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1.
Sci Rep ; 11(1): 19478, 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34593870

RESUMO

Immunomodulation is an ability of several particular probiotics. However, it still remains unclear whether the immunomodulatory effects of specific probiotics vary for different antigen presentation models with the same antigen. To investigate this matter, six groups of BALB/c mice (n = 10) were exposed to one of two antigen presentation models: ovalbumin (OVA) by injection alone, or injection plus intranasal administration. Moreover, the mice were fed distilled water or Lactobacillus casei Shirota fermented beverage (LcSFB) at low (2.5 × 109 CFU/kg body weight) or high doses (5 × 109 CFU/kg body weight) by gavage for 8 weeks. LcSFB enhanced the proliferation of splenocytes, production of OVA-specific immunoglobulin (Ig)-G and IgA, and the ratio of T-helper (Th)-2/Th1 cytokines in mice injected with OVA. Conversely, in the mice treated with OVA by injection plus intranasal administration, LcSFB attenuated the immune responses against OVA by reducing the proliferation of splenocytes, levels of OVA-specific IgE, IgG, and IgM, and ratio of Th2/Th1 cytokines. Moreover, LcSFB increased the percentage of regulatory T cells in the injection plus intranasal administration group. Taken together, this work indicates the immunoregulatory effects of LcSFB depend on how the antigen is presented. Therefore, the use of probiotics to boost the immune system must be carefully considered.

2.
Cell Death Dis ; 12(11): 965, 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34667160

RESUMO

Expression of endoplasmic reticulum (ER) stress-associated genes is often dysregulated in cancer progression. ER protein 29 (ERp29) is abnormally expressed in many neoplasms and plays an important role in tumorigenesis. Here, we showed ERp29 is a novel target for microRNA-135a-5p (miR-135a-5p) to inhibit the progression of colorectal cancer (CRC); correspondingly, ERp29 acts as an oncoprotein in CRC by promoting proliferation and metastasis of CRC cells, and suppressing apoptosis of the cells. More importantly, we found that miR-135a-5p expression is reversely upregulated by ERp29 through suppressing IL-1ß-elicited methylation of miR-135a-5p promoter region, a process for enterocyte to maintain a balance between miR-135a-5p and ERp29 but dysregulated in CRC. Our study reveals a novel feedback regulation loop between miR-135a-5p and ERp29 that is critical for maintaining appropriate level of each of them, but partially imbalanced in CRC, resulting in abnormal expression of miR-135a-5p and ERp29, which further accelerates CRC progression. We provide supporting evidence for ERp29 and miR-135a-5p as potential biomarkers for diagnosis and treatment of CRC.

3.
Strahlenther Onkol ; 2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34476531

RESUMO

PURPOSE: Development of a safe and effective systemic chemotherapeutic agent for concurrent administration with definitive thoracic radiotherapy remains a major goal of lung cancer management. The synergistic effect of PEGylated liposomal doxorubicin and irradiation was evaluated in lung cancer cell lines both in vitro and in vivo. METHODS: In vitro radiosensitization of A549 and LLC cell lines was evaluated by colony formation assay, γH2AX fluorescent staining and western blot assay, and annexin V staining. A radiosensitization study with healthy human lung-derived cell line BEAS-2B was performed for comparative purposes. In vivo radiosensitization was evaluated by tumor ectopic growth, cell survival, pharmacokinetics, and biodistribution analyses. Cleaved caspase­3, the marker for apoptosis, was assessed immunohistochemically in A549 xenograft tumors. RESULTS: Treatment with PEGylated liposomal doxorubicin decreased A549 and LLC cell proliferation in a dose-dependent manner. In vitro studies revealed comparable radiosensitizer advantages of PEGylated liposomal doxorubicin and free doxorubicin, showing equivalent DNA double-strand breaks according to γH2AX fluorescent staining and western blot assays, similar numbers of apoptotic cells in the annexin­V staining assay, and moderately decreased clonogenic survival. In vivo studies demonstrated markedly slow ectopic tumor growth with prolonged survival following treatment with PEGylated liposomal doxorubicin plus irradiation in both A549 and LLC mouse models, suggesting that PEGylated liposomal doxorubicin is more effective as a radiosensitizer than free doxorubicin in vivo. Pharmacokinetics evaluation showed a longer half-life of approximately 40 h for PEGylated liposomal doxorubicin, confirming that the liposomal carrier achieved controlled release. Biodistribution evaluation of PEGylated liposomal doxorubicin confirmed high accumulation of doxorubicin in tumors, indicating the promising drug delivery attributes of PEGylated liposomal doxorubicin. Although free doxorubicin caused histopathologic myocarditis with the cardiac muscle fibers showing varying degrees of damage, PEGylated liposomal doxorubicin caused no such effects. The immunohistochemical expression of cleaved caspase-3-positive cells was greatest expressed in the irradiation and PEGylated liposomal doxorubicin combined treatment group, indicating prolonged tumoricidal effects. CONCLUSIONS: Our study provides preclinical in vitro and in vivo evidence of the effectiveness of PEGylated liposomal doxorubicin as a radiosensitizer, supporting its potential clinical development as a component of chemoradiotherapy.

