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BACKGROUND: Type 2 diabetes mellitus (T2DM) is a metabolic syndrome characterized by chronic inflammation, insulin resistance, and islet cell damage. The prevention of T2DM and its associated complications is an urgent public health issue that affects hundreds of millions of people globally. Numerous studies suggest that disturbances in gut metabolites are important driving forces for the pathogenesis of diabetes. However, the functions and mechanisms of action of most commensal bacteria in T2DM remain largely unknown. METHODS: The quantification of bile acids (BAs) in fecal samples was performed using ultra-performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS). The anti-diabetic effects of Bacteroides uniformis (B. uniformis) and its metabolites cholic acid (CA) and chenodeoxycholic acid (CDCA) were assessed in T2DM mice induced by streptozocin (STZ) plus high-fat diet (HFD). RESULTS: We found that the abundance of B. uniformis in the feces and the contents of CA and CDCA were significantly downregulated in T2DM mice. B. uniformis was diminished in diabetic individuals and this bacterium was sufficient to promote the production of BAs. Colonization of B. uniformis and intragastric gavage of CA and CDCA effectively improved the disorder of glucose and lipid metabolism in T2DM mice by inhibiting gluconeogenesis and lipolysis in the liver. CA and CDCA improved hepatic glucose and lipid metabolism by acting on the Takeda G protein-coupled receptor 5 (TGR5)/adenosine monophosphate-activated protein kinase (AMPK) signaling pathway since knockdown of TGR5 minimized the benefit of CA and CDCA. Furthermore, we screened a natural product-vaccarin (VAC)-that exhibited anti-diabetic effects by promoting the growth of B. uniformis in vitro and in vivo. Gut microbiota pre-depletion abolished the favorable effects of VAC in diabetic mice. CONCLUSIONS: These data suggest that supplementation of B. uniformis may be a promising avenue to ameliorate T2DM by linking the gut and liver.
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Diabetic nephropathy (DN) is recognized as one of the primary causes of chronic kidney disease and end-stage renal disease. Vaccarin (VAC) confers favorable effects on cardiovascular and metabolic diseases, including type 2 diabetes mellitus (T2DM). Nonetheless, the potential role and mechanism of VAC in the etiology of DN have yet to be completely elucidated. In this study, a classical mouse model of T2DM is experimentally induced via a high-fat diet (HFD)/streptozocin (STZ) regimen. Renal histological changes are assessed via H&E staining. Masson staining and immunohistochemistry (IHC) are employed to assess renal fibrosis. RT-PCR is utilized to quantify the mRNA levels of renal fibrosis, oxidative stress and inflammation markers. The levels of malondialdehyde (MDA) and reactive oxygen species (ROS), as well as the content of glutathione peroxidase (GSH-Px), are measured. The protein expressions of collagen I, TGF-ß1, α-SMA, E-cadherin, Nrf2, catalase, SOD3, SOD2, SOD1, p-ERK, p-EGFR (Y845), p-EGFR (Y1173), p-NFκB P65, t-ERK, t-EGFR and t-NFκB P65 are detected by western blot analysis. Our results reveal that VAC has a beneficial effect on DN mice by improving renal function and mitigating histological damage. This is achieved through its inhibition of renal fibrosis, inflammatory cytokine overproduction, and ROS generation. Moreover, VAC treatment effectively suppresses the process of epithelial-mesenchymal transition (EMT), a crucial characteristic of renal fibrosis, in high glucose (HG)-induced HK-2 cells. Network pharmacology analysis and molecular docking identify epidermal growth factor receptor (EGFR) as a potential target for VAC. Amino acid site mutations reveal that Lys-879, Ile-918, and Ala-920 of EGFR may mediate the direct binding of VAC to EGFR. In support of these findings, VAC reduces the phosphorylation levels of both EGFR and its downstream mediator, extracellular signal-regulated kinase 1/2 (ERK1/2), in diabetic kidneys and HG-treated HK-2 cells. Notably, blocking either EGFR or ERK1/2 yields renal benefits similar to those observed with VAC treatment. Therefore, this study reveals that VAC attenuates renal damage via inactivation of the EGFR/ERK1/2 signaling axis in T2DM patients.
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Acute kidney injury (AKI) remains a global public health problem with high incidence, high mortality rates, expensive medical costs, and limited treatment options. AKI can further progress to chronic kidney disease (CKD) and eventually end-stage renal disease (ESRD). Previous studies have shown that trauma, adverse drug reactions, surgery, and other factors are closely associated with AKI. With further in-depth exploration, the role of gut microbiota in AKI is gradually revealed. After AKI occurs, there are changes in the composition of gut microbiota, leading to disruption of the intestinal barrier, intestinal immune response, and bacterial translocation. Meanwhile, metabolites of gut microbiota can exacerbate the progression of AKI. Therefore, elucidating the specific mechanisms by which gut microbiota is involved in the occurrence and development of AKI can provide new insights from the perspective of intestinal microbiota for the prevention and treatment of AKI.
