proliferación Celular/fisiología , Proteínas de Insectos/genética , Unión Proteica , Proteínas Virales/genética , Proteínas Virales/metabolismo , Replicación Viral/genética

RESUMEN

A dual-band terahertz (THz) absorber using the periodic cross-shaped graphene arrays is presented. It is shown that the dual-band light absorption enhancement of graphene results from the edge graphene plasmon (EGP) resonance, and the locations of the two absorption peaks can be precisely estimated by using the Fabry-Pérot (F-P) cavity model. Slight residual reflection remains at the two absorption peaks because the input impedance of the cross-arm cannot be perfectly matched with the free space impedance. In addition, the locations of the two absorption bands can be simultaneously tuned by changing the Fermi level of graphene, and they can be independently tuned by changing the width or the length of the cross-arm of graphene. Excellent angle-insensitivity dual-band absorption enhancement of graphene can be maintained for both the transverse electric (TE) and transverse magnetic (TM) polarizations.

RESUMEN

An angle-insensitive broadband absorber of graphene covering the whole visible spectrum is numerically demonstrated, which is resulted from multiple couplings of the electric and magnetic dipole resonances in the narrow metallic grooves. This is achieved by integrating the graphene sheet with a multi-grooved metasurface separated by a polymethyl methacrylate (PMMA) spacer, and an average absorption efficiency of 71.1% can be realized in the spectral range from 450 to 800 nm. The location of the absorption peak of graphene can be tuned by the groove depth, and the bandwidth of absorption can be flexibly controlled by tailoring both the number and the depth of the groove. In addition, broadband light absorption enhancement of graphene is robust to the variations of the structure parameters, and good absorption properties can be maintained even the incident angle is increased to 60°.

RESUMEN

We perform a comprehensive analysis of multiband absorption properties in a metal-dielectric-metal-dielectric (MDMD) nanostructure under TM wave illumination. The multiband absorption can be attributed to the hybridization of the surface plasmon resonance (SPR) and the guide-mode resonance (GMR), and we identify the hybrid GMR/SPR by the dispersion relation equations of the SPR and GMR, respectively. More importantly, the MDMD nanostructure is very sensitive to the change of the dielectric environment for the special hybrid structure; thus, it can function as a good candidate for ultrasensitive biochemical sensing. The highest sensitivity of the MDMD nanostructure reaches 1087 nm/RIU with the figure of merit (FoM) of 23 and the new figure of merit (FoM*) of 483; it is performed by the absorption peak at 1796.1 nm of the double surface plasmon polariton with the strongest field enhancement at the surface.

RESUMEN

Anoikis is a form of apoptosis induced upon cell detachment from extracellular matrix. It has been determined that acquisition of resistance to anoikis is a critical step for tumor cell metastasis. MiR-21, the most prominent oncomiR, plays an important role in tumor progression. In this study, we revealed that up-regulation of miR-21 in human esophageal adenocarcinoma (EA) is associated with lymph node metastasis and poor survival rate. Because of the established anti-apoptosis effect of miR-21, it is tempting to speculate that miR-21 might contribute to tumor metastasis by regulating anoikis. qRT-PCR analysis demonstrated that miR-21 expression in OE33/AR cells (subpopulation of human EA OE33 cells that acquired resistance to anoikis) was significantly increased. Also, transfection of miR-21 mimics provided OE33 cells resisting to anoikis. By luciferase assays, we verified that PDCD4 and PTEN were the functional targets of miR-21. In mouse model, via tail vein injection experiment, we showed that the metastasis formation of OE33 cells in vivo could be mediated by changing the miR-21 expression pattern. Taken together, our findings suggested that miR-21 was involved in the regulation of anoikis in human EA cells. Targeting miR-21 may provide a novel strategy to prevent metastasis.

