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1.
Viral Immunol ; 37(3): 149-158, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38573237

RESUMO

Hepatitis B Virus (HBV) is posing as a serious public health threat mainly due to its asymptomatic nature of infection in pregnancy and vertical transmission. Viral sensing toll-like receptors (TLR) and Interleukins (IL) are important molecules in providing an antiviral state. The study aimed to assess the role of TLR7-mediated immune modulation, which might have an impact in the intrauterine transmission of HBV leading to mother to child transmission of the virus. We investigated the expression pattern of TLR7, IL-3, and IL-6 by RT-PCR in the placentas of HBV-infected pregnant women to see their role in the intrauterine transmission of HBV. We further validated the expression of TLR7 in placentas using Immunohistochemistry. Expression analysis by RT-PCR of TLR7 revealed significant downregulation among the Cord blood (CB) HBV DNA positive and negative cases with mean ± standard deviation (SD) of 0.43 ± 0.22 (28) and 1.14 ± 0.57 (44) with p = 0.001. IL-3 and IL-6 expression revealed significant upregulation in the CB HBV DNA-positive cases with p = 0.001. Multinomial logistic regression analysis revealed that TLR7 and IL-3 fold change and mother HBeAg status are important predictors for HBV mother to child transmission. Immunohistochemistry revealed the decreased expression of TLR7 in CB HBV DNA-positive cases. This study reveals that the downregulation of TLR7 in the placenta along with CB HBV DNA-positive status may lead to intrauterine transmission of HBV, which may lead to vertical transmission of HBV.


Assuntos
Hepatite B , Complicações Infecciosas na Gravidez , Feminino , Humanos , Gravidez , DNA Viral , Antígenos E da Hepatite B , Antígenos de Superfície da Hepatite B , Vírus da Hepatite B , Transmissão Vertical de Doenças Infecciosas , Interleucina-3 , Interleucina-6/genética , Receptor 7 Toll-Like/genética , Recém-Nascido
2.
J Cardiothorac Surg ; 19(1): 208, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38616256

RESUMO

BACKGROUND: Cardiac fibroblasts (CFs) are activated after initial injury, and then differentiate into myofibroblasts (MFs), which play a pivotal role as the primary mediator cells in pathological remodeling. Sodium butyrate (NaB), being a metabolite of gut microbiota, exhibits anti-inflammatory property in local therapies on sites other than the intestine. Thus, this study aimed to probe the mechanism by which NaB regulates CFs transdifferentiation through the NLRP3/Caspase-1 pyroptosis pathway. METHODS: CFs were cultured in vitro and induced into MFs by TGFß1. CFs were identified by immunofluorescence labelling technique of vimentin and α-SMA, followed by treatment with NaB or NLRP3 inflammasome inhibitor (CY-09) and its activator [nigericin sodium salt (NSS)]. The expression levels of α-SMA, GSDMD-N/NLRP3/cleaved Caspase-1 proteins, and inflammatory factors IL-1ß/IL-18/IL-6/IL-10 were determined using immunofluorescence, Western blot and ELISA. Cell proliferation and migration were evaluated using the CCK-8 assay and the cell scratch test, respectively. RESULTS: Following the induction of TGFß1, CFs exhibited increased expression levels of α-SMA proteins and IL-6/IL-10, as well as cell proliferative and migratory abilities. TGFß1 induced CFs to differentiate into MFs, while NaB inhibited this differentiation. NaB inactivated the NLRP3/Caspase-1 pyroptosis pathway. CY-09 demonstrated inhibitory effects on the NLRP3/Caspase-1 pyroptosis pathway, leading to a reduction in TGFß1-induced CFs transdifferentiation. NSS activated the NLRP3/Caspase-1 pyroptosis pathway, and thus partially counteracting the inhibitory effect of intestinal microbiota metabolite NaB on CFs transdifferentiation. CONCLUSION: NaB, a metabolite of the gut microbiota, inhibited the activation of the NLRP3/Caspase-1 pyroptosis pathway in TGFß1-induced CFs, repressed the transdifferentiation of CFs into MFs.


Assuntos
Microbioma Gastrointestinal , Humanos , Caspase 1 , Proteína 3 que Contém Domínio de Pirina da Família NLR , Ácido Butírico , Interleucina-10 , Transdiferenciação Celular , Interleucina-6 , Piroptose , Fibroblastos
3.
Antimicrob Resist Infect Control ; 13(1): 42, 2024 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-38616284

RESUMO

BACKGROUND: COVID-19 and bacterial/fungal coinfections have posed significant challenges to human health. However, there is a lack of good tools for predicting coinfection risk to aid clinical work. OBJECTIVE: We aimed to investigate the risk factors for bacterial/fungal coinfection among COVID-19 patients and to develop machine learning models to estimate the risk of coinfection. METHODS: In this retrospective cohort study, we enrolled adult inpatients confirmed with COVID-19 in a tertiary hospital between January 1 and July 31, 2023, in China and collected baseline information at admission. All the data were randomly divided into a training set and a testing set at a ratio of 7:3. We developed the generalized linear and random forest models for coinfections in the training set and assessed the performance of the models in the testing set. Decision curve analysis was performed to evaluate the clinical applicability. RESULTS: A total of 1244 patients were included in the training cohort with 62 healthcare-associated bacterial/fungal infections, while 534 were included in the testing cohort with 22 infections. We found that patients with comorbidities (diabetes, neurological disease) were at greater risk for coinfections than were those without comorbidities (OR = 2.78, 95%CI = 1.61-4.86; OR = 1.93, 95%CI = 1.11-3.35). An indwelling central venous catheter or urinary catheter was also associated with an increased risk (OR = 2.53, 95%CI = 1.39-4.64; OR = 2.28, 95%CI = 1.24-4.27) of coinfections. Patients with PCT > 0.5 ng/ml were 2.03 times (95%CI = 1.41-3.82) more likely to be infected. Interestingly, the risk of coinfection was also greater in patients with an IL-6 concentration < 10 pg/ml (OR = 1.69, 95%CI = 0.97-2.94). Patients with low baseline creatinine levels had a decreased risk of bacterial/fungal coinfections(OR = 0.40, 95%CI = 0.22-0.71). The generalized linear and random forest models demonstrated favorable receiver operating characteristic curves (ROC = 0.87, 95%CI = 0.80-0.94; ROC = 0.88, 95%CI = 0.82-0.93) with high accuracy, sensitivity and specificity of 0.86vs0.75, 0.82vs0.86, 0.87vs0.74, respectively. The corresponding calibration evaluation P statistics were 0.883 and 0.769. CONCLUSIONS: Our machine learning models achieved strong predictive ability and may be effective clinical decision-support tools for identifying COVID-19 patients at risk for bacterial/fungal coinfection and guiding antibiotic administration. The levels of cytokines, such as IL-6, may affect the status of bacterial/fungal coinfection.


