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Atherosclerosis (AS) is a chronic inflammatory disease that involves cell death and endothelial dysfunction. Melatonin is an endocrine hormone with anti-inflammatory and anti-AS effects. However, the underlying molecular mechanisms for the anti-AS effects of melatonin are unknown. A previous study has shown that pyroptosis plays a detrimental role in the development of AS, therefore, this study was designed to investigate the anti-pyroptotic effects and potential mechanisms of melatonin in atherosclerotic endothelium. Our results show that melatonin attenuated the expression of genes related to pyroptosis, including NLRP3, caspase-1, and IL-1ß, in human umbilical vein endothelial cells treated with oxidized low-density lipoprotein. Furthermore, melatonin up-regulated the expression of ten-eleven translocation 2 (TET2), inhibited the methylation of ubiquinol-cytochrome c reductase core protein 1 (UQCRC1), and reduced pyroptosis. The up-regulation of UQCRC1 by melatonin improved mitochondrial function, thereby inhibiting oxidative stress and endothelial cell pyroptosis. Collectively, our results indicate that melatonin prevents endothelial cell pyroptosis by up-regulating TET2 to inhibit the methylation of UQCRC1 and improving mitochondrial function.
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Antioxidantes/farmacologia , Desmetilação , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Endotélio Vascular/efeitos dos fármacos , Melatonina/farmacologia , Mitocôndrias/metabolismo , Piroptose , Complexo III da Cadeia de Transporte de Elétrons/genética , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Humanos , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Transdução de SinaisRESUMO
Fibroblast growth factor 21(FGF21) is an endocrine cytokine that targets inflammation and atherosclerosis (AS). However, the underlying molecular mechanisms of the FGF21 anti-AS effect remain to be explored. Pyroptosis induced by hyperlipidemia or oxidized low-density lipoprotein (oxLDL) in vascular endothelial cells (VECs) is a significant step in the advancement of AS. This work aimed to evaluate the mechanisms and functioning of FGF21 against AS using an atherosclerotic animal model and oxLDL mimic in vitro. We found that exogenous treatments with FGF21 significantly reduced the aortic sinus plaque area and ameliorated dyslipidemia in apoE-/- mice. FGF21 attenuated the expression of pyroptosis-related proteins both in vivo and in vitro. Possibly, FGF21 improves mitochondrial function, inhibits mitochondrial division, and reduces ROS production by maintaining mitochondrial dynamics and function to reduce NLRP3 related pyroptosis and inhibits VECs endoplasmic reticulum stress, thereby exerting an anti-atherosclerotic effect.
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Células Endoteliais/efeitos dos fármacos , Fatores de Crescimento de Fibroblastos/farmacologia , Inflamassomos/efeitos dos fármacos , Piroptose/efeitos dos fármacos , Animais , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células Endoteliais/metabolismo , Humanos , Inflamassomos/metabolismo , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: Clinically relevant postoperative pancreatic fistula (CR-POPF) is the most common and severe complication after pancreaticoduodenectomy (PD). Despite the development of numerous anastomotic surgical techniques to minimize CR-POPF, more than 30% of patients who undergo PD develop CR-POPF. Herein, we propose a novel pancreaticojejunostomy (PJ) technique and evaluate its efficacy and safety compared to traditional PJ. METHODS: This retrospective study enrolled 164 consecutive patients who underwent PJ after PD between January 2012 and June 2017. Of them, 78 (47.6%) underwent traditional PJ and 86 (52.4%) underwent six-stitch PJ. The primary outcome was CR-POPF at 1-month follow-up defined according to the revised 2016 International Study Group on Pancreatic Fistula definition. To adjust for baseline differences and selection bias, patients were matched by propensity scores, which left 63 patients with traditional PJ and 63 with six-stitch PJ. RESULTS: Compared to patients who underwent traditional PJ (mean age 56.2 ± 9.4 years), patients who underwent six-stitch PJ (mean age 57.4 ± 11.4 years) had a lower CR-POPF rate. The risk of CR-POPF among patients who underwent six-stitch PJ was decreased by 81.7% after adjustment for age, sex, body mass index, and disease severity compared to patients who underwent traditional PJ. Additionally, the surgery time was reduced from 29 min for traditional PJ to 15 min for six-stitch PJ (P <0.001). Adverse effects such as abdominal fluid collection, abdominal bleeding, and wound infection were similar between two groups. CONCLUSION: Six-stitch PJ may be an effective and efficient PJ technique for patients who undergo PD surgery.