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Lesión Renal Aguda , Microbioma Gastrointestinal , Humanos , Microbioma Gastrointestinal/fisiología , Lesión Renal Aguda/microbiología , Lesión Renal Aguda/etiología , Animales , Traslocación Bacteriana , Insuficiencia Renal Crónica/microbiología , Progresión de la EnfermedadRESUMEN
BACKGROUND: Sepsis often leads to significant morbidity and mortality due to severe myocardial injury. As is known, the activation of NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome crucially contributes to septic cardiomyopathy (SCM) by facilitating the secretion of interleukin (IL)-1ß and IL-18. The removal of palmitoyl groups from NLRP3 is a crucial step in the activation of the NLRP3 inflammasome. Thus, the potential inhibitors that regulate the palmitoylation and inactivation of NLRP3 may significantly diminish sepsis-induced cardiac dysfunction. PURPOSE: The present study sought to explore the effects of the prospective flavonoid compounds targeting NLRP3 on SCM and to elucidate the associated underlying mechanisms. STUDY DESIGN: The palmitoylation and activation of NLRP3 were detected in H9c2 cells and C57BL/6 J mice. METHODS/RESULTS: Echocardiography, histological staining, western blotting, co-immunoprecipitation, qPCR, ELISA and network pharmacology were used to assess the impact of vaccarin (VAC) on SCM in mice subjected to lipopolysaccharide (LPS) injection. From the collection of 74 compounds, we identified that VAC had the strongest capability to suppress NLRP3 luciferase report gene activity in cardiomyocytes, and the anti-inflammatory characteristics of VAC were further ascertained by the network pharmacology. Exposure of LPS triggered apoptosis, inflammation, oxidative stress, mitochondrial disorder in cardiomyocytes. The detrimental alterations were significantly reversed upon VAC treatment in both septic mice and H9c2 cells exposed to LPS. In vivo experiments demonstrated that VAC treatment alleviated septic myocardial injury, indicated by enhanced cardiac function parameters, preserved cardiac structure, and reduced inflammation/oxidative response. Mechanistically, VAC induced NLRP3 palmitoylation to inactivate NLRP3 inflammasome by acting on zDHHC12. In support, the NLRP3 agonist ATP and the acylation inhibitor 2-bromopalmitate (2-BP) prevented the effects of VAC. CONCLUSION: Our findings suggest that VAC holds promise in protecting against SCM by mitigating cardiac oxidative stress and inflammation via priming NLRP3 palmitoylation and inactivation. These results lay the solid basis for further assessment of the therapeutic potential of VAC against SCM.
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Cardiomiopatías , Inflamasomas , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR , Sepsis , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Animales , Cardiomiopatías/tratamiento farmacológico , Sepsis/tratamiento farmacológico , Sepsis/complicaciones , Ratones , Masculino , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacos , Lipoilación/efectos de los fármacos , Ratas , Estrés Oxidativo/efectos de los fármacos , Línea Celular , Lipopolisacáridos , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Interleucina-1beta/metabolismo , Interleucina-18/metabolismoRESUMEN
Cardiometabolic diseases (CMDs) are major contributors to global mortality, emphasizing the critical need for novel therapeutic interventions. Hydrogen sulfide (H2S) has garnered enormous attention as a significant gasotransmitter with various physiological, pathophysiological, and pharmacological impacts within mammalian cardiometabolic systems. In addition to its roles in attenuating oxidative stress and inflammatory response, burgeoning research emphasizes the significance of H2S in regulating proteins via persulfidation, a well known modification intricately associated with the pathogenesis of CMDs. This review seeks to investigate recent updates on the physiological actions of endogenous H2S and the pharmacological roles of various H2S donors in addressing diverse aspects of CMDs across cellular, animal, and clinical studies. Of note, advanced methodologies, including multiomics, intestinal microflora analysis, organoid, and single-cell sequencing techniques, are gaining traction due to their ability to offer comprehensive insights into biomedical research. These emerging approaches hold promise in characterizing the pharmacological roles of H2S in health and diseases. We will critically assess the current literature to clarify the roles of H2S in diseases while also delineating the opportunities and challenges they present in H2S-based pharmacotherapy for CMDs. SIGNIFICANCE STATEMENT: This comprehensive review covers recent developments in H2S biology and pharmacology in cardiometabolic diseases CMDs. Endogenous H2S and its donors show great promise for the management of CMDs by regulating numerous proteins and signaling pathways. The emergence of new technologies will considerably advance the pharmacological research and clinical translation of H2S.
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Enfermedades Cardiovasculares , Sulfuro de Hidrógeno , Sulfuro de Hidrógeno/metabolismo , Humanos , Animales , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/metabolismo , Enfermedades Metabólicas/tratamiento farmacológico , Enfermedades Metabólicas/metabolismo , Gasotransmisores/metabolismoRESUMEN
Cichoric acid (CA), a widely utilized polyphenolic compound in medicine, has garnered significant attention due to its potential health benefits. Sepsis-induced acute kidney disease (AKI) is related with an elevated risk of end-stage kidney disease (ESKD). However, it remains unclear whether CA provides protection against septic AKI. The aim of this study is to investigated the protective effect and possible mechanisms of CA against LPS-induced septic AKI. Sepsis-induced AKI was induced in mice through intraperitoneal injection of lipopolysaccharide (LPS), and RAW264.7 macrophages were incubated with LPS. LPS exposure significantly increased the levels of M1 macrophage biomarkers while reducing the levels of M2 macrophage indicators. This was accompanied by the release of inflammatory factors, superoxide anion production, mitochondrial dysfunction, activation of succinate dehydrogenase (SDH), and subsequent succinate formation. Conversely, pretreatment with CA mitigated these abnormalities. CA attenuated hypoxia-inducible factor-1α (HIF-1α)-induced glycolysis by lifting the NAD+/NADH ratio in macrophages. Additionally, CA disrupted the K (lysine) acetyltransferase 2A (KAT2A)/α-tubulin complex, thereby reducing α-tubulin acetylation and subsequently inactivating the NLRP3 inflammasome. Importantly, administration of CA ameliorated LPS-induced renal pathological damage, apoptosis, inflammation, oxidative stress, and disturbances in mitochondrial function in mice. Overall, CA restrained HIF-1α-mediated glycolysis via inactivation of SDH, leading to NLRP3 inflammasome inactivation and the amelioration of sepsis-induced AKI.
