RESUMEN
Diabetic coronary artery injury is closely associated with Ca2+ dysregulation, although the underlying mechanism remains unclear. This study explored the role and mechanism of Ca2+ handling in coronary artery dysfunction in type 2 diabetic rats. Zucker diabetic fatty (ZDF) rats were used as the type 2 diabetes mellitus model. The contractility of coronary artery rings induced by KCl, CaCl2 , 5-HT and U46619 was significantly lower in ZDF rats than in Zucker lean rats. Vasoconstriction induced by 5-HT and U46619 was greatly inhibited by nifedipine. However, in the presence of 1 µM nifedipine or in the Ca2+ -free KH solution containing 1 µM nifedipine, there was no difference in the vasoconstriction between Zucker lean and ZDF rats. Store-operated calcium channels (SOCs) were not involved in coronary vasoconstriction. The downregulation of contractile proteins and the upregulation of synthesized proteins were in coronary artery smooth muscle cells (CASMCs) from ZDF rats. Metformin reversed the reduction of vasoconstriction in ZDF rats. Taken together, L-type calcium channel is important for regulating the excitation-contraction coupling of VSMCs in coronary arteries, and dysregulation of this channel contributes to the decreased contractility of coronary arteries in T2DM.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Ratas , Animales , Vasos Coronarios/metabolismo , Calcio/metabolismo , Ratas Zucker , Diabetes Mellitus Tipo 2/metabolismo , Nifedipino , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacología , Diabetes Mellitus Experimental/metabolismo , Serotonina/metabolismo , Canales de Calcio Tipo L/metabolismoRESUMEN
In the practice of forensic pathology, fat embolism is one of the common causes of death, which can be divided into two categories: traumatic and non-traumatic. Non-traumatic fat embolism refers to the blockage of small blood vessels by fat droplets in the circulatory blood flow caused by non-traumatic factors such as underlying diseases, stress, poisoning and lipid metabolism disorders. At present, it is believed that the production of non-traumatic fat embolism is related to the disturbance of lipid metabolism, C-reactive protein-related cascade reaction, the agglutination of chylomicron and very low-density lipoprotein. The forensic identification of the cause of death of non-traumatic fat embolism is mainly based on the case, systematic autopsy, HE staining and fat staining, but it is often missed or misdiagnosed by forensic examiners because of its unknown risk factors, hidden onset, the difficulty of HE staining observation and irregular implementation of fat staining. In view of the lack of attention to non-traumatic fat embolism in forensic identification, this paper reviews the concepts, pathophysiological mechanism, research progress, existing problems and countermeasures of non-traumatic fat embolism, providing reference for forensic scholars.
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Embolia Grasa , Embolia Pulmonar , Autopsia , Embolia Grasa/diagnóstico , Embolia Grasa/etiología , Embolia Grasa/patología , Medicina Legal , Patologia Forense , Humanos , Embolia Pulmonar/complicaciones , Embolia Pulmonar/patologíaRESUMEN
Constitutive activation of Hedgehog (Hh) pathway is intimately related with the occurrence and development of several malignancies, such as medulloblastoma (MB) and other tumors. Therefore, small molecular inhibitors of Hh pathway are urgently needed. In this study, three new steroidal alkaloids, â¿5 (20R, 24R) 23-oxo-24-methylsolacongetidine, â¿5 (20S, 24R) 23-oxo-24-methylsolacongetidine and veralinine 3-O-α-l-rhamnopyranosyl-(1 â 2)-ß-D-glucopyranoside, together with six known alkaloids, 20-epi-verazine, verazine, protoverine 15-(l)-2'-methylbutyrate, jervine, veramarine and ß1-chaconine, were isolated and determined from Veratrum grandiflorum Loes. The dual-luciferase bioassay indicated that all compounds exhibited significant inhibitions of Hh pathway with IC50 values of 0.72-14.31 µM against Shh-LIGHT 2 cells. To determine whether these Hh pathway inhibitors act with the Smoothened (Smo) protein, which is an important oncoprotein and target for this pathway, BODIPY-cyclopamine (BC) competitive binding assay was preferentially performed. Compared with BC alone, all compounds obviously reduced the fluorescence intensities of BC binding with Smo in Smo-overexpression HEK293T cells through fluorescence microscope and flow cytometer. By directly interacting with Smo, it revealed that they were actually novel natural Smo inhibitors. Then, their anti-tumor effects were investigated against the human MB cell line DAOY, which is a typical pediatric brain tumor cells line with highly expressed Hh pathway. Interestingly, most of compounds had slight proliferation inhibitions on DAOY cells after treatment for 24 h same as vismodegib, while ß1-chaconine showed the strongest inhibitory effect on the growth of DAOY with IC50 value of 5.35 µM. In conclusion, our studies valuably provide several novel natural Smo inhibitors for potential targeting treatment of Hh-dependent tumors.
