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1.
Toxicol Ind Health ; : 7482337221127148, 2022 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-36120900

RESUMO

C/EBP-homologous protein (CHOP) and histone H3 lysine 4 (H3K4) methylation have been verified to be correlated with apoptosis, whereas their biological function in arsenic-induced hepatocyte apoptosis through the mitochondrial pathway is still unclear. This study aimed to explore the specific regulatory mechanism of CHOP and H3K4me1/2 in arsenic-induced mitochondrial apoptosis in hepatocytes. Apoptosis and proliferation results showed arsenic promoted apoptosis and inhibited cell growth in BRL-3A cells. Meanwhile, arsenic treatment significantly upregulated the 78-kDa glucose-regulated protein (GRP78), CHOP, su(var)-3-9,enhancer-of-zeste,trithorax (SET) domain containing 7/9 (SET7/9), H3K4me1/2, BIM and BAX expression, while markedly downregulated lysine-specific histone demethylase 1 (LSD1) and BCL2 expression. After down-regulating CHOP, LSD1, and (su(var)-3-9,enhancer-of-zeste,trithorax) domain-containing protein 7/9 (SET7/9) in BRL-3A cells by siRNA, silencing CHOP and SET7/9 notably attenuated the pro-apoptotic and anti-proliferative effects of arsenic treatment on BRL-3A cells, which was reversed after inhibiting LSD1. In addition, our results suggested that knockdown of CHOP altered the expression of mitochondrial-associated proteins BCL2 and BIM, whereas knockdown of LSD1 and SET7/8 regulated the level of H3K4me1/2 modification and BAX protein. Coupled with chromatin immunoprecipitation results, we found that the level of CHOP in the promoter regions of BCL2 and BIM was significantly increased in BRL-3A cells exposed to 30 µmol/L NaAsO2 for 24 h, whereas the levels of H3K4me1/2 in the promoter regions of BAX were unchanged. Collectively, these data indicated that arsenic triggered the mitochondrial pathway to induce hepatocyte apoptosis by up-regulating the levels of CHOP and H3K4me1/2.

2.
J Phys Chem Lett ; : 8888-8892, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36125432

RESUMO

Combining Raman scattering and Raman optical activity (ROA) with computer simulations reveals fine structural and physicochemical properties of chiral molecules. Traditionally, the region of interest comprised fundamental transitions within 200-1800 cm-1. Only recently, nonfundamental bands could be observed as well. However, theoretical tools able to match the observed spectral features and thus assist their assignment are rather scarce. In this work, we present an accurate and simple protocol based on a three-quanta anharmonic perturbative approach that is fully fit to interpret the observed signals of methyloxirane within 150-4500 cm-1. An unprecedented agreement even for the low-intensity combination and overtone transitions has been achieved, showing that anharmonic Raman and ROA spectroscopies can be valuable tools to understand vibrations of chiral molecules or to calibrate computational models.

3.
Biochem Pharmacol ; 204: 115240, 2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36070847

RESUMO

Chronic kidney disease (CKD) is an increasing public health concern, characterized by a reduced glomerular filtration rate and increased urinary albumin excretion. Renal fibrosis is an important pathological condition in patients with CKD. In this study, we evaluated the anti-fibrotic effect of Cpd-0225, a novel transforming growth factor-ß (TGF-ß) type I receptor (also known as ALK5) inhibitor, in vitro and in vivo, by comparing its effect with that of SB431542, a classic ALK5 inhibitor, which has not entered the clinical trial stage owing to multiple side effects. Our data showed that Cpd-0225 attenuated fibrotic response in TGF-ß1-stimulated human kidney tubular epithelial cells and repeated hypoxia/reoxygenation-treated mouse tubular epithelial cells. We further confirmed that Cpd-0225 improved renal tubular injury and ameliorated collagen deposition in unilateral ureteral obstruction-, ischemia/reperfusion-, and aristolochic acid-induced mouse models of renal fibrosis. In addition, molecular docking and site-directed mutagenesis showed that Cpd-0225 exerted a higher reno-protective effect than SB431542, by physically binding to the key amino acid residues, Lys232 and Lys335 of ALK5, thereby suppressing the phosphorylation of Smad3 and ERK1/2. Taken together, these findings suggest that Cpd-0225 administration attenuates renal fibrosis via ALK5-dependent mechanisms and displays a more effective therapeutic effect than SB431542. Thus, Cpd-0225 may serve as a potential therapeutic agent for the treatment of CKD.

