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Ischemic stroke involves various pathological processes, among which ferroptosis is crucial. Previous studies by our group have indicated that electroacupuncture (EA) mitigates ferroptosis after ischemic stroke; however, the precise mechanism underlying this effect remains unclear. In the present study, we developed a rat model of middle cerebral artery occlusion/reperfusion. We chose the main acupoint of the treatment methods of the "Awakening and Opening of the Brain". Rats' neurological function and motor coordination were evaluated by neurological function score and the rotarod test, respectively, and the volume of cerebral infarction was analyzed by 2,3,5-triphenyltetrazolium chloride Staining. The cerebrovascular conditions were visualized by time-of-flight magentic resonance angiography. In addition, we detected changes in lipid peroxidation and endogenous antioxidant activity by measuring the malondialdehyde, glutathione, superoxide dismutase activities, glutathione/oxidized glutathione and reduced nicotinamide adenine dinucleotide phosphate/oxidized nicotinamide adenine dinucleotide phosphate ratios. Inductively coupled plasma-mass spectrometry, western blot, reverse transcription-polymerase chain reaction, fluoro-jade B staining, immunofluorescence analysis, and transmission electron microscopy were utilized to examine the influence of EA. The results indicate that EA treatment was effective in reversing neurological impairment, neuronal damage, and protecting mitochondrial morphology and decreasing the cerebral infarct volume in the middle cerebral artery occlusion/reperfusion rat model. EA reduced iron levels, inhibited lipid peroxidation, increased endogenous antioxidant activity, modulated the expression of several ferroptosis-related proteins, and promoted nuclear factor-E2-related factor 2 (Nrf2) nuclear translocation. However, the protective effect of EA was hindered by the Nrf2 inhibitor ML385. These findings suggest that EA can suppress ferroptosis and decrease damage caused by cerebral ischemia/reperfusion by activating Nrf2 and increasing the protein expression of solute carrier family 7 member 11 and glutathione peroxidase 4.
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Eletroacupuntura , Ferroptose , Infarto da Artéria Cerebral Média , Fator 2 Relacionado a NF-E2 , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Ratos Sprague-Dawley , Animais , Ferroptose/fisiologia , Eletroacupuntura/métodos , Fator 2 Relacionado a NF-E2/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Masculino , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/terapia , Traumatismo por Reperfusão/metabolismo , Ratos , Neurônios/metabolismo , Regulação para Baixo/fisiologiaRESUMO
Patients with rheumatoid arthritis (RA) have a much higher incidence of cardiac dysfunction, which contributes to the high mortality rate of RA despite anti-arthritic drug therapy. In this study, we investigated dynamic changes in cardiac function in classic animal models of RA and examined the potential effectors of RA-induced heart failure (HF). Collagen-induced arthritis (CIA) models were established in rats and mice. The cardiac function of CIA animals was dynamically monitored using echocardiography and haemodynamics. We showed that cardiac diastolic and systolic dysfunction occurred in CIA animals and persisted after joint inflammation and that serum proinflammatory cytokine (IL-1ß, TNF-α) levels were decreased. We did not find evidence of atherosclerosis (AS) in arthritic animals even though cardiomyopathy was significant. We observed that an impaired cardiac ß1AR-excitation contraction coupling signal was accompanied by sustained increases in blood epinephrine levels in CIA rats. Furthermore, serum epinephrine concentrations were positively correlated with the heart failure biomarker NT-proBNP in RA patients (r2 = +0.53, P < 0.0001). In CIA mice, treatment with the nonselective ßAR blocker carvedilol (2.5 mg·kg-1·d-1, for 4 weeks) or the specific GRK2 inhibitor paroxetine (2.5 mg·kg-1·d-1, for 4 weeks) effectively rescued heart function. We conclude that chronic and persistent ß-adrenergic stress in CIA animals is a significant contributor to cardiomyopathy, which may be a potential target for protecting RA patients against HF.