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Fístula Pancreática/etiologia , Pancreaticojejunostomia/efeitos adversos , Pancreaticojejunostomia/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Pancreaticoduodenectomia/efeitos adversos , Pontuação de Propensão , Estudos Retrospectivos , Adulto JovemRESUMO
High concentrations of plasma lipoprotein(a) [Lp(a)] have been inferred to be an independent risk factor for cardiovascular and cerebrovascular diseases, such as coronary artery diseases, restenosis, and stroke. Apolipoprotein(a) [apo(a)] is one of the most important components of Lp(a) and contributes greatly to the increased concentration of plasma Lp(a). As a critical positive transacting factor of apo(a) gene, Ets1 has been proven as a target gene of several miRNAs, such as miR-193b, miR-125b-5p, miR-200b, miR-1, and miR-499. In this study, a series of experiments on miRNAs and relative miRNAs inhibitor delivered HepG2 cells were conducted, and two miRNAs that downregulate the apo(a) by targeting the 3'-UTR of Ets1 were identified. Results showed that apo(a) and Ets1 were differentially expressed in SMMC7721 and HepG2 cell lines. Meanwhile, apo(a) and Ets1 were inversely correlated with several hepatic endogenous miRNAs, such as miR-125b-5p, miR-23b-3p, miR-26a-5p, and miR-423-5p, which were predicted to bind to Ets1. Results show that miR-125b-5p and miR-23b-3p mimics could inhibit the synthesis of apo(a) by directly targeting Ets1 in HepG2, thereby reducing the plasma Lp (a) concentration.
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Apolipoproteínas A/biossíntese , MicroRNAs/metabolismo , Proteína Proto-Oncogênica c-ets-1/metabolismo , Regiões 3' não Traduzidas , Apolipoproteínas A/genética , Apolipoproteínas A/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Regulação para Baixo , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , MicroRNAs/genética , Proteína Proto-Oncogênica c-ets-1/genéticaRESUMO
OBJECTIVES: To investigate the predictors of platelet increment and risk factors for major complications after partial splenic embolization (PSE) in cirrhosis. METHODS: Between March 2010 and June 2012, 52 cirrhotic patients with severe thrombocytopenia underwent PSE. Multiple variables were analyzed to identify the correlated factors affecting platelet increment and major complications after PSE. RESULTS: Linear mixed model analysis indicated the splenic infarction ratio (P < 0.001), non-infarcted splenic volume (P = 0.012), and cholinesterase level (P < 0.001) were significantly associated with the platelet increment after PSE. In receiver operating characteristic (ROC) analysis, the cut-off values of the splenic infarction ratio, and non-infarcted splenic volume for achieving an increment of ≥60.0 × 10(9)/L in platelet counts at 1 year after PSE were 64.3% and 245.8 mL, respectively. After PSE, eight patients developed major complications. Multivariate logistic regression analysis indicated major complications were significantly associated with the infarcted splenic volume (P = 0.024) and Child-Pugh score (P = 0.018). In ROC analysis, the cut-off values of these two factors for discriminating the uncomplicated and complicated were 513.1 mL and 9.5, respectively. CONCLUSIONS: The platelet increment after PSE depends on the splenic infarction ratio, non-infarcted splenic volume and cholinesterase level. But a large infarcted splenic volume and a high Child-Pugh score may cause complications. KEY POINTS: ⢠The platelet increment after PSE greatly depends on the splenic infarction ratio. ⢠The non-infarcted splenic volume significantly affects the efficacy of PSE. ⢠A high cholinesterase level contributes to the improvement of thrombocytopenia after PSE. ⢠The non-infarcted splenic volume significantly affects the relapse of hypersplenism. ⢠Complications are significantly associated with the infarcted splenic volume and Child-Pugh score.
