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1.
Regen Ther ; 18: 391-400, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34722835

RESUMO

Introduction: Osteoporosis, a common skeletal disorder mainly affecting postmenopausal women, is characterized by the imbalance between osteogenesis and osteoclastogenesis. Circ_0134944 has been recently found to be upregulated in postmenopausal osteoporosis (PMOP) patients. However, its role in osteogenesis remains unknown. Here we aimed to explore the role of circ_0134944 in osteogenesis and reveal the underlying mechanism. Methods: qRT-PCR was used to determine the expression of circ_0134944, miR-127-5p, PDX1 and SPHK1 in the blood mononuclear cells (BMCs) of PMOP patients. Bone marrow mesenchymal stem cells (BMSCs) were used as the cellular model. Western blotting and qRT-PCR were used to determine the expression of osteogenesis-related genes (Runx2, OPN, OCN). ALP and Alizarin Red S staining were performed to evaluate osteogenic differentiation. The interactions between circ_0134944 and miR-127-5p, miR-127-5p and PDX1, PDX1 and SPHK1 were determined by dual-luciferase reporter and ChIP assay. Results: Circ_0134944, PDX1 and SPHK1 were upregulated while miR-127-5p was downregulated in PMOP patients. Enhanced expression of circ_0134944 suppressed osteogenesis, which was then reversed by miR-127-5p overexpression. The binding between circ_0134944 and miR-127-5p, PDX1 and miR-127-5p were confirmed by dual-luciferase reporter assay. Moreover, PDX1 was enriched in the promoter region of SPHK1, and SPHK1 overexpression prevented the promotion of osteogenesis induced by miR-127-5p overexpression. Conclusions: Taken together, these results demonstrate that circ_0134944 inhibit osteogenesis via miR-127-5p/PDX1/SPHK1 axis. Thus, the present study offered evidence that circ_0134944/miR-127-5p/PDX1/SPHK1 axis could be a potential therapeutic target for PMOP.

2.
Sci Rep ; 11(1): 19022, 2021 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-34561473

RESUMO

Phosphatidylinositol glycan anchor biosynthesis class N (PIGN) has been linked to the suppression of chromosomal instability. The spindle assembly checkpoint complex is responsible for proper chromosome segregation during mitosis to prevent chromosomal instability. In this study, the novel role of PIGN as a regulator of the spindle assembly checkpoint was unveiled in leukemic patient cells and cell lines. Transient downregulation or ablation of PIGN resulted in impaired mitotic checkpoint activation due to the dysregulated expression of spindle assembly checkpoint-related proteins including MAD1, MAD2, BUBR1, and MPS1. Moreover, ectopic overexpression of PIGN restored the expression of MAD2. PIGN regulated the spindle assembly checkpoint by forming a complex with the spindle assembly checkpoint proteins MAD1, MAD2, and the mitotic kinase MPS1. Thus, PIGN could play a vital role in the spindle assembly checkpoint to suppress chromosomal instability associated with leukemic transformation and progression.

3.
Mol Brain ; 14(1): 124, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34384467

RESUMO

To understand the role of intracellular zinc ion (Zn2+) dysregulation in mediating age-related neurodegenerative changes, particularly neurotoxicity resulting from the generation of excessive neurotoxic amyloid-ß (Aß) peptides, this study aimed to investigate whether N, N, N', N'-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN), a Zn2+-specific chelator, could attenuate Aß25-35-induced neurotoxicity and the underlying electrophysiological mechanism. We used the 3-(4, 5-dimethyl-thiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay to measure the viability of hippocampal neurons and performed single-cell confocal imaging to detect the concentration of Zn2+ in these neurons. Furthermore, we used the whole-cell patch-clamp technique to detect the evoked repetitive action potential (APs), the voltage-gated sodium and potassium (K+) channels of primary hippocampal neurons. The analysis showed that TPEN attenuated Aß25-35-induced neuronal death, reversed the Aß25-35-induced increase in intracellular Zn2+ concentration and the frequency of APs, inhibited the increase in the maximum current density of voltage-activated sodium channel currents induced by Aß25-35, relieved the Aß25-35-induced decrease in the peak amplitude of transient outward K+ currents (IA) and outward-delayed rectifier K+ currents (IDR) at different membrane potentials, and suppressed the steady-state activation and inactivation curves of IA shifted toward the hyperpolarization direction caused by Aß25-35. These results suggest that Aß25-35-induced neuronal damage correlated with Zn2+ dysregulation mediated the electrophysiological changes in the voltage-gated sodium and K+ channels. Moreover, Zn2+-specific chelator-TPEN attenuated Aß25-35-induced neuronal damage by recovering the intracellular Zn2+ concentration.

