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1.
Front Pharmacol ; 12: 770610, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34899324

RESUMO

Fluoxetine is a classic antidepressant drug, and its immunomodulatory effects have recently been reported in many disease models. In addition, it has strong antineuroinflammatory effects in stroke and neurodegenerative animal models. However, the effect of fluoxetine on microglia phagocytosis and its molecular mechanisms have not yet been studied. In this study, we investigated whether fluoxetine has a regulatory effect on microglial function. Microglia cell lines and primary mouse microglia were treated with fluoxetine, and the production of inflammatory cytokines and neurotrophic factors and the phagocytosis of amyloid ß were measured. Fluoxetine significantly attenuated the production of lipopolysaccharide-induced proinflammatory cytokines and oxidative stress in microglia. Fluoxetine also significantly potentiated microglia phagocytosis and autophagy. In addition, autophagy flux inhibitors attenuated fluoxetine-induced phagocytosis. In conclusion, fluoxetine induces autophagy and potentiates phagocytosis in microglia, which can be a novel molecular mechanism of the neuroinflammatory and neuroprotective effects of fluoxetine.

2.
Plant Pathol J ; 37(5): 489-493, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34847635

RESUMO

Bacterial canker is a devastating disease of kiwifruit caused by the bacterium Pseudomonas syringe pv. actinidiae. Canker disease of kiwifruit in Korea has been controlled using streptomycin for more than two decades. Four streptomycin-resistant strains, belonging to biovar 2, which are found only in Korea, were collected between 2013 and 2014 from different orchards located in Jeju, Korea. The genetic background for streptomycin resistance among P. syringe pv. actinidiae strains were determined by examining the presence of strA-strB or aadA, which are genes frequently found in streptomycin-resistant bacteria, and a point mutation at codon 43 in the rpsL gene. All four streptomycin-resistant strains of P. syringe pv. actinidiae investigated in this study contained strA-strB as a resistant determinant. The presence of the aadA gene and a mutation in codon 43 of the rpsL gene was not identified.

3.
Artigo em Inglês | MEDLINE | ID: mdl-34662436

RESUMO

BACKGROUND: Despite antiviral therapy, liver function often fails to recover in patients with hepatitis B virus (HBV)-related decompensated cirrhosis. AIM: To establish a prognostic model to predict re-compensation in patients starting potent nucleos(t)ide analogue (NUC) therapy METHODS: We analysed 311 consecutive patients with HBV-related decompensated cirrhosis treated with entecavir or tenofovir. The primary outcome was re-compensation, defined as recovery to a Child-Pugh score of 5. The BC2AID score was developed from a cohort of 152 subjects based on competing risk models and validated in another cohort of 159 subjects. RESULTS: Re-compensation occurred in 57.2% and 66.7% of the subjects in the derivation and validation cohorts, respectively. Six independent predictors for re-compensation were identified in the derivation cohort and these comprised the BC2AID score: bilirubin ≤5 mg/dL (adjusted sub-distribution hazard ratio [aSHR] 2.18), absence of severe complications (aSHR 2.78), alpha-fetoprotein (AFP) ≥50 ng/mL (aSHR 2.54), alanine aminotransferase ≥200 IU/L (aSHR 2.62), international normalised ratio ≤1.5 (aSHR 2.37) and ≤6 months from initial decompensation until initiation of NUCs (aSHR 4.79). In the validation cohort, the area under the receiver operating characteristic curve of the BC2AID score for re-compensation within 1 year of NUC therapy was significantly higher than that of the Child-Pugh, MELD, MELDNa and BE3A scores (0.813 vs 0.691, 0.638, 0.645 and 0.624, respectively; all P < 0.05). CONCLUSIONS: Six clinical parameters, including AFP and the timing of antiviral therapy, were combined into a scoring system to accurately predict early re-compensation in patients with HBV-related decompensated cirrhosis.

