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1.
Int J Mol Sci ; 25(15)2024 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-39125645

RESUMO

Stress-induced alterations in central neuron metabolism and function are crucial contributors to depression onset. However, the metabolic dysfunctions of the neurons associated with depression and specific molecular mechanisms remain unclear. This study initially analyzed the relationship between cholesterol and depression using the NHANES database. We then induced depressive-like behaviors in mice via restraint stress. Applying bioinformatics, pathology, and molecular biology, we observed the pathological characteristics of brain cholesterol homeostasis and investigated the regulatory mechanisms of brain cholesterol metabolism disorders. Through the NHANES database, we initially confirmed a significant correlation between cholesterol metabolism abnormalities and depression. Furthermore, based on successful stress mouse model establishment, we discovered the number of cholesterol-related DEGs significantly increased in the brain due to stress, and exhibited regional heterogeneity. Further investigation of the frontal cortex, a brain region closely related to depression, revealed stress caused significant disruption to key genes related to cholesterol metabolism, including HMGCR, CYP46A1, ACAT1, APOE, ABCA1, and LDLR, leading to an increase in total cholesterol content and a significant decrease in synaptic proteins PSD-95 and SYN. This indicates cholesterol metabolism affects neuronal synaptic plasticity and is associated with stress-induced depressive-like behavior in mice. Adeno-associated virus interference with NR3C1 in the prefrontal cortex of mice subjected to short-term stress resulted in reduced protein levels of NRIP1, NR1H2, ABCA1, and total cholesterol content. At the same time, it increased synaptic proteins PSD95 and SYN, effectively alleviating depressive-like behavior. Therefore, these results suggest that short-term stress may induce cholesterol metabolism disorders by activating the NR3C1/NRIP1/NR1H2 signaling pathway. This impairs neuronal synaptic plasticity and consequently participates in depressive-like behavior in mice. These findings suggest that abnormal cholesterol metabolism in the brain induced by stress is a significant contributor to depression onset.


Assuntos
Colesterol , Depressão , Lobo Frontal , Estresse Psicológico , Animais , Masculino , Camundongos , Colesterol/metabolismo , Depressão/metabolismo , Depressão/etiologia , Modelos Animais de Doenças , Lobo Frontal/metabolismo , Metabolismo dos Lipídeos , Camundongos Endogâmicos C57BL , Estresse Psicológico/metabolismo
2.
Front Med (Lausanne) ; 11: 1441032, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39139790

RESUMO

Background: Light chain (AL) amyloidosis stands as the most prevalent subtype of systemic amyloidosis, encompassing a group of rare diseases. Here, we evaluated the scientific landscape of AL amyloidosis to investigate research trends and identify hotspots within the field. Methods: Relevant studies on AL amyloidosis published over the past two decades were retrieved from the Web of Science Core Collection. The publications between 2005 and 2024 were subjected to bibliometric analyses, leveraging tools including CiteSpace, VOSviewer, RStudio and MS Excel to analyse and visualize the annual publication trend, co-occurrence patterns, collaborative networks among countries, organizations, and authors. Burst keywords and references were also examined to obtain the research history, and emerging hotspots. Results: The bibliometric analysis included 2,864 articles published between 2005 and 2024. The most productive journal is Amyloid-Journal of Protein Folding Disorders. The United States, along with several developed nations, emerges as a dominant force in international AL amyloidosis research. "AL amyloidosis" and "cardiac amyloidosis" were the primary hotspots over the past two decades, and "Biomarkers," "Cardiac amyloidosis," and "treatment" would be future trends. Conclusion: This bibliometric analysis examined the research developments in AL amyloidosis over the past two decades using bibliometric software. Recent research in this field primarily focuses on two main areas: clinical diagnosis and treatment of AL amyloidosis, as well as cardiac amyloidosis. Emphasis is placed on understanding the mechanisms underlying immunoglobulin light chain aggregation and deposition to mitigate organ involvement.