Assuntos
COVID-19 , Coinfecção , Infecção Hospitalar , Micoses , Adulto , Humanos , Pacientes Internados , Coinfecção/epidemiologia , Interleucina-6 , Estudos Retrospectivos , COVID-19/epidemiologia , Infecção Hospitalar/epidemiologia , Aprendizado de Máquina , Micoses/epidemiologia , Atenção à Saúde
4.
Zhongguo Zhong Yao Za Zhi ; 49(3): 779-788, 2024 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-38621882

RESUMO

This study aims to investigate the essential oil(EOL) of Cinnamomum camphora regarding its anti-depression effect and mechanism in regulating inflammatory cytokines and the nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase-1(HO-1) pathway. A mouse model of depression was established by intraperitoneal injection of lipopolysaccharide(LPS). Open field, elevated plus maze, and forced swimming tests were carried out to examine mouse behaviors. Western blot and qRT-PCR were employed to determine the expression of proteins and genes in the Nrf2/HO-1 pathway in the hippocampus. The levels of tumor necrosis factor(TNF)-α, interleukin(IL)-6, and IL-1ß in the serum were measured by enzyme-linked immunosorbent assay(ELISA). The changes of apoptosis in mouse brain were detected by Tunel staining. Compared with the blank control group, the model group showed shortened distance travelled and time spent in the central zone and reduced number of entries in the central zone in the open field test. In the elevated plus maze test, the model group showed reduced open arm time(OT%) and open arm entries(OE%). In the force swimming test, the model group showed extended duration of immobility compared with the blank control group. Compared with the model group, the treatment with EOL significantly increased the distance travelled and time spent in the central zone and increased the number of entries in the central zone in the open field test. In addition, EOL significantly increased the OT% and OE% in the elevated plus maze and shor-tened the immobility duration in the forced swimming test. The model group showed lower expression levels of Nrf2 and HO-1 and hig-her levels of TNF-α, IL-6, and IL-1ß than the blank control group. Compared with the model group, the treatment with EOL up-regulated the expression levels of Nrf2 and HO-1 and lowered the levels of TNF-α, IL-6, and IL-1ß. The Tunel staining results showed that the apoptosis rate in the brain tissue of mice decreased significantly after the treatment with EOL. To sum up, EOL can mitigate the depression-like behaviors of mice by up-regulating the expression of Nrf2 and HO-1 and preventing hippocampal inflammatory damage. The findings provide empirical support for the application of EOL and aromatherapy in the treatment of depression.


Assuntos
Cinnamomum camphora , Óleos Voláteis , Feminino , Camundongos , Animais , Citocinas/metabolismo , Fator de Necrose Tumoral alfa , Interleucina-6 , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Depressão/tratamento farmacológico , Óleos Voláteis/farmacologia , Lipopolissacarídeos/farmacologia
5.
Zhongguo Zhong Yao Za Zhi ; 49(4): 989-999, 2024 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-38621906

RESUMO

This study aims to investigate the effect of Naotaifang(NTF) on the proteins associated with microglial polarization and glial scar in the rat model of cerebral ischemia reperfusion injury(CIRI). The CIRI model was established by middle cerebral artery occlusion/reperfusion. The 48 successfully modeled rats were randomized into model 7 d, model 14 d, NTF 7 d, and NTF 14 d groups(n=12). In addition, 12 SD rats were selected as the sham group. The NTF group was administrated with NTF suspension at 27 g·kg~(-1)·d~(-1) by gavage, and the sham, model 7 d, and model 14 d groups were administrated with the same volume of normal saline every day by gavage for 7 and 14 days, respectively. After the intervention, Longa score was evaluated. The infarct volume was measured by 2,3,5-triphenyl-2H-tetrazolium chloride(TTC) staining. Morris water maze and open field tests were carried out to evaluate the spatial learning, memory, cognitive function, and anxiety degree of rats. Hematoxylin-eosin(HE) staining was employed to observe the morphological structure and damage of the brain tissue. The immunofluorescence assay was employed to measure the expression of glial fibrillary acidic protein(GFAP) and glial scar. Western blot was employed to determine the protein levels of GFAP, neurocan, phosphacan, CD206, arginase-1(Arg-1), interleukin(IL)-1ß, IL-6, and IL-4. Compared with the sham, model 7 d and model 14 d groups showed cerebral infarction of different degrees, severe pathological injury of cerebral cortex and hippocampus, neurological impairment, reduced spatial learning and memory, cognitive dysfunction, severe anxiety, astrocyte hyperplasia, thickening penumbra glial scar, and up-regulated protein levels of IL-1ß, IL-6, GFAP, neurocan, phosphacan, CD206, and Arg-1(P<0.01). Compared with the model group, NTF 7 d and NTF 14 d groups improved spatial learning, memory, and cognitive function, reduced anxiety, improved nerve function, reduced cerebral infarction volume, reduced astrocyte hyperplasia, thinned penumbra glial scar, down-regulated the protein levels of GFAP, neurocan, phosphacan, IL-6, and IL-1ß, and up-regulated the protein levels of IL-4, CD206, and Arg-1(P<0.05 or P<0.01). NTF exerts a neuroprotective effect on CIRI by inducing the M2 polarization of microglia, inhibiting inflammatory response, and reducing the formation of glial scar.