4.
Calcif Tissue Int ; 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34499185

RESUMO

Growth and differentiation factor 15 (GDF-15) is associated with muscle, fat, and bone metabolism; however, this association has not been well characterized. Plasma GDF-15, appendicular skeletal muscle mass (ASM), fat mass (FM), and bone mineral density (BMD) were measured in 146 postmenopausal women. GDF-15 levels were higher in subjects with low Body Mass Index (BMI)-adjusted ASM than in those without (median [interquartile range] 831.3 [635.4-1011.4] vs. 583.8 [455.8-771.1] pg/mL, p = 0.018). The GDF-15 level was inversely correlated with BMI-adjusted ASM (r = - 0.377, p < 0.001) and BMD at femur neck (FN-BMD; r = - 0.201, p = 0.015), and positively correlated with percent FM (pFM; r = 0.328, p < 0.001). After adjusting for confounders, the GDF-15 level was inversely associated with BMI-adjusted ASM (ß = -0.250, p = 0.006) and positively associated with pFM (ß = 0.272, p = 0.004), and tended to be inversely associated with FN-BMD (ß = - 0.176, p = 0.076). The area under the receiver-operating characteristic curve of GDF-15 level > 618.4 pg/mL for sarcopenia was 0.706 (95% confidence interval (CI) 0.625-0.779) with a sensitivity of 83.3% and a specificity of 54.5%. Using a GDF-15 level of 618.4 pg/mL as a cut-off, the GDF-15 level was associated with a significantly greater likelihood of sarcopenia (odds ratio [OR] 2.35; 95% CI 1.00-5.51; p = 0.049), obesity (OR 3.28; 95% CI 1.48-7.27; p = 0.001), osteopenic obesity (OR 3.10; 95% CI 1.31-7.30; p = 0.010), and sarcopenic or osteosarcopenic obesity (OR 4.84; 95% CI 0.88-26.69; p = 0.070). These findings support the potential of GDF-15 as a biomarker for age-related changes in muscle, fat, and bone.

6.
BMB Rep ; 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34488924

RESUMO

Melanoma, the most serious type of skin cancer, exhibits a high risk of metastasis. Although chemotherapeutic treatment for metastatic melanoma improves disease outcome and patient survival, some patients exhibit resistance or toxicity to the drug treatment regime. OTUB1 is a deubiquitinating enzyme overexpressed in several cancers. In this study, we investigated the effects of inhibiting OTUB1 expression on melanoma-cell proliferation and viability and identified the underlying molecular mechanism of action of OTUB1. We did endogenous OTUB1 knockdown in melanoma cells using short interfering RNA, and assessed the resulting phenotypes via MTT assays, Western blotting, and cell-cycle analysis. We identified differentially expressed genes between OTUB1-knockdown cells and control cells using RNA sequencing and confirmed them via Western blotting and reverse transcription polymerase chain reaction. Furthermore, we investigated the involvement of apoptotic and cell survival signaling pathways upon OTUB1 depletion. OTUB1 depletion in melanoma cells decreased cell viability and caused simultaneous accumulation of cells in the sub-G1 phase, indicating an increase in the apoptotic-cell population. RNA sequencing of OTUB1-knockdown cells revealed an increase in the levels of the apoptosis-inducing protein TRAIL. Additionally, OTUB1-knockdown cells exhibited increased sensitivity to PLX4032, a BRAF inhibitor, implying that OTUB1 and BRAF act collectively in regulating apoptosis. Taken together, our findings show that OTUB1 induces apoptosis of melanoma cells in vitro, likely by upregulating TRAIL, and suggest that approaches targeting OTUB1 can be developed to provide novel therapeutic strategies for treating melanoma.

7.
Nat Commun ; 12(1): 5053, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417459

RESUMO

Previous studies have suggested that PTEN loss is associated with p110ß signaling dependency, leading to the clinical development of p110ß-selective inhibitors. Here we use a panel pre-clinical models to reveal that PI3K isoform dependency is not governed by loss of PTEN and is impacted by feedback inhibition and concurrent PIK3CA/PIK3CB alterations. Furthermore, while pan-PI3K inhibition in PTEN-deficient tumors is efficacious, upregulation of Insulin Like Growth Factor 1 Receptor (IGF1R) promotes resistance. Importantly, we show that this resistance can be overcome through targeting AKT and we find that AKT inhibitors are superior to pan-PI3K inhibition in the context of PTEN loss. However, in the presence of wild-type PTEN and PIK3CA-activating mutations, p110α-dependent signaling is dominant and selectively inhibiting p110α is therapeutically superior to AKT inhibition. These discoveries reveal a more nuanced understanding of PI3K isoform dependency and unveil novel strategies to selectively target PI3K signaling nodes in a context-specific manner.


