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BACKGROUND: Coronary inflammation plays crucial role in type 2 diabetes mellitus (T2DM) induced cardiovascular complications. Both glucose-lowering drug interventions (GLDIS) and glycemic control (GC) status potentially correlate coronary inflammation, as indicated by changes in pericoronary adipose tissue (PCAT) attenuation, and thus influence cardiovascular risk. This study evaluated the impact of GLDIS and GC status on PCAT attenuation in T2DM patients. METHODS: This retrospective study collected clinical data and coronary computed tomography angiography (CCTA) images of 1,342 patients, including 547 T2DM patients and 795 non-T2DM patients in two tertiary hospitals. T2DM patients were subgroup based on two criteria: (1) GC status: well: HbA1c < 7%, moderate: 7 ≤ HbA1c ≤ 9%, and poor: HbA1c > 9%; (2) GLDIS and non-GLDIS. PCAT attenuations of the left anterior descending artery (LAD-PCAT), left circumflex artery (LCX-PCAT), and right coronary artery (RCA-PCAT) were measured. Propensity matching (PSM) was used to cross compare PCAT attenuation of non-T2DM and all subgroups of T2DM patients. Linear regressions were conducted to evaluate the impact of GC status and GLDIS on PCAT attenuation in T2DM patients. RESULTS: Significant differences were observed in RCA-PCAT and LCX-PCAT between poor GC-T2DM and non-T2DM patients (LCX: - 68.75 ± 7.59 HU vs. - 71.93 ± 7.25 HU, p = 0.008; RCA: - 74.37 ± 8.44 HU vs. - 77.2 ± 7.42 HU, p = 0.026). Higher PCAT attenuation was observed in LAD-PCAT, LCX-PCAT, and RCA-PCAT in non-GLDIS T2DM patients compared with GLDIS T2DM patients (LAD: - 78.11 ± 8.01 HU vs. - 75.04 ± 8.26 HU, p = 0.022; LCX: - 71.10 ± 8.13 HU vs. - 68.31 ± 7.90 HU, p = 0.037; RCA: - 78.17 ± 8.64 HU vs. - 73.35 ± 9.32 HU, p = 0.001). In the linear regression, other than sex and duration of diabetes, both metformin and acarbose were found to be significantly associated with lower LAD-PCAT (metformin: ß coefficient = - 2.476, p=0.021; acarbose: ß coefficient = - 1.841, p = 0.031). CONCLUSION: Inadequate diabetes management, including poor GC and lack of GLDIS, may be associated with increased coronary artery inflammation in T2DM patients, as indicated by PCAT attenuation on CCTA, leading to increased cardiovascular risk. This finding could help healthcare providers identify T2DM patients with increased cardiovascular risk, develop improved cardiovascular management programs, and reduce subsequent cardiovascular related mortality.
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Doença da Artéria Coronariana , Diabetes Mellitus Tipo 2 , Metformina , Placa Aterosclerótica , Humanos , Angiografia Coronária/métodos , Estudos Retrospectivos , Tecido Adiposo Epicárdico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Acarbose , Hemoglobinas Glicadas , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/terapia , Angiografia por Tomografia Computadorizada/métodos , Tecido Adiposo/diagnóstico por imagem , Inflamação/diagnóstico por imagem , Vasos Coronários/diagnóstico por imagemRESUMO
BACKGROUND: Pregnancy toxemia is a common disease, which occurs in older does that are pregnant with multiple lambs in the third trimester. Most of the sick goats die within a few days, which can seriously impact the economic benefits of goat breeding enterprises. The disease is believed to be caused by malnutrition, stress, and other factors, that lead to the disorder of lipid metabolism, resulting in increased ketone content, ketosis, ketonuria, and neurological symptoms. However, the changes in gut microbes and their metabolism in this disease are still unclear. The objective of this experiment was to evaluate the effect of toxemia of pregnancy on the fecal microbiome and metabolomics of does. RESULTS: Eight pregnant does suspected of having toxemia of pregnancy (PT group) and eight healthy does during the same pregnancy (NC group) were selected. Clinical symptoms and pathological changes at necropsy were observed, and liver tissue samples were collected for pathological sections. Jugular venous blood was collected before morning feeding to detect biochemical indexes. Autopsy revealed that the liver of the pregnancy toxemia goat was enlarged and earthy yellow, and the biochemical results showed that the serum levels of aspartate aminotransferase (AST) and ß-hydroxybutyric acid (B-HB) in the PT group were significantly increased, while calcium (Ca) levels were significantly reduced. Sections showed extensive vacuoles in liver tissue sections. The microbiome analysis found that the richness and diversity of the PT microbiota were significantly reduced. Metabolomic analysis showed that 125 differential metabolites were screened in positive ion mode and enriched in 12 metabolic pathways. In negative ion mode, 100 differential metabolites were screened and enriched in 7 metabolic pathways. CONCLUSIONS: Evidence has shown that the occurrence of pregnancy toxemia is related to gut microbiota, and further studies are needed to investigate its pathogenesis and provide research basis for future preventive measures of this disease.