3.
Sci Rep ; 14(1): 13543, 2024 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-38866996

RESUMO

The objective of this study was to investigate spleen pathology and immune cell subset alterations in mice exposed to acute and chronic restraint stress over various timeframes. A deeper understanding of stress-induced spleen injuries can provide new insights into the mechanisms underlying stress-induced disorders. C57BL/6N mice were restrained for different durations (1, 3, 7, 14 and 21 days) for 6-8 h daily. The control mice were observed at the same time points. Post restraint, behavioural experiments were conducted to assess spleen weight, gross morphology and microscopic histological changes. Immunohistochemical staining was used to detect changes in glucocorticoid receptor (GR) expression, immune cell subsets and cell proliferation in response to stress. Our analysis revealed significant behavioural abnormalities in the stressed mice. In particular, there was an increase in the nuclear expression of GR beginning on Day 3, and it peaked on Day 14. The spleens of stressed mice displayed a reduction in size, disordered internal tissue structure and reduced cell proliferation. NK cells and M2-type macrophages exhibited immune cell subset alterations under stress, whereas T or B cells remained unaltered. Restraint stress can lead to pathomorphological alterations in spleen morphology, cell proliferation and immune cell counts in mice. These findings suggest that stress-induced pathological changes can disrupt immune regulation during stress.


Assuntos
Camundongos Endogâmicos C57BL , Receptores de Glucocorticoides , Restrição Física , Baço , Estresse Psicológico , Animais , Baço/patologia , Baço/metabolismo , Receptores de Glucocorticoides/metabolismo , Camundongos , Masculino , Estresse Psicológico/imunologia , Proliferação de Células , Fatores de Tempo , Células Matadoras Naturais/imunologia , Estresse Fisiológico , Macrófagos/imunologia , Macrófagos/metabolismo
4.
J Cell Mol Med ; 28(12): e18494, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38890797

RESUMO

Stress triggers a comprehensive pathophysiological cascade in organisms. However, there is a substantial gap in the research regarding the effects of stress on liver function. This study aimed to investigate the impact of restraint stress on hepatocellular damage and elucidate the underlying molecular mechanisms. An effective mouse restraint stress model was successfully developed, and liver function analysis was performed using laser speckle imaging, metabolomics and serum testing. Alterations in hepatocyte morphology were assessed using haematoxylin and eosin staining and transmission electron microscopy. Oxidative stress in hepatocytes was assessed using lipid reactive oxygen species and malondialdehyde. The methylation status and expression of GSTP1 were analysed using DNA sequencing and, real-time PCR, and the expression levels of GPX4, TF and Nrf2 were evaluated using real-time quantitative PCR, western blotting, and immunohistochemical staining. A stress-induced model was established in vitro by using dexamethasone-treated AML-12 cells. To investigate the underlying mechanisms, GSTP1 overexpression, small interfering RNA, ferroptosis and Nrf2 inhibitors were used. GSTP1 methylation contributes to stress-induced hepatocellular damage and dysfunction. GSTP1 is involved in ferroptosis-mediated hepatocellular injury induced by restraint stress via the TF/Nrf2 pathway. These findings suggest that stress-induced hepatocellular injury is associated with ferroptosis, which is regulated by TF/Nrf2/GSTP1.

5.
Front Mol Neurosci ; 17: 1381098, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38685915

RESUMO

Prolonged or repeated exposure to stress elevates the risk of various psychological diseases, many of which are characterized by central nervous system dysfunction. Recent studies have demonstrated that circular RNAs (circRNAs) are highly abundant in the mammalian brain. Although their precise expression and function remain unknown, they have been hypothesized to regulate transcriptional and post-transcriptional gene expression. In this investigation, we comprehensively analyzed whether restraint stress for 2 days altered the circRNA expression profile in the amygdala of male rats. The impact of restraint stress on behavior was evaluated using an elevated plus maze and open field test. Serum corticosterone levels were measured using an enzyme-linked immunosorbent assay. A total of 10,670 circRNAs were identified using RNA sequencing. Ten circRNAs were validated by reverse transcription and quantitative polymerase chain reaction analysis. Gene ontology and Kyoto encyclopedia of genes and genomes pathway analyzes supported the notion that genes associated with differentially expressed circRNAs are primarily implicated in neuronal activity and neurotransmitter transport. Moreover, the three differentially expressed circRNAs showed high specificity in the amygdala. Overall, these findings indicate that differentially expressed circRNAs are highly enriched in the amygdala and offer a potential direction for further research on restraint stress.

