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1.
Anat Rec (Hoboken) ; 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34469051

RESUMO

Alzheimer's disease (AD) is a fatal neurodegenerative disease for which currently no cure is available. Electroacupuncture (EA) has been widely used in China as an alternative therapeutic approach for neurological diseases. The cognitive decline in patients with AD has been reported to be closely related to the deposition of amyloid-ß (Aß) in the hippocampus of the brain, and the Morris water maze (MWM) test is a widely used method for assessing the behavior of animal models. In this study, the MWM test was performed to evaluate the effects of EA treatment on cognitive function and memory, and the micro-positron emission tomography scan was used to assess the hippocampal Aß deposition. The results showed that the cognitive function of APP/PS1 mice was significantly improved and the rate of [18F]AV-45 uptake was reduced in the EA group, compared with the AD group. Our study suggested that EA can exert a therapeutic effect in AD by improving spatial learning and memory and inhibiting the hippocampal Aß deposition.

2.
Ecotoxicol Environ Saf ; 225: 112763, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34544025

RESUMO

In this research, micro Coix lacryma-jobi L. vertical flow constructed wetlands (VFCWs) were set up using domestic sewage (DWS) and 1/2 Hoagland nutrient solution (HNS) as VFCWs water sources. 0, 20 mg L-1 and 40 mg L-1 of Cr6+ (in the form of K2Cr7O2) were added into the water sources separately in order to study the response of Coix lacryma-jobi L. under Cr6+ stress. The results showed that the inhibition rates of Cr6 + on plant height, stem diameter, shoot and root dry weight treated with HNS were 2.88~10.16%, 5.12~11.86%, 3.53~6.51% and 2.89~6.34% higher than those in DWS treatment. SEM analysis showed that the nuclear bilayer membrane was slightly damaged, the chromatin decreased and the number of mitochondrial cristae decreased when treated with 20 mg L-1 of Cr6+, however, organelle damage was more severe under 40 mg L-1 of Cr6+exposure. The X-ray energy spectrum analysis results indicated that the accumulation of chromium in epidermis and endodermis were higher than those in stele. The contents of total Cr in roots, stems and leaves treated with HNS were higher than those of DWS treatment. The highest content of Cr was observed in cell wall (32.12-188.1 mg kg-1), followed by vacuole (5.0-38.14 mg kg-1). The contents of Cr in each subcellular component in roots, stems, and leaves treated with HNS were higher than those of DWS, except for organelle components in the 14th week. DWS was used as water influent, the contents of easily migrated combined Cr (ETM) in roots, stems and leaves were significantly lower than those in HNS treatment. Improving the nutritional conditions of constructed wetlands might be beneficial to the improvement of their ability to purify chrome-containing waste water.


Assuntos
Coix , Cromo/toxicidade , Esgotos , Águas Residuárias , Áreas Alagadas
3.
BMC Pediatr ; 21(1): 253, 2021 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-34058999

RESUMO

BACKGROUND: Griscelli syndrome type 2 (GS2) is a rare autosomal recessive disease caused by mutations in RAB27A gene. It is primarily characterized by a combination of partial albinism, hemophagocytic lymphohistiocytosis (HLH) or other immunodeficiency. However, neurological involvement at onset in GS2 and treatment has rarely been described. CASE PRESENTATION: We describe a 3-year-old boy with GS2 in an Asian Chinese family. He presented with progressive neurological abnormalities following unremitting fever at onset. He developed HLH during the clinical course. A novel homozygous mutation (c.1 A > G) in RAB27A gene was subsequently identified. He was then treated by HLH-1994 protocol combined with ruxolitinib and experienced a dramatic remission. He subsequently underwent a successful haploidentical hematopoietic stem cell transplantation and stayed at a good condition. CONCLUSIONS: We reported an atypical form of GS2 manifesting as severe central nervous system involvement at onset and subsequent HLH, which was successfully rescued in time. This case also highlights the need for early consideration of immunologic and genetic evaluation for HLH in unexplained neuroinflammation in the diagnostic work up.


