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1.
Sci Rep ; 10(1): 1549, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005877

RESUMO

The growth trajectory of Chinese preschoolers still remains unclear. Our objective was to determine whether there was an association between adverse pregnancy outcomes and overweight offspring. We analyzed population-based retrospective cohort data from the Medical Birth Registry of Xiamen, which comprised 33,157 children examined from 1 to 6 years of age. Longitudinal analyses were used to evaluate the growth trajectories of offspring body mass index (BMI). Multivariate logistic regression was used to assess the effects of two adverse pregnancy outcomes, gestational diabetes mellitus (GDM) and being large-for-gestational age (LGA), on childhood overweight. Offspring of mothers with GDM and LGA has a higher annual BMI z-score from 1 to 6 years of age (all P < 0.05). But, a higher annual BMI z-score was only observed in children aged 1-5 years in models 1-3. Overall BMI z-score of offspring aged 1-6 who were born to mothers with GDM and LGA were also higher in models 1-3 (all P < 0.05). Additionally, offspring of mothers with GDM and LGA had a higher risk for overweight in model 1, from 1 to 6 years of age (odds ratio (OR), 1.814; 95% confidence interval (CI), 1.657-1.985; P < 0.0001). However, this association was attenuated after adjusting for maternal pre-pregnancy BMI (OR, 1.270; 95% CI, 0.961-1.679; P = 0.0930). Offspring of mothers with GDM and LGA had a higher BMI z-score and increased risk for overweight. Indeed, intrauterine exposure to maternal GDM and LGA could bias offspring to overweight, whereas maternal pre-pregnancy BMI may play a key role in offspring overweight for children born to mothers with GDM and LGA.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32029273

RESUMO

Gene knock-in using the CRISPR/Cas9 system can be achieved in a specific population of neurons in the mouse brain, by using in utero electroporation to introduce DNA fragments into neural progenitor cells. Using this strategy, we previously knocked-in the EGFP coding sequence into the N-terminal region of the ß-actin gene specifically in the pyramidal neurons in layer 2/3 of the somatosensory cortex. However, the knock-in efficiency was less than 2% of the transfected neurons. In this study, we sought to improve the knock-in efficiency using this system. First, we varied the length of the homology arms of the ß-actin donor template DNA, and found that the knock-in efficiency was increased to ∼14% by extending the length of the 5' and 3' homology arms to 1.6 kb and 2.0 kb, respectively. We then tested the effect of the DNA repair protein RAD51 and the knock-in efficiency was increased up to 2.5-fold when co-transfecting with two different ß-actin and a camk2a targeting EGFP knock-in modules. The RAD51 overexpression did not alter the migration of developing neurons, density or morphology of the dendritic spines compared to those in neurons not transfected with RAD51. RAD51 expression will be useful for increasing the knock-in efficiency in neurons in vivo by CRISPR/Cas9-mediated homology directed repair (HDR).

3.
J Biol Chem ; 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029476

RESUMO

It has been well established that the deubiquitinating enzyme ubiquitin-specific peptidase 7 (USP7) supports cancer growth by up-regulating multiple cellular pathways, including Wnt/ß-catenin signaling. Therefore, considerable efforts are directed at identifying and developing USP7 inhibitors. Here, we report that sesquiterpene lactone parthenolide (PTL) inhibits USP7 activity, assessed with deubiquitinating enzyme activity assays, including fluorogenic Ub-AMC/Ub-Rho110, Ub-VME/PA labeling and Di-Ub hydrolysis assays. Further investigations using cellular thermal shift (CETSA), surface plasmon resonance (SPR), and mass spectrum (MS) assays revealed that PTL directly interacts with USP7. Consistent with the role of USP7 in stimulating Wnt signaling and carcinogenesis, PTL treatment inhibited the activity of Wnt signaling partly by destabilizing ß-catenin. Moreover, using cell viability assays, we found that PTL suppresses the proliferation of colorectal cancer cells and induces apoptosis in these cells. Additionally, we examined the effects of two other sesquiterpene lactones (costunolide and α-santonin) on USP7 and Wnt signaling and found that α-methylene-γ-butyrolactone maybe provide a scaffold for future USP7 inhibitors. In summary, our findings reveal that PTL inhibits USP7 activity, identifying a potential mechanism by which PTL suppresses Wnt/ß-catenin signaling. We further suggest that sesquiterpene lactones might represent a suitable scaffold for developing USP7 inhibitors and indicate that PTL holds promise as an anticancer agent targeting aberrant USP7/Wnt signaling.

