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1.
Endocr Connect ; 10(10): 1299-1306, 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34524970

RESUMO

Objective: To investigate the relationship between serum uric acid (SUA) level and renal outcome in patients with type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN). Methods: A total of 393 Chinese patients with T2DM and biopsy-proven DN and followed at least 1 year were enrolled in this study. Patients were stratified by the quartiles of baseline level of SUA: Q1 group: 286.02 ± 46.66 µmol/L (n = 98); Q2 group: 358.23 ± 14.03 µmol/L (n = 99); Q3 group: 405.50 ± 14.59 µmol/L (n = 98) and Q4 group: 499.14 ± 56.97µmol/L (n = 98). Renal outcome was defined by progression to end-stage renal disease (ESRD). Kaplan-Meier survival analysis and Cox proportional hazards model were used to analyze the association between SUA quartiles and the renal outcomes. Results: During the median 3-year follow-up period, there were 173 ESRD outcome events (44.02%). No significant difference between SUA level and the risk of progression of DN (P = 0.747) was shown in the Kaplan-Meier survival analysis. In multivariable-adjusted model, hazard ratios for developing ESRD were 1.364 (0.621-2.992; P = 0.439), 1.518 (0.768-3.002; P = 0.230) and 1.411 (0.706-2.821; P = 0.330) for the Q2, Q3 and Q4, respectively, in comparison with the Q1 (P = 0.652). Conclusions: No significant association between SUA level and renal outcome of ESRD in Chinese patients with T2DM and DN was found in our study. Besides, the role of uric acid-lowering therapy in delaying DN progression and improving ESRD outcome had not yet been proven. Further study was needed to clarify the renal benefit of the uric acid-lowering therapy in the treatment of DN.

2.
Cell Death Dis ; 12(9): 829, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34480018

RESUMO

Recent studies indicate that Toll-like receptors (TLRs) and C-type lectin receptors (CLRs) can function as the signal of pattern recognition receptors, which play a pivotal role in the pathogenesis of the autoimmune disease. Systemic lupus erythematosus (SLE) is a classic autoimmune disease. Previous reports mainly focused on the potential role of TLRs in regulating the development of SLE, but little is known about the role of CLRs in the progression of SLE. Our previous studies showed that the inflammation-mediated accumulation of myeloid-derived suppressor cells (MDSCs) including granulocytic (G-MDSCs) and monocytic (M-MDSCs) participated in the pathogenesis of lupus. Mice deficient in Card9 (the downstream molecule of CLRs) were more susceptible to colitis-associated cancer via promoting the expansion of MDSCs. Whether the abnormal activation of CLRs regulates the expansion of MDSCs to participate in the pathogenesis of lupus remains unknown. In the present study, the expressions of CLRs were examined in both SLE patients and mouse models, revealing the expression of Dectin3 was positively correlated with SLEDAI. Dectin3 deficiency retarded the lupus-like disease by regulating the expansion and function of MDSCs. The mechanistic analysis revealed that Dectin3 deficiency promoted FoxO1-mediated apoptosis of MDSCs. Syk-Akt1-mediated nuclear transfer of FoxO1 increased in Dectin3-deficient MDSCs. Notedly, the accumulation of M-MDSCs mainly decreased in Dectin3-/- lupus mice, and the nuclear transfer of FoxO1 negatively correlated with the expression of LOX-1 on M-MDSCs. The silencing of FoxO1 expression in Dectin3-/- mice promoted the expansion of LOX-1+ M-MDSCs in vivo, and LOX-1+ M-MDSCs increased the differentiation of Th17 cells. Both LOX-1 expression on M-MDSCs and Dectin3 expression on MDSCs increased in patients with SLE. These data indicated that increased LOX-1+ M-MDSCs were related to the exacerbation of SLE development and might be potential target cells for the treatment of SLE.