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Artrite Experimental , Artrite Reumatoide , Cardiomiopatias , Insuficiência Cardíaca , Humanos , Camundongos , Ratos , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/induzido quimicamente , Roedores , Adrenérgicos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Citocinas , Insuficiência Cardíaca/tratamento farmacológico , Epinefrina/efeitos adversosRESUMO
BACKGROUND: Liver transplantation and liver resection are curative options for early hepatocellular carcinoma (HCC). The outcome is in part depended on the immunological response to the malignancy. In this study, we aimed to identify immunological profiles of non-HCV/non-HBV HCC patients. METHODS: Thirty-nine immune cell subsets were measured with multicolor flow cytometry. This immunophenotyping was performed in peripheral blood (PB) and tumor specimens of 10 HCC resection patients and 10 healthy donors. The signatures of the highly differential leukocyte count (hDIF) were analyzed using multidimensional techniques. Functional capability was measured using intracellular IFN-γ staining (Trial Registration DRKS00013567). RESULTS: The hDIF showed activation (subsets of T-, B-, NK- and dendritic cells) and suppression (subsets of myeloid-derived suppressor cells and T- and B-regulatory cells) of the antitumor response. Principal component analysis of PB and tumor infiltrating leukocytes (TIL) illustrated an antitumor activating gradient. TILs showed functional capability by secreting IFN-γ but did not kill HCC cells. CONCLUSIONS: In conclusion, the measurement of the hDIF shows distinct differences in immune reactions against non-HBV/non-HCV HCC and illustrates an immunosuppressive gradient toward peripheral blood. TRIAL REGISTRATION: DRKS00013567.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Células Supressoras Mieloides , Hepatectomia , Humanos , ImunofenotipagemRESUMO
NEW FINDINGS: What is the central question of this study? Do normal adult DBA/1 mice have cardiac function and performance equal to those of C57BL/6J mice? What is the main finding and its importance? Male adult DBA/1 mice show equivalent cardiac function to C57BL/6J mice up to 8 months old. Therefore, cardiac dysfunction could be investigated in an autoimmune diseases model established with DBA/1 mice. ABSTRACT: Cardiovascular mortality has been increasing, and in particular, cardiovascular damage caused by some chronic autoimmune diseases accounts for a large proportion of this. C57BL/6J mice have been used mostly in studies of cardiovascular diseases. However, for purposes of modelling, this strain of mouse has a very low incidence of some chronic immune diseases such as rheumatoid arthritis, to which instead DBA/1 mice are more susceptible. Basic cardiac function differs between mice with different genetic backgrounds. Therefore, we monitored cardiac function and structure of normal male C57BL/6J and DBA/1 mice for six consecutive months. Echocardiography was used to monitor cardiac functions once a month and cardiac systolic function was measured upon isoproterenol challenge at the end of observation. The Excitation-contraction coupling-related proteins were measured by western blotting. Heart tissue sections were subject to haematoxylin-eosin, TUNEL and Alizarin red staining. The results demonstrated that systolic and diastolic function did not vary significantly and both strains were indistinguishable in appearance and structure of hearts. DBA/1 mice showed a good cardiac ß-adrenergic response comparable to C57BL/6J mice with isoproterenol treatment. The phosphorylation of phospholamban at either its protein kinase A or its Ca2+ /calmodulin-dependent protein kinase II site, as well as the activation of troponin I showed no significant difference between strains. These findings suggested that there was no obvious difference in the heart structure and function of normal male DBA/1 mice compared with C57BL/6J mice. The DBA/1 mouse is a strain applicable to investigating autoimmune disease-induced heart dysfunction and exploring potential interventions.
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Coração , Animais , Isoproterenol , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Especificidade da EspécieRESUMO
BACKGROUND: Establishing a high-accuracy and non-invasive method is essential for evaluating cardiovascular disease. Skin cholesterol is a novel marker for assessing the risk of atherosclerosis and can be used as an independent risk factor of early assessment of atherosclerotic risk. METHODS: We propose a non-invasive skin cholesterol detection method based on absorption spectroscopy. Detection reagents specifically bind to skin cholesterol and react with indicator to produce colored products, the skin cholesterol content can be obtained through absorption spectrum information on colored products detected by non-invasive technology. Gas chromatography is used to measure cholesterol extracted from the skin to verify the accuracy and reliability of the non-invasive test method. A total of 342 subjects were divided into normal group (n = 115), disease group (n = 110) and risk group (n = 117). All subjects underwent non-invasive skin cholesterol test. The diagnostic accuracy of the measured value was analyzed by receiver-operating characteristic (ROC) curve. RESULTS: The proposed method is able to identify porcine skin containing gradient concentration of cholesterol. The values measured by non-invasive detection method were significantly correlated with gas chromatography measured results (r = 0.9074, n = 73, p < 0.001). Bland-Altman bias was - 72.78 ± 20.03 with 95% limits of agreement - 112.05 to - 33.51, falling within the prespecified clinically non-significant range. We further evaluated the method of patients with atherosclerosis and risk population as well as normal group, patients and risk atherosclerosis group exhibited higher skin cholesterol content than normal group (all P < 0.001). The area under the ROC curve for distinguishing Normal/Disease group was 0.8642 (95% confidence interval, 0.8138 to 0.9146), meanwhile, the area under the ROC curve for distinguishing Normal/Risk group was 0.8534 (95% confidence interval, 0.8034 to 0.9034). CONCLUSIONS: The method demonstrated its capability of detecting different concentration of skin cholesterol. This non-invasive skin cholesterol detection system may potentially be used as a risk assessment tool for atherosclerosis screening, especially for a large population.
