RESUMO
Studies investigating the relationship between dietary vitamin B1 intake and risk of Hyperuricemia (HU) are scarce, the present study aimed to examine the association of dietary vitamin B1 intake and HU among adults. This cross-sectional study included 5750 adults whose data derived from National Health and Nutrition Examination Survey (NHANES) from March 2017 to March 2020. The dietary intake of vitamin B1 was assessed using 24-h dietary recall interviews. The characteristics of study participants were grouped into five levels according to the levels of vitamin B1 quintile. Multivariate logistic regression analysis was used to estimate the odds ratio (OR) and 95% confidence interval (CI) of HU, according to the vitamin B1 intake quintile for male and female separately. The dose-response relationship was determined by the restricted cubic spline (RCS). Smoothed curve fitting was used to assess serum uric acid concentration versus dietary vitamin B1 intake in the study population. The prevalence of hyperuricemia was 18.90% (20.15% and 17.79% for males and females, respectively) in the United States from March 2017 to March 2020. Multiple logistic regression analyses showed that in the male population, the HU ratio (OR) of vitamin B1 intake in Q2 to Q5 compared with the lowest quintile (Q1) was 0.75 (95% CI 0.52, 1.09), 0.70 (95% CI 0.48, 1.02), 0.66 (95% CI 0.44, 0.99) and 0.55 (95% CI 0.34, 0.90). The P for trend was 0.028. In women, the ORs for vitamin B1 intake Q2 to Q5 were 0.87 (95% CI 0.64, 1.19), 0.97 (0.68-1.38), 1.05 (0.69-1.60) and 0.75 (0.42-1.34), respectively. The P for trend was 0.876. The RCS curve revealed a linear relationship between vitamin B1 intake and the risk of hyperuricemia in men (P nonlinear = 0.401). Smoothed curve fitting demonstrated a negative association between vitamin B1 intake and serum uric acid concentration in men, whereas there was no significant association between dietary vitamin B1 intake and the risk of hyperuricemia in women. In the US adult population, dietary vitamin B1 intake was negatively associated with hyperuricemia in males.
Assuntos
Hiperuricemia , Inquéritos Nutricionais , Tiamina , Ácido Úrico , Humanos , Hiperuricemia/epidemiologia , Hiperuricemia/sangue , Hiperuricemia/etiologia , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Estudos Transversais , Ácido Úrico/sangue , Tiamina/administração & dosagem , Tiamina/sangue , Prevalência , Dieta , Razão de Chances , Fatores de Risco , Idoso , Estados Unidos/epidemiologiaRESUMO
Treatment of advanced triple-negative breast cancer (TNBC) is a great challenge in clinical practice. The immune checkpoints are a category of immunosuppressive molecules that cancer could hijack and impede anti-tumor immunity. Targeting immune checkpoints, such as anti-programmed cell death 1 (PD-1) therapy, is a promising therapeutic strategy in TNBC. The efficacy and safety of PD-1 monoclonal antibody (mAb) with chemotherapy have been validated in TNBC patients. However, the precise mechanisms underlying the synergistic effect of chemotherapy and anti-PD-1 therapy have not been elucidated, causing the TNBC patients that might benefit from this combination regimen not to be well selected. In the present work, we found that IL-23, an immunological cytokine, is significantly upregulated after chemotherapy in TNBC cells and plays a vital role in enhancing the anti-tumor immune response of cytotoxic T cells (CTLs), especially in combination with PD-1 mAb. In addition, the combination of IL-23 and PD-1 mAb could synergistically inhibit the expression of Phosphoinositide-3-Kinase Regulatory Subunit 1 (PIK3R1), which is a regulatory subunit of PI3K and inhibit p110 activity, and promote phosphorylation of AKT in TNBC-specific CTLs. Our findings might provide a molecular marker that could be used to predict the effects of combination chemotherapy therapy and PD-1 mAb in TNBC.