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Alcaloides/aislamiento & purificación , Alcaloides/farmacología , Proliferación Celular/efectos de los fármacos , Meduloblastoma/patología , Receptor Smoothened/antagonistas & inhibidores , Esteroides/química , Veratrum/química , Alcaloides/química , Línea Celular Tumoral , Células HEK293 , Humanos , Estructura Molecular , Análisis Espectral/métodosRESUMEN
Hypertension is an independent risk factor for atrial fibrillation (AF), although its specific mechanisms remain unclear. Previous research has been focused on cyclic stretch, ignoring the role of high hydrostatic pressure. The present study aimed to explore the effect of high hydrostatic pressure stimulation on electrical remodeling in atrial myocytes and its potential signaling pathways. Experiments were performed on left atrial appendages from patients with chronic AF or sinus rhythm, spontaneously hypertensive rats (SHRs) treated with or without valsartan (10 mg/kg/day) and HL-1 cells were exposed to high hydrostatic pressure using a self-developed device. Whole-cell patch-clamp recordings and western blots demonstrated that the amplitudes of ICa,L, Ito, and IKur were reduced in AF patients with corresponding changes in protein expression. Angiotensin protein levels increased and Ang1-7 decreased, while focal adhesion kinase (FAK) and Src kinase were enhanced in atrial tissue from AF patients and SHRs. After rapid atrial pacing, AF inducibility in SHR was significantly higher, accompanied by a decrease in ICa,L, upregulation of Ito and IKur, and a shortened action potential duration. Angiotensin upregulation and FAK/Src activation in SHR were inhibited by angiotensin type 1 receptor inhibitor valsartan, thus, preventing electrical remodeling and reducing AF susceptibility. These results were verified in HL-1 cells treated with high hydrostatic pressure, and demonstrated that electrical remodeling regulated by the FAK-Src pathway could be modulated by valsartan. The present study indicated that high hydrostatic pressure stimulation increases AF susceptibility by activating the renin-angiotensin system and FAK-Src pathway in atrial myocytes.
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Angiotensina II/metabolismo , Angiotensina I/metabolismo , Remodelación Atrial/efectos de los fármacos , Quinasa 1 de Adhesión Focal/metabolismo , Fragmentos de Péptidos/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Familia-src Quinasas/metabolismo , Animales , Antiarrítmicos/farmacología , Apéndice Atrial/metabolismo , Fibrilación Atrial/patología , Línea Celular Tumoral , Humanos , Presión Hidrostática , Ratones , Miocitos Cardíacos/metabolismo , Ratas , Ratas Endogámicas SHR , Receptor de Angiotensina Tipo 1/metabolismo , Valsartán/farmacologíaRESUMEN
Vascular dysfunction is a common pathological basis for complications in individuals affected by diabetes. Previous studies have established that endothelial dysfunction is the primary contributor to vascular complications in type 2 diabetes (T2DM). However, the role of vascular smooth muscle cells (VSMCs) in vascular complications associated with T2DM is still not completely understood. The aim of this study is to explore the potential mechanisms associated with Ca2+ handling dysfunction and how this dysfunction contributes to diabetic vascular smooth muscle impairment. The results indicated that endothelium-dependent vasodilation was impaired in diabetic aortae, but endothelium-independent vasodilation was not altered. Various vasoconstrictors such as phenylephrine, U46619 and 5-HT could induce vasoconstriction in a concentration-dependent manner, such that the dose-response curve was parallel shifted to the right in diabetic aortae, compared to the control. Vasoconstrictions mediated by L-type calcium (Cav1.2) channels were attenuated in diabetic aortae, but effects mediated by store-operated calcium (SOC) channels were enhanced. Intracellular Ca2+ concentration ([Ca2+]i) in VSMCs was detected by Fluo-4 calcium fluorescent probes, and demonstrated that SOC-mediated Ca2+ entry was increased in diabetic VSMCs. VSMC-specific knockout of STIM1 genes decreased SOC-mediated and phenylephrine-induced vasoconstrictive response in mice aortae. Additionally, Orai1 expression was up-regulated, Cav1.2 expression was downregulated, and the phenotypic transformation of diabetic VSMCs was determined in diabetic aortae. The overexpression of Orai1 markedly promoted the OPN expression of VSMCs, whereas SKF96365 (SOC channel blocker) reversed the phenotypic transformation of diabetic VSMCs. Our results demonstrated that the vasoconstriction response of aortic smooth muscle was weakened in type 2 diabetic rats, which was related to the downregulation of the Cav1.2 channel and the up-regulation of the SOC channel signaling pathway.