Assuntos
Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/enzimologia , Transdução de Sinais , Animais , Linhagem Celular Tumoral , Retroalimentação Fisiológica , Humanos , Isoenzimas/metabolismo , Masculino , Camundongos , Modelos Biológicos , Organoides/efeitos dos fármacos , Organoides/metabolismo , PTEN Fosfo-Hidrolase/deficiência , PTEN Fosfo-Hidrolase/metabolismo , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Receptor IGF Tipo 1/metabolismo , Regulação para Cima/efeitos dos fármacos
8.
Proc Natl Acad Sci U S A ; 118(32)2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34353917

RESUMO

The increasing complexity of different cell types revealed by single-cell analysis of tissues presents challenges in efficiently elucidating their functions. Here we show, using prostate as a model tissue, that primary organoids and freshly isolated epithelial cells can be CRISPR edited ex vivo using Cas9-sgRNA (guide RNA) ribotnucleoprotein complex technology, then orthotopically transferred in vivo into immunocompetent or immunodeficient mice to generate cancer models with phenotypes resembling those seen in traditional genetically engineered mouse models. Large intrachromosomal (∼2 Mb) or multigenic deletions can be engineered efficiently without the need for selection, including in isolated subpopulations to address cell-of-origin questions.

9.
PLoS One ; 16(8): e0255822, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34358264

RESUMO

Noninvasive techniques for evaluating the severity of nonalcoholic fatty liver disease (NAFLD) have shown limited diagnostic performance. MicroRNAs (miRNAs) are useful biomarkers for diagnosing and monitoring the progression and treatment response to several diseases. Here, we evaluated whether serum exosomal miRNAs could be used for the diagnosis and prognosis of NAFLD severity. Exosomal miRNAs were isolated from the sera of 41 patients with NAFLD (diagnosed using liver biopsy) for microarray profiling. The degree of NAFLD severity was determined using inflammation, steatosis, and ballooning scores and the NAFLD activity score (NAS). Correlations between miRNA expression, clinical and biochemical parameters, and mRNA expression were analyzed. Overall, 25, 11, 13, and 14 miRNAs correlated with the inflammation score, steatosis score, ballooning score, and NAS, respectively, with 33 significant correlations observed between 27 miRNAs and six clinical variables. Eight miRNAs (let-7b-5p, miR-378h, -1184, -3613-3p, -877-5p, -602, -133b, and 509-3p) showed anticorrelated patterns with the corresponding mRNA expression. In fibrosis, 52 and 30 interactions corresponding to high miRNA-low mRNA and low miRNA-high mRNA expression, respectively, were observed. The present results therefore suggest that serum exosomal miRNAs can be used to evaluate NAFLD severity and identify potential targets for NAFLD treatment.

10.
World J Gastroenterol ; 27(28): 4687-4696, 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34366629

RESUMO

BACKGROUND: Diagnostic accuracy of various tumor markers and their combinations for hepatocellular carcinoma (HCC) was not fully investigated. AIM: To evaluate the diagnostic accuracy of alpha-fetoprotein (AFP), the Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), and protein induced by vitamin K absence or antagonist-II (PIVKA-II) and their combination for HCC diagnosis. METHODS: Patients with newly detected liver mass or elevated serum AFP levels were considered eligible. Serum AFP level, AFP-L3 fraction, and PIVKA-II level were measured at the first visit. RESULTS: In total, 622 patients were included; 355 patients (57.1%) had chronic liver disease, and 208 (33.4%) had liver cirrhosis. HCC was diagnosed in 160 patients (25.7%). The area under the receiver operating characteristics curves (AUROCs) of the serum AFP, AFP-L3 fraction, AFP-L3, and PIVKA-II levels for the diagnosis of HCC were 0.775, 0.792, 0.814, and 0.834, respectively. A novel diagnostic model was developed by classifying patients in a 1:1 ratio into training and validation sets. Using the binary regression analysis of the training cohort, the AFP, AFP-L3 fraction, and PIVKA-II (ALPs) score was calculated as follows: ALPs score = 3.8 × [serum AFP level (ng/mL) × AFP-L3 fraction (%) × 0.01] + 0.2 × PIVKA-II level (mAU/mL). The AUROC of the ALPs score for diagnosis of HCC was 0.878, significantly higher than that of serum AFP level (P < 0.001), AFP-L3 fraction (P < 0.001), PIVKA-II level (P = 0.036), and AFP-L3 level (P = 0.006). The optimal ALPs score cut-off was 5.3 (sensitivity, 85.0%, specificity 80.1%). The validation cohort showed similar results. CONCLUSION: The ALPs score calculated using serum AFP level, AFP-L3 fraction, and PIVKA-II level showed improved accuracy in HCC diagnosis.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Biomarcadores , Biomarcadores Tumorais , Carcinoma Hepatocelular/diagnóstico , Humanos , Neoplasias Hepáticas/diagnóstico , Lectinas de Plantas , Precursores de Proteínas , Protrombina , alfa-Fetoproteínas
11.
Artigo em Inglês | MEDLINE | ID: mdl-34423586

