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RATIONALE AND OBJECTIVES: This study aims to assess whether a radiomics-based nomogram correlates with a higher risk of future cerebro-cardiovascular events in patients with asymptomatic carotid plaques. Additionally, it investigates the nomogram's contribution to the revised Framingham Stroke Risk Profile (rFSRP) for predicting cerebro-cardiovascular risk. MATERIALS AND METHODS: Predictive models aimed at identifying an increased risk of future cerebro-cardiovascular events were developed and internally validated at one center, then externally validated at two other centers. Survival curves, constructed using the Kaplan-Meier method, were compared through the log-rank test. RESULTS: This study included a total of 2009 patients (3946 images). The final nomogram was generated using multivariate Cox regression variables, including dyslipidemia, lumen diameter, plaque echogenicity, and ultrasonography (US)-based radiomics risk. The Harrell's concordance index (C-index) for predicting events-free survival (EFS) was 0.708 in the training cohort, 0.574 in the external validation cohort 1, 0.632 in the internal validation cohort, and 0.639 in the external validation cohort 2. The final nomogram showed a significant increase in C-index compared to the clinical, conventional US, and US-based radiomics models (all P < 0.05). Furthermore, the final nomogram-assisted method significantly improved the sensitivity and accuracy of radiologists' visual qualitative score of plaque (both P < 0.001). Among 1058 patients with corresponding 1588 plaque US images classified as low-risk by the rFSRP, 75 (7.1%) patients with corresponding 93 (5.9%) carotid plaque images were appropriately reclassified to the high-risk category by the final nomogram. CONCLUSION: The radiomics-based nomogram demonstrated accurate prediction of cerebro-cardiovascular events in patients with asymptomatic carotid plaques. It also improved the sensitivity and accuracy of radiologists' visual qualitative score of carotid plaque and enhanced the risk stratification ability of rFSRP. SUMMARY: The radiomics-based nomogram allowed accurate prediction of cerebro-cardiovascular events, especially ipsilateral ischemic stroke in patients with asymptomatic carotid atherosclerotic plaques. KEY RESULTS: The radiomics-based nomogram allowed accurate prediction of cerebro-cardiovascular events, especially ipsilateral ischemic stroke in patients with asymptomatic carotid atherosclerotic plaques. The radiomics-based nomogram improved the sensitivity and accuracy of radiologists' visual qualitative score of carotid plaque. The radiomics-based nomogram improved the discrimination of high-risk populations from low-risk populations in asymptomatic patients with carotid atherosclerotic plaques and the risk stratification capability of the rFSRP.
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Autophagy is a cellular degradation system that recycles or degrades damaged organelles, viral particles, and aggregated proteins through the lysosomal pathway. Autophagy plays an indispensable role in cellular homeostasis and communication processes. An interesting aspect is that autophagy also mediates the secretion of cellular contents, a process known as secretory autophagy. Secretory autophagy differs from macroautophagy, which sequesters recruited proteins, organelles, or viral particles into autophagosomes and degrades these sequesters in lysosomes, while the secretory autophagy pathway participates in the extracellular export of cellular contents sequestered by autophagosomes through autophagy and endosomal modulators. Recent evidence reveals that secretory autophagy is pivotal in the occurrence and progression of diseases. In this review, we summarize the molecular mechanisms of secretory autophagy. Furthermore, we review the impact of secretory autophagy on diseases, including cancer, viral infectious diseases, neurodegenerative diseases, and cardiovascular diseases. Considering the pleiotropic actions of secretory autophagy on diseases, studying the mechanism of secretory autophagy may help to understand the relevant pathophysiological processes.
