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BACKGROUND: Tuberculosis (TB), a highly contagious respiratory disease, presents a significant global health threat, with a notable increase in incidence reported by the WHO in 2022. Particularly, the interplay between TB and non-small cell lung cancer (NSCLC) gains attention, especially considering the rising use of immune checkpoint inhibitors (ICIs) in cancer treatment. This interplay may influence TB diagnostics and reactivation, warranting a closer examination. METHODS: A retrospective analysis was conducted on clinical data of NSCLC patients with positive T-SPOT results before undergoing anti-tumor treatment at Zhongshan Hospital (Xiamen), Fudan University, from January 1, 2021 to December 31, 2022. We assessed the incidence of tuberculosis reactivation and treatment outcomes among these patients. Moreover, we compared the differences in tuberculosis activity between the ICIs and non-ICIs treatment groups. Additionally, we observed the changes in T-SPOT spot count before and after immunotherapy, analyzing their association with tuberculosis activity and prognosis. RESULTS: A total of 40 NSCLC patients with positive T-SPOT results before treatment were included in the study, with 26 patients in the ICIs treatment group and 14 patients in the non-ICIs treatment group. The study found no significant differences between the two groups in terms of gender, age, stage, histological type, performance status, driver gene expression, and distant metastasis. With a median follow-up time of 10.0 (6.0-14.5) months, three cases (11.5%) in the ICIs treatment group developed tuberculosis activity, diagnosed at 2, 3, and 12 months after ICIs treatment initiation. Conversely, no tuberculosis activity was observed in the non-ICIs treatment group, and the difference between the two groups was not significant (P = 0.186). Among the 32 patients who received ICIs treatment, spot count dynamics were diverse: four cases (12.5%) showed an increase, 12 cases (37.5%) had no change, and 16 cases (50.0%) had a decrease. During the follow-up, the progression rate (PD) was 50.0%, 75.0%, and 62.5% in the three groups, respectively (P = 0.527). Similarly, the mortality rate was 0%, 25.0%, and 25.0%, respectively (P = 0.106). Interestingly, among the patients with decreased spot counts, three cases (18.75%) were diagnosed with active pulmonary tuberculosis. CONCLUSIONS: For NSCLC patients with a positive T-SPOT response undergoing ICIs treatment, our study observed indications of active tuberculosis. The varied T-SPOT spot count changes post-ICIs treatment suggest a complex interaction, potentially linking T-SPOT spot count reduction to tuberculosis reactivation risk. These preliminary findings underscore the importance of further research to more accurately assess T-SPOT's diagnostic utility in this context.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Tuberculosis Pulmonar , Humanos , Ensayos de Liberación de Interferón gamma , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Estudios Retrospectivos , Neoplasias Pulmonares/tratamiento farmacológicoRESUMEN
The toxic heavy metal cadmium has been proven to cause pancreatic dysfunction and lead to the development of DM. However, the underlying mechanisms have not been completely elucidated. Here, we investigated the effects of cadmium on the pancreatic ß cell line MIN6 and explored the underlying mechanisms. The Cell Counting Kit-8 (CCK8) assay and flow cytometry were used to determine cell viability and apoptosis in MIN6 cells. The expression levels of signal transducer and activator of transcription 6 (STAT6) were assessed by western blotting. We further assessed the effects of cadmium on the function of pancreatic ß cells under high glucose levels using enzyme-linked immunosorbent assay (ELISA) and western blotting. Insulin secretion and expression were decreased by cadmium in MIN6 cells. In addition, cadmium suppressed cell viability and promoted apoptosis of MIN6 cells, downregulated insulin secretion and genesis of MIN6 cells under high glucose conditions, while inhibiting STAT6. Furthermore, after treatment with IL-4, the activator of STAT6, the MIN6 cell viability suppression and apoptosis promotion effect caused by cadmium were blocked. In conclusion, cadmium inhibits pancreatic ß cell MIN6 growth by regulating the activation of STAT6. Our findings reveal a new mechanism of cadmium toxicity in pancreatic ß cells.
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Células Secretoras de Insulina , Apoptosis , Cadmio/metabolismo , Cadmio/toxicidad , Glucosa/metabolismo , Glucosa/farmacología , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Factor de Transcripción STAT6 , Transducción de SeñalRESUMEN
Neutral ceramidase (NCDase) is a class of ceramidases, a key enzyme in ceramide degradation. Recently, it was observed that NCDase activity was suppressed by saturated fatty acids to increase ceramide content in rat muscle. However, little is known about its changes in activity and roles in palmitate (Palm)-induced lipotoxicity in pancreatic ß cells. Here, we demonstrated that Palm treatment significantly down-regulated NCDase activity, mRNA and protein levels in rat INS-1 cells. In addition, Palm caused a significant accumulation of ceramide, while SPH level remained unchanged, suggesting that inhibition of NCDase activity led to no change of SPH level after treatment with Palm for 24 h. Furthermore, NCDase overexpression significantly reduced Palm-induced apoptosis in INS-1 cells. Conversely, NCDase siRNA knockdown markedly exacerbated Palm-induced apoptosis. In conclusion, Palm treatment suppressed the activity of NCDase and down-regulated its mRNA and protein expression. Furthermore, NCDase inhibition was involved in Palm-induced apoptosis by blocking ceramide degradation in INS-1 cells.