3.
Immunobiology ; 226(5): 152133, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34469785

RESUMO

BACKGROUND AND AIMS: Pyroptosis is a relatively newly discovered form of programmed cell death that plays an important role in the development of atherosclerosis. Many studies have reported that lncRNAs participated in the regulation of atherosclerosis development. However, the regulatory mechanism of lncRNAs in pyroptosis must be studied further. METHODS: In a previous study, microarray analysis was used to detect the lncRNA expression profile in three human advanced atherosclerotic plaques and three normal arterial intimae. In the present research, in vitro assays were performed to investigate the role of lncRNA RP11-490M8.1 on pyroptosis. The relative gene mRNA and lncRNA expression levels were tested by quantitative real-time PCR, and protein levels were evaluated by western blot analysis. The RNA hybrid structure was analyzed using the DINAMelt server. RESULTS: The lncRNA RP11-490M8.1 was significantly downregulated in atherosclerotic plaques and serum. Lipopolysaccharide (LPS) markedly reduced the expression of lncRNA RP11-490M8.1 and induced pyroptosis by increasingthe mRNA and protein levels of NLRP3, caspase-1, ASC, IL-1ß, and IL-18 in HUVECs. The promotion effects ofLPS on pyroptosis were markedly suppressed by overexpression of lncRNA RP11-490M8.1. In addition, LPS increased the mRNA and protein levels ofTLR4 and NF-κB, which was also markedly offsetby overexpression of lncRNA RP11-490M8.1. CONCLUSIONS: These findings indicated that lncRNA RP11-490M8.1 inhibited LPS-induced pyroptosis via the TLR4/NF-κB pathway. Thus, lncRNA RP11-490M8.1 may provide a therapeutic target to ameliorate atherosclerosis.

4.
HLA ; 98(5): 431-447, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34505410

RESUMO

Antibody-mediated rejection (AMR) induced by donor-specific anti-HLA antibodies (DSA) remains a major cause of long-term graft loss after kidney transplantation. Currently, the presence of DSA cannot always be determined at a specific allele level, because existing donor HLA typing is low resolution and often incomplete, lacking HLA-DP, and occasionally HLA-C and HLA-DQ information and historical donor DNA samples are not available for HLA retyping. Here we present a novel, non-invasive technique for obtaining donor DNA from selectively expanded donor cells from urine of renal transplant recipients. Urine-derived cells were successfully expanded ex vivo from 31 of 32 enrolled renal transplant recipients, and with DNA obtained from these cells, donor HLA typing was unambiguously determined for HLA-A, -B, -C, -DRB1, -DQA1, -DQB1, -DPA1 and -DPB1 loci by next-generation sequencing. Our results showed 100% concordance of HLA typing data between donor peripheral blood and recipient urine-derived cells. In comparison, HLA typing showed that DNA derived from urine sediments mainly contained recipient-derived DNA. We also present the successful application of our novel technique in a clinical case of AMR in a renal transplant recipient. Urine-derived donor cells can be isolated from kidney transplant recipients and serve as a suitable source of donor material for reliable high-resolution HLA genotyping. Thus, this approach can aid the assessment of DSA specificity to support the diagnosis of AMR as well as the evaluation of treatment efficacy in kidney transplant recipients when complete donor HLA information and donor DNA are unavailable.

5.
Biomolecules ; 11(8)2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34439865

RESUMO

Integrin ß4 (ITGß4) is a class of transmembrane adhesion molecules composed of hemidesmosomes (HDs). Its unique long intracellular domain provides intricate signal transduction functions. These signal transduction effects are especially prominent in tumors. Many recent studies have shown that integrin ß4 is differentially expressed in various tumors, and it plays a vital role in tumor invasion, proliferation, epithelial-mesenchymal transition, and angiogenesis. Therefore, we categorize the research related to integrin ß4, starting from its structure and function in tumor tissues, and provide a basic description. Based on its structure and function, we believe that integrin ß4 can be used as a tumor marker. In clinical practice, it is described as a diagnostic marker for the targeted treatment of cancer and will be helpful in the clinical diagnosis and treatment of tumors.