6.
Lipids Health Dis ; 23(1): 68, 2024 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-38431645

RESUMO

BACKGROUND: Stress is implicated in various pathological conditions leading to liver injury. Existing evidence suggests that excessive stress can induce mitochondrial damage in hepatocytes, yet the underlying mechanism remains unclear. Ceramide synthase 6 (CerS6)-derived C16:0 ceramide is recognised as a lipotoxic substance capable of causing mitochondrial damage. However, the role of CerS6 in stress has received insufficient attention. This study aimed to explore the involvement of CerS6 in stress-induced hepatic damage and its associated mechanisms. METHODS: The rat restraint stress model and a corticosterone (CORT)-induced hepatocyte stress model were employed for in vivo and in vitro experimental analyses, respectively. Changes in mitochondrial damage and ceramide metabolism in hepatocytes induced by stress were evaluated. The impact of CORT on mitochondrial damage and ceramide metabolism in hepatocytes was assessed following CerS6 knockdown. Mitochondria were isolated using a commercial kit, and ceramides in liver tissue and hepatocytes were detected by LC-MS/MS. RESULTS: In comparison to the control group, rats subjected to one week of restraint exhibited elevated serum CORT levels. The liver displayed significant signs of mitochondrial damage, accompanied by increased CerS6 and mitochondrial C16:0 ceramide, along with activation of the AMPK/p38 MAPK pathway. In vitro studies demonstrated that CORT treatment of hepatocytes resulted in mitochondrial damage, concomitant with elevated CerS6 and mitochondrial C16:0 ceramide. Furthermore, CORT induced sequential phosphorylation of AMPK and p38 MAPK proteins, and inhibition of the p38 MAPK pathway using SB203580 mitigated the CORT-induced elevation in CerS6 protein. Knocking down CerS6 in hepatocytes inhibited both the increase in C16:0 ceramide and the release of mitochondrial cytochrome c induced by CORT. CONCLUSIONS: CerS6-associated C16:0 ceramide plays a mediating role in stress-induced mitochondrial damage in hepatocytes. The molecular mechanism is linked to CORT-induced activation of the AMPK/p38 MAPK pathway, leading to upregulated CerS6.


Assuntos
Proteínas Quinases Ativadas por AMP , Espectrometria de Massas em Tandem , Ratos , Animais , Proteínas Quinases Ativadas por AMP/metabolismo , Cromatografia Líquida , Ceramidas/metabolismo , Hepatócitos/metabolismo , Fígado/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Apoptose , Esfingosina N-Aciltransferase/genética , Esfingosina N-Aciltransferase/metabolismo
7.
Int J Mol Sci ; 25(5)2024 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-38474189

RESUMO

Coronary artery spasm (CAS) plays an important role in the pathogeneses of various ischemic heart diseases and has gradually become a common cause of life-threatening arrhythmia. The specific molecular mechanism of CAS has not been fully elucidated, nor are there any specific diagnostic markers for the condition. Therefore, this study aimed to examine the specific molecular mechanism underlying CAS, and screen for potential diagnostic markers. To this end, we successfully constructed a rat CAS model and achieved in vitro culture of a human coronary-artery smooth-muscle cell (hCASMC) contraction model. Possible molecular mechanisms by which protein kinase C (PKC) regulated CAS through the C kinase-potentiated protein phosphatase 1 inhibitor of 17 kDa (CPI-17)/myosin II regulatory light chain (MLC2) pathway were studied in vivo and in vitro to screen for potential molecular markers of CAS. We performed hematoxylin and eosin staining, myocardial zymogram, and transmission electron microscopy to determine myocardial and coronary artery injury in CAS rats. Then, using immunohistochemical staining, immunofluorescence staining, and Western blotting, we further demonstrated a potential molecular mechanism by which PKC regulated CAS via the CPI-17/MLC2 pathway. The results showed that membrane translocation of PKCα occurred in the coronary arteries of CAS rats. CPI-17/MLC2 signaling was observably activated in coronary arteries undergoing CAS. In addition, in vitro treatment of hCASMCs with angiotensin II (Ang II) increased PKCα membrane translocation while consistently activating CPI-17/MLC2 signaling. Conversely, GF-109203X and calphostin C, specific inhibitors of PKC, inactivated CPI-17/MLC2 signaling. We also collected the coronary artery tissues from deceased subjects suspected to have died of CAS and measured their levels of phosphorylated CPI-17 (p-CPI-17) and MLC2 (p-MLC2). Immunohistochemical staining was positive for p-CPI-17 and p-MLC2 in the tissues of these subjects. These findings suggest that PKCα induced CAS through the CPI-17/MLC2 pathway; therefore, p-CPI-17 and p-MLC2 could be used as potential markers for CAS. Our data provide novel evidence that therapeutic strategies against PKC or CPI-17/MLC2 signaling might be promising in the treatment of CAS.