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Apoptosis/efectos de los fármacos , Células Secretoras de Insulina/efectos de los fármacos , Ceramidasa Neutra/metabolismo , Ácido Palmítico/farmacología , Páncreas/efectos de los fármacos , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Células Secretoras de Insulina/citología , Células Secretoras de Insulina/enzimología , Páncreas/citología , Páncreas/enzimología , RatasRESUMEN
Cadmium (Cd), a toxic environmental contaminant, induces neurodegenerative diseases. Celastrol, a plant-derived triterpene, has shown neuroprotective effects in various disease models. However, little is known regarding the effect of celastrol on Cd-induced neurotoxicity. Here, we show that celastrol protected against Cd-induced apoptotic cell death in neuronal cells. This is supported by the findings that celastrol strikingly attenuated Cd-induced viability reduction, morphological change, nuclear fragmentation, and condensation, as well as activation of caspase-3 in neuronal cells. Concurrently, celastrol remarkably blocked Cd-induced phosphorylation of c-Jun N-terminal kinase (JNK), but not extracellular signal-regulated kinases 1/2 and p38, in neuronal cells. Inhibition of JNK by SP600125 or over-expression of dominant negative c-Jun potentiated celastrol protection against Cd-induced cell death. Furthermore, pre-treatment with celastrol prevented Cd down-regulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and activation of phosphoinositide 3'-kinase/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling in neuronal cells. Over-expression of wild-type PTEN enhanced celastrol inhibition of Cd-activated Akt/mTOR signaling and cell death in neuronal cells. The findings indicate that celastrol prevents Cd-induced neuronal cell death via targeting JNK and PTEN-Akt/mTOR network. Our results strongly suggest that celastrol may be exploited for the prevention of Cd-induced neurodegenerative disorders. Celastrol, a plant-derived triterpene, has shown neuroprotective effects. However, little is known regarding the effect of celastrol on cadmium (Cd) neurotoxicity. This study underscores that celastrol prevents Cd-induced neuronal apoptosis via inhibiting activation of JNK (c-Jun N-terminal kinase) and Akt/mTOR network. Celastrol suppresses Cd-activated Akt/mTOR pathway by elevating PTEN (phosphatase and tensin homolog). The findings suggest that celastrol may be exploited for the prevention of Cd-induced neurodegenerative disorders.
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Cloruro de Cadmio/toxicidad , Contaminantes Ambientales/toxicidad , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Triterpenos/farmacología , Animales , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Neuronas/citología , Neuronas/metabolismo , Células PC12 , Fosfohidrolasa PTEN/metabolismo , Triterpenos Pentacíclicos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
AIMS: This study explores the neuroprotective effects and mechanisms of N-acetyl-L-cysteine (NAC) in mice exposed to cadmium (Cd). METHODS: NAC (150 mg/kg) was intraperitoneally administered to mice exposed to Cd (10-50 mg/L) in drinking water for 6 weeks. The changes of cell damage and death, reactive oxygen species (ROS), antioxidant enzymes, as well as Akt/mammalian target of rapamycin (mTOR) signalling pathway in brain neurones were assessed. To verify the role of mTOR activation in Cd-induced neurotoxicity, mice also received a subacute regimen of intraperitoneally administered Cd (1 mg/kg) with/without rapamycin (7.5 mg/kg) for 11 days. RESULTS: Chronic exposure of mice to Cd induced brain damage or neuronal cell death, due to ROS induction. Co-administration of NAC significantly reduced Cd levels in the plasma and brain of the animals. NAC prevented Cd-induced ROS and significantly attenuated Cd-induced brain damage or neuronal cell death. The protective effect of NAC was mediated, at least partially, by elevating the activities of Cu/Zn-superoxide dismutase, catalase and glutathione peroxidase, as well as the level of glutathione in the brain. Furthermore, Cd-induced activation of Akt/mTOR pathway in the brain was also inhibited by NAC. Rapamycin in vitro and in vivo protected against Cd-induced neurotoxicity. CONCLUSIONS: NAC protects against Cd-induced neuronal apoptosis in mouse brain partially by inhibiting ROS-dependent activation of Akt/mTOR pathway. The findings highlight that NAC may be exploited for prevention and treatment of Cd-induced neurodegenerative diseases.