Assuntos
Subunidade p19 da Interleucina-23 , Fosfatidilinositol 3-Quinases , Receptor de Morte Celular Programada 1 , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Linfócitos T Citotóxicos , Neoplasias de Mama Triplo Negativas , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/imunologia , Transdução de Sinais/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Linhagem Celular Tumoral , Feminino , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Subunidade p19 da Interleucina-23/metabolismo , Animais , Camundongos , Anticorpos Monoclonais/farmacologiaRESUMO
We aimed to examine the association of traditional Chinese herbal dietary formulas with ability of daily life and physical function in elderly patients with mild cognitive impairment. The current study included 60 cases of elderly patients with mild cognitive impairment from Yueyang Hospital of Integrated Traditional Chinese Medicine and Western Medicine, Shanghai University of Traditional Chinese Medicine and Hongkou District, Shanghai. The participants were randomly divided into two groups: group A (herbal dietary formula group, consisting of Alpiniae Oxyphyllae Fructus, Nelumbinis plumula, Chinese Yam, Poria cocos, and Jineijin), 30 cases, and group B (vitamin E), 30 cases, treatment for 3 months. Cognitive function was measured using the Montreal Cognitive Assessment (MOCA) and Mini-Mental State Examination (MMSE); body function was measured using the Chinese Simplified Physical Performance Test (CMPPT), including stand static balance, sitting-up timing, squat timing, and six-meter walk timing. Daily life based on ability was measured by grip strength and the Activity of Daily Living Scale (ADL). The lower the scores of the above items, the poorer the disease degree, except for ADL: the lower the score, the higher the self-care ability. After 3 months of treatment, the two-handed grip strength of both the herbal dietary formula group and vitamin E group increased; the ADL, sitting-up timing, squatting timing, and six-meter walking timing decreased after medication, being statistically significantly different (p < 0.05). The two-handed grip strength of group A increased significantly, and the ADL, sitting-up timing, squatting timing, and six-meter walking timing decreased distinctly compared with the vitamin E group. There was a statistically significant difference (p < 0.05). The scores of MMSE, MOCA, total CMPPT, and standing static balance of the herbal dietary formula group increased after medication. The difference was statistically significant (p < 0.05). The vitamin E group's MMSE and MOCA scores, CMPPT total scores, and standing resting balance scores did not change significantly after medication (p > 0.05). In summary, a traditional Chinese herbal dietary formula can improve body and cognitive function in patients with MCI, and the curative effect is better than that of vitamin E. Traditional Chinese herbal dietary formulas can improve the daily life quality of MCI patients, which has clinical application value.
RESUMO
Background: Owing to the complex pathophysiological features and heterogeneity of sepsis, current diagnostic methods are not sufficiently precise or timely, causing a delay in treatment. It has been suggested that mitochondrial dysfunction plays a critical role in sepsis. However, the role and mechanism of mitochondria-related genes in the diagnostic and immune microenvironment of sepsis have not been sufficiently investigated. Methods: Mitochondria-related differentially expressed genes (DEGs) were identified between human sepsis and normal samples from GSE65682 dataset. Least absolute shrinkage and selection operator (LASSO) regression and the Support Vector Machine (SVM) analyses were carried out to locate potential diagnostic biomarkers. Gene ontology and gene set enrichment analyses were conducted to identify the key signaling pathways associated with these biomarker genes. Furthermore, correlation of these genes with the proportion of infiltrating immune cells was estimated using CIBERSORT. The expression and diagnostic value of the diagnostic genes were evaluated using GSE9960 and GSE134347 datasets and septic patients. Furthermore, we established an in vitro sepsis model using lipopolysaccharide (1 µg/mL)-stimulated CP-M191 cells. Mitochondrial morphology and function were evaluated in PBMCs from septic patients and CP-M191 cells, respectively. Results: In this study, 647 mitochondrion-related DEGs were obtained. Machine learning confirmed six critical mitochondrion-related DEGs, including PID1, CS, CYP1B1, FLVCR1, IFIT2, and MAPK14. We then developed a diagnostic model using the six genes, and receiver operating characteristic (ROC) curves indicated that the novel diagnostic model based on the above six critical genes screened sepsis samples from normal samples with area under the curve (AUC) = 1.000, which was further demonstrated in the GSE9960 and GSE134347 datasets and our cohort. Importantly, we also found that the expression of these genes was associated with different kinds of immune cells. In addition, mitochondrial dysfunction was mainly manifested by the promotion of mitochondrial fragmentation (p<0.05), impaired mitochondrial respiration (p<0.05), decreased mitochondrial membrane potential (p<0.05), and increased reactive oxygen species (ROS) generation (p<0.05) in human sepsis and LPS-simulated in vitro sepsis models. Conclusion: We constructed a novel diagnostic model containing six MRGs, which has the potential to be an innovative tool for the early diagnosis of sepsis.