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Lesión Renal Aguda , Ácidos Cafeicos , Lipopolisacáridos , Macrófagos , Proteína con Dominio Pirina 3 de la Familia NLR , Sepsis , Succinatos , Animales , Sepsis/complicaciones , Sepsis/tratamiento farmacológico , Ratones , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/etiología , Lesión Renal Aguda/patología , Masculino , Succinatos/farmacología , Succinatos/uso terapéutico , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ácidos Cafeicos/farmacología , Ácidos Cafeicos/uso terapéutico , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Células RAW 264.7 , Estrés Oxidativo/efectos de los fármacos , Inflamasomas/metabolismo , Ratones Endogámicos C57BL , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Glucólisis/efectos de los fármacos , Apoptosis/efectos de los fármacos , Riñón/patología , Riñón/efectos de los fármacos , Riñón/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Activación de Macrófagos/efectos de los fármacosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: The Tibetan medicine Ganlu Formula, as a classic prescription, is widely used across the Qinghai-Tibet Plateau area of China, which has a significant effect on relieving the course of rheumatoid arthritis (RA). However, the active compounds and underlying mechanisms of Ganlu Formula in RA treatment remain largely unexplored. AIM OF THE STUDY: This study aimed to elucidate the active substances and potential mechanisms of the ethyl acetate extract of Ganlu Formula ethyl acetate extract (GLEE) in the treatment of RA. MATERIALS AND METHODS: Ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) was utilized to analyze and identify the chemical constituents within GLEE. Discovery Studio molecular virtual docking technology was utilized to dock the interaction of GLEE with inflammation-related pathway proteins. The GLEE gene library was obtained by transcriptome sequencing. Collagen-induced arthriticï¼CIA) rats were utilized to assess the antiarthritic efficacy of GLEE. Micro-CT imaging was employed to visualize the rat paw, and ultrasound imaging revealed knee joint effusion. Evaluation of synovial tissue pathological changes was conducted through hematoxylin-eosin staining and saffranine solid green staining, while immunohistochemical staining was employed to assess NLRP3 expression along with inflammatory markers. Immunofluorescence staining was utilized to identify M1 macrophages. RESULTS: Metabolomic analysis via UPLC-Q-TOF-MS identified 28 potentially bioactive compounds in GLEE, which interacted with the active sites of key proteins such as NLRP3, NF-κB, and STAT3 through hydrogen bonds, C-H bonds, and electrostatic attractions. In vitro analyses demonstrated that GLEE significantly attenuated NLRP3 inflammasome activation and inhibited the polarization of bone marrow-derived macrophages (BMDMs) towards the M1 phenotype. In vivo, GLEE not only prevented bone mineral density (BMD) loss but also reduced ankle swelling in CIA rats. Furthermore, it decreased the expression of the NLRP3 inflammasome and curtailed the release of inflammatory mediators within the knee joint. CONCLUSION: GLEE effectively mitigated inflammatory responses in both blood and knee synovial membranes of CIA rats, potentially through the down-regulation of the NLRP3/Caspase-1/IL-1ß signaling pathway and reduction in M1 macrophage polarization.
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Artritis Experimental , Macrófagos , Proteína con Dominio Pirina 3 de la Familia NLR , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/patología , Ratas , Masculino , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/química , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Simulación del Acoplamiento Molecular , Antiinflamatorios/farmacología , Antiinflamatorios/química , Artritis Reumatoide/tratamiento farmacológico , Ratas Sprague-Dawley , Ratones , Antirreumáticos/farmacología , Antirreumáticos/aislamiento & purificación , Antirreumáticos/química , AcetatosRESUMEN
BACKGROUND: Neutral cholesterol ester hydrolase 1 (NCEH1) plays a critical role in the regulation of cholesterol ester metabolism. Deficiency of NCHE1 accelerated atherosclerotic lesion formation in mice. Nonetheless, the role of NCEH1 in endothelial dysfunction associated with diabetes has not been explored. The present study sought to investigate whether NCEH1 improved endothelial function in diabetes, and the underlying mechanisms were explored. METHODS: The expression and activity of NCEH1 were determined in obese mice with high-fat diet (HFD) feeding, high glucose (HG)-induced mouse aortae or primary endothelial cells (ECs). Endothelium-dependent relaxation (EDR) in aortae response to acetylcholine (Ach) was measured. RESULTS: Results showed that the expression and activity of NCEH1 were lower in HFD-induced mouse aortae, HG-exposed mouse aortae ex vivo, and HG-incubated primary ECs. HG exposure reduced EDR in mouse aortae, which was exaggerated by endothelial-specific deficiency of NCEH1, whereas NCEH1 overexpression restored the impaired EDR. Similar results were observed in HFD mice. Mechanically, NCEH1 ameliorated the disrupted EDR by dissociating endothelial nitric oxide synthase (eNOS) from caveolin-1 (Cav-1), leading to eNOS activation and nitric oxide (NO) release. Moreover, interaction of NCEH1 with the E3 ubiquitin-protein ligase ZNRF1 led to the degradation of Cav-1 through the ubiquitination pathway. Silencing Cav-1 and upregulating ZNRF1 were sufficient to improve EDR of diabetic aortas, while overexpression of Cav-1 and downregulation of ZNRF1 abolished the effects of NCEH1 on endothelial function in diabetes. Thus, NCEH1 preserves endothelial function through increasing NO bioavailability secondary to the disruption of the Cav-1/eNOS complex in the endothelium of diabetic mice, depending on ZNRF1-induced ubiquitination of Cav-1. CONCLUSIONS: NCEH1 may be a promising candidate for the prevention and treatment of vascular complications of diabetes.