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Acetilcisteína/farmacología , Apoptosis/efectos de los fármacos , Encéfalo/efectos de los fármacos , Cadmio/toxicidad , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Animales , Encéfalo/metabolismo , Encéfalo/ultraestructura , Cadmio/sangre , Masculino , Ratones , Ratones Endogámicos ICR , Neuronas/metabolismo , Neuronas/ultraestructura , Estrés Oxidativo/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
OBJECTIVE: Weight regain after weight loss is a challenge in obesity management. The metabolic changes and underlying mechanisms in obese people with weight fluctuation remain to be elucidated. In the present study, we aimed to profile the features and clinical significance of liver transcriptome in obese mice with weight regain after weight loss. METHODS: The male C57BL/6J mice were fed with standard chow diet or high-fat diet (HFD). After 9 weeks, the HFD-induced obese mice were randomly divided into weight gain (WG), weight loss (WL) and weight regain (WR) group. After 10 weeks of dietary intervention, body weight, fasting blood glucose (FBG), intraperitoneal glucose tolerance, triglycerides (TG), total cholesterol (T-CHO) and low-density lipoprotein cholesterol (LDL-C) were measured. Morphological structure and lipid droplet accumulation in the liver were observed by H&E staining and oil red O staining, respectively. The liver transcriptome was detected by RNA sequencing. Protein expressions of liver cytochrome P450 3a11 (Cyp3a11) and E4 promoter-binding protein 4 (E4bp4) were determined by Western blot. RESULTS: After 10 weeks of dietary intervention, the body weight, FBG, glucose area under the curve, T-CHO and LDL-C in WL group were significantly lower than those in WG group (P < 0.05). At 4 weeks of HFD re-feeding, the mice in WR group presented body weight and T-CHO significantly lower than those in WG group, whereas higher than those in WL group (P < 0.05). Hepatic vacuolar degeneration and lipid droplet accumulation in the liver were significantly alleviated in WL group and WR group, compared to those in WG group. The liver transcriptome associated with lipid metabolism was significantly altered during weight fluctuation in obese mice. Compared with those in WG group, Cyp3a11 in the liver was significantly upregulated, and E4bp4 was significantly downregulated in WL and WR groups. CONCLUSION: Obese mice experience weight regain after weight loss by HFD re-feeding, but their glucose and lipid metabolism disorders are milder than those induced by the persistence of obesity. Downregulated E4bp4 and upregulated Cyp3a11 are detected in obese mice after weight loss, suggesting that the E4bp4-Cyp3a11 axis may involved in metabolic mechanisms underlying weight regulation.
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Thymoma with Immunodeficiency (Good's Syndrome, GS) is a rare association between thymoma and immunodeficiency, first described over 60 years ago. Patients with GS typically present with thymomas, reduced or absent B cells in the peripheral blood, hypogammaglobulinemia, and defects in cell-mediated immunity. We report the case of a 67-year-old woman diagnosed with GS following the development of a progressive, severe, refractory pulmonary infection and diffuse panbronchiolitis (DPB). She also had diabetes, characterized by anti-glutamic acid decarboxylase antibody positivity, leading to a diagnosis of latent autoimmune diabetes in adults (LADA). A thorough review of existing literature revealed that GS is often confirmed after multiple episodes of opportunistic infections or autoimmune diseases post-thymoma surgery. Due to their immunodeficiency, GS patients frequently suffer from recurrent infections over extended periods, and some succumb to severe infections. Regular immunoglobulin infusions may be effective in treating GS.
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Background and Aims: To construct a bleeding events prediction model of nonvalvular atrial fibrillation (NVAF) patients receiving rivaroxaban. Methods: We conducted a retrospective cohort study in patients with NVAF who received rivaroxaban from June 2017 to March 2019. Demographic information and clinical characteristics were obtained from the electronic medical system. Univariate analysis was used to find the primary predictive factors of bleeding events in patients receiving rivaroxaban. Multiple analysis was conducted to screen the primary independent predictive factors selected from the univariate analysis. Finally, the independent influencing factors were applied to build a prediction model by using R software; then, a nomogram was established according to the selected variables visually, and the sensitivity and specificity of the model was evaluated. Results: Twelve primary predictive factors were selected by univariate analysis from 46 variables, and multivariate analysis showed that older age, higher prothrombin time (PT) values, history of heart failure and stroke were independent risk factors of bleeding events. The area under curve (AUC) for this novel nomogram model was 0.828 (95% CI: 0.763-0.894). The mean AUC over 10-fold stratified cross-validation was 0.787, and subgroup analysis validation also showed a satisfied AUC. In addition, the decision curve analysis showed that the PT in combination with CHA2DS2-VASc and HASBLED was more practical and accurate for predicting bleeding events than using CHA2DS2-VASc and HASBLED alone. Conclusions: PT in combination with CHA2DS2-VASc and HASBLED could be considered as a more practical and accurate method for predicting bleeding events in patients taking rivaroxaban.