Assuntos
Mitocôndrias , Sepse , Humanos , Mitocôndrias/genética , DNA Mitocondrial , Sepse/diagnóstico , Sepse/genética , Área Sob a Curva , Ontologia Genética , LipopolissacarídeosRESUMO
Risk avoidance behaviors are essential for survival. "Uncontrollable" risk-taking behaviors in animals or humans may have severe adverse consequences. In humans, a large proportion of psychiatric disorders are accompanied by impairments in risk avoidance. Obesity is associated with psychiatric disorders. Peroxisome proliferator-activated receptor α (PPARα) takes part in regulating lipid metabolism and neuronal function. Here, we investigated the effect of high-fat diet (HFD)-induced obesity on risk avoidance and the role of PPARα in this behavior. Male PPARα-null (KO) mice and wild-type (WT) mice were assigned to four different groups: WT-CON and KO-CON (normal diet); WT-HFD and KO-HFD (high fat diet). The HFD began at week 6 and was continued until sampling. A series of behavioral tests were performed at week 11. We found that WT but not KO mice fed with a HFD exhibited weight gain and risk avoidance impairment, compared with the mice fed with a normal diet. The staining of c-Fos revealed that the hippocampus was the main brain region involved in risk avoidance behavior. Moreover, biochemical analysis suggested that the decreased levels of the brain-derived neurotrophic factor (BDNF) in the hippocampus might contribute to risk avoidance impairment induced by a HFD. These results indicated that PPARα is involved in HFD-induced risk avoidance impairment via the regulation of hippocampal BDNF.
Assuntos
Dieta Hiperlipídica , PPAR alfa , Humanos , Camundongos , Masculino , Animais , Dieta Hiperlipídica/efeitos adversos , PPAR alfa/genética , PPAR alfa/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/metabolismo , Obesidade/metabolismo , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
Polyurethane (PUR) plastics is widely used because of its unique physical and chemical properties. However, unreasonable disposal of the vast amount of used PUR plastics has caused serious environmental pollution. The efficient degradation and utilization of used PUR plastics by means of microorganisms has become one of the current research hotspots, and efficient PUR degrading microbes are the key to the biological treatment of PUR plastics. In this study, an Impranil DLN-degrading bacteria G-11 was isolated from used PUR plastic samples collected from landfill, and its PUR-degrading characteristics were studied. Strain G-11 was identified as Amycolatopsis sp. through 16S rRNA gene sequence alignment. PUR degradation experiment showed that the weight loss rate of the commercial PUR plastics upon treatment of strain G-11 was 4.67%. Scanning electron microscope (SEM) showed that the surface structure of G-11-treated PUR plastics was destroyed with an eroded morphology. Contact angle and thermogravimetry analysis (TGA) showed that the hydrophilicity of PUR plastics increased along with decreased thermal stability upon treatment by strain G-11, which were consistent with the weight loss and morphological observation. These results indicated that strain G-11 isolated from landfill has potential application in biodegradation of waste PUR plastics.
Assuntos
Plásticos , Poliuretanos , Plásticos/metabolismo , Poliuretanos/química , RNA Ribossômico 16S , Bactérias/genética , Biodegradação AmbientalRESUMO
Introduction: Cognitive impairment includes the abnormality of learning, memory and judgment, resulting in severe learning and memory impairment and social activity impairment, which greatly affects the life quality of individuals. However, the specific mechanisms underlying cognitive impairment in different behavioral paradigms remain to be elucidated. Methods: The study utilized two behavioral paradigms, novel location recognition (NLR) and novel object recognition (NOR), to investigate the brain regions involved in cognitive function. These tests comprised two phases: mice were presented with two identical objects for familiarization during the training phase, and a novel (experiment) or familiar (control) object/location was presented during testing. Immunostaining quantification of c-Fos, an immediate early gene used as a neuronal activity marker, was performed in eight different brain regions after the NLR or NOR test. Results: The number of c-Fos-positive cells was significantly higher in the dorsal part of the lateral septal nucleus (LSD) in the NLR and dentate gyrus (DG) in the NOR experiment group than in the control group. We further bilaterally lesioned these regions using excitotoxic ibotenic acid and replenished the damaged areas using an antisense oligonucleotide (ASO) strategy. Discussion: These data reinforced the importance of LSD and DG in regulating spatial and object recognition memory, respectively. Thus, the study provides insight into the roles of these brain regions and suggests potential intervention targets for impaired spatial and object recognition memory.