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Embolização Terapêutica/métodos , Hiperesplenismo/terapia , Cirrose Hepática/complicações , Trombocitopenia/terapia , Adulto , Idoso , Plaquetas , Embolização Terapêutica/efeitos adversos , Feminino , Humanos , Contagem de Leucócitos , Cirrose Hepática/sangue , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Curva ROC , Recidiva , Fatores de Risco , Infarto do Baço/patologia , Trombocitopenia/sangue , Trombocitopenia/etiologia , Adulto JovemRESUMO
Sepsis, a life-threatening syndrome of organ damage resulting from dysregulated inflammatory response, is distinguished by overexpression of inflammatory cytokines, excessive generation of reactive oxygen/nitrogen species (RONS), heightened activation of pyroptosis, and suppression of autophagy. However, current clinical symptomatic supportive treatment has failed to reduce the high mortality. Herein, we developed self-assembled multifunctional carbon monoxide nanogenerators (Nano CO), as sepsis drug candidates, which can release CO in response to ROS, resulting in clearing bacteria and activating the heme oxygenase-1/CO system. This activation strengthened endogenous protection and scavenged multiple inflammatory mediators to alleviate the cytokine storm, including scavenging RONS and cfDNA, inhibiting macrophage activation, blocking pyroptosis and activating autophagy. Animal experiments show that Nano CO has a good therapeutic effect on mice with LPS-induced sepsis, which is manifested in hypothermia recovery, organ damage repair, and a 50% decrease in mortality rates. Taken together, these results illustrated the efficacy of multifunctional Nano CO to target clearance of multiple mediators in sepsis treatment and act against other refractory inflammation-related diseases.
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Vascular calcification in diabetes patients is a major independent risk factor for developing diabetic cardiovascular complications. However, the mechanisms by which diabetes leads to vascular calcification are complex and not yet fully understood. Our previous study revealed that miR-32-5p is a potential new diagnostic marker for coronary artery calcification. In this study, we found that miR-32-5p levels were significantly greater in the plasma of type 2 diabetes patients with coronary artery calcification and were positively correlated with the coronary artery calcification score. In type 2 diabetic mice, miR-32-5p levels were also elevated in the aorta, and knockout of miR-32-5p inhibited the osteogenic differentiation of vascular smooth muscle cells in vivo. Furthermore, overexpression of miR-32-5p promoted vascular smooth muscle cell calcification, while antagonism of miR-32-5p inhibited vascular smooth muscle cell calcification under high-glucose conditions. GATA binding protein 6 (GATA6) was identified as the key target gene through which miR-32-5p promotes vascular smooth muscle cell calcification. Overexpression of GATA6 antagonized the effects of miR-32-5p on vascular calcification. Additionally, high glucose levels were shown to induce the upregulation of miR-32-5p by activating CCAAT/enhancer binding protein beta (CEBPB). These results suggest that miR-32-5p is an important procalcification factor in vascular calcification associated with type 2 diabetes and identify the CEBPB/miR-32-5p/GATA6 axis as a potential biomarker and therapeutic target for preventing and treating vascular calcification in type 2 diabetes.
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Proteína beta Intensificadora de Ligação a CCAAT , Diabetes Mellitus Tipo 2 , Fator de Transcrição GATA6 , MicroRNAs , Calcificação Vascular , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Calcificação Vascular/metabolismo , Calcificação Vascular/patologia , Calcificação Vascular/genética , Animais , Humanos , Camundongos , Masculino , Fator de Transcrição GATA6/metabolismo , Fator de Transcrição GATA6/genética , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Proteína beta Intensificadora de Ligação a CCAAT/genética , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Feminino , Camundongos KnockoutRESUMO
Objective: To analyze the antibiotic resistance profile, virulence genes, and molecular typing of Staphylococcus aureus (S. aureus) strains isolated in skin and soft tissue infections at the First Affiliated Hospital, Gannan Medical University, to better understand the molecular epidemiological characteristics of S. aureus. Methods: In 2023, 65 S. aureus strains were isolated from patients with skin and soft tissue infections. Strain identification and susceptibility tests were performed using VITEK 2 and gram-positive bacteria identification cards. DNA was extracted using a DNA extraction kit, and all genes were amplified using polymerase chain reaction. Multilocus sequence typing (MLST) was used for molecular typing. Results: In this study, of the 65 S. aureus strains were tested for their susceptibility to 16 antibiotics, the highest resistance rate to penicillin G was 95.4%. None of the staphylococcal isolates showed resistance to ceftaroline, daptomycin, linezolid, tigecycline, teicoplanin, or vancomycin. fnbA was the most prevalent virulence gene (100%) in S. aureus strains isolated in skin and soft tissue infections, followed by arcA (98.5%). Statistical analyses showed that the resistance rates of methicillin-resistant S. aureus isolates to various antibiotics were significantly higher than those of methicillin-susceptible S. aureus isolates. Fifty sequence types (STs), including 44 new ones, were identified by MLST. Conclusion: In this study, the high resistance rate to penicillin G and the high carrying rate of virulence gene fnbA and arcA of S.aureus were determine, and 44 new STs were identified, which may be associated with the geographical location of southern Jiangxi and local trends in antibiotic use. The study of the clonal lineage and evolutionary relationships of S. aureus in these regions may help in understanding the molecular epidemiology and provide the experimental basis for pathogenic bacteria prevention and treatment.