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Autofagia , Humanos , Autofagia/fisiologia , Animais , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Neoplasias/patologia , Neoplasias/metabolismo , Viroses/metabolismo , Viroses/patologia , Autofagossomos/metabolismo , Lisossomos/metabolismo , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/fisiopatologiaRESUMO
BACKGROUND: According to the World Health Organisation's Health Report 2019, approximately 17.18 million people die from cardiovascular disease each year, accounting for more than 30% of all global deaths. Therefore, the occurrence of cardiovascular disease is still a global concern. The transcription factor 21 (TCF21) plays an important role in cardiovascular diseases. This article reviews the regulation mechanism of TCF21 expression and activity and focuses on its important role in atherosclerosis in order to contribute to the development of diagnosis and treatment of cardiovascular diseases. SUMMARY: TCF21 is involved in the phenotypic regulation of vascular smooth muscle cells (VSMCs), promotes the proliferation and migration of VSMCs, and participates in the activation of inflammatory sequences. Increased proliferation and migration of VSMCs can lead to neointimal hyperplasia after vascular injury. Abnormal hyperplasia of neointima and inflammation are one of the main features of atherosclerosis. Therefore, targeting TCF21 may become a potential treatment for relieving atherosclerosis. KEY MESSAGES: TCF21 as a member of basic helix-loop-helix transcription factors regulates cell growth and differentiation by modulating gene expression during the development of different organs and plays an important role in cardiovascular development and disease. VSMCs and cells derived from VSMCs constitute the majority of plaques in atherosclerosis. TCF21 plays a key role in regulation of VSMCs' phenotype, thus accelerating atherogenesis in the early stage. However, TCF21 enhances plaque stability in late-stage atherosclerosis. The dual role of TCF21 should be considered in the translational medicine.
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Fatores de Transcrição Hélice-Alça-Hélice Básicos , Doenças Cardiovasculares , Músculo Liso Vascular , Humanos , Animais , Músculo Liso Vascular/metabolismo , Doenças Cardiovasculares/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Aterosclerose/metabolismo , Miócitos de Músculo Liso/metabolismo , Proliferação de Células , Movimento CelularRESUMO
AIMS/INTRODUCTION: To assess the effect of empagliflozin treatment on left ventricular (LV), right ventricular (RV) and left atrial (LA) functions in diabetes patients with normal ejection fraction. MATERIALS AND METHODS: The study included a total of 128 diabetes patients with multiple cardiovascular risk factors who were subjected to a 6-month follow up from the initiation of empagliflozin treatment. Before and after treatment with empagliflozin, LV, RV and LA strain, and noninvasive myocardial work parameters were evaluated by speckle tracking echocardiography. RESULTS: In 128 diabetes patients (mean age 56 ± 8 years, 85 men) with multiple cardiovascular risk factors, myocardial strain and work parameters were impaired, despite the absence of significant clinical symptoms of heart failure. After 6-month treatment with empagliflozin, the absolute value of LV strain in all directions increased, represented by LV global longitudinal strain (-18.0 ± 1.7% to -19.2 ± 1.7% [mean ± SD]). The same trend in LV global work efficiency (93 [91-94] % to 94 [93-95] % [median (IQR)]), RV free-wall longitudinal strain (-24.0 ± 2.7% to -25.0 ± 2.8%), LA reservoir (31 ± 5% to 34 ± 5%) and conduit strain (-14 ± 4% to -16 ± 4%) was also observed. LV mass index (106.9 ± 16.8-103.6 ± 16.4 g/m2) and LV global wasted work (143 [111-185] mmHg% to 108 [88-141] mmHg%) decreased after treatment (P < 0.05 for all). LV volume and LA volume index remained unchanged after treatment. In the multivariable analysis, the change in LA reservoir strain (ß = 0.050, P = 0.035) and baseline global longitudinal strain (ß = -0.488, P < 0.001) were independent predictors of improvement in LV global longitudinal strain. CONCLUSIONS: This study suggests that 6-month treatment with empagliflozin improved LV, RV and LA functions in diabetes patients with normal ejection fraction.