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Doenças das Cabras , Microbiota , Pré-Eclâmpsia , Doenças dos Ovinos , Toxemia , Feminino , Gravidez , Ovinos , Animais , Pré-Eclâmpsia/veterinária , Cabras/metabolismo , Toxemia/veterinária , Metaboloma , Metabolômica , Carneiro Doméstico/metabolismo , RNA Ribossômico 16SRESUMO
Aplastic anaemia (AA) is a life-threatening hematopoietic disorder characterized by hypoplasia and pancytopenia with increasing fat cells in the bone marrow (BM). The BM-derived mesenchymal stem cells (MSCs) from AA are more susceptible to be induced into adipogenic differentiation compared with that from control, which may be causatively associated with the fatty BM and defective hematopoiesis of AA. Here in this study, we first demonstrated that levamisole displayed a significant suppressive effect on the in vitro adipogenic differentiation of AA BM-MSCs. Mechanistic investigation revealed that levamisole could increase the expression of ZFP36L1 which was subsequently demonstrated to function as a negative regulator of adipogenic differentiation of AA BM-MSCs through lentivirus-mediated ZFP36L1 knock-down and overexpression assay. Peroxisome proliferator-activated receptor gamma coactivator 1 beta (PPARGC1B) whose 3'-untranslated region bears adenine-uridine-rich elements was verified as a direct downstream target of ZFP36L1, and knock-down of PPARGC1B impaired the adipogenesis of AA BM-MSCs. Collectively, our work demonstrated that ZFP36L1-mediated post-transcriptional control of PPARGC1B expression underlies the suppressive effect of levamisole on the adipogenic differentiation of AA BM-MSCs, which not only provides novel therapeutic targets for alleviating the BM fatty phenomenon of AA patients, but also lays the theoretical and experimental foundation for the clinical application of levamisole in AA therapy.
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Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Anemia Aplástica/genética , Fator 1 de Resposta a Butirato/genética , Proteínas de Transporte/genética , Levamisol/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Adipócitos/metabolismo , Adipócitos/patologia , Adipogenia/genética , Adolescente , Adulto , Anemia Aplástica/metabolismo , Anemia Aplástica/patologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Fator 1 de Resposta a Butirato/agonistas , Fator 1 de Resposta a Butirato/metabolismo , Proteínas de Transporte/metabolismo , Estudos de Casos e Controles , Diferenciação Celular , Feminino , Regulação da Expressão Gênica , Genes Reporter , Humanos , Luciferases/genética , Luciferases/metabolismo , Masculino , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Pessoa de Meia-Idade , Cultura Primária de Células , Proteínas de Ligação a RNA , Transdução de SinaisRESUMO
Human epidermal growth factor receptor-2 (HER2) is overexpressed in various solid tumor types, acting as an established therapeutic target. Over the last three decades, the fast-paced development of diverse HER2-targeted agents, notably marked by the introduction of the antibody-drug conjugate (ADC), yielding substantial improvements in survival rates. However, resistance to anti-HER2 treatments continues to pose formidable challenges. The complex structure and dynamic dimerization properties of HER2 create significant hurdles in the development of novel targeted therapeutics. In this review, we synthesize the latest insights into the structural intricacies of HER2 and present an unprecedented overview of the epitope characteristics of HER2-targeted antibodies and their derivatives. Furthermore, we delve into the correlation between anti-HER2 antibody binding epitopes and their respective functions, with a particular focus on their efficacy against resistant tumors. In addition, we highlight the potential of emerging anti-HER2 agents that target specific sites or non-overlapping epitopes, poised to transform the therapeutic landscape for HER2-positive tumors in the foreseeable future.
