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1.
PLoS One ; 15(1): e0226961, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31899784

RESUMO

OBJECTIVE: To determine whether the coexistence of carotid atherosclerosis plaque affects the neurological function of cerebral infarction. METHODS: A total of 1078 patients with acute cerebral infarction were enrolled, all patients were divided into carotid plaque group (n = 702) and non-carotid plaque group (n = 376). Meanwhile, all patients were divided into mild group (n = 624) and moderate to severe group (n = 454). The difference of the incidence of carotid plaque between the mild and moderate to severe group was analyzed. RESULTS: In the 1078 patients with cerebral infarction, the NIHSS score in the carotid plaque group was significantly higher than that in the non-carotid plaque group (P<0.05). The number of mild cases without carotid artery plaque group was larger than that of plaque group (P<0.05), and the number of moderate to severe cases in carotid plaque group was larger than that in non-plaque group (P<0.05). In patients with carotid atherosclerotic plaque, the risk of moderate to severe cerebral infarction was 2.11 times higher than that without carotid artery plaque. Lastly, patients with single plaques were 1.82 times more likely to develop moderate to severe cerebral infarction than those without carotid plaque, while patients with multiple carotid plaques were 2.41 times higher to get moderate or severe cerebral infarction than those without carotid plaque. CONCLUSIONS: The incidence of carotid atherosclerotic plaques may be related to neurological deficits in patients with acute cerebral infarction.

2.
Shock ; 53(2): 217-222, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30998645

RESUMO

OBJECTIVE: The aim of this study was to investigate the changes of bile acids in the liver during hemorrhagic shock (HS) and their potential to attenuate liver injury via activation of SIRT1 (sirtuin 1)-FXR (farnesoid X receptor) signaling. METHODS: A Sprague-Dawley (SD) rat HS model was established, whereas HepG2 cells were hypoxically cultured to simulate HS in vitro. Liver bile acids (BA) were profiled with ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). FXR expression was detected by western blot and immunohistochemistry. The mRNA levels of SIRT1 and FXR were detected by polymerase chain reaction. Protein expression of SIRT1, FoxM1, NF-κB, acetyl-NF-κB, p53, and acetyl-p53 was analyzed by western blot. Hepatocyte apoptosis and proliferation were measured by TUNEL assay and Ki-67 staining, respectively. Serum and supernatant cytokines were analyzed using ELISA assays. Liver injury was also assessed. To investigate the possible mechanisms, SIRT1 agonist (SRT1720), SIRT1 inhibitor (EX527), and FXR inhibitor (Z-guggulsterone) were used. RESULTS: Tauroursodeoxycholic acid (TUDCA) in the liver decreased significantly after HS. SIRT1 and FXR expression was time-dependently downregulated by HS or hypoxia condition. TUDCA upregulated SIRT1-FXR activity, which inhibited expression and acetylation of NF-κB and p53 and increased FoxM1 expression, leading to decreased inflammatory response and apoptosis and increased proliferative capacity in hepatocytes, and attenuation of liver injury. EX527 pretreatment reversed the protective effect of TUDCA. Moreover, Z-guggulsterone supplementation decreased the protective effect of TUDCA in vitro. CONCLUSION: TUDCA in the liver decreased during HS. TUDCA supplementation might attenuate HS-induced liver injury by upregulating SIRT1-FXR signaling.

3.
Biomed Pharmacother ; 121: 109580, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31704614

RESUMO

Colorectal cancer (CRC) is a malignant tumor with a high incidence and death rate in the world. Molecular interactions inside cells or tissues during tumor occurrence, development, and drug resistance are important for disease prevention and treatment. The long non-coding RNA SNHG14 has been proven to exert its oncogenic function in multiple cancers. However, there is no study regarding the role of SNHG14 in CRC research. In the present study, we applied RT-qPCR and western blot to determine the gene expression levels. MTT and TUNEL assays were used to detect cell proliferation and apoptosis rate. Cell migration and invasion abilities were determined by wound healing and transwell assays, respectively. StarBase was used to predict the potential binding sites and luciferase reporter assay was applied to confirm the direct interactions. Besides, we conducted a xenograft experiment to detect tumor growth rate in vivo. Our results showed that SNHG14 and ATG14 were both significantly higher in CRC tumor tissues than the normal ones, while miR-186 was decreased. The similar results were also observed in CRC cell lines. We confirmed that SNHG14 could directly interact with miR-186 and inhibited its expression. Meanwhile, miR-186 could directly bind ATG14 to inhibit its expression level. In vitro experiments showed that higher expression of SNHG14 led to higher cell proliferation, migration and invasion, while miR-186 significantly inhibited these tumor phenotypes. Furthermore, overexpression of ATG14 could strongly recover the CRC phenotypes attenuated by shSNHG14 or miR-186 mimics. Interestingly, we constructed cisplatin-resistant CRC cells and found that overexpression of ATG14 significantly enhanced the cell proliferation rate and inhibited cell apoptosis. Our research indicated that the novel axis of SNHG14/miR-186/ATG14 could play a vital role in regulating CRC cell progression. Moreover, this axis showed its clinical potential in regulating cisplatin resistance during CRC treatment.