RESUMO
Introduction: Lung metastasis (LM) implies a very dismal event in patients with thyroid cancer. We aimed to construct a nomogram to predict LM for newly diagnosed stage IV thyroid cancer. Methods: A total of 1407 stage IV thyroid cancer patients were gathered from the surveillance, epidemiology, and end results (SEER) database. Pearson's Chi-squared test or Fisher's exact test was used to identify LM-related factors, and logistic regression analysis was employed to identify independent risk parameters of LM, which were included to establish a nomogram model by R software. The discriminative ability and predictive accuracy of the nomogram were assessed using the area under the curve (AUC) and calibration plots. Cox regression analysis and Kaplan-Meier analysis were applied to evaluate the clinical utility of this model. A simulation trial was conducted to verify the health economic value of this nomogram in predicting TCLM. Results: Five variables were found to be independent risk predictors of LM, including grade, histology, N stage, bone metastasis, and liver metastasis. The results of the AUC and calibration curves demonstrated that the nomogram exhibited outstanding performance for predicting the risk of LM patients both internally and externally. The LM prediction risk was an independent prognostic factor for stage IV thyroid cancer patients [P = .009, hazard ratio (HR): 1.812, 95% CI: 1.163-2.824]. Conclusion: We successfully developed a predictive model for stage IV thyroid cancer, which provides important information for identifying patients at high risk of LM and implementing early preventive interventions to improve their outcomes.
Assuntos
Neoplasias Pulmonares , Neoplasias da Glândula Tireoide , Humanos , Nomogramas , Área Sob a Curva , Calibragem , Neoplasias Pulmonares/epidemiologia , Programa de SEERRESUMO
Gonadotropin-releasing hormone (GnRH) is at the head of the neuroendocrine reproductive axis. However, the non-reproductive functions of GnRH expressed in various tissues, including hippocampus, are still not known. Here, we unveil a previously unknown effect of GnRH, which mediates depression-like behaviors through the modulation of microglia function during immune challenge. Specifically, we found that either systemic treatment with GnRH agonist or over-expression of endogenous hippocampal GnRH via viral tool abolished the depression-like behavior after LPS challenges in mice. And the anti-depressant of GnRH was dependent on the hippocampal GnRHR signaling, since antagonizing GnRHR by drug treatment or by hippocampal GnRHR knockdown could block the antidepressant-effect of GnRH agonist. Interestingly, we found that the peripheral GnRH treatment prevented the microglia activation mediated inflammation in the hippocampus of mice. In light of the research findings presented here, we propose that, at least in the hippocampus, GnRH appears to act on GnRHR to regulate higher order non-reproductive functions associated with the microglia mediated neuroinflammation. These findings also provide insights into the function and cross-talk of GnRH, a known neuropeptide hormone, in neuro-immune response.
Assuntos
Depressão , Lipopolissacarídeos , Masculino , Camundongos , Animais , Depressão/induzido quimicamente , Depressão/tratamento farmacológico , Hormônio Liberador de Gonadotropina/farmacologia , Transdução de Sinais , Antidepressivos/farmacologiaRESUMO
Based on the comprehensive development of the emission inventory of air pollution sources, the emission inventory of self-owned mobile sources of Tianjin coastal ports was researched and formulated. In this study, a gridded emission inventory with a resolution of 3 km×3 km was established for six types of air pollutants from road and non-road mobile sources. The spatial and temporal distribution characteristics of pollutant emissions were analyzed, and the uncertainty of the inventory was analyzed using the Monte Carlo method. The results showed that in 2020, the self-owned mobile sources of coastal ports emitted 148.22 t PM10, 135.34 t PM2.5, 1061.04 t SO2, 4027.16 t NOx, 756.60 t CO, and 237.07 t VOCs, of which the total emissions of road and non-road mobile sources accounted for 6.66% and 93.34% of the mobile source emissions, respectively. The main contributors to motor vehicle pollutant emissions from road mobile sources in the whole port area were small, medium, and large passenger vehicles (gasoline) and heavy trucks (diesel). The main contributors to the pollutants emitted by non-road mobile sources were ships and construction machinery. Uncertainty analysis results showed that the overall uncertainty of mobile sources ranged from -13.3% to 16.53%.