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Epitopos , Neoplasias , Receptor ErbB-2 , Humanos , Receptor ErbB-2/imunologia , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Epitopos/imunologia , Imunoconjugados/uso terapêutico , Imunoconjugados/farmacologia , Terapia de Alvo Molecular/métodosRESUMO
BACKGROUND: Increasing evidence indicate that enhanced adipogenic differentiation of bone marrow mesenchymal stem cells (BM-MSCs) could contribute to the adiposity alteration in marrow microenvironment of aplastic anemia (AA). Identifying small molecule drugs with role in inhibiting adipogenesis of BM-MSCs may represent a novel direction in AA therapy by improving BM-MSCs mediated marrow microenvironment. METHODS: For the purpose, we isolated AA BM-MSCs through whole bone marrow cell culture, evaluated a series of small molecule drugs using the in vitro adipogenic differentiation model of BM-MSCs, and finally focused on emodin, a natural anthraquinone derivative. Subsequently, we systematically investigated the molecular mechanism of emodin in attenuating adipogenic process by means of microarray profiling, bioinformatics analysis and lentivirus-mediated functional studies and rescue assay. RESULTS: We found that emodin presented significantly suppressive effect on the in vitro adipogenic differentiation of AA BM-MSCs. Further mechanistic investigation revealed that emodin could increase the expression of Tribbles homolog 3 (TRIB3) which exhibited remarkably decreased expression in AA BM-MSCs compared with the normal counterparts and was subsequently demonstrated as a negative regulator in adipogenesis of AA BM-MSCs. Besides, TRIB3 depletion alleviated the suppressive effect of emodin on the adipogenic differentiation of AA BM-MSCs. CONCLUSION: Our findings propose that emodin mediated TRIB3 up-regulation alleviates the adipogenic capacity of AA BM-MSCs, and emodin could serve as a potential therapeutic regimen for AA therapy.
Assuntos
Anemia Aplástica , Emodina , Células-Tronco Mesenquimais , Humanos , Adipogenia/genética , Anemia Aplástica/tratamento farmacológico , Anemia Aplástica/metabolismo , Medula Óssea , Emodina/farmacologia , Células da Medula Óssea , Diferenciação Celular , Células Cultivadas , Proteínas Repressoras/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas de Ciclo Celular/metabolismoRESUMO
WASP homolog associated with actin, membranes and microtubules (WHAMM) is a newly discovered nucleation-promoting factor that links actin and microtubule cytoskeleton and regulates transport from the endoplasmic reticulum to the Golgi apparatus. However, knowledge of WHAMM is limited to interphase somatic cells. In this study, we examined its localization and function in mouse oocytes during meiosis. Immunostaining showed that in the germinal vesicle (GV) stage, there was no WHAMM signal; after meiosis resumption, WHAMM was associated with the spindle at prometaphase I (Pro MI), metaphase I (MI), telophase I (TI) and metaphase II (MII) stages. Nocodazole and taxol treatments showed that WHAMM was localized around the MI spindle. Depletion of WHAMM by microinjection of specific short interfering (si)RNA into the oocyte cytoplasm resulted in failure of spindle migration, disruption of asymmetric cytokinesis and a decrease in the first polar body extrusion rate during meiotic maturation. Moreover, actin cap formation was also disrupted after WHAMM depletion, confirming the failure of spindle migration. Taken together, our data suggest that WHAMM is required for peripheral spindle migration and asymmetric cytokinesis during mouse oocyte maturation.