Assuntos
Vasoespasmo Coronário , Animais , Humanos , Ratos , Biomarcadores/metabolismo , Morte Súbita Cardíaca , Fosfoproteínas/metabolismo , Fosforilação , Proteína Quinase C/metabolismo , Proteína Quinase C-alfa/metabolismo
8.
Brain Sci ; 14(2)2024 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-38391735

RESUMO

The amygdala is a core region in the limbic system that is highly sensitive to stress. Astrocytes are key players in stress disorders such as anxiety and depression. However, the effects of stress on the morphology and function of amygdala astrocytes and its potential mechanisms remain largely unknown. Hence, we performed in vivo and in vitro experiments using a restraint stress (RS) rat model and stress-induced astrocyte culture, respectively. Our data show that norepinephrine (NE) content increased, cytotoxic edema occurred, and aquaporin-4 (AQP4) expression was up-regulated in the basolateral amygdala (BLA) obtained from RS rats. Additionally, the p38 mitogen-activated protein kinase (MAPK) pathway was also observed to be significantly activated in the BLA of rats subjected to RS. The administration of NE to in vitro astrocytes increased the AQP4 level and induced cell edema. Furthermore, p38 MAPK signaling was activated. The NE inhibitor alpha-methyl-p-tyrosine (AMPT) alleviated cytotoxic edema in astrocytes, inhibited AQP4 expression, and inactivated the p38 MAPK pathway in RS rats. Meanwhile, in the in vitro experiment, the p38 MAPK signaling inhibitor SB203580 reversed NE-induced cytotoxic edema and down-regulated the expression of AQP4 in astrocytes. Briefly, NE-induced activation of the p38 MAPK pathway mediated cytotoxic edema in BLA astrocytes from RS rats. Thus, our data provide novel evidence that NE-induced p38 MAPK pathway activation may be one of the mechanisms leading to cytotoxic edema in BLA under stress conditions, which also could enable the development of an effective therapeutic strategy against cytotoxic edema in BLA under stress and provide new ideas for the treatment of neuropsychiatric diseases.

9.
Forensic Sci Int ; 354: 111912, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38103455

RESUMO

INTRODUCTION: Objective assessment of cardiac hypertrophy in forensic pathology practice is of great significance for forensic pathologists, for whom reference values for normal heart weights are needed. Developed regions such as Europe, the United States, and Japan recalculate the weight of human organs at regular intervals, but in China, there has been no systematic calculation of the weights of human organs since 2006. AIMS: To statistically analyse the heart weight of Chinese adults postmortem and obtain a reference range. MATERIALS AND METHODS: 4170 adult autopsy reports were collected from 12 forensic departments in 10 provinces in China. The causes of death were classified by sex, and heart weight and the heart weight/body height ratio reference values were further calculated according to different body mass index and body heights. Finally, the cutoff value of cardiac hypertrophy in Chinese adults was calculated. RESULTS: In the group of non-cardiovascular disease causes of death, the cardiac weight of the electric death group was higher, while the heart weight of the prolonged bed-rest group was significantly reduced. After the electric death and prolonged bed-rest groups were excluded, heart weight, the heart weight/body height ratio, and cutoff values for cardiac hypertrophy were further classified and analysed according to body mass index. The mean reference values for heart weight in men and women with normal weight status were 325.82 ± 41.60 g and 286.39 ± 44.84 g, and the heart weight/body height ratios were 1.95 ± 0.23 in men and 1.82 ± 0.27, respectively. The cutoff values for cardiac hypertrophy were 387.35 g for men and 346.80 g for women. CONCLUSION: The heart weight reference values of both sexes in this study were significantly higher than those in 2006, which is considered related to the development of China's economy and the improvement of people's living standards. This study also suggests the need for a new round of statistical surveys and updated data on the weight of other organs.