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Compostos Benzidrílicos , Glucosídeos , Inibidores do Transportador 2 de Sódio-Glicose , Volume Sistólico , Humanos , Glucosídeos/uso terapêutico , Masculino , Compostos Benzidrílicos/uso terapêutico , Pessoa de Meia-Idade , Feminino , Volume Sistólico/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/fisiopatologia , Ecocardiografia , Função Ventricular Esquerda/efeitos dos fármacos , Idoso , SeguimentosRESUMO
As an essential trace element for organisms, zinc participates in various physiological processes, such as RNA transcription, DNA replication, cell proliferation, and cell differentiation. The destruction of zinc homeostasis is associated with various diseases. Zinc homeostasis is controlled by the cooperative action of zinc transporter proteins that are responsible for the influx and efflux of zinc. Zinc transporter proteins are mainly categorized into two families: Zrt/Irt-like protein (SLC39A/ZIP) family and zinc transporter (SLC30A/ZNT) family. ZIP transporters contain 14 members, namely ZIP1-14, which can be further divided into four subfamilies. Currently, ZIP transporters-regulated zinc homeostasis is one of the research hotspots. Cumulative evidence suggests that ZIP transporters-regulated zinc homeostasis may cause physiological dysfunction and contribute to the onset and progression of diverse diseases, such as cancers, neurological diseases, and cardiovascular diseases. In this review, we initially discuss the structure and distribution of ZIP transporters. Furthermore, we comprehensively review the latest research progress of ZIP transporters-regulated zinc homeostasis in diseases, providing a new perspective into new therapeutic targets for treating related diseases.
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Doenças Cardiovasculares , Proteínas de Transporte de Cátions , Neoplasias , Doenças do Sistema Nervoso , Zinco , Animais , Humanos , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/genética , Proteínas de Transporte de Cátions/metabolismo , Proteínas de Transporte de Cátions/genética , Homeostase/fisiologia , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Zinco/metabolismo , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/metabolismoRESUMO
Background: Distinguishing light-chain cardiac amyloidosis (AL CA) from left ventricular wall thickening (LVWT) resulted from other etiologies has proven to be challenging. This study aimed to determine the sensitivity and specificity of relative apical sparing in diagnosing AL CA and investigate the differences in clinical and echocardiographic characteristics between AL CA patients with apical sparing and those with non-apical sparing. Methods: A total of 63 consecutive patients with AL CA, 102 consecutive patients with LVWT (including 51 hypertrophic cardiomyopathy (HCM) and 51 hypertension) and 33 healthy individuals were recruited retrospectively at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. Conventional and speckle tracking echocardiography were performed on all subjects. Results: Although wall thickening was observed in all patients, almost all functional parameters were worse in AL CA, except for relative apical longitudinal strain (LS) (P=0.906). Of 63 patients with AL CA, only 17.5% (n=11) showed an apical sparing pattern. Patients with apical sparing had poorer cardiac performance than those with non-apical sparing. Relative apical sparing showed the lowest diagnostic accuracy with an area under the curve (AUC) of 0.58 [95% confidence interval (CI): 0.49-0.67, sensitivity: 17.5%, specificity: 98.0%, P=0.095] to detect AL CA, but right ventricular strain (RVS) (AUC: 0.86, P<0.001) showed the highest among all echocardiographic parameters. When diagnosing AL CA patients with non-apical sparing, RVS continued to maintain excellent diagnostic accuracy (AUC: 0.84, P<0.001), followed by left atrial reservoir strain (LASr) (AUC: 0.77, P<0.001). Conclusions: The diagnostic value of relative apical sparing for AL CA was limited with low sensitivity. In clinical practice, the diagnosis of early AL CA patients should not solely rely on relative apical sparing.
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Various disorders are accompanied by histamine-independent itching, which is often resistant to the currently available therapies. Here, it is reported that the pharmacological activation of Slack (Kcnt1, KNa1.1), a potassium channel highly expressed in itch-sensitive sensory neurons, has therapeutic potential for the treatment of itching. Based on the Slack-activating antipsychotic drug, loxapine, a series of new derivatives with improved pharmacodynamic and pharmacokinetic profiles is designed that enables to validate Slack as a pharmacological target in vivo. One of these new Slack activators, compound 6, exhibits negligible dopamine D2 and D3 receptor binding, unlike loxapine. Notably, compound 6 displays potent on-target antipruritic activity in multiple mouse models of acute histamine-independent and chronic itch without motor side effects. These properties make compound 6 a lead molecule for the development of new antipruritic therapies targeting Slack.