Assuntos
Proteínas de Transporte/metabolismo , Citocinese , Microtúbulos/metabolismo , Oócitos/citologia , Oócitos/metabolismo , Fuso Acromático/metabolismo , Animais , Transporte Biológico , Proteínas de Transporte/genética , Proteínas de Ciclo Celular , Células Cultivadas , Proteínas do Citoesqueleto , Retículo Endoplasmático/metabolismo , Feminino , Complexo de Golgi/metabolismo , Meiose , Camundongos , Camundongos Endogâmicos ICR , Nocodazol/farmacologia , Paclitaxel/farmacologia , Interferência de RNA , RNA Interferente Pequeno , Moduladores de Tubulina/farmacologiaRESUMO
Memory T cells play an important role in graft rejection. In this study, we investigated the potential effect of Irinotecan (CPT-11), a topoisomerase I inhibitor used in the treatment of a variety of solid tumor malignancies, on memory T cells. CPT-11 treatment alone or combined with blocking monoclonal antibodies (mAb) against co-stimulatory molecules (LFA-1 and CD154) was evaluated in the prevention of heart transplant rejection in alloantigen-primed mice. Our data suggest that CPT-11 reduced the expression of IL-2/IFN-γ and increased IL-10/TGF-ß expression in both peripheral blood and within the grafts. CPT-11 could also inhibit alloresponses of memory T cells, while decreasing the proportion of CD4(+) memory T cells in the spleen of the recipients and significantly reducing serum alloantibody levels. Our study highlights obvious synergistic effects of CPT-11 when combined with co-stimulatory molecule blockade in prolonging the survival of cardiac allografts in alloantigen-primed mice.
Assuntos
Anticorpos Monoclonais/farmacologia , Camptotecina/análogos & derivados , Sobrevivência de Enxerto/efeitos dos fármacos , Transplante de Coração/métodos , Animais , Anticorpos Bloqueadores/imunologia , Anticorpos Bloqueadores/farmacologia , Anticorpos Monoclonais/imunologia , Ligante de CD40/imunologia , Camptotecina/farmacologia , Ensaio de Imunoadsorção Enzimática , Feminino , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/imunologia , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/imunologia , Transplante de Coração/imunologia , Memória Imunológica/imunologia , Interferon gama/sangue , Interferon gama/genética , Interferon gama/imunologia , Interleucina-10/sangue , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-2/sangue , Interleucina-2/genética , Interleucina-2/imunologia , Irinotecano , Isoantígenos/imunologia , Antígeno-1 Associado à Função Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fator de Crescimento Transformador beta/sangue , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/imunologia , Transplante HomólogoRESUMO
Lower limb arterial calcification (LLAC) is associated with an increased risk of mortality and it predicts poor outcomes after endovascular interventions in patients with peripheral artery disease (PAD). Detailed histological analysis of human lower artery specimens pinpointed the presence of LLAC in two distinct layers: the intima and the media. Intimal calcification has been assumed to be an atherosclerotic pathology and it is associated with smoking and obesity. It becomes instrumental in lumen stenosis, thereby playing a crucial role in disease progression. On the contrary, medial calcification is a separate process, systematically regulated and linked with age advancement, diabetes, and chronic kidney disease. It prominently interacts with vasodilation and arterial stiffness. Given that both types of calcifications frequently co-exist in PAD patients, it is vital to understand their respective mechanisms within the context of PAD. Calcification can be easily identifiable entity on imaging scans. Considering the highly improved abilities of novel imaging technologies in differentiating intimal and medial calcification within the lower limb arteries, this review aimed to describe the distinct histological and imaging features of the two types of LLAC. Additionally, it aims to provide in-depth insight into the risk factors, the effects on hemodynamics, and the clinical implications of LLAC, either occurring in the intimal or medial layers.