Assuntos
Cardiomegalia , Coração , Masculino , Adulto , Humanos , Feminino , Autopsia , Patologia Legal , China , Peso Corporal , Tamanho do Órgão
10.
Brain Res Bull ; 206: 110861, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38141789

RESUMO

Based on the successful establishment of a rat model of chronic restraint stress, we used multiple algorithms to quantify the morphological changes of rat hypothalamic microglia from various perspectives, providing a pathomorphological basis for the subsequent study of molecular mechanisms of hypothalamic stress injury, such as neuroinflammation. To verify the successful establishment of the chronic stress model, an enzyme-linked immunosorbent assay was performed to detect serum glucocorticoid levels. Microglia labeled with Iba1 in frozen sections of rat hypothalamus were scanned and photographed at multiple levels using confocal microscopy. Subsequently, images were processed for external contouring and skeletonization, and morphological indices of microglia were calculated and analyzed using fractal, skeleton, and Sholl analysis. In addition, the co-expression of CD68 (a marker that can reflect phagocytic activity) and Iba1 was observed by immunofluorescence technique. Compared with the control group, microglia in the chronic stress group displayed reduced fractal dimension and lacunarity, increased density and circularity, enlarged soma areas, and shortened and reduced branches. Sholl analysis confirmed the reduced complexity of microglia following chronic stress. Meanwhile, microglia CD68 increased significantly, indicating that the microglia in the chronic stress group have greater phagocytosis activity. In summary, chronic restraint stress promoted the conversion of microglia in the rat hypothalamus to a less complex form, manifested as larger soma, shorter and fewer branches, more uniform and dense texture, and increased circularity; indeed, the shape of these microglia resembled that of amoeba and they displayed strong phagocytosis activity.


Assuntos
Hipotálamo , Microglia , Ratos , Animais
11.
Exp Biol Med (Maywood) ; 248(20): 1718-1731, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37787155

RESUMO

Immune balance is crucial for an organism's survival and is inseparable from the regulation of the nervous system. Accumulating evidence indicates that cholecystokinin (CCK) plays an important role in mediating the immune response through the activation of cholecystokinin receptors (CCKRs). However, it remains unclear whether CCKRs deficiency may impair immune balance. Here, we showed that CCK2R-deficient adult mice were immunocompromised and had an increased risk of shock and even death in an endotoxemia (ETM)/endotoxin shock (ES) model. In addition, in both adult and juvenile mice, CCK2R deficiency not only influenced the development of CD4 single-positive (SP) thymocytes in thymic positive selection but also decreased the population of CD3+ CD4+ T cells in the spleen. More importantly, CCK2R deficiency inhibited the expression of major histocompatibility complex class II (MHC II) and CD83 on cortical thymic epithelial cells (cTECs) in juvenile and adult mice. Overall, our study suggests that CCK2R is essential for maintaining CD4+ T cell development in the thymus and reveals that CCK2R plays an important role in maintaining immune balance.


Assuntos
Receptor de Colecistocinina B , Linfócitos T , Camundongos , Animais , Receptor de Colecistocinina B/genética , Antígenos de Histocompatibilidade Classe II/metabolismo , Timo , Células Epiteliais/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Camundongos Endogâmicos C57BL
12.
Materials (Basel) ; 16(17)2023 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-37687456

RESUMO

The duration of ball milling greatly influences the characteristics of high-silicon-aluminum composite during the ball milling process. This study examines how the microstructure, thermal conductivity, and hardness of a high-silicon-aluminum composite are affected by different ball milling times. We exposed the powder to various durations of ball milling and employed different pellet ratios. Following this treatment, the powder underwent consolidation via discharge plasma sintering. Our findings show that with a pellet ratio of 10:1 and a milling duration of 8 h, the powder particles were refined, resulting in a more uniform and dense material composition. This refined material boasted a thermal conductivity of 111.6 W/m·K, a Brinell hardness of 136.8 HBW, and a density of 2.304 g/cm3. This method facilitates the creation of a uniform composite powder composition. It encourages the development of a fine-grain structure, which enables the production of particle-reinforced composites with superior properties.