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BACKGROUND: In the last decade, studies in hepatocellular carcinoma (HCC) demonstrate dysregulation of miRNAs expression. For instance, miR-650 has been implicated in gastric and colorectal cancer tumorigenicity; however, the role of miR-650 remains unknown in HCC. METHODS: In this study, we performed a comprehensive analysis to examine the miR-650 expression level in 248 HCC and 120 paracarcinomatous liver (PCL) tissues. The correlations between miR-650 expression level and the clinicopathological characteristics (HCC tumorigenicity) were evaluated. The role of miR-650 played in HCC was investigated by Q-PCR, western blot, and MTT. RESULTS: We found that miR-650 expression was significantly increased in HCC patients and significantly associated with the patients' age (P = 0.0019), differentiation capability (P = 0.0108), and also tumor stage (P = 0.0069). Moreover, we compared the expression level of both ING4 and miR-650 in 122 HCC patients by western blot and real-time PCR. Statistical result showed a significant negative correlation between them (r(s) = -0.2011, P = 0.0264). Transfection and MTT test suggested that miR-650 decreased the expression of ING4 and stimulate liver cells proliferation significantly. CONCLUSION: These data suggested that miR-650 is correlated with the pathogenesis of HCC and is involved in the HCC tumorigenesis process by inhibiting the expression of ING4.
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Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Homeodomínio/metabolismo , Neoplasias Hepáticas/genética , Fígado/metabolismo , MicroRNAs/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Western Blotting , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Células Cultivadas , Regulação para Baixo , Feminino , Marcadores Genéticos , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Reação em Cadeia da Polimerase em Tempo Real , Regulação para CimaRESUMO
Vascular calcification (VC) is highly correlated with cardiovascular disease morbidity and mortality, but anti-VC treatment remains an area to be tackled due to the ill-defined molecular mechanisms. Regardless of the type of VC, it does not depend on a single cell but involves multi-cells/organs to form a complex cellular communication network through the vascular microenvironment to participate in the occurrence and development of VC. Therefore, focusing only on the direct effect of pathological factors on vascular smooth muscle cells (VSMCs) tends to overlook the combined effect of other cells and VSMCs, including VSMCs-VSMCs, ECs-VMSCs, Macrophages-VSMCs, etc. Extracellular vesicles (EVs) are a collective term for tiny vesicles with a membrane structure that are actively secreted by cells, and almost all cells secrete EVs. EVs docked on the surface of receptor cells can directly mediate signal transduction or transfer their contents into the cell to elicit a functional response from the receptor cells. They have been proven to participate in the VC process and have also shown attractive therapeutic prospects. Based on the advantages of EVs and the ability to be detected in body fluids, they may become a novel therapeutic agent, drug delivery vehicle, diagnostic and prognostic biomarker, and potential therapeutic target in the future. This review focuses on the new insight into VC molecular mechanisms from the perspective of crosstalk, summarizes how multi-cells/organs interactions communicate via EVs to regulate VC and the emerging potential of EVs as therapeutic methods in VC. We also summarize preclinical experiments on crosstalk-based and the current state of clinical studies on VC-related measures.