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Aterosclerose , Humanos , Masculino , Pessoa de Meia-Idade , Placa Aterosclerótica , PeleRESUMO
BACKGROUND: Lipid management is the first line of treatment for decreasing the incidence of cardiovascular events in patients with coronary heart disease (CHD), and a variety of indicators are used to evaluate lipid management. This work analyses the differences in LDL-C and apoB for lipid management evaluation, as well as explores the feasibility of skin cholesterol as a marker that can be measured non-invasively for lipid management. METHODS: The prospective study enrolled 121 patients who had been diagnosed with acute coronary syndrome (ACS) at the department of emergency medicine of the First Affiliated Hospital of the USTC from May 2020 to January 2021, and the patients were grouped into Group I (n=53) and Group II (n=68) according to whether they had comorbid hyperlipidemia and/or diabetes mellitus. All patients were administered 10 mg/day of rosuvastatin and observed for 12 weeks. Lipid management was assessed on the basis of LDL-C and apoB, and linear correlation models were employed to assess the relationship between changes in these well accepted markers to that of changes in skin cholesterol. RESULTS: Out of 121 patients with ACS, 53 patients (43.80 %) had combined hyperlipidemia and/or diabetes mellitus (Group I), while 68 patients (56.20 %) did not (Group II). Cardiovascular events occur at earlier ages in patients with CHD who are comorbid for hyperlipidemia and/or diabetes (P<0.05). LDL-C attainment rate is lower than apoB attainment rate with rosuvastatin therapy (P<0.05), which is mainly attributable to patients with low initial LDL-C. Skin cholesterol reduction correlated with LDL-C reduction. (r=0.501, P<0.001) and apoB reduction (r=0.538, P<0.001). Skin cholesterol reduction continued over all time points measured. CONCLUSIONS: Examination of changes in apoB levels give patients with low initial LDL-C more informative data on lipid management than LDL-C readings. In addition, non-invasive skin cholesterol measurements may have the potential to be used independently for lipid management evaluation.
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Apolipoproteínas B/sangue , LDL-Colesterol/sangue , Colesterol/análise , Pele/química , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/metabolismo , Feminino , Humanos , Hiperlipidemias/sangue , Hiperlipidemias/diagnóstico , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
BACKGROUND: G protein coupled receptor kinase 2 (GRK2) inhibitor, paroxetine, has been approved to ameliorate diabetic cardiomyopathy (DCM). GRK2 is also involved in regulating T cell functions; the potential modifications of paroxetine on the immune response to DCM is unclear.MethodsâandâResults:DCM mouse was induced by high-fat diet (HFD) feeding. A remarkable reduction in the regulatory T (Treg) cell subset in DCM mouse was found by flow cytometry, with impaired cardiac function evaluated by echocardiography. The inhibited Treg differentiation was attributable to insulin chronic stimulation in a GRK2-PI3K-Akt signaling-dependent manner. The selective GRK2 inhibitor, paroxetine, rescued Treg differentiation in vitro and in vivo. Furthermore, heart function, as well as the activation of excitation-contraction coupling proteins such as phospholamban (PLB) and troponin I (TnI) was effectively promoted in paroxetine-treated DCM mice compared with vehicle-treated DCM mice. Blockade of FoxP3 expression sufficiently inhibited the proportion of Treg cells, abolished the protective effect of paroxetine on heart function as well as PLB and TnI activation in HFD-fed mice. Neither paroxetine nor carvedilol could effectively ameliorate the metabolic disorder of HFD mice. CONCLUSIONS: The impaired systolic heart function of DCM mice was effectively improved by paroxetine therapy, partially through restoring the population of circulating Treg cells by targeting the GRK2-PI3K-Akt pathway.