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Caveolina 1 , Dieta Alta en Grasa , Células Endoteliales , Endotelio Vascular , Ratones Endogámicos C57BL , Óxido Nítrico Sintasa de Tipo III , Vasodilatación , Animales , Masculino , Ratones , Aorta/enzimología , Aorta/fisiopatología , Aorta/metabolismo , Aorta/efectos de los fármacos , Aorta/patología , Caveolina 1/metabolismo , Caveolina 1/deficiencia , Caveolina 1/genética , Células Cultivadas , Diabetes Mellitus Experimental/enzimología , Diabetes Mellitus Experimental/fisiopatología , Células Endoteliales/enzimología , Células Endoteliales/metabolismo , Células Endoteliales/efectos de los fármacos , Endotelio Vascular/fisiopatología , Endotelio Vascular/metabolismo , Endotelio Vascular/enzimología , Endotelio Vascular/efectos de los fármacos , Ratones Noqueados , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Obesidad/enzimología , Obesidad/fisiopatología , Obesidad/metabolismo , Transducción de Señal , Esterol Esterasa/metabolismo , Esterol Esterasa/genética , Ubiquitinación , Vasodilatación/efectos de los fármacosRESUMEN
BACKGROUND: Myricetin, a type of flavonol commonly found in fruits and herbs, has demonstrated anticancer properties by triggering the process of apoptosis or programmed cell death in tumor cells. Despite the absence of mitochondria and nuclei, erythrocytes can undergo programmed cell death, also known as eryptosis.This process is characterized by cell shrinkage, externalization of phosphatidylserine (PS) on the cell membrane, and the formation of membrane blebs. The signaling of eryptosis involves Ca2+ influx, the formation of reactive oxygen species (ROS), and the accumulation of cell surface ceramide. The present study explored the effects of myricetin on eryptosis. METHODS AND RESULTS: Human erythrocytes were exposed to various concentrations of myricetin (2-8 µM) for 24 h. Flow cytometry was used to assess the markers of eryptosis, including PS exposure, cellular volume, cytosolic Ca2+ concentration, and ceramide accumulation. In addition, the levels of intracellular ROS were measured using the 2',7'-dichlorofluorescin diacetate (DCFDA) assay. The myricetin-treated (8 µM) erythrocytes significantly increased Annexin-positive cells, Fluo-3 fluorescence intensity, DCF fluorescence intensity, and the accumulation of ceramide. The impact of myricetin on the binding of annexin-V was significantly reduced, but not completely eliminated, by the nominal removal of extracellular Ca2+. CONCLUSION: Myricetin triggers eryptosis, which is accompanied and, at least in part, caused by Ca2+ influx, oxidative stress and increase of ceramide abundance.
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Eriptosis , Humanos , Especies Reactivas de Oxígeno/metabolismo , Estrés Oxidativo , Eritrocitos/metabolismo , Ceramidas , Anexinas/metabolismo , Anexinas/farmacología , Calcio/metabolismo , Fosfatidilserinas/metabolismo , Fosfatidilserinas/farmacología , Tamaño de la Célula , HemólisisRESUMEN
BACKGROUND/AIMS: Vasopressin is a powerful stimulator of vascular calcification, augmenting osteogenic signaling in vascular smooth muscle cells (VSMCs) including upregulation of transcription factors such as core-binding factor α-1 (CBFA1), msh homeobox 2 (MSX2), and SRY-Box 9 (SOX9), as well as of tissue-nonspecific alkaline phosphatase (ALPL). Vasopressin-induced osteogenic signaling and calcification require the serum- and glucocorticoid-inducible kinase 1 (SGK1). Known effects of SGK1 include upregulation of Na+/H+ exchanger 1 (NHE1). NHE1 further participates in the regulation of reactive oxygen species (ROS). NHE1 has been shown to participate in the orchestration of bone mineralization. The present study, thus, explored whether vasopressin modifies NHE1 expression and ROS generation, as well as whether pharmacological inhibition of NHE1 disrupts vasopressin-induced osteogenic signaling and calcification in VSMCs. METHODS: Human aortic smooth muscle cells (HAoSMCs) were treated with vasopressin in the absence or presence of SGK1 silencing, SGK1 inhibitor GSK-650394, and NHE1 blocker cariporide. Transcript levels were determined by using quantitative real-time polymerase chain reaction, protein abundance by Western blotting, ROS generation with 2',7'-dichlorofluorescein diacetate fluorescence, and ALP activity and calcium content by using colorimetric assays. RESULTS: Vasopressin significantly enhanced the NHE1 transcript and protein levels in HAoSMCs, effects significantly blunted by SGK1 inhibition with GSK-650394 or SGK1 silencing. Vasopressin increased ROS accumulation, an effect significantly blocked by the NHE1 inhibitor cariporide. Vasopressin further significantly increased osteogenic markers CBFA1, MSX2, SOX9, and ALPL transcript levels, as well as ALP activity and calcium content in HAoSMCs, all effects significantly blunted by SGK1 silencing or in the presence of GSK-650394 or cariporide. CONCLUSION: Vasopressin stimulates NHE1 expression and ROS generation, an effect dependent on SGK1 and required for vasopressin-induced stimulation of osteogenic signaling and calcification of VSMCs.