4.
Biomol NMR Assign ; 15(2): 421-425, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34296398

RESUMO

Human Atg3 (hAtg3) is an E2-like enzyme that catalyzes the conjugation of LC3 family proteins to phosphatidylethanolamine (PE) lipids in the autophagosomal membrane during autophagy. The reaction product, LC3-PE, acts as a marker for autophagic cargo and is required for the effective construction of functional autophagosomes. However, the structural and molecular basis of this conjugation reaction remains elusive, at least in part, because of the absence of lipid bilayers in structural studies conducted to date. Here, we report a sequential resonance assignment for an hAtg3 construct both in aqueous solution and in bicelles. hAtg3 has 314 residues, and our construct lacks the unstructured region from residues 90 to 190. Our results demonstrate a structural rearrangement of hAtg3 N-terminus when it interacts with membranes.

5.
World J Gastroenterol ; 27(21): 2834-2849, 2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34135557

RESUMO

BACKGROUND: Emerging evidence has demonstrated that fecal microbiota transplantation (FMT) has a promising therapeutic effect on mice with experimental colitis and patients with ulcerative colitis (UC), although the mechanism of FMT is unclear. AIM: To evaluate the protective effect of FMT on UC and clarify its potential dependence on the gut microbiota, through association analysis of gut microbiota with colon transcriptome in mice. METHODS: Dextran sodium sulfate (DSS)-induced experimental colitis was established and fecal microbiota was transplanted by gavage. Severity of colon inflammation was measured by body weight, disease activity index, colon length and histological score. Gut microbiota alteration was analyzed through 16S ribosomal ribonucleic acid sequencing. The differentially expressed genes (DEGs) in the colon were obtained by transcriptome sequencing. The activation status of colonic T lymphocytes in the lamina propria was evaluated by flow cytometry. RESULTS: Compared with the DSS group, the weight loss, colon length shortening and inflammation were significantly alleviated in the FMT group. The scores of disease activity index and colon histology decreased obviously after FMT. FMT restored the balance of gut microbiota, especially by upregulating the relative abundance of Lactobacillus and downregulating the relative abundance of Clostridium_sensu_stricto_1 and Turicibacter. In the transcriptomic analysis, 128 DEGs intersected after DSS treatment and FMT. Functional annotation analysis suggested that these DEGs were mainly involved in T-lymphocyte activation. In the DSS group, there was an increase in colonic T helper CD4+ and T cytotoxic CD8+ cells by flow cytometry. FMT selectively downregulated the ratio of colonic CD4+ and CD8+ T cells to maintain intestinal homeostasis. Furthermore, Clostri dium_sensu_stricto_1 was significantly related to inflammation-related genes including REG3G, CCL8 and IDO1. CONCLUSION: FMT ameliorated DSS-induced colitis in mice via regulating the gut microbiota and T-cell modulation.


Assuntos
Colite Ulcerativa , Colite , Microbioma Gastrointestinal , Animais , Linfócitos T CD8-Positivos , Colite/induzido quimicamente , Colite/terapia , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/terapia , Colo , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Transplante de Microbiota Fecal , Humanos , Camundongos
6.
JCI Insight ; 6(15)2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34156984

RESUMO

SCN2A, encoding the neuronal voltage-gated Na+ channel NaV1.2, is one of the most commonly affected loci linked to autism spectrum disorders (ASDs). Most ASD-associated mutations in SCN2A are loss-of-function mutations, but studies examining how such mutations affect neuronal function and whether Scn2a mutant mice display ASD endophenotypes have been inconsistent. We generated a protein truncation variant Scn2a mouse model (Scn2aΔ1898/+) by CRISPR that eliminates the NaV1.2 channel's distal intracellular C-terminal domain, and we analyzed the molecular and cellular consequences of this variant in a heterologous expression system, in neuronal culture, in brain slices, and in vivo. We also analyzed multiple behaviors in WT and Scn2aΔ1898/+ mice and correlated behaviors with clinical data obtained in human subjects with SCN2A variants. Expression of the NaV1.2 mutant in a heterologous expression system revealed decreased NaV1.2 channel function, and cultured pyramidal neurons isolated from Scn2aΔ1898/+ forebrain showed correspondingly reduced voltage-gated Na+ channel currents without compensation from other CNS voltage-gated Na+ channels. Na+ currents in inhibitory neurons were unaffected. Consistent with loss of voltage-gated Na+ channel currents, Scn2aΔ1898/+ pyramidal neurons displayed reduced excitability in forebrain neuronal culture and reduced excitatory synaptic input onto the pyramidal neurons in brain slices. Scn2aΔ1898/+ mice displayed several behavioral abnormalities, including abnormal social interactions that reflect behavior observed in humans with ASD and with harboring loss-of-function SCN2A variants. This model and its cellular electrophysiological characterizations provide a framework for tracing how a SCN2A loss-of-function variant leads to cellular defects that result in ASD-associated behaviors.