4.
BMC Infect Dis ; 19(1): 961, 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31711425

RESUMO

BACKGROUND: Clostridioides difficile is considered the main pathogen responsible for hospital-acquired infections. This prospective study determined the prevalence, molecular epidemiological characteristics, and risk factors for C. difficile infection (CDI) and C. difficile colonization (CDC) among patients in the intensive care unit (ICU) of a large-scale tertiary hospital in China, with the aim of providing strategies for efficient CDI and CDC prevention and control. METHODS: Stool samples were collected and anaerobically cultured for C. difficile detection. The identified isolates were examined for toxin genes and subjected to multilocus sequence typing. Patients were classified into CDI, CDC, and control groups, and their medical records were analyzed to determine the risk factors for CDI and CDC. RESULTS: Of the 800 patients included in the study, 33 (4.12%) and 25 (3.12%) were identified to have CDI and CDC, respectively. Associations with CDI were found for fever (OR = 13.993), metabolic disorder (OR = 7.972), and treatment with fluoroquinolone (OR = 42.696) or combined antibiotics (OR = 2.856). CDC patients were characterized by prolonged hospital stay (OR = 1.137), increased number of comorbidities (OR = 36.509), respiratory diseases (OR = 0.043), and treatment with vancomycin (OR = 18.168). Notably, treatment with metronidazole was found to be a protective factor in both groups (CDI: OR = 0.042; CDC: OR = 0.013). Eighteen sequence types (STs) were identified. In the CDI group, the isolated strains were predominantly toxin A and toxin B positive (A + B+) and the epidemic clone was genotype ST2. In the CDC group, the dominant strains were A + B+ and the epidemic clone was ST81. CONCLUSIONS: The prevalences of CDC and CDI in our ICU were relatively high, suggesting the importance of routine screening for acquisition of C. difficile. Future prevention and treatment strategies for CDC and CDI should consider hospital stay, enteral nutrition, underlying comorbidities, and use of combined antibiotics. Moreover, metronidazole may be a protective factor for both CDI and CDC, and could be used empirically.

5.
Drug Des Devel Ther ; 13: 3391-3404, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576113

RESUMO

Purpose: It has been reported that approximately 40% of ALI (acute lung injury) incidence resulted from sepsis. Paclitaxel, as a classic anti-cancer drug, plays an important role in the regulation of inflammation. However, we do not know whether it has a protective effect against CLP (cecal ligation and puncture)-induced septic ALI. Our study aims to illuminate the mitigative effects of paclitaxel on sepsis-induced ALI and its relevant mechanisms. Materials and methods: The survival rates and organ injuries were used to evaluate the effects of paclitaxel on CLP mice. The levels of inflammatory cytokines were tested by ELISA. MUC1 siRNA pre-treatment was used to knockdown MUC1 expression in vitro. GO203 was used to inhibit the homodimerization of MUC1-C in vivo. The expression levels of MUC1, TLR 4 and p-NF-κB/p65 were detected by Western blot. Results: Our results showed that paclitaxel improved the survival rates and ameliorated organ injuries especially lung injury in CLP-induced septic mice. These were accompanied by reduced inflammatory cytokines in sera and BALF (bronchoalveolar lavage fluid). We also found paclitaxel could attenuate TLR 4-NF-κB/p65 activation both in lung tissues of septic mice and LPS-stimulated lung type II epithelial cell line A549. At the upstream level, paclitaxel-upregulated expression levels of MUC1 in both in vivo and in vitro experiments. The inhibitory effects of paclitaxel on TLR 4-NF-κB/p65 activation were reversed in lung tissues of septic mice pre-treated with MUC1 inhibitor and in MUC1-knockdown A549 cells. Protection of paclitaxel on sepsis-induced ALI and decrease of inflammatory cytokines were also abolished by inhibition of MUC1. Conclusion: Collectively, these results indicated paclitaxel could significantly alleviate acute lung injury in CLP-induced septic mice and LPS-stimulated lung type II epithelial cell line A549 by activating MUC1 and suppressing TLR-4/NF-κB pathway.

6.
Scand J Immunol ; 90(6): e12823, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31489646

RESUMO

Sepsis is associated with significant mortality. Early diagnosis and prognosis of patients with sepsis is still a difficult clinical challenge. In this study, the ability of plasma PTX3 (pentraxin 3), MCP1 (monocyte chemoattractant protein 1) and Ang (angiopoietin)1/2 was investigated to evaluate the severity of sepsis. Blood samples were obtained from 43 patients with sepsis. A total of 33 post-surgery patients with infections and 25 healthy individuals served as controls. The results showed that plasma PTX3, MCP1 and Ang2 significantly increased in patients on the first day of septic shock onset, while sepsis patients had significantly higher Ang2 level, compared with controls. Furthermore, PTX3, MCP1 and Ang2 had high AUROC values in patients with septic shock on the first day of sepsis onset. The findings suggest that PTX3, MCP1 and Ang2 maybe early predictors to evaluate the severity of sepsis and septic shock with the latest Sepsis 3.0 definitions.