RESUMO
Over-activated microglia and inflammatory mediators are found in patients with depression, while manipulation of the microglia function might represent a potential therapeutic strategy. Insulin-like growth factor 2 (IGF2) has been implicated in bacterial infections and autoimmune disorders, but the role of IGF2 on the active phenotype of microglia and neuroinflammation has not been well established. IGF2 influences in modulating microglia responding to neuroinflammation induced by lipopolysaccharideï¼LPSï¼challenge will be carefully examined. In the current study, we verified that systemic IGF2 treatment could produce an anti-depression effect in LPS-treated mice. Particularly, we found that systemic IGF2 treatment inhibited microglia over-activation and prevented its transformation to a pro-inflammatory phenotype, thereby protecting hippocampal neurogenesis. Since microglia reactive to neuroinflammation is a common feature of neuropsychiatric disorders, the discoveries from the present study may provide therapeutic innovation for these diseases.
Assuntos
Depressão , Fator de Crescimento Insulin-Like II , Microglia , Animais , Masculino , Camundongos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Doenças Neuroinflamatórias , Fenótipo , Fator de Crescimento Insulin-Like II/metabolismo , Fator de Crescimento Insulin-Like II/farmacologia , Depressão/tratamento farmacológicoRESUMO
Pyroptosis, a newly discovered proinflammatory programmed cell death, is involved in the regulation of cognitive dysfunction, such as Alzheimer's disease. Exploring potential drug targets that prevent pyroptotic procedures might benefit the development of a cure for these diseases. In the present study, we explored whether the transient receptor potential vanilloid 4 (TRPV4) blocker HC067047 and knockdown of TRPV4 in the hippocampus could improve cognitive behavior through the inhibition of pyroptosis in a mouse model developed using systemic administration of lipopolysaccharide (LPS). We found that systemic administration of HC067047 or knockdown of hippocampal TRPV4 prevented the activation of canonical and noncanonical pyroptosis in the hippocampus of LPS-treated mice. Consistent with the inhibition of the hippocampal pyroptosis pathway, a knockdown of hippocampal TRPV4 lowered expression of TNF-α, IL-1ß, IL-18, and IL-6. Furthermore, we verified that the main pyroptosis cell type might be a neuron, indicated by reduced neuronal marker expression. Mechanically, we also found that knockdown of hippocampal TRPV4 might inhibit phosphorylation of Camkâ ¡α which results in NFκb mediated inflammasome reduction in the hippocampus of LPS-treated mice. More interestingly, mice intraperitoneally injected with HC067047 or the hippocampus injected with TRPV4 shRNA showed improved cognitive behavior, as indicated by the enhanced discrimination ratio in the NORT, NOPT, and SNPT. Collectively, we consider that HC067047 might be a small molecular drug that prevents pyroptosis, and TRPV4 could be an effective therapeutic target for preventing pyroptosis-induced cognitive dysfunction.