Assuntos
Isquemia Encefálica , Medicamentos de Ervas Chinesas , Traumatismo por Reperfusão , Ratos , Animais , Microglia/metabolismo , Gliose/patologia , Ratos Sprague-Dawley , Hiperplasia , Interleucina-4 , Interleucina-6 , Neurocam , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores , Infarto da Artéria Cerebral Média , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo
6.
Zhongguo Zhong Yao Za Zhi ; 49(4): 1000-1006, 2024 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-38621907

RESUMO

This study aims to investigate the effect and mechanism of Maxingshigan Decoction on inflammation in the rat model of cough variant asthma(CVA). The SPF-grade SD rats of 6-8 weeks were randomized into normal, model, Montelukast sodium, and low-, medium-, and high-dose Maxing Shigan Decoction groups, with 8 rats in each group. The CVA rat model was induced by ovalbumin(OVA) and aluminum hydroxide sensitization and ovalbumin stimulation. The normal group and model group were administrated with equal volume of normal saline by gavage, and other groups with corresponding drugs by gavage. After the experiment, the number of white blood cells in blood and the levels of interleukin-6(IL-6), interleukin-10(IL-10), and tumor necrosis factor-α(TNF-α) in the serum were measured. The lung tissue was stained with hematoxylin-eosin(HE). Western blot was employed to determine the protein levels of nuclear factor-κB(NF-κB), Toll-like receptor 4(TLR4), myeloid differentiation protein(MyD88), and mitogen-activated protein kinase(MAPK) in the lung tissue. Real-time PCR was carried out to measure the mRNA levels of TLR4 and MyD88 in the lung tissue. Compared with the normal group, the model group showed increased white blood cells, elevated IL-6 and TNF-α levels(P<0.01), lowered IL-10 level(P<0.01), up-regulated protein levels of TLR4, MyD88, p-p65/NF-κB p65, and p-p38 MAPK/p38 MAPK(P<0.01) and mRNA levels of TLR4 and MyD88(P<0.01) in the lung tissue. HE staining showed obvious infiltration of inflammatory cells around the airway and cell disarrangement in the model group. Compared with the model group, Montelukast sodium and high-dose Maxing Shigan Decoction reduced the white blood cells, lowered the IL-6 and TNF-α levels(P<0.01), and elevated the IL-10 level(P<0.01). Moreover, they down-regulated the protein levels of TLR4, MyD88, p-p65/NF-κB p65, p-p38 MAPK/p38 MAPK in the lung tissue(P<0.01) and the mRNA levels of TLR4 and MyD88 in the lung tissue(P<0.01). HE staining showed that Montelukast sodium and high-dose Maxing Shigan Decoction reduced inflammatory cell infiltration and cell disarrangement. The number of white blood cells, the levels of IL-10 and TNF-α in the serum, the protein levels of TLR4, MyD88, p-p65/NF-κB p65, and p-p38 MAPK/p38 MAPK, and the mRNA levels of TLR4 and MyD88 in the lung tissue showed no significant differences between the Montelukast sodium group and high-dose Maxing Shigan Decoction group. Maxing Shigan Decoction can inhibit airway inflammation in CVA rats by inhibiting the activation of TLR4/MyD88/NF-κB and p38 MAPK signaling pathways.


Assuntos
Acetatos , 60522 , Ciclopropanos , NF-kappa B , Quinolinas , Sulfetos , Ratos , Animais , NF-kappa B/genética , NF-kappa B/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Interleucina-10/genética , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Ratos Sprague-Dawley , Ovalbumina , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Inflamação , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , RNA Mensageiro
7.
Zhongguo Zhong Yao Za Zhi ; 49(6): 1621-1631, 2024 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-38621947

RESUMO

Network pharmacology was employed to probe into the mechanism of Fushen Granules in treating peritoneal dialysis-rela-ted peritonitis(PDRP) in rats. The main active components of Fushen Granules were searched against the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, and their targets were predicted. PDRP-related targets were retrieved from DisGeNET and other databases. The common targets shared by the drug and the disease were identified by the online tool, and protein-protein interaction(PPI) network of the common targets. The obtained 276 common targets were imported into DAVID for GO function enrichment and KEGG pathway enrichment. The main signaling pathway of Fushen Granules in the treatment of PDRP was predicted as Toll-like receptor 4(TLR4)/nuclear factor(NF)-κB. The rat model of uremia was induced by 5/6 nephrectomy. From two weeks after operation, the rat model of peritoneal dialysis(PD) was established by intraperitoneal injection of 20 mL dialysate with 1.25% glucose every day. The sham operation group and model group received 2 mL normal saline by gavage every day. The rats in Fushen Gra-nules groups were administrated with 2 mL solutions of low-(0.54 g·kg~(-1)), medium-(1.08 g·kg~(-1)) and high-dose(2.16 g·kg~(-1)) Fushen Granules every day. The bifico group received 2 mL(113.4 mg·kg~(-1)) of bifico solution every day. At the end of the 8th week, the levels of serum creatinine(Scr) and blood urea nitrogen(BUN) in each group were measured. The serum levels of hypersensitive C reactive protein(hs-CRP), tumor necrosis factor(TNF)-α, and interleukin(IL)-6 were measured, and the pathological changes in the colon tissue were observed by hematoxylin-eosin(HE) staining. The serum levels of lipopolysaccharide(LPS) and lipopolysaccharide-binding protein(LBP) of rats were measured, and the expression levels of LBP, TLR4, NF-κB p65, inhibitor of κB kinase α(IκBα), TNF-α, and IL-1ß in the colon tissue were determined. Compared with sham operation group, the model group had abnormal structure of all layers of colon tissue, sparse and shorter intestinal villi, visible edema in mucosal layer, wider gap, obvious local inflammatory cell infiltration, significantly decreased body weight(P<0.01), and significantly increased kidney function index(Scr, BUN) content(P<0.01). Serum levels of inflammatory cytokines(hs-CRP, TNF-α, IL-6), LPS and LBP were significantly increased(P<0.01), protein expressions of LBP, TLR4, NF-κB p65, TNF-α and IL-1ß were significantly increased(P<0.01), and protein expressions of IκBα were significantly decreased(P<0.01). Compared with model group, intestinal villi damage in colonic tissue of rats in low-, medium-and high-dose Fushen Granules groups and bifico group were alleviated to different degrees, edema in submucosa was alleviated, space was narrowed, and inflammatory cell infiltration in lamina propria was reduced. The contents of renal function index(Scr, BUN) and serum inflammatory factors(hs-CRP, TNF-α, IL-6) were significantly decreased(P<0.05 or P<0.01) in medium-and high-dose Fushen Granules groups and bifico group(P<0.05 or P<0.01). Serum LPS and LBP contents in Fushen Granules group and bifico group were significantly decreased(P<0.01), protein expressions of LBP, TLR4, NF-κB p65, TNF-α and IL-1ß in Fushen Granules group were significantly decreased(P<0.05 or P<0.01), and protein expressions of IκBα were significantly increased(P<0.01). The expression of LBP protein in bifico group was significantly decreased(P<0.01). The results suggest that Fushen Granules can protect the residual renal function of PD rats, reduce the inflammatory response, and protect the colon tissue. Based on network pharmacology, TLR4/NF-κB pathway may be the main signaling pathway of Fushen granule in the treatment of PDRP. The results showed that Fushen Granules could improve intestinal inflammation and protect intestinal barrier to prevent PDRP by regulating the expression of key factors in TLR4/NF-κB pathway in colon of PD rats.