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Canais de Potássio , Prurido , Animais , Camundongos , Antipruriginosos/uso terapêutico , Histamina/metabolismo , Loxapina/uso terapêutico , Canais de Potássio/metabolismo , Prurido/tratamento farmacológico , Prurido/metabolismoRESUMO
OBJECTIVES: To evaluate the changes of cardiac morphology and function in fetuses conceived through assisted reproductive technologies (ART) by speckle tracking echocardiography. METHODS: A retrospective study was conducted in 101 spontaneously conceived (SC) fetuses and 99 ART-conceived ones. Fetal echocardiography was performed, fetal cardiac morphology and function were analyzed using two-dimensional speckle tracking software, including global sphericity index (GSI), global longitudinal strain (GLS), fractional area change (FAC) of the left and right ventricles, as well as segmental sphericity index (SI), end-diastolic diameter (ED), and fractional shortening (FS) in 24 segments. RESULTS: Compared to the SC fetuses, the ART-conceived fetuses exhibited decreased GSI (median [interquartile range], 1.22 [1.16-1.27] vs. 1.18 [1.11-1.24], p=0.007), decreased right ventricular GLS (24.9 [21.5-27.6] vs. 23.2 [20.4-26.8], p=0.026), and decreased right ventricular FAC (mean ± standard deviation, 39.7 ± 6.4 vs. 37.2 ± 7.1, p=0.003). Analysis of the 24 segments showed that ART-conceived fetuses had reduced SI in the apical segments of right ventricle and increased ED in several segments of the right ventricle. CONCLUSIONS: Fetuses conceived through ART had a more spherical shape of the global heart and predominantly right-sided cardiac remodeling and systolic function impairment.
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Ecocardiografia , Coração Fetal , Humanos , Estudos Retrospectivos , Coração Fetal/diagnóstico por imagem , Ecocardiografia/métodos , Ventrículos do Coração/diagnóstico por imagem , Técnicas de Reprodução AssistidaRESUMO
Laboratory studies have revealed that strigolatone (SL) and karrikin (KAR) signalling mediate responses to abiotic and biotic stresses, and reshape branching architecture that could increase reproductive performance and crop yields. To understand the ecological function of SL and KAR signalling, transgenic lines of wild tobacco Nicotiana attenuata, silenced in SL/KAR biosynthesis/signalling were grown in the glasshouse and in two field plots in the Great Basin Desert in Utah over four field seasons. Of the lines silenced in SL and KAR signalling components (irMAX2, irD14, irKAI2 and irD14 × irKAI2 plants), which exhibited the expected increases in shoot branching, only irMAX2 plants showed a strong leaf-bleaching phenotype when grown in the field. In the field, irMAX2 plants had lower sugar and higher leaf amino acid contents, lower lifetime fitness and were more susceptible to herbivore attack compared to wild-type plants. These irMAX2 phenotypes were not observed in glasshouse-grown plants. Transcriptomic analysis revealed dramatic responses to high-light intensity in irMAX2 leaves in the field: lutein contents decreased, and transcriptional responses to high-intensity light, singlet oxygen and hydrogen peroxide increased. PAR and UV-B manipulations in the field revealed that the irMAX2 bleaching phenotype is reversed by decreasing PAR, but not UV-B fluence. We propose that NaMAX2 functions in high-light adaptation and fitness optimisation by regulating high-light responses independently of its roles in the SL and KAR signalling pathways. The work provides another example of the value of studying the function of genes in the complex environments in which plants evolved, namely nature.