4.
Cereb Cortex ; 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32008040

RESUMO

De novo microdeletion of chromosome 2p15-16.1 presents clinically recognizable phenotypes that include mental retardation, autism, and microcephaly. Chromosomal maintenance 1 (CRM1) is a gene commonly missing in patients with 2p15-16.1 microdeletion and one of two genes found in the smallest deletion case. In this study, we investigate the role and mechanism of Crm1 in the developing mouse brain by inhibiting the protein or knocking down the gene in vivo. Inhibition of Crm1 reduces the proliferation and increases p53-dependent apoptosis of the cortical neural progenitors, thereby impeding the growth of embryonic cerebral cortex. Live imaging of mitosis in ex vivo embryonic brain slices reveals that inhibition of CRM1 arrests the cortical progenitors at metaphase. The arrested cells eventually slip into a pseudo-G1 phase without chromosome segregation. The mitotic slippage cells are marked by persistent expression of the spindle assembly checkpoint (SAC), repressing of which rescues the cells from apoptosis. Our study reveals that activating the SAC and inducing the mitotic slippage may lead to apoptosis of the cortical neural progenitors. The resulting cell death may well contribute to microcephaly associated with microdeletion of chromosome 2p15-16.1 involving CRM1.

5.
ACS Infect Dis ; 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32011115

RESUMO

Killing more than one million people each year, tuberculosis remains the leading cause of death from a single infectious agent. The growing threat of multidrug resistant strains of Mycobacterium tuberculosis stresses the need for alternative therapies. EthR, a mycobacterial transcriptional regulator, is involved in the control of the bioactivation of the second-line drug ethionamide. We have previously reported the discovery of in vitro nanomolar boosters of ethionamide through fragment-based approaches. In this study, we have further explored the structure-activity and structure-property relationships in this chemical family. By combining structure-based drug-design and in vitro evaluation of the compounds, we identified a new oxadiazole compound being the first fragment-based ethionamide booster which proved to be active in vivo, in an acute model of tuberculosis infection.

6.
J Clin Neurophysiol ; 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32011355

RESUMO

PURPOSE: Previous studies have proved that the people with subthreshold depression (SD) had negative cognitive bias in conscious level. However, it still remains a point of controversy whether they have impairment in unconscious level. The present study aimed to explore whether the implicit emotional processing differed between people with SD and healthy controls (HCs) and the details by analyzing the event-related potentials. METHODS: We recruited 35 SD participants and 35 age- and sex-matched HCs to collect event-related potential data. A visual oddball task was used to investigate implicit emotional processing with three types of emotional pictures (positive, negative, and neutral as stimuli). The N2 and P3 components were used to compare the neurocognitive differences of implicit emotional processing between two groups. RESULTS: Compared with the HC group, the SD participants showed no significant differences in the amplitudes or latencies of the N2 component for any kind of emotional stimuli but smaller P3 amplitudes for all kinds of emotional stimuli. The P3 latencies for positive stimuli were slower than the negative ones in the SD group but not in the HC group. The SD group showed slower P3 latencies than the HC group only for positive stimuli. There was a positive correlation between Center for Epidemiological Survey, Depression Scale score and average N2 and P3 amplitudes. CONCLUSIONS: The SD people demonstrate implicit cognitive processing impairments, and the impairments of emotional cognitive processing in SD may exist mainly in evaluative stage and primarily for positive stimuli.

7.
Chem Biol Interact ; 317: 108972, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32017914

RESUMO

BACKGROUND: Heart failure (HF) is an epidemic disease with increased incidence annually. It has been reported that taurine can improve cardiac function. This study investigated the cardioprotective effects of taurine in pressure-loaded HF mice and elucidated the possible mechanism. METHODS: HF models were established by transverse aortic constriction (TAC). Animals were treated with either taurine for 9 weeks and/or the SIRT1 inhibitor EX527 (5 mg/kg/day, every 2days) after TAC operation. Cardiac function and geometry were revealed by echocardiography. Myocardial hypertrophy and fibrosis were assessed using Fluorescent wheat germ agglutinin (WGA) staining and Masson's trichrome staining. Western blot and RT-PCR were performed to elucidate the expression of target proteins and genes respectively. Apoptosis in cardiomyocytes was detected by TUNEL staining. Myocardial oxidative stress was assessed by detecting the concentration of myocardial super oxidative dismutase (SOD) and malonyldialdehyde (MDA) and reactive oxygen species (ROS). Taurine concentrations and NAD+/NADH ratio were determined by taurine and NAD+/NADH assay kit. RESULTS: Taurine notably relieved cardiac dysfunction after TAC. The mechanisms were attributed to reduced myocyte hypertrophy and fibrosis, and alleviated apoptosis and oxidative stress. Meanwhile, taurine increased NAD+/NADH ratio,promoted the expression of SIRT1 and suppressed p53 acetylation. However, EX-527(inhibitor of SIRT1) decreased NAD+/NADH ratio and increased acetyl-p53 levels, and abolished the cardioprotective effects of taurine on mice subjected to TAC and increased apoptosis and oxidative stress. CONCLUSION: The mechanism responsible for cardiac-protective effects of taurine in HF induced by pressure overload is associated with the activation of the SIRT1-p53 pathway.