Assuntos
Experimentação Animal , Diálise Peritoneal , Peritonite , Ratos , Animais , NF-kappa B/genética , NF-kappa B/metabolismo , Inibidor de NF-kappaB alfa , Farmacologia em Rede , Fator de Necrose Tumoral alfa/metabolismo , Proteína C-Reativa , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Interleucina-6 , Lipopolissacarídeos , Peritonite/tratamento farmacológico , Diálise Peritoneal/efeitos adversos , Edema
8.
Zhongguo Zhong Yao Za Zhi ; 49(5): 1266-1274, 2024 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-38621974

RESUMO

This paper investigates the intervention effect and mechanism of Banxia Xiexin Decoction(BXD) on colitis-associated colorectal cancer(CAC) infected with Fusobacterium nucleatum(Fn). C57BL/6 mice were randomly divided into a control group, Fn group, CAC group [azoxymethane(AOM)/dextran sulfate sodium salt(DSS)](AOM/DSS), model group, and BXD group. Except for the control and AOM/DSS groups, the mice in the other groups were orally administered with Fn suspension twice a week. The AOM/DSS group, model group, and BXD group were also injected with a single dose of 10 mg·kg~(-1) AOM combined with three cycles of 2.5% DSS taken intragastrically. The BXD group received oral administration of BXD starting from the second cycle until the end of the experiment. The general condition and weight changes of the mice were monitored during the experiment, and the disease activity index(DAI) was calculated. At the end of the experiment, the colon length and weight of the mice in each group were compared. Hematoxylin-eosin(HE) staining was used to observe the pathological changes in the colon tissue. Enzyme-linked immunosorbent assay(ELISA) was used to detect the levels of interleukin(IL)-2, IL-4, and IL-6 inflammatory factors in the serum. Immunohistochemistry(IHC) was used to detect the expression of Ki67, E-cadherin, and ß-catenin in the colon tissue. Western blot was used to detect the protein content of Wnt3a, ß-catenin, E-cadherin, annexin A1, cyclin D1, and glycogen synthase kinase-3ß(GSK-3ß) in the colon tissue. The results showed that compared with the control group, the Fn group had no significant lesions. The mice in the AOM/DSS group and model group had decreased body weight, increased DAI scores, significantly increased colon weight, and significantly shortened colon length, with more significant lesions in the model group. At the same time, the colon histology of the model group showed more severe adenomas, inflammatory infiltration, and cellular dysplasia. The levels of IL-4 and IL-6 in the serum were significantly increased, while the IL-2 content was significantly decreased. The IHC results showed low expression of E-cadherin and high expression of Ki67 and ß-catenin in the model group, with a decreased protein content of E-cadherin and GSK-3ß and an increased protein content of Wnt3a, ß-catenin, annexin A1, and cyclin D1. After intervention with BXD, the body weight of the mice increased; the DAI score decreased; the colon length increased, and the tumor decreased. The histopathology showed reduced tumor proliferation and reduced inflammatory infiltration. The levels of IL-6 and IL-4 in the serum were significantly decreased, while the IL-2 content was increased. Meanwhile, the expression of E-cadherin was upregulated, and that of Ki67 and ß-catenin was downregulated. The protein content of E-cadherin and GSK-3ß increased, while that of Wnt3a, ß-catenin, annexin A1, and cyclin D1 decreased. In conclusion, BXD can inhibit CAC infected with Fn, and its potential mechanism may be related to the inhibition of Fn binding to E-cadherin, the decrease in annexin A1 protein level, and the regulation of the Wnt/ß-catenin pathway.


Assuntos
Anexina A1 , Neoplasias Associadas a Colite , Colite , Medicamentos de Ervas Chinesas , Camundongos , Animais , Colite/complicações , Colite/tratamento farmacológico , Colite/genética , beta Catenina/genética , beta Catenina/metabolismo , Ciclina D1/metabolismo , Fusobacterium nucleatum/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Antígeno Ki-67/metabolismo , Interleucina-2/metabolismo , Interleucina-4/metabolismo , Camundongos Endogâmicos C57BL , Caderinas/metabolismo , Peso Corporal , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Azoximetano
9.
Zhongguo Zhong Yao Za Zhi ; 49(5): 1310-1317, 2024 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-38621978