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Nicotiana , Folhas de Planta , Nicotiana/metabolismo , Perfilação da Expressão GênicaRESUMO
The artificially synthesized strigolactone (SL) analogue GR24 is currently the most widely used reference compound in studying the biological functions of SLs. To elucidate the structure-activity relationship and find more promising derivatives with unique molecular profiles, we design and synthesized three series of novel GR24 derivatives and explored their activities in hypocotyl and root development of Arabidopsis. Among the 50 synthesized compounds, A11a, A12a, and A20d were found to have high activities comparable to GR24 for hypocotyl and/or primary root elongation inhibition in Arabidopsis. Some new analogues have been discovered to exhibit unique activities: (1) A20c, A21e, and A21o are specific inhibitors in primary root elongation; (2) A21c, A26c, and A27a exhibit a high promotion effect on Arabidopsis primary root elongation; and (3) A27e possesses the most unique profiles completely opposite to GR24 that promotes both hypocotyl elongation and primary root development. Moreover, we revealed that the AtD14 receptor does not affect the inhibitory effect of SL analogues in Arabidopsis root development. The ligand-receptor interactions for the most representative analogues A11a and A27e were deciphered with a long time scale molecular dynamics simulation study, which provides the molecular basis of their distinct functions, and may help scientists design novel phytohormones.
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Arabidopsis , Arabidopsis/genética , Compostos Heterocíclicos com 3 Anéis/farmacologia , Lactonas/farmacologia , Crescimento e DesenvolvimentoRESUMO
The transient receptor potential (TRP) ankyrin type 1 (TRPA1) channel is highly expressed in a subset of sensory neurons where it acts as an essential detector of painful stimuli. However, the mechanisms that control the activity of sensory neurons upon TRPA1 activation remain poorly understood. Here, using in situ hybridization and immunostaining, we found TRPA1 to be extensively co-localized with the potassium channel Slack (KNa1.1, Slo2.2, or Kcnt1) in sensory neurons. Mice lacking Slack globally (Slack-/-) or conditionally in sensory neurons (SNS-Slack-/-) demonstrated increased pain behavior after intraplantar injection of the TRPA1 activator allyl isothiocyanate. By contrast, pain behavior induced by the TRP vanilloid 1 (TRPV1) activator capsaicin was normal in Slack-deficient mice. Patch-clamp recordings in sensory neurons and in a HEK cell line transfected with TRPA1 and Slack revealed that Slack-dependent potassium currents (IKS) are modulated in a TRPA1-dependent manner. Taken together, our findings highlight Slack as a modulator of TRPA1-mediated, but not TRPV1-mediated, activation of sensory neurons.
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Nociceptividade , Canais de Potencial de Receptor Transitório , Animais , Camundongos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Dor/metabolismo , Canais de Potássio/metabolismo , Canais de Potássio Ativados por Sódio , Células Receptoras Sensoriais/metabolismo , Canal de Cátion TRPA1/metabolismo , Canais de Potencial de Receptor Transitório/metabolismoRESUMO
BACKGROUND: Slick, a sodium-activated potassium channel, has been recently identified in somatosensory pathways, but its functional role is poorly understood. The authors of this study hypothesized that Slick is involved in processing sensations of pain and itch. METHODS: Immunostaining, in situ hybridization, Western blot, and real-time quantitative reverse transcription polymerase chain reaction were used to investigate the expression of Slick in dorsal root ganglia and the spinal cord. Mice lacking Slick globally (Slick-/-) or conditionally in neurons of the spinal dorsal horn (Lbx1-Slick-/-) were assessed in behavioral models. RESULTS: The authors found Slick to be enriched in nociceptive Aδ-fibers and in populations of interneurons in the spinal dorsal horn. Slick-/- mice, but not Lbx1-Slick-/- mice, showed enhanced responses to noxious heat in the hot plate and tail-immersion tests. Both Slick-/- and Lbx1-Slick-/- mice demonstrated prolonged paw licking after capsaicin injection (mean ± SD, 45.6 ± 30.1 s [95% CI, 19.8 to 71.4]; and 13.1 ± 16.1 s [95% CI, 1.8 to 28.0]; P = 0.006 [Slick-/- {n = 8} and wild-type {n = 7}, respectively]), which was paralleled by increased phosphorylation of the neuronal activity marker extracellular signal-regulated kinase in the spinal cord. In the spinal dorsal horn, Slick is colocalized with somatostatin receptor 2 (SSTR2), and intrathecal preadministration of the SSTR2 antagonist CYN-154806 prevented increased capsaicin-induced licking in Slick-/- and Lbx1-Slick-/- mice. Moreover, scratching after intrathecal delivery of the somatostatin analog octreotide was considerably reduced in Slick-/- and Lbx1-Slick-/- mice (Slick-/- [n = 8]: 6.1 ± 6.7 bouts [95% CI, 0.6 to 11.7]; wild-type [n =8]: 47.4 ± 51.1 bouts [95% CI, 4.8 to 90.2]; P = 0.039). CONCLUSIONS: Slick expressed in a subset of sensory neurons modulates heat-induced pain, while Slick expressed in spinal cord interneurons inhibits capsaicin-induced pain but facilitates somatostatin-induced itch.