Assuntos
Linfo-Histiocitose Hemofagocítica , Piebaldismo , Doenças da Imunodeficiência Primária , Pré-Escolar , Humanos , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/terapia , Masculino , Piebaldismo/complicações , Piebaldismo/diagnóstico , Piebaldismo/genética , Proteínas rab27 de Ligação ao GTP/genética
4.
Zhen Ci Yan Jiu ; 46(5): 353-61, 2021 May 25.
Artigo em Chinês | MEDLINE | ID: mdl-34085456

RESUMO

OBJECTIVE: To explore the effect of electroacupuncture (EA) on the ability of spatial learning-memory and the expression of IL-1ß, IL-6 and TNF-α in the hippocampus and spleen tissues and the number of hippocampal neurons and spleen lymphocytes in Alzheimer's disease (AD) mice, so as to study its mechanisms underlying improvement of AD. METHODS: Twenty-four SAMP8 mice were randomly and equally divided into AD model, EA and medication groups, and 8 SAMR1 mice were used as the control group. EA (2 Hz, 0.1 mA) was applied to "Baihui"(GV20) and "Yintang"(EX-HN3) for 20 min in the EA group, and intragastric administration of donepezil hydrochloride (0.92 mg/kg) was applied in the medication group, once daily for 15 d. The learning-memory ability was determined by Morris water maze task, and the histopathological changes of hippocampus were observed after H.E. staining, followed by determining neurons and the number of splenic lymphocytes. The expression levels of IL-1ß, IL-6 and TNF-α in the hippocampus and spleen were detected by immunohistochemistry and Western blot, respectively. RESULTS: After mode-ling, the escape latency of place navigation test in the Morris water maze, the spleen index, immunoactivity and expression levels of IL-1ß, IL-6 and TNF-α proteins in the hippocampus and spleen tissues were significantly increased (P<0.05, P<0.01). Compared with the model group, the escape latency, spleen index, immunoactivity and expression levels of IL-1ß, IL-6 and TNF-α proteins in both hippocampus and spleen were significantly down-regulated in the medication (except the escape latency) and EA groups (P<0.01, P<0.05). The effect of EA was evidently superior to that of medication in shortening the escape latency, lowering the spleen index, and immunoactivity of hippocampal IL-6 and splenic TNF-α immunoactivity (P<0.01, P<0.05). Outcomes of H.E. staining showed disordered arrangement of neurons with nuclear pyknosis or apoptosis in partial neurons in the hippocampus, and thickened and swollen spleen capsule tissue with loose structure and an increased number of lymphocytes in the model group, which was relatively milder in the EA and medication groups. CONCLUSION: EA can improve the learning-memory ability of AD mice, which may be associated with its effect in relieving the inflammation reaction in the hippocampus and spleen tissues.


Assuntos
Doença de Alzheimer , Eletroacupuntura , Doença de Alzheimer/genética , Doença de Alzheimer/terapia , Animais , Hipocampo , Interleucina-6/genética , Camundongos , Baço , Fator de Necrose Tumoral alfa/genética
5.
Zhen Ci Yan Jiu ; 46(6): 497-504, 2021 Jun 25.
Artigo em Chinês | MEDLINE | ID: mdl-34190454

RESUMO

OBJECTIVE: To observe the changes of microvascular structure of acupoints caused by myocardial ischemia, so as to explore the application of photoacoustic imaging technology in the research of acupoint sensitization. METHODS: Twelve BALB/c mice were randomly divided into normal, sham operation and acute myocardial ischemia (AMI) model groups, with 4 mice in each group. AMI model was established by ligating the left anterior descending coronary artery. Electrocardiogram (ECG) was recorded by physiological signal acquisition system at 12 h and on the 14th day after modeling, and serum cardiac troponin T (cTnT) and creatine kinase isoenzyme MB (CK-MB) levels were detected by enzyme-linked immunosorbent assay. The microvascular structure changes of acupoints "Feishu"(BL13), "Jueyinshu"(BL14), "Quze"(PC3) and "Chize"(LU5) were observed by photoacoustic imaging technology, and distance (DM), inflection count metric (ICM), sum of angle metric(SOAM)and microvessel density (MVD) were calculated by microvascular quantification algorithm. RESULTS: Compared with the normal and sham operation groups, the ST segment of ECG was obviously elevated, serum cTnT and CK-MB were significantly increased in AMI model group at 12 h and on the 14th day after AMI (P<0.01). The ICM of BL14 in AMI model group was significantly decreased on the 14th day than that on the 7th day after AMI. Compared with the normal group, the ICM of BL14 was significantly increased in AMI model group on the 7th day after AMI(P<0.05). There were no significant changes in DM, ICM, SOAM and MVD at other acupoints on the 7th and 14th day (P>0.05) among the three groups. CONCLUSION: The change of ICM may be one of the characteristics of acupoint sensitization and photoacoustic imaging technology can be used to study the structure of acupoint microvessels.