RESUMO

This study investigated the effect of Erchen Decoction(ECD) on the prevention of non-alcoholic steatohepatitis(NASH) in mice and explored its possible mechanism, so as to provide scientific data for the clinical application of ECD in the prevention of NASH. C57BL/6 male mice were randomly divided into normal group(methionine and choline supplement, MCS), model group(methionine and choline deficient, MCD), low-dose ECD group(ECD_L, 6 g·kg~(-1)), medium-dose ECD group(ECD_M, 12 g·kg~(-1)), and high-dose ECD group(ECD_H, 24 g·kg~(-1)), with eight mice in each group. The MCS group was fed with an MCS diet, and the other groups were fed with an MCD diet. The mice in each group were given corresponding diets, but the drug intervention group was given low-, medium-, and high-dose ECD(10 mL·kg~(-1)·d~(-1)) by intragastric administration for six weeks on the basis of MCD diet feeding, and the mice could eat and drink freely during the whole experiment. At the end of the experiment, mice were fasted overnight(12 h) and were anesthetized with 20% urethane. Thereafter, the blood and liver tissue were collected. The serum was used to detect the levels of alanine aminotransferase(ALT), aspartate aminotransaminase(AST), interleukin-1ß(IL-1ß), interleukin-6(IL-6), interleukin-10(IL-10), and tumor necrosis factor-α(TNF-α). Liver tissue was processed by hematoxylin-eosin(HE) staining and used for hepatic histological analysis and detection of the expression levels of genes and proteins related to nuclear factor erythroid 2-related factor 2/glutathione peroxidase 4(Nrf2/GPX4) pathway by real-time quantitative reverse transcriptase-polymerase chain reaction(RT-qPCR) and Western blot analysis, respectively. The results showed that compared with the MCS group, the MCD group showed higher serum ALT and AST levels; the HE staining exhibited fat vacuoles and obvious inflammatory cell infiltration in liver tissue; serum IL-1ß, IL-6, and TNF-α levels were significantly increased, and the serum IL-10 level was significantly decreased. The mRNA expressions of fatty acid synthase(FASN), monocyte chemoattractant protein-1(MCP-1), and IL-1ß in liver tissue were significantly up-regulated, while those of GPX4, Nrf2, and NAD(P)H:quinine oxidoreductase(NQO1) were significantly down-regulated. Compared with the MCD group, the serum ALT and AST levels of ECD_M and ECD_H groups were significantly decreased, and the AST level in the ECD_L group was significantly decreased. The number of fat vacuoles and the degree of inflammatory cell infiltration in liver tissue were improved; serum IL-1ß, IL-6, and TNF-α levels were significantly decreased, but the serum IL-10 level was significantly increased only in the ECD_H group. The mRNA expressions of FASN, MCP-1, and IL-1ß in liver tissue were significantly down-regulated, and those of GPX4 and NQO1 were significantly up-regulated. The mRNA expressions of Nrf2 in ECD_M and ECD_H groups were significantly up-regulated. Western blot results showed that compared with the MCD group, the protein expression levels of Nrf2 and GPX4 in each group were significantly increased after ECD administration, and the protein expression level of FASN was significantly decreased; the protein expression of NQO1 was increased in ECD_M and ECD_H groups. In summary, ECD can reduce hepatic lipid accumulation, oxidative stress, liver inflammation, and liver injury in NASH mice, which may be related to the activation of the Nrf2/GPX4 pathway.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Camundongos , Masculino , Animais , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/genética , Metionina/metabolismo , Metionina/farmacologia , Interleucina-10/genética , Colina/metabolismo , Colina/farmacologia , Colina/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Camundongos Endogâmicos C57BL , Fígado , Racemetionina/metabolismo , Racemetionina/farmacologia , Dieta , RNA Mensageiro/metabolismo
10.
Vet Res ; 55(1): 52, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38622656

RESUMO

Clostridium perfringens (C. perfringens) infection is recognized as one of the most challenging issues threatening food safety and perplexing agricultural development. To date, the molecular mechanisms of the interactions between C. perfringens and the host remain poorly understood. Here, we show that stimulator of interferon genes (STING)-dependent trained immunity protected against C. perfringens infection through mTOR signaling. Heat-killed Candida albicans (HKCA) training elicited elevated TNF-α and IL-6 production after LPS restimulation in mouse peritoneal macrophages (PM). Although HKCA-trained PM produced decreased levels of TNF-α and IL-6, the importance of trained immunity was demonstrated by the fact that HKCA training resulted in enhanced bacterial phagocytic ability and clearance in vivo and in vitro during C. perfringens infection. Interestingly, HKCA training resulted in the activation of STING signaling. We further demonstrate that STING agonist DMXAA is a strong inducer of trained immunity and conferred host resistance to C. perfringens infection in PM. Importantly, corresponding to higher bacterial burden, reduction in cytokine secretion, phagocytosis, and bacterial killing were shown in the absence of STING after HKCA training. Meanwhile, the high expression levels of AKT/mTOR/HIF1α were indeed accompanied by an activated STING signaling under HKCA or DMXAA training. Moreover, inhibiting mTOR signaling with rapamycin dampened the trained response to LPS and C. perfringens challenge in wild-type (WT) PM after HKCA training. Furthermore, STING­deficient PM presented decreased levels of mTOR signaling-related proteins. Altogether, these results support STING involvement in trained immunity which protects against C. perfringens infection via mTOR signaling.


Assuntos
Infecções por Clostridium , Doenças dos Roedores , Animais , Camundongos , Imunidade Inata/genética , Imunidade Treinada , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-6 , Lipopolissacarídeos , Infecções por Clostridium/veterinária , Clostridium perfringens , Serina-Treonina Quinases TOR
11.
Clin Lab ; 70(4)2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38623665

RESUMO

BACKGROUND: This study aims to ascertain the predictive value of platelet and inflammation markers in severe cases of COVID-19. METHODS: A retrospective real-world cohort study was conducted using propensity score matching (PSM). Patients were classified into severe and non-severe COVID-19 groups based on the severity of the disease, and the correlation between severe COVID-19 and laboratory parameters at admission was analyzed. RESULTS: The study included 397 adult patients, comprising 212 (53%) males and 185 (47%) females. Among these, 309 were non-severe and 88 were severe cases. The severe group had a higher median age than the non-severe group (60 vs. 42 years, p < 0.001). Independent risk factors for severe COVID-19 included age, diabetes comorbidity, fever, respiratory symptoms, platelet count, high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and the ratio of arterial oxygen partial pressure (PaO2) to the fraction of inspired oxygen (FiO2) (P/F ratio). After one-to-one PSM, adjusted for age, diabetes comorbidities, fever, and respiratory symptoms, significant differences in laboratory parameters at admission were observed. Compared to the non-severe group (n = 71), in the severe group (n = 71), elevated levels of hsCRP (median: 27.1 mg/L vs. 14.6 mg/L, p = 0.005) and IL-6 (median: 16.2 pg/mL vs. 15.3 pg/mL, p = 0.005) were observed, while platelet count (164 ± 36 × 109 vs. 180 ± 50 × 109, p = 0.02) and P/F ratio (median: 351 vs. 397, p = 0.001) were reduced. CONCLUSIONS: Elevated levels of hsCRP and IL-6, along with reduced platelet count and P/F ratio at admission, were significantly associated with severe COVID-19 and may serve as predictive indicators.