RESUMO

BACKGROUND: Sarcopenia and osteoporosis frequently co-occur in the elderly and have common pathophysiological determinants. Slit guidance ligand 3 (SLIT3) has been recently discovered as a novel therapeutic factor against osteoporosis, and a SLIT3 fragment containing the second leucine-rich repeat domain (LRRD2) had a therapeutic efficacy against osteoporosis. However, a role of SLIT3 in the skeletal muscle is unknown. METHODS: Skeletal muscle mass, strength, and/or physical activity were evaluated in Slit3-/- , ovariectomized, and aged mice, based on the measurements of muscle weight and grip strength, Kondziella's inverted hanging test, and/or wheel-running test. Skeletal muscles were also histologically evaluated by haematoxylin and eosin staining and/or immunofluorescence. The ovariectomized and aged mice were intravenously injected with recombinant SLIT3 LRRD2 for 4 weeks. C2C12 cells were used to know cellular effects of SLIT3, such as in vitro myogenesis, fusion, cell viability, and proliferation, and also used to evaluate its molecular mechanisms by immunocytochemistry, immunoprecipitation, western blotting, real-time PCR, siRNA transfection, and receptor-ligand binding ELISA. RESULTS: Slit3-deficient mice exhibited decreased skeletal muscle mass, muscle strength, and physical activity. The relative masses of gastrocnemius and soleus were lower in the Slit3-/- mice (0.580 ± 0.039% and 0.033 ± 0.003%, respectively) than those in the WT littermates (0.622 ± 0.043% and 0.038 ± 0.003%, respectively) (all, P < 0.05). Gastrocnemius of Slit3-/- mice showed the reduced number of Type I and Type IIa fibres (all, P < 0.05), but not of Type IIb and Type IIx fibres. SLIT3 activated ß-catenin signalling by promoting its release from M-cadherin, thereby increasing myogenin expression to stimulate myoblast differentiation. In vitro experiments involving ROBO2 expression, knockdown, and interaction with SLIT3 indicated that ROBO2 functions as a SLIT3 receptor to aid myoblast differentiation. SLIT3 LRRD2 dissociated M-cadherin-bound ß-catenin and up-regulated myogenin expression to increase myoblast differentiation, in a manner similar to full-length SLIT3. Systemic treatment with SLIT3 LRRD2 increased skeletal muscle mass in both ovariectomized and aged mice (all, P < 0.05). The relative masses of gastrocnemius and soleus were higher in the treated aged mice (0.548 ± 0.045% and 0.033 ± 0.005%, respectively) than in the untreated aged mice (0.508 ± 0.016% and 0.028 ± 0.003%, respectively) (all, P < 0.05). SLIT3 LRRD2 treatment increased the hanging duration of the aged mice by approximately 1.7-fold (P < 0.05). CONCLUSIONS: SLIT3 plays a sarcoprotective role by activating ß-catenin signalling. SLIT3 LRRD2 can potentially be used as a therapeutic agent against muscle loss.