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Calcificación Fisiológica , Calcificación Vascular , Calcio/metabolismo , Células Cultivadas , Humanos , Miocitos del Músculo Liso , Especies Reactivas de Oxígeno/metabolismo , Intercambiador 1 de Sodio-Hidrógeno , Calcificación Vascular/metabolismo , Vasopresinas/metabolismoRESUMEN
In chronic kidney disease, hyperphosphatemia upregulates the Ca2+ channel ORAI and its activating Ca2+ sensor STIM in megakaryocytes and platelets. ORAI1 and STIM1 accomplish store-operated Ca2+ entry (SOCE) and play a key role in platelet activation. Signaling linking phosphate to upregulation of ORAI1 and STIM1 includes transcription factor NFAT5 and serum and glucocorticoid-inducible kinase SGK1. In vascular smooth muscle cells, the effect of hyperphosphatemia on ORAI1/STIM1 expression and SOCE is suppressed by Mg2+ and the calcium-sensing receptor (CaSR) agonist Gd3+. The present study explored whether sustained exposure to Mg2+ or Gd3+ interferes with the phosphate-induced upregulation of NFAT5, SGK1, ORAI1,2,3, STIM1,2 and SOCE in megakaryocytes. To this end, human megakaryocytic Meg-01 cells were treated with 2 mM ß-glycerophosphate for 24 h in the absence and presence of either 1.5 mM MgCl2 or 50 µM GdCl3. Transcript levels were estimated utilizing q-RT-PCR, protein abundance by Western blotting, cytosolic Ca2+ concentration ([Ca2+]i) by Fura-2 fluorescence and SOCE from the increase in [Ca2+]i following re-addition of extracellular Ca2+ after store depletion with thapsigargin (1 µM). As a result, Mg2+ and Gd3+ upregulated CaSR and blunted or virtually abolished the phosphate-induced upregulation of NFAT5, SGK1, ORAI1,2,3, STIM1,2 and SOCE in megakaryocytes. In conclusion, Mg2+ and the CaSR agonist Gd3+ interfere with phosphate-induced dysregulation of [Ca2+]i in megakaryocytes.
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Señalización del Calcio , Gadolinio/farmacología , Cloruro de Magnesio/farmacología , Megacariocitos/efectos de los fármacos , Proteína ORAI1/metabolismo , Células Cultivadas , Humanos , Proteínas Inmediatas-Precoces/genética , Proteínas Inmediatas-Precoces/metabolismo , Megacariocitos/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteína ORAI1/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Molécula de Interacción Estromal 1/genética , Molécula de Interacción Estromal 1/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND: The stigma of tuberculosis (TB) poses a significant challenge to TB control because it leads to delayed diagnosis and non-adherence. However, few studies on TB-related stigma have been completed in China. The aim of the current study was to explore the status of TB-related stigma and its associated predictive factors among TB patients in Dalian, Northeast China. METHODS: An institution-based, cross-sectional survey was conducted among outpatients at Dalian Tuberculosis Hospital in Liaoning Province, Northeast China. Data were collected by using a questionnaire that measured TB-related stigma, treatment status, anxiety, social support, doctor-patient communication and so on. A multiple linear regression model was used to determine the predictors of TB-related stigma. RESULTS: A total of 601 eligible participants were recruited. The mean score for TB-related stigma was 9.07, and the median score was 10. The average scores for anxiety, social support and doctor-patient communication were 4.03, 25.41 and 17.17, respectively. Multiple linear regression analysis revealed that patients who were female (ß = 1.19, 95% CI: 0.38-2.01, P < 0.05), had self-assessed moderate or severe disease (ß = 1.08, 95% CI: 0.12-2.03 and ß = 1.36, 95% CI: 0.03-2.70, respectively, P < 0.05), and had anxiety (ß = 0.38, 95% CI: 0.30-0.46, P < 0.001) were more likely to have a greater level of TB-related stigma than their counterparts. However, a significantly lower level of TB-related stigma was observed in patients with good social support (ß = - 0.25, 95% CI: - 0.33--0.17, P < 0.001) and doctor-patient communication (ß = - 0.14, 95% CI: - 0.29--0.00, P < 0.05). CONCLUSIONS: This study showed that stigma among TB patients was high. Targeted attention should be paid to female patients and patients with moderate or severe disease in TB stigma-related interventions. Moreover, the important role of social support and doctor-patient communication in reducing TB-related stigma should also be emphasized.