Asunto(s)

Adenocarcinoma/genética , Adenocarcinoma/patología , Anoicis , Proteínas Reguladoras de la Apoptosis/metabolismo , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , MicroARNs/metabolismo , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Proteínas de Unión al ARN/metabolismo , Animales , Secuencia de Bases , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Metástasis Linfática , Masculino , Ratones Endogámicos BALB C , MicroARNs/genética , Persona de Mediana Edad , Pronóstico

RESUMEN

The present study was to investigate the role of the interaction between canonical transient receptor potential channel 1 (TRPC1) and calcium release-activated calcium modulator 1 (Orai1) in extracellular Ca2+-sensing receptor (CaR)-induced extracellular Ca2+ influx and nitric oxide (NO) production. Human umbilical vein endothelial cells (HUVECs) were incubated with CaR agonist Spermine [activating store-operated calcium channels (SOC) and receptor-operated calcium channels (ROC)] alone or in combination with the following reagents: CaR negative allosteric modulator Calhex231 plus ROC analogue TPA (activating ROC and blocking SOC), Ro31-8220 (PKC inhibitor that activates SOC and blocks ROC) or Go6967 (PKCs and PKCµ inhibitor that activates SOC and blocks ROC). The protein expressions and co-localization of TRPC1 and Orai1 were determined using immunofluorescent staining. The interaction between TRPC1 and Orai1 was examined by co-immunoprecipitation. We silenced the expressions of their genes in the HUVECs by transfection of constructed TRPC1 and Orai1 shRNA plasmids. Intracellular Ca2+ concentration ([Ca2+]i) was detected using Ca2+ indicator Fura-2/AM, and NO production was determined by DAF-FM staining. The results showed that TRPC1 and Orai1 protein expressions were co-located on the cell membrane of the HUVECs. Compared with Spermine+Ca2+ group, Calhex231+ TPA+Spermine+Ca2+, Ro31-8220+Spermine+Ca2+ and Go6976+Spermine+Ca2+ groups exhibited down-regulated protein expressions of TRPC1 and Orai1 in cytoplasm and decreased co-localization on the cell membrane. Co-immunoprecipitation results showed that the interaction between TRPC1 and Orai1 was reduced by Calhex231 plus TPA, Ro31-8220 or Go6976 addition in the Spermine-stimulated HUVECs. Double knockdown of Trpc1 and Orai1 genes significantly decreased [Ca2+]i level and NO production in all of the Spermine+Ca2+, Calhex231+TPA+Spermine+Ca2+, Ro31-8220+Spermine+Ca2+ and Go6976+Spermine+Ca2+ groups. These results suggest that TRPC1/Orai1 may form a complex that mediates Ca2+ influx and No production via SOC and ROC activation.

Asunto(s)

Calcio/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Óxido Nítrico/metabolismo , Proteína ORAI1/metabolismo , Canales Catiónicos TRPC/metabolismo , Benzamidas/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Señalización del Calcio , Membrana Celular , Ciclohexilaminas/farmacología , Silenciador del Gen , Humanos , Indoles/farmacología , ARN Interferente Pequeño , Receptores Sensibles al Calcio/agonistas , Espermina/farmacología

RESUMEN

Human cytomegalovirus (HCMV) infection, chronic inflammation and oxidative stress, the renin-angiotensin system (RAS), endothelial function, and DNA methylation play roles in the pathogenesis of essential hypertension (EH); however, the mechanism by which HCMV predisposes patients to hypertension remain unclear. Our group previously demonstrated an association between EH and HCMV infection in Kazakh Chinese. Here, we investigated the relationship between HCMV infection and other clinicopathological features in 720 Kazakh individuals with or without hypertension (n=360 each; age: 18-80). Multiple linear and logistic regression analyses were used to determine the associations between HCMV infection, clinical characteristics, and EH. Notably, patients with EH, particularly those with HCMV infection, exhibited a marked increase in tumor necrosis factor-α (TNF-α) and 8-hydroxy-2-deoxyguanosine (8-OHDG) levels, but a decrease in endothelial nitric oxide synthase (eNOS) and renin levels. Similarly, elevated TNF-α and 8-OHDG levels were independent predictors of increased HCMV antibody titers, whereas eNOS and renin were negatively correlated with the latter. Moreover, serum angiotensin-converting enzyme (sACE, ACE) methylation was increased, whereas 11-ß hydroxysteroid dehydrogenase 2 (HSD11ß2; HSD3B2) methylation was decreased in patients with EH who were also infected with HCMV. A positive correlation between HSD3B2 methylation and HCMV IgG titer and blood pressure was additionally observed, whereas angiotensin-converting enzyme (ACE) methylation was inversely correlated with blood pressure. Collectively, these data indicate that HCMV may contribute to EH development in the Kazakh Chinese by increasing TNF-α and 8-OHDG levels, suppressing eNOS and renin, and manipulating HSD3B2 and ACE methylation.