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Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/imunologia , Quinase 2 de Receptor Acoplado a Proteína G/antagonistas & inibidores , Imunidade/efeitos dos fármacos , Paroxetina/administração & dosagem , Substâncias Protetoras/administração & dosagem , Linfócitos T Reguladores/imunologia , Animais , Carvedilol/administração & dosagem , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Cardiomiopatias Diabéticas/sangue , Cardiomiopatias Diabéticas/etiologia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Quinase 2 de Receptor Acoplado a Proteína G/metabolismo , Insulina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Resultado do TratamentoRESUMO
We perform the phase-field modeling to investigate the growth pattern selections of the complex dendritic structures in constrained growth with different solidification and orientation conditions. The results show that hexagonal close-packed (hcp) crystals emerge as dendritic and cellular arrays in different planes, originating from the specific hcp anisotropy that allows different growth preferences between the basal and cylindrical planes. A morphological transition of the titled dendrites to tip-splitting dendrites arises reflecting the competition between the preferred orientation induced primary growth and the misorientation induced sidebranching formation. Furthermore, the dendritic patterns exhibit sharper tips and the more significant sidebranches, while the cellular pattern is changed from the symmetric cells to the tip-splitting cells, and to seaweeds with the increase of anisotropy strength, indicating the competitive mechanism of the in-plane anisotropy induced growth promotion and the out-plane anisotropy induced growth restriction. We expect to understand the growth competition, the morphology selection, as well as the orientation dependence of the complex dendritic structures in the three-dimensional (3D) constrained growth.
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The adsorption processes of ions into charged nanospace are associated with many practical applications. Whereas a large number of microporous materials have been prepared toward efficient adsorption of ions from solutions, theoretical models that allow for capturing the characteristics of ion dynamic adsorption into like-charged nanopores are still few. The difficulty originates from the overlapping of electric potentials inside the pores. Herein, a theoretical model is proposed by incorporating dynamic density functional theory with modified Poisson equation for investigating the dynamic adsorption of ions into like-charged nanoslits. This model is rationalized by comparing the theoretical predictions with corresponding simulation results. Afterward, by analyzing the adsorption dynamics, we show that the overlapping effect is associated with the pore size, ion bulk concentration, and surface charge density, and it plays a dominant role in the coupling between the total adsorption amount of ions and total adsorption time. Specifically, with weak overlapping effect, the total adsorption amount is intuitively proportional to the total adsorption time; however, when the overlapping effect is strong, the total adsorption amount may be inversely proportional to the total adsorption time, indicating that both high adsorption amount and short adsorption time can be achieved simultaneously. This work provides a meaningful insight toward the rational design and optimization of microporous materials for efficient ion adsorption.
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Cord blood transplantation (CBT) is an effective option for treating hematological malignancies, but graft failure (GF) remains the primary cause of therapy failure. Thus, based on myeloablative conditioning (MAC) of busulfan with cyclophosphamide (Bu/Cy) or total body irradiation with Cy (TBI/Cy), fludarabine (Flu) was added to Bu/Cy and cytarabine (CA) to TBI/Cy for a modified myeloablative conditioning (MMAC). To compare the prognosis of MMAC with MAC, we conducted a retrospective study including 58 patients who underwent CBT with MAC or MMAC from 2000 to 2011. Neutrophil and platelet engraftment rate, overall survival (OS) and disease free survival (DFS) were significantly higher in the MMAC group (adjusted hazard ratio [HR], 2.58, 2.43, 0.36 and 0.37; p < 0.01, p = 0.01, p = 0.02 and p = 0.02, separately). Nonrelapse mortality (NRM) was comparable (p = 0.183). To validate the outcomes noted in the MMAC group, we conducted a prospective single-arm clinical trial including 188 patients who underwent CBT with MMAC from 2011 to 2015. Engraftment rate, survival and NRM of the MMAC group in the prospective trail (MMAC-P) were similar to the MMAC group in the retrospective study (MMAC-R). This study is the first to demonstrate the superiority of MMAC to MAC in CBT for hematological malignancies.