RESUMO
BACKGROUND: Tibial artery calcification (TAC) is correlated with an increased risk of amputation and mortality in patients with chronic limb-threatening ischemia (CLTI). The association between calcification characteristics and adverse limb events of CLTI. However, it has not been assessed. This study aims to assess the relationship between the characteristics of TAC based on computed tomography angiography (CTA) scans and postoperative outcomes in patients with CLTI undergoing infrapopliteal endovascular therapy. METHODS: This was a retrospective study of patients who underwent infrapopliteal endovascular revascularization for CLTI and had a preoperative CTA scan. Based on CTA, TAC was divided into the following categories: annularity, thickness, continuity and severity. Cox regression models using generalized estimating equations were performed to assess the relationship between calcification characteristics and postoperative outcomes. The outcomes evaluated were the occurrence of all cause mortality (ACM) and unplanned amputation. RESULTS: Among the 148 patients undergoing endovascular, there were 50 (33.8%) patients died and 26 (17.6%) patients underwent unplanned amputation. Annular calcification was more common in the ACM group than in the non-ACM group. No significant differences were found between the two groups with regard to the probability of calcification in the thickness and the continuity (P>0.05). Patients in the unplanned amputation group had significantly annular, thin and continuity calcifications (P<0.05) than those in the non-unplanned amputation group. The presence of annular calcification was an independent predictor of ACM (hazard ratio (HR), 3.186; 95% confidence interval (CI), 1.781-5.702; P<0.001) and unplanned amputation (HR, 3.739; 95% CI, 1.707-8.191; P<0.05). CONCLUSIONS: Among patients with CLTI, the occurrence of annular calcification in the tibial artery are related to a greater chance of ACM and unplanned amputation in the postoperative period. The circumferential degree of TAC of the operated limb can be considered as a marker of clinical prognosis in this group of patients.
Assuntos
Procedimentos Endovasculares , Doença Arterial Periférica , Humanos , Isquemia Crônica Crítica de Membro , Artérias da Tíbia/diagnóstico por imagem , Artérias da Tíbia/cirurgia , Procedimentos Endovasculares/métodos , Fatores de Risco , Estudos Retrospectivos , Doença Arterial Periférica/diagnóstico por imagem , Doença Arterial Periférica/cirurgia , Resultado do Tratamento , Isquemia/diagnóstico por imagem , Isquemia/cirurgia , Salvamento de Membro/efeitos adversos , Salvamento de Membro/métodos , Doença CrônicaRESUMO
Increased propensity of bone marrow-derived mesenchymal stem cells (BM-MSCs) toward adipogenic differentiation at the expense of osteogenesis has been implicated in obesity, diabetes, and age-related osteoporosis as well as various hematopoietic disorders. Defining small molecules with role in rectifying the adipo-osteogenic differentiation imbalance is of great significance. Here, we unexpectedly found that Chidamide, a selective histone deacetylases inhibitor, exhibited remarkably suppressive effect on the in vitro induced adipogenic differentiation of BM-MSCs. Multifaceted alterations in the spectrum of gene expression were observed in Chidamide-managed BM-MSCs during adipogenic induction. Finally, we focused on REEP2, which presented decreased expression in BM-MSCs-mediated adipogenesis and was restored by Chidamide treatment. REEP2 was subsequently demonstrated as a negative regulator of adipogenic differentiation of BM-MSCs and mediated the suppressive effect of Chidamide on adipocyte development. Our findings provide the theoretical and experimental foundation for the clinical application of Chidamide for disorders associated with excessive marrow adipocytes.
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Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by abnormal cell proliferation, apoptosis repression and myeloid differentiation blockade of hematopoietic stem/progenitor cells. Developing and identifying novel therapeutic agents to reverse the pathological processes of AML are of great significance. Here in this study, we found that a fungus-derived histone deacetylase inhibitor, Apicidin, presents promising therapeutic effect on AML by inhibiting cell proliferation, facilitating apoptosis and inducing myeloid differentiation of AML cells. Mechanistic investigation revealed that QPCT is identified as a potential downstream target of Apicidin, which exhibits significantly decreased expression in AML samples compared with the normal controls and is remarkably up-regulated in AML cells upon Apicidin management. Functional study and rescue assay demonstrated that QPCT depletion further promotes cell proliferation, inhibits apoptosis and impairs myeloid differentiation of AML cells, alleviating the anti-leukemic effect of Apicidin on AML. Our findings not only provide novel therapeutic target for AML, but also lay theoretical and experimental foundation for the clinical application of Apicidin in AML patients.