12.
Sci Rep ; 11(1): 14639, 2021 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-34282172

RESUMO

Nonalcoholic steatohepatitis (NASH) is considered as a progressive form of nonalcoholic fatty liver disease (NAFLD). To distinguish NASH from nonalcoholic fatty liver (NAFL), we evaluated the diagnostic value of circulating miRNAs. Small RNA sequencing was performed on 12 NAFL patients and 12 NASH patients, and the miRNA expression was compared. After selecting miRNAs for the diagnosis of NASH, we analyzed the diagnostic accuracy of each miRNA and the combination of miRNAs. External validation was performed using quantitative reverse transcription PCR. Among the 2,588 miRNAs, 26 miRNAs significantly increased in the NASH group than in the NAFL group. Among the 26 elevated miRNAs in the NASH group, 8 miRNAs were selected, and in silico analysis was performed. Only four miRNAs (miR-21-5p, miR-151a-3p, miR-192-5p, and miR-4449) showed significant area under the receiver operating characteristic curve (AUC) values for NASH diagnosis. The combination of the four miRNAs showed satisfactory diagnostic accuracy for NASH (AUC 0.875; 95% CI 0.676-0.973). External validation revealed similar diagnostic accuracy for NASH (AUC 0.874; 95% CI 0.724-0.960). NASH represents significantly distinct miRNA expression profile compared with NAFL. The combination of serum circulating miRNAs can be used as a novel biomarker for the NASH diagnosis in NAFLD.

13.
J Clin Med ; 10(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073357

RESUMO

Hepatitis B virus (HBV) is a main cause of chronic liver disease worldwide and can lead to severe liver diseases. The World Health Organization has planned to eliminate viral hepatitis, including hepatitis caused by HBV and hepatitis C virus, by 2030. As mother-to-child transmission (MTCT) of HBV is a main cause of chronic HBV infection, MTCT prevention is the main target to reduce the risk of chronic HBV infection and eliminate the disease. Recent clinical trials and meta-analyses found that antiviral therapy could prevent MTCT effectively in mothers with ≥200,000 IU/mL of HBV DNA, in combination with serial vaccination and hepatitis B immune globulin administration in infants. Despite the preventive role of antivirals for MTCT of HBV, there are several concerns regarding antiviral therapy with respect to the safety of the mother and fetus during pregnancy. This review summarizes the benefits and risks of antiviral treatment during pregnancy in women with chronic HBV infection.

14.
J Proteomics ; 245: 104278, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34089894

RESUMO

Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are typically asymptomatic and slow-progressing but potentially fatal diseases that are common causes of liver cirrhosis and related complications. Exosomes are nano-sized extracellular vesicles that have been linked to various intercellular communication processes and can carry biological materials reflecting the state and severity of disease. In this study, shotgun proteomic analysis of the protein expression profiles of extracellular vesicles, including exosomes and microvesicles, enriched from human serum samples of 24 patients diagnosed with various fatty liver diseases was performed using liquid chromatography tandem mass spectrometry (LC-MS/MS) followed by protein identification and label-free quantification using the MaxQuant platform. A total of 329 proteins, including 190 previously reported exosome-specific proteins, were identified from four types of liver disease, where significant differences in protein expression were found in apolipoproteins, immunoglobulins, and other previously reported markers of liver disease. Principal component analysis of 61 proteins identified from MaxQuant analysis of the LC-MS/MS data provided a confident differentiation between ALD and NAFLD. SIGNIFICANCE: The current investigation revealed the difference among various types of liver disease using LC-MS/MS of exosomes enriched from human serum samples of 24 patients where the most significantly up-regulation proteins were alpha-2-macroglobulin for alcoholic hepatitis and apolipoprotein C3 for nonalcoholic fatty liver disease.


Assuntos
Vesículas Extracelulares , Hepatopatia Gordurosa não Alcoólica , Cromatografia Líquida , Humanos , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Proteômica , Espectrometria de Massas em Tandem
15.
Front Med (Lausanne) ; 8: 672658, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34124102

RESUMO

Background: Crosstalk between brown adipose tissue (BAT) and the liver is receiving increasing attention. This study investigated the effect of BAT dysfunction by thermoneutral (TN) housing on liver fibrosis in mice and examined the effect of secreted factors from brown adipocytes on the activation of hepatic stellate cells (HSCs). Methods: The carbon tetrachloride (CCl4)-induced liver fibrosis mouse model was used to evaluate fibrotic changes in the livers of mice housed under standard and TN conditions. The effect of BAT on the activation of HSCs was examined using cultured cells treated with conditioned media from brown adipocytes. Results: Under TN conditions, mice with CCl4-induced liver fibrosis exhibited increased liver injury, collagen deposition, and alpha smooth muscle actin (α-SMA) expression in the liver compared with mice maintained at room temperature. The numbers of liver-infiltrating immune cells and T cells producing IL-17A and IFN-γ were also significantly increased in the livers of mice housed under TN conditions. Treatment of HSCs with conditioned media from brown adipocytes markedly attenuated HSC activation, as shown by down-regulated α-SMA expression at day 4, day 7 and day 10 of culture. At thermoneutrality, with CCl4 administration, IL-10-deficient mice exhibited more severe liver fibrosis than wild-type mice. Interestingly, conditioned media from IL-10-deficient brown adipocytes could up-regulate the expression of α-SMA and induce HSCs activation. Conclusions: BAT inactivation by thermoneutrality contributes to the activation of pro-inflammatory and pro-fibrotic pathways in mice with CCl4-induced liver fibrosis. Normal brown adipocytes secreted factors that impair the activation of HSCs, while this protective effect was lost in IL-10-deficient brown adipocytes. Thus, the BAT-liver axis may serve as a potential therapeutic target for liver fibrosis, and IL-10 may be a key factor regulating the activation of HSCs by BAT.