Assuntos
Antineoplásicos , Disfunção Cognitiva , Camundongos , Animais , Lipopolissacarídeos/farmacologia , Piroptose , Canais de Cátion TRPV , Inflamassomos/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Antineoplásicos/farmacologia , Hipocampo/metabolismoRESUMO
BACKGROUND: Ischemic stroke has been a public concern, while its pathogenesis is not fully understood. Increasing evidence suggests that circular RNAs (circRNAs) are involved in this disorder. The purpose of this study was to explore the role of circ_0101874 in ischemic stroke. METHODS: The in vivo model of ischemic stroke was established in mice with middle cerebral artery occlusion (MCAO) treatment. The in vitro model of ischemic stroke was established in SK-N-SH cells with oxygen-glucose deprivation (OGD) treatment. The expression of circ_0101874, miR-335-5p and phosphodiesterase 4D (PDE4D) mRNA was measured by quantitative real-time PCR (qPCR). The release of inflammatory factors was checked by ELISA. Cell viability, cell proliferation and cell apoptosis were detected using CCK-8 assay, EdU assay and flow cytometry assay, respectively. The protein levels of cyclinD1, cleaved-caspase-3 and PDE4D were detected by western blot. The interaction between miR-335-5p and circ_0101874 or PDE4D was validated by dual-luciferase reporter assay and RIP assay. RESULTS: Circ_0101874 was highly expressed in MCAO animal models and OGD-induced SK-N-SH cells. Circ_0101874 knockdown suppressed OGD-enhanced inflammation, cell apoptosis and oxidative stress and promoted OGD-inhibited cell viability and cell proliferation in SK-N-SH cells. Circ_0101874 directly bound to miR-335-5p, and miR-335-5p inhibition reversed the effects of circ_0101874 knockdown. PDE4D was a target gene of miR-335-5p, and PDE4D overexpression recovered OGD-promoted SK-N-SH cell injuries that were blocked by miR-335-5p enrichment. Circ_0101874 bound to miR-335-5p to enhance the expression of PDE4D. CONCLUSION: Circ_0101874 knockdown alleviated OGD-induced neuronal cell injury by suppressing PDE4D via regulating miR-335-5p.
Assuntos
AVC Isquêmico , MicroRNAs , Animais , Camundongos , Diester Fosfórico Hidrolases , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética , Proliferação de Células , Apoptose/fisiologia , Glucose , Infarto da Artéria Cerebral Média/genéticaRESUMO
Aim: Chronic pancreatitis (CP) is a complex and intractable disease mainly manifested as chronic inflammation and fibrosis. Aspirin(acetylsalicylic acid, ASA) has been reported to be used in the treatment of acute pancreatitis (AP), but its effectiveness on CP is unclear. This study aimed to investigate the therapeutic effects of ASA in CP mice. Methods: A murine model of CP was induced by intraperitoneal injection with 20% L-arginine. After one week of L-arginine administration, mice in the ASA treatment group were administered aspirin (100mg/kg/d) by intragastric gavage. At two, four, and six weeks after the first injection of L-arginine, mice were euthanized and the pancreas was collected for histological and molecular analysis. A second model of CP (caeruelin-induced) was used as a validation experiment to test the effect of ASA. Results: L-arginine-induced CP resulted in over-expression of the inflammatory enzyme cyclooxygenase (COX)-2. COX-2 expression decreased after ASA treatment. Pancreatic-injury inflammatory response (measured by changes in amylase, CK-19, F4/80, CD3, MCP-1, IL-6) and fibrosis degree (measured by expression of COL1A1, MMP-1 and TIMP-1) was reduce in ASA -treated mice model. The therapeutic effect of ASA was also observed in caeruelin-induced CP. Conclusion: ASA has an ameliorating effect in murine models of CP through inhibition of pancreatic inflammation and fibrosis, which may be a promising option for clinical treatment.
RESUMO
Ulcerative colitis (UC) is one of the primary types of inflammatory bowel disease, the occurrence of which has been increasing worldwide. Research in recent years has found that the level of lysozyme in the feces and blood of UC patients is abnormally elevated, and the bacterial product after the action of lysozyme can be used as an agonist to recognize different cell pattern receptors, thus regulating the process of intestinal inflammation. Berberine (BBR), as a clinical anti-diarrhea and anti-inflammatory drug, has been used in China for hundreds of years. In this study, results showed that BBR can significantly inhibit the expression and secretion of lysozyme in mice. Therefore, we try to investigate the mechanism behind it and elucidate the new anti-inflammatory mechanism of BBR. In vitro, lipopolysaccharide (LPS) was used to establish an inflammatory cell model, and transcriptomic was used to analyze the differentially expressed genes (DEGs) between the LPS group and the LPS + BBR treatment group. In vivo, dextran sulfate sodium salt (DSS) was used to establish a UC mice model, and histologic section and immunofluorescence trails were used to estimate the effect of BBR on UC mice and the expression of lysozyme in Paneth cells. Research results showed that BBR can inhibit the expression and secretion of lysozyme by promoting autophagy via the AMPK/MTOR/ULK1 pathway, and BBR promotes the maturation and expression of lysosomes. Accordingly, we conclude that inhibiting the expression and secretion of intestinal lysozyme is a new anti-inflammatory mechanism of BBR.