Assuntos
Biomarcadores Tumorais/biossíntese , Regulação Neoplásica da Expressão Gênica , Integrina beta4/biossíntese , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Antineoplásicos/administração & dosagem , Biomarcadores Tumorais/genética , Humanos , Integrina beta4/genética , Invasividade Neoplásica/patologia , Neoplasias/diagnóstico , Neoplasias/genética
6.
Artigo em Inglês | MEDLINE | ID: mdl-34418286

RESUMO

Poor angiogenesis and bony ingrowth are the major factors causing unsatisfactory healing between the tendon graft and the bone tunnel surface. Exogenous biological factors, biomaterials, and cells have been considered as new strategies to promote healing quality in recent years. However, it remains challenging for their clinical use because of insufficient in-situ retention time and release efficiency. Increasing attention has been paid to the hydrogel microspheres (HMPs) as potential drug-loading deliveries in biomedicine due to their minimally invasive manner, extended drug retention time, and high loading efficiency. In this review, the healing mechanism between the tendon graft and the bone tunnel is introduced, which is followed by a brief summarization of current methods applied for enhancement of the healing quality. Then, the preclinical studies focusing on HMPs as novel drug carriers are summarized to address the aforementioned concerns in the treatment of tendon-bone healing. Of note, the challenges and perspectives of HMPs in clinical conversion are also outlooked. Collectively, this review may inspire researchers and clinicians to develop clinical available HMPs in orthopedics such as sports medicine from both material and biomedical aspects.

7.
Toxicol Lett ; 350: 152-161, 2021 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-34311048

RESUMO

As nephrogenic systemic fibrosis (NSF) and increased signal intensities in deep cerebellar nuclei (DCN) were successively discovered in renal insufficiency patients and healthy persons after gadolinium-based contrast agents (GBCAs) exposure, an awareness of potential toxicity with GBCAs exposure has been heightening. Herein, we performed a multi-organ/tissue toxicity assessment after different GBCAs administration with a large number of samples, and long-term, time-course schedule investigation. ICR mice were randomized to five exposure groups (n = 42/group) and received intravenous injection of GBCAs (2.5 mmol Gd/kg) or saline four time a week for 5 consecutive weeks. Gadolinium concentration detection, sensory tests, histological and hematological analyses were performed at corresponding timepoints (4th or 6th or 10th week). Our results showed that (i) gadodiamide could cause reversible vacuolar changes in the renal tubular epithelial cells, which appeared at 6th week and recovered at 10th week, and severe skin lesion in mice tail with consecutive injection for 10 weeks, that (ii) linear GBCAs (gadodiamide and gadopentetate dimeglumine) markedly elevated heat hyperalgesia and white blood cells of mice at 6th week and most of these changes could recovery at 10th week, and that (iii) linear GBCAs exhibited more gadolinium retention in multi-organ/tissue versus macrocyclic GBCAs and in most case, linear GBCAs showed faster accumulation and regression speed in examined tissues than macrocyclic GBCAs excepting gadodiamide in skin which showed slowest regression speed. Collectively, macrocyclic GBCAs presents more stable, lower propensity to release Gd and safer profiles versus linear GBCAs.


Assuntos
Estruturas Animais/citologia , Estruturas Animais/efeitos dos fármacos , Meios de Contraste/toxicidade , Gadolínio/toxicidade , Compostos Macrocíclicos/toxicidade , Estrutura Molecular , Animais , Feminino , Camundongos , Camundongos Endogâmicos ICR , Modelos Animais , Testes de Toxicidade
8.
JCI Insight ; 6(15)2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34228649

RESUMO

The mitochondrial enzyme aldehyde dehydrogenase 2 (ALDH2) catalyzes the detoxification of acetaldehyde and endogenous lipid aldehydes. Approximately 40% of East Asians, accounting for 8% of the human population, carry the E504K mutation in ALDH2 that leads to accumulation of toxic reactive aldehydes and increases the risk for cardiovascular disease, cancer, and Alzheimer disease, among others. However, the role of ALDH2 in acute kidney injury (AKI) remains poorly defined and is therefore the subject of the present study using various cellular and organismal sources. In murine models, in which AKI was induced by either the contrast agent iohexol or renal ischemia/reperfusion, KO, activation/overexpression of ALDH2 were associated with increased and decreased renal injury, respectively. In murine renal tubular epithelial cells (RTECs), ALDH2 upregulated Beclin-1 expression, promoted autophagy activation, and eliminated ROS. In vivo and in vitro, both 3-MA and Beclin-1 siRNAs inhibited autophagy and abolished ALDH2-mediated renoprotection. In mice with iohexol-induced AKI, ALDH2 knockdown in RTECs using AAV-shRNA impaired autophagy activation and aggravated renal injury. In human renal proximal tubular epithelial HK-2 cells exposed to iohexol, ALDH2 activation potentiated autophagy and attenuated apoptosis. In mice with AKI induced by renal ischemia/reperfusion, ALDH2 overexpression or pretreatment regulated autophagy mitigating apoptosis of RTECs and renal injury. In summary, our data collectively substantiate a critical role of ALDH2 in AKI via autophagy activation involving the Beclin-1 pathway.