Assuntos
Isquemia Miocárdica , Técnicas Fotoacústicas , Pontos de Acupuntura , Animais , Camundongos , Camundongos Endogâmicos BALB C , Microvasos , Isquemia Miocárdica/terapia
6.
Zhen Ci Yan Jiu ; 46(6): 523-6, 2021 Jun 25.
Artigo em Chinês | MEDLINE | ID: mdl-34190459

RESUMO

At present, acupuncture and moxibustion widely spread around the world, and its development is closely rela-ted to multidisciplinary integration. Interdisciplinary approaches are of great concern to the innovation and promotion of acupuncture-moxibustion therapy. Acupuncture and moxibustion, combined with optics, electrics, magnetics, infrared ray, microwave and other technologies, create the advanced and practical instrument for diagnosis and treatment of acupuncture and moxibustion and have made important contribution to clinical and teaching work. In the paper, focusing on the unique advantages of the science of acupuncture and moxibustion, the application of interdisciplinary approaches was explored to the promotion of acupuncture-moxibustion technology in its innovation and development, while the existing problems and countermeasures are further considered in the translational process of acupuncture-moxibustion technology to clinical application.


Assuntos
Terapia por Acupuntura , Acupuntura , Moxibustão , Tecnologia , Pesquisa Médica Translacional
7.
Nat Commun ; 12(1): 3059, 2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-34031390

RESUMO

Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease in the world, however, no drug treatment has been approved for this disease. Thus, it is urgent to find effective therapeutic targets for clinical intervention. In this study, we find that liver-specific knockout of PPDPF (PPDPF-LKO) leads to spontaneous fatty liver formation in a mouse model at 32 weeks of age on chow diets, which is enhanced by HFD. Mechanistic study reveals that PPDPF negatively regulates mTORC1-S6K-SREBP1 signaling. PPDPF interferes with the interaction between Raptor and CUL4B-DDB1, an E3 ligase complex, which prevents ubiquitination and activation of Raptor. Accordingly, liver-specific PPDPF overexpression effectively inhibits HFD-induced mTOR signaling activation and hepatic steatosis in mice. These results suggest that PPDPF is a regulator of mTORC1 signaling in lipid metabolism, and may be a potential therapeutic candidate for NAFLD.


Assuntos
Fígado Gorduroso/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fígado/metabolismo , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Proteínas Culina/metabolismo , Proteínas de Ligação a DNA/metabolismo , Células HEK293 , Células Hep G2 , Humanos , Metabolismo dos Lipídeos , Fígado/patologia , Masculino , Camundongos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/metabolismo
8.
Mol Cancer Ther ; 20(7): 1316-1323, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33879554