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Aorta/fisiopatología , Señalización del Calcio , Calcio/metabolismo , Diabetes Mellitus Experimental/fisiopatología , Contracción Muscular/fisiología , Músculo Liso Vascular/fisiopatología , Miocitos del Músculo Liso/patología , Animales , Biomarcadores/metabolismo , Canales de Calcio/metabolismo , Diabetes Mellitus Experimental/sangre , Técnicas de Silenciamiento del Gen , Concentración 50 Inhibidora , Masculino , Fenotipo , Fenilefrina/farmacología , Ratas Zucker , Molécula de Interacción Estromal 1/metabolismo , Vasoconstricción , Vasodilatación/fisiologíaRESUMEN
BACKGROUND: Ca2+ plays an important role in the regulation of vasoconstriction. Ca2+ signaling is regulated by a number of Ca2+-handling proteins. However, whether differences in Ca2+ handling affect the regulation of vasoconstriction in different arteries remains elusive. OBJECTIVE: To determine whether differences in Ca2+ handling affect the response to vasoconstrictors in different arteries. METHODS: Arterial ring contraction was measured using a Multi Myograph System. Vascular smooth muscle cells (VSMCs) were digested with type 2 collagenase in DMEM, then intracellular calcium concentration was measured with the Ca2+ probe fluo-4/AM in the isolated cells. Calcium-related proteins were assayed by Western blotting. RESULTS: Phenylephrine did not induce -coronary arterial contraction. There were differences in -5-hydroxytryptamine, 9,11-dideoxy-11a,9a-epoxymethano-prostaglandin F2a, and endothelin 1-induced vasoconstriction in different solutions between coronary and renal arteries. Vasoconstrictions in the presence of Bay K8644 were stronger in coronary than in renal arteries. Store-operated calcium (SOC) channels could mediate Ca2+ influx in VSMCs of both groups. SOC channels did not participate in the contraction of coronary arteries. In addition, there were significant differences in the expressions of receptors and ion channels between the two groups. CONCLUSIONS: Ca2+ handling contributed to the different responses to vasoconstrictors between coronary and renal arteries.
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Señalización del Calcio , Calcio , Vasos Coronarios/metabolismo , Arteria Renal/metabolismo , Vasoconstricción , Animales , Señalización del Calcio/efectos de los fármacos , Vasos Coronarios/efectos de los fármacos , Técnicas In Vitro , Masculino , Ratas Wistar , Arteria Renal/efectos de los fármacos , Vasoconstricción/efectos de los fármacos , Vasoconstrictores/farmacologíaRESUMEN
Thromboxane A2 (TXA2 ) has been implicated in the pathogenesis of vascular complications, but the underlying mechanism remains unclear. The contraction of renal arterial rings in mice was measured by a Multi Myograph System. The intracellular calcium concentration ([Ca2+ ]i ) in vascular smooth muscle cells (VSMCs) was obtained by using a fluo-4/AM dye and a confocal laser scanning microscopy. The results show that the U46619-induced vasoconstriction of renal artery was completely blocked by a TXA2 receptor antagonist GR32191, significantly inhibited by a selective phospholipase C (PI-PLC) inhibitor U73122 at 10 µmol/L and partially inhibited by a Phosphatidylcholine - specific phospholipase C (PC-PLC) inhibitor D609 at 50 µmol/L. Moreover, the U46619-induced vasoconstriction was inhibited by a general protein kinase C (PKC) inhibitor chelerythrine at 10 µmol/L, and a selective PKCδ inhibitor rottlerin at 10 µmol/L. In addition, the PKC-induced vasoconstriction was partially inhibited by a Rho-kinase inhibitor Y-27632 at 10 µmol/L and was further completely inhibited together with a putative IP3 receptor antagonist and store-operated Ca2+ (SOC) entry inhibitor 2-APB at 100 µmol/L. On the other hand, U46619-induced vasoconstriction was partially inhibited by L-type calcium channel (Cav1.2) inhibitor nifedipine at 1 µmol/L and 2-APB at 50 and 100 µmol/L. Last, U46619-induced vasoconstriction was partially inhibited by a cell membrane Ca2+ activated C1- channel blocker 5-Nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) at 50 and 100 µmol/L. Our results suggest that the U46619-induced contraction of mouse intrarenal arteries is mediated by Cav1.2 and SOC channel, through the activation of thromboxane-prostanoid receptors and its downstream signaling pathway.