16.
BMC Gastroenterol ; 21(1): 258, 2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-34118869

RESUMO

BACKGROUND: Natural killer (NK) cells have been known to contribute to surveillance and control of hepatocellular carcinoma (HCC). However, the association of NK cell activity with stage and recurrence risk of HCC have not been fully evaluated. METHODS: Untreated patients with newly diagnosed HCC were prospectively enrolled. Peripheral blood mononuclear cells were isolated at the time of diagnosis. Patients who had undergone surgery or radiofrequency ablation were classified as the curative treatment group, and their blood samples were collected again at 1 month after treatment. RESULTS: A total of 80 patients with HCC were enrolled. The mean age was 62.5 years. At baseline, interferon (IFN)-γ producing NK cell proportion was significantly lower in patients with Barcelona clinic liver cancer (BCLC) stage B, C, or D than in those with BCLC stage 0 (42.9% vs. 56.8%, P = 0.045). Among all patients, 56 patients had undergone curative treatment, and 42 patients re-visited at 1 month after curative treatment. There was no significant change in total NK cell and IFN-γ producing NK cell proportion from baseline to 1 month after treatment (all P > 0.05). During a median follow-up of 12.4 months, HCC recurred in 14 patients (33.3%). When patients were classified according to the IFN-γ producing NK cell proportion (group 1, ≥ 45%; and group 2, < 45%), HCC recurrence rate did not differ according to the IFN-γ producing NK cell proportion at baseline (log-rank test, P = 0.835). However, patients with < 45% IFN-γ producing NK cell proportion at 1 month after treatment had a significantly higher HCC recurrence rate than patients with that of ≥ 45% (log-rank test, P < 0.001). Multivariate analysis revealed that BCLC stage B (hazard ratio [HR] = 3.412, P = 0.045) and < 45% IFN-γ producing NK cell proportion at 1 month after treatment (HR = 6.934, P = 0.001) independently predicted an increased risk of HCC recurrence. CONCLUSIONS: Decreased NK cell activity is significantly associated with the advanced stage of HCC, and the increased recurrence risk of HCC after curative treatment.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/cirurgia , Humanos , Células Matadoras Naturais , Leucócitos Mononucleares , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Estudos Retrospectivos , Fatores de Risco
17.
Sci Adv ; 7(26)2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34162541

RESUMO

Pancreatic ß cell therapy for type 1 diabetes is limited by low cell survival rate owing to physical stress and aggressive host immune response. In this study, we demonstrate a multilayer hydrogel nanofilm caging strategy capable of protecting cells from high shear stress and reducing immune response by interfering cell-cell interaction. Hydrogel nanofilm is fabricated by monophenol-modified glycol chitosan and hyaluronic acid that cross-link each other to form a nanothin hydrogel film on the cell surface via tyrosinase-mediated reactions. Furthermore, hydrogel nanofilm formation was conducted on mouse ß cell spheroids for the islet transplantation application. The cytoprotective effect against physical stress and the immune protective effect were evaluated. Last, caged mouse ß cell spheroids were transplanted into the type 1 diabetes mouse model and successfully regulated its blood glucose level. Overall, our enzymatic cross-linking-based hydrogel nanofilm caging method will provide a new platform for clinical applications of cell-based therapies.