4.
Zhongguo Zhong Yao Za Zhi ; 46(15): 3832-3837, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34472256

RESUMO

Freshly collected seeds of Amomum tsaoko demonstrate obvious dormancy. Therefore, the selection of stable reference genes during seed dormancy release is very important for the subsequent functional research of related genes. In this study, ten commonly used reference genes(GAPDH, 40S, actin, tubulin, EIF4A-9, EIF2α, UBC, UBCE2, 60S, and UBQ) were selected as candidates for quantitative Real-time polymerase chain reaction(qRT-PCR) of the embryo samples of A. tsaoko at different dormancy release stages. Three kinds of software(BestKeeper, geNorm, and Normfinder) and the Delta CT method were used to evaluate the expression stability of the candidate reference genes, and the RefFinder online tool was employed to integrate the results and generate a comprehensive ranking. The results showed that the expression levels of the ten candidate reference genes differed greatly in different embryo samples. GAPDH and UBC had high expression levels, as manifested by the small Ct values. GeNorm identified 40S and UBCE2 as the most stable genes. NormFinder ranked EIF2α as the most stable gene and UBC as the least stable gene. UBCE2 was found to be the most stable gene and actin the least stable one by BestKeeper. Delta CT analysis suggested that the expression of 40S was most stable. UBCE2 was recommended as the most stably expressed gene by RefFinder. Thus, UBCE2 is the ideal reference gene for qRT-PCR analysis of A. tsaoko seeds at different dormancy release stages. The results may lay a foundation for analyzing the expression of related genes during seed dormancy release of A. tsaoko.


Assuntos
Amomum , Perfilação da Expressão Gênica , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sementes/genética
5.
Aust N Z J Psychiatry ; : 48674211046891, 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34558298

RESUMO

OBJECTIVE: Medical comorbidities are prevalent in patients with bipolar disorder. Evaluating longitudinal trends of the incidence of medical illnesses enables implementation of early prevention strategies to reduce the high mortality rate in this at-risk population. However, the incidence risks of medical illnesses in the early stages of bipolar disorder remain unclear. This study investigated the incidence and 5-year trend of medical illnesses following bipolar disorder diagnosis. METHODS: We identified 11,884 patients aged 13-40 years who were newly diagnosed as having bipolar disorder during 1996-2012 and 47,536 age- and sex-matched controls (1:4 ratio) who represented the general population from Taiwan's National Health Insurance Research Database. We estimated the prevalence and incidence of individual medical illnesses yearly across the first 5 years after the index date. The adjusted incidence rate ratio was calculated to compare the occurrence of specific medical illnesses each year between the bipolar disorder group and control group using the Poisson regression model. RESULTS: Apart from the prevalence, the adjusted incidence rate ratios of most medical illnesses were >1.00 across the first 5-year period after bipolar disorder diagnosis. Cerebrovascular diseases, ischaemic heart disease, congestive heart failure, other forms of heart disease, renal disease and human immunodeficiency virus infection exhibited the highest adjusted incidence rate ratios during the first year. Except for that of renal disease, the 5-year trends of the adjusted incidence rate ratios decreased for cerebrovascular diseases, cardiovascular diseases (e.g. ischaemic heart disease, other forms of heart disease, and vein and lymphatic disease), gastrointestinal diseases (e.g. chronic hepatic disease and ulcer disease) and communicable diseases (e.g. human immunodeficiency virus infection, upper respiratory tract infection and pneumonia). CONCLUSION: Incidence risks of medical illnesses are increased in the first year after bipolar disorder diagnosis. Clinicians must carefully evaluate medical illnesses during this period because the mortality rates from medical illnesses are particularly high in people with bipolar disorder.