9.
J Agric Food Chem ; 69(28): 7884-7897, 2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34251802

RESUMO

This study investigated the effects of oleanolic acid (OA) on hepatic lipid metabolism and gut-liver axis homeostasis in an obesity-related non-alcoholic fatty liver disease (NAFLD) nutritional animal model and explored possible molecular mechanisms behind its effects. The results revealed that OA ameliorated the development of metabolic disorders, insulin resistance, and hepatic steatosis in obese rats. Meanwhile, OA restored high-fat-diet (HFD)-induced intestinal barrier dysfunction and endotoxin-mediated induction of toll-like-receptor-4-related pathways, subsequently inhibiting endotoxemia and systemic inflammation and balancing the homeostasis of the gut-liver axis. OA also reshaped the composition of the gut microbiota of HFD-fed rats by reducing the Firmicutes/Bacteroidetes ratio and increasing the abundance of butyrate-producing bacteria. Our results support the applicability of OA as a treatment for obesity-related NAFLD through its anti-inflammatory, antioxidant, and prebiotic integration responses mediated by the gut-liver axis.


Assuntos
Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica , Ácido Oleanólico , Animais , Dieta Hiperlipídica/efeitos adversos , Fígado , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Ratos
10.
BMC Psychiatry ; 21(1): 376, 2021 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-34315438

RESUMO

BACKGROUND: The coping theory shows that stressful life events are associated with individuals' psychology/behaviors; meanwhile, the coronavirus disease of 2019 (COVID-19) pandemic is known to have impacted individuals' physical and mental health. Prior studies revealed that undergraduates have many sexual behavior and emotion disorders, which may be impacted during an isolation period, such as the one brought by COVID-19. However, few studies have explored the longitudinal associations between COVID-19-related stress and sexual compulsivity symptoms (SCS), and the mediating effect of emotions (i.e., depression and anxiety) on this relationship. This longitudinal study aimed to investigate these associations. METHODS: We employed a cross-lagged design (2020/2/12: Time 1, 3219 participants; 2020/6/6: Time 2, 2998 participants) and recruited Chinese undergraduates through an online system to respond to a survey. RESULTS: Our results showed that COVID-19-related stress at Time 1 directly influenced SCS at Time 1, and there was an indirect influence via depression and anxiety at Time 1. COVID-19-related stress at Time 1 positively correlated with depression, anxiety, and SCS at Time 2, and the first could directly and positively predict SCS at Time 2. Moreover, albeit depression at Time 2 was negatively linked to SCS at Time 2, anxiety at Time 2 enhanced the effect of COVID-19-related stress on SCS. CONCLUSIONS: Our findings extend the literature on SCS, showing that the higher the COVID-19-related stress, the higher the SCS, and the longer-lasting effect was associated with anxiety in undergraduates. Furthermore, depression does not mediate the relationship between COVID-19-related stress and SCS.


Assuntos
COVID-19 , Depressão , Ansiedade , China , Estudos Transversais , Humanos , Estudos Longitudinais , SARS-CoV-2 , Estresse Psicológico
11.
Artigo em Inglês | MEDLINE | ID: mdl-34258990