Assuntos
Angiopoietina-2/sangue , Proteína C-Reativa , Quimiocina CCL2/sangue , Sepse/sangue , Sepse/diagnóstico , Componente Amiloide P Sérico , Choque Séptico/sangue , Choque Séptico/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Estudos de Casos e Controles , Humanos , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Sepse/terapia , Índice de Gravidade de Doença , Choque Séptico/terapia
8.
Med Sci Monit ; 25: 2009-2015, 2019 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-30880326

RESUMO

BACKGROUND Hypoxia is an important feature of solid tumors and related to a perturbed blood supply in pathophysiologies. The aim of our research was to analyze the hypoxia response and elaborate its potential functions in colorectal cancer. MATERIAL AND METHODS The lncRNAs and mRNAs expression profile were analyzed in colorectal cancer cell line SW480 by RNA sequencing, and the functions and pathways of differentially expressed genes were screened by Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis. RESULTS In this study, 77 lncRNAs and 1327 mRNAs were identified as differentially expressed. We discovered several novel lncRNAs, such as RP11-126K1.2, RP3-438O4.4, LINC01119, CTB-22K21.2, RP11-798M19.6, and RP11-2B6.3, which had not been previously reported in regulation by hypoxia. KEGG and GO analyses identified that the differentially expressed changes in mRNAs were mainly related to regulation of basic metabolic processes and gene transcription processes and were involved in several classical pathways which were linked to cancer. CONCLUSIONS Taken together, the present findings elucidate a set of differentially expressed lncRNAs and mRNAs involved in the hypoxia response process of colorectal cancer, which may serve as a candidate diagnostic biomarker and help to explain the mechanism of initial event in colorectal carcinogenesis in colorectal cancer.


Assuntos
Neoplasias Colorretais/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Moduladores da Angiogênese/metabolismo , Linhagem Celular Tumoral , China , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/genética , Ontologia Genética , Humanos , Hipóxia/genética , Análise de Sequência com Séries de Oligonucleotídeos , RNA Longo não Codificante/análise , RNA Longo não Codificante/metabolismo , RNA Mensageiro/análise , RNA Mensageiro/metabolismo , Análise de Sequência de RNA/métodos , Transcriptoma/genética , Hipóxia Tumoral/genética
9.
Exp Ther Med ; 17(1): 437-443, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30651818

RESUMO

Acute pancreatitis is an acute abdominal disease, with 10-20% of the cases deteriorating rapidly, accompanied by persistent organ failure and further development into severe acute pancreatitis (SAP). The aim of the present study was to investigate the mechanism of fluid resuscitation via the rectum in the early stages of SAP and the role of aquaporins (AQPs). An SAP model was constructed by injection of 5% sterile sodium taurocholate into the biliopancreatic duct of Sprague Dawley rats, and the mean arterial pressure (MAP) was continuously monitored via femoral artery catheterization. At 30 min after the construction of the SAP model, the rats in the fluid resuscitation groups were resuscitated with normal saline at a rate of 4 ml/kg/h through the venous or the rectal route. The AQP and Na+-K+-ATPase levels, and the correlation of the MAP and colon AQPs at the early stages of SAP were analyzed. The results demonstrated that the mRNA level of AQP-3 and AQP-4 in the distal colon decreased significantly in the group subjected to fluid resuscitation via the rectum, while no significant differences were identified in the Na+-K+-ATPase levels of the colon in that group. Furthermore, a negative correlation was identified between the expression of AQPs and the MAP (P<0.01). Thus, fluid resuscitation via the rectum appears to ameliorate hemodynamic disorders through adjusting the expression of AQP-3 and AQP-4 in the distal colon in an experimental SAP model.

10.
Shock ; 52(4): 434-442, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30335674

RESUMO

OBJECTIVE: The aim of the study was to investigate the role of dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) in intestinal epithelial cells (IECs) in regulating sepsis-induced acute intestinal injury and systemic inflammatory response. METHODS: To induce sepsis condition, Male C57BL/6 mice were exposed to cecal ligation and puncture (CLP) in vivo, whereas a normal human IECs line (FHs74Int) was stimulated with lipopolysaccharide (LPS) in vitro. DC-SIGN siRNA pretreatment was used to knock down DC-SIGN expression both in vivo and in vitro. The expression of DC-SIGN was detected by western blot and immunohistochemistry. The expression of total and phosphorylation of ERK1/2 and NF-κB/p65 was examined by western blot. The levels of cytokines in serum and culture supernatant were measured by ELISA. The survival rate and organ injures of septic mice were also assessed. RESULTS: In vivo, DC-SIGN expression in mouse IECs was time-dependently upregulated by CLP. CLP-induced phosphorylation of ERK1/2 and NF-κB/p65 was effectively inhibited by DC-SIGN siRNA pretreatment, leading to the decrease of systemic inflammatory cytokines (TNF-α, IL-1ß, IL-6, IL-10, and IFN-γ), which alleviated multiple organ injuries and increased the survival rate of septic mice. In vitro, DC-SIGN expression in FHs74Int was significantly upregulated by LPS stimulation in a time- and dose-dependent manner. DC-SIGN knockdown abolished LPS-induced ERK1/2 and NF-κB/p65 phosphorylation, resulting in the decrease of cytokines release by FHs74Int. CONCLUSIONS: Sepsis-induced DC-SIGN expression in IECs plays a significant role in regulating acute intestinal injury and systemic inflammatory response. The inhibition of DC-SIGN exhibited protective effects on sepsis-associated organ injury and systemic inflammation.