13.
Int J Mol Sci ; 24(16)2023 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-37629166

RESUMO

The dorsomedial hypothalamus nucleus (DMH) is an important component of the autonomic nervous system and plays a critical role in regulating the sympathetic outputs of the heart. Stress alters the neuronal activity of the DMH, affecting sympathetic outputs and triggering heart rate variability. However, the specific molecular mechanisms behind stress leading to abnormal DMH neuronal activity have still not been fully elucidated. Therefore, in the present study, we successfully constructed a stressed rat model and used it to investigate the potential molecular mechanisms by which IL-6 regulates GABAA receptors in the DMH through activation of the JAK/STAT pathway and thus affects heart rate variability in rats. By detecting the c-Fos expression of neurons in the DMH and electrocardiogram (ECG) changes in rats, we clarified the relationship between abnormal DMH neuronal activity and heart rate variability in stressed rats. Then, using ELISA, immunohistochemical staining, Western blotting, RT-qPCR, and RNAscope, we further explored the correlation between the IL-6/JAK/STAT signaling pathway and GABAA receptors. The data showed that an increase in IL-6 induced by stress inhibited GABAA receptors in DMH neurons by activating the JAK/STAT signaling pathway, while specific inhibition of the JAK/STAT signaling pathway using AG490 obviously reduced DMH neuronal activity and improved heart rate variability in rats. These findings suggest that IL-6 regulates the expression of GABAA receptors via the activation of the JAK/STAT pathway in the DMH, which may be an important cause of heart rate variability in stressed rats.


Assuntos
Interleucina-6 , Receptores de GABA-A , Animais , Ratos , Frequência Cardíaca , Interleucina-6/genética , Janus Quinases , Fatores de Transcrição STAT , Transdução de Sinais , Hipotálamo
14.
J Cell Mol Med ; 27(21): 3313-3325, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37593898

RESUMO

Mitochondria are sensitive organelles that sense intrinsic and extrinsic stressors and maintain cellular physiological functions through the dynamic homeostasis of mitochondrial fusion and fission. Numerous pathological processes are associated with mitochondrial fusion and fission disorders. However, the molecular mechanism by which stress induces cardiac pathophysiological changes through destabilising mitochondrial fusion and fission is unclear. Therefore, this study aimed to investigate whether the endoplasmic reticulum stress signalling pathway initiated by the turbulence of mitochondrial fusion and fission under stressful circumstances is involved in cardiomyocyte damage. Based on the successful establishment of the classical stress rat model of restraint plus ice water swimming, we measured the content of serum lactate dehydrogenase. We used haematoxylin-eosin staining, special histochemical staining, RT-qPCR and western blotting to clarify the cardiac pathology, ultrastructural changes and expression patterns of mitochondrial fusion and fission marker proteins and endoplasmic reticulum stress signalling pathway proteins. The results indicated that mitochondrial fusion and fission markers and proteins of the endoplasmic reticulum stress JNK signalling pathway showed significant abnormal dynamic changes with the prolongation of stress, and stabilisation of mitochondrial fusion and fission using Mdivi-1 could effectively improve these abnormal expressions and ameliorate cardiomyocyte injury. These findings suggest that stress could contribute to pathological cardiac injury, closely linked to the endoplasmic reticulum stress JNK signalling pathway induced by mitochondrial fusion and fission turbulence.