Asunto(s)

Infecciones por Citomegalovirus/virología , Desoxiguanosina/análogos & derivados , Hipertensión Esencial/virología , Óxido Nítrico Sintasa de Tipo III/inmunología , Renina/inmunología , Factor de Necrosis Tumoral alfa/inmunología , 8-Hidroxi-2'-Desoxicoguanosina , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Antivirales/sangre , Presión Sanguínea , Estudios de Casos y Controles , China , Citomegalovirus/genética , Citomegalovirus/aislamiento & purificación , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/etnología , Infecciones por Citomegalovirus/inmunología , Desoxiguanosina/sangre , Desoxiguanosina/inmunología , Hipertensión Esencial/complicaciones , Hipertensión Esencial/etnología , Hipertensión Esencial/inmunología , Etnicidad , Femenino , Humanos , Masculino , Metilación , Persona de Mediana Edad , Óxido Nítrico Sintasa de Tipo III/sangre , Peptidil-Dipeptidasa A/sangre , Peptidil-Dipeptidasa A/inmunología , Progesterona Reductasa/sangre , Progesterona Reductasa/inmunología , Renina/sangre , Factor de Necrosis Tumoral alfa/sangre

RESUMEN

BACKGROUND: Human cytomegalovirus (CMV) has been linked to the pathogenesis of elevated arterial blood pressure (BP). Our study aimed to determine the association between anti-CMV titers and arterial BP in the Kazakh and Han Chinese populations. MATERIAL AND METHODS: Kazakh and Han (n = 800 each) (age, ≥18 years) subjects from Xinjiang, China were examined for anti-CMV immunoglobulin (Ig)G titers using a commercially available enzyme-linked immunosorbent assay (ELISA) kit. The highest anti-CMV titer tertiles determined within gender and ethnicity groups were compared against the two lower tertiles and seronegative samples. RESULTS: Multivariate linear regression analysis revealed that anti-CMV titers were independent determinants for elevated systolic (p = 0.006) BP in Kazakh women and inversely associated with systolic (p = 0.004) and mean arterial (p = 0.019) BP in Han women. CONCLUSION: The association between CMV infection and/or resulting immune response and BP elevation differed by sex and ethnicity. In Kazakh women, they were associated with elevated BP and the opposite was true among Han women.

Asunto(s)

Anticuerpos Antivirales/sangre , Pueblo Asiatico/etnología , Presión Sanguínea/fisiología , Infecciones por Citomegalovirus/inmunología , Citomegalovirus/inmunología , Inmunoglobulina G/sangre , Adolescente , Adulto , Anciano , China , Correlación de Datos , Comparación Transcultural , Infecciones por Citomegalovirus/etnología , Femenino , Encuestas Epidemiológicas , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Factores de Riesgo , Adulto Joven

RESUMEN

Store­operated Ca2+ entry (SOCE) via store­operated Ca2+ channels (SOCC), encoded by transient receptor potential canonical (TRPC) channel proteins, is an important underlying mechanism regulating intracellular Ca2+ concentration ([Ca2+]i) and various intracellular functions in endothelial cells (ECs). TRPC1, the probable candidate for SOCC, is expressed in ECs. Ca2+­sensing receptor (CaSR) is functionally expressed in vascular endothelium and is important in Ca2+ mobilization and cardiovascular functions. To date, there have been no reports demonstrating an association between CaSR and TRPC1 in ECs. The present study investigated the effects of TRPC1 on CaSR­induced Ca2+ influx and nitric oxide (NO) production in human umbilical vein ECs (HUVECs). TRPC1 and CaSR proteins in HUVECs were measured by immunostaining and western blot analysis. [Ca2+]i levels were measured using the Fura­2­acetoxymethyl ester method. The indicator 3­amino, 4­aminomethyl­2, 7­difluorescein diacetate was used to measure NO production in HUVECs. The expression of TRPC1 protein in HUVECs was silenced by transfecting HUVECs with small interfering RNA (siRNA) against TRPC1. Although changes in extracellular Ca2+ failed to alter [Ca2+]i in HUVECs, the CaSR agonist spermine increased [Ca2+]i and NO production in HUVECs. NO production in HUVECs was diminished in Ca2+­free medium or following treatment with a CaSR negative allosteric modulator (Calhex231), SOCC inhibitor (MRS1845) or TRPC inhibitor (SKF96365). The spermine­induced increases in [Ca2+]i and NO production were reduced in HUVECs transfected with TRPC1 siRNA. These results suggested that TRPC1 is a primary candidate in forming SOCC that stimulates CaSR­induced SOCE and NO production in HUVECs and is a potential therapeutic target for vascular diseases.