11.
Scand J Immunol ; 88(5): e12713, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30176060

RESUMO

Metabolic reprogramming plays a critical role in the important cellular metabolic alterations that occur during the activation of immune cells to enable them to adapt to the extracellular environment. Here, we review recent studies on how substrate availability and metabolites mediate the signalling pathways that regulate fatty acid synthesis (FAS) in different immune cells and how FAS determines cellular fate and function. The major regulators sterol regulatory element-binding proteins and liver X receptors, the key enzyme ATP citrate lyase and the PI3K-Akt-mTOR signalling axis play important roles in de novo FAS during a variety of biological events, including cellular proliferation and differentiation and the development of organelles and intracellular membrane components in immune cells. In addition, the regulation of FAS substantially contributes to the inflammatory response of immune cells. Post-transcriptional modifications in FAS are also closely associated with the functional processes of immune cells. Understanding and investigating the intrinsic regulatory mechanism of FAS is of great significance for developing novel therapies for inflammation-induced diseases.


Assuntos
Ácidos Graxos/biossíntese , Sistema Imunitário/citologia , Sistema Imunitário/metabolismo , ATP Citrato (pro-S)-Liase/metabolismo , Linfócitos B/metabolismo , Vias Biossintéticas , Células Dendríticas/metabolismo , Ácido Graxo Sintase Tipo I/metabolismo , Humanos , Receptores X do Fígado/metabolismo , Macrófagos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Processamento de Proteína Pós-Traducional , Transdução de Sinais , Proteínas de Ligação a Elemento Regulador de Esterol/metabolismo , Linfócitos T/metabolismo , Serina-Treonina Quinases TOR/metabolismo
12.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 30(7): 640-645, 2018 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-30045790

RESUMO

OBJECTIVE: To investigate the effectiveness and safety of clinical pharmacists-directed vancomycin dosing and therapeutic drug monitoring (TDM), and to promote the individualized medication of vancomycin. METHODS: Information of hospitalized patients treated by vancomycin admitted to Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from January 2011 to October 2017 was collected retrospectively during study period, the patients were divided into pharmacists intervention and non-pharmacists intervention groups according to pharmacist-directed vancomycin dosing guideline or not. The individualized dosing regimen of vancomycin for the patients in pharmacists intervention group was guided by clinical pharmacists, this guideline was that pharmacists offered the TDM guidance, made the individualized dosage regimen of vancomycin, etc., which based on the patients' pathophysiology, condition, and the adjustments of increased dose or 24-hour continuous infusion vancomycin were made for patients if the steady-state trough concentrations fell below the target level. Vancomycin dosage was made for patients in the non-pharmacists intervention group by physicians only based on vancomycin instructions or clinical experience. The vancomycin dosing, TDM, microorganism culture, renal function, 30-day mortality rate, and length of hospital stay were recorded. The appropriateness of TDM for vancomycin was defined as a blood collection within 1 hour of the next scheduled dose after steady state achieved. The rationality of the initial dosing regimen was determined based on the vancomycin application guidelines issued by Infectious Diseases Society of America (IDSA) in 2009. RESULTS: A total of 258 patients were enrolled, and there were 158 patients in the non-pharmacists intervention group and 100 in pharmacists intervention group. The appropriateness of TDM for vancomycin in pharmacists intervention group was significantly improved as compared with that in non-pharmacists intervention group [87.0% (87/100) vs. 69.6% (110/158), P < 0.01], the percentage of first trough serum concentrations drawn on day 3 after steady state achieved was significantly increased [51.0% (51/100) vs. 37.3% (53/142), P < 0.05]. Compared with the non-pharmacists intervention group, the percentages of patients who received appropriate initial dosing and attained the initial target therapeutic range in pharmacists intervention group were significantly increased [87.4% (76/87) vs. 68.2% (75/110), 51.7% (45/87) vs. 30.9% (34/110), both P < 0.01], the percentage of patients whose vancomycin dosing regimen was adjusted based on TDM results was also significantly increased [54.0% (47/87) vs. 15.5% (17/110), P < 0.01], the rate of vancomycin serum concentrations reaching the standard was increased [70.1% (61/87) vs. 32.7% (36/110), P < 0.01], and a lower number of patients in sub- or supra-therapeutic range was observed in pharmacists intervention group [27.6% (24/87) vs. 46.4% (51/110), 2.3% (2/87) vs. 20.9% (23/110), both P < 0.01]. In addition, a lower incidence of vancomycin-induced acute kidney injury (AKI) was observed in pharmacists intervention group as compared with that in non-pharmacists intervention group [0 (0/87) vs. 6.4% (7/110), P < 0.01]. No significant difference was observed in the microorganism culture, 30-day mortality rate or length of hospital stay between the two groups. Among the 87 patients in pharmacists intervention group, the vancomycin dosing was adjusted for 42 patients who did not attain the target therapeutic range, increasing the dose of vancomycin was made for 22 patients, 24-hour continuous infusion was made for 20 patients. Compared with the only increasing vancomycin dose group, vancomycin continuous infusion for 24 hours could significantly increase the serum trough concentration (mg/L: 18.0±6.7 vs. 12.5±5.8, P < 0.05), and reduce daily dosage (mg/kg: 27.1±7.1 vs. 36.6±9.2, P < 0.01). CONCLUSIONS: The implementation of a pharmacist-directed vancomycin dosing guideline based on TDM optimized vancomycin dosing regimen, improved the accuracy and timeliness of TDM for vancomycin, achieved a higher percentage of levels within the therapeutic range, and a lower incidence of vancomycin-induced AKI.