RESUMO

To reach a carbon-neutral future, electrochemical CO2 reduction reaction (eCO2RR) has proven to be a strong candidate for the next-generation energy system. Among potential materials, single-atom catalysts (SACs) serve as a model to study the mechanism behind the reduction of CO2 to CO, given their well-defined active metal centers and structural simplicity. Moreover, using metal-organic frameworks (MOFs) as supports to anchor and stabilize central metal atoms, the common concern, metal aggregation, for SACs can be addressed well. Furthermore, with their turnability and designability, MOF-derived SACs can also extend the scope of research on SACs for the eCO2RR. Herein, we synthesize sulfurized MOF-derived Mn SACs to study effects of the S dopant on the eCO2RR. Using complementary characterization techniques, the metal moiety of the sulfurized MOF-derived Mn SACs (MnSA/SNC) is identified as MnN3S1. Compared with its non-sulfur-modified counterpart (MnSA/NC), the MnSA/SNC provides uniformly superior activity to produce CO. Specifically, a nearly 30% enhancement of Faradaic efficiency (F.E.) in CO production is observed, and the highest F.E. of approximately 70% is identified at -0.45 V. Through operando spectroscopic characterization, the probing results reveal that the overall enhancement of CO production on the MnSA/SNC is possibly caused by the S atom in the local MnN3S1 moiety, as the sulfur atom may induce the formation of S-O bonding to stabilize the critical intermediate, *COOH, for CO2-to-CO. Our results provide novel design insights into the field of SACs for the eCO2RR.

12.
Front Immunol ; 12: 662441, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248942

RESUMO

Objective: To investigate the efficacy and safety of bone marrow-derived mesenchymal stem cells (BM-MSCs) on chronic active antibody-mediated rejection (cABMR) in the kidney allograft. Methods: Kidney recipients with biopsy-proven cABMR were treated with allogeneic third-party BM-MSCs in this open-label, single-arm, single-center, two-dosing-regimen phase I/II clinical trial. In Regimen 1 (n=8), BM-MSCs were administered intravenously at a dose of 1.0×106 cells/kg monthly for four consecutive months, while in Regimen 2 (n=15), the BM-MSCs dose was 1.0×106 cells/kg weekly during four consecutive weeks. The primary endpoints were the absolute change of estimated glomerular filtration rate (eGFR) from baseline (delta eGFR) and the incidence of adverse events associated with BM-MSCs administration 24 months after the treatment. Contemporaneous cABMR patients who did not receive BM-MSCs were retrospectively analyzed as the control group (n =30). Results: Twenty-three recipients with cABMR received BM-MSCs. The median delta eGFR of the total BM-MSCs treated patients was -4.3 ml/min per 1.73m2 (interquartile range, IQR -11.2 to 1.2) 2 years after BM-MSCs treatment (P=0.0233). The median delta maximum donor-specific antibody (maxDSA) was -4310 (IQR -9187 to 1129) at 2 years (P=0.0040). The median delta eGFR of the control group was -12.7 ml/min per 1.73 m2 (IQR -22.2 to -3.5) 2 years after the diagnosis, which was greater than that of the BM-MSCs treated group (P=0.0342). The incidence of hepatic enzyme elevation, BK polyomaviruses (BKV) infection, cytomegalovirus (CMV) infection was 17.4%, 17.4%, 8.7%, respectively. There was no fever, anaphylaxis, phlebitis or venous thrombosis, cardiovascular complications, or malignancy after BM-MSCs administration. Flow cytometry analysis showed a significant decreasing trend of CD27-IgD- double negative B cells subsets and trend towards the increase of CD3+CD4+PD-1+/lymphocyte population after MSCs therapy. Multiplex analysis found TNF-α, CXCL10, CCL4, CCL11 and RANTES decreased after MSCs treatment. Conclusion: Kidney allograft recipients with cABMR are tolerable to BM-MSCs. Immunosuppressive drugs combined with intravenous BM-MSCs can delay the deterioration of allograft function, probably by decreasing DSA level and reducing DSA-induced injury. The underlying mechanism may involve immunomodulatory effect of MSCs on peripheral B and T cells subsets.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Transplante de Rim/efeitos adversos , Transplante de Células-Tronco Mesenquimais/métodos , Transplante Homólogo/efeitos adversos , Adolescente , Adulto , Idoso , Anticorpos , Células da Medula Óssea/imunologia , Feminino , Humanos , Imunomodulação , Imunossupressores/uso terapêutico , Rim/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
13.
Cell Death Dis ; 12(6): 587, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099633