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OBJECTIVE: The aim of this study was to explore the effect of the ketogenic diet (KD) on ß-cell dedifferentiation and hepatic lipid accumulation in db/db mice. METHODS: After a 3-wk habituation, male db/db mice ages 8 wk were assigned into one of three groups: normal diet (ND), KD, and 75% calorie restriction (CR) group. Free access to a standard diet, a KD, and 75% of a standard diet, respectively, were given to each group. Additionally, sex-matched 8-wk-old C57BL/6 mice were used to construct a control (C) group. After a 4-wk dietary intervention, mouse body weight, fasting blood glucose (FBG), blood lipids, fasting insulin (FINS), glucose tolerance, and ß-hydroxybutyric acid level were measured. The morphologies of the islet and liver were observed by hematoxylin and eosin staining. Positive expressions of ß-cell-specific transcription factors in mouse islets were determined by double immunofluorescence staining. The size and number of lipid droplets in mouse liver were examined by Oil Red O staining. Real-time quantitative reverse transcription polymerase chain reaction detected relative levels of adipogenesis-associated and lipolysis-associated genes in mouse liver. Additionally, expressions of CD36 protein in the mouse liver were determined by immunohistochemical staining and Western blot. RESULTS: After a 4-wk dietary intervention, FBG, FINS, and glucose area under the curve in the KD group became significantly lower than in the ND group (all P < 0.05). Regular morphology of mouse islets was observed in the KD group, with an increased number of islet cells. The KD significantly reversed the decrease in ß-cell number, disarrangement of ß-cells, decline of ß/α-cell ratio, and downregulation of ß-cell-specific transcription factors in db/db mice. Serum levels of triacylglycerol, total cholesterol, and low-density lipoprotein cholesterol were comparable between the ND and KD groups. In contrast, serum triacylglycerol levels were significantly lower in the CR group than in the ND group (P < 0.05). Vacuolar degeneration and lipid accumulation in the liver were more prominent in the KD group than in the ND and CR groups. The mRNA levels of Pparα and Acox1 in the KD group were lower than those in the ND group, although no significant differences were detected. Relative levels of Cd36 and inflammatory genes in the mouse liver were significantly higher in the KD group than in the ND group (all P < 0.05). CONCLUSION: The KD significantly reduced FBG and FINS and improved glucose tolerance in db/db mice by upregulating ß-cell-specific transcription factors and reversing ß-cell dedifferentiation. However, the KD also induced hepatic lipid accumulation and aggravated inflammatory response in the liver of db/db mice.
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Dieta Cetogénica , Masculino , Ratones , Animales , Desdiferenciación Celular , Ratones Endogámicos C57BL , Hígado/metabolismo , Glucosa/metabolismo , Triglicéridos , Lípidos , Colesterol , Factores de Transcripción/metabolismo , Glucemia/metabolismoRESUMEN
BACKGROUND: The pathophysiology of Graves' disease (GD) involves imbalances between follicular helper T (Tfh) and follicular regulatory T (Tfr) cells, as well as oxidative stress (OS). Prunella vulgaris L. (Xia Ku Cao, XKC) and its primary bioactive compound, luteolin, are recognized for their potential in treating GD. Yet, the mechanism accounting for the immune-modulatory and antioxidant effects of XKC remains elusive. PURPOSE: This study aims to evaluate the pharmacological effects and elucidate the underlying mechanism of XKC and luteolin in a GD mouse model induced by recombinant adenovirus of TSH receptor A subunit (Ad-hTSHR-289). METHODS: High-Performance Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry (HPLC-QTOF MS) was used to detect the constituents of XKC. The GD model was established through inducing female BALB/c mice with three intramuscular injections of Ad-TSHR-289. Thyroid function, autoantibody and OS parameters were measured by ELISA. Changes of Tfh cells and Tfr cells were detected by flow cytometry. RT-qPCR, Western Blotting, immunohistochemistry were used to explore the related molecular mechanisms. RESULTS: A total of 37 chemical components from XKC were identified by HPLC-QTOF MS, represented by flavonoids, steroids, terpenoids, and luteolin. XKC and luteolin reduced T4, TRAb levels and facilitated the recovery from thyroid damage in GD mice. Meanwhile, XKC and luteolin effectively alleviated OS by decreasing the levels of MDA, NOX2, 4-HNE, 8-OHdG, while increasing GSH level. Flow cytometry showed that XKC and luteolin restored the abnormal proportions of Tfh/Tfr and Tfh/Treg, and the mRNA levels of IL-21, Bcl-6 and Foxp3 in GD mice. In addition, XKC and luteolin inhibited PI3K, Akt, p-PI3K and p-Akt, but activated Nrf2 and HO-1. CONCLUSION: XKC and luteolin could inhibit the development of GD in vivo by rebalancing Tfh/Tfr cells and alleviating OS. This therapeutic mechanism may involve the Nrf2/HO-1 and PI3K/Akt signaling pathways. Luteolin is the main efficacy material basis of XKC in countering GD. For the first time, we revealed the mechanism of XKC and luteolin in the treatment of GD from the perspective of autoimmune and OS.