Assuntos
Dinâmica Mitocondrial , Miócitos Cardíacos , Ratos , Animais , Miócitos Cardíacos/metabolismo , Transdução de Sinais , Estresse do Retículo Endoplasmático/genética
15.
Adv Healthc Mater ; 12(22): e2202871, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37276021

RESUMO

In situ vaccines have revolutionized immunotherapy as they can stimulate tumor-specific immune responses, with the cancer being the antigen source. However, the heterogeneity of tumor antigens and insufficient dendritic cells (DCs) activation result in low cancer immunogenicity and hence poor vaccine response. Herein, a new in situ vaccine composed of acid-responsive liposome-coated polydopamine (PDA) nanoparticles modified with mannose and loaded with resiquimod (R848) is designed to promote the efficacy of immunotherapy. The in situ vaccine can actively target the tumor site based on the decomposition of the liposome, while the PDA nanoparticles promote photothermal therapy and capture the immunogenic cell-death-induced tumor-associated antigens based on the adsorption effect of dopamine-mimetic mussels. The PDA nanoparticles, which are modified with a mannose ligand, target the DCs and release R848 for activated antigen presentation. As a result, the in situ vaccine not only effectively activates the maturation of the DCs but also significantly enhances their effect on cytotoxic T lymphocyte cells. Furthermore, the vaccine effectively inhibits the distant recurrence and metastasis of tumors via long-term immune memory effects. Therefore, the in situ vaccine provides a potential strategy for improving the efficacy of cancer immunotherapy.


Assuntos
Vacinas Anticâncer , Nanopartículas , Lipossomos , Terapia Fototérmica , Manose , Imunoterapia , Apresentação de Antígeno , Antígenos de Neoplasias , Vacinação , Vacinas Anticâncer/farmacologia , Células Dendríticas
16.
Anal Cell Pathol (Amst) ; 2023: 9979291, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37035018

RESUMO

Stress has become a universal biological phenomenon in the body, which leads to pathophysiological changes. However, the molecular network interactions between endoplasmic reticulum (ER) stress and ferroptosis under stressful conditions are not clear. For this purpose, we screened the gene expression profile of GSE173795 for intersection with ferroptosis genes and screened 68 differentially expressed genes (DEGs) (63 up-regulated, 5 down-regulated), mainly related to lipid and atherosclerosis, autophagy-animal, mitophagy-animal, focal adhesion, DNA replication, proteasome, oocyte meiosis, toll-like receptor signaling pathway, cell cycle, etc. Immune infiltration analysis revealed that stress resulted in decreased B cells memory, T cells CD8 and T cells CD4 memory resting, monocytes, macrophages M2, and increased B cells naive, T cells follicular helper, and macrophages M1. 19 core-DEGs (ASNS, TRIB3, ATF4, EIF2S1, CEBPG, RELA, HSPA5, DDIT3, STAT3, MAP3K5, HIF1A, HNF4A, MAPK14, HMOX1, CDKN1A, KRAS, SP1, SIRT1, EGFR) were screened, all of which were up-regulated DEGs. These biological processes and pathways were mainly involved in responding to ER stress, lipid and atherosclerosis, cellular response to stress, cellular response to chemical stress, and regulation of DNA-templated transcription in response to stress, etc. Spearman analysis did not find MAPK14 to be significantly associated with immune cells. Other core-DEGs were associated with immune cells, including B cells naive, T cells follicular helper, and monocytes. Based on core-DEGs, 283 miRNAs were predicted. Among the 22 miRNAs with highly cross-linked DEGs, 11 had upstream lncRNA, mainly targeting STAT3, SP1, CDKN1A, and SIRT1, and a total of 39 lncRNA were obtained. 85 potential drugs targeting 11 core-DEGs were identified and were expected to be potential immunotherapeutic agents for stress injury. Our experiments also confirmed that Liproxstatin-1 alleviates common cross-linked proteins between ER stress and ferroptosis. In conclusion, our study explored the molecular mechanisms and network interactions among stress-ER stress-ferroptosis from a novel perspective, which provides new research ideas for studying stressful injury.


Assuntos
Aterosclerose , Ferroptose , MicroRNAs , Proteína Quinase 14 Ativada por Mitógeno , RNA Longo não Codificante , Animais , Ferroptose/genética , Sirtuína 1 , Estresse do Retículo Endoplasmático/genética , Biologia Computacional/métodos , Lipídeos
17.
RSC Adv ; 13(4): 2631-2634, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36741167

RESUMO

A novel and metal catalyst-free synthesis of aryloxyacetamides from the corresponding arylboronic acids and 2-bromoacetonitrile promoted by alkaline solutions of hydrogen peroxide has been developed involving an oxidation-reduction of eco-friendly H2O2 with simultaneous reaction ipso-hydroxylation of arylboronic acid and hydration of the nitrile. This protocol is compatible with sensitive substituents attached to the arylboronic acid and provides desired products in moderate to good yields in pure water.