RESUMO
BACKGROUND: Breast neuroendocrine carcinoma (NEC) is a rare malignancy with unclear treatment options and prognoses. This study aimed to construct a high-quality model to predict overall survival (OS) and breast cancer-specific survival (BCSS) and help clinicians choose appropriate breast NEC treatments. PATIENTS AND METHODS: A total of 378 patients with breast NEC and 349,736 patients with breast invasive ductal carcinoma (IDC) were enrolled in the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2018. Propensity score matching (PSM) was performed to balance the clinical baseline. Prognostic factors determined by multivariate Cox analysis were included in the nomogram. C-index and calibration curves were used to verify the performance of the nomogram. RESULTS: Nomograms were constructed for the breast NEC and breast IDC groups after PSM. The C-index of the nomograms ranged from 0.834 to 0.880 in the internal validation and 0.818-0.876 in the external validation, indicating that the nomogram had good discrimination. The risk stratification system showed that patients with breast NEC had worse prognoses than those with breast IDC in the low-risk and intermediate-risk groups but had a similar prognosis that those in the high-risk group. Moreover, patients with breast NEC may have a better prognosis when undergoing surgery plus chemotherapy than when undergoing surgery alone or chemotherapy alone. CONCLUSIONS: We established nomograms with a risk stratification system to predict OS and BCSS in patients with breast NEC. This model could help clinicians evaluate prognosis and provide individualized treatment recommendations for patients with breast NEC.
RESUMO
PURPOSE: The aim of this study was to explore the role of galectin-3 in human epidermal growth factor receptor 2 (HER2)-positive breast cancer cells and the potential mechanism. METHODS: Kaplan-Meier (KM)-plot and The Cancer Genome Atlas (TCGA) databases were used to study the role of galectin-3 in the prognosis of HER2-positive breast cancer. The effects of galectin-3 on cell proliferation, migration, invasion, and colony formation ability in HER2-positive breast cancer cells were examined. The relationship between galectin-3 and important components in the HER2 pathways, including HER2, epidermal growth factor receptor (EGFR), protein kinase B (AKT), and phosphatase and tensin homolog (PTEN), was further studied. Lentivirus and CRISPR/Cas9 were used to construct stable cell lines. Cell counting kit-8 (CCK-8) and apoptosis assays were used to study the relationship between galectin-3 and trastuzumab. The effect of galectin-3 on cell stemness was studied by mammosphere formation assay. The effects of galectin-3 on stemness biomarkers and the Notch1 pathway were examined. Tumorigenic models were used to evaluate the effects of galectin-3 on tumorigenesis and the therapeutic effect of trastuzumab in vivo. RESULTS: HER2-positive breast cancer patients with a high expression level of LGALS3 (the gene encoding galectin-3) messenger RNA (mRNA) showed a poor prognosis. Galectin-3 promoted cancer malignancy through phosphoinositide 3-kinase (PI3K)/AKT signaling pathway activation and upregulated stemness by activating the Notch1 signaling pathway in HER2-positive breast cancer cells. These two factors contributed to the enhancement of trastuzumab resistance in cells. Knockout of LGALS3 had a synergistic therapeutic effect with trastuzumab both in vitro and in vivo. CONCLUSIONS: Galectin-3 may represent a prognostic predictor and therapeutic target for HER2-positive breast cancer.