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Modelos Animales de Enfermedad , Enfermedad de Graves , Luteolina , Ratones Endogámicos BALB C , Estrés Oxidativo , Prunella , Linfocitos T Reguladores , Animales , Luteolina/farmacología , Estrés Oxidativo/efectos de los fármacos , Enfermedad de Graves/tratamiento farmacológico , Femenino , Linfocitos T Reguladores/efectos de los fármacos , Prunella/química , Ratones , Células T Auxiliares Foliculares/efectos de los fármacos , Extractos Vegetales/farmacología , Extractos Vegetales/química , Glándula Tiroides/efectos de los fármacos , Antioxidantes/farmacología , Linfocitos T Colaboradores-Inductores/efectos de los fármacosRESUMEN
B-cell activating factor of the TNF family (BAFF, also called BLyS, TALL-1, THANK, or zTNF4) has revealed its critical function in B lymphocyte proliferation and survival, as well as the pathogenesis of autoimmune disease. However, the molecular mechanisms of excess BAFF-extended aggressive B lymphocytes have not been completely defined. Here we show that excessive hsBAFF-elevated [Ca(2+)]i activated mammalian target of rapamycin (mTOR) signaling pathway, leading to proliferation and survival in B lymphocytes. This is supported by the findings that intracellular Ca(2+) chelator (BAPTA/AM) or mTOR inhibitor (rapamycin) abolished the events. Sequentially, we observed that preventing [Ca(2+)]i elevation using EGTA or 2-APB dramatically inhibited hsBAFF activation of mTOR signaling, as well as cell growth and survival, suggesting that hsBAFF-induced extracellular Ca(2+) influx and ER Ca(2+) release elevates [Ca(2+)]i contributing to B lymphocyte proliferation and survival via activation of mTOR signaling. Further, we noticed that pretreatment with BAPTA/AM, EGTA or 2-APB blocked hsBAFF-increased phosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII), and inhibiting CaMKII with KN93 attenuated hsBAFF-activated mTOR signaling, as well as cell growth and survival, revealing that the effects of hsBAFF-elevated [Ca(2+)]i on mTOR signaling as well as proliferation and survival in B lymphocytes is through stimulating phosphorylation of CaMKII. The results indicate that hsBAFF activates mTOR pathway triggering B lymphocyte proliferation and survival by calcium signaling. Our findings suggest that manipulation of intracellular Ca(2+) level or CaMKII and mTOR activity may be exploited for the prevention of excessive BAFF-induced aggressive B lymphocyte disorders and autoimmune diseases.
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Factor Activador de Células B/metabolismo , Linfocitos B/fisiología , Señalización del Calcio , Activación de Linfocitos , Serina-Treonina Quinasas TOR/metabolismo , Animales , Linfocitos B/metabolismo , Compuestos de Boro/química , Calcio/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular , Células Cultivadas , Quelantes/farmacología , Ácido Egtácico/análogos & derivados , Ácido Egtácico/farmacología , Activación Enzimática , Humanos , Inmunosupresores/farmacología , Activación de Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos ICR , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidoresRESUMEN
[This corrects the article DOI: 10.3389/fmed.2022.996442.].