4.
Elife ; 112022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36107478

RESUMO

Mechanisms that control 'beige/brite' thermogenic adipose tissue development may be harnessed to improve human metabolic health. To define these mechanisms, we developed a species-hybrid model in which human mesenchymal progenitor cells were used to develop white or thermogenic/beige adipose tissue in mice. The hybrid adipose tissue developed distinctive features of human adipose tissue, such as larger adipocyte size, despite its neurovascular architecture being entirely of murine origin. Thermogenic adipose tissue recruited a denser, qualitatively distinct vascular network, differing in genes mapping to circadian rhythm pathways, and denser sympathetic innervation. The enhanced thermogenic neurovascular network was associated with human adipocyte expression of THBS4, TNC, NTRK3 and SPARCL1, which enhance neurogenesis, and decreased expression of MAOA and ACHE, which control neurotransmitter tone. Systemic inhibition of MAOA, which is present in human but absent in mouse adipocytes, induced browning of human but not mouse adipose tissue, revealing the physiological relevance of this pathway. Our results reveal species-specific cell type dependencies controlling the development of thermogenic adipose tissue and point to human adipocyte MAOA as a potential target for metabolic disease therapy.

5.
Cancers (Basel) ; 14(17)2022 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-36077725

RESUMO

Pneumonia accounts for a significant cause of morbidity and mortality in multiple myeloma (MM) patients. It has been previously shown that intestinal Klebsiella pneumonia (K. pneumonia) enriches in MM and promotes MM progression. However, what role the altered gut microbiota plays in MM with pneumonia remains unknown. Here, we show that intestinal K. pneumonia is significantly enriched in MM with pneumonia. This enriched intestinal K. pneumonia links to the incidence of pneumonia in MM, and intestinal colonization of K. pneumonia contributes to pneumonia in a 5TGM1 MM mice model. Further targeted metabolomic assays reveal the elevated level of glutamine, which is consistently increased with the enrichment of K. pneumonia in MM mice and patients, is synthesized by K. pneumonia, and leads to the elevated secretion of TNF-α in the lung normal fibroblast cells for the higher incidence of pneumonia. Inhibiting glutamine synthesis by establishing glnA-mutated K. pneumonia alleviates the incidence of pneumonia in the 5TGM1 MM mice model. Overall, our work proposes that intestinal K. pneumonia indirectly contributes to pneumonia in MM by synthesizing glutamine. Altogether, we unveil a gut-lung axis in MM with pneumonia and establish a novel mechanism and a possible intervention strategy for MM with pneumonia.

6.
Zhongguo Gu Shang ; 35(9): 836-42, 2022 Sep 25.
Artigo em Chinês | MEDLINE | ID: mdl-36124453

RESUMO

OBJECTIVE: To evaluate clnical effect of minimally invasive osteotomy with absorbable screws in treating hallux valgus deformity. METHODS: Clnical data of 31 patients with hallux valgus deformity were retrospective analyzed from January 2019 to December 2020, and divided into absorbable screws group (17 patients) and titanium cannulated screw group (14 patients). In absorbable screws group, there were 1 male and 16 females aged from 32 to 72 years old with an average of (54.53±12.12) years old;6 patients on the left side, 5 on bilateral and 6 on the right side;1 patient was mild, 11 moderate and 5 severe;treated with minimally invasive osteotomy and fixation of absorbable screws. In titanium cannulated screw group, there were 2 males and 12 females aged from 18 to 71 years old with an average of (47.57±15.68) years old;4 patients on the left side, 4 on bilateral and 6 on the right side;1 patient was mild, 9 moderate and 4severe;treated with minimally invasive osteotomy and fixation of titanium cannulated screw. Complications between two groups were observed, changes of hallux valgus angle (HVA)and intermetatarsal angle (IMA)were detected and compared before and after operation at 12 months, American Orthopedic Foot and Ankle Society(AOFAS) and visual analogue scale(VAS) before and after operation at 12 months were also compared. RESULTS: All 31 patients were followed up from 13 to 20 months with an average of (16.61±2.47) months. Patients in absorbable screws group were followed up from 14 to 20 months with an average of (16.88±2.80) months, while patients in titanium cannulated screw group were followed up from 13 to 19 months with an average of (16.29±2.05) months;there was no difference between two groups(P>0.05). One patient in absorbable screws group occurred numbness around incision, 3 patients in titanium cannulated screw group occurred complications, including numbness around incision in 1 patient, skin irritation due to internal fixation in 1 patient, and recurrence in 1 case;there was no statistic difference between two groups (χ2=1.651, P=0.199). There were no statistic difference in HVA and IMA between two groups before and after operation at 12 months(P>0.05). There were no statistic difference between two groups in AOFAS and VAS before and after operation at 12 months(P>0.05). CONCLUSION: Compare with mainstream fixation with titanium hollow screw after minmally invasive osteotomy, fixation with absorbable screw could achieve comparable clinical outcome on the basis of images and function evaluation.