Assuntos
Vancomicina/administração & dosagem , Antibacterianos , China , Monitoramento de Medicamentos , Humanos , Farmacêuticos , Estudos Retrospectivos
13.
BMC Pharmacol Toxicol ; 19(1): 41, 2018 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-29973293

RESUMO

BACKGROUND: Polymyxin B (PMB), which is regarded as the ultimate antibacterial treatment against some intractable gram-negative bacteria with its outstanding anti-bacterial activities, inflicts several adverse effects on patients. However, skin hyperpigmentaion (SH) induced by PMB is very rare. Here, we report a case of polymyxin B-induced skin hyperpigmentation (PMB-iSH) in a 21-year-old female. To the best of our knowledge, this is the first case of PMB-iSH in China. CASE PRESENTATION: A 21-year-old female patient with sepsis received the administration of PMB by intravenous injection for the treatment of multi-drug resistant Klebsiella pneumoniae (MDR-KP) infection. She later suffered from a rare adverse drug reaction (ADR), namely PMB-iSH, after 5-day PMB administration during her treatment. There were multiple red rashes spread on the whole body skin at first. With the rashes fading away, SH with dark round spots appeared, associated with no pain or pruritus. The skin of the head and neck was darkened evidently, and dark brown spots were spread on the skin of trunk and limbs. About a month after her admission, urged by the relatives, the patient was transferred back to the local hospital for further treatment in the end, and her skin color didn't recover to the previous state at that time. CONCLUSION: Both our case and the literature review highlight that PMB can give rise to SH indeed. Clinicians and pharmacists should attach great importance to this rare pigmentary disorder and further investigation is warranted.


Assuntos
Antibacterianos/efeitos adversos , Hiperpigmentação/induzido quimicamente , Infecções por Klebsiella/tratamento farmacológico , Polimixina B/efeitos adversos , Adulto , Feminino , Humanos , Klebsiella pneumoniae , Adulto Jovem
14.
Biochem Biophys Res Commun ; 501(2): 358-364, 2018 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-29673592

RESUMO

To investigate the effect of intravenous Vitamin C (VC) on hemorrhagic shock (HS)-associated rat renal injury and the involved mechanism. Thirty SD rats were randomly assigned to the sham surgery (sham), hemorrhagic shock (HS), HS+100 mg/kg VC (H + VL), HS+500 mg/kg VC (H + VH) and HS+100 mg/kg VC + EX527 (H + VL + E) groups. Tissue and blood samples were collected 6 h after surgery. Kidney pathological changes were scored. Creatinine (CRE), blood urea nitrogen (BUN), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß) levels in serum and Vitamin C levels and superoxide dismutase (SOD) activity and the ability to suppress hydroxyl radical (RAFHR) in plasma were measured. The expression of Sirtuin1 (SIRT1), Acetyl-NF-κB (Ace-NF-κB), heme oxygenase-1 (HO-1), TNF-α, and IL-1ß in tissues was analyzed by ELISA or western-blot. In the HS group, the kidney pathological score and CRE, BUN, TNF-α, and IL-1ß levels in serum were significantly higher than in the Sham group (P < 0.05), while SOD and RAFHR were significantly decreased in the plasma (P < 0.05). SOD activity and SIRT1 expression were remarkably lower in the kidney in the HS group than in the Sham group (P < 0.05), while MDA, TNF-α, and IL-1ß concentrations and Acetyl-NF-κB andHO-1 expression in the kidney showed a noteworthy increase compared to the Sham group (P < 0.05). Compared to the HS group, VC treatment led to a remarkable reduction in the kidney pathological score and CRE,BUN,TNF-α, and IL-1ß levels (P < 0.05), and a significant increase in Vitamin C, SOD, and RAFHR levels in the plasma (P < 0.05). Additionally, MDA, TNF-α, IL-1ß and Acetyl-NF-κB expression levels were decreased in the kidney (P < 0.05), while SOD, SIRT1 and HO-1 levels were notably enhanced. There were no differences between the H + VL and H + VH groups aside from plasma Vitamin C levels. The effect of Vitamin C was decreased after the addition of EX527, which inhibits SIRT1. Intravenous Vitamin C might attenuate HS-related renal injury via the SIRT1 pathway, and it appears that there were no differences in the effects between the high and low doses.