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Estigma Social , Tuberculosis , China/epidemiología , Estudios Transversales , Femenino , Humanos , Masculino , Apoyo Social , Encuestas y Cuestionarios , Tuberculosis/epidemiologíaRESUMEN
Vascular calcification may result from stimulation of osteogenic signalling with upregulation of the transcription factors CBFA1, MSX2 and SOX9, as well as alkaline phosphatase (ALPL), which degrades and thus inactivates the calcification inhibitor pyrophosphate. Osteogenic signalling further involves upregulation of the Ca2+-channel ORAI1. The channel is activated by STIM1 and then accomplishes store-operated Ca2+ entry. ORAI1 and STIM1 are upregulated by the serum & glucocorticoid inducible kinase 1 (SGK1) which is critically important for osteogenic signalling. Stimulators of vascular calcification include vasopressin. The present study explored whether exposure of human aortic smooth muscle cells (HAoSMCs) to vasopressin upregulates ORAI1 and/or STIM1 expression, store-operated Ca2+ entry and osteogenic signalling. To this end, HAoSMCs were exposed to vasopressin (100 nM, 24 h) without or with additional exposure to ORAI1 blocker MRS1845 (10 µM) or SGK1 inhibitor GSK-650394 (1 µM). Transcript levels were measured using q-RT-PCR, cytosolic Ca2+-concentration ([Ca2+]i) by Fura-2-fluorescence, and store-operated Ca2+ entry from increase of [Ca2+]i following re-addition of extracellular Ca2+ after store depletion with thapsigargin (1 µM). As a result, vasopressin enhanced the transcript levels of ORAI1 and STIM1, store-operated Ca2+ entry, as well as the transcript levels of CBFA1, MSX2, SOX9 and ALPL. The effect of vasopressin on store-operated Ca2+ entry as well as on transcript levels of CBFA1, MSX2, SOX9 and ALPL was virtually abrogated by MRS1845 and GSK-650394. In conclusion, vasopressin stimulates expression of ORAI1/STIM1, thus augmenting store-operated Ca2+ entry and osteogenic signalling. In HAoSMCs, vasopressin (VP) upregulates Ca2+ channel ORAI1 and its activator STIM1. VP upregulates store-operated Ca2+ entry (SOCE) and osteogenic signalling (OS). VP-induced SOCE, OS and Ca2+-deposition are disrupted by ORAI1 inhibitor MRS1845. VP-induced SOCE, OS and Ca2+-deposition are disrupted by SGK1 blocker GSK-650394. KEY MESSAGES: ⢠In HAoSMCs, vasopressin (VP) upregulates Ca2+ channel ORAI1 and its activator STIM1. ⢠VP upregulates store-operated Ca2+ entry (SOCE) and osteogenic signalling (OS). ⢠VP-induced SOCE, OS and Ca2+-deposition are disrupted by ORAI1 inhibitor MRS1845. ⢠VP-induced SOCE, OS and Ca2+-deposition are disrupted by SGK1 blocker GSK-650394.
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Señalización del Calcio/efectos de los fármacos , Músculo Liso Vascular/citología , Miocitos del Músculo Liso/efectos de los fármacos , Proteína ORAI1/biosíntesis , Calcificación Vascular/metabolismo , Vasopresinas/farmacología , Aorta/citología , Benzoatos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Señalización del Calcio/fisiología , Células Cultivadas , Evaluación Preclínica de Medicamentos , Humanos , Proteínas Inmediatas-Precoces/antagonistas & inhibidores , Proteínas Inmediatas-Precoces/fisiología , Miocitos del Músculo Liso/metabolismo , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/fisiología , Nitrendipino/análogos & derivados , Nitrendipino/farmacología , Proteína ORAI1/antagonistas & inhibidores , Proteína ORAI1/genética , Osteogénesis/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/fisiología , Molécula de Interacción Estromal 1/biosíntesis , Molécula de Interacción Estromal 1/genética , Molécula de Interacción Estromal 1/fisiología , Transcripción Genética/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Calcificación Vascular/prevención & controlRESUMEN
A photosensitizer with high phototoxicity, suitable amphipathy and low dark toxicity could play a pivotal role in photodynamic therapy (PDT). In this study, a facile and versatile approach was adopted to synthesize a series of novel fluorinated hematoporphyrin ether derivatives (I1-I5 and II1-II4), and the photodynamic activities of these compounds were studied. Compared to hematoporphyrin monomethyl ether (HMME), all PSs showed preferable photodynamic activity against A549 lung tumor cells. The longest visible absorption wavelength of these compounds was approximately 622 nm. Among them, II3 revealed the highest singlet oxygen yield (0.0957 min-1), the strongest phototoxicity (IC50 = 1.24 µM), the lowest dark toxicity in vitro, and exhibited excellent anti-tumor effects in vivo. So compound II3 could act as new drug candidate for photodynamic therapy.
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Antineoplásicos/uso terapéutico , Éteres/uso terapéutico , Hematoporfirinas/uso terapéutico , Hidrocarburos Fluorados/uso terapéutico , Neoplasias/tratamiento farmacológico , Fármacos Fotosensibilizantes/uso terapéutico , Células A549 , Animales , Antineoplásicos/síntesis química , Antineoplásicos/efectos de la radiación , Teoría Funcional de la Densidad , Éteres/síntesis química , Éteres/efectos de la radiación , Femenino , Hematoporfirinas/síntesis química , Hematoporfirinas/efectos de la radiación , Humanos , Hidrocarburos Fluorados/síntesis química , Hidrocarburos Fluorados/efectos de la radiación , Luz , Ratones Endogámicos BALB C , Ratones Desnudos , Modelos Químicos , Neoplasias/patología , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/efectos de la radiación , Oxígeno Singlete/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Doctor-patient trust is not strong in China, but studies examining this factor remain insufficient. The present study aimed to explore the effect of doctor-patient communication, medical service quality, and service satisfaction on patient trust in doctors. Five hundred sixty-four patients with tuberculosis participated in this cross-sectional study in Dalian, China. They completed questionnaires assessing socio-demographic characteristics, doctor-patient communication, medical service quality, service satisfaction and patient trust in medical staff. A structural equation model was applied to examine the hypotheses, and all the study hypotheses were supported: (1) doctor-patient communication, medical service quality and service satisfaction were positively associated with building doctor-patient trust; (2) service quality positively mediated the relationship between doctor-patient communication and trust; (3) medical service satisfaction positively mediated the relationship between doctor-patient communication and trust; (4) medical service satisfaction positively mediated the relationship between medical service quality and doctor-patient trust; and (5) medical service quality and service satisfaction were the positively sequential mediators between communication and doctor-patient trust. Based on these findings, improvements in doctor-patient communication, medical service quality, and service satisfaction are the important issues contributing to the rebuilding of doctor-patient trust in medical service delivery.