Assuntos
Joanete , Hallux Valgus , Ossos do Metatarso , Adolescente , Adulto , Idoso , Feminino , Hallux Valgus/diagnóstico por imagem , Hallux Valgus/cirurgia , Humanos , Hipestesia , Masculino , Ossos do Metatarso/cirurgia , Pessoa de Meia-Idade , Osteotomia/métodos , Radiografia , Estudos Retrospectivos , Titânio , Adulto Jovem
7.
J Immunol Res ; 2022: 8025055, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36052280

RESUMO

One of the most prevalent malignant primary brain tumors is primary glioma. Although glutathione peroxidase 8 (GPX8) is intimately associated with carcinogenesis, its function in primary gliomas has not yet been thoroughly understood. Here, we leveraged Chinese Glioma Genome Atlas (CGGA), The Cancer Genome Atlas (TCGA), and Genotype-Tissue Expression (GTEx) database to investigate the association between GPX8 and overall survival (OS) of patients with primary gliomas, and our results showed that GPX8 expression was negatively correlated with OS. Moreover, the expression of GPX8 is significantly lower in normal tissue when compared to glioma tissue. According to results of univariate and multivariate analysis from CGGA using R studio, GPX8 is a valuable primary glioma prognostic indicator. Interestingly, high GPX8 expression is correlated positively with the hedgehog and kras signaling pathways and negatively with G2 checkpoint, apoptosis, reactive oxygen species (ROS) pathway, and interferon gamma pathway, which could be beneficial for the proliferation of glioma cells. Furthermore, GPX8 knockdown caused G1 cell cycle arrest, increased cell death, and reduced colony formation in U87MG and U118MG cells. In conclusion, GPX8 is a promising therapeutic target and meaningful prognostic biomarker of primary glioma.


Assuntos
Neoplasias Encefálicas , Glioma , Peroxidases , Apoptose/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Carcinogênese , Glioma/genética , Glioma/metabolismo , Glioma/terapia , Humanos , Peroxidases/genética , Prognóstico
8.
J Int Med Res ; 50(9): 3000605221118680, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36071631

RESUMO

OBJECTIVE: Sepsis is a systemic and deleterious host reaction to severe infection. Cardiac dysfunction is an established serious outcome of multiorgan failure associated with this condition. Therefore, it is important to develop drugs targeting sepsis-induced cardiac damage and inflammation. Thymoquinone (TQ) has anti-inflammatory, anti-oxidant, anti-fibrotic, anti-tumor, and anti-apoptotic effects. This study examined the effects of thymoquinone on sepsis-induced cardiac damage. METHODS: Male BALB/c mice were randomly segregated into four groups: control, TQ, cecal ligation and puncture (CLP), and CLP + TQ groups. CLP was performed after gavaging the mice with TQ for 2 weeks. After 48 hours, we estimated the histopathological changes in the cardiac tissue and the serum levels of cardiac troponin-T. We evaluated the expression of factors associated with inflammation, apoptosis, oxidative stress, and the PI3K/AKT pathway. RESULTS: TQ significantly reduced intestinal histological alterations and inhibited the upregulation of interleukin-6, tumor necrosis factor-α, Bax, NOX4, p-PI3K, and p-AKT. TQ also increased Bcl-2, HO-1, and NRF2 expression. CONCLUSION: These results suggest that TQ effectively modulates pro-inflammatory, apoptotic, oxidative stress, and PI3K/AKT pathways, making it indispensable in the treatment of sepsis-induced cardiac damage.


Assuntos
Fosfatidilinositol 3-Quinases , Sepse , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Benzoquinonas , Inflamação/complicações , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sepse/complicações , Sepse/tratamento farmacológico , Sepse/patologia
9.
ACS Appl Mater Interfaces ; 14(37): 42402-42411, 2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36070607

RESUMO

Flexible electrochromic devices (FECDs) have been regarded as an ideal stratagem for wearable displays. However, it remains a great challenge to achieve long-term stability for high-performance FECDs due to their severe electrolyte deformation/leakage under repeated bending. Herein, inspired by the rough and fluffy microstructure of cobwebs, we prepared a porous polylactic acid (PLA) network through electrospinning and nonsolvent-induced phase separation. This loosely interlaced PLA network can be well infiltrated by electrolytes and exhibits extraordinarily high transparency; in addition, its surface contains numerous tiny holes to effectively load electrolytes to mitigate deformation. Furthermore, we also introduced silver nanowires (AgNWs) as the supporting network to load and connect electrochromic materials. After assembling them with graphene (GR) electrodes, a wearable FECD with a quintuple network structure (two GR networks, two AgNW networks, and one PLA network) was successfully prepared. The resulting FECD can realize high optical modulation (more than 70%), excellent cyclic stability (retain 95% after 1000 cycles), and innovative bending resistance (retain 84.8% after 6000 bending cycles). This work not only solves the long-lasting challenge of developing FECD with high optical modulation and bending resistances but also provides an energetic paradigm for diverse soft electronics used in harsh environments.