Assuntos
Ácido Ascórbico/administração & dosagem , Insuficiência Renal/tratamento farmacológico , Choque Hemorrágico/complicações , Sirtuína 1/metabolismo , Administração Intravenosa , Animais , Ácido Ascórbico/sangue , Citocinas/sangue , Citocinas/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Rim/metabolismo , Rim/patologia , Masculino , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Insuficiência Renal/etiologia , Choque Hemorrágico/metabolismo , Choque Hemorrágico/fisiopatologia , Regulação para Cima
15.
Int Immunopharmacol ; 59: 40-46, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29621735

RESUMO

Excessive production of pro-inflammatory cytokines in early sepsis causes high early mortality rates. Membrane proteinase 3 (mPR3) expression on neutrophils plays a critical role in pro-inflammatory cytokine production. However, the mechanism underlying mPR3 overexpression in early sepsis is unknown. Here, we explored mPR3 expression in early sepsis and its regulatory mechanism. Thirty-two patients with sepsis and 20 healthy controls were prospectively enrolled. On day 1 after the onset of sepsis, mPR3 and jumonji domain-containing protein D3 (JMJD3) expression levels were measured in peripheral blood neutrophils. Lipopolysaccharide (LPS) was employed to induce JMJD3 expression in vitro, and GSK-J4 was used to inhibit JMJD3. Neutrophils were divided into four groups, control, LPS, LPS + GSK-J4, and GSK-J4, and cultured with THP-1 cells respectively. Plasma and culture supernatant cytokine levels were measured by enzyme-linked immunosorbent assays. Neutrophil mPR3 levels were significantly higher in patients with early sepsis than in healthy controls. Plasma cytokine (IL-1ß and TNF-α) levels were increased in patients with sepsis exhibiting high mPR3 expression. Additionally, JMJD3 expression levels in neutrophils were increased in early sepsis. In vitro, both mPR3 on neutrophils and IL-1ß in culture supernatants increased in response to LPS stimulation. Neutrophil mPR3 expression and IL-1ß levels were significantly reduced by GSK-J4 in cells treated with LPS. IL-1ß level was significantly higher in LPS-stimulated co-culture supernatants than in the corresponding individual cultured cells. Thus, our results suggest that JMJD3 contributes to the high expression of neutrophil mPR3, which promotes the production of proinflammatory IL-1ß in early sepsis.


Assuntos
Interleucina-1beta/imunologia , Histona Desmetilases com o Domínio Jumonji/imunologia , Mieloblastina/imunologia , Neutrófilos/imunologia , Sepse/imunologia , Idoso , Linhagem Celular , Citocinas/sangue , Citocinas/imunologia , Feminino , Humanos , Lipopolissacarídeos/farmacologia , Masculino , Pessoa de Meia-Idade , Sepse/sangue
16.
Inflammation ; 41(3): 1008-1020, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29455288

RESUMO

Due to the imbalance between hyper-inflammation and hypo-inflammation, which are characterized by excessive cytokine productions and programmed death 1 (PD-1) upregulation, respectively, sepsis remains a highly lethal inflammatory syndrome with limited effective therapies. Mycophenolate mofetil (MMF), an immunosuppressant, has been reported to attenuate various inflammatory diseases. However, the role of MMF in sepsis therapy remains to be elucidated. C57BL-6J mice underwent cecal ligation and puncture (CLP) and were treated either with or without MMF. Survival rate and organ injuries were compared. Cytokine levels, bacteria clearance, apoptosis of spleen and peritoneal macrophages, and PD-1 expression were assessed. At the beginning of CLP, 60 mg/kg MMF administered by gavage significantly protected septic mice, which was evidenced by improved survival and attenuated organ injuries, decreased cytokines, lower bacterial loads, and alleviated immune cell apoptosis. In addition, immune cells in the MMF mice showed lower PD-1 expression and improved immune response to pathogeny stimuli. MMF protects septic mice via the dual inhibition of cytokine releasing and PD-1 expression.


Assuntos
Citocinas/antagonistas & inibidores , Ácido Micofenólico/farmacologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Sepse/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Carga Bacteriana/efeitos dos fármacos , Inflamação/tratamento farmacológico , Camundongos , Ácido Micofenólico/imunologia , Substâncias Protetoras/farmacologia , Sepse/mortalidade , Sepse/patologia , Taxa de Sobrevida
17.
Mycoses ; 61(7): 430-440, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29464833

RESUMO

Recently, Candida glabrata has emerged as a health-threatening pathogen and the rising resistance to antifungal agent in C. glabrata often leads to clinical treatment failure. To investigate the evolution of drug resistance and adherence ability in four paired clinical isolates collected before and after antifungal treatment. Sequence analysis, gene disruption, drug-susceptibility, adhesion tests and real-time quantitative PCR were performed. The azole-susceptible strains acquired azole resistance after antifungal therapy. Four gain-of-function (GOF) mutations in CgPDR1 were revealed by sequence analysis, namely G1099D, G346D, L344S and P927S, the last being reported for the first time. CDR1, CDR2 and SNQ2 efflux pump gene expression levels were elevated in strains harbouring GOF mutations in CgPDR1, resulting in decreased azole susceptibility. CgPDR1 alleles with distinct GOF mutations displayed different expression profiles for the drug-related genes. CgPDR1GOF mutations led to increased efflux pumps expression levels in a strain background independent way. Hyperactive Pdr1G1099D and Pdr1P927S displayed strain background-dependent increased adherence to host cells via upregulation of EPA1 transcription. Interestingly, the drug transporter gene expression levels did not always correspond with that of the adhesin EPA1 gene. GOF mutations in CgPDR1 conferred drug resistance and increased adherence in the clinical strains, possibly endowing C. glabrata with increased viability and pathogenicity.