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Capsaicina , Células do Corno Posterior , Animais , Capsaicina/efeitos adversos , Capsaicina/metabolismo , Gânglios Espinais/metabolismo , Camundongos , Dor , Células do Corno Posterior/metabolismo , Canais de Potássio , Prurido/induzido quimicamente , Células Receptoras Sensoriais/metabolismo , Canais de Sódio , Somatostatina/efeitos adversos , Somatostatina/metabolismo , Medula Espinal/metabolismoRESUMO
As the most known therapeutic component of bear bile acids, ursodeoxycholic acid (UDCA) is an FDA-approved drug for the treatment of primary biliary cirrhosis (PBC), the dissolution of cholesterol gallstones. UDCA produces many beneficial effects on metabolism and immune responses via its interaction with the membrane G protein-coupled bile acid receptor (GPBAR); however, how UDCA interacts with GPBAR and its selective cellular effects remain elusive. In this study, we delineated the interaction of UDCA with GPBAR and activation mechanism of GPBAR by scattered alanine scanning and molecular docking. Our results indicated that transmembrane helix 2 (TM2), TM3, TM5 and TM6 of GPBAR contribute to the interaction of UDCA in GPBAR binding pocket. Moreover, we predicted that the engagement of the 3-OH of UDCA with phenolic oxygen of Y2406.51 in GPBAR plays a key role in GPBAR activation. Unexpectedly, in addition to the well-known roles of intracellular loop2 (ICL2) residues, we identified that ICL3 residues play an important role in G protein coupling to GPBAR in response to UDCA binding. Our study provides a preliminary molecular mechanism of how GPBAR recognizes UDCA and subsequent activation and G protein interaction, which may facilitate the development of new bile acid derivatives as therapeutics.
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Ácidos e Sais Biliares , Ácido Ursodesoxicólico , Alanina , Proteínas de Ligação ao GTP/metabolismo , Simulação de Acoplamento Molecular , Receptores Acoplados a Proteínas G/metabolismo , Ácido Ursodesoxicólico/uso terapêuticoRESUMO
Previous studies suggest that adenosine A1 receptors (A1R) modulate the processing of pain. The aim of this study was to characterize the distribution of A1R in nociceptive tissues and to evaluate whether targeting A1R with the partial agonist capadenoson may reduce neuropathic pain in mice. The cellular distribution of A1R in dorsal root ganglia (DRG) and the spinal cord was analyzed using fluorescent in situ hybridization. In behavioral experiments, neuropathic pain was induced by spared nerve injury or intraperitoneal injection of paclitaxel, and tactile hypersensitivities were determined using a dynamic plantar aesthesiometer. Whole-cell patch-clamp recordings were performed to assess electrophysiological properties of dissociated DRG neurons. We found A1R to be expressed in populations of DRG neurons and dorsal horn neurons involved in the processing of pain. However, administration of capadenoson at established in vivo doses (0.03-1.0 mg/kg) did not alter mechanical hypersensitivity in the spared nerve injury and paclitaxel models of neuropathic pain, whereas the standard analgesic pregabalin significantly inhibited the pain behavior. Moreover, capadenoson failed to affect potassium currents in DRG neurons, in contrast to a full A1R agonist. Despite expression of A1R in nociceptive neurons, our data do not support the hypothesis that pharmacological intervention with partial A1R agonists might be a valuable approach for the treatment of neuropathic pain.