Assuntos
COVID-19 , Diabetes Mellitus , Masculino , Adulto , Feminino , Humanos , Estudos Retrospectivos , Proteína C-Reativa , Interleucina-6 , Estudos de Coortes , Pontuação de Propensão , Inflamação , Oxigênio , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiologia
12.
Bratisl Lek Listy ; 125(5): 281-288, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38624052

RESUMO

AIM: We aimed to investigate the possible cardioprotective effects of paricalcitol (PR), its vitamin D receptor agonist, and vitamin D3 (VIT-D3) on an experimental model of doxorubicin (DX) cardiotoxicity by 99mTc-PYP scintigraphy, electrocardiographic (ECG) and biochemical methods. METHOD: Forty-two male Wistar/Albino rats (250‒300 g; aged 10‒12 weeks) were randomly separated into six groups, namely into control (CN), doxorubicin (DX), paricalcitol (PR), vitamin D3 (VIT-D3), paricalcitol + doxorubicin (PR+DX), and vitamin D3 + doxorubicin (VIT-D3+DX) groups. Cardiotoxicity was induced by three doses of DX (18 mg/kg, i.p.) at 24-hour intervals on days 18, 19 and 20. PR (0.5 ug/ kg, i.p) and VIT-D3 (5,000 IU/kg, i.p) were injected for 20 days before and after the application of DX (18 mg/kg, i.p.). On day 21 of the experiment, biochemical parameters [tumor necrosis factor TNF-alpha (TNF-α); interleukin-6 (IL-6), nitric oxide (NO), and cardiac troponin T (cTnT)], as well as ECG and scintigraphic (99mTc-PYP) features were assessed. RESULTS: Compared to CN, DX significantly raised TNF-α, IL-6, and NO in heart tissue, cTnT in serum, 99mTc-PYP uptake in the myocardium, and ECG parameters, specifically QRS complex duration, QT interval duration, and ST-segment amplitude, while also reducing heart rate (p<0.001). Pretreatment with PR and VIT-D3 mitigated these abnormalities produced by DX in the heart (p<0.001). CONCLUSION: Results show that vitamin D receptor agonist paricalcitol and vitamin D protect against DX-induced cardiotoxicity through anti-inflammatory and antioxidant effects (Fig. 4, Ref. 59). Text in PDF www.elis.sk Keywords: paricalcitol, doxorubicin, vitamin D, ECG, 99mTc-PYP scintigraphy, cardiotoxicity, inflammation.


Assuntos
Cardiotoxicidade , Ergocalciferóis , Receptores de Calcitriol , Ratos , Masculino , Animais , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/prevenção & controle , Receptores de Calcitriol/uso terapêutico , Ratos Wistar , Colecalciferol/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-6 , Eletrocardiografia , Doxorrubicina/toxicidade , Antioxidantes/farmacologia , Cintilografia , Estresse Oxidativo
13.
Exp Lung Res ; 50(1): 96-105, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38625585

RESUMO

Background: Acute Respiratory Distress syndrome (ARDS) is a clinical syndrome of noncardiac pulmonary edema and inflammation leading to acute respiratory failure. We used the oleic acid infusion pig model of ARDS resembling human disease to explore cytokine changes in white blood cells (WBC) and plasma proteins, comparing baseline to ARDS values. Methods: Nineteen juvenile female swine were included in the study. ARDS defined by a PaO2/FiO2 ratio < 300 was induced by continuous oleic acid infusion. Arterial blood was drawn before and during oleic acid infusion, and when ARDS was established. Cytokine expression in WBC was analyzed by RT-qPCR and plasma protein expression by ELISA. Results: The median concentration of IFN-γ mRNA was estimated to be 59% (p = 0.006) and of IL-6 to be 44.4% (p = 0.003) of the baseline amount. No significant changes were detected for TNF-α, IL-17, and IL-10 mRNA expression. In contrast, the concentrations of plasma IFN-γ and IL-6 were significantly higher (p = 0.004 and p = 0.048 resp.), and TNF-α was significantly lower (p = 0.006) at ARDS compared to baseline. Conclusions: The change of proinflammatory cytokines IFN-γ and IL-6 expression is different comparing mRNA and plasma proteins at oleic acid-induced ARDS compared to baseline. The migration of cells to the lung may be the cause for this discrepancy.


Assuntos
Lesão Pulmonar Aguda , Síndrome do Desconforto Respiratório , Humanos , Feminino , Animais , Suínos , Ácido Oleico , Fator de Necrose Tumoral alfa , Interleucina-6 , Citocinas , Lesão Pulmonar Aguda/induzido quimicamente , Síndrome do Desconforto Respiratório/induzido quimicamente
14.
BMC Oral Health ; 24(1): 463, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38627806

RESUMO

BACKGROUND: To compare presence and levels of serum cytokines in smokers and non-smokers with periodontitis following periodontal therapy. METHODS: Thirty heavy smokers and 30 non-smokers with stage III or IV periodontitis were included in this prospective cohort study. Clinical data and blood serum were collected at baseline (T0), after step I-III (T1), and after 12 months step IV periodontal therapy (T2). Cytokine IL-1ß, IL-6, IL-8, TNF-α, IL-10, and IP-10 levels were measured using multiplex kit Bio-Plex Human Pro™ Assay. Linear regression models with cluster robust variance estimates to adjust for repeated observations were used to test intra- and intergroup levels for each marker, IL-6 and IL-8 defined as primary outcomes. RESULTS: Clinical outcomes improved in both groups following therapy (p < 0.05). IL-6 levels increased with 75.0% from T0-T2 among smokers (p = 0.004). No significant intra- or intergroup differences were observed for IL-8. Higher levels of TNF-α (44.1%) and IL-10 (50.6%) were detected in smokers compared with non-smokers at T1 (p = 0.007 and p = 0.037, respectively). From T1-T2, differences in mean change over time for levels of TNF-α and IL-10 were observed in smokers compared with non-smokers (p = 0.005 and p = 0.008, respectively). CONCLUSION: Upregulated levels of serum cytokines in smokers indicate a systemic effect of smoking following periodontal therapy. Differences in cytokine levels between smokers and non-smokers demonstrate a smoking induced modulation of specific systemic immunological responses in patients with severe periodontitis.