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ETHNOPHARMACOLOGICAL RELEVANCE: Xiehuo Xiaoying decoction (XHXY) has shown great potential in the treatment of GD, but its mechanism remains obscure. Increase of follicular helper T (Tfh) cells and reduction of follicular regulatory T (Tfr) cells contribute to a high thyrotropin receptor antibodies (TRAb) level and possible Graves' disease (GD). Oxidative stress (OS) disrupts T helper cell differentiation and aggravates autoimmunity. AIM OF THE STUDY: This study aimed to investigate whether XHXY decoction can ameliorate autoimmunity in GD via inhibiting OS and regulating Tfh and Tfr cells. MATERIALS AND METHODS: The main XHXY bioactive compounds were identified using high-performance liquid chromatography quadrupole time-of-flight mass spectrometry. GD was induced in the mice through three intramuscular injections of adenovirus expressing the TSH receptor. Then, the mice received oral gavage of XHXY (17 g/kg·d) and 34 g/kg·d) for 4 weeks. OS indicators were assessed. Flow cytometry was used to confirm the proportion of Tfh and Tfr cells in the lymph nodes and spleens of the mice. Cytokine expression levels were determined using enzyme-linked immunosorbent assay. Factors including interleukin-21, B-cell lymphoma-6, and forkhead box P3 (Foxp3) were detected using quantitative polymerase chain reaction. The mRNA and protein expression levels of Kelch-like ECH-associated protein 1 (Keap1), nuclear factor erythroid-2-related factor 2 (Nrf2), and haem oxygenase 1 (HO-1) were detected using quantitative polymerase chain reaction and Western blotting, respectively. RESULTS: Twelve main ingredients of XHXY were identified. XHXY relieved GD by lowering thyroxine (p < 0.01) and TRAb levels (p < 0.01). XHXY ameliorated OS by decreasing the levels of NADPH oxidase 2 (p < 0.05), 4-hydroxynonenal (p < 0.01), and 8-oxo-2'-deoxyguanosine (p < 0.001). It inhibited Tfh cell expansion (p < 0.05), as well as the production of cytokine interleukin -21 (p < 0.01), interleukin -4 (p < 0.01) and transcription factor B-cell lymphoma 6 (p < 0.05). XHXY also induced Tfr cell amplification (p < 0.05), increased the production of interleukin -10 (p < 0.05) and transforming growth factor ß (p < 0.05) and the mRNA levels of Foxp3 (p < 0.05). Finally, the Tfh/Tfr ratio returned to normal. In addition, XHXY activated Nrf2 and HO-1 expression, but inhibited Keap1 activation. CONCLUSIONS: XHXY relieves autoimmunity in GD via inhibiting Tfh cell amplification and Tfr cell reduction, a mechanism which probably involves the Keap1/Nrf2 signaling pathway.
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Enfermedad de Graves , Linfoma de Células B , Animales , Ratones , Citocinas/metabolismo , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Enfermedad de Graves/tratamiento farmacológico , Enfermedad de Graves/metabolismo , Interleucinas/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Linfoma de Células B/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , ARN Mensajero/metabolismo , Células T Auxiliares Foliculares , Linfocitos T Colaboradores-Inductores , Linfocitos T Reguladores , Medicina Tradicional ChinaRESUMEN
Objective: The objective of the present study was to describe and analyze the clinical characteristics of nocardiosis. Materials and methods: We described and analyzed the clinical characteristics of nocardiosis cases from two centers over the past 5 years from the following aspects: age and sex, Nocardia species, sites of Nocardia infection, test specimens, detection methods, concurrent pathogens, symptoms, imaging features, co-conditions, drug susceptibility tests, antibiotic therapy/duration, outcomes, and follow-up. Results: The median age of the 19 cases was 64 years, with an interquartile range (IQR) of 56-68 years. Eight cases (42.1%) were immunocompromised [those who had been on corticosteroid use (62.5%), those who had used immunosuppressants (50.0%), or those who had suffered from chronic nephrosis (37.5%) or diabetes mellitus (DM) (25.0%)]. The plethora of comorbidities of these cases included diabetes (10.5%), chronic kidney disease (CDK) (15.8%), chronic lung disease (36.8%), and rheumatic diseases (10.5%). Cough and expectoration (73.7%) was the most common symptom of nocardiosis. The respiratory tract (89.5%) was the most common site of the clinical disease. Nearly half (9 cases, 47.3%) of these patients had concurrent infections. The most common Nocardia isolation site was the respiratory tract (73.7%). All patients were given antibiotic therapies, out of whom as many as 63.6% of patients were treated with two concurrent antimicrobial agents, 15.8% of patients were treated under monotherapy and 21.1% of patients were treated with three or more concurrent antimicrobial agents. Conclusions: An uncommon life-threatening infection, nocardiosis, affects those patients with structural lung disease or immunosuppression. Although nocardiosis is capable of progressing into a serious and metastatic disease, early recognition and prompt treatment usually result in successful outcomes benefitting the patient.
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Olanzapine is a second-generation antipsychotic drug that is often used to treat schizophrenia and manic attacks. An increasing number of cases in recent years have shown that olanzapine is associated with vascular thromboembolic disease (VTD). Here, we reported a case of patient with history of taking aripiprazole, benzhexol, olanzapine, and sertraline for 5 years. He was admitted because of aggravated chest tightness, chest pain, and shortness of breath sustaining for 3 days. Laboratory examination and computed tomography angiography of the chest revealed new pulmonary embolus which involved the main trunk of the pulmonary artery and bilateral pulmonary arteries, with pneumonic infiltration in the left upper lobe. After thrombolytic therapy, the patient was out of danger.