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Agonistas do Receptor A1 de Adenosina/uso terapêutico , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Receptor A1 de Adenosina/biossíntese , Agonistas do Receptor A1 de Adenosina/farmacologia , Animais , Células Cultivadas , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Receptor A1 de Adenosina/genética , Resultado do TratamentoRESUMO
Diabetic kidney disease (DKD) is one of the major microvascular complications of diabetes and an important cause of end-stage renal disease. Previous studies have shown that the damage to podocyte autophagy is related to the pathogenesis of DKD, and this damage is closely mediated by the Janus kinase (JAK)/signal transductors and the transcription (STAT) signaling pathway. Here, the underlying molecular mechanism of the JAK/STAT signaling pathway regulating podocyte autophagy was investigated. In the present study, compared to controls, DKD mice showed glomerular hypertrophy, increased kidney weight/weight ratio, and increased urinary protein levels, as well as decreased desmin and synaptopodin expression. Meanwhile, levels of triglyceride, total cholesterol, reduced glutathione, and malondialdehyde were also increased in the serum of DKD mice. Further, a lower number of autophagosomes, reduced expression of MAP1LC3 (LC3) in glomeruli, and increased expression of JAK/STAT pathway-related proteins, namely JAK1, JAK2, STAT1, STAT3, STAT5, and STAT6, were observed in DKD mice. In the in vitro experiments, we observed impaired autophagy, enhanced apoptosis, and activated JAK/STAT pathway in podocytes under high glucose conditions. Studies using ruxolitinib inhibitors have showed that suppression of the JAK/STAT pathway in podocytes subjected to high glucose could increase autophagic flux and autophagy-related protein expression. Taken together, the present study demonstrates that high glucose inhibits autophagy by activating the JAK/STAT pathway in mice and podocytes, thereby preventing the efficient removal of damaged proteins and organelles from the body to prevent apoptosis, and ultimately aggravating the progression of podocyte injury and DKD.
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Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Janus Quinases/metabolismo , Podócitos/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Autofagia/efeitos dos fármacos , Autofagia/fisiologia , Linhagem Celular Transformada , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/fisiopatologia , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/fisiopatologia , Progressão da Doença , Glucose/toxicidade , Masculino , Camundongos Endogâmicos C57BL , Podócitos/patologiaRESUMO
The sodium-activated potassium channel Slack (KNa1.1, Slo2.2, or Kcnt1) is highly expressed in populations of sensory neurons, where it mediates the sodium-activated potassium current (IKNa) and modulates neuronal activity. Previous studies suggest that Slack is involved in the processing of neuropathic pain. However, mechanisms underlying the regulation of Slack activity in this context are poorly understood. Using whole-cell patch-clamp recordings we found that Slack-mediated IKNa in sensory neurons of mice is reduced after peripheral nerve injury, thereby contributing to neuropathic pain hypersensitivity. Interestingly, Slack is closely associated with ATP-sensitive P2X3 receptors in a population of sensory neurons. In vitro experiments revealed that Slack-mediated IKNa may be bidirectionally modulated in response to P2X3 activation. Moreover, mice lacking Slack show altered nocifensive responses to P2X3 stimulation. Our study identifies P2X3/Slack signaling as a mechanism contributing to hypersensitivity after peripheral nerve injury and proposes a potential novel strategy for treatment of neuropathic pain.