8.
J Org Chem ; 2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32043358

RESUMO

Evaluation of the hemilability of hybrid ligands provides a key to understand the metal-ligand cooperation in transition metal catalysis. Here, we design and synthesize a type of RuII complexes based on the hemilability of N-heterocyclic carbenes (NHCs), pyridine, and pyrazole, to compare their activity with other reported Ru catalysts in benzylic C-H oxidation. The RuII catalysts showed ultrastrong catalytic activity in water at room temperature and achieved a turnover frequency (TOF) of 114 h-1, which is the highest TOF value ever reported for Ru-catalyzed benzylic C-H oxidation. The addition of tridentate hybrid ligands in the Ru central position has two beneficial effects: NHCs with a stronger donor ability stabilize the Ru center; however, nitrogen ligands with a relatively weaker donor ability release from the Ru center, so that they induce a reaction. UV-vis, high-resolution electrospray ionization mass spectrometry (ESI-MS), electron paramagnetic resonance (EPR) spectrometry, the trapping of radicals, and the density functional theory calculations (DFT) suggested that a cation catalyst L-RuII-tBuO2H is formed via the reaction between starting RuII catalysts and tert-butyl hydroperoxide, which further undergoes a cleavage of the O-O bond to generate a radical and a cation L-RuIII-OH active intermediate.

9.
Ecotoxicol Environ Saf ; 192: 110294, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32044601

RESUMO

Cadmium (Cd) and nickel (Ni) in soil have caused serious environmental problems and increased healthy risks to humans and biota, it is vital important and necessary to develop effective methods to resolve the combined contaminated problems. In this study, strains L5 and L6 with good heavy metal resistant and immobilizing capacities were isolated from Cd and Ni contaminated soil. Bacterial characteristic experiment illustrated that many functional groups (-OH, -NH2 and -COO et al.) were distributed on the surface of L5 and L6. Under the stress of heavy metals, bacterial appearances were distorted. The pot experiment indicated that the concentrations of HOAc-extractable Cd and Ni in soil reduced 6.26-15.33% and 13.31-19.53% with the inoculation of L5 and L6. In addition, the immobilization rates on Cd and Ni improved 61.27-128.50% and 23.69-39.66% with re-inoculation of strains L5 and L6 at 30 days, respectively. After inoculation of strains L5 and L6 for 60 days, the activities of FDA hydrolysis, acid phosphatase, urease, invertase and dehydrogenase in soil increased obviously. Furthermore, bacterial diversity indexes and community structure of soil were also improved. Thus, given the beneficial remediation effects of the isolated strains, L5 and L6 have great potentials for heavy metals contaminated soil remediation.

10.
Int J Biol Macromol ; 150: 141-151, 2020 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-32045613

RESUMO

Toll-like receptors (TLRs) are the earliest reported pathogen recognition receptors (PRRs), and these receptors play pivotal roles in the innate immune system. Systematic studies of TLR family at the genome-wide level are important to understand its functions but are currently lacking in the insect lineage. Here, 6 TLR genes were identified and characterized in housefly (Musca domestica). The TLR genes of housefly were classified into five families according to the phylogenetic analysis of insect TLRs. The domain organization analyses indicated that the TLRs were composed by three major components: a leucine-rich repeat (LRR) domain, a transmembrane region (TM) and a Toll/interleukin-1 receptor (TIR) domain. Primary and tertiary structure analysis showed that the ectodomains of arthropod TLRs were longer than that of other phyla or classes. The mRNA expression levels of all 6 TLRs downregulated in the resistant housefly strain. Moreover, the expression levels of 6 TLRs varied between tissue and gender. Additionally, the 3D structures of the TIR domain were highly conserved during evolution. Collectively, these results help elucidate the crucial roles of TLRs in the immune response of housefly and provide a foundation for further understanding of innate immunity of the housefly.