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Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacología , Arterias/efectos de los fármacos , Arterias/fisiología , Vasoconstricción/efectos de los fármacos , Animales , Canales de Calcio/metabolismo , Canales de Cloruro/antagonistas & inhibidores , Riñón/irrigación sanguínea , Masculino , Ratones , Ratones Endogámicos C57BL , Fosfolipasas de Tipo C/metabolismo , Quinasas Asociadas a rho/metabolismoRESUMEN
BACKGROUND: In the early stage of diabetes, the cardiac ejection fraction is preserved, despite the existence of the subclinical cardiac dysfunction to some extent. However, the detailed phenotype of this dysfunction and the underlying mechanism remain unclear. To improve our understanding of this issue, we used low-dose STZ and high-fat diet to induce type 2 diabetic models in rats. The effects and the mechanism associated with the early stages of the disease were analyzed. METHODS: The type 2 diabetic mellitus (T2DM) in SD rats were induced through 30 mg/kg STZ and high-fat diet. Two-dimensional spackle-tracking echocardiography (STE) and the dobutamine test were performed to examine the cardiac function. Calcium transients of left ventricular myocytes were detected and the related intracellular signalling factors were analyzed by western blotting. RESULTS: After 6-weeks, T2DM rats in left ventricular (LV) diastole showed decreased global and segment strain(S) levels (P < 0.05), both in the radial and circumferential directions. Strain rate (Sr) abatement occurred in three segments in the radial and circumferential directions (P < 0.05), and the radial global Sr also decreased (P < 0.05). In the systolic LV, radial Sr was reduced, except the segment of the anterior septum, and the Sr of the lateral wall and post septum decreased in the circumferential direction (P < 0.05). Conventional M-mode echocardiography failed to detect significant alterations of cardiac performance between the two groups even after 12 weeks, and the decreased ejection fraction (EF%), fractional shortening (FS%) and end-systolic diameters (ESD) could be detected only under stress conditions induced by dobutamine (P < 0.05). In terms of calcium transients in cardiac myocytes, the Tpeak in model rats at 6 weeks was not affected, while the Tdecay1/2 was higher than that of the controls (P < 0.05), and both showed a dose-dependent delay after isoproterenol treatment (P < 0.05). Western blot analysis showed that in 6-week T2DM rats, myocardial p-PLB expression was elevated, whereas p-CaMKII, p-AMPK and Sirt1 were significantly down-regulated (P < 0.05). CONCLUSION: A rat model of T2DM was established by low dose STZ and a high-fat diet. LV deformation was observed in the early stages of T2DM in association with the delay of Ca(2+) transients in cardiomyocytes due to the decreased phosphorylation of CaMKII. Myocardial metabolism remodeling might contribute to the early LV function and calcium transportation abnormalities.
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Calcio/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Cardiomiopatías Diabéticas/metabolismo , Dieta Alta en Grasa , Ventrículos Cardíacos/metabolismo , Miocitos Cardíacos/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Western Blotting , Proteínas de Unión al Calcio/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Cardiomiopatías Diabéticas/diagnóstico por imagen , Cardiomiopatías Diabéticas/etiología , Modelos Animales de Enfermedad , Ecocardiografía , Ecocardiografía de Estrés , Electroforesis en Gel de Poliacrilamida , Ventrículos Cardíacos/citología , Ventrículos Cardíacos/diagnóstico por imagen , Immunoblotting , Fosfoproteínas/metabolismo , Ratas , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Sirtuina 1/metabolismoRESUMEN
Cyclins/retinoblastoma protein (pRb) pathway participates in cardiomyocyte hypertrophy. MicroRNAs (miRNAs), the endogenous small non-coding RNAs, were recognized to play significant roles in cardiac hypertrophy. But, it remains unknown whether cyclin/Rb pathway is modulated by miRNAs during cardiac hypertrophy. This study investigates the potential role of microRNA-16 (miR-16) in modulating cyclin/Rb pathway during cardiomyocyte hypertrophy. An animal model of hypertrophy was established in a rat with abdominal aortic constriction (AAC), and in a mouse with transverse aortic constriction (TAC) and in a mouse with subcutaneous injection of phenylephrine (PE) respectively. In addition, a cell model of hypertrophy was also achieved based on PE-promoted neonatal rat ventricular cardiomyocyte and based on Ang-II-induced neonatal mouse ventricular cardiomyocyte respectively. We demonstrated that miR-16 expression was markedly decreased in hypertrophic myocardium and hypertrophic cardiomyocytes in rats and mice. Overexpression of miR-16 suppressed rat cardiac hypertrophy and hypertrophic phenotype of cultured cardiomyocytes, and inhibition of miR-16 induced a hypertrophic phenotype in cardiomyocytes. Expressions of cyclins D1, D2 and E1, and the phosphorylated pRb were increased in hypertrophic myocardium and hypertrophic cardiomyocytes, but could be reversed by enforced expression of miR-16. Cyclins D1, D2 and E1, not pRb, were further validated to be modulated post-transcriptionally by miR-16. In addition, the signal transducer and activator of transcription-3 and c-Myc were activated during myocardial hypertrophy, and inhibitions of them prevented miR-16 attenuation. Therefore, attenuation of miR-16 provoke cardiomyocyte hypertrophy via derepressing the cyclins D1, D2 and E1, and activating cyclin/Rb pathway, revealing that miR-16 might be a target to manage cardiac hypertrophy.