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BACKGROUND: Stimulator of IFN genes (STING) is highly expressed in the livers of non-alcoholic fatty liver disease (NAFLD) patients and high fat diet (HFD) induced NAFLD mice model. The STING signaling-mediated inflammation has been shown to play a critical role in metabolic disorders. Lingguizhugan decoction (LGZG), a Traditional Chinese herbal decoction, has been applied to treat metabolic disorders for many years. However, whether LGZG can alleviate the progression of NAFLD through inhibiting inflammation remains unclear. This study was to determine the role of STING-mediated inflammation in the HFD-induced hepatic-lipid deposition treated with LGZG. METHODS: The anti-inflammatory and anti-steatotic effects of LGZG in vivo were detected by H&E staining, immunofluorescence and immuno-chemistry. Mice bone-marrow-derived macrophages (BMDMs) and primary liver macrophages were treated with STING-specific agonist (DMXAA), LGZG and its critical components respectively. The treated culture supernatant of BMDMs and primary liver macrophages from each group was co-cultured with palmitic acid-treated mouse primary hepatocytes or mouse liver cell line AML-12 respectively to detect whether the activation of STING-mediated pathway is involved in the anti-steatotic effect of LGZG. The hepatocyte lipid deposition in vivo and in vitro were detected by oil red staining. Mitochondrial DNA release of mouse liver extracts were detected by real time PCR. The expression of proteins and inflammatory cytokines related to STING-TBK1-NF-κB pathway was detected by western blotting and ELISA. RESULTS: LGZG significantly ameliorated HFD induced hepatic steatosis, oxidative stress, hepatic mitochondrial damage and mitochondrial DNA release, which was correlated with reduction of the expression level of STING as well as the infiltration of STING-positive macrophages in the livers of HFD fed mice. The critical components of LGZG directly inhibited the activation of STING-TBK1-NF-κB pathway in liver macrophages induced by DMXAA, LPS, thereby reducing the release of IFNß and TNFα. Co-incubating the culture supernatant of LGZG treated liver macrophages and PA-stimulated hepatocytes significantly inhibited the PA-induced lipid deposition. CONCLUSION: This study demonstrates that LGZG can ameliorate HFD-induced hepatic-lipid deposition through inhibiting STING-TBK1-NF-κB pathway in liver macrophages, which provides novel insight for elucidating the molecular mechanism of LGZG alleviating HFD induced hepatic steatosis.
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Reactive oxygen species (ROS) produced in the ischemic myocardium can induce cardiomyocyte injury and death, resulting in cardiac remodeling. Ferroptosis, known as a newly type of cell death caused by iron-dependent oxidative stress, which is an essential death mechanism in cardiomyocytes. However, it is unclear whether oxidative stress products can further induce ferroptosis and aggravate cardiomyocyte injury. Geniposide (GEN), a major active component of Gardenia jasminoides J. Ellis, possesses the natural antioxidant activity and cardioprotective effect. Herein, we evaluated the role of ferroptosis in myocardial oxidative injury and the protective effect of GEN on myocardial ferroptosis. We first detected iron overload, massive ROS, and lipid peroxidation in ferric ammonium citrate (FAC)-treated cardiomyocytes, which were typical characteristics of ferroptosis. The iron overload-induced oxidative stress and ferroptosis aggravated cardiomyocyte injury, which were significantly alleviated by GEN treatment. Similar phenotypic changes of ferroptosis were consistently discovered in hydrogen peroxide (H2O2)-induced cells, which were reversed by GEN treatment as well. Interestingly, the RNA-binding protein Grsf1, which directly upregulated Gpx4 at the translational level, was activated by GEN following myocardial oxidative injury. The specific knockdown of Grsf1 increased their sensitivity to ferroptosis and weakened the cardioprotective effect of GEN in H2O2-treated cardiomyocytes. Moreover, GEN treatment reduced iron overload and lipid peroxidation in myocardial infarction (MI) rats, thereby fighting against the cardiac ischemic injury. Collectively, our study revealed the pathogenesis of oxidative stress and ferroptosis associated with myocardial ischemia, and indicated the antioxidant and anti-ferroptosis effects of GEN on preventing myocardial injury by activating the Grsf1/GPx4 axis, serving as a potential therapeutic target.