7.
J Pers Med ; 11(3)2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33799721

RESUMO

FLT3-mutant acute myeloid leukemia (AML) is an aggressive form of leukemia with poor prognosis. Treatment with FLT3 inhibitors frequently produces a clinical response, but the disease nevertheless often recurs. Recent studies have revealed system-wide gene expression changes in FLT3-mutant AML cell lines in response to drug treatment. Here we sought a systems-level understanding of how these cells mediate these drug-induced changes. Using RNAseq data from AML cells with an internal tandem duplication FLT3 mutation (FLT3-ITD) under six drug treatment conditions including quizartinib and dexamethasone, we identified seven distinct gene programs representing diverse biological processes involved in AML drug-induced changes. Based on the literature knowledge about genes from these modules, along with public gene regulatory network databases, we constructed a network of FLT3-ITD AML. Applying the BooleaBayes algorithm to this network and the RNAseq data, we created a probabilistic, data-driven dynamical model of acquired resistance to these drugs. Analysis of this model reveals several interventions that may disrupt targeted parts of the system-wide drug response. We anticipate co-targeting these points may result in synergistic treatments that can overcome resistance and prevent eventual recurrence.

9.
World J Clin Cases ; 9(2): 334-343, 2021 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-33521101

RESUMO

BACKGROUND: The inverse association between systemic immune-inflammation index (SII) and overall survival in tumors has been studied. AIM: To evaluate the hematological indexes for assessing the activity of ulcerative colitis (UC). METHODS: In this case-control study, 172 UC patients and healthy participants were included. Comparisons were made among groups of white blood cells, hemoglobin, platelets, neutrophils, lymphocytes, monocytes, SII, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR). The relationship with hematological inflammation was verified by Spearman correlation analyses. The efficiency of SII, NLR, and PLR for distinguishing between UC and severe disease status was assessed by the receiver operator curve and logistic regression analyses. RESULTS: The values of SII, NLR, and PLR were higher in UC patients than in controls (P < 0.001) and were positively correlated with the Mayo endoscopic score, extent, Degree of Ulcerative Colitis Burden of Luminal Inflammation (DUBLIN) score, and Ulcerative Colitis Endoscopic Index of Severity (UCEIS). The cut-off NLR value of 562.22 predicted UC with a sensitivity of 79.65% and a specificity of 76.16%. Logistic regression analysis revealed that patients with SII and NLR levels above the median had a significantly higher risk of UC (P < 0.05). Risk factors independently associated with DUBLIN ≥ 3 included SII ≥ 1776.80 [odds ratio (OR) = 11.53, P = 0.027] and NLR value of 2.67-4.23 (OR = 2.96, P = 0.047) on multivariate analysis. Compared with the first quartile, SII ≥ 1776.80 was an independent predictor of UCEIS ≥ 5 (OR = 18.46, P = 0.012). CONCLUSION: SII has a certain value in confirming UC and identifying its activity.

10.
Nat Commun ; 12(1): 374, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33446636

RESUMO

During autophagy the enzyme Atg3 catalyzes the covalent conjugation of LC3 to the amino group of phosphatidylethanolamine (PE) lipids, which is one of the key steps in autophagosome formation. Here, we have demonstrated that an N-terminal conserved region of human Atg3 (hAtg3) communicates information from the N-terminal membrane curvature-sensitive amphipathic helix (AH), which presumably targets the enzyme to the tip of phagophore, to the C-terminally located catalytic core for LC3-PE conjugation. Mutations in the putative communication region greatly reduce or abolish the ability of hAtg3 to catalyze this conjugation in vitro and in vivo, and alter the membrane-bound conformation of the wild-type protein, as reported by NMR. Collectively, our results demonstrate that the N-terminal conserved region of hAtg3 works in concert with its geometry-selective AH to promote LC3-PE conjugation only on the target membrane, and substantiate the concept that highly curved membranes drive spatial regulation of the autophagosome biogenesis during autophagy.