11.
Artigo em Inglês | MEDLINE | ID: mdl-32019208

RESUMO

Groundwater quality degradation has raised widespread concerns about water supplies and ecological crises in China. In this study, hydrogeochemistry, environmental stable isotopes (δ18O, δD), and principal component analysis were conducted together to reveal the mechanism's response to the hydrogeochemical and quality degradation of groundwater in Yuncheng Basin, Northern China, so that reasonable water resource management strategies can be developed. The study reveals that groundwater faces a tremendous risk of quality decrease during the past decade: (1) the hydrochemical facies of groundwater shows that the bicarbonate and chloride type water was replaced with sulfate type water and the occupying area of SO4·Cl-Na, SO4·HCO3-Na type water expanded dramatically in shallow and intermediate-deep aquifers. (2) Major ion chemistry and hydrogen and oxygen isotope compositions indicate that the major hydrogeochemical processes responsible for groundwater quality deterioration include the dissolution of evaporates (i.e., halite, gypsum, and mirabilite), ion exchange, and evaporation process. Additionally, (3) anthropogenic activities (overutilization of fertilizer) have resulted in nitrate contamination, and have thereby led to groundwater quality degradation.

12.
Neurochem Res ; 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32052258

RESUMO

Neuroinflammation plays a vital role in the process of a variety of retinal ganglion cells (RGCs) degenerative diseases including traumatic optic neuropathy (TON). Retinal microglial activation is believed as a harbinger of TON, and robust microglial activation can aggravate trauma-induced RGCs degeneration, which ultimately leads to RGCs loss. Toll like receptor 4 (TLR4)-triggered inflammation is of great importance in retinal inflammatory response after optic nerve injury. CD11b on macrophage and brain microglia can inhibit TLR4-triggered inflammation. However, the functional role of CD11b in retinal microglia is not well understood. Here, using an optic nerve crush model and CD11b gene deficient mice, we found that CD11b protein expression was mainly on retinal microglia, significantly increased after optic nerve injury, and still maintained at a high level till at least 28 days post crush. Compared with wild type mice, following acute optic nerve injury, CD11b deficient retinae exhibited more exacerbated microglial activation, accelerated RGCs degeneration, less growth associated protein-43 expression, as well as more proinflammatory cytokines such as interleukin-6 and tumor necrosis factor α while less anti-inflammatory factors such as arginase-1 and interleukin-10 production. We conclude that CD11b is essential in regulating retinal microglial activation and neuroinflammatory responses after acute optic nerve injury, which is critical for subsequent RGCs degeneration and loss.

13.
J Magn Reson Imaging ; 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32030832

RESUMO

BACKGROUND: Although biopsy is essential for the diagnosis and management of kidney transplant recipients, it is invasive. Intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) is a noninvasive technique that can assess both capillary perfusion and tissue diffusion. PURPOSE: To evaluate the capability of IVIM-DWI as a differentiation of kidney transplant patients who need clinical intervention from those who need not. STUDY TYPE: Prospective. SUBJECTS: In all, 33 kidney transplant patients who needed clinical intervention and 19 who need not. FIELD STRENGTH/SEQUENCE: 3.0T; IVIM-DWI with a single-shot echo planar imaging sequence. ASSESSMENT: All patients underwent kidney transplant biopsy and IVIM-DWI scans. Patients were dichotomized into those who needed clinical intervention (CHANGE group) and those who need not (Non-CHANGE group) based on biopsy results. The values of total apparent diffusion coefficient (ADCT ), diffusion coefficient (D), and perfusion fraction (f) were acquired from renal cortex and medulla, respectively. The area under the curve (AUC) was calculated and compared. STATISTICAL TESTS: Independent Student's t-test, receiver-operating characteristic curve, and Spearman correlation analysis. RESULTS: All the cortical and medullary DWI parameters in the CHANGE group were significantly lower than those in the Non-CHANGE group (all P ≤ 0.012). Except for medullary fp, all DWI parameters in both the cortex and the medulla were inversely correlated with both the chronic (ρ ranging from -0.33 to -0.54, all P ≤ 0.02) and acute (ρ ranging from -0.35 to -0.60, all P ≤ 0.01) composite scores. Cortical ADCT and D had the largest AUC and specificity of 0.84 and 75.8%, respectively. Combined use of cortical D and medullary fp at each optimal cutoff point yielded a specificity of 90.9%. DATA CONCLUSION: DWI demonstrated potential as a noninvasive biomarker to allow the stratification of patients into categories in which kidney allograft biopsy results are or are not likely to change clinical management. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 5.