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Cardiomegalia/genética , Ciclina D1/metabolismo , Ciclina D2/metabolismo , Ciclinas/metabolismo , MicroARNs/genética , Animales , Aorta Abdominal/cirugía , Línea Celular , Ciclina D1/biosíntesis , Ciclina D2/biosíntesis , Ciclinas/biosíntesis , Modelos Animales de Enfermedad , Activación Enzimática , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , MicroARNs/biosíntesis , Miocitos Cardíacos/patología , Fenilefrina/farmacología , Fosforilación , Proteínas Proto-Oncogénicas c-myc , Ratas , Ratas Sprague-Dawley , Proteína de Retinoblastoma/metabolismo , Factor de Transcripción STAT3/metabolismoRESUMEN
The contractile function of vascular smooth muscle cells (VSMCs) typically undergoes significant changes with advancing age, leading to severe vascular aging-related diseases. The precise role and mechanism of stromal interaction molecule-1 (STIM1) in age-mediated Ca2+ signaling and vasocontraction remain unclear. The connection between STIM1 and age-related vascular dysfunction was investigated using a multi-myograph system, immunohistochemical analysis, protein blotting, and SA-ß-gal staining. Results showed that vasoconstrictor responses in the thoracic aorta, intrarenal artery, and coronary artery decreased with age. STIM1 knockdown in the intrarenal and coronary arteries reduced vascular tone in young mice, while no change was observed in the thoracic aorta. A significant reduction in vascular tone occurred in the STIM1 knockout group with nifedipine. In the thoracic aorta, vasoconstriction significantly decreased with age following the use of nifedipine and thapsigargin and almost disappeared after STIM1 knockdown. The proportion of senescent VSMCs increased significantly in aged mice and further increased in sm-STIM1 KO aged mice. Moreover, the expression of senescence markers p21, p16, and IL-6 significantly increased with age, with p21 expression further increased in the STIM1 knockdown aged group, but not p16 or IL-6. These findings indicate that different arteries exhibit distinct organ-specific features and that STIM1 downregulation may contribute to age-related vasoconstrictive dysfunction through activation of the p21 pathway.
RESUMEN
Atrial fibrosis induced by aging is one of the main causes of atrial fibrillation (AF), but the potential molecular mechanism is not clear. Acetyltransferase p300 participates in the cellular senescence and fibrosis, which might be involved in the age-related atrial fibrosis. Four microarray datasets generated from atrial tissue of AF patients and sinus rhythm (SR) controls were analyzed to find the possible relationship of p300 (EP300) with senescence and fibrosis. And then, biochemical assays and in vivo electrophysiological examination were performed on older AF patients, aging mice, and senescent atrial fibroblasts. The results showed that (1) the left atrial tissues of older AF patients, aging mouse, and senescence human atrial fibroblasts had more severe atrial fibrosis and higher protein expression levels of p300, p53/acetylated p53 (ac-p53)/p21, Smad3/p-Smads, and fibrosis-related factors. (2) p300 inhibitor curcumin and p300 knockdown treated aging mouse and senescence human atrial fibroblasts reduced the senescence ratio of atrial fibroblasts, ameliorated the atrial fibrosis, and decreased the AF inducibility. In contrast, over-expression of p300 can lead to the senescence of atrial fibroblasts and atrial fibrosis. (3) p53 knockdown decreased the expression of aging and fibrosis-related proteins. (4) Co-immunoprecipitation and immunofluorescence showed that p53 forms a complex with smad3 and directly regulates the expression of smad3 in atrial fibroblasts. Our findings suggest that the mechanism of atrial fibrosis induced by aging is, at least, partially dependent on the regulation of p300, which provides new sights into the AF treatment, especially for the elderly.
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Fibrilación Atrial , Proteína p53 Supresora de Tumor , Humanos , Animales , Ratones , Anciano , Proteína p53 Supresora de Tumor/metabolismo , Fibrilación Atrial/metabolismo , Fibrilación Atrial/patología , Acetiltransferasas/metabolismo , Fibrosis , Fibroblastos/metabolismo , Senescencia Celular/fisiología , Proteína smad3/metabolismoRESUMEN
AIM: Sacubitril/valsartan (Sac/Val, LCZ696), the world's first angiotensin receptor-neprilysin inhibitor (ARNi), has been widely used in the treatment of heart failure. However, the use of Sac/Val in the treatment of atrial fibrillation (AF), especially AF with hypertension, has been less reported. We investigated the effect of Sac/Val on atrial remodeling and hypertension-related AF. METHODS: The AF induction rate and electrophysiological characteristics of spontaneously hypertensive rats (SHRs) treated with Sac/Val or Val were detected by rapid atrial pacing and electrical mapping/optical mapping. The whole-cell patch-clamp and Western blot were used to observe electrical/structural remodeling of atrial myocytes/tissue of rats and atrium-derived HL-1 cells cultured under 40 mmHg in vitro. RESULTS: Sac/Val was superior to Val in reducing blood pressure, myocardial hypertrophy and susceptibility of AF in SHRs. The shorten action potentials duration (APD), decreased L type calcium channel current (ICa,L) and Cav1.2, increased ultrarapid delayed rectified potassium current (Ikur) and Kv1.5 in atrial myocytes/tissue of SHRs could be better improved by Sac/Val, as well as the levels of atrial fibrosis. While the protein expression of angiotensin-converting enzyme-1 (ACE-1), angiotensin, angiotensin II type I AT1 receptor (AT1R) and neprilysin (NEP) were increased, which could be more effective ameliorated by Sac/Val than Val. Furthermore, Val + Sacubitrilat (LBQ657) (an active NEP inhibitor) was also superior to LBQ657 or Val in improving the electrical and structural remodeling of HL-1 cells through inhibiting NEP. CONCLUSION: Sac/Val can improve atrial structural and electrical remodeling induced by hypertension and reduce the AF susceptibility by inhibiting RAS and NEP. The above effects of Sac/Val were superior to Val alone.