6.
Biomolecules ; 11(9)2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34572570

RESUMO

The activity and function of proteins can be improved by incorporation of non-canonical amino acids (ncAAs). To avoid the tedious synthesis of a large number of chiral phenylalanine derivatives, we synthesized the corresponding phenylpyruvic acid precursors. Escherichia coli strain DH10B and strain C321.ΔA.expΔPBAD were selected as hosts for phenylpyruvic acid bioconversion and genetic code expansion using the MmPylRS/pyltRNACUA system. The concentrations of keto acids, PLP and amino donors were optimized in the process. Eight keto acids that can be biotransformed and their coupled genetic code expansions were identified. Finally, the genetic encoded ncAAs were tested for incorporation into fluorescent proteins with keto acids.

7.
BMC Gastroenterol ; 21(1): 332, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34433418

RESUMO

BACKGROUND: Acute pancreatitis is a common and potentially lethal gastrointestinal disease, but literatures for the disease burden are scarce for many countries. Understanding the current burden of acute pancreatitis and the different trends across various countries is essential for formulating effective preventive intervenes. We aimed to report the incidence, mortality, and disability-adjusted life-years (DALYs) caused by acute pancreatitis in 204 countries and territories between 1990 and 2019. METHODS: Estimates from the Global Burden of Disease Study 2019 (GBD 2019) were used to analyze the epidemiology of acute pancreatitis at the global, regional, and national levels. We also reported the correlation between development status and acute pancreatitis' age-standardized DALY rates, and calculated DALYs attributable to alcohol etiology that had evidence of causation with acute pancreatitis. All of the estimates were shown as counts and age-standardized rates per 100,000 person-years. RESULTS: There were 2,814,972.3 (95% UI 2,414,361.3-3,293,591.8) incident cases of acute pancreatitis occurred in 2019 globally; 1,273,955.2 (1,098,304.6-1,478,594.1) in women and 1,541,017.1 (1,307,264.4-1,814,454.3) in men. The global age-standardized incidence rate declined from 37.9/100,000 to 34.8/100,000 during 1990-2019, an annual decrease of 8.4% (5.9-10.4%). In 2019, there were 115,053.2 (104,304.4-128,173.4) deaths and 3,641,105.7 (3,282,952.5-4,026,948.1) DALYs due to acute pancreatitis. The global age-standardized mortality rate decreased by 17.2% (6.6-27.1%) annually from 1.7/100,000 in 1990 to 1.4/100,000 in 2019; over the same period, the age-standardized DALY rate declined by 17.6% (7.8-27.0%) annually. There were substantial differences in the incidence, mortality and DALYs across regions. Alcohol etiology attributed to a sizable fraction of acute pancreatitis-related deaths, especially in the high and high-middle SDI regions. CONCLUSION: Substantial variation existed in the burden of acute pancreatitis worldwide, and the overall burden remains high with aging population. Geographically targeted considerations are needed to tailor future intervenes to relieve the burden of acute pancreatitis in specific countries, especially for Eastern Europe.


Assuntos
Saúde Global , Pancreatite , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Feminino , Carga Global da Doença , Humanos , Incidência , Masculino , Pancreatite/epidemiologia
8.
Theranostics ; 11(16): 7640-7657, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335955

RESUMO

Background: Since primary prostate cancer (PCa) can advance to the life-threatening metastatic PCa, exploring the molecular mechanisms underlying PCa metastasis is crucial for developing the novel targeted preventive strategies for decreasing the mortality of PCa. RNA N6-methyladenosine (m6A) is an emerging regulatory mechanism for gene expression and its specific roles in PCa progression remains elusive. Methods: Western blotting, quantitative real-time PCR and immunohistochemical analyses were used to detect target gene expression in PCa cells in vitro and prostate tissues from patients. RNA immunoprecipitation was conducted to analyze the specific binding of mRNA to the target protein. Migration and invasion assays were used to assess the migratory capacities of cancer cells. The correlation between target gene expression and survival rate of PCa patients was analyzed based the TCGA database. Results: We found that total RNA N6-methyladenosine (m6A) modification levels were markedly upregulated in human PCa tissues due to increased expression of methyltransferase like 3 (METTL3). Further studies revealed that the migratory and invasive capacities of PCa cells were markedly suppressed upon METTL3 knockdown. Mechanistically, METTL3 mediates m6A modification of USP4 mRNA at A2696, and m6A reader protein YTHDF2 binds to and induces degradation of USP4 mRNA by recruiting RNA-binding protein HNRNPD to the mRNA. Decrease of USP4 fails to remove the ubiquitin group from ELAVL1 protein, resulting in a reduction of ELAVL1 protein. Lastly, downregulation of ELAVL1 in turn increases ARHGDIA expression, promoting migration and invasion of PCa cells. Conclusions: Our findings highlight the role of METTL3 in modulating invasion and metastasis of PCa cells, providing insight into promising therapeutic strategies for hindering PCa progressing to deadly metastases.