RESUMO

Long noncoding RNAs (lncRNAs) emerge as essential roles in the regulation of alternative splicing (AS) in various malignancies. Serine- and arginine-rich splicing factor 1 (SRSF1)-mediated AS events are the most important molecular hallmarks in cancer. Nevertheless, the biological mechanism underlying tumorigenesis of lncRNAs correlated with SRSF1 in esophageal squamous cell carcinoma (ESCC) remains elusive. In this study, we found that lncRNA DiGeorge syndrome critical region gene 5 (DGCR5) was upregulated in ESCC clinical samples, which associated with poor prognosis. Through RNA interference and overexpression approaches, we confirmed that DGCR5 contributed to promote ESCC cell proliferation, migration, and invasion while inhibited apoptosis in vitro. Mechanistically, DGCR5 could directly bind with SRSF1 to increase its stability and thus stimulate alternative splicing events. Furthermore, we clarified that SRSF1 regulated the aberrant splicing of myeloid cell leukemia-1 (Mcl-1) and initiated a significant Mcl-1L (antiapoptotic) isoform switch, which contributed to the expression of the full length of Mcl-1. Moreover, the cell-derived xenograft (CDX) model was validated that DGCR5 could facilitate the tumorigenesis of ESCC in vivo. Collectively, our findings identified that the key biological role of lncRNA DGCR5 in alternative splicing regulation and emphasized DGCR5 as a potential biomarker and therapeutic target for ESCC.

14.
Nat Commun ; 12(1): 3913, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34162888

RESUMO

Human FOXP3+ regulatory T (Treg) cells are central to immune tolerance. However, their heterogeneity and differentiation remain incompletely understood. Here we use single-cell RNA and T cell receptor sequencing to resolve Treg cells from healthy individuals and patients with or without acute graft-versus-host disease (aGVHD) who undergo stem cell transplantation. These analyses, combined with functional assays, separate Treg cells into naïve, activated, and effector stages, and resolve the HLA-DRhi, LIMS1hi, highly suppressive FOXP3hi, and highly proliferative MKI67hi effector subsets. Trajectory analysis assembles Treg subsets into two differentiation paths (I/II) with distinctive phenotypic and functional programs, ending with the FOXP3hi and MKI67hi subsets, respectively. Transcription factors FOXP3 and SUB1 contribute to some Path I and Path II phenotypes, respectively. These FOXP3hi and MKI67hi subsets and two differentiation pathways are conserved in transplanted patients, despite having functional and migratory impairments under aGVHD. These findings expand the understanding of Treg cell heterogeneity and differentiation and provide a single-cell atlas for the dissection of Treg complexity in health and disease.


Assuntos
Diferenciação Celular/genética , Fatores de Transcrição Forkhead/imunologia , Transdução de Sinais/genética , Análise de Célula Única/métodos , Linfócitos T Reguladores/imunologia , Transcriptoma/genética , Western Blotting , Ensaio de Imunoadsorção Enzimática , Fatores de Transcrição Forkhead/metabolismo , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/metabolismo , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , RNA-Seq/métodos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo
15.
Food Funct ; 12(15): 6712-6724, 2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34160501

RESUMO

Branched chain amino acids (BCAA), especially leucine (Leu), have been reported to decrease fat deposition. However, opposite effects of BCAA on lipid metabolism have been observed. To determine the role of BCAA in lipid metabolism, an amino acid-defined diet was formulated and C57BL/6J mice were assigned into the following groups: amino acid-defined control diet and control diet supplemented with Leu, isoleucine, or valine. Nitrogen was balanced by proportionally mixed amino acids except BCAA. Results showed that dietary Leu supplementation significantly increased the levels of serum triglycerides, total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol and urea nitrogen. Metabolomics showed that biosynthesis of unsaturated fatty acids was altered by Leu supplementation. Leu treatment up-regulated the expression of genes related to fat synthesis and down-regulated the expression of genes related to fatty acid synthesis. Furthermore, the genes and proteins of selective markers involved in browning of white adipose tissue (WAT) were up-regulated by dietary supplementation with Leu. This study indicated that dietary supplementation with Leu, but not isoleucine or valine, significantly affected lipid metabolism by regulating lipid metabolism-related genes and serum fatty acid concentration, providing a new tool in the management of obesity and metabolic disorders.