RESUMO

The aim of this study was to investigate the prognostic significance of BRAFV600E in cell-free (cf) DNA (cfBRAFV600E) and lesion tissues (ltBRAFV600E) in pediatric Langerhans cell histiocytosis (LCH). This study included a total of 140 patients with successfully detected cfBRAFV600E and ltBRAFV600E at diagnosis. Treatment response at week 6 was correlated with both cfBRAFV600E and ltBRAFV600E Moreover, the patients with positive cfBRAFV600E had a much lower 3-year progression-free survival (PFS) rate and a higher progression/reactivation rate than those with negative cfBRAFV600E (47.1% ± 7.6% vs. 78.4% ± 5.1%, P < 0.0001; 44.6% vs. 19.0%, P = 0.001, respectively). However, no significant difference was found in the 3-year PFS rate or progression/reactivation rate between patients with positive and negative ltBRAFV600E (P = 0.348 and 0.596, respectively). In addition, after patients were divided into group A (both cfBRAFV600E and ltBRAFV600E positive, n = 56), group B (ltBRAFV600E positive and cfBRAFV600E negative, n = 28), and group C (both cfBRAFV600E and ltBRAFV600E negative, n = 56), there was a significant difference in the 3-year PFS rate and progression/reactivation rate among the three groups (47.1% ± 7.6%, 92.9% ± 6.1%, and 72.2% ± 6.1%, P < 0.001; 44.6%, 3.6%, and 26.8%, P < 0.001, respectively). In the multivariate analysis, cfBRAFV600E and age at diagnosis remained independent prognostic factors for 3-year PFS in childhood LCH. Therefore, cfBRAFV600E was more closely associated with important clinical characteristics, treatment response at week 6, and prognosis than ltBRAFV600E.

9.
Small ; : e2006021, 2021 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-33719203

RESUMO

Managing elastic properties of ABX3 type molecular perovskite ferroelectrics is critical to their future applications since these parameters determine their service durability and reliability in devices. The abundant structural and chemical viability of these compounds offer a convenient way to manipulate their elastic properties through a facile chemical approach. Here, the elastic properties and high-pressure behaviors of two isostructural perovskite ferroelectrics, MDABCO-NH4 I3 and MDABCO-KI3 (MDABCO = N-methyl-N'-diazabicyclo[2.2.2]octonium) is systematically investigated, via the first principles calculations and high-pressure synchrotron X-ray diffraction experiments. It is show that the simple replacement of NH4 + by K+ on the B-site respectively results in up to 48.1%, 52.4%, and 56.3% higher Young's moduli, shear moduli and bulk moduli, which is attributed to the much stronger KI coordination bonding than NH4 …I hydrogen bonding. These findings demonstrate that it is possible to tune elastic properties of molecular perovskite ferroelectrics via simply varying the framework assembling interactions.

10.
Dalton Trans ; 2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33527956

RESUMO

Two-dimensional (2D) organometallic halide perovskites (OHPs) are promising optoelectronic materials because of their excellent stability and tunable band gaps. Herein, we report the optical and elastic properties of a newly synthesized 2D lead halide perovskite, (C9H14ON)2PbI4 (C9H14ON+ = 4-methoxyphenethylammonium), by a combined experimental and theoretical approach. Our experiments demonstrate that (C9H14ON)2PbI4 shows a strong green emission under ambient conditions which is ascribed to its band gap of 2.4 eV. Moreover, our temperature-dependent photoluminescence (PL) experiments in the temperature range of 143-283 K reveal that the green emission red-shifts with increasing temperature, which is primarily attributed to the synergistic effect of thermal expansion and electron-phonon interactions. The elastic properties, obtained from density functional theory calculations, reveal that (C9H14ON)2PbI4 has relatively low modulus and anisotropy compared with other 2D materials.

11.
Cancer Res Treat ; 53(1): 261-269, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32972045

RESUMO

PURPOSE: We sought to investigate the effectiveness and safety of dabrafenib in children with BRAFV600E-mutated Langerhans cell histiocytosis (LCH). Materials and Methods: A retrospective analysis was performed on 20 children with BRAFV600E-mutated LCH who were treated with dabrafenib. RESULTS: The median age at which the patients started taking dabrafenib was 2.3 years old (range, 0.6 to 6.5 years). The ratio of boys to girls was 2.3:1. The median follow-up time was 30.8 months (range, 18.9 to 43.6 months). There were 14 patients (70%) in the risk organ (RO)+ group and six patients (30%) in the RO- group. All patients were initially treated with traditional chemotherapy and then shifted to targeted therapy due to poor control of LCH or intolerance to chemotherapy. The overall objective response rate and the overall disease control rate were 65% and 75%, respectively. During treatment, circulating levels of cell-free BRAFV600E (cfBRAFV600E) became negative in 60% of the patients within a median period of 3.0 months (range, 1.0 to 9.0 months). Grade 2 or 3 adverse effects occurred in five patients. CONCLUSION: Some children with BRAFV600E-mutated LCH may benefit from monotherapy with dabrafenib, especially high-risk patients with concomitant hemophagocytic lymphohistiocytosis and intolerance to chemotherapy. The safety of dabrafenib is notable. A prospective study with a larger sample size is required to determine the optimal dosage and treatment duration.