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Fibrilación Atrial , Remodelación Atrial , Hipertensión , Ratas , Animales , Fibrilación Atrial/tratamiento farmacológico , Ratas Endogámicas SHR , Neprilisina , Valsartán/farmacología , Valsartán/uso terapéutico , Compuestos de Bifenilo/farmacología , Compuestos de Bifenilo/uso terapéutico , Aminobutiratos/farmacología , Aminobutiratos/uso terapéutico , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Antihipertensivos/farmacología , Combinación de Medicamentos , Angiotensinas , Tetrazoles/farmacologíaRESUMEN
Objectives: Capsaicin is a specific agonist of TRPV1 (multimodal sensory receptor), which improves oropharyngeal dysphagia by increasing sensory input from the oropharynx and hypopharynx and by increasing repetitive stimulation of the cerebral cortex. The aim of this systematic review was to evaluate the therapeutic effect of capsaicin on swallowing disorders in stroke patients and the elderly. Method: We searched Medline, Embase, PubMed, and Cochrane Library databases. We used the Mesh terms search database to screen all clinical trials that complied with the inclusion criteria. Studies were subjected to literature screening, quality assessment, and data extraction to remove studies that did not meet the inclusion criteria. After literature screening, quality assessment, and data extraction, a systematic review and meta-analysis of the included study were performed. Results: This systematic review and meta-analysis were prospectively registered on PROSPERO under registration number CRD42022313958. Five high-quality randomized controlled trials were ultimately included. The results of our meta-analysis showed a more significant reduction in swallowing function score change in the capsaicin group compared to the control group [SMD = -1.30, 95% CI: (-2.35, -0.25), P = 0.01] and on the Water swallowing test the improvement was significantly higher in the capsaicin group [RR = 2.46, 95% CI: (1.73, 3.50), P < 0.0001]. Conclusions: Although the results of our meta-analysis showed that capsaicin improved swallowing function, most studies had an unclear bias and included few studies. More studies are needed to support this in the future. Systematic review registration: www.crd.york.ac.uk/prospero/display_record.php?RecordID=304061, identifier: 304061.
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Four new species are described from Jinggang Mountain National Nature Reserve, Jiangxi Province of southern China: Draconarius lingdang sp. nov. (ââ), D. substrophadatus sp. nov. (â), Orumcekia cipingensis sp. nov. (â) and Tonsilla shuikouensis sp. nov. (â). Additionally, Coelotes septus Wang, Yin, Peng & Xie, 1990 is redescribed and its male is described for the first time.
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We collected remote sensing images of lower reaches of the Shiyang River Basin in 1995, 2000, 2005, 2010, 2015, and 2018. We analyzed the dynamics of desertification in Minqin County by constructing desertification difference index, using RS and GIS theories and methods. We established the Albedo-NDVI feature space based on the normalized vegetation index (NDVI) and surface albedo (Albedo). The results showed that the desertification area in the lower reaches of Shi-yang River Basin accounted for more than 90% of the total area of the Minqin. Oasis scattered in large areas of desertified land. Moderate desertification accounted for more than 70% of the total area of the county. The area of desertification in Minqin showed an decreasing trend from 1995 to 2018, with an average annual reduction area of 22.06 km2 and an average annual reduction rate of 0.1%. During the study period, various types of desertification area contracted and expanded simultaneously, and the relative changes of severe, moderate, mild, and slight desertification areas were -1.5%, 0.2%, -0.9%, and 3.8% respectively. Those results indicated that the severity of desertification was reduced. The desertification area was generally at a stable state. There was no large-scale desertification process and no obvious trends of desertification. Desertification control had achieved phased results. In the study area, the area where the desertification decreased in a fluctuation way accounted for 15.2%, while the area with increased desertification only accounted for 3.9%. The areas with irregular fluctuations of desertification were mainly distributed in the transitional area of desert oasis and the edge area of oasis, with an area of 17.7% of the total land area. The desertification change was more active in the ecotone of oasis and desert area, which was the key control and repair region in the future.
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Conservación de los Recursos Naturales , Ríos , China , Monitoreo del AmbienteRESUMEN
MicroRNA-199a-5p (miR-199a-5p) and -3p are enriched in the myocardium, but it is unknown whether miR-199a-5p and -3p are co-expressed in cardiac remodeling and what roles they have in cardiac hypertrophy and fibrosis. We show that miR-199a-5p and -3p are co-upregulated in the mouse and human myocardium with cardiac remodeling and in Ang-II-treated neonatal mouse ventricular cardiomyocytes (NMVCs) and cardiac fibroblasts (CFs). miR-199a-5p and -3p could aggravate cardiac hypertrophy and fibrosis in vivo and in vitro. PPAR gamma coactivator 1 alpha (Ppargc1a) and sirtuin 1 (Sirt1) were identified as target genes to mediate miR-199a-5p in promoting both cardiac hypertrophy and fibrosis. However, miR-199a-3p aggravated cardiac hypertrophy and fibrosis through targeting RB transcriptional corepressor 1 (Rb1) and Smad1, respectively. Serum response factor and nuclear factor κB p65 participated in the upregulation of miR-199a-5p and -3p in Ang-II-treated NMVCs and mouse CFs, and could be conversely elevated by miR-199a-5p and -3p. Together, Ppargc1a and Sirt1, Rb1 and Smad1 mediated the pathological effect of miR-199a-5p and -3p by promoting cardiac hypertrophy and fibrosis, respectively. This study suggests a possible new strategy for cardiac remodeling therapy by inhibiting miR-199a-5p and -3p.