14.
J Biol Dyn ; 14(1): 116-142, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32065067

RESUMO

We propose a model of a joint spread of heroin use and HIV infection. The unique disease-free equilibrium always exists and it is stable if the basic reproduction numbers of heroin use and HIV infection are both less than 1. The semi-trivial equilibrium of HIV infection (heroin use) exists if the basic reproduction number of HIV infection (heroin use) is larger than 1 and it is locally stable if and only if the invasion number of heroin use (HIV infection) is less than 1. When both semi-trivial equilibria lose their stability, a coexistence equilibrium occurs, which may not be unique. We compare the model to US data on heroin use and HIV transmission. We conclude that the two diseases in the US are in a coexistence regime. Elasticities of the invasion numbers suggest two foci for control measures: targeting the drug abuse epidemic and reducing HIV risk in drug-users.

15.
Cell Death Dis ; 11(2): 125, 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32071292

RESUMO

Sestrin2 (SESN2) is a highly evolutionary conserved protein and involved in different cellular responses to various stresses. However, the potential function of SESN2 in immune system remains unclear. The present study was designed to test whether dendritic cells (DCs) could express SESN2, and investigate the underlying molecular mechanism as well as its potential significance. Herein, we firstly reported that SESN2 was expressed in DCs after high mobility group box-1 protein (HMGB1) stimulation and the apoptosis of DCs was obviously increased when SESN2 gene silenced by siRNA. Cells undergone SESN2-knockdown promoted endoplasmic reticulum (ER) stress (ERS)-related cell death, markedly exacerbated ER disruption as well as the formation of dilated and aggregated structures, and they significantly aggravated the extent of ERS response. Conversely, overexpressing SESN2 DCs markedly decreased apoptotic rates and attenuated HMGB1-induced ER morphology fragment together with inhibition of ERS-related protein translation. Furthermore, sesn2-/--deficient mice manifested increased DC apoptosis and aggravated ERS extent in septic model. These results indicate that SESN2 appears to be a potential regulator to inhibit apoptotic ERS signaling that exerts a protective effect on apoptosis of DCs in the setting of septic challenge.

16.
Cell Biochem Funct ; 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32077118

RESUMO

Ovarian cancer is one of the common malignant tumours of female reproductive organs. Due to early diagnosis difficulties and lack of effective treatment in the late stage, ovarian cancer has the highest mortality rate in female reproductive system malignancies. Therefore, finding reliable early diagnosis indicators and new therapeutic targets for ovarian cancer is an urgent problem to be solved. Chemokine (C-X-C motif) ligand 14 (CXCL14) is a small cytokine belonging to the CXC chemokine family, which has been found to possess multi-effects in tumourigenesis and development. Here, we reported that CXCL14 was preferentially expressed in ovarian cancer. By analysing the TCGA database, we found that CXCL14 was highly expressed in advanced ovarian cancer patients and correlated with poor prognosis. In addition, the abnormal high CXCL14 levels were observed in serum and ovarian tissue of ovarian cancer patients by qRT-PCR and ELISA. In vitro and in vivo experiments both confirmed that overexpression of CXCL14 promoted the ovarian cancer cell proliferation. Moreover, transfection of CXCL14 increased the phosphorylation level of signal transducer and activator of transcription 3 (STAT3), and administration of STAT3 inhibitor III inhibited the tumour-promoting effects of CXCL14. Therefore, our study suggests that CXCL14 could be utilised as a novel adjunct biomarker for early diagnosis of ovarian cancer and provides new targets and ideas for the treatment of advanced ovarian cancer. SIGNIFICANCE PARAGRAPH: CXCL14 could be utilised as a novel adjunct biomarker for early diagnosis of ovarian cancer and provides new targets and ideas for the treatment of advanced ovarian cancer.

17.
Sci Rep ; 10(1): 3133, 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32081949

RESUMO

In the central nervous system (CNS), γ-aminobutyric acid A (GABAA) receptors mediate two types of inhibitory effects. Phasic inhibition involves the activation of synaptic GABAA receptors, and tonic inhibition is mediated by extrasynaptic GABAA receptors. GABAA receptors are important regulators of neuronal activity and are involved in a range of neurological disorders. In this study, we conducted sIPSCs recordings on hippocampal CA1 pyramidal neurons in WT SD rats and found that exposure to blue light could specifically block the tonic inhibition and sIPSCs, and regulate neuronal activity. These observations indicate the existence of a non-opsin photosensitive pathway that regulates the GABA inhibitory system in the CNS.