Assuntos
Proteínas Relacionadas à Autofagia/química , Proteínas Relacionadas à Autofagia/metabolismo , Autofagia , Membrana Celular/metabolismo , Enzimas de Conjugação de Ubiquitina/química , Enzimas de Conjugação de Ubiquitina/metabolismo , Proteínas Relacionadas à Autofagia/genética , Biocatálise , Membrana Celular/genética , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo , Conformação Proteica em alfa-Hélice , Domínios Proteicos , Enzimas de Conjugação de Ubiquitina/genética
11.
Cancer Res ; 81(2): 452-463, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33115808

RESUMO

Although neoadjuvant chemotherapy is a standard component of breast cancer treatment, recent evidence suggests that chemotherapeutic drugs can promote metastasis through poorly defined mechanisms. Here we utilize xenograft mouse models of triple-negative breast cancer to explore the importance of chemotherapy-induced tumor-derived small extracellular vesicles (sEV) in metastasis. Doxorubicin (DXR) enhanced tumor cell sEV secretion to accelerate pulmonary metastasis by priming the premetastatic niche. Proteomic analysis and CRISPR/Cas9 gene editing identified the inflammatory glycoprotein PTX3 enriched in DXR-elicited sEV as a critical regulator of chemotherapy-induced metastasis. Both genetic inhibition of sEV secretion from primary tumors and pharmacologic inhibition of sEV uptake in secondary organs suppressed metastasis following chemotherapy. Taken together, this research uncovers a mechanism of chemotherapy-mediated metastasis by which drug-induced upregulation of sEV secretion and PTX3 protein cargo primes the premetastatic niche and suggests that inhibition of either sEV uptake in secondary organs or secretion from primary tumor cells may be promising therapeutic strategies to suppress metastasis. SIGNIFICANCE: These findings show that chemotherapy-induced small extracellular vesicles accelerate breast cancer metastasis, and targeted inhibition of tumor-derived vesicles may be a promising therapeutic strategy to improve the efficacy of chemotherapy treatment.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Proteína C-Reativa/metabolismo , Doxorrubicina/efeitos adversos , Vesículas Extracelulares/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Componente Amiloide P Sérico/metabolismo , Animais , Antibióticos Antineoplásicos/efeitos adversos , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Proteína C-Reativa/genética , Movimento Celular , Proliferação de Células , Vesículas Extracelulares/efeitos dos fármacos , Feminino , Humanos , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/metabolismo , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Componente Amiloide P Sérico/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Cell Death Differ ; 28(2): 657-670, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32807832

RESUMO

Autophagosomal membranes can serve as activation platforms for intracellular death-inducing signaling complexes (iDISCs) to initiate Caspase-8-dependent apoptosis. In this study, we explore the impact of ESCRT-III-dependent phagophore closure on iDISC assemblies and cell death in osteosarcoma and neuroblastoma cells. Inhibition of phagophore closure by conditional depletion of CHMP2A, an ESCRT-III component, stabilizes iDISCs on immature autophagosomal membranes and induces Caspase-8-dependent cell death. Importantly, suppression of the iDISC formation via deletion of ATG7, an E1 enzyme for ubiquitin-like autophagy-related proteins, blocks Caspase-8 activation and cell death following CHMP2A depletion. Although DR5 expression and TRAIL-induced apoptosis are enhanced in CHMP2A-depleted cells, the canonical extrinsic pathway of apoptosis is not responsible for the initiation of cell death by CHMP2A depletion. Furthermore, the loss of CHMP2A impairs neuroblastoma tumor growth associated with decreased autophagy and increased apoptosis in vivo. Together, these findings indicate that inhibition of the ESCRT-III-dependent autophagosome sealing process triggers noncanonical Caspase-8 activation and apoptosis, which may open new avenues for therapeutic targeting of autophagy in cancer.