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AIMS: Hypertension is an independent risk factor for atrial fibrillation (AF). However, the direct effect of hydrostatic pressure on atrial electrical remodeling is unclear. The present study investigated whether hydrostatic pressure is responsible for atrial electrical remodeling and addressed a potential role of inflammation in this pathology. MAIN METHODS: Whole-cell patch-clamp recordings and biochemical assays were used to study the regulation and expression of ion channels in left atrial appendages in patients with AF, spontaneously hypertensive rats (SHRs), and atrium-derived cells (HL-1 cells) exposed to standard (0 mmHg) and elevated (20, 40 mmHg) hydrostatic pressure. KEY FINDINGS: Both TNF-α and MIF were highly expressed in patients with AF and SHRs. AF inducibility in SHRs was higher after atrial burst pacing, accompanied by a decrease in the L-type calcium current (ICa,L), an increase in the transient outward K+ current (Ito) and ultra-rapid delayed rectifier K+ current (IKur), and a shortened action potential duration (APD), which could be inhibited by atorvastatin. Furthermore, exposure to elevated pressure was associated with electrical remodeling of the HL-1 cells. The peak current density of ICa,L was reduced, while Ito and IKur were increased. Moreover, the expression levels of Kv4.3, Kv1.5, TNF-α, and MIF were upregulated, while the expression of Cav1.2 was downregulated in HL-1 cells after treatment with high hydrostatic pressure (40 mmHg). Atorvastatin alleviated the electrical remodeling and increased inflammatory markers in HL-1 cells induced by high hydrostatic pressure. SIGNIFICANCE: Elevated hydrostatic pressure led to atrial electrical remodeling and increased AF susceptibility by upregulating inflammation.
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Remodelación Atrial , Citocinas/metabolismo , Presión Hidrostática/efectos adversos , Adulto , Animales , Western Blotting , Femenino , Atrios Cardíacos/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Miocitos Cardíacos/metabolismo , Técnicas de Placa-Clamp , Ratas Endogámicas SHR , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Regulación hacia ArribaRESUMEN
OBJECTIVE: To investigate the expression of dipeptidyl peptidase IV (DPPIV) in patients with epithelial ovarian carcinoma (EOC) and its clinical significance. METHODS: Immunohistochemistry (IHC) was used to detect the expression of DPPIV protein in 378 formalin-fixed paraffin-embedded EOC tissue samples. The expression of DPPIV mRNA in 86 EOC tissue samples were examined by in situ hybridization (ISH) using specific FITC-labelled RNA probes. Forty-two samples of normal ovarian tissues were used as control. Statistical analyses were carried out by Chi-square test, Spearman rank correlation and Kaplan-Meier method. RESULTS: Among the 378 epithelial ovarian carcinomas, 351 (92.9%) showed a positive expression of DPPIV protein, while only 25/42 (59.5%) of normal ovaries had a positive expression by semi-quantitative IHC analysis. The expression level of DPPIV protein was significantly lower in the normal ovaries than that in ovarian carcinomas (chi(2) = 18.4, P = 0.001). There was no significant correlation between the expression of DPPIV protein and age, FIGO stage and histological grade (P > 0.05). However, the expression of DPPIV protein was significantly associated with histological type (chi(2) = 28.5, P = 0.005). The patients with high level expression of DPPIV protein likely had a poor prognosis in terms of overall survival (P = 0.02). Of the 86 patients, 84 (97.7%)showed positive expression of DPPIV mRNA, also higher than that in normal ovarian tissues (P < 0.05). A statistically significant correlation between DPPIV mRNA and protein expression was observed (r(s) = 0.66, P = 0.001). CONCLUSION: DPPIV may be involved in the carcinogenesis of ovarian cancer, and may become a potential prognostic marker for epithelial ovarian carcinoma.