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Atención a la Salud/organización & administración , Relaciones Médico-Paciente , Confianza , Adulto , China , Femenino , Hospitales Rurales/organización & administración , Hospitales Urbanos/organización & administración , Humanos , Masculino , Persona de Mediana Edad , Satisfacción del Paciente , Encuestas y Cuestionarios , Adulto JovenRESUMEN
OBJECTIVES: The aim of this study was to analyse the status regarding inequities in adult obesity and central obesity in China. Thus, income-related inequality for both diseases and the underlying factors were examined. METHODS AND DESIGN: The China Health and Nutrition Survey (CHNS)-conducted from 1997 to 2011-included 128 307 participants; in this study, 79 566 individuals classified as obese and 65 250 regarded as suffering from central obesity according to the CHNS were analysed. A body mass index greater than 27 was considered indicative of obesity; men and women with a waist circumference of more than 102 cm and 80 cm, respectively, were considered as suffering from central obesity. The concentration index was employed to analyse inequality in adult obesity and central obesity. The decomposition of this index based on a probit model was used to calculate the horizontal inequality index. RESULTS: The prevalence of adult obesity increased from 8.34% in 1997 to 17.74% in 2011, and that of central obesity increased from 6.52% in 1997 to 16.79% in 2011. The horizontal inequality index for adult obesity decreased from 0.1377 in 1997 to 0.0164 in 2011; for central obesity, it decreased from 0.0806 in 1997 to -0.0193 in 2011. The main causes of inequality for both diseases are, among others, economic status, marital status and educational attainment. CONCLUSIONS: From 1997 to 2011, the prevalence of adult obesity and central obesity increased annually. The pro-rich inequalities in both adult and central obesity decreased from 1997 to 2011. The inequality in central obesity was more prominent in the low-income group in 2011. Future policies may need to address obesity reduction among the poor.
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Obesidad Abdominal , Adulto , China/epidemiología , Femenino , Disparidades en el Estado de Salud , Humanos , Renta , Masculino , Encuestas Nutricionales , Obesidad/epidemiología , Obesidad Abdominal/epidemiología , Factores SocioeconómicosRESUMEN
BACKGROUND: Non-adherence to tuberculosis (TB) treatment is the most important cause of poor TB outcomes, and improving support for TB patients is a primary priority for governments, but there has been little research on the effects of family, social and national policy support factors on TB treatment adherence. The current study evaluated treatment adherence among newly diagnosed TB patients in Dalian, north-eastern China, and determined the effects of family, society, and national policy support factors on treatment adherence. METHODS: A cross-sectional survey was conducted among newly diagnosed TB patients treated at the outpatient department of Dalian Tuberculosis Hospital from September 2019 to January 2020. Data were collected using a questionnaire that measured medication adherence, family support, social support, and national policy support and so on. Differences between groups were assessed using Chi-square tests and Fisher's exact tests. Ordinal logistic regression analysis was used to determine the predictors of adherence. RESULTS: A total of 481 newly diagnosed TB patients were recruited, of whom 45.7% had good adherence, and 27.4 and 26.8% had moderate and low adherence, respectively. Patients who had family members who frequently supervised medication (OR:0.34, 95% CI:0.16-0.70), family members who often provided spiritual encouragement (OR:0.13, 95% CI:0.02-0.72), a good doctor-patient relationship (OR:0.61, 95% CI:0.40-0.93), more TB-related knowledge (OR:0.49, 95% CI:0.33-0.72) and a high need for TB treatment policy support (OR:0.38, 95% CI:0.22-0.66) had satisfactory medication adherence. However, patients who had a college degree or higher (OR:1.69, 95% CI:1.04-2.74) and who suffered adverse drug reactions (OR:1.45, 95% CI:1.00-2.11) were more likely to have lower adherence. CONCLUSIONS: Our findings suggested that non-adherence was high in newly diagnosed TB patients. Patients who had family members who frequently supervised medication and provided spiritual encouragement and a good doctor-patient relationship and TB-related knowledge and a high need for policy support contributed to high adherence. It is recommended to strengthen medical staff training and patient and family health education and to increase financial support for improving adherence.
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Política de Salud , Cumplimiento de la Medicación , Tuberculosis/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antituberculosos/efectos adversos , Antituberculosos/uso terapéutico , China , Estudios Transversales , Familia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Relaciones Médico-Paciente , Apoyo Social , Factores Socioeconómicos , Encuestas y Cuestionarios , Adulto JovenRESUMEN
PURPOSE: Medication adherence is crucial for decreasing the burden of tuberculosis, but few relevant studies have been conducted in northeast China. This study aimed to explore the level of medication adherence among pulmonary tuberculosis outpatients and the predictive factors based on the bio-psycho-social medical model. PATIENTS AND METHODS: A cross-sectional multi-center survey was conducted in four tuberculosis medical institutions in Dalian, northeast China. Medication adherence was measured using the eight-item Chinese version of the Morisky Medication Adherence Scale, which divides adherence into three levels. The independent variables consisted of sociodemographic characteristics, treatment factors, knowledge about TB, mental health, and behavioral characteristics. Descriptive statistics, the chi-square test, and multivariate ordinal logistic regression were applied to analyze the data using Stata/MP 14.0. RESULTS: Among the 564 eligible participants, 236 (41.84%) and 183 (32.45%) exhibited high and medium medication adherence, respectively, but 145 (25.71%) exhibited low medication adherence. Multivariate ordinal logistic regression showed that patients who were older (OR: 1.02, p=0.013) were employed (OR: 1.61, p=0.011), had better tuberculosis knowledge (OR: 1.34, p<0.001), and did not consume alcohol (OR: 1.84, p=0.032) exhibited higher medication adherence. However, patients who did not follow their doctors' advice to take adjuvant drugs (OR: 0.44, p=0.001), had a history of TB treatment (OR: 1.76, p=0.009), experienced adverse drug reactions (OR: 0.65, p=0.017), experienced stigma (OR: 0.67, p=0.032), and needed supervised treatment (OR: 0.66, p=0.012) exhibited lower medication adherence. CONCLUSION: Tuberculosis patients' medication adherence was not very high and it was influenced by diverse and complex factors involving sociodemographic characteristics, treatment factors, knowledge about TB, mental health, and behavioral characteristics.