16.
Eur J Immunol ; 51(10): 2501-2512, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34138470

RESUMO

Intrauterine adhesions (IUA) are characterized by endometrial fibrosis and impose a great challenge for female reproduction. IL-34 is profoundly involved in various fibrotic diseases through regulating the survival, proliferation, and differentiation of monocytes/macrophages. However, it remains unclear how IL-34 regulates monocytes/macrophages in context of IUA. Here, we showed that the expression level of IL-34 and the amount of CX3CR1+ monocytes/macrophages were significantly increased in endometrial tissues of IUA patients. IL-34 promoted the differentiation of monocytes/macrophages, which express CX3CR1 via CSF-1R/P13K/Akt pathway in vitro. Moreover, IL-34-induced CX3CR1+ monocytes/macrophages promoted the differentiation of endometrial stromal cells into myofibroblasts. Of note, IL-34 caused endometrial fibrosis and increased the amount of CX3CR1+ monocytes/macrophages in endometrial tissues in vivo. IL-34 modulated endometrial fibrosis by regulating monocytes/macrophages since the elimination of endometrial monocytes/macrophages significantly suppressed the profibrotic function of IL-34. Finally, blocking of IL-34 in the LPS-IUA model resulted in the improvement of endometrial fibrosis and decreased number of CX3CR1+ monocytes/macrophages. Our studies uncover the novel mechanism of interaction between IL-34-induced CX3CR1+ monocytes/macrophages and endometrial stromal cells in endometrial fibrosis pathogenesis, and highlight IL-34 as a critical target for treating IUA.

17.
Blood ; 2021 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-34041523

RESUMO

Recent studies have demonstrated that maternal anti-CD36 antibodies represent a frequent cause of fetal/neonatal alloimmune thrombocytopenia (FNAIT) in Asian and African populations. However, little is known about the pathomechanism and antenatal treatment of anti-CD36-mediated FNAIT. Here, we established a novel animal model to examine the clinical features of pups from immunized Cd36-/- female mice after breeding with wild-type male mice. Mild thrombocytopenia was observed, but high pup mortality was also documented (40.26%). IVIG (1 g/kg) administration on days 7, 12, and 17 to immunized Cd36-/- mothers after breeding reduced fetal death (12.70%). However, delaying the IVIG administration series on days 10, 15, and 20 did not reduce fetal death (40.00%). In contrast, injection of deglycosylated anti-CD36 (deg-anti-CD36) polyclonal antibodies (5 mg/kg) on days 10, 15, and 20 significantly reduced fetal death (5.26%). Subsequently, monoclonal antibodies (mAbs) against mouse CD36 were developed, and one clone producing high-affinity anti-CD36 (termed 32-106) effectively inhibited maternal antibody binding and was therefore selected. Using the same approach of deg-anti-CD36, the administration of deg-32-106 significantly reduced fetal death (2.17%). Furthermore, immunized Cd36-/- mothers showed placenta deficiency. Accordingly, maternal anti-CD36 antibodies inhibited angiogenesis of placenta endothelial cells, which could be restored by deg-32-106. In summary, maternal anti-CD36 antibodies caused a high frequency of fetal death in our animal model, associated with placental dysfunction. This deleterious effect could be diminished by the antenatal administration of IVIG and deg-mAb 32-106. Interestingly, treatment with deg-32-106 appears more beneficial considering the lower dose, later start of treatment, and therapy success.

18.
Stem Cells ; 39(9): 1178-1191, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33938099

RESUMO

Yap is the key effector of Hippo signaling; however, its role in embryonic stem cells (ESCs) remains controversial. Here, we identify two Yap splicing isoforms (Yap472 and Yap488), which show equal expression levels but heterogeneous distribution in ESCs. Knockout (KO) of both isoforms reduces ESC self-renewal, accelerates pluripotency exit, but arrests terminal differentiation, while overexpression of each isoform leads to the reverse phenotype. The effect of both Yap isoforms on self-renewal is Teads-dependent and mediated by c-Myc. Nonetheless, different isoforms are found to affect overlapping yet distinct genes, and confer different developmental potential to Yap-KO cells, with Yap472 exerting a more pronounced biological effect and being more essential for neuroectoderm differentiation. Constitutive activation of Yaps, particularly Yap472, dramatically upregulates p53 and Cdx2, inducing trophectoderm trans-differentiation even under self-renewal conditions. These findings reveal the combined roles of different Yap splicing isoforms and mechanisms in regulating self-renewal efficiency and differentiation potential of ESCs.