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Apoptose , Leucemia Mieloide Aguda , Humanos , Proliferação de Células , Leucemia Mieloide Aguda/tratamento farmacológicoRESUMO
BACKGROUND: Hepcidin plays a central role in iron homeostasis, which is regulated by iron stores, the rate of erythropoiesis, inflammation, and hypoxia. Aberrant expression of hepcidin was found in many diseases, however, there is scant information on hepcidin expression in acute leukemia (AL). MATERIALS AND METHODS: 32 patients with AL which diagnosis according to FAB criteria were studied. Serum hepcidin levels, erythropoietin (EPO), interleukin-6 (IL-6), hematological parameters, intracellular and extracellular iron store were evaluated. RESULTS: Hepcidin was elevated significantly with increased iron storage in patients at onset of AL when erythropoiesis was depressed by blast cells, then decreased significantly with AL remission, while soluble transferrin receptor (sTfR) concentration was elevated. Negative correlations were found between serum hepcidin and erythropoietic markers including RBC, Hb, Ret and sTfR. Positive correlations were shown between hepcidin and ferritin, between hepcidin and ratio of sideroblasts, as well as between hepcidin and IL-6. CONCLUSIONS: Hepcidin production was regulated by iron stores, inflammation and erythropoietic activity in AL patients. Erythropoietic activity may play the main role among the regulators of hepcidin expresssion.
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Peptídeos Catiônicos Antimicrobianos/sangue , Eritropoese/fisiologia , Leucemia/sangue , Adulto , Eritropoetina/sangue , Feminino , Ferritinas/sangue , Hepcidinas , Humanos , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Receptores da Transferrina/metabolismo , Estatística como Assunto , Transferrina/metabolismo , Adulto JovemRESUMO
Urban water pollution has been well controlled by strict management in the past few decades in China. Thus, the central government started to place emphasis on rural water pollution, and increasing number of sewage treatment facilities have been constructed, and currently, they are operating in China. Therefore, thoroughly assessing the operating conditions and the performance of these facilities is important. This article analyzes life cycle assessment and life cycle cost to evaluate the environmental and economic performance of four common technologies to determine how the emerging rural sewage treatment facilities in China are running. The results showed that the plant-adopted anaerobic-anoxic-oxic process was an optimal scheme for lower environmental impact that was also cost-effective. All technologies had similar impacts on eleven environmental categories. Due to cement consumption during the construction phase and electricity consumption during the operation phase, the marine aquatic ecotoxicity potential was the greatest contributor, accounting for approximately 90% of the total potential impact. In addition, this research revealed that electricity consumption during the operation phase was responsible for almost all environmental impact categories, except for eutrophication potential and ozone layer depletion potential categories. Lastly, scenario analysis indicated that reusing treated water and adjusting power structure could be useful measures to promote the sustainable development of rural water environments.
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Meio Ambiente , Esgotos , China , Eutrofização , Água , Poluição da ÁguaRESUMO
Corilagin is the primary active component of the Euphorbia phyllanthus plant and has significant anticancer properties. However, the biological effects and mechanisms of corilagin on acute myeloid leukemia (AML) have not been clarified. The Cell Counting Kit8 and Carboxyfluorescein Diacetate Succinimidyl Ester assay results showed that corilagin significantly inhibited proliferation of the AML cell line HL60 in a time and dosedependent manner. Western blotting and flow cytometry analysis were performed to determine the levels of apoptosis in HL60 cells. The protein levels of cleaved caspase3 and Bak were upregulated, while Bclxl was downregulated in cells treated with corilagin. The percentage of early and latestage apoptotic cells increased following corilagin treatment in a dosedependent manner, indicating that the intrinsic mitochondrial apoptosis pathway was activated by corilagin. Simultaneously, western blotting and immunofluorescence results revealed that autophagy was suppressed; this was accompanied by a decrease in light chain 3II (LC3II) conversion and autophagosomes. MicroRNA (miRNA/miR) profile analysis showed that corilagin elevated the expression of the tumor suppressor miR451, while the mRNA and protein levels of high mobility group protein B1 (HMGB1), the target of miR451, decreased following exposure to corilagin. Knockdown of miR451 decreased the downregulation of HMGB1 caused by corilagin, indicating negative regulation of HMGB1 by miR451 during corilagin treatment. Furthermore, knockdown of miR451 also attenuated corilagininduced proliferation inhibition of HL60 cells, implying that miR451 was essential for the proliferation inhibitory effect of corilagin. In conclusion, these results indicated that corilagin induced apoptosis and inhibited autophagy in HL60 cells by regulating the miR451/HMGB1 axis, and corilagin may be a novel therapeutic drug for the treatment of AML.