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Soro Antilinfocitário/uso terapêutico , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Condicionamento Pré-Transplante , Adolescente , Adulto , Idoso , Plaquetas , Criança , Pré-Escolar , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Feminino , Doença Enxerto-Hospedeiro/etiologia , Neoplasias Hematológicas/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Neutrófilos , Estudos Retrospectivos , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Resultado do Tratamento , Adulto JovemRESUMO
Wilson's disease (WD) is a disease of copper metabolism characterized by excessive copper deposition in the body. It is reported abnormal copper metabolism has been associated with cardiovascular disease. BNP and MMP2/9 were biomarkers of congestive heart failure (CHF). There is rare study to explore whether serum concentrations of BNP, MMP2, and or MMP9 are altered in patients with WD. In this study we determine whether serum concentrations of brain natriuretic peptide (BNP) and matrix metalloproteinases (MMP) 2 and 9 are increased in patients with WD. Serum BNP, MMP2 and MMP9 were measured by an ELISA in 34 patients with hepatic WD, in 68 patients with neurological WD, and in 33 healthy controls. We found serum BNP levels were higher in patients with neurological WD than in healthy controls (p = 0.033). Serum MMP2 levels were higher in patients with hepatic (p = 0.009) and neurologic (p = 0.0004) WD than in controls. Serum MMP9 levels were higher in patients with neurologic WD than in patients with hepatic WD (p = 0.002) and controls (p = 0.00005), and were higher in patients with hepatic WD than in controls (p = 0.03). Serum BNP levels were negatively correlated with ceruloplasmin (p = 0.017, r = -0.215), while serum (p = 0.019, r = -0.221) and MMP9 (p = 0.011, r = -0.231) in patients with WD were negatively correlated with ceruloplasmin. BNP, MMP2, and MMP9 may reflect the deposition of copper in the heart.
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Degeneração Hepatolenticular/sangue , Degeneração Hepatolenticular/diagnóstico , Metaloproteinase 2 da Matriz/sangue , Metaloproteinase 9 da Matriz/sangue , Peptídeo Natriurético Encefálico/sangue , Adolescente , Adulto , Biomarcadores/sangue , Feminino , Humanos , Masculino , Adulto JovemRESUMO
AIM: The aim of this study was to explore the relationship between peripheral circulating serum soluble suppression of tumorigenicity-2 (sST2) levels and inflammatory biomarkers in patients with acute heart failure (AHF). METHODS: One hundred and eleven consecutive AHF patients with NYHA class II-IV were enrolled, and peripheral blood was collected within 24âh of admission for the detection of NT-ProBNP, sST2, hypersensitive troponin I, cytokines, precalcitoninogen, C-reactive protein, in addition to routine standard of care blood tests. RESULTS: The median sST2 of 111 patients was 47.50âng/ml (24.25-86.15 IQR), of whom 43 patients (38.7%) had sST2 35âng/ml or less; linear correlation analysis showed that serum sST2 correlated with NT-ProBNP ( r2 â=â0.32), NEU% ( r2 â=â0.41), NLR ( r2 â=â0.36), CRP ( r2 â=â0.50), IL-18 ( r2 â=â0.43) ( P â<â0.001), and correlated with Hs-cTnI ( r2 â=â0.19), NUE ( r2 â=â0.25), LYM ( r2 â=â-0.23), IL-2RA ( r2 â=â0.29) ( P â<â0.05). Multiple linear regression analysis depicted that CRP (ßâ=â0.318), IL-18 (ßâ=â0.368), NEU% (ßâ=â0.346), NLR (ßâ=â-0.304), and NT-ProBNP (ßâ=â0.324) significantly correlated with sST2 values, respectively ( P â<â0.05). ST2 levels have a linear association with length of hospitalization. CONCLUSION: Peripheral blood inflammatory markers (CRP, IL-18, NEU%, NLR) in patients with AHF had a close relationship with sST2 levels, and the mechanism of action of sST2 may be related to the inflammatory response.