19.
Transplant Cell Ther ; 27(8): 666.e1-666.e9, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34020086

RESUMO

Marrow fibrosis (MF) is usually accompanied with primary myelodysplastic syndromes (MDS) and no consensus has been reached on the relationship between MF and prognosis. We retrospectively analyzed 239 MDS and MDS derived acute myeloid leukemia patients with known grade of MF who received allogeneic stem cell transplantation (allo-HSCT). Of these, it included 121 (50.6%) without fibrosis (MF-0), 81 (33.9%) with mild fibrosis (MF-1), 37 (15.5%) with moderate to severe fibrosis (MF-2/3). MF-2/3 was associated with more pronounced dysmegakaryopoiesis (P =.002), more frequent karyotype abnormality (P = .039) and increased leukemic transformation. Spliceosome and ras pathway mutation occurred more frequently in patients with MF-2/3. After allo-HSCT, neutrophil and platelet engraftment was significantly delayed in patients with MF-2/3 than those with MF-1 and MF-0 (P = .031, P = .05, respectively). The estimated 3-year overall survival (OS) rates and disease-free survival (DFS) rates were significantly lower in patients with MF-2/3 than in those with MF-0 or MF-1 (P = .018, P = .018, respectively). Notably, in the subgroup of patients with more than 10% bone marrow blasts, MF-2/3 was independently associated with shorter OS and DFS (P = .012, P = .012, respectively) and has improved outcomes for these patients who achieved complete remission (CR) before allo-HSCT. Overall, MF-2/3 as an additional risk factor have the inferior prognosis for MDS and MDS-AML patients with bone marrow blasts ≥10%. Using pretransplantation cytoreductive therapy to obtain CR for these patients may benefit from allo-HSCT.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Mielofibrose Primária , Medula Óssea , Humanos , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/terapia , Estudos Retrospectivos , Fatores de Risco , Condicionamento Pré-Transplante , Transplante Homólogo
20.
J Int Med Res ; 49(4): 300060521998568, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33866842

RESUMO

Listeria monocytogenes is a Gram-positive facultative intracellular bacterium that causes central nervous system infection. We report a case of rhombencephalitis caused by L. monocytogenes infection, which mimicked Bickerstaff's brainstem encephalitis, and GQ1b antibody positivity and multiple intracranial foci were observed. A 68-year-old male patient presented with a nonspecific prodrome of faintness, forehead tightness, and walking instability. This was followed by progressive cranial nerve palsies, limb weakness, cerebellar signs, hyperpyrexia, and impaired consciousness. Brain imaging showed multiple abnormal brainstem and cerebellar signals that were accompanied by blood infiltration without any lesion enhancement. Serum GQ1b antibody positivity led to an initial diagnosis of Bickerstaff's brainstem encephalitis, which was treated with immunosuppressive therapy with limited efficacy. A pathogen examination helped confirm L. monocytogenes infection. A combination of meropenem and trimethoprim-sulfamethoxazole therapy was applied and the patient recovered without sequelae. The symptoms and imaging of Listeria rhombencephalitis are nonspecific. Accurate diagnosis and prompt treatment of this condition are essential. Whether Listeria infection triggers an autoimmune response remains unclear.


Assuntos
Hemorragias Intracranianas/etiologia , Listeria monocytogenes/isolamento & purificação , Listeriose/diagnóstico , Rombencéfalo/diagnóstico por imagem , Idoso , Infecções do Sistema Nervoso Central , Encefalite/diagnóstico por imagem , Encefalite/tratamento farmacológico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Listeria monocytogenes/genética , Listeriose/tratamento farmacológico , Masculino , Neuroimagem
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