Assuntos
Periodontite , Fumantes , Humanos , Fumar , Interleucina-10 , não Fumantes , Fator de Necrose Tumoral alfa , Interleucina-6/análise , Estudos Prospectivos , Interleucina-8 , Periodontite/terapia , Citocinas , Biomarcadores , Líquido do Sulco Gengival/química
15.
Cancer Imaging ; 24(1): 53, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38627864

RESUMO

BACKGROUND: Imaging features of colorectal cancers on 2-deoxy-2-[18F]fluoro-d-glucose (FDG) positron emission tomography/computed tomography (PET/CT) have been considered to be affected by tumor characteristics and tumor immune microenvironment. However, the relationship between PET/CT imaging features and immune reactions in tumor tissue has not yet been fully evaluated. This study investigated the association of FDG PET/CT imaging features in the tumor, bone marrow, and spleen with immunohistochemical results of cancer tissue and recurrence-free survival (RFS) in patients with colorectal cancer. METHODS: A total of 119 patients with colorectal cancer who underwent FDG PET/CT for staging work-up and received curative surgical resection were retrospectively enrolled. From PET/CT images, 10 first-order imaging features of primary tumors, including intensity of FDG uptake, volumetric metabolic parameters, and metabolic heterogeneity parameters, as well as FDG uptake in the bone marrow and spleen were measured. The degrees of CD4+, CD8+, and CD163 + cell infiltration and interleukin-6 (IL-6) and matrix metalloproteinase-11 (MMP-11) expression were graded through immunohistochemical analysis of surgical specimens. The relationship between FDG PET/CT imaging features and immunohistochemical results was assessed, and prognostic significance of PET/CT imaging features in predicting RFS was evaluated. RESULTS: Correlation analysis with immunohistochemistry findings showed that the degrees of CD4 + and CD163 + cell infiltration and IL-6 and MMP-11 expression were correlated with cancer imaging features on PET/CT. Patients with enhanced inflammatory response in cancer tissue demonstrated increased FDG uptake, volumetric metabolic parameters, and metabolic heterogeneity. FDG uptake in the bone marrow and spleen was positively correlated with the degree of CD163 + cell infiltration and IL-6 expression, respectively. In multivariate survival analysis, the coefficient of variation of FDG uptake in the tumor (p = 0.019; hazard ratio, 0.484 for 0.10 increase) and spleen-to-liver uptake ratio (p = 0.020; hazard ratio, 24.901 for 1.0 increase) were significant independent predictors of RFS. CONCLUSIONS: The metabolic heterogeneity of tumors and FDG uptake in the spleen were correlated with tumor immune microenvironment and showed prognostic significance in predicting RFS in patients with colorectal cancer.


Assuntos
Neoplasias Colorretais , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Fluordesoxiglucose F18/metabolismo , Estudos Retrospectivos , Metaloproteinase 11 da Matriz , Compostos Radiofarmacêuticos/metabolismo , Interleucina-6 , Prognóstico , Neoplasias Colorretais/patologia , Microambiente Tumoral
16.
Front Cell Infect Microbiol ; 14: 1340075, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38628549

RESUMO

Purpose: To determine the effects of EV-A71 (Enterovirus A71) infection on ocular surface and its mechanism. Methods: AG6 mice aged two to three weeks were randomly divided into control and EV-A71 infected groups. Slit-lamp observation, fluorescein staining, and phenol red thread test were used to assess symptoms of ocular surface at 4 dpi (days post infection). The pathological changes of cornea and lacrimal gland were observed by H&E staining, PAS staining, TUNEL assay, IHC staining and qRT-PCR. Corneas and lacrimal glands from mice were obtained and processed for RNA sequencing analysis. Newly diagnosed HFMD patients caused by EV-A71 were recruited and ensured they met the inclusion criteria. Ocular surface parameters (TMH and NIKBUT) were measured using the OCULUS Keratograph 5M. Tear samples were taken to examine Cxcl1 and IL-6 levels through the ELISA method. Results: Mice studies revealed that EV-A71 infection caused tear film instability, decreased tear secretions, decreased in lacrimal gland size, and distinct goblet cell loss. It also resulted in increased large vacuoles within acinar cells and structural damage in lacrimal gland. Apart from minor damage to the epidermis, there was no obvious inflammatory changes or apoptosis in the cornea. However, there were significant inflammatory injury and apoptosis in the lacrimal gland. RNA-seq analysis showed IL-17 and NF-κB signaling pathways were activated in the lacrimal glands of mice infected with EV-A71. In HFMD patients, the THM was in a low range and NITBUT was significantly shorter than the control group by Oculus Keratograph 5M. ELISA assay showed a higher tear Cxcl1 and IL-6 level in them. Conclusion: EV-A71 infection affected lacrimal gland structure and function and induced dry eye-like symptoms.


Assuntos
Síndromes do Olho Seco , Enterovirus Humano A , Infecções por Enterovirus , Enterovirus , Aparelho Lacrimal , Humanos , Animais , Camundongos , Interleucina-6 , Síndromes do Olho Seco/etiologia
17.
Front Immunol ; 15: 1371753, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38629073

RESUMO

The risk of cancer is higher in patients with asthma compared to those with allergic rhinitis for many types of cancer, except for certain cancers where a contrasting pattern is observed. This study offers a potential explanation for these observations, proposing that the premalignant levels of circulating transforming growth factor-ß (TGF-ß), IL-1ß, and IL-6 as well as the reactivity of the TGF-ß/Smad signaling pathway at the specific cancer site, are crucial factors contributing to the observed disparities. Circulating TGF-ß, IL- ß and IL-6 levels also help clarify why asthma is positively associated with obesity, Type 2 diabetes, hypertension, and insulin resistance, whereas allergic rhinitis is negatively linked to these conditions. Furthermore, TGF-ß/Smad pathway reactivity explains the dual impact of obesity, increasing the risk of certain types of cancer while offering protection against other types of cancer. It is suggested that the association of asthma with cancer and metabolic dysregulations is primarily linked to the subtype of neutrophilic asthma. A binary classification of TGF-ß activity as either high (in the presence of IL-1ß and IL-6) or low (in the presence or absence of IL-1ß and IL-6) is proposed to differentiate between allergy patients prone to cancer and metabolic dysregulations and those less prone. Glycolysis and oxidative phosphorylation, the two major metabolic pathways utilized by cells for energy exploitation, potentially underlie this dichotomous classification by reprogramming metabolic pathways in immune cells.