12.
Leuk Lymphoma ; 62(2): 410-418, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33054468

RESUMO

This study aimed to investigate the combined impact of IKZF1 deletions/high expression of CRLF2 on the prognosis of pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). IKZF1 deletions and CRLF2 expression were assessed in bone marrow samples from 117 children with newly diagnosed BCP-ALL. Sixteen (13.7%) patients were found to harbor IKZF1 deletions, which was associated with inferior outcomes. The event-free survival (EFS) for patients with high -CRLF2 expression was significantly worse than that for low -CRLF2 expression. Moreover, combined modeling of IKZF1+ /CRLF2 high identified 7.8% of cases as the highest risk subgroup (7-year EFS 33.3 ± 15.7%). In a multivariate analysis, IKZF1+ /CRLF2 high remained a strong independent prognostic factor for EFS (HR: 14.263, p = 0.019). IKZF1 deletions and high -CRLF2 expression were associated with inferior outcomes, and the coexistence of IKZF1+ /CRLF2 high had a significant impact on an integrated prognostic model for high-risk BCP-ALL.


Assuntos
Linfoma de Burkitt , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Linfócitos B , Criança , Humanos , Fator de Transcrição Ikaros/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Prognóstico , Receptores de Citocinas/genética
13.
Insects ; 11(11)2020 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-33171708

RESUMO

Trichogramma spp. is an important egg parasitoid wasp for biocontrol of agriculture and forestry insect pests. Trehalose serves as an energy source or stress protectant for insects. To study the potential role of trehalose in cold resistance on an egg parasitoid, cDNA for trehalose-6-phosphate synthase (TPS) and soluble trehalase (TRE) from Trichogramma dendrolimi were cloned and characterized. Gene expressions and enzyme activities of TdTPS and TdTRE were determined in larvae, prepupae, pupae, and adults at sustained low temperatures, 13 °C and 16 °C. TdTPS and TdTRE expressions had similar patterns with higher levels in prepupae at 13 °C and 16 °C. TdTPS enzyme activities increased with a decrease of temperature, and TdTRE activity in prepupae decreased sharply at these two low temperatures. In vitro reared T. dendrolimi could complete entire development above 13 °C, and the development period was prolonged without cold injury. Results indicated trehalose might regulate growth and the metabolic process of cold tolerance. Moreover, 13 °C is the cold tolerance threshold temperature and the prepupal stage is a critical developmental period for in vitro reared T. dendrolimi. These findings identify a low cost, prolonged development rearing method, and the cold tolerance for T. dendrolimi, which will facilitate improved mass rearing methods for biocontrol.