10.
Free Radic Biol Med ; 192: 13-24, 2022 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-36108935

RESUMO

Diabetic cardiomyopathy (DCM) is ventricular dysfunction that occurs in patients with diabetes mellitus (DM), independent of recognized risk factors, such as coronary artery disease, hypertension, and valvular heart disease. Dual-specificity phosphatase 12 (DUSP12) is a dual-specificity phosphatase expressed in all tissues. Genome-wide linkage studies have found an association between DUSP12 and type 2 diabetes (T2D). However, the role of DUSP12 in DCM remains largely unknown. Ubiquitously expressed DUSP12 is involved in nonalcoholic fatty liver disease, bacterial infection, and myocardial hypertrophy and plays a critical role in tumorigenesis. Herein, we observed an increased expression of DUSP12 in a hyperglycemia cell model and a high-fat diet (HFD) mouse model. Heart-specific DUSP12-deficient mice showed severe cardiac dysfunction and remodeling induced by an HFD. DUSP12 deficiency exacerbated oxidative stress injury and apoptosis, whereas DUSP12 overexpression had the opposite effect. At the molecular level, DUSP12 physically bound to apoptotic signal-regulated kinase 1 (ASK1), promoted its dephosphorylation, and inhibited its action on c-Jun N-terminal kinase and p38 mitogen-activated protein kinase. Rescue experiments have shown that oxidative stress injury and apoptosis, exacerbated by DUSP12 deficiency, are alleviated by ASK1 inhibition. Therefore, we consider DUSP12 an important signaling pathway in DCM.

11.
Comput Biol Med ; 148: 105886, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35973372

RESUMO

Hepatocellular carcinoma (HCC) patients, featured by markedly heterogeneous tumor microenvironment (TME), meet diverse clinical outcome and neoadjuvant response. Yet the comprehensive influences of aberrant glycosylation on the TME of HCC remain elusive. In this study, by integrated transcriptome profiling, we systemically analyzed the considerable value of glycosylation-regulating signature in diagnosis and prognosis of HCC. A diagnostic model for HCC based on glycosylation-regulating REOs (relative expression orderings) was constructed. A robust glycoscore system was developed to evaluate distinct glycosylation patterns of patients in both the discovery and independent validation cohorts. Mechanisms for prognostic discrepancies between these patterns were dissected in tumor immunoediting, metabolic reprogramming, somatic mutations, and copy number variation (CNV). An individual survival prediction webserver based on a nomogram model (https://survpredict.shinyapps.io/DynNom/) was also established, which facilitates the translational and clinical application of glycoscore. The glycoscore could also effectively predict therapeutic response to sorafenib, Transhepatic Arterial Chemotherapy and Embolization (TACE), and anti-PD-1 therapies in patients with divergent glycosylation patterns, which was validated by a machine learning model. In summary, our study provided a unique insight into the HCC diagnosis and prognostic stratification based on integrated glycosylation-regulating signature. The robust glycosylation scoring system could comprehensively evaluate TME traits, predict prognosis and clinical benefits from neoadjuvant therapies, which may hold promise for promoting personalized clinical decision-making.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Variações do Número de Cópias de DNA , Glicosilação , Humanos , Transcriptoma , Microambiente Tumoral
12.
Chin J Nat Med ; 20(8): 589-600, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36031231

RESUMO

Recent studies have showed that thrombosis is closely related to leucocytes involved in immunity. Interfering with the binding of leukocyte integrin Mac-1 and platelet GPIbα can inhibit thrombosis without affecting physiological coagulation. Mac-1-GPIbα is proposed as a potential safety target for antithrombotic agents. Guanxinning tablet (GXNT) is an oral Chinese patent medicine used for the treatment of angina pectoris, which contains phenolic acid active ingredients, such as salvianolic acids, ferulic acid, chlorogenic acid, caffeic acid, rosmarinic acid, tanshinol, and protocatechualdehyde. Our previous studies demonstrated that GXN exhibited significant antithrombotic effects, and clinical studies suggested that it did not increase bleeding risk. In addition, GXN exerted a significantly regulatory effect on immune inflammation. In the current study, we intended to evaluate the effects of GXN on bleeding events and explore the safety antithrombotic mechanism of GXN based on leukocyte-platelet interaction. First, we established a gastric ulcer model induced by acetic acid in rats and found that GXN not only did not increase the degree of gastrointestinal bleeding when gastric ulcer occurred, but also had a certain promoting effect on the healing of gastric ulcer. Second, in vitroexperiments showed that after pretreatment with GXN and activation by phorbol 12-myristate-13-acetate (PMA), the adhesion and aggregation of leukocytes with human platelets were reduced. It was also found that GXN reduced the expression and activation of Mac-1 in leucocytes, and inhibited platelet activation due to leukocyte engagement via Mac-1. Overall, the results suggest that GXN may be a safe antithrombotic agent, and its low bleeding risk mechanism is probably related to inhibited leukocyte-platelet aggregation and its interaction target Mac-1-GPIbα.