Assuntos
Metiltransferases/genética , Neoplasias da Próstata/metabolismo , Adenosina/análogos & derivados , Adenosina/genética , Adenosina/metabolismo , Movimento Celular/genética , Proliferação de Células/genética , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Inativação Gênica/fisiologia , Humanos , Masculino , Metiltransferases/metabolismo , Invasividade Neoplásica/genética , Metástase Neoplásica/genética , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/genética , RNA Mensageiro/genética , Proteínas de Ligação a RNA/metabolismo , Proteases Específicas de Ubiquitina/genética
9.
Int J Mol Sci ; 22(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34445528

RESUMO

Restenosis is a common vascular complication after balloon angioplasty. Catheter balloon inflation-induced transient ischemia (hypoxia) of local arterial tissues plays a pathological role in neointima formation. Phosphoglycerate kinase 1 (PGK1), an adenosine triphosphate (ATP)-generating glycolytic enzyme, has been reported to associate with cell survival and can be triggered under hypoxia. The purposes of this study were to investigate the possible role and regulation of PGK1 in vascular smooth muscle cells (VSMCs) and balloon-injured arteries under hypoxia. Neointimal hyperplasia was induced by a rat carotid artery injury model. The cellular functions and regulatory mechanisms of PGK1 in VSMCs were investigated using small interfering RNAs (siRNAs), chemical inhibitors, or anaerobic cultivation. Our data indicated that protein expression of PGK1 can be rapidly induced at a very early stage after balloon angioplasty, and the silencing PGK1-induced low cellular energy circumstance resulted in the suppressions of VSMC proliferation and migration. Moreover, the experimental results demonstrated that blockage of PDGF receptor-ß (PDGFRB) or its downstream pathway, the phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) axis, effectively reduced hypoxia-induced factor-1 (HIF-1α) and PGK1 expressions in VSMCs. In vivo study evidenced that PGK1 knockdown significantly reduced neointima hyperplasia. PGK1 was expressed at the early stage of neointimal formation, and suppressing PGK1 has a potential beneficial effect for preventing restenosis.


Assuntos
Angioplastia com Balão/efeitos adversos , Lesões das Artérias Carótidas/terapia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Neointima/patologia , Fosfoglicerato Quinase/metabolismo , Animais , Movimento Celular , Células Cultivadas , Masculino , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Neointima/etiologia , Neointima/metabolismo , Fosfoglicerato Quinase/genética , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
10.
Ann Palliat Med ; 10(8): 8557-8570, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34379989

RESUMO

BACKGROUND: Since 2020 COVID-19 pandemic became an emergent public sanitary incident. The epidemiology data and the impact on prognosis of secondary infection in severe and critical COVID-19 patients in China remained largely unclear. METHODS: We retrospectively reviewed medical records of all adult patients with laboratory-confirmed COVID-19 who were admitted to ICUs from January 18th 2020 to April 26th 2020 at two hospitals in Wuhan, China and one hospital in Guangzhou, China. We measured the frequency of bacteria and fungi cultured from respiratory tract, blood and other body fluid specimens. The risk factors for and impact of secondary infection on clinical outcomes were also assessed. RESULTS: Secondary infections were very common (86.6%) when patients were admitted to ICU for >72 hours. The majority of infections were respiratory, with the most common organisms being Klebsiella pneumoniae (24.5%), Acinetobacter baumannii (21.8%), Stenotrophomonas maltophilia (9.9%), Candida albicans (6.8%), and Pseudomonas spp. (4.8%). Furthermore, the proportions of multidrug resistant (MDR) bacteria and carbapenem resistant Enterobacteriaceae (CRE) were high. We also found that age ≥60 years and mechanical ventilation ≥13 days independently increased the likelihood of secondary infection. Finally, patients with positive cultures had reduced ventilator free days in 28 days and patients with CRE and/or MDR bacteria positivity showed lower 28-day survival rate. CONCLUSIONS: In a retrospective cohort of severe and critical COVID-19 patients admitted to ICUs in China, the prevalence of secondary infection was high, especially with CRE and MDR bacteria, resulting in poor clinical outcomes.