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BACKGROUND: Gasdermin (GSDM) B is a member of the GSDM family, which is a protein that may be involved in the cell pyroptosis process and is associated with inflammatory diseases. OBJECTIVE: To explore the correlation between GSDMB and psoriasis vulgaris. METHODS: Skin lesions from 33 patients with psoriasis vulgaris and 69 normal controls were collected. ELISA and Western blot were adopted to detect proteins. The HaCaT cell line was transfected with 3 sets of interfering sequence siRNA, and the mRNA and protein levels before and after the transfection were measured by qPCR and Western blot respectively, so as to establish a cell model with low GSDMB gene expression; the MTT method was used to detect cells viability, flow cytometry to detect cell apoptosis. RESULTS: The level of GSDMB protein in the skin lesions of patients with psoriasis vulgaris was lower than that in normal skin tissues (P < 0.05). The mRNA and protein expression levels of the target gene in the siRNA-GSDMB-3 group were lower than those in the control group (P < 0.05). The proliferation of HaCaT cells was decreased by MTT method and flow cytometry, and the apoptosis rate was increased (P < 0.05). CONCLUSION: The expression level of GSDMB in psoriasis vulgaris lesion tissue is lower than that of normal skin tissue. The down-regulation of GSDMB expression can inhibit cell proliferation and promote cell apoptosis. GSDMB may play a role in the pathogenesis of psoriasis by affecting the differentiation of keratinocytes and the function of T cells.
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Psoríase , Humanos , Psoríase/patologia , Pele/metabolismo , Queratinócitos/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Proliferação de Células , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Citotóxicas Formadoras de Poros/metabolismoRESUMO
Akkermansia muciniphila (A. muciniphila) is an anaerobic bacterium that widely colonizes the mucus layer of the human and animal gut. The role of this symbiotic bacterium in host metabolism, inflammation, and cancer immunotherapy has been extensively investigated over the past 20 years. Recently, a growing number of studies have revealed a link between A. muciniphila, and aging and aging-related diseases (ARDs). Research in this area is gradually shifting from correlation analysis to exploration of causal relationships. Here, we systematically reviewed the association of A. muciniphila with aging and ARDs (including vascular degeneration, neurodegenerative diseases, osteoporosis, chronic kidney disease, and type 2 diabetes). Furthermore, we summarize the potential mechanisms of action of A. muciniphila and offer perspectives for future studies.
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Accumulating evidence suggests that the therapeutic role of mesenchymal stem cells (MSCs) in bone diseases is closely related to paracrine-generated extracellular vesicles (EVs). MSC-derived EVs (MSC-EVs) carry proteins, nucleic acids, and lipids to the extracellular space and affect the bone microenvironment. They have similar biological functions to MSCs, such as the ability to repair organ and tissue damage. In addition, MSC-EVs also have the advantages of long half-life, low immunogenicity, attractive stability, ability to pass through the blood-brain barrier, and demonstrate excellent performance with potential practical applications in bone diseases. In this review, we summarise the current applications and mechanisms of MSC-EVs in osteoporosis, osteoarthritis, bone tumours, osteonecrosis of the femoral head, and fractures, as well as the development of MSC-EVs combined with materials science in the field of orthopaedics. Additionally, we explore the critical challenges involved in the clinical application of MSC-EVs in orthopaedic diseases.
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Cognitive impairment is a severe diabetes-related complication and seriously challenges the demand for future health resources. However, the potential therapeutic targets and mechanisms are not fully understood. Herein, we investigated the expression of the m6A enzyme in the hippocampus of mice with diabetes-induced cognitive impairment and possible improvement with overexpression of YTHDF1. A type 1 diabetes (T1D) mouse model was established by streptozotocin (STZ) intraperitoneal injection. Diabetic mice showed significant cognitive dysfunction, which was detected by novel object recognition tests and novel place recognition tests. Western blot analysis showed that compared with the control group, the protein levels of YTHDC2 and ALKBH5 were significantly upregulated in the hippocampus in the STZ group, while the expression of YTHDF1, YTHDF3 and WTAP was significantly downregulated. Furthermore, overexpression of YTHDF1 by AAV-YTHDF1 injection in the hippocampus significantly improved STZ-induced diabetic cognitive dysfunction. These results indicate that the m6A enzyme may play a key role in the cognitive dysfunction induced by diabetes, and YTHDF1 may be a promising therapeutic target.