13.
Nat Commun ; 11(1): 6118, 2020 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-33257658

RESUMO

Inhibitors of poly-ADP-ribose polymerase 1 (PARPi) are highly effective in killing cells deficient in homologous recombination (HR); thus, PARPi have been clinically utilized to successfully treat BRCA2-mutant tumors. However, positive response to PARPi is not universal, even among patients with HR-deficiency. Here, we present the results of genome-wide CRISPR knockout and activation screens which reveal genetic determinants of PARPi response in wildtype or BRCA2-knockout cells. Strikingly, we report that depletion of the ubiquitin ligase HUWE1, or the histone acetyltransferase KAT5, top hits from our screens, robustly reverses the PARPi sensitivity caused by BRCA2-deficiency. We identify distinct mechanisms of resistance, in which HUWE1 loss increases RAD51 levels to partially restore HR, whereas KAT5 depletion rewires double strand break repair by promoting 53BP1 binding to double-strand breaks. Our work provides a comprehensive set of putative biomarkers that advance understanding of PARPi response, and identifies novel pathways of PARPi resistance in BRCA2-deficient cells.


Assuntos
Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Inibidores de Poli(ADP-Ribose) Polimerases/isolamento & purificação , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/efeitos dos fármacos , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Biomarcadores , Dano ao DNA , Reparo do DNA , Técnicas de Inativação de Genes , Células HeLa , Recombinação Homóloga/efeitos dos fármacos , Humanos , Lisina Acetiltransferase 5/metabolismo , Proteínas Mad2/metabolismo , Rad51 Recombinase/genética , Rad51 Recombinase/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Proteína 1 de Ligação à Proteína Supressora de Tumor p53 , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
14.
J Hematol Oncol ; 13(1): 155, 2020 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-33213500

RESUMO

Acute myeloid leukemia (AML) is a heterogeneous disease caused by several gene mutations and cytogenetic abnormalities affecting differentiation and proliferation of myeloid lineage cells. FLT3 is a receptor tyrosine kinase commonly overexpressed or mutated, and its mutations are associated with poor prognosis in AML. Although aggressive chemotherapy often followed by hematopoietic stem cell transplant is the current standard of care, the recent approval of FLT3-targeted drugs is revolutionizing AML treatment that had remained unchanged since the 1970s. However, despite the dramatic clinical response to targeted agents, such as FLT3 inhibitors, remission is almost invariably short-lived and ensued by relapse and drug resistance. Hence, there is an urgent need to understand the molecular mechanisms driving drug resistance in order to prevent relapse. In this review, we discuss FLT3 as a target and highlight current understanding of FLT3 inhibitor resistance.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Terapia de Alvo Molecular , Mutação/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Tirosina Quinase 3 Semelhante a fms/química , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo
15.
Nat Commun ; 11(1): 5424, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33110073

RESUMO

Tumor necrosis commonly exists and predicts poor prognoses in many cancers. Although it is thought to result from chronic ischemia, the underlying nature and mechanisms driving the involved cell death remain obscure. Here, we show that necrosis in glioblastoma (GBM) involves neutrophil-triggered ferroptosis. In a hyperactivated transcriptional coactivator with PDZ-binding motif-driven GBM mouse model, neutrophils coincide with necrosis temporally and spatially. Neutrophil depletion dampens necrosis. Neutrophils isolated from mouse brain tumors kill cocultured tumor cells. Mechanistically, neutrophils induce iron-dependent accumulation of lipid peroxides within tumor cells by transferring myeloperoxidase-containing granules into tumor cells. Inhibition or depletion of myeloperoxidase suppresses neutrophil-induced tumor cell cytotoxicity. Intratumoral glutathione peroxidase 4 overexpression or acyl-CoA synthetase long chain family member 4 depletion diminishes necrosis and aggressiveness of tumors. Furthermore, analyses of human GBMs support that neutrophils and ferroptosis are associated with necrosis and predict poor survival. Thus, our study identifies ferroptosis as the underlying nature of necrosis in GBMs and reveals a pro-tumorigenic role of ferroptosis. Together, we propose that certain tumor damage(s) occurring during early tumor progression (i.e. ischemia) recruits neutrophils to the site of tissue damage and thereby results in a positive feedback loop, amplifying GBM necrosis development to its fullest extent.