18.
Front Pharmacol ; 12: 612981, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34025399

RESUMO

Dimethyl fumarate (DMF), which has been approved by the Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis, is considered to exert anti-inflammatory and antioxidant effects. Microglia maintain homeostasis in the central nervous system and play a key role in neuroinflammation, while autophagy controls numerous fundamental biological processes, including pathogen removal, cytokine production, and clearance of toxic aggregates. However, the role of DMF in autophagy induction and the relationship of this effect with its anti-inflammatory functions in microglia are not well known. In the present study, we investigated whether DMF inhibited neuroinflammation and induced autophagy in microglia. First, we confirmed the anti-neuroinflammatory effect of DMF in mice with streptozotocin-induced diabetic neuropathy. Next, we used in vitro models including microglial cell lines and primary microglial cells to examine the anti-inflammatory and neuroprotective effects of DMF. We found that DMF significantly inhibited nitric oxide and proinflammatory cytokine production in lipopolysaccharide-stimulated microglia and induced the switch of microglia to the M2 state. In addition, DMF treatment increased the expression levels of autophagy markers including microtubule-associated protein light chain 3 (LC3) and autophagy-related protein 7 (ATG7) and the formation of LC3 puncta in microglia. The anti-inflammatory effect of DMF in microglia was significantly reduced by pretreatment with autophagy inhibitors. These data suggest that DMF leads to the induction of autophagy in microglia and that its anti-inflammatory effects are partially mediated through an autophagy-dependent pathway.

19.
J Clin Med ; 10(9)2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33922708

RESUMO

Potent antiviral agents effectively reduce liver-related events in patients with chronic hepatitis B. This study aimed to determine whether alanine aminotransferase normalization using potent antiviral agents was related to hepatocellular carcinoma development. From 2007 to 2017, we included 610 patients with chronic hepatitis B who received entecavir or tenofovir disoproxil fumarate. The patients were divided into the alanine aminotransferase normalization group (Gr.1) and non-normalization group (Gr.2) within a year of potent antiviral treatment. Liver-related events included hepatic encephalopathy, variceal bleeding, and ascites. The mortality rate and hepatocellular carcinoma incidence were investigated for each group. The patients who showed ALT normalization at 1 year of treatment were 397 (65.1%) of 610. During a median follow-up period of 86 months, 65 (10.7%) patients developed hepatocellular carcinoma. The cumulative incidence of hepatocellular carcinoma was significantly lower in Gr.1 than in Gr.2 (p < 0.001). Risk factors for alanine aminotransferase non-normalization were body mass index, cholesterol, and liver cirrhosis at baseline. Male sex, age, platelet level, alcohol use, presence of cirrhosis at baseline, and non-normalization after 1 year of treatment were independent risk factors for hepatocellular carcinoma. Alanine aminotransferase normalization within 1 year of initiating antiviral agents reduces the risk of hepatocellular carcinoma development.

20.
J Clin Densitom ; 24(3): 414-421, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33846060

RESUMO

Despite the potential roles of sphingosine 1-phosphate (S1P) as a biomarker of osteoporotic fracture (OF), independent of bone mineral density (BMD) and clinical risk factors (CRFs), its association with bone microarchitecture, a key determinant of bone quality, have not been studied yet. We here investigated the association of S1P with the trabecular bone score (TBS), an index of the bone microarchitecture. The plasma S1P concentrations, TBS, and BMD were measured in the 339 postmenopausal women. The S1P level was inversely correlated with the TBS (γ=-0.096, p=0.049) and BMD at the femur neck (FN-BMD: γ=-0.122, p=0.025) and tended to be inversely correlated the BMD at the total hip (TH-BMD: γ=-0.096, p=0.079), but not at the lumbar spine (LS-BMD). After adjusting for fracture risk assessment tool probabilities of major OF from CRFs, the S1P level was inversely associated with the TBS (ß=-0.096, p=0.049) and FN-BMD (ß=-0.118, p=0.025) and tended to be inversely associated with the TH-BMD (ß=-0.092, p=0.083). Compared with subjects in the lowest S1P tertile, those in the highest S1P tertile had a significantly lower TBS (p=0.032) and BMD at femur (p=0.004-0.036). These findings indicated that a high S1P level in postmenopausal women was inversely associated with the both bone mass and microarchitecture, reflecting the compromised bone strength.


Assuntos
Densidade Óssea , Fraturas por Osteoporose , Absorciometria de Fóton , Osso Esponjoso/diagnóstico por imagem , Feminino , Humanos , Vértebras Lombares/diagnóstico por imagem , Lisofosfolipídeos , Fraturas por Osteoporose/diagnóstico por imagem , Pós-Menopausa , Esfingosina/análogos & derivados
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