Assuntos
Úlcera Gástrica , Trombose , Animais , Fibrinolíticos , Humanos , Integrinas , Leucócitos , Antígeno de Macrófago 1 , Ratos , Comprimidos
13.
Front Psychiatry ; 13: 946450, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36003984

RESUMO

Experiencing a serious natural disaster may place survivors at particularly high risk for post-traumatic stress disorder (PTSD); however, very limited data are available on the prevalence and clinical characteristics of PTSD among survivors of a tornado disaster. The present study examined the prevalence of PTSD and correlates and clinical symptoms of possible PTSD in survivors 1.5 months after a tornado disaster. A total of 237 survivors were recruited and administered the Structured Clinical Interview for DSM-V (SCID) to measure the prevalence of PTSD and the Essen Trauma Inventory (ETI) to measure the incidence of symptoms in each dimension. Survivors'demographic information and characteristics of exposure to the tornado were collected via self-report questionnaires. Thirty-two of the survey respondents were diagnosed with PTSD (13.6%, total =237). Correlates of PTSD in survivors were being female (OR=3.62, P = 0.023), living in an area severely affected by the tornado (OR = 3.94, P = 0.032), and having severe property damage (OR = 3.72, P = 0.010). Less common symptoms mainly focused on the avoidance dimension and included feeling alienated or distant from the people around oneself (21.90%), not being able to recall important parts of the event (28.10%), being emotionally numb (31.20%), and feeling like one's plans for the future and hopes will not come true (37.50%). In the sample of rural residents, nearly two-thirds of people with PTSD were not willing to seek psychological help; increasing the accessibility of mental health services and administering more active mental health services are necessary for this vulnerable population, whether or not they claim to need help.

14.
J Immunol Res ; 2022: 7978042, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35983076

RESUMO

Background: The cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) plays critical functions in innate immune responses via the production of the second messenger cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), which stimulates the adaptor stimulator of interferon genes (STING). However, the clinical relevance and prognostic value of the cGAS-STING pathway in human cancers remains largely unexplored. Methods: A gene signature related to the cGAS-STING score was identified. The pan-cancer landscape of cGAS-STING expression was calculated using the RNAseq data acquired from the TCGA cohort. Tumor-infiltrating immune cells (TIICs) were determined by the ssGSEA method. Kaplan-Meier curves, Cox regression analyses, and the area under the curve (AUC) were employed to decipher the predictive value of cGAS-STING risk score and TIICs across several human cancers. Results: Most tumor tissues displayed a higher cGAS-STING score compared with their corresponding nontumor tissues, except for prostate adenocarcinoma (PRAD) and uterine corpus endometrial carcinoma (UCEC). Higher cGAS-STING score was closely associated with poor clinical outcome of kidney renal clear cell carcinoma (KIRC) and kidney renal papillary cell carcinoma (KIRP), whereas the cGAS-STING score predicted a better prognosis in pheochromocytoma and paraganglioma (PCPG). Enrichment analysis showed that cGAS-STING was profoundly implicated in diverse immune-related pathways in KIRC, KIRP, and PCPG. Significant positive correlations were noticed between cGAS-STING score and TIICs, including activated CD8+ T cells, activated CD4+ T cells, monocytes, and mast cells. Finally, the cGAS-STING score was revealed to be an independent prognostic factor for KIRC patients and possessed a strong predictive power for the prognostic evaluation of KIRC and KIRP patients. Conclusions: We constructed a cGAS-STING gene signature to predict survival and tumor immunity across human cancers, which can serve as a novel prognostic indicator and therapeutic target, especially in KIRC and KIRP.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Proteínas de Membrana , Nucleotidiltransferases , Carcinoma de Células Renais/genética , DNA , Humanos , Neoplasias Renais/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , Fatores de Risco , Transdução de Sinais
15.
Front Biosci (Landmark Ed) ; 27(8): 244, 2022 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-36042177