Assuntos
COVID-19 , Coinfecção , Infecção Hospitalar , Adulto , Antibacterianos/uso terapêutico , Coinfecção/tratamento farmacológico , Infecção Hospitalar/tratamento farmacológico , Infecção Hospitalar/epidemiologia , Humanos , Pessoa de Meia-Idade , Pandemias , Estudos Retrospectivos , SARS-CoV-2
11.
Curr Med Sci ; 41(4): 680-686, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34403092

RESUMO

OBJECTIVE: Age-related hearing loss (AHL), characterized by degeneration of cochlea structures, is the most common sensory disorder among the elderly worldwide. The calcium channel is considered to contribute to normal hearing. However, the role of the T-type voltage-activated calcium channel, Cav3.1, remains unclear in AHL. Here, we investigate the age-related change of Cav3.1 expression in the cochlea and D-gal-induced senescent HEI-OC1 cells. METHODS: Cochleae from C57BL/6 mice at 2 months and 12 months of age were assessed. Senescence in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells was induced by D-gal treatment. The immunofluorescence technique was employed to investigate the distribution of Cav3.1 in vivo and in vitro. Quantitative assessment was achieved by Western blotting and real-time PCR. RESULTS: In comparison with 2-month-old animals, 12-month old C57BL/6 mice exhibited great loss of hair cells and elevated auditory brainstem threshold. The Cav3.1 was located in hair cells, spiral ganglion cells, lateral walls, and the expression of Cav3.1 protein and mRNA decreased in the aged cochleae. D-gal-induced senescence assay confirmed the down-regulation of Cav3.1 expression in senescent HEI-OC1 cells. CONCLUSION: Our results show that age-related down-regulated expression of Cav3.1 in the cochleae is associated with AHL and may contribute to the pathogenesis of AHL.

12.
Environ Pollut ; 288: 117966, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34435561

RESUMO

Microcystins (MCs) produced by cyanobacteria are potent toxins to humans that cannot be ignored. However, the toxicity of MCs to humans remains largely unknown. The study explored the role of MCs in the development of hematological parameters through human observations and a chronic mouse model to explore related mechanisms. The adjusted odds ratio of MC-LR to the risk of anemia was 4.954 (95 % CI, 2.423-10.131) in a case-control study in Nanjing. An inverse correlation between serum MC-LR and hemoglobin (HGB), hematocrit (HCT), mean corpuscular volume (MCV), and red blood cell count (RBC) was observed. MC-LR in the serum of the population was an independent risk factor for microcytic anemia. Animal experiments demonstrated that MC-LR resulted in microcytic anemia, which is associated with inflammation, dysregulation of iron homeostasis, and erythropoiesis. We first identified the possible signaling pathway of MC-LR-induced anemia that MC-LR significantly upregulated the levels of hepcidin via EPO/EPOR signaling pathway and the decreased levels of Twsg1 and Gdf15, thereby resulting in the decreased levels of Hbb and Fpn, and the increased expression of Fth1, and Tf in a chronic mouse model. Our study first identified that prolonged environmental exposure to MCs probably contribute to the occurrence of microcytic anemia in humans, which provides new insights into the toxicity of MCs for public health.


Assuntos
Anemia Hipocrômica , Anemia , Cianobactérias , Anemia/induzido quimicamente , Animais , Estudos de Casos e Controles , Homeostase , Humanos , Camundongos , Microcistinas
13.
Dev Cell ; 56(12): 1770-1785.e12, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-33984269

RESUMO

Mitochondrial functions across different tissues are regulated in a coordinated fashion to optimize the fitness of an organism. Mitochondrial unfolded protein response (UPRmt) can be nonautonomously elicited by mitochondrial perturbation in neurons, but neuronal signals that propagate such response and its physiological significance remain incompletely understood. Here, we show that in C. elegans, loss of neuronal fzo-1/mitofusin induces nonautonomous UPRmt through multiple neurotransmitters and neurohormones, including acetylcholine, serotonin, glutamate, tyramine, and insulin-like peptides. Neuronal fzo-1 depletion also triggers nonautonomous mitochondrial fragmentation, which requires autophagy and mitophagy genes. Systemic activation of UPRmt and mitochondrial fragmentation in C. elegans via perturbing neuronal mitochondrial dynamics improves resistance to pathogenic Pseudomonas infection, which is supported by transcriptomic signatures of immunity and stress-response genes. We propose that C. elegans surveils neuronal mitochondrial dynamics to coordinate systemic UPRmt and mitochondrial connectivity for pathogen defense and optimized survival under bacterial infection.