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Trifosfato de Adenosina/análogos & derivados , Cálcio/farmacologia , Proteínas do Tecido Nervoso/metabolismo , Neuralgia/metabolismo , Canais de Potássio Ativados por Sódio/metabolismo , Receptores Purinérgicos P2X3/metabolismo , Células Receptoras Sensoriais/fisiologia , Trifosfato de Adenosina/farmacologia , Animais , Escala de Avaliação Comportamental , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Técnicas de Patch-Clamp , Nervos Periféricos/patologia , Canais de Potássio/metabolismo , Canais de Potássio/fisiologia , Canais de Potássio Ativados por Sódio/genética , Receptores Purinérgicos P2X3/fisiologia , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/fisiologiaRESUMO
Acute kidney injury (AKI) is a serious disease characterized by a rapid decline in kidney function. Oxidative stress is the primary pathogenesis of AKI. Salvianolic acid B (SalB), a water-soluble compound extracted from Salvia miltiorrhiza, possesses a potent antioxidant activity. Here, we investigated the protective effect of SalB against renal ischemia-reperfusion injury (I/R) in mice. Briefly, by analyzing renal function, oxidative stress markers and inflammatory biomarkers, we found that SalB could improve kidney damage, reduce oxidative stress and inflammatory factor levels. Interestingly, the expression of the NLR family pyrin domain-containing 3 (NLRP3), caspase-1, pyroptosis related proteins gasdermin D (GSDMD) and interleukin (IL)-1ß, which were significantly upregulated in the kidney tissues of I/R group, was effectively reversed by SalB. Meanwhile, renal tubular epithelial cells hypoxia and reoxygenation model was used to explore pyroptosis of caspase-1-dependent. Further mechanism study showed that the SalB pretreatment could promote the increase of nuclear factor erythroid-2 related factor 2 (Nrf2) nuclear accumulation, which significantly suppressed oxidative stress, proinflammatory cytokines, NLRP3 inflammasome activation and pyroptosis. These results indicate that SalB can inhibit caspase-1/GSDMD-mediated pyroptosis by activating Nrf2/NLRP3 signaling pathway, resulting in alleviating I/R injury in mice.
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Parkinson's disease (PD) decreases the quality of life of the affected individuals. The incidence of PD is expected to increase given the growing aging population. Motor symptoms associated with PD render the patients unable to self-care and function properly. Given that several drugs have been developed to control motor symptoms, highly sensitive scales for clinical evaluation of drug efficacy are needed. Among such scales, the objective and continuous evaluation of wearable devices is increasingly utilized by clinicians and patients. Several electronic technologies have revolutionized the clinical monitoring of PD development, especially its motor symptoms. Here, we review and discuss the recent advances in the development of wearable devices for bradykinesia, tremor, gait, and myotonia. Our aim is to capture the experiences of patients and clinicians, as well as expand our understanding on the application of wearable technology. In so-doing, we lay the foundation for further research into the use of wearable technology in the management of PD.
RESUMO
Immunoglobulin A nephropathy (IgAN) is one of the most frequent kinds of primary glomerulonephritis characterized by IgA immune complexes deposition and glomerular proliferation. Zhen-wu-tang (ZWT), a well-known traditional Chinese formula has been reported to ameliorate various kidney diseases. However, its pharmacological mechanism remains unclear. Exosomes have been described in diverse renal diseases by mediating cellular communication but rarely in the IgAN. The purpose of the present study is to explore whether the underlying mechanisms of the effect of ZWT on IgAN is correlated to exosomes. Our results demonstrated that in human renal tubular epithelial cells (HK-2) stimulated by lipopolysaccharide, exosomes are obviously released after ZWT-containing serum treatment especially with 10% ZWT. In addition, once released, HK-2-derived exosomes were uptaked by human mesangial cells (HMC), which impeded the activation of NF-κB/NLRP3 signaling pathway to exert anti-inflammatory effects in a lipopolysaccharide induced proliferation model. Moreover, IgAN rat model was established by bovine serum albumin, CCL4 mixed solution and LPS. We found that 10% ZWT could significantly promote the release of exosomes from HK-2 and inhibit HMC proliferation to improve inflammation. Thus HK-2-derived exosomes treated with 10% ZWT (ZWT-EXO) were administered to the rats by tail vein injection. Our results showed that ZWT-EXO decreased the levels of 24 h proteinuria, urinary erythrocyte, IgA deposition in glomerulus and renal pathological injury which ameliorated the kidney damage. In addition, ZWT was able to dramatically promote secretion of exosomes in renal tissues while blocked NF-κB nuclear translocation as well as activation of NLRP3 inflammasome, leading to the inhibition of IL-1ß and caspase-1. In conclusion, our study reveal that ZWT has protective effects on IgAN by regulating exosomes secretion to inhibit the activation of NF-κB/NLRP3 pathway, thereby attenuating the renal dysfunction. These findings may provide a new therapeutic target for the treatment of IgAN.