Assuntos
Ferroptose , Glioblastoma/fisiopatologia , Neutrófilos/imunologia , Animais , Linhagem Celular Tumoral , Coenzima A Ligases/genética , Coenzima A Ligases/imunologia , Progressão da Doença , Feminino , Glioblastoma/genética , Glioblastoma/imunologia , Glioblastoma/patologia , Humanos , Ferro/imunologia , Camundongos , Camundongos Nus , Necrose , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/imunologia
16.
World J Clin Cases ; 8(17): 3786-3796, 2020 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-32953854

RESUMO

BACKGROUND: Transendoscopic enteral tubing (TET) has been used in China as a novel delivery route for fecal microbiota transplantation (FMT) into the whole colon with a high degree of patient satisfaction among adults. AIM: To explore the recognition and attitudes of FMT through TET in patients with inflammatory bowel disease (IBD). METHODS: An anonymous questionnaire, evaluating their awareness and attitudes toward FMT and TET was distributed among IBD patients in two provinces of Eastern and Southwestern China. Question formats included single-choice questions, multiple-choice questions and sorting questions. Patients who had not undergone FMT were mainly investigated for their cognition and acceptance of FMT and TET. Patients who had experience of FMT, the way they underwent FMT and acceptance of TET were the main interest. Then all the patients were asked whether they would recommend FMT and TET. This study also analyzed the preference of FMT delivery in IBD patients and the patient-related factors associated with it. RESULTS: A total of 620 eligible questionnaires were included in the analysis. The survey showed that 44.6% (228/511) of patients did not know that FMT is a therapeutic option in IBD, and 80.6% (412/511) of them did not know the concept of TET. More than half (63.2%, 323/511) of the participants stated that they would agree to undergo FMT through TET. Of the patients who underwent FMT via TET [62.4% (68/109)], the majority [95.6% (65/68)] of them were satisfied with TET. Patients who had undergone FMT and TET were more likely to recommend FMT than patients who had not (94.5% vs 86.3%, P = 0.018 and 98.5% vs 87.8%, P = 0.017). Patients' choice for the delivery way of FMT would be affected by the type of disease and whether the patient had the experience of FMT. When compared to patients without experience of FMT, Crohn's disease and ulcerative colitis patients who had experience of FMT preferred mid-gut TET (P < 0.001) and colonic TET (P < 0.001), respectively. CONCLUSION: Patients' experience of FMT through TET lead them to maintain a positive attitude towards FMT. The present findings highlighted the significance of patient education on FMT and TET.

17.
Medicine (Baltimore) ; 99(35): e22035, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871960

RESUMO

Imbalances in the gut microbiota mediate the progression of neurodegenerative diseases such as Parkinson's disease (PD). Fecal microbiota transplantation (FMT) is currently being explored as a potential therapy for PD. The objective of this study was to assess the efficacy and safety of FMT on PD. Fifteen PD patients were included, 10 of them received FMT via colonoscopy (colonic FMT group) and 5 received FMT via nasal-jejunal tube (nasointestinal FMT group). The score of PSQI, HAMD, HAMA, PDQ-39, NMSQ and UPDRS-III significantly decreased after FMT treatment (all P < .05). Colonic FMT group showed significant improvement and longer maintenance of efficacy compared with nasointestinal FMT (P = .002). Two patients achieved self-satisfying outcomes that last for more than 24 months. However, nasointestinal FMT group had no significant therapeutic effect, although UPDRS-III score slightly reduced. There were no patients were satisfied with nasointestinal FMT for more than 3 months. Among 15 PD patients, there were 5 cases had adverse events (AEs), including diarrhea (2 cases), abdominal pain (2 cases) and flatulence (1 case). These AEs were mild and self-limiting. We conclude that FMT can relieve the motor and non-motor symptoms with acceptable safety in PD. Compared with nasointestinal FMT, colonic FMT seems better and preferable.


Assuntos
Transplante de Microbiota Fecal/estatística & dados numéricos , Doença de Parkinson/terapia , Idoso , Colonoscopia , Transplante de Microbiota Fecal/efeitos adversos , Transplante de Microbiota Fecal/métodos , Feminino , Humanos , Intubação Gastrointestinal , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Projetos Piloto , Adulto Jovem
18.
Arch Biochem Biophys ; 693: 108561, 2020 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-32857999