Assuntos
Asma , Diabetes Mellitus Tipo 2 , Neoplasias , Rinite Alérgica , Humanos , Fator de Crescimento Transformador beta/metabolismo , Interleucina-6 , Obesidade
18.
Virulence ; 15(1): 2342276, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38629410

RESUMO

Host immune dysfunction plays a crucial role in the onset, progression, and outcome of hemophagocytic lymphohistiocytosis (HLH). This study aimed to comprehensively evaluate the peripheral immune profiles in patients with newly diagnosed secondary hemophagocytic lymphohistiocytosis (sHLH), and explore their predictive value for patient prognosis. A total of 77 patients with sHLH were enrolled in this study, with 31 of them experiencing mortality. Flow cytometry was used to assess the percentages, absolute numbers, and phenotypes of lymphocyte subsets. Simultaneously, cytokine levels and routine laboratory indicators were also collected. In sHLH patients, lymphocyte subset absolute numbers were significantly impaired, accompanied by T cell hyperactivation, B cell hyperactivation, and increased plasmablast proliferation. Prognostic analysis revealed that lower CD8+ T cell percentages, elevated APTT, IL-6, IL-10 levels, and increased CD4+CD28null T cell proportions were associated with poor patient outcomes. The study demonstrates dysregulation in the counts and phenotypes of lymphocyte subsets in sHLH patients. Several key factors, including IL-6, IL-10, APTT, and various T cell percentages, have potential as prognostic markers and therapeutic targets in sHLH.


Assuntos
Linfo-Histiocitose Hemofagocítica , Humanos , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/genética , Interleucina-10 , Interleucina-6 , Linfócitos T CD8-Positivos , Citocinas
19.
J Biochem Mol Toxicol ; 38(5): e23714, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38629493

RESUMO

Parkinson's disease (PD) is a neurodegenerative disease featured by progressive loss of nigrostriatal dopaminergic neurons, the etiology of which is associated with the existence of neuroinflammatory response and oxidative stress. Vincamine is an indole alkaloid that was reported to exhibit potent anti-inflammatory and antioxidant properties in many central and/or peripheral diseases. Nevertheless, the specific role of vincamine in PD development remains unknown. In our study, dopaminergic neuron loss was determined through immunohistochemistry staining and western blot analysis of tyrosine hydroxylase (TH) expression in the substantia nigra (SN) of PD mice. Reactive oxygen species (ROS) production and malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) levels were detected through DHE staining and commercially available kits to assess oxidative stress. Pro-inflammatory cytokine (TNF-α, IL-1ß, and IL-6) levels in the SN were measured via RT-qPCR and western blot analysis. Microglial and astrocyte activation was examined through immunofluorescence staining of Iba-1 (microglia marker) and GFAP (astrocyte marker) in the SN. The regulation of vincamine on the NF-κB and Nrf2/HO-1 pathway was estimated through western blot analysis. Our results showed that vincamine treatment decreased TNF-α, IL-1ß, and IL-6 mRNA and protein levels, reduced GFAP and Iba-1 expression, decreased ROS production and MDA level, and increased SOD activity and GSH level in the SN of PD mice. Mechanically, vincamine repressed the phosphorylation levels of p65, IKKß, and IκBα but enhanced the protein levels of Nrf2 and HO-1 in PD mice. Collectively, vincamine plays a neuroprotective role in PD mouse models by alleviating neuroinflammation and oxidative damage via suppressing the NF-κB pathway and activating the Nrf2/HO-1 pathway.


Assuntos
Lesões Encefálicas , Doenças Neurodegenerativas , Doença de Parkinson , Vincamina , Camundongos , Animais , NF-kappa B/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Oxigênio , Fator de Necrose Tumoral alfa/metabolismo , Doenças Neuroinflamatórias , Interleucina-6/metabolismo , Transdução de Sinais , Estresse Oxidativo , Superóxido Dismutase/metabolismo
20.
Clin Transl Sci ; 17(2): e13731, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38564661

RESUMO

Organic anion-transporting polypeptides (OATP)1B are drug transporters mainly expressed in the sinusoidal membrane. Many studies have suggested that OATP1B activity is affected by genetic factor, the uremic toxin 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), and inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Coproporphyrin-I (CP-I) is spotlighted as a highly accurate endogenous substrate of OATP1B. We previously reported a positive correlation between plasma CMPF and CP-I concentrations in patients with chronic kidney disease (CKD). The present study evaluated the impact of genetic polymorphisms, CMPF, IL-6, TNF-α, and estimated glomerular filtration rate (eGFR) on individual differences in OATP1B activity in patients with CKD. Seventy-three patients with CKD who received kidney transplant at least 3 months earlier were analyzed. Plasma CP-I concentration was higher in OATP1B1*15 carriers than in non-carriers. In all patients, CP-I did not correlate significantly with CMPF, IL-6, TNF-α, or eGFR. However, when the dataset was cut off at CMPF concentration of 8 and 7 µg/mL, 4 µg/mL, 3 µg/mL or 2 µg/mL, CMPF correlated positively with CP-I, and correlation coefficient tended to be higher as plasma CMPF concentration was lower. In conclusion, OATP1B1*15 impacted OATP1B activity in patients with CKD, but IL-6 and TNF-α did not. However, the impact of CMPF on OATP1B activity was limited to low CMPF concentrations, and the effect could be saturated at high concentrations. When prescribing an OATP1B substrate drug for patients with CKD, the OATP1B1*15 carrier status and plasma CMPF concentration may need to be considered to decide the dose regimen.


Assuntos
Interleucina-6 , Propionatos , Insuficiência Renal Crônica , Humanos , Fator de Necrose Tumoral alfa , Furanos
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