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Insuficiência Cardíaca , Proteína 1 Semelhante a Receptor de Interleucina-1 , Humanos , Interleucina-18 , Biomarcadores , Insuficiência Cardíaca/diagnóstico , Inflamação/diagnóstico , Prognóstico , Fragmentos de Peptídeos , Peptídeo Natriurético EncefálicoRESUMO
We presented a case of a 34-year-old male with postoperative brainstem cavernous malformations complicated with LGI1 encephalitis and secondary hypertrophic olivary degeneration (HOD). Due to recurrent dizziness and headache, the patient was diagnosed as brainstem cavernous malformations with recurrent hemorrhage and underwent resection. He subsequently developed unexplained abnormal mental behavior 1 month after the surgery, and diagnosed with LGI1 encephalitis. Six months later, cranial MRI showed HOD. This condition is rare in clinical practice,and a complex mechanism underlies the occurrence.
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Peptídeos e Proteínas de Sinalização Intracelular , Humanos , Masculino , Adulto , Encefalite/complicações , Encefalite/diagnóstico por imagem , Núcleo Olivar/patologia , Núcleo Olivar/diagnóstico por imagem , Proteínas , Hemangioma Cavernoso do Sistema Nervoso Central/complicações , Hemangioma Cavernoso do Sistema Nervoso Central/cirurgia , Hemangioma Cavernoso do Sistema Nervoso Central/diagnóstico por imagem , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/diagnóstico por imagem , Imageamento por Ressonância Magnética , Tronco Encefálico/diagnóstico por imagem , Tronco Encefálico/patologia , Hipertrofia , Degeneração OlivarRESUMO
Osteoarthritis (OA) is a prevalent bone and joint disease characterized by degeneration. The dysregulation between chondrocyte synthesis and breakdown is a key factor in OA development. Targeting the degenerative changes in cartilage tissue degradation could be a potential treatment approach for OA. Previous research has established a strong link between autophagy and the regulation of chondrocyte functions. Activating autophagy has shown promise in mitigating cartilage tissue degeneration. Currently, osteoarthritis treatment primarily focuses on symptom management, as there is no definitive medication to stop disease progression. Previous studies have demonstrated that luteolin, a flavonoid present in Chinese herbal medicine, can activate autophagy and reduce the expression of MMP1 and ADAMTS-5. This study utilized an in vitro osteoarthritis model with chondrocytes stimulated by IL-1ß, treated with varying concentrations of luteolin. Treatment with luteolin notably increased the levels of synthesis factors Aggrecan and Collagen II, while decreasing the levels of decomposition factors MMP-1 and ADAMTS-5. Moreover, inhibition of autophagy by Chloroquine reversed the imbalances in chondrocyte activities induced by IL-1ß. In an in vivo model of knee osteoarthritis induced by medial meniscal instability (DMM), luteolin was administered as a therapeutic regimen. After 12 weeks, knee cartilage tissues from mice were analyzed. Immunofluorescence and immunohistochemical staining revealed a decrease in P62 expression and an increase in Beclin-1 in the cartilage tissues. Additionally, cartilage wear in the knee joints of mice was alleviated by safranin O and fast green staining. Our study findings underscore the significant role of luteolin in effectively rebalancing chondrocyte activities disrupted by IL-1ß. Our results strongly indicate that luteolin has the potential to be developed as a novel therapeutic agent for the treatment of osteoarthritis, offering promising prospects for future drug development.
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Sepsis-induced myocardial dysfunction (SIMD) is a severe complication in sepsis, manifested as myocardial systolic dysfunction, which is associated with poor prognosis and higher mortality. Mitophagy, a self-protective mechanism maintaining cellular homeostasis, plays an indispensable role in cardioprotection. This study aimed to unveil the cardioprotective effects of Baricitinib on LPS-induced myocardial dysfunction and its effect on mitophagy. Herein, we demonstrated that LPS induced severe myocardial dysfunction and initiated mitophagy in septic mice hearts. Despite the initiation of mitophagy, a significant number of apoptotic cells and damaged mitochondria persisted in the myocardium, and myocardial energy metabolism remained impaired, indicating that the limited mitophagy was insufficient to mitigate LPS-induced damage. The JAK2-AKT-mTOR signaling pathway is activated in LPS-induced cardiomyocytes and in the hearts of septic mice. Baricitinib administration remarkably improved cardiac function, suppressed systemic inflammatory response, attenuated histopathological changes, inhibited cardiac cell apoptosis and alleviated myocardial damage in septic mice. Furthermore, Baricitinib treatment significantly enhanced PINK1-Parkin-mediated mitophagy, increased autophagosomes, decreased impaired mitochondria, and restored myocardial energy metabolism. Mechanically, the limited mitophagy in septic myocardium was associated with increased p-ULK1 (Ser757), which was regulated by p-mTOR. Baricitinib reduced p-ULK1 (Ser757) and enhanced mitophagy by inhibiting the JAK2-AKT-mTOR signaling pathway. Inhibition of mitophagy with Mdivi-1 reversed the cardiac protective and anti-inflammatory effects of Baricitinib in septic mice. These findings suggest that Baricitinib attenuates SIMD by enhancing mitophagy in cardiomyocytes via the JAK2-AKT-mTOR signaling pathway, providing a novel mechanistic and therapeutic insight into the SIMD.