15.
Mol Med Rep ; 22(4): 2905-2915, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32945392

RESUMO

Low expression levels of CREB­binding protein (CREBBP) have been demonstrated to be associated with high minimal residual disease at the end of induction therapy and adverse long­term outcomes in pediatric patients with acute lymphoblastic leukemia (ALL). However, the effect of low CREBBP expression on the prognosis of ALL has not yet been investigated. In the present study, CREBBP was downregulated and overexpressed in ALL cell lines (Jurkat and Reh). Sensitivity to chemotherapy and cell proliferation activity was determined via a Cell Counting Kit­8 assay. Cell cycle analysis was performed using flow cytometry. Immunofluorescence confocal microscopy and co­immunoprecipitation (Co­IP) assays were performed to determine the interaction between CREBBP and E2F transcription factor 3a (E2F3a). The binding of CREBBP to downstream gene caspase 8 associated protein 2 (CASP8AP2) promoters was assessed using a chromatin immunoprecipitation assay, and mRNA expression levels were detected via reverse transcription­quantitative PCR. Western blot analysis was performed to detect protein expression of CREBBP, E2F3a and CASP8AP2. Downregulation of CREBBP increased the IC50 value of daunorubicin; however, no significant affects were observed on the IC50 values of vincristine and L­asparaginase. Furthermore, downregulation of CREBBP notably inhibited leukemia cell proliferation, accumulated cells in the G0/G1 phase and decreased cell proportions in the S and G2/M phases. Co­IP analysis demonstrated that CREBBP interacted with E2F3a, a transcription factor involved in G1/S transition. Immunofluorescence confocal microscopy indicated co­localization of CREBBP and E2F3a at the cell nucleus. Furthermore, E2F3a protein expression decreased in CREBBP RNA interference treated Jurkat and Reh cells. CASP8AP2, a target gene of E2F3a, was also identified to be a downstream gene of CREBBP. In addition, decreased IC50 value and cell proportions in the G0/G1 phase, accelerated cell proliferation and upregulated E2F3a and CASP8AP2 expression were exhibited in CREBBP overexpressed cells. Taken together, the results of the present study suggested that CREBBP downregulation affects proliferation and cell cycle progression in leukemia cells, potentially via the interaction and regulation of E2F3a, resulting in chemotherapy resistance. Thus, targeting CREBBP may be a therapeutic strategy for treating pediatric patients with ALL.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Proteína de Ligação a CREB/metabolismo , Pontos de Checagem do Ciclo Celular/genética , Proliferação de Células/genética , Daunorrubicina/farmacologia , Regulação para Baixo/genética , Resistencia a Medicamentos Antineoplásicos/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Proteína de Ligação a CREB/genética , Proteínas de Ligação ao Cálcio/metabolismo , Núcleo Celular/metabolismo , Fator de Transcrição E2F3/metabolismo , Humanos , Concentração Inibidora 50 , Células Jurkat , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Interferência de RNA , Transdução de Sinais/genética , Transfecção
16.
Chin Med J (Engl) ; 133(16): 1943-1951, 2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32826458

RESUMO

BACKGROUND: Hematopoietic stem cells (HSCs) have the ability to differentiate into all subsets of blood cells and self-renew. Large tumor suppressor 1 (LATS1) and large tumor suppressor 2 (LATS2) kinases are essential for cell cycle regulation, organism fitness, genome integrity, and cancer prevention. Here, we investigated whether Lats1 and Lats2 are critical for the maintenance of the self-renewal and quiescence capacities of HSCs in mice. METHODS: Quantitative reverse transcription-polymerase chain reaction was used to determine the expression levels of Lats1 and Lats2 in subsets of progenitor cells and mature bone marrow cells. A clustered regularly interspaced short palindromic repeats system was used to generate Lats1 or Lats2 knockout mice. Complete blood cell counts were used to compare the absolute number of white blood cells, lymphocytes, monocytes, neutrophils, and platelets between Lats1 or Lats2 heterozygotes and littermates. Flow cytometry was used to assess the size of hematopoietic progenitor cells (HPCs) and HSC pools in Lats1 or Lats2 heterozygotes and littermates. The comparison between the two groups was analyzed using Student's t test. RESULTS: Lats1 and Lats2 were widely expressed in hematopoietic cells with higher expression levels in primitive hematopoietic cells than in mature cells. Lats1 or Lats2 knockout mice were generated, with the homozygotes showing embryonic lethality. The size of the HPC and HSC pools in Lats1 (HPC: wild-type [WT] vs. heterozygote, 220,426.77 ±â€Š54,384.796 vs. 221,149.4 ±â€Š42,688.29, P = 0.988; HSC: WT vs. heterozygote, 2498.932 ±â€Š347.856 vs. 3249.763 ±â€Š370.412, P = 0.105) or Lats2 (HPC: WT vs. heterozygote, 425,540.52 ±â€Š99,721.86 vs. 467,127.8 ±â€Š89,574.48, P = 0.527; HSC: WT vs. heterozygote, 4760.545 ±â€Š1518.01 vs. 5327.437 ±â€Š873.297, P = 0.502) heterozygotes were not impaired. Moreover, the depletion of Lats1 or Lats2 did not affect the overall survival of the heterozygotes (Lats1: P = 0.654; Lats2: P = 0.152). CONCLUSION: These results indicate that a single allele of Lats1 or Lats2 may be sufficient for normal hematopoiesis.