RESUMO

PURPOSE: To explore genistein, the most active component of soy isoflavones, on viability, expression of estrogen receptor (ER) subtypes, choline acetyltransferase (ChAT), and glutamate receptor subunits in amyloid peptide 25-35-induced hippocampal neurons, providing valuable data and basic information for neuroprotective effect of genistein in Aß25-35-induced neuronal injury. METHODS: We established an in vitro model of Alzheimer's disease by exposing primary hippocampal neurons of newborn rats to amyloid peptide 25-35 (20 µM) for 24 h and observing the effects of genistein (10 µM, 3 h) on viability, expression of ER subtypes, ChAT, NMDA receptor subunit NR2B and AMPA receptor subunit GluR2 in Aß25-35-induced hippocampal neurons. RESULTS: We found that amyloid peptide 25-35 exposure reduced the viability of hippocampal neurons. Meanwhile, amyloid peptide 25-35 exposure decreased the expression of ER subtypes, ChAT and GluR2, and increased the expression of NR2B. Genistein at least partially reversed the effects of amyloid peptide 25-35 in hippocampal neurons. CONCLUSION: Genistein could increase the expression of ChAT as a consequence of activating estrogen receptor subtypes, modulating the expression of NR2B and GluR2, and thereby ameliorating the status of hippocampal neurons and exerting neuroprotective effects against amyloid peptide 25-35. Our data suggest that genistein might represent a potential cell-targeted therapy which could be a promising approach to treating AD.


Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Morte Celular/fisiologia , Colina O-Acetiltransferase/antagonistas & inibidores , Genisteína/farmacologia , Neurônios/efeitos dos fármacos , Fragmentos de Peptídeos/antagonistas & inibidores , Receptores de Estrogênio/efeitos dos fármacos , Receptores de Glutamato/efeitos dos fármacos , Peptídeos beta-Amiloides/fisiologia , Animais , Neurônios/citologia , Neurônios/enzimologia , Neurônios/metabolismo , Fragmentos de Peptídeos/fisiologia , Ratos , Ratos Wistar
19.
Cancers (Basel) ; 12(8)2020 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-32731407

RESUMO

Neuroblastoma is a common cancer in children, affected by a number of genes that interact with each other through intricate but coordinated networks. Traditional approaches can only reconstruct a single regulatory network that is topologically not informative enough to explain the complexity of neuroblastoma risk. We implemented and modified an advanced model for recovering informative, omnidirectional, dynamic, and personalized networks (idopNetworks) from static gene expression data for neuroblastoma risk. We analyzed 3439 immune genes of neuroblastoma for 217 high-risk patients and 30 low-risk patients by which to reconstruct large patient-specific idopNetworks. By converting these networks into risk-specific representations, we found that the shift in patients from a low to high risk or from a high to low risk might be due to the reciprocal change of hub regulators. By altering the directions of regulation exerted by these hubs, it may be possible to reduce a high risk to a low risk. Results from a holistic, systems-oriented paradigm through idopNetworks can potentially enable oncologists to experimentally identify the biomarkers of neuroblastoma and other cancers.

20.
Front Cell Dev Biol ; 8: 469, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32637411

RESUMO

Purpose: To investigate the role of protein misfolding in retinal pigment epithelial (RPE) cell dysfunction, the effects of R345W-Fibulin-3 expression on RPE cell phenotype were studied. Methods: Primary RPE cells were cultured to confluence on Transwells and infected with lentivirus constructs to express wild-type (WT)- or R345W-Fibulin-3. Barrier function was assessed by evaluating zonula occludens-1 (ZO-1) distribution and trans-epithelial electrical resistance (TER). Polarized secretion of vascular endothelial growth factor (VEGF), was measured by Enzyme-linked immunosorbent assay (ELISA). Differentiation status was assessed by qPCR of genes known to be preferentially expressed in terminally differentiated RPE cells, and conversion to an epithelial-mesenchymal transition (EMT) phenotype was assessed by a migration assay. Results: Compared to RPE cells expressing WT-Fibulin-3, ZO-1 distribution was disrupted and TER values were significantly lower in RPE cells expressing R345W-Fibulin-3. In cells expressing mutant Fibulin-3, VEGF secretion was attenuated basally but not in the apical direction, whereas Fibulin-3 secretion was reduced in both the apical and basal directions. Retinal pigment epithelial signature genes were downregulated and multiple genes associated with EMT were upregulated in the mutant group. Migration assays revealed a faster recovery rate in ARPE-19 cells overexpressing R345W-Fibulin-3 compared to WT. Conclusions: The results suggest that expression of R345W-Fibulin-3 promotes EMT in RPE cells.

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