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Adenosina/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Diabetes Mellitus Tipo 1/complicações , Hipocampo/metabolismo , Animais , Complicações do Diabetes/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Regulação para Baixo , Masculino , Camundongos , Estreptozocina , Regulação para CimaRESUMO
Purpose: Our previous study observed that long non-coding RNA PKD2-2-3 (lnc-PKD2-2-3) is related to advanced tumor features and worse prognosis in cholangiocarcinoma (CCA). Then, this study aimed to further explore the linkage between lnc-PKD2-2-3, miR-328, and GPAM, as well as their effects on regulating CCA viability, mobility, and chemosensitivity. Methods: Lnc-PKD2-2-3, miR-328, and GPAM expression in 30 pairs of CCA tumor and adjacent tissues, as well as in CCA cell lines, were determined. Two CCA cell lines (HuCCT1 and TFK1) were transfected by lnc-PKD2-2-3 overexpression plasmid, lnc-PKD2-2-3 siRNA, miR-328 inhibitor, and GPAM siRNA alone or in combination, followed by cell proliferation, apoptosis, invasion, and 5-FU chemosensitivity detection. Besides, xenograft mice were established for validation. Results: Lnc-PKD2-2-3 and GPAM were higher, whereas miR-328 was lower in CCA tissues versus adjacent tissues and also in CCA cell lines versus control cells; meanwhile, they were correlated with each other (all P <0.05). Lnc-PKD2-2-3 knockdown decreased CCA cell proliferation, invasion, and increased apoptosis (all P <0.05), but lnc-PKD2-2-3 overexpression exhibited the opposite and weaker effect. MiR-328 knockdown induced CCA cell proliferation and invasion and also attenuated the effect of lnc-PKD2-2-3-knockdown in these functions (all P <0.05). Subsequently, GPAM knockdown reduced CCA cell proliferation and invasion and also weakened the effect of miR-328-knockdown in these functions (all P <0.05). Additionally, lnc-PKD2-2-3 positively regulated GPAM while negatively regulating miR-328. MiR-328 negatively modified GPAM in CCA cells. Luciferase gene reporter assays verified that lnc-PKD2-2-3 directly bound miR-328 and miR-328 directly bound GPAM. Finally, the lnc-PKD2-2-3/miR-328/GPAM network also regulated the 5-FU chemosensitivity of CCA cells. In vivo experiments further revealed that lnc-PKD2-2-3 overexpression promoted tumor volume and weight but repressed tumor apoptosis in xenograft mice; meanwhile, it increased GPAM expression but decreased miR-328 expression (all P <0.05). Conversely, lnc-PKD2-2-3 knockdown exhibited the opposite effects (all P <0.05). Conclusion: Lnc-PKD2-2-3/miR-328/GPAM ceRNA network promotes CCA proliferation, invasion, and 5-FU chemoresistance.
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BACKGROUND: Many ant species can harm humans; however, only a few cause life-threatening allergic reactions. Normally, reactions caused by ants occur in patients who come into contact with ant venom. Venom contains various biologically active peptides and protein components, of which acids and alkaloids tend to cause anaphylaxis. Ant venom can cause both immediate and delayed reactions. The main histopathological changes observed in ant hypersensitivity are eosinophil recruitment and Th2 cytokine production. CASE SUMMARY: A 70-year-old man was bitten by a large number of ants when he was in a drunken stupor and was hospitalized at a local hospital. Five days later, because of severe symptoms, the patient was transferred to our hospital for treatment. Numerous pustules were observed interspersed throughout the body, with itching and pain reported. He had experienced fever, vomiting, hematochezia, mania, soliloquy, sleep disturbances, and elevated levels of myocardial enzymes since the onset of illness. The patient had a history of hypertension for more than 1 year, and his blood pressure was within the normal range after hypotensive drug treatment. He had no other relevant medical history. Based on the clinical history of an ant bite and its clinical manifestations, the patient was diagnosed with an ant venom allergy. The patient was treated with 60 mg methylprednisolone for 2 d, 40 mg methylprednisolone for 3 d, and 20 mg methylprednisolone for 2 d. Oral antihistamines and diazepam were administered for 12 d and 8 d, respectively. Cold compresses were used to treat the swelling during the process. After 12 d of treatment, most pustules became crusts, whereas some had faded away. No symptoms of pain, itching, or psychological disturbances were reported during the follow-up visits within 6 mo. CONCLUSION: This case report emphasizes the dangers of ant stings.