Assuntos
Proteínas Sanguíneas/metabolismo , Neoplasias da Mama , Galectinas/metabolismo , Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Feminino , Galectina 3/genética , Galectina 3/uso terapêutico , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Trastuzumab/uso terapêuticoRESUMO
Background: Breast cancer (BRCA) is the most common cancer worldwide and a serious threat to human health. MDN1 mutations have been observed in several cancers. However, the associations of MDN1 mutation with tumor mutation burden (TMB) and prognosis of BRCA have not been investigated. Methods: Genomic, transcriptomic, and clinical data of 973 patients with BRCA from The Cancer Genome Atlas (TCGA) database were analyzed. The clinical attributes of BRCA based on the MDN1 mutation status were assessed by comparing TMB and tumor infiltrating immune cells. Gene ontology analysis and gene set enrichment analysis (GSEA) were conducted to identify the key signaling pathways associated with MDN1 mutation. Moreover, univariate and multivariate Cox regression analyses were performed to assess the association between prognostic factors and survival outcomes. Finally, nomograms were used to determine the predictive value of MDN1 mutation on clinical outcomes in patients with BRCA. Results: MDN1 was found to have a relatively high mutation rate (2.77%). Compared to the MDN1 wild-type patients, the TMB value was significantly higher in MDN1 mutant patients (p < 0.001). Prognostic analysis revealed that MDN1 mutant patients had a worse survival probability than MDN1 wild-type patients (hazard ratio = 2.91; 95% CI:1.07-7.92; p = 0.036). GSEA revealed samples with MDN1 mutation enriched in retinol metabolism, drug metabolism cytochrome P450, glucuronidation, miscellaneous transport, and binding event pathways. Conclusion: MDN1 mutation was found to be associated with high TMB and inferior prognosis, suggesting that MDN1 mutation may play a potential role in prognosis prediction and immunotherapy guidance in BRCA.
RESUMO
Background & objectives: An effective tool for forecasting the survival of BCLM is lacking. This study aims to construct nomograms to predict overall survival (OS) and breast cancer-specific survival (BCSS) in breast cancer patients with de novo lung metastasis, and to help clinicians develop appropriate treatment regimens for breast cancer lung metastasis (BCLM) individuals. Methods: We gathered clinical data of 2,537 patients with BCLM between 2010 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database. Cox regression analysis was employed to identify independent prognostic parameters for BCLM, which were integrated to establish nomograms by R software. The discriminative ability and predictive accuracy of the nomograms were assessed using the concordance index (C-index), receiver operating characteristic (ROC) curves, and calibration plots. Kaplan-Meier analyses were applied to evaluate the clinical utility of the risk stratification system and investigate the survival benefit of primary site surgery, chemotherapy, and radiotherapy for BCLM patients. Results: Two nomograms shared common prognostic indicators including age, marital status, race, laterality, grade, AJCC T stage, subtype, bone metastasis, brain metastasis, liver metastasis, surgery, and chemotherapy. The results of the C-index, ROC curves, and calibration curves demonstrated that the nomograms exhibited an outstanding performance in predicting the prognosis of BCLM patients. Significant differences in the Kaplan-Meier curves of various risk groups corroborated the nomograms' excellent stratification. Primary site surgery and chemotherapy remarkably improved OS and BCSS of BCLM patients whether the patients were at low-risk or high-risk, but radiotherapy did not. Conclusions: We successfully developed prognostic stratification nomograms to forecast prognosis in BCLM patients, which provide important information for indicating prognosis and facilitating individualized treatment regimens for BCLM patients.
RESUMO
A novel sandwich-type photoelectrochemical (PEC) aptasensor for the carcinoembryonic antigen (CEA) assay was fabricated using the CEA aptamer, Au/BiVO4 and CdS quantum dots (CdS QDs). In virtue of the localized surface plasmon resonance effect of Au nanoparticles, Au/BiVO4 showed an effective utilization of visible light and excellent photoactivity, and was employed as the photoanode. After CdS QDs were conjugated to Au/BiVO4 through the sandwich structure based on the hybridization of the CEA aptamer with two partially complementary single-stranded DNA molecules, the photocurrents were further enhanced by a resonance energy transfer between CdS QDs and Au nanoparticles. Meanwhile, the consumption of the photo-induced holes by ascorbic acid could also retard the combination of the electron-hole pairs and cause an increase of the photocurrents. However, the specific recognition of CEA by the CEA aptamer could destroy the sandwich structure and remarkably weaken the photocurrent response. Thus, the quantitative detection of CEA was connected with the decrease of the photocurrent. Benefitting from the above methods for signal enhancement, the PEC aptasensor showed a wide sensing range of 0.0001-10 ng mL-1 and a low detection limit of 0.047 pg mL-1 for CEA detection. The specificity, stability and recoveries of the PEC aptasensor were also excellent. Therefore, the construction of the present PEC aptasensor provides a universal and practical method for sensing other substances.