RESUMO

BACKGROUND: Cardiovascular disease is associated with high morbidity and mortality. Doxorubicin (DOX) is an effective adjunct to cancer chemotherapy but leads to cardiovascular-related side effects. Because coenzyme Q10 (CoQ10) has been shown to protect against cardiac damage, this study was conducted to investigate the protective effects of CoQ10 against cardiac damage in mice. METHODS: We randomly divided six-week-old male C57BL/6 mice into four groups: control (n = 7), CoQ10 (n = 7), heart failure (HF) (n = 7), and HF+CoQ10 (n = 6) groups. HF group was induced via intraperitoneal injections with DOX (5 mg/kg) once weekly for 4 weeks. CoQ10 was solube in corn oil. The mice of CoQ10 and HF+CoQ10 group were given CoQ10 (100 mg/kg) once a day for 8 weeks. All mice were subjected to different treatment regimens for eight weeks. Metabolic characteristics, cardiac damage, oxidative stress markers (SIRT1, SIRT3, eNOS, TE, P53, SIRT5, CAT, HO-1, and SOD), energy metabolism markers (PARP-1 and PPAR-γ), myocardial fibrosis markers (Smad3 and TGF-ß), and apoptosis markers (BAK, BCL-XL, and caspase-8) were analyzed at eight weeks after the different treatments. RESULTS: CoQ10 reduced the levels of molecules related to cardiac damage, oxidative stress, energy metabolism, and myocardial fibrosis in mice with doxorubicin-induced HF. CoQ10 also exerted anti-apoptotic effects in HF mice. CONCLUSIONS: CoQ10 may be useful for preventing cardiac damage in DOX-induced HF.


Assuntos
Insuficiência Cardíaca , Ubiquinona , Animais , Doxorrubicina/efeitos adversos , Fibrose , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Ubiquinona/análogos & derivados , Ubiquinona/farmacologia , Ubiquinona/uso terapêutico
16.
Sci Rep ; 12(1): 13646, 2022 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-35953696

RESUMO

Lung squamous cell carcinoma (LUSC) comprises 20-30% of all lung cancers. Immunotherapy has significantly improved the prognosis of LUSC patients; however, only a small subset of patients responds to the treatment. Therefore, we aimed to develop a novel multi-gene signature associated with the immune phenotype of the tumor microenvironment for LUSC prognosis prediction. We stratified the LUSC patients from The Cancer Genome Atlas dataset into hot and cold tumor according to a combination of infiltration status of immune cells and PD-L1 expression level. Kaplan-Meier analysis showed that hot tumors were associated with shorter overall survival (OS). Enrichment analyses of differentially expressed genes (DEGs) between the hot and cold tumors suggested that hot tumors potentially have a higher immune response ratio to immunotherapy than cold tumors. Subsequently, hub genes based on the DEGs were identified and protein-protein interactions were constructed. Finally, we established an immune-related 13-gene signature based on the hub genes using the least absolute shrinkage and selection operator feature selection and multivariate cox regression analysis. This gene signature divided LUSC patients into high-risk and low-risk groups and the former inclined worse OS than the latter. Multivariate cox proportional hazard regression analysis showed that the risk model constructed by the 13 prognostic genes was an independent risk factor for prognosis. Receiver operating characteristic curve analysis showed a moderate predictive accuracy for 1-, 3- and 5-year OS. The 13-gene signature also performed well in four external cohorts (three LUSC and one melanoma cohorts) from Gene Expression Omnibus. Overall, in this study, we established a reliable immune-related 13-gene signature that can stratify and predict the prognosis of LUSC patients, which might serve clinical use of immunotherapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/terapia , Regulação Neoplásica da Expressão Gênica , Humanos , Imunoterapia , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Prognóstico , Microambiente Tumoral/genética
17.
World J Gastroenterol ; 28(23): 2569-2581, 2022 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-35949353

RESUMO

BACKGROUND: Endoplasmic reticulum (ER) stress-related hepatocyte apoptosis is responsible for multiple hepatic diseases. Previous studies have revealed that endoplasmic reticulophagy (ER-phagy) promotes the selective clearance of damaged ER fragments during ER stress, playing a crucial role in maintaining ER homeostasis and inhibiting apoptosis. Family with sequence similarity 134 member B (FAM134B) is a receptor involved in ER-phagy that can form a complex with calnexin (CNX) and microtubule-associated protein 1 light chain 3 (LC3). The complex can mediate the selective isolation of ER fragments to attenuate hepatocyte apoptosis. However, the precise regulatory mechanisms remain unclear. AIM: To elucidate the effect of FAM134B-mediated ER-phagy on ER stress-induced apoptosis in buffalo rat liver 3A (BRL-3A) rat hepatocytes and the potential regulatory mechanisms. METHODS: ER stress-related hepatocyte apoptosis was induced using dithiothreitol (DTT). Proteins related to ER stress and autophagy were measured with western blotting. Protein complex interactions with FAM134B were isolated by co-immunoprecipitation. ER-phagy was evaluated in immunofluorescence experiments. Cell cycle distribution and apoptosis were measured by flow cytometry. Mitochondrial Ca2+ levels were evaluated by the co-localization of intracellular Ca2+-tracker and Mito-tracker. The small interfering RNA against FAM134B was used to knockdown FAM134B in BRL-3A cells. RESULTS: ER stress-related and autophagy-related proteins in BRL-3A cells were elevated by both short and long-term DTT treatment. Furthermore, co-immunoprecipitation confirmed an interaction between FAM134B, CNX, FAM134B, and LC3 in BRL-3A cells. Immunofluorescence assays revealed that autolysosomes significantly decreased following short-term DTT treatment, but increased after long-term treatment. Mitochondrial Ca2+ levels and apoptotic rates were dramatically elevated, and more cells were arrested in the G1 stage after short-term DTT treatment; however, these decreased 48 h later. Moreover, FAM134B downregulation accelerated mitochondrial apoptotic pathway activation and aggravated hepatocyte apoptosis under ER stress. CONCLUSION: FAM134B-mediated ER-phagy attenuates hepatocyte apoptosis by suppressing the mitochondrial apoptotic pathway. Our findings provide new evidence highlighting the importance of FAM134B-mediated ER-phagy in attenuating hepatocyte apoptosis.