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Cistadenocarcinoma Mucinoso/metabolismo , Cistadenocarcinoma Seroso/metabolismo , Dipeptidil Peptidasa 4/biosíntesis , Neoplasias Ováricas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Carcinoma Endometrioide/metabolismo , Carcinoma Endometrioide/patología , Cistadenocarcinoma Mucinoso/patología , Cistadenocarcinoma Seroso/patología , Dipeptidil Peptidasa 4/genética , Femenino , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Hibridación in Situ , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Ováricas/patología , Pronóstico , ARN Mensajero/metabolismo , Tasa de SupervivenciaRESUMEN
INTRODUCTION AND OBJECTIVE: The relationship between either paraoxonase 1 (PON1) gene promoter DNA methylation or genetic variations and bleeding or major adverse cardiac events after dual antiplatelet therapy has been incompletely characterized. We aimed to systematically investigate the role of genetic variations and DNA methylation of the PON1 CpG island promoter on the clinical outcomes of dual antiplatelet therapy for patients with coronary artery disease (CAD) who underwent percutaneous coronary intervention (PCI). METHODS: This study included 653 patients with CAD undergoing PCI and receiving dual antiplatelet therapy. Genomic DNAs were isolated from whole blood and were genotyped for the three single nucleotide polymorphisms (SNPs) of the PON1 gene. The DNA methylation levels in the PON1 promoter region were determined by bisulfite sequencing or pyrosequencing at five CpG sites (positions -142, -161, -163, -170, and -184 from the transcription start site). Clopidogrel and its metabolites in plasma were examined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), and platelet function analysis was performed using the VerifyNow assay. RESULTS: Statistically significant associations between methylation levels at five PON1 CpG sites and bleeding were observed: -184 [odds ratio (OR) 0.98, 95% confidence interval (CI) 0.96-1.00, p = 0.028]; -170 (OR 0.99, 95% CI 0.97-1.00, p = 0.048); -163 (OR 0.98, 95% CI 0.96-1.00, p = 0.029); -161 (OR 0.98, 95% CI 0.97-1.00, p = 0.026); and -142 (OR 0.98, 95% CI 0.97-1.00, p = 0.042) at a false discovery rate of <5%. Statistical analysis also revealed that aspirin reaction units (ARUs) were significantly associated with PON1 methylation level at CpG site -163 (p = 0.0342). The ARUs of patients with the PON1 126 CC genotype was 527 ± 94, which was higher than the ARUs (473 ± 89) of patients with the 126 CG genotype (p = 0.0163). Multivariate logistic regression analysis indicated that the PON1 methylation level at CpG site -161 (OR 0.95, 95% CI 0.92-0.98, p = 0.002) and the use of angiotensin-converting enzyme inhibitors (OR 0.48, 95% CI 0.26-0.89, p = 0.021) were associated with a decreased risk of bleeding events. CONCLUSIONS: Hypomethylation of CpGs in the PON1 promoter may be a weak, albeit statistically significant, risk factor of bleeding after dual antiplatelet therapy. Further large-scale studies are needed to verify our results.
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Arildialquilfosfatasa/genética , Metilación de ADN/genética , Variación Genética/genética , Intervención Coronaria Percutánea/tendencias , Inhibidores de Agregación Plaquetaria/administración & dosificación , Regiones Promotoras Genéticas/genética , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Bases , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/genética , Enfermedad de la Arteria Coronaria/terapia , Metilación de ADN/efectos de los fármacos , Femenino , Variación Genética/efectos de los fármacos , Hemorragia/inducido químicamente , Hemorragia/diagnóstico , Hemorragia/genética , Humanos , Masculino , Persona de Mediana Edad , Intervención Coronaria Percutánea/efectos adversos , Inhibidores de Agregación Plaquetaria/efectos adversos , Polimorfismo de Nucleótido Simple/genética , Regiones Promotoras Genéticas/efectos de los fármacos , Resultado del TratamientoRESUMEN
BACKGROUND: Seprase plays an important role in malignant cell invasion and metastasis by degrading the extracellular matrix. However, its clinical significance remains largely unknown. The objective of the current study was to evaluate the expression of seprase in effusions from patients with epithelial ovarian carcinoma and its clinical values. METHODS: Immunohistochemistry was used to examine the expression of seprase protein in a series of 74 malignant peritoneal (n = 64) and pleural (n = 10) effusions from Norwegian patients with epithelial ovarian carcinoma. Additionally, 34 effusions were evaluated using the Western blotting. Nine reactive effusions, obtained from patients with benign lesions, served as a control group. Statistical analyses were carried out by Chi-square test and Kaplan-Meier method. RESULTS: In the 74 malignant effusion specimens, 57 (77.02%) were positive for seprase, while only 2 (22.22%) of the control group were positively stained (P = 0.001). In the malignant effusions, 17 (22.97%), 22 (29.73%), 22 (29.73%), 13 (17.57%) had negative, weak, moderate and strong seprase protein expression, respectively. The expression of seprase protein was predominant in cytoplasm of carcinoma cells. Increased seprase protein was negatively associated with the overall survival rate of the patients (P = 0.03). However, there was no significant correlation between protein expression and FIGO stage, age, histology, and histological grade. By Western blotting, 27 of the 34 effusions showed the presence of both 170-kD dimeric form and 97-KD monomeric form of seprase while only 1 of the 34 had 170-KD dimeric form, which was consistent with the results of immunohistochemistry (P = 0.05). CONCLUSIONS: Seprase may be involved in the development of ovarian cancer, and is a potential predictive marker for the disease.