Assuntos
Azóis/farmacologia , Candida glabrata/genética , Candida glabrata/fisiologia , Adesão Celular , Farmacorresistência Fúngica Múltipla/genética , Mutação com Ganho de Função , Azóis/uso terapêutico , Candida glabrata/efeitos dos fármacos , Candida glabrata/patogenicidade , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Proteínas de Ligação a DNA/genética , Proteínas Fúngicas/genética , Humanos , Lectinas/genética , Proteínas de Membrana Transportadoras/genética
18.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 29(9): 810-814, 2017 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-28936957

RESUMO

OBJECTIVE: To evaluate the serum trough concentration and the pharmacokinetics/pharmacodynamics (PK/PD) of vancomycin in patients with severe acute pancreatitis (SAP), and analyze the effect of vancomycin continuous infusion for optimizing the characteristics of its PK/PD. METHODS: The inhospital patients with SAP received vancomycin treatment and admitted to emergency intensive care unit (EICU) of Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine from January 2011 to December 2016 were enrolled. Steady-state trough concentrations of vancomycin from patients were collected retrospectively. The SAP patients were divided into augmented renal clearance (ARC) and non-ARC groups, as well as systemic inflammatory response syndrome (SIRS) and non-SIRS groups according to the patients with or without symptom above. Adjustments of increased dosage or 24-hour continuous infusion or increase vancomycin dose were made for patients if the steady-state trough concentrations fell below the target level. Steady state trough concentration for vancomycin intermittent infusion or steady state concentration for vancomycin continuous infusion was determined by the fluorescence polarization immunoassay method. PK parameters of vancomycin were calculated using the Bayesian estimator and the area under the serum drug concentration-time curve (AUCc-t), the minimum inhibitory concentration (MIC) and AUCc-t/MIC was recorded and calculated. RESULTS: The steady state trough concentration or steady state concentration from 61 patients with SAP were collected with mean steady state trough concentration of vancomycin of (7.7±4.4) mg/L, which was significantly lower than standard concentration (15 mg/L, P < 0.001). Apparent volume of distribution (Vd) and clearance of vancomycin was (1.06±0.26) L/kg and (8.9±2.8) L/h. The serum steady state trough concentration of vancomycin in ARC group (n = 33) was significantly lower than that in non-ARC group (n = 28; mg/L: 6.7±3.5 vs. 8.2±4.1, P < 0.01), clearance was significantly increased (L/h: 9.8±2.9 vs. 7.7±2.2, P < 0.01). Compared with non-SIRS group (n = 31), the serum steady state trough concentration of vancomycin in SIRS group (n = 30) was significantly lowered (mg/L: 6.1±3.2 vs. 13.0±4.2, P < 0.01), and clearance was significantly increased (L/h: 9.4±2.0 vs. 7.1±2.1, P < 0.05). Compared with the only increasing vancomycin dose group (n = 29), vancomycin continuous infusion for 24 hours (n = 21) could significantly reduce daily dosage (mg/kg: 13.6±3.9 vs. 19.1±3.5, P < 0.01), increase the serum trough concentration (mg/L: 18.1±7.0 vs. 12.6±5.3, P < 0.01), and improve the AUCc-t/MIC. CONCLUSIONS: The serum trough concentration of vancomycin was significantly reduced in SAP patients with ARC. The more serious of the SIRS is, the lower the vancomycin trough concentration is. Vancomycin 24-hour continuous infusion could optimize the PK/PD parameters, decrease the daily dose, increase the clinical effect, and reduce the bacterial resistance.


Assuntos
Pancreatite/sangue , Vancomicina/farmacologia , Vancomicina/farmacocinética , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Teorema de Bayes , China , Humanos , Rim/metabolismo , Taxa de Depuração Metabólica , Pancreatite/tratamento farmacológico , Estudos Retrospectivos
19.
Crit Care ; 21(1): 186, 2017 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-28705256