Assuntos
Autofagia , Retículo Endoplasmático , Animais , Apoptose , Autofagia/fisiologia , Ditiotreitol/farmacologia , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático , Hepatócitos , Ratos
18.
Int J Med Sci ; 19(9): 1460-1472, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36035373

RESUMO

Objectives: Endoplasmic reticulum (ER) stress and soluble epoxide hydrolase (sEH) upregulation/activation have been implicated in myocardial ischemia/reperfusion (I/R) injury. We previously reported that ER stress mediates angiotensin II-induced sEH upregulation in coronary endothelium, whether and how ER stress regulates sEH expression to affect postischemic cardiac function remain unexplored. This study aimed to unravel the signaling linkage between ER stress and sEH in an ex vivo model of myocardial I/R injury. Methods: Hearts from male Wistar-Kyoto rats were mounted on a Langendorff apparatus and randomly allocated to 7 groups, including control, I/R (30-min ischemia and 60-min reperfusion), and I/R groups pretreated with one of the following inhibitors: 4-PBA (targeting: ER stress), GSK2850163 (IRE1α), SP600125 (JNK), SR11302 (AP-1), and DCU (sEH). The inhibitor was administered for 15 min before ischemia with a peristaltic pump. Hemodynamic parameters including left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), and maximal velocity of contraction (+dp/dtmax) and relaxation (-dp/dtmax) of the left ventricle were continuously recorded using an intraventricular balloon. Endothelial dilator function of the left anterior descending artery was studied in a wire myograph upon completion of reperfusion. The expression of ER stress molecules, JNK, c-Jun, and sEH was determined by western-blot. Results: I/R decreased LVSP (105.5±6.4 vs. 146.9±13.4 mmHg), and increased LVEDP (71.4±3.0 vs. 6.0±2.7 mmHg), with a resultant decreased LVDP (34.1±9.2 vs. 140.9±13.1 mmHg). I/R attenuated +dp/dtmax (651.7±142.1 vs. 2806.6±480.6 mmHg/s) and -dp/dtmax (-580.0±109.6 vs. -2118.0±244.9 mmHg/s) (all ps<0.001). The I/R-induced cardiac dysfunction could be alleviated by 4-PBA (LVSP 119.5±15.6 mmHg, p<0.01; LVEDP 21.2±4.2 mmHg, LVDP 98.3±12.0 mmHg, +dp/dtmax 2166.7±208.4 mmHg/s, and -dp/dtmax -1350.9±99.8 mmHg/s, all ps<0.001), GSK2850163 (LVSP 113.4±10.9 mmHg, p<0.01; LVEDP 37.1±3.1 mmHg, LVDP 76.3±13.9 mmHg, +dp/dtmax 1586.5±263.3 mmHg/s, -dp/dtmax -1127.7±159.9 mmHg/s, all ps<0.001), SP600125 (LVSP 113.9±5.6 mmHg, LVDP 40.5±3.3 mmHg, +dp/dtmax 970.1±89.8 mmHg/s, all ps<0.01), SR11302 (LVSP 97.9±7.5 mmHg, p<0.01; LVEDP 52.7±8.6mmHg, p<0.001; LVDP 45.2±9.8mmHg, p<0.05; +dp/dtmax 1231.5±196.6 mmHg/s, p<0.01; -dp/dtmax -658.3±68.9 mmHg/s, p<0.05), or DCU (LVSP 109.9±4.1 mmHg, p<0.01; LVEDP 11.7±1.8 mmHg, LVDP 98.2±4.9 mmHg, +dp/dtmax 1869.8±121.9 mmHg/s, and -dp/dtmax -1492.3±30.8 mmHg/s, all ps<0.001). The relaxant response of the coronary artery to acetylcholine was decreased after I/R in terms of both magnitude and sensitivity (p<0.001). All inhibitors improved acetylcholine-induced relaxation. Global I/R increased sEH expression and induced ER stress in both myocardium and coronary artery. Inhibition of ER stress or IRE1α downregulated I/R-induced sEH expression and inhibited JNK and c-Jun phosphorylation. Both JNK and AP-1 inhibitors lowered sEH level in myocardium and coronary artery in I/R-injured hearts. Conclusions: This study deciphered the molecular linkage between ER stress and sEH regulation in global I/R insult by uncovering a novel signaling axis of IRE1α-JNK-c-Jun/AP-1-sEH, which provided basis for future research on the therapeutic potential of targeting the IRE1α-JNK-c-Jun/AP-1-sEH axis for ischemic myocardial injury.