RESUMEN
Accumulating evidence has highlighted the role of ferroptosis, a novel type of programmed cell death involved in the pathological process of myocardial infarction (MI). However, the underlying mechanism of ferroptosis in mediating MI is complicated that needs to be further investigated. Salvianolic acid B (Sal B) extracted from the traditional Chinese medicine (TCM) herb Salvia miltiorrhiza possesses pharmacological function against MI, which provides us with a new direction to explore the effect of Sal B on ferroptosis after myocardial ischemic injury. In the present study, iron accumulation and expression levels of ferroptosis-related proteins in MI rats altered in a time-dependent manner. Importantly, treatment of ferroptosis inhibitors ferrostatin-1 (Fer-1) or deferoxamine (DFO) reversed typical changes of ferroptosis, including iron overload, lipid peroxide accumulation, mitochondrial damage, and specific expression levels of ferroptosis-related proteins, thereby alleviating myocardial injury in rats. Similar results were observed in Sal B-treated MI rats in a dose-dependent manner. In addition, NFE2-related factor 2 (Nrf2) was strongly activated by the treatment of Sal B. In vivo knockdown of Nrf2 in MI rats enhanced ferroptosis and damaged the protective effect of Sal B on MI. Furthermore, Sal B administration was unable to significantly reverse expression levels of target genes of Nrf2 that were associated with iron homeostasis and oxidative stress (e.g., HO-1, xCT, Gpx4, Fth1, and Fpn1) in MI rats after knockdown of Nrf2. Taken together, Sal B contributed to protecting MI by inhibiting ferroptosis via activating the Nrf2 signaling pathway.
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Ferroptosis , Infarto del Miocardio , Ratas , Animales , Factor 2 Relacionado con NF-E2/metabolismo , Deferoxamina , Peróxidos Lipídicos/farmacología , Transducción de Señal , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/patología , HierroRESUMEN
Cadmium (Cd), a toxic environmental contaminant, induces neurodegenerative diseases. Recently, we have shown that Cd elevates intracellular free calcium ion ([Ca(2+) ](i) ) level, leading to neuronal apoptosis partly by activating mitogen-activated protein kinases (MAPK) and mammalian target of rapamycin (mTOR) pathways. However, the underlying mechanism remains to be elucidated. In this study, we show that the effects of Cd-elevated [Ca(2+) ](i) on MAPK and mTOR network as well as neuronal cell death are through stimulating phosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII). This is supported by the findings that chelating intracellular Ca(2+) with 1,2-bis(o-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl) ester or preventing Cd-induced [Ca(2+) ](i) elevation using 2-aminoethoxydiphenyl borate blocked Cd activation of CaMKII. Inhibiting CaMKII with KN93 or silencing CaMKII attenuated Cd activation of MAPK/mTOR pathways and cell death. Furthermore, inhibitors of mTOR (rapamycin), c-Jun N-terminal kinase (SP600125) and extracellular signal-regulated kinase 1/2 (U0126), but not of p38 (PD169316), prevented Cd-induced neuronal cell death in part through inhibition of [Ca(2+) ](i) elevation and CaMKII phosphorylation. The results indicate that Cd activates MAPK/mTOR network triggering neuronal cell death, by stimulating CaMKII. Our findings underscore a central role of CaMKII in the neurotoxicology of Cd, and suggest that manipulation of intracellular Ca(2+) level or CaMKII activity may be exploited for prevention of Cd-induced neurodegenerative disorders.
Asunto(s)
Cadmio/fisiología , Señalización del Calcio/genética , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/fisiología , Líquido Intracelular/enzimología , Sistema de Señalización de MAP Quinasas , Neuronas/enzimología , Neuronas/patología , Serina-Treonina Quinasas TOR/fisiología , Animales , Cadmio/toxicidad , Señalización del Calcio/efectos de los fármacos , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/genética , Muerte Celular/efectos de los fármacos , Muerte Celular/genética , Líquido Intracelular/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/genética , Células PC12 , Fosforilación/efectos de los fármacos , Fosforilación/genética , RatasRESUMEN
Microcystin -leucine-arginine (MC-LR), produced by freshwater cyanobacteria, is a potential pancreatic ß-cell toxin. In this study, the function of the mouse pancreatic ß-cell line, MIN6, was evaluated after MC-LR exposure, and the underlying molecular mechanisms were explored. Exposure to MC-LR for 24 h was found to inhibit cell viability and impair insulin secretion. Such findings indicate that ß-cell function would be impaired following MC-LR treatment. The microarray results revealed altered miRNA and mRNA expression profiles that might be responsible for the abnormal function of MIN6 cells. Further, miRNA-gene network analysis demonstrated that miR-29b-3p, miR-6967-5p, miR-3473, miR-7061-5p, Xkr4, Tmem178b, Scp2, Ypel2, and Kcnj11 are key miRNAs and genes in the MC-LR-induced MIN6-cell toxicity. The altered expression levels of several miRNAs (e.g., miR-320-5p, miR-770-5p, miR-99a-3p, and miR-375-5p) and genes (e.g., Pklr and Gpd2) involved in insulin secretion or the onset of diabetes were also identified in MIN6 cells after treatment with MC-LR. Collectively, these findings provide evidence of the toxic effects of MC-LR on ß-cells and the underlying molecular mechanisms of its glycometabolism toxicity. MCs may thus possibly play an important role in the development of diabetes mellitus in humans.