18.
Int J Neurosci ; : 1-13, 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32083963

RESUMO

Background and purpose: Mechanical thrombectomy (MT) is a standard care for most acute ischemic stroke (AIS) patients. For AIS patients underwent MT, predicting the patients at high risk of unfavorable outcome and adjusting therapeutic strategies accordingly can greatly improve patient outcomes. We aimed to develop and validate a nomogram for individualized prediction of Chinese AIS patients underwent MT. Methods: We conducted a multicenter prospective study including 238 AIS patients who underwent MT from January 2014 to December 2018. The main outcome measure was three-month unfavorable outcome (modified Rankin Scale 3-6). A nomogram was generated based on multivariate logistic model. We assessed the discriminative performance by using the area under the receiver-operating characteristic curve and calibration of risk prediction model by using the Hosmer-Lemeshow test. Results: In NAC nomogram, NIHSS (National Institutes of Health Stroke Scale) score on admission (OR: 1.193, p < 0.0001), Age (OR: 1.025, p = 0.037) and Creatinine (OR: 1.028, p < 0.0001) remained independent predictors of 3-month unfavorable outcome in Chinese AIS patients treated with MT. The NAC nomogram exhibited an area under the curve of 0.816 for predicting functional impairment. Calibration was good (p = 0.560 for the Hosmer-Lemeshow test). Conclusions: The NAC nomogram is the first nomogram developed and validated in Chinese AIS patients treated with MT and it may be used to predict 3 months unfavorable outcome for these patients.

19.
J Autoimmun ; : 102424, 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32085893

RESUMO

Autoimmune mediated inflammation and renal damage in lupus nephritis (LN) depends partly on the infiltration of lymphocytes in glomeruli and renal interstitium. Here we identified a population of CD8+ T cells with a CD103+-phenotype in the healthy kidneys of human and mouse. These cells were typically CD69+CD103+ tissue-resident memory T cells (TRM) in the kidney. CD8+ TRM cells were expanded in the kidneys of patients with LN or MRL/lpr mice. The expansion of renal CD8+ TRM cells correlated significantly with kidney disease activity. These cells were active in producing cytokines, perforin and granzyme B in the kidney of MRL/lpr mice. Importantly, renal CD8+ TRM cells underwent proliferation and self-renewal to maintain a stable TRM pool in the kidney of MRL/lpr mice, contributing to renal inflammation and damage. JAK/STAT signaling in the MRL/lpr mice was required for renal TRM self-renewal as well as maintenance of effector functions. Targeting JAK/STAT signaling by tofacitinib effectively suppressed effector functions and impaired the survival of renal TRM cells in the kidney, contributing to improved kidney function in MRL/lpr mice. These results provided evidences that renal CD8+ TRM cells play a role in the pathogenesis of LN. They could serve as a therapeutic target for LN.

20.
Reprod Sci ; 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32086756

RESUMO

The incidence of diabetes in women of childbearing age has been increasing recently and implantation failure and early abortion are important reasons for infertility in diabetic women. Glycogen synthesis and decomposition are the cores of glucose homeostasis in endometrium and AMPK is activated when cellular energy consumption increases. Embryo implantation is a complex process required huge energy. Yet the changes of glucose metabolism in endometrium and its impact on embryo implantation in diabetic women are still unclear. In this research, we established diabetic pregnancy mice model by intraperitoneal injecting streptozotocin on pregnant day 1. We first tested the changes of endometrial glucose homeostasis and embryo implantation. Next, we demonstrated abnormal activation of AMPK in the endometrium of diabetic mice and its affecting endometrial glucose homeostasis. Finally, we compared the endometrial glucose homeostasis and embryo implantation outcome in diabetic pregnant mice treated with insulin or insulin combined with metformin. The results indicated that there was disturbed glucose homeostasis associated with excessive activation of AMPK in endometrium of diabetic pregnant mice. AMPK inhibitor improved the over-activation of AMPK pathway in the endometrium, meanwhile, partially corrected the abnormal glycogen metabolism and improved the implantation. Insulin improved the disorder of endometrial glucose homeostasis and implantation of diabetic mice. Our research explores the causes of high abortion and infertility rate in diabetic women which is to provide a therapeutic reference for patients with diabetes complicated with infertility and early abortion.

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