14.
Eur J Nutr ; 2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34041583

RESUMO

PURPOSE: Atherosclerosis and its related clinical complications are the leading cause of death. MicroRNA (miR)-92a in the inflammatory endothelial dysfunction leads to atherosclerosis. Krüppel-like factor 2 (KLF2) is required for vascular integrity and endothelial function maintenance. Flavonoids possess many biological properties. This study investigated the vascular protective effects of chrysin in balloon-injured carotid arteries. MATERIALS AND METHODS: Exosomes were extracted from human coronary artery endothelial cell (HCAEC) culture media. Herb flavonoids and chrysin were the treatments in these atheroprotective models. Western blotting and real-time PCRs were performed. In situ hybridization, immunohistochemistry, and immunofluorescence analyses were employed. RESULTS: MiR-92a increased after balloon injury and was present in HCAEC culture media. Chrysin was treated, and significantly attenuated the miR-92a levels after balloon injury, and similar results were obtained in HCAEC cultures in vitro. Balloon injury-induced miR-92a expression, and attenuated KLF2 expression. Chrysin increased the KLF2 but reduced exosomal miR-92a secretion. The addition of chrysin and antagomir-92a, neointimal formation was reduced by 44.8 and 49.0% compared with balloon injury after 14 days, respectively. CONCLUSION: Chrysin upregulated KLF2 expression in atheroprotection and attenuated endothelial cell-derived miR-92a-containing exosomes. The suppressive effect of miR-92a suggests that chrysin plays an atheroprotective role. Proposed pathway for human coronary artery endothelial cell (HCAEC)-derived exosomes induced by chrysin to suppress microRNA (miR)-92a expression and counteract the inhibitory effect of miR-92a on KLF2 expression in HCAECs. This provides an outline of the critical role of the herbal flavonoid chrysin, which may serve as a valuable therapeutic supplement for atheroprotection.

15.
EBioMedicine ; 68: 103408, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34051440

RESUMO

BACKGROUND: There is a high incidence of leprosy among house-contacts compared with the general population. We aimed to establish a predictive model using these genetic factors along with epidemiological factors to predict leprosy risk of leprosy household contacts (HHCs). METHODS: Weighted genetic risk score (wGRS) encompassing genome wide association studies (GWAS) variants and five non-genetic factors were examined in a case-control design associated with leprosy risk including 589 cases and 647 controls from leprosy HHCs. We constructed a risk prediction nomogram and evaluated its performance by concordance index (C-index) and calibration curve. The results were validated using bootstrap resampling with 1000 resamples and a prospective design including 1100 HHCs of leprosy patients. FINDING: The C-index for the risk model was 0·792 (95% confidence interval [CI] 0·768-0·817), and was confirmed to be 0·780 through bootstrapping validation. The calibration curve for the probability of leprosy showed good agreement between the prediction of the nomogram and actual observation. HHCs were then divided into the low-risk group (nomogram score ≤ 81) and the high-risk group (nomogram score > 81). In prospective analysis, 12 of 1100 participants had leprosy during 63 months' follow-up. We generated the nomogram for leprosy in the validation cohort (C-index 0·773 [95%CI 0·658-0·888], sensitivity75·0%, specificity 66·8%). Interpretation The nomogram achieved an effective prediction of leprosy in HHCs. Using the model, the risk of an individual contact developing leprosy can be determined, which can lead to a rational preventive choice for tracing higher-risk leprosy contacts. FUNDING: The ministry of health of China, ministry of science and technology of China, Chinese academy of medical sciences, Jiangsu provincial department of science and technology, Nanjing municipal science and technology bureau.

16.
Carbohydr Polym ; 263: 117967, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33858570

RESUMO

Immunological adjuvants are an important part of tumor vaccines and are critical for stimulating anti-tumor immune responses. However, the clinical needs of strong adjuvants have not been met. In this work, we found that the purified acidic polysaccharide from Sarcandra glabra, named p-SGP, is an ideal adjuvant for tumor vaccines. Cancer vaccines could induce stronger humoral and cellular immune responses when they are adjuvanted with p-SGP. Compared with CpG, a well-studied adjuvant, p-SGP significantly augmented the anti-tumor immunity of various cancer vaccines, which is leading to noticeable inhibition of tumor growth and metastasis in tumor-bearing mice. Moreover, p-SGP promoted dendritic cells (DCs) maturation and Th1-polarized immune response. Toll-like receptor 4 (TLR4) inhibitor TAK-242 could significantly inhibit the expression of mature molecules on the surface of DCs stimulated by p-SGP, suggesting that p-SGP could play the role of activating DCs through the TLR4 receptor. Results of RNA-seq showed that the Delta-like ligand 4 (DLL4) gene in the pathway Th1 and Th2 cell differentiation was significantly up-regulated in the DCs treated with p-SGP, suggesting that p-SGP has a unique mechanism of enhancing anti-tumor immunity.