Assuntos
Proteínas Serina-Treonina Quinases , Células-Tronco , Animais , Hematopoese/genética , Camundongos , Proteínas Serina-Treonina Quinases/genética
17.
Pediatr Hematol Oncol ; 37(8): 732-746, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32804017

RESUMO

CtBP is a known corepressor abundantly expressed in cancer and regulates genes involved in cancer initiation, progression, and metastasis. This study aimed to investigate the prognostic significance of CTBP2 expression in a cohort of pediatric patients with B cell precursor acute lymphoblastic leukemia (BCP-ALL). It further evaluated the role of combined CTBP2 and CASP8AP2 expression in risk of relapse of BCP-ALL. The expression of CTBP2 mRNA was retrospectively detected by a qRT-PCR approach in bone marrow samples from 104 children with newly diagnosed BCP-ALL. CASP8AP2 was assessed simultaneously in the 100 patients included in this study. The receiver operating characteristic (ROC) curve analysis determined the cut off levels for CTBP2 and CASP8AP2 expression with good predictive significance for relapse of BCP-ALL. Patients with low CTBP2 expression had inferior relapse-free survival (RFS) and event-free survival (EFS) when compared to patients with high-CTBP2 expression. The expression level of CTBP2 was significantly associated with CASP8AP2 expression (r = 0.449, P < 0.001). Patients were stratified into three groups according to the combined evaluation of the two gene expression, and patients with simultaneous low-expression had the worst outcome (6-year RFS: 64.6%±12.8%, P < 0.001). Multivariate analysis demonstrated the expression of CTBP2 and CASP8AP2, minimal residual disease (MRD) at day 33 remained as independent prognostic factors for RFS. Based on the final Cox hazards model, we proposed an algorithm to calculate the risk index, which was more precise for predicting relapse. In conclusion, low expression of CTBP2 and CASP8AP2 correlated with poor outcome and predicted risk of relapse in pediatric BCP-ALL.


Assuntos
Oxirredutases do Álcool/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Medula Óssea/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas Correpressoras/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Adolescente , Oxirredutases do Álcool/genética , Proteínas Reguladoras de Apoptose/genética , Proteínas de Ligação ao Cálcio/genética , Criança , Pré-Escolar , Proteínas Correpressoras/genética , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Reação em Cadeia da Polimerase em Tempo Real , Recidiva , Estudos Retrospectivos , Fatores de Risco
18.
Haematologica ; 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732367

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) is an immune-regulatory disorder characterized by excessive production of inflammatory cytokines. The treatment recommendations of the HLH-1994 and HLH-2004 protocols have long been used in HLH therapy, but some patients still do not respond well to or have unacceptable side effects from conventional therapies. It is believed that cytokine-targeted strategies that directly target disease-driving pathways will be promising options for HLH. This prospective study aimed to investigate the efficacy and safety of ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor, as a front-line therapy in children with secondary HLH. Twelve newly diagnosed patients without previous treatment were enrolled in this study with a median follow-up of 8.2 (7.1-12.0) months, including 8 cases of Epstein-Barr virus associated HLH (EBV-HLH), 2 cases of autoinflammatory disorder (AID)- associated HLH, and 2 cases of unknown etiology. Patients received oral ruxolitinib dosed on 2.5 mg, 5 mg or 10 mg twice daily depending on the body weight for 28 consecutive days. The overall response rate at the end of treatment (day 28) was 83.3% (10/12), with 66.7% (8/12) in complete response (CR), 8.3% (1/12) in partial response (PR), and 8.3% (1/12) in HLH improvement. Among the patients achieving CR, 87.5% (7/8) maintained CR condition for>6 months, and one patient with EBV-HLH relapsed following CR. For the EBV-HLH subgroup, all 8 patients responded to ruxolitinib, with a CR rate of 75% and a PR rate of 25%. Two patients with AID-associated HLH had quite different responses, with one showing reversal of the HLH abnormalities soon and the other showing no improvement, as did the two cases of unknown etiology. Patients who had no response or discontinued ruxolitinib all responded well to the subsequent HLH-1994 regimen. The expected 6-month event-free survival (EFS) rate was 58.3%±10.2%. No serious adverse effects were reported. Our study provides further support for the possibility of ruxolitinib targeted therapy for secondary HLH in children. This study was registered in the Chinese Clinical Trials Registry Platform (http://www.chictr.org.cn/) as ChiCTR2000029977.