RESUMEN
Diabetes and chronic kidney disease (CKD) both trigger vascular osteogenic signaling and calcification leading to early death by cardiovascular events. Osteogenic signaling involves upregulation of the transcription factors CBFA1, MSX2, and SOX9, as well as alkaline phosphatase (ALP), an enzyme fostering calcification by degrading the calcification inhibitor pyrophosphate. In CKD, osteogenic signaling is triggered by hyperphosphatemia, which upregulates the serum and glucocorticoid-inducible kinase SGK1, a strong stimulator of the Ca2+-channel ORAI1. The channel is activated by STIM1 and accomplishes store-operated Ca2+-entry (SOCE). The present study explored whether exposure of human aortic smooth muscle cells (HAoSMCs) to high extracellular glucose concentrations similarly upregulates ORAI1 and/or STIM1 expression, SOCE, and osteogenic signaling. To this end, HAoSMCs were exposed to high extracellular glucose concentrations (15 mM, 24 h) without or with additional exposure to the phosphate donor ß-glycerophosphate. Transcript levels were estimated using qRT-PCR, protein abundance using Western blotting, ALP activity using a colorimetric assay kit, calcium deposits utilizing Alizarin red staining, cytosolic Ca2+-concentration ([Ca2+]i) by Fura-2-fluorescence, and SOCE from increase of [Ca2+]i following re-addition of extracellular Ca2+ after store depletion with thapsigargin (1 µM). As a result, glucose enhanced the transcript levels of SGK1 and ORAI1, ORAI2, and STIM2, protein abundance of ORAI1, SOCE, the transcript levels of CBFA1, MSX2, SOX9, and ALPL, as well as calcium deposits. Moreover, glucose significantly augmented the stimulating effect of ß-glycerophosphate on transcript levels of SGK1 and ORAI1, SOCE, the transcript levels of osteogenic markers, as well as calcium deposits. ORAI1 inhibitor MRS1845 (10 µM) significantly blunted the glucose-induced upregulation of the CBFA1 and MSX2 transcript levels. In conclusion, the hyperglycemia of diabetes stimulates expression of SGK1 and ORAI1, thus, augmenting store-operated Ca2+-entry and osteogenic signaling in HAoSMCs.
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Aorta/metabolismo , Calcio/metabolismo , Glucosa/metabolismo , Miocitos del Músculo Liso/metabolismo , Proteína ORAI1/metabolismo , Osteogénesis/fisiología , Transducción de Señal/fisiología , Biomarcadores/metabolismo , Células Cultivadas , Diabetes Mellitus/metabolismo , Humanos , Hiperglucemia/metabolismo , Regulación hacia Arriba/fisiologíaRESUMEN
In chronic kidney disease, renal phosphate retention leads to hyperphosphatemia with subsequent vascular osteogenic signaling and calcification. Osteogenic signaling involves up-regulation of the transcription factors CBFA1, MSX2, and SOX9, as well as alkaline phosphatase (ALP), an enzyme stimulating calcification by degrading the calcification inhibitor pyrophosphate. Stimulation of osteogenic signaling and calcification by phosphate donor ß-glycerophosphate in human aortic smooth muscle cells (HAoSMCs) is attenuated by MgCl2, an effect mimicked by Ca2+-sensing receptor agonist GdCl3. Most recent observations revealed that the effect of ß-glycerophosphate on osteogenic signaling requires ORAI1, a Ca2+-channel accomplishing store-operated Ca2+-entry (SOCE), which is stimulated by Ca2+-sensor STIM1. The present study explored whether ORAI1 and/or STIM1 expression and, thus, SOCE and osteogenic signaling in HAoSMCs are sensitive to MgCl2 and/or GdCl3. To this end, transcript levels were estimated using q-RT-PCR, protein abundance with western blotting, cytosolic Ca2+-concentration ([Ca2+]i) by Fura-2-fluorescence, and SOCE from increase of [Ca2+]i following re-addition of extracellular Ca2+ after store depletion with thapsigargin (1â¯â¯µM). As a result, 24â¯h exposure to ß-glycerophosphate (2â¯mM) significantly enhanced transcript levels of ORAI1 and STIM1 as well as SOCE, effects significantly blunted or virtually abrogated by 1.5â¯mM MgCl2 and by 50â¯â¯µM GdCl3. In conclusion, MgCl2 and GdCl3 are powerful inhibitors of ORAI1 and STIM1 expression and store-operated Ca2+-entry, effects affecting osteogenic signalling in vascular smooth muscle cells.