Assuntos
Adjuvantes Imunológicos/farmacologia , Vacinas Anticâncer/farmacologia , Magnoliopsida/química , Neoplasias/tratamento farmacológico , Polissacarídeos/imunologia , Ácidos/química , Proteínas Adaptadoras de Transdução de Sinal/genética , Adjuvantes Imunológicos/administração & dosagem , Animais , Proteínas de Ligação ao Cálcio/genética , Vacinas Anticâncer/administração & dosagem , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Imunidade Celular/efeitos dos fármacos , Imunidade Humoral/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias/patologia , Polissacarídeos/administração & dosagem , Polissacarídeos/química , Células Th1/imunologia , Receptor 4 Toll-Like/metabolismo , Regulação para Cima
17.
Nutrients ; 13(4)2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805289

RESUMO

Probiotics are reported to improve gastrointestinal (GI) function via regulating gut microbiota (GM). However, exactly how probiotics influence GM and GI function in elders is poorly characterized. Therefore, in this study, we assessed the effect of the probiotic Lacticaseibacillus paracasei PS23 (LPPS23) on the GM and GI function of aged mice. There were four groups of senescence-accelerated mouse prone-8 (SAMP8) mice (n = 4): a non-treated control group, a saline control group, a low dose LPPS23 group (1 × 108 colony-forming unit (CFU)/mouse/day), and a high dose LPPS23 group (1 × 109 CFU/mouse/day). Non-treated mice were euthanized at 16 weeks old, and others were euthanized at 28 weeks old. The next-generation sequencing results revealed that LPPS23 enriched Lactobacillus and Candidatus_Saccharimonas, while the abundance of Lachnospiraceae_UCG_001 decreased in aged mice given LPPS23. The abundance of Lactobacillus negatively correlated with the abundance of Erysipelotrichaceae. Moreover, LPPS23 improved the GI function of aged mice due to the longer intestine length, lower intestinal permeability, and higher phagocytosis in LPPS23-treated mice. The ELISA results showed that LPPS23 attenuated the alterations of pro-inflammatory factors and immunoglobulins. The abundance of LPPS23-enriched Lactobacillus was positively correlated with healthy GI function, while Lachnospiraceae_UCG_001, which was repressed by LPPS23, was negatively correlated with a healthy GI function in the aged mice according to Spearman's correlation analysis. Taken together, LPPS23 can effectively modulate GM composition and improve GI function in aged SAMP8 mice.


Assuntos
Envelhecimento , Microbioma Gastrointestinal , Lactobacillus , Probióticos , Animais , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Imunoglobulinas/sangue , Camundongos , RNA Bacteriano/genética , RNA Ribossômico 16S/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
18.
FEBS J ; 288(18): 5406-5429, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33705609

RESUMO

Transcription factor SOX9 was a biomarker for prostate cancer (Pca) with poor prognosis. Nevertheless, the regulatory mechanism underlying SOX9 upregulation still remains unclear. Several cytokines have been reported to be involved in the regulation of SOX9, suggesting that cancer-associated fibroblasts (CAFs), one of the main sources of secreted factors in the tumor microenvironment (TME), may play a role in regulating SOX9 expression. Herein, an in vitro model of paracrine interaction between primary CAFs and Pca cells was applied to investigate the molecular mechanism of SOX9 upregulation during Pca progression. The regulatory axis was validated by in vivo experiments and The Cancer Genome Atlas data. Conditional medium of CAFs (CAF-CM) upregulated the expression of SOX9, which was mutually proved to be essential for CAF-induced tumor progression. Further analysis showed that hepatocyte growth factor (HGF) secreted by CAFs was responsible for SOX9 elevation in Pca cells, via the activation of c-Met signaling. Mechanistically, HGF/c-Met signaling specifically activated MEK1/2-ERK1/2 pathway, which induced phosphorylation and upregulation of FRA1, which then transcriptionally upregulated SOX9 by binding to the promoter of SOX9 gene. Moreover, we identified that HGF/c-Met-ERK1/2-FRA1-SOX9 axis was relatively conserved between human and mouse species by validating in mouse Pca cells. Our results reveal a novel insight into the molecular mechanism that SOX9 in Pca cells is promoted by CAFs through HGF/c-Met-ERK1/2-FRA1 axis. Furthermore, SOX9 may serve as an alternative marker for the activated HGF/c-Met signaling to enroll the optimal Pca patients for HGF/c-Met inhibition treatment, since it is much more stable and easier to detect.