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Triple-negative breast cancer (TNBC), an aggressive histological subtype of breast cancer, exhibits a high risk of early recurrence rate and a poor prognosis, and it is primarily associated with the abundance of cancer stem cells (CSCs). At present, the strategies for effectively eradicating or inhibiting TNBC CSCs are still limited, which makes the development of novel drugs with anti-CSCs function be of great value for the treatment of TNBC, especially the refractory TNBC. In this study, we found that the small-molecule tyrosine kinase inhibitor DCC-2036 suppressed TNBC stem cells by inhibiting the tyrosine kinase AXL and the transcription factor KLF5. DCC-2036 downregulated the expression of KLF5 by decreasing the protein stability of KLF5 via the AXL-Akt-GSK3ß signal axis, and in turn, the downregulation of KLF5 further reduced the expression of AXL via binding to its promotor (-171 to -162 bp). In addition, p-AXL/AXL levels were positively correlated with KLF5 expression in human TNBC specimens. These findings indicated that DCC-2036 is able to suppress the CSCs in TNBC by targeting the AXL-KLF5 positive feedback loop. Moreover, our findings indicated that DCC-2036 increased the sensitivity of TNBC chemotherapy. Therefore, this study proposes a potential drug candidate and several targets for the treatment of refractory TNBC.
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Neoplasias de Mama Triplo Negativas , Linhagem Celular Tumoral , Proliferação de Células , Receptor DCC , Retroalimentação , Humanos , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Células-Tronco Neoplásicas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismoRESUMO
Colorectal cancer (CRC) is one of the most common digestive tract tumors worldwide. Catalpol exerts inhibitory effects on the progression of several cancer types by regulating microRNAs (miRs). However, the precise role and carcinostatic mechanism of catalpol on CRC cells are poorly understood which limits the application of catalpol treatment. In the present study, miR34a and sirtuin 1 (SIRT1) expression levels were detected in CRC tissues and CRC cell lines by RTqPCR. Computational software analysis, luciferase assays and western blotting were used to demonstrate the downstream target of miR34a in CRC cells. Effects of catalpol on cell viability, apoptosis, autophagic flux and the miR34a/SIRT1 axis in the CRC cells were assessed by CCK8 assay, flow cytometry, electron microscopy and western blotting, respectively. Whether the miR34a/SIRT1 axis participated in catalpolmediated autophagy and apoptosis was investigated. The effects of catalpol on the miR34a/SIRT1 axis and malignant behavior were evaluated in a rat model of azoxymethane (AOM)induced CRC. It was revealed that miR34a expression levels were significantly decreased while SIRT1 was overexpressed in most of the CRC tissues and all the CRC cell lines. Clinically, a low level of miR34a was correlated with poor clinicopathological characteristics in CRC patients. Catalpol reduced cell viability, suppressed autophagy, promoted apoptosis, and regulated the expression of SIRT1 by inducing miR34a in vitro and in vivo. The autophagyinhibiting effect of catalpol may be a mechanism to promote apoptosis of CRC cells. miR34a mimic transfection resulted in autophagysuppressive activity similar to that of catalpol, while the miR34a inhibitor attenuated the antiautophagic effects of catalpol. In conclusion, miR34a is involved in regulating catalpolmediated autophagy and malignant behavior by directly inhibiting SIRT1 in CRC.