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Apoptose , Autofagia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glucosídeos/farmacologia , Proteína HMGB1/metabolismo , Taninos Hidrolisáveis/farmacologia , Leucemia Mieloide Aguda/patologia , MicroRNAs/genética , Proliferação de Células , Células HL-60 , Proteína HMGB1/genética , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismoRESUMO
OBJECTIVE: To evaluate the impact of hypertension on the clinical outcome of COVID-19 patients aged 60 years old and older. METHODS: This single-center retrospective cohort study enrolled consecutive COVID-19 patients aged 60 years old and older, who were admitted to Liyuan Hospital from January 1, 2020 to April 25, 2020. All included patients were divided into two groups: hypertension and nonhypertension group. The baseline demographic characteristics, laboratory test results, chest computed tomography (CT) images and clinical outcomes were collected and analyzed. The prognostic value of hypertension was determined using binary logistic regression. RESULTS: Among the 232 patients included in the analysis, 105 (45.3%) patients had comorbid hypertension. Compared to the nonhypertension group, patients in the hypertension group had higher neutrophil-to-lymphocyte ratios, red cell distribution widths, lactate dehydrogenase, high-sensitivity C-reactive protein, D-dimer and severity of lung lesion, and lower lymphocyte counts (all P<0.05). Furthermore, the hypertension group had a higher proportion of intensive care unit admissions [24 (22.9%) vs. 14 (11.0%), P=0.02) and deaths [16 (15.2%) vs. 3 (2.4%), P<0.001] and a significantly lower probability of survival (P<0.001) than the nonhypertension group. Hypertension (OR: 4.540, 95% CI: 1.203-17.129, P=0.026) was independently correlated with all-cause in-hospital death in elderly patients with COVID-19. CONCLUSION: The elderly COVID-19 patients with hypertension tend to have worse conditions at baseline than those without hypertension. Hypertension may be an independent prognostic factor of poor clinical outcome in elderly COVID-19 patients.
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COVID-19 , Hipertensão , Idoso , COVID-19/complicações , Mortalidade Hospitalar , Humanos , Hipertensão/complicações , Hipertensão/epidemiologia , Pessoa de Meia-Idade , Estudos Retrospectivos , SARS-CoV-2RESUMO
Maternal diabetes adversely affects preimplantation embryo development and oocyte maturation. Thus, it is important to identify ways to eliminate the effects of maternal diabetes on preimplantation embryos and oocytes. The objectives of this study were to investigate whether islet transplantation could reverse the effects of diabetes on oocytes. Our results revealed that maternal diabetes induced decreased ovulation; increased the frequency of meiotic spindle defects, chromosome misalignment, and aneuploidy; increased the relative expression levels of Mad2 and Bub1; and enhanced the sensitivity of oocytes to parthenogenetic activation. Islet transplantation prevented these detrimental effects. Therefore, we concluded that islet transplantation could reverse the effects of diabetes on oocytes, and that this technique may be useful to treat the fundamental reproductive problems of women with diabetes mellitus.