18.
Cell Death Dis ; 13(12): 1056, 2022 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-36539414

RESUMO

Retinal degeneration is a kind of neurodegeneration characterized by progressive neuronal death and dysfunction of retinal pigment epithelium (RPE) cells, leading to permanent visual impairment. It still lacks effective therapeutic options and new drugs are highly warranted. In this study, we found the expression of IL-4, a critical regulator of immunity, was reduced in both patients and mouse models. Importantly, exogenous intravitreal IL-4 application could exert a novel neuroprotective effect, characterized by well-preserved RPE layer and neuroretinal structure, as well as amplified wave-amplitudes in ERG. The RNA-seq analysis revealed that IL-4 treatment suppressed the essential oxidative and pro-inflammatory pathways in the degenerative retina. Particularly, IL-4 upregulated the IL-4Rα on RPE cells and induced a reparative phenotype via the activation of Nrf2 both in vitro and in vivo. Furthermore, the Nrf2-/- mice displayed no recovery in response to IL-4 application, highlighting a significant role of Nrf2 in IL-4-mediated protection. Our data provides evidence that IL-4 protects against retinal neurodegeneration by its antioxidant and anti-inflammatory property through IL-4Rα upregulation and Nrf2 activation in RPE cells. The IL-4/IL-4Rα-Nrf2 axis maybe the potential targets for the development of novel therapies for neurodegenerative diseases.


Assuntos
Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Animais , Camundongos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Interleucina-4/genética , Interleucina-4/farmacologia , Interleucina-4/metabolismo , Transdução de Sinais , Epitélio Pigmentado da Retina/metabolismo , Retina/metabolismo
19.
Front Cardiovasc Med ; 9: 970045, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36158819

RESUMO

We report findings in a 34-year-old female patient who presented with fulminant myocarditis 8 days after receiving the first dose of the ZF2001 RBD-subunit vaccine against coronavirus disease 2019 (COVID-19). Autopsy showed severe interstitial myocarditis, including multiple patchy infiltrations of lymphocytes and monocytes in the myocardium of the left and right ventricular walls associated with myocyte degeneration and necrosis. This report highlights the details of clinical presentations and autopsy findings of myocarditis after ZF2001 (RBD-subunit vaccine) vaccination. The correlation between vaccination and death due to myocarditis is discussed.

20.
Nano Lett ; 22(15): 6418-6427, 2022 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-35856800

RESUMO

Aberrant energy metabolism not only endows tumor cells with unlimited proliferative capacity but also contributes to the establishment of the glucose-deficient/lactate-rich immunosuppressive tumor microenvironment (ITM) impairing antitumor immunity. Herein, a novel metabolic nanoregulator (D/B/CQ@ZIF-8@CS) was developed by enveloping 2-deoxy-d-glucose (2-DG), BAY-876, and chloroquine (CQ) into zeolitic imidazolate framework-8 (ZIF-8) to simultaneously deprive the energy/nutrition supply of tumor cells and relieve the ITM for synergetic tumor starvation-immunotherapy. Aerobic glycolysis, glucose uptake, and autophagy flux could be concurrently blocked by D/B/CQ@ZIF-8@CS, cutting off the nutrition/energy supply and the source of lactate. Furthermore, inhibition of glucose uptake and aerobic glycolysis could effectively reverse the glucose-deficient/lactate-rich ITM, thus functionally inactivating regulatory T cells and augmenting anti-CTLA-4 immunotherapy. Such a two-pronged strategy would provide new insights for the design of metabolic intervention-based synergistic cancer therapy.


Assuntos
Glicólise , Neoplasias , Linhagem Celular Tumoral , Metabolismo Energético , Glucose/metabolismo , Humanos , Terapia de Imunossupressão , Lactatos , Neoplasias/tratamento farmacológico , Microambiente Tumoral
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