Assuntos
Fator de Crescimento de Hepatócito/genética , Neoplasias da Próstata/genética , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-met/genética , Fatores de Transcrição SOX9/genética , Idoso , Animais , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Progressão da Doença , Feminino , Xenoenxertos , Humanos , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Comunicação Parácrina/genética , Ativação Transcricional/genética , Microambiente Tumoral/genética
19.
Addiction ; 116(11): 3127-3138, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-33788344

RESUMO

BACKGROUND AND AIMS: Although methamphetamine use is a serious public health problem, large-scale cohort studies assessing methamphetamine-related mortality are scant. This study investigated all-cause mortality and suicide methods in people with methamphetamine use disorder. DESIGN: A cohort record-linkage study using data from Taiwan's National Health Research Institute Database (NHIRD) linked to Taiwan's National Death Certification System. SETTING: Taiwan. PARTICIPANTS: A total of 23 248 individuals with methamphetamine use disorder between 1 January 2001 and 31 December 2005. MEASUREMENTS: The outcome variables included mortality rates and standardized mortality ratios (SMRs) for all causes of death and for each suicide method. FINDINGS: Compared with the general population, the current cohort had an increased all-cause mortality (SMR = 5.4), with the SMR for unnatural causes (14.8) higher than that for natural causes (7.5). Among all causes of death, suicide had the highest SMR (16.3), followed by neurological diseases (9.7). Among the methods of choice for suicide, drug overdose had the highest SMR (24.9). The incidence of charcoal burning and hanging was significantly higher in men and that of jumping from a high place was significantly higher in women. CONCLUSION: People in Taiwan with methamphetamine use disorder appear to have a significantly increased all-cause mortality rate compared with the general population, with suicide having the highest contribution, particularly suicide via drug overdose. The methods of choice for suicide revealed distinct patterns between men and women.


Assuntos
Metanfetamina , Suicídio , Estudos de Coortes , Humanos , Taiwan/epidemiologia
20.
BMC Cardiovasc Disord ; 21(1): 77, 2021 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-33557763

RESUMO

BACKGROUND: Patients who receive percutaneous coronary intervention (PCI) have different chances of developing in-stent restenosis (ISR). To date, no predictable biomarker can be applied in the clinic. MicroRNAs (miRNAs or miRs) play critical roles in transcription regulation, and their circulating levels were reported to have potential as clinical biomarkers. METHODS: In total, 93 coronary stent-implanted patients without pregnancy, liver or renal dysfunction, malignancy, hemophilia, or autoimmune diseases were recruited in this clinical study. All recruited participants were divided into an ISR group (n = 45) and a non-ISR group (n = 48) based on their restenotic status as confirmed by cardiologists at the first follow-up visit (6 months after surgery). Blood samples of all participants were harvested to measure circulating levels of miRNA candidates (miR-132, miR-142-5p, miR-15b, miR-24-2, and miR-424) to evaluate whether these circulating miRNAs can be applied as predictive biomarkers of ISR. RESULTS: Our data indicated that circulating levels of miR-142-5p were significantly higher in the ISR population, and results from the receiver operating characteristic (ROC) curve analysis also demonstrated superior discriminatory ability of miR-142-5p in predicting patients' restenotic status. In addition, circulating levels of miR-15b, miR-24-2, and miR-424 had differential expressions in participants with diabetes, hyperlipidemia, and hypertension, respectively. CONCLUSIONS: The current study revealed that the circulating level of miR-142-5p has potential application as a clinical biomarker for predicting the development of ISR in stent-implanted patients.


Assuntos
MicroRNA Circulante/sangue , Doença da Artéria Coronariana/terapia , Reestenose Coronária/sangue , MicroRNAs/sangue , Intervenção Coronária Percutânea/instrumentação , Stents , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , MicroRNA Circulante/genética , Reestenose Coronária/diagnóstico , Reestenose Coronária/etiologia , Feminino , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Valor Preditivo dos Testes , Fatores de Risco , Taiwan , Resultado do Tratamento , Regulação para Cima
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