Assuntos
Transplante das Ilhotas Pancreáticas/fisiologia , Oócitos/fisiologia , Gravidez em Diabéticas/terapia , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Aneuploidia , Animais , Glicemia/análise , Glicemia/fisiologia , Peso Corporal , Aberrações Cromossômicas/embriologia , Aberrações Cromossômicas/estatística & dados numéricos , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Experimental/terapia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Oócitos/metabolismo , Oócitos/patologia , Ovulação/fisiologia , Gravidez , Gravidez em Diabéticas/sangue , Gravidez em Diabéticas/patologia , Gravidez em Diabéticas/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/genética , Fuso Acromático/genética , Fuso Acromático/metabolismo , Fuso Acromático/patologia , EstreptozocinaRESUMO
BACKGROUND: Memory T cells are a significant barrier to the induction of transplant tolerance. Our previous study demonstrated that multiple applications of anti-CD44 monoclonal antibody (mAb) could significantly inhibit CD4(+) memory T cells from mediating rejection of cardiac allografts. Now, we sought to explore the effect and mechanism of anti-CD44 mAb on the rejection of islet allografts and xenografts mediated by CD4(+) memory T cells. METHODS: In this study, we first engrafted skin grafts of C57BL/6 (B6) mice or Dark Agouti (DA) rats onto BALB/c mice to induce donor-reactive memory T cells. We adoptively transferred purified CD4(+) memory T cells to BALB/c origin nude mice and then transplanted islet allografts and xenografts to produce the Allo-Tx and Xeno-Tx models, respectively. We subsequently administered multiple anti-CD44 mAb and observed changes in the survival times of the islet grafts. RESULTS: In the Allo-Tx model, the mean survival time (MST) of the grafts was 7.7 days in the isotype group, and 20.3 days in the anti-CD44 group. In the Xeno-Tx model, the MST of the grafts was 7.2 days in the isotype group and 8.2 days in the anti-CD44 group. Compared with the isotype group, CD4(+) T cells on the grafts in the anti-CD44 group were significantly decreased in both the Allo-Tx and Xeno-Tx models, but the proportion of CD4(+) memory T cells in the spleens and draining lymph nodes of the recipient nude mice in the anti-CD44 group was significantly decreased in the Allo-Tx model, while it was increased in the Xeno-Tx model. The production of donor-specific IgG antibody in the anti-CD44 group did not vary in the Allo-Tx model, while it was markedly elevated in the Xeno-Tx model. Furthermore, the expression of interferon gamma in the anti-CD44 group was markedly decreased in both the Allo-Tx and Xeno-Tx models, while the expression of IL-4 in the anti-CD44 group was significantly increased only in the Xeno-Tx model. CONCLUSION: Multiple applications of the anti-CD44 mAb could significantly inhibit donor-reactive CD4(+) memory T cells from rejecting grafts via a Th1-dependent pathway, but xenoreactive CD4(+) memory T cells can avoid the effects of anti-CD44 mAb to reject islet xenografts via a Th2-dependent pathway.
Assuntos
Anticorpos Monoclonais/imunologia , Linfócitos T CD4-Positivos/imunologia , Receptores de Hialuronatos/imunologia , Transplante das Ilhotas Pancreáticas/imunologia , Células Th2/imunologia , Transplante Heterólogo/imunologia , Transplante Homólogo/imunologia , Animais , Antígenos CD4/imunologia , Proliferação de Células , Diabetes Mellitus Experimental , Feminino , Sobrevivência de Enxerto/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Ratos , Transplante Heterólogo/patologia , Transplante Homólogo/patologiaRESUMO
Sewage treatment is an important public service, but it consumes a lot of energy and chemicals in the process of removing wastewater pollutants, which may cause the risk of pollution transfer. To find the corresponding hot issues, this paper took the lead in integrating life cycle assessment (LCA) with life cycle costing (LCC) to evaluate four most typical sewage treatment technologies with more than 85% share in China. It is found that anaerobic/anoxic/oxic (AAO) was the optimal treatment scheme with relatively small potential environmental impact and economic load. The normalized results show that the trends of the four technologies on eleven environmental impact categories were basically the same. Marine aquatic ecotoxicity potential accounted for more than 70% of the overall environmental impact. Contribution analysis indicates that electricity and flocculant consumption were the main processes responsible for the environmental and economic burden. Overall, electricity consumption was the biggest hot spot. Sensitivity analysis verifies that a 10% reduction in electricity could bring high benefits to both the economy and the environment. These findings are expected to provide effective feedback on the operation and improvement of sewage treatment. Graphical abstract.