Assuntos
Doença da Artéria Coronariana , Isquemia Miocárdica , Traumatismo por Reperfusão Miocárdica , Acetilcolina , Animais , Endorribonucleases , Endotélio , Isquemia , Masculino , Miocárdio , Proteínas Serina-Treonina Quinases , Ratos , Ratos Endogâmicos WKY , Reperfusão , Transdução de Sinais , Fator de Transcrição AP-1
19.
Front Genet ; 13: 805960, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35795202

RESUMO

Non-small-cell lung cancer (NSCLC) is divided into three major histological types, namely, lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), and large-cell lung carcinoma (LCLC). We previously identified that 4.1N/EPB41L1 acts as a tumor suppressor and is reduced in NSCLC patients. In the current study, we explored the underlying epigenetic mechanisms of 4.1N/EPB41L1 reduction in NSCLC. The 4.1N/EPB41L1 gene promoter region was highly methylated in LUAD and LUSC patients. LUAD patients with higher methylation level in the 4.1N/EPB41L1 gene promoter (TSS1500, cg13399773 or TSS200, cg20993403) had a shorter overall survival time (Log-rank p = 0.02 HR = 1.509 or Log-rank p = 0.016 HR = 1.509), whereas LUSC patients with higher methylation level in the 4.1N/EPB41L1 gene promoter (TSS1500 cg13399773, TSS1500 cg07030373 or TSS200 cg20993403) had a longer overall survival time (Log-rank p = 0.045 HR = 0.5709, Log-rank p = 0.018 HR = 0.68 or Log-rank p = 0.014 HR = 0.639, respectively). High methylation of the 4.1N/EPB41L1 gene promoter appeared to be a relatively early event in LUAD and LUSC. DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine restored the 4.1N/EPB41L1 expression at both the mRNA and protein levels. MiR-454-3p was abnormally highly expressed in NSCLC and directly targeted 4.1N/EPB41L1 mRNA. MiR-454-3p expression was significantly correlated with 4.1N/EPB41L1 expression in NSCLC patients (r = -0.63, p < 0.0001). Therefore, we concluded that promoter hypermethylation of the 4.1N/EPB41L1 gene and abnormally high expressed miR-454-3p work at different regulation levels but in concert to restrict 4.1N/EPB41L1 expression in NSCLC. Taken together, this work contributes to elucidate the underlying epigenetic disruptions of 4.1N/EPB41L1 deficiency in NSCLC.

20.
Sci Total Environ ; 845: 157279, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-35830916

RESUMO

Microbial immobilization of fertilizer nitrogen (N) can effectively reduce N losses in soil. However, the effects of crop residue on microbial assimilation of fertilizer-N and the underlying microbial mechanisms in upland soils are unclear. We evaluated the influence of maize residue (13C) addition on the microbial assimilation of ammonium-N (15N) in DNA from fertilizer, and quantified the bacterial 13C or 15N assimilation by quantitative stable isotope probing (DNA-qSIP). We found that the straw addition did increase total microbial assimilation of ammonium from fertilizer during the 2-week incubation. However, bacterial taxa varied in their responses to straw addition: Bacteriodetes and Proteobacteria accounted for large fractions of ammonium assimilation and their N assimilations were increased, while N assimilations of Acidobacteria were decreased. We revealed that highly 13C-labeled taxa were the main contributors of N assimilation under straw addition. The straw primarily enhanced the contributions of bacterial taxa to ammonium assimilation through increasing the extent of N assimilation, or enhancing the abundance of the N-assimilating bacterial taxa. Overall, our study elucidated an interaction between microbial assimilation of fertilizer-N and straw-C, showing a close element coupling of the keystone functional microbial taxa in N immobilization driven by organic carbon.


Assuntos
Compostos de Amônio , Fertilizantes , Bactérias , Carbono , DNA , Fertilizantes/análise , Nitrogênio/análise , Solo/química , Microbiologia do Solo
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