RESUMO

BACKGROUND: Acute pancreatitis (AP) is a life-threatening disease that requires early identification of patients at risk of developing infectious complications. Immunosuppression is an initial event that is key to AP pathogenesis. The programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) system is reported to mediate evasion of host immune surveillance in many diseases; however, the relationship between PD-1/PD-L1 expression and these parameters or infectious complications in AP has not been elucidated. This study was conducted to determine whether PD-1 and PD-L1 are upregulated and to reveal the relationship between PD-1/PD-L1 expression and the development of infectious complications in AP. METHODS: Sixty-three patients with AP and 32 sex- and age-matched healthy control subjects were prospectively enrolled. On days 1 and 3 after the onset of AP, we measured PD-1 expression in peripheral CD4+ T cells and PD-L1 and human leukocyte antigen-DR (HLA-DR) expression in CD14+ monocytes using flow cytometry. Plasma interleukin (IL)-10 levels were measured by enzyme-linked immunosorbent assay. RESULTS: Compared with healthy volunteers, the percentages of PD-1-expressing CD4+ lymphocytes and PD-L1-expressing CD14+ monocytes were increased in patients with AP on days 1 and 3 after onset, especially those with infectious complications. Moreover, increased PD-1/PD-L1 expression was associated with increased occurrence of infectious complications, decreased circulating lymphocytes, and increased plasma IL-10 concentration. Multivariate regression analysis indicated that the increased percentage of PD-L1-expressing CD14+ monocytes was an independent risk factor for infectious complications in AP. Area under the ROC curve analysis showed the combination of Acute Physiology and Chronic Health Evaluation II score and PD-L1 and HLA-DR expression in CD14+ monocytes had high accuracy in predicting infectious complications in patients with AP. CONCLUSIONS: The PD-1/PD-L1 system plays an essential role in the early immunosuppression of AP. PD-L1 expression in CD14+ monocytes may be a new marker for predicting risk of infectious complications in patients with AP.


Assuntos
Antígeno B7-H1/metabolismo , Monócitos/metabolismo , Pancreatite/complicações , APACHE , Adulto , Antígeno B7-H1/análise , Antígeno B7-H1/sangue , Biomarcadores/análise , Biomarcadores/sangue , Feminino , Subtipos Sorológicos de HLA-DR/análise , Subtipos Sorológicos de HLA-DR/sangue , Humanos , Imunossupressão/métodos , Interleucina-10/análise , Interleucina-10/sangue , Masculino , Pessoa de Meia-Idade , Pancreatite/fisiopatologia , Estudos Prospectivos , Curva ROC , Estatísticas não Paramétricas
20.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 29(6): 491-495, 2017 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-28625235

RESUMO

OBJECTIVE: To observe the change of the serum trough concentration and its pharmacokinetics of vancomycin in patients with severe acute pancreatitis (SAP), and to analyze the factors influencing vancomycin concentration. METHODS: A retrospective analysis was conducted. Steady-state trough concentrations of vancomycin from patients (18-80 years old) with SAP concomitantly with G+ infection admitted to Intensive Care Unit (ICU) of Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine from January 2010 to December 2016 were enrolled. According to the usage time of vancomycin, the patients with SAP were divided into early group (onset within 21 days), middle group (onset between 21-28 days) and late group (onset over 28 days). The gender, age, body weight, clinical diagnosis, acute physiology and chronic health evaluation II (APACHE II) score, renal function, and the pharmacokinetic parameters were recorded. Influencing factors of vancomycin was analyzed by multiple linear regression and stepwise regression. RESULTS: Fifty-eight patients were enrolled who contained 134 times trough concentrations of vancomycin. There were 41 patients enrolled and 61 times of trough concentrations in the early group, 24 patients enrolled and 33 times of trough concentrations in the middle group, and 28 patients enrolled and 40 times of trough concentrations in the late group. There was no significant difference in gender, age, body weight, serum creatinine, creatinine clearance (CCr), albumin, APACHE II score among the three groups. There was significantly difference in the duration from the onset time to vancomycin administration between early, middle groups and late group (days: 15.9±3.2, 23.3±2.2 vs. 35.0±6.7, both P < 0.05). The positive liquid balance in early group was lower than that of late group (mL: 1 565.2±3 132.1 vs. 3 675.1±3 411.5, P < 0.01), while it was increased in the middle group as compared with that of late group (mL: 5 078.7±3 892.4 vs. 3 675.1±3 411.5, P < 0.05). The average daily dose of vancomycin in the early, middle and late groups were (14.7±5.0), (15.0±2.8), (17.0±4.2) mg/kg, respectively, and there was no significant difference (P > 0.05). Compared with the standard concentration (15 mg/L) of vancomycin, the serum trough concentration of vancomycin was significantly reduced in SAP patients [(7.5±4.3) mg/L, P < 0.01]. Apparent volume of distribution (Vd) was (72.4±15.4) L, and clearance rate (CL) was (9.0±2.8) L/h. According to the Bayesian, the serum trough concentration of vancomycin was significantly reduced in early group and middle group compared with late group (mg/L: 5.0±2.1, 7.3±2.5 vs. 11.5±5.1, both P < 0.01), CL was significantly increased (L/h: 10.5±3.0, 8.1±1.9 vs. 7.4±1.9, both P < 0.05), and Vd was significantly increased in early group compared with late group (L: 73.7±15.5 vs. 71.0±12.6, P < 0.05). It was shown by multiple linear regression analysis that there was strong relationship between serum trough concentration and the serum creatinine, CCr, average daily dose and the starting time of vancomycin treatment (r value were 0.449, -0.318, 0.373, 0.763, respectively, all P < 0.05). CONCLUSIONS: The serum trough concentration of vancomycin was significantly reduced in SAP patients. And the earlier usage of vancomycin, the lower of the trough concentration is. Therefore, higher dosage regimen was needed to ensure the clinical effect, and reduce the bacterial resistance.


Assuntos
Pancreatite , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos , Teorema de Bayes , China , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Vancomicina , Adulto Jovem
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