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BACKGROUND/AIMS: Angiotensin II (AngII) activated cardiac fibroblasts (CFs) predominantly through AngII subtype 1a receptor (AT1aR). This study was carried out to explore the potential inhibitory effects and mechanisms of epigallocatechin gallate (EGCG) on AngII induced rat CFs. METHODS: Viability, proliferation and collagen production of CFs were measured by MTT assay, [3H]-thymidine and [3H]-proline incorporation respectively. ß-arrestin1 (ßarr1), AT1aR and AT1bR mRNA levels were determined by quantitative PCR. AT1R, Gq, ßarr 1/2, phosphorylated kinase C (p-PKC)-delta expressions were detected by western blotting. We blocked ßarr1 expression using ßarr1 small interfering RNA (siRNA). RESULTS: EGCG inhibited the activation of CFs induced by AngII. ßarr1 mRNA level revealed a positive correlation with the viability of CFs. SiRNA targeting ßarr1 blocked the activation of CFs. In vitro, AngII increased ßarr1 mRNA, total and membrane ßarr1 protein expressions, but reduced AT1aR mRNA, global and membrane AT1R, total Gq and cytoplasmic p-PKC-delta levels. Administration of EGCG restored the above abnormalities, whereas Gq levels were not affected. CONCLUSION: Our findings showed that ßarr1 is essential for AngII-mediated activation of CFs. EGCG attenuated CFs activation induced by AngII via regulating ßarr1 and thus, modulating AT1aR mediated signaling.
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Angiotensina II/farmacologia , Arrestinas/metabolismo , Catequina/análogos & derivados , Fibroblastos/efeitos dos fármacos , Animais , Arrestinas/antagonistas & inibidores , Arrestinas/genética , Catequina/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Colágeno/metabolismo , Fibroblastos/citologia , Fibroblastos/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Miocárdio/citologia , Proteína Quinase C-delta/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ratos , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , beta-ArrestinasRESUMO
OBJECTIVE: To perform immunophenotyping and molecular genetic analysis for diffuse large B-cell lymphoma (DLBCL), and to explore their correlation and implication for prognosis. METHODS: Immunohistochemical streptavidin peroxidase (SP) method was used to determine the expression of CD10, BCL6 and MUM1 in 59 cases of DLBCL. A Hans algorithm was used to classify DLBCL into germinal center B-cell (GCB) and non-GCB subtypes. Interphase fluorescence in situ hybridization (FISH) assay was performed on paraffin-embedded lymphoma tissue sections to detect translocations and amplifications of BCL6, BCL2 and MYC genes with dual-color break-apart BCL6 probe, dual-color dual-fusion IgH/ BCL2 probe and dual-color break-apart MYC probe, respectively. RESULTS: In the 59 cases of DLBCL, 28.8% (17/59) belonged to GCB subtype, and 71.2% (42/59) belonged to non-GCB subtype. The incidences of BCL6, BCL2 and MYC gene translocations were 24.1% (14/58), 1.7% (1/59) and 5.3% (3/57), respectively. The incidences of BCL6, BCL2 and MYC gene amplifications were 17.2% (10/58), 22.0% (13/59) and 21.1% (12/57), respectively. BCL6 amplification was not correlated with BCL6 translocation (P=0.424), but was correlated with amplifications of BCL2 and MYC (C=0.405 and 0.403, respectively, P <0.01). The incidence of BCL6 translocation in GCB type was higher than that in non-GCB type, and amplifications of BCL6, BCL2 or MYC were more frequently encountered in non-GCB type, though no statistical significance was detected (P=0.089 and 0.106, respectively). By univariate analysis, immunophenotyping and international prognostic index (IPI) exerted a significant effect on overall survival (OS) (P=0.047 and 0.001, respectively), but to which BCL6 translocation and amplification of the 3 genes were not related (P=0.150 and 0.444, respectively). By multivariate analysis, IPI score was the only independent prognostic factor for OS (RR =3.843, P=0.017). CONCLUSION: The GCB subtype of DLBCL is less common in the patient cohort. Common genetic aberrations have included BCL6 translocation and BCL6, BCL2 and MYC amplifications. Amplification of the 3 genes is strongly correlated with each other, and the incidence of BCL2 translocation is low. Immunophenotyping only has minor significance for the prognosis. Genetic aberrations cannot predict the clinical outcome of DLBCL.