Asunto(s)

Calcio/metabolismo , Células Endoteliales/metabolismo , Óxido Nítrico/metabolismo , Receptores Sensibles al Calcio/metabolismo , Canales Catiónicos TRPC/metabolismo , Señalización del Calcio , Células Cultivadas , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Interferencia de ARN , ARN Interferente Pequeño/genética , Canales Catiónicos TRPC/genética

RESUMEN

Human cytomegalovirus (CMV) infection is associated with hypertension and has been linked with the pathogenesis of increased arterial blood pressure (BP). Currently, whether CMV infection is associated with the progression of hypertension and hypertensive target organ damage (TOD) remains to be identified. We aimed to examine the relationship between CMV infection and the progression of hypertension and hypertensive TOD, which could provide clues on the possible mediating mechanisms, in the Han Chinese population. A total of 372 patients with hypertension and 191 healthy controls (Han participants from Xinjiang, China) were included in the study. Enzyme-linked immunosorbent assay (ELISA) and qPCR were used to detect CMV infection. C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) titers were also analyzed using an ELISA kit. Moreover, cardiovascular disease markers were evaluated by echocardiography, carotid ultrasonography, and tomographic scans. Essential hypertension (EH) patients exhibited a marked increase in CMV IgG antibody, CRP, TNF-α, and IL-6 levels. Higher grade of hypertension and hypertensive TOD had higher CMV IgG antibody and CRP levels. The CMV IgG antibody titers were positively correlated with arterial BP, greater grade of hypertension and hypertensive TOD, and CRP and IL-6 levels. The higher quartile of CMV IgG titer and CRP level were associated with the incidence of hypertension and the progression of hypertension and hypertensive TOD. In the Han Chinese population, high CMV IgG titers are associated with the progression of hypertension and hypertensive TOD. CMV IgG titer >4.25 U could be an independent predictor of hypertension and progression of hypertension, while that >4.85 U could be an independent risk factor for hypertensive TOD. The underlying mechanism may be largely mediated by chronic inflammation.

Asunto(s)

Anticuerpos Antivirales/sangre , Citomegalovirus/inmunología , Etnicidad , Hipertensión/patología , Adulto , Encéfalo/diagnóstico por imagen , China , Progresión de la Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Hipertensión/inmunología , Masculino , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la Polimerasa

RESUMEN

Thermotolerance is important particularly for poikilotherms such as insects. Understanding the mechanisms by which insects respond to high temperatures can provide insights into their adaptation to the environment. Therefore, in this study, we performed a transcriptome analysis of two silkworm strains with significantly different resistance to heat as well as humidity; the thermo-resistant strain 7532 and the thermos-sensitive strain Knobbed. We identified in total 4,944 differentially expressed genes (DEGs) using RNA-Seq. Among these, 4,390 were annotated and 554 were novel. Gene Ontology (GO) analysis of 747 DEGs identified between RT_48h (Resistant strain with high-temperature Treatment for 48 hours) and ST_48h (Sensitive strain with high-temperature Treatment for 48 hours) showed significant enrichment of 12 GO terms including metabolic process, extracellular region and serine-type peptidase activity. Moreover, we discovered 12 DEGs that may contribute to the heat-humidity stress response in the silkworm. Our data clearly showed that 48h post-exposure may be a critical time point for silkworm to respond to high temperature and humidity. These results provide insights into the genes and biological processes involved in high temperature and humidity tolerance in the silkworm, and advance our understanding of thermal tolerance in insects.

Asunto(s)

Bombyx/genética , Bombyx/fisiología , Perfilación de la Expresión Génica , Calor , Humedad , Estrés Fisiológico/genética , Termotolerancia/genética , Animales , Ontología de Genes , Análisis de Secuencia de ARN , Especificidad de la Especie