Assuntos
Autofagia , Neoplasias do Colo/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Glucosídeos Iridoides/farmacologia , MicroRNAs/genética , Rehmannia/química , Sirtuína 1/metabolismo , Idoso , Animais , Apoptose , Azoximetano/química , Carcinógenos/química , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Ratos , Ratos Wistar , Regulação para CimaRESUMO
The present study aimed to explore the long noncoding RNA (lncRNA) expression profiles and correlation of lncPKD223 with tumor features and prognosis, and to investigate its effect on regulating cancercell stemness and its potential as a cancer stem cell (CSC) marker in cholangiocarcinoma (CCA). lncRNA expression profiles were determined in 3 pairs of CCA tumors and adjacent tissues by microarray analysis, and lncPKD223 expression was then validated in 60 paired samples by reverse transcriptionquantitative polymerase chain reaction (RTqPCR). Expression of common CSC markers [(CD44, CD133 and octamerbinding transcription factor 4 (OCT4)], CD44+CD133+ cell proportions, sphere formation efficiency and drug resistance to 5fluorouracil (5FU) were measured following ectopic overexpression of lncPKD223 or silencing via small hairpin RNA lentivirus transfection into the TFK1 and Huh28 CCA cell lines. Finally, lncPKD223 expression was measured in CCA stemlike cells and normal CCA cells. The results from the microarray analysis identified a total of 4,223 upregulated and 4,596 downregulated lncRNAs between CCA tumor tissue and paired adjacent tissue, which were enriched in regulating cancerassociated pathways. RTqPCR validation revealed that lncPKD223 was upregulated in CCA and associated with a higher Eastern Cooperative Oncology Group performance score, poor differentiation, advanced TNM stage, increased carcinoembryonic antigen and poor overall survival in CCA patients. In vitro, lncPKD223 increased CD44, CD133 and OCT4 expression as well as the CD44+CD133+ cell proportion, raised the sphere formation efficiency and enhanced drug resistance to 5FU in TFK1 and Huh28 cells. In addition, lncPKD223 was positively correlated with CSC markers in CCA tumor tissues and was markedly upregulated in CCA stemlike cells compared with that in normal CCA cells. In conclusion, lncPKD223, selected by lncRNA expression profiling, was associated with pejorative tumor features and poor prognosis, enhanced cancer stemness and may serve as a CSC marker in CCA.
Assuntos
Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/patologia , Resistencia a Medicamentos Antineoplásicos , Perfilação da Expressão Gênica/métodos , Células-Tronco Neoplásicas/patologia , RNA Longo não Codificante/genética , Neoplasias dos Ductos Biliares/genética , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Colangiocarcinoma/genética , Feminino , Fluoruracila , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Estadiamento de Neoplasias , Células-Tronco Neoplásicas/química , Prognóstico , Análise de Sobrevida , Regulação para CimaRESUMO
Chiral ruthenium(II) complexes have long been considered as potential anticancer agents. Herein, in vivo inhibitory activity of a chiral ruthenium(II) complex coordinated by ligand 2-(2'-trifluoromethyphenyl) imidazo [4,5-f][1,10]phenanthroline, Δ-[Ru(bpy)2(o-FMPIP)] (D0402) on Kunming(KM) mice bearing tumor (H22 hepatic cancer) has been evaluated, and the results showed that the tumor weight of mice treated with 0.22â¯mg/(kg·day) D0402 via i.v. administration for 7 days decreased about 31.79% compared to the control group, while the body weight, as well as the thymus, spleen, liver, lung, and kidney indices of mice treated with D0402 observed almost no loss compared to the control group. Furthermore, the mechanism studies on anti-angiogenic showed that D0402 could inhibit the formation of angiogenesis in the transgenic Tg(fli1a: EGFP) zebrafish. After treated with D0402, the sub-intestinal vessels(SIVs) of the zebrafish became disordered and chaotic, and was dosage dependent. Moreover, the TUNEL analysis and comet assays revealed that D0402 can induce apoptosis of HepG2 cell through DNA damage, and this was further demonstrated by immunofluorescence analysis with the number of γ-H2AX increased following the increasing amount of D0402. Besides, in vivo toxicity of D0402 has also been investigated on the development of zebrafish embryo, and the results showed that there were no death or development delay occurred for zebrafish embryo treated with D0402 up to concentration of 60⯵M. All in together, this study suggested that D0402 can be developed as a potential inhibitor against liver cancer through co-junction of anti-angiogenesis and apoptosis-inducing via DNA damage in the near future.