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Linfoma Difuso de Grandes Células B/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas de Ligação a DNA/genética , Feminino , Genes bcl-2 , Genes myc , Humanos , Imunofenotipagem , Hibridização in Situ Fluorescente , Linfoma Difuso de Grandes Células B/imunologia , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-bcl-6RESUMO
Botulinum toxin type A (BoNT-A) has been recommended in various neurological disorders as a useful tool for alleviating dystonia. In Wilson disease (WD) patients with dystonia, BoNT-A injection can be used as a treatment modality when conventional treatment is ineffective for alleviating symptoms. The purpose of this study was to thoroughly evaluate the efficacy of BoNT-A injection in treating WD complicated by lower extremity dystonia. The efficacy of these injections was assessed by clinical scales, surface electromyography (EMG), and gait analysis. A comparative analysis of all gait parameters, EMG parameters, and clinical scales revealed a significant increase in velocity, decrease in integrated EMG (iEMG), and improvement in modified Ashworth scale (MAS), Burke Fahn Marsden (BFM), and activities of daily living (ADL) scores (all P < 0.05). Overall, our findings indicated that BoNT-A injection led to marked relief of symptoms in patients with WD with lower extremity dystonia.
Assuntos
Toxinas Botulínicas Tipo A , Distonia , Distúrbios Distônicos , Degeneração Hepatolenticular , Fármacos Neuromusculares , Humanos , Toxinas Botulínicas Tipo A/uso terapêutico , Distonia/tratamento farmacológico , Estudos Prospectivos , Degeneração Hepatolenticular/tratamento farmacológico , Atividades Cotidianas , Distúrbios Distônicos/tratamento farmacológico , Resultado do Tratamento , Fármacos Neuromusculares/uso terapêuticoRESUMO
An operation in itself is a kind of trauma and may lead to immunosuppression followed by a bounce back. Not many studies exist that describe dynamics of the distribution of peripheral blood (PB) immune cells during the perioperative period. Considering this scarcity, we aggregated the data on the dynamics of immune cells in patients with digestive system resections during the perioperative period and the relationship with short- and long-term prognoses. By the systematic retrieval of documents, we collected perioperative period data on white blood cells (WBC), lymphocytes, neutrophil-lymphocyte ratio (NLR), CD4+ T cells, CD8+ T cells, helper T cells (Th), B cells, natural killer cells (NK), dendritic cells (DCs), regulatory T cells (Tregs), regulatory B cells (Bregs), and Myeloid derived suppressor cells (MDSC). The frequency and distribution of these immune cells and the relationship with the patient's prognosis were summarized. A total of 1916 patients' data were included. Compared with before surgery, WBC, lymphocytes, CD4+ cells, CD8+ T cells, MDSC, and NK cells decreased after surgery, and then returned to preoperative levels. After operation DCs increased, then gradually recovered to the preoperative level. No significant changes were found in B cell levels during the perioperative period. Compared with the preoperative time-point, Tregs and Bregs both increased postoperatively. Only high levels of the preoperative and/or postoperative NLR were found to be related to the patient's prognosis. In summary, the surgery itself can cause changes in peripheral blood immune cells, which might change the immunogenicity. Therefore, the immunosuppression caused by the surgical trauma should be minimized. In oncological patients this might even influence long-term results.