19.
J Med Food ; 23(9): 943-951, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32721265

RESUMO

Tea and citrus maxima are natural, medicinal homologous plants, typically used for making beverages, which have anticancer, antiobesity, and antioxidation properties. Green tea, yellow tea, and black tea were combined with citrus maxima to obtain green tea and Citrus maxima (GTCM), yellow tea and Citrus maxima (YTCM), and black tea and Citrus maxima (BTCM). The biochemical components of these mixtures were analyzed, and their possible effects and mechanisms on relieving liver lipid deposition were explored. The tea polyphenols, free amino acids, phenolamine ratio, and caffeine were comparable in YTCM and GTCM, being significantly higher than those in BTCM. In addition, the content of esterified catechins, nonesterified catechins, and total catechins in YTCM was significantly higher than those in GTCM and BTCM. All three mixtures of Citrus maxima tea significantly reduced lipid deposition in HepG2 cells, with GTCM and YTCM being slightly more effective than BTCM. Regarding the possible mechanism, Western blot analysis revealed that the three Citrus maxima tea mixtures could activate the AMPK/ACC signaling pathway, upregulate the expression of p-AMPK, p-ACC, and CPT-1 proteins, and downregulate the expression of SREBP1c and fatty acid synthase proteins to inhibit fat synthesis, thereby relieving lipid deposition in liver cells. In conclusion, as a novel and healthy beverage, Citrus maxima tea has the potential to alleviate liver lipid deposition, and further could be responsible for obesity treatment.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Citrus/química , Lipídeos , Preparações de Plantas/farmacologia , Chá/química , Catequina , Células Hep G2 , Humanos , Transdução de Sinais , Chá/classificação
20.
Cancer Cell Int ; 20: 271, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32587478

RESUMO

Background: Aberrant activation of ß-catenin has been shown to play important roles in the chemoresistance of acute lymphoblastic leukemia (ALL), but the involvement and mechanism of ß-catenin in methotrexate (MTX) resistance is poorly understood. In the present study, we demonstrate a critical role of ß-catenin-NF-κB-FPGS pathway in MTX resistance in the human T-lineage ALL cell lines. Methods: Lentivirus sh-ß-catenin was used to silence the expression of ß-catenin. Flow cytometry was performed to detect apoptosis after MTX treatment. Western blot, real-time PCR, Co-immunoprecipitation (Co-IP), Chromatin immunoprecipitation (ChIP), Re-ChIP, and Luciferase assay were utilized to investigate the relationship among ß-catenin, nuclear factor (NF)-κB, and folypoly-γ-glutamate synthetase (FPGS). Results: Depletion of ß-catenin significantly increased the cytotoxicity of MTX. At the molecular level, knockdown of ß-catenin caused the increase of the protein level of FPGS and NF-κB p65. Furthermore, ß-catenin complexed with NF-κB p65 and directly bound to the FPGS promoter to regulate its expression. In addition, ß-catenin repression prolonged the protein turnover of FPGS. Conclusions: Taken together, our results demonstrate that ß-catenin may contribute to MTX resistance in leukemia cells via the ß-catenin-NF-κB-FPGS pathway, posing ß-catenin as a potential target for combination treatments during ALL therapy.

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