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1.
J Exp Med ; 220(2)2023 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-36350314

RESUMO

Disruption of endothelial cell (ECs) and pericytes interactions results in vascular leakage in acute lung injury (ALI). However, molecular signals mediating EC-pericyte crosstalk have not been systemically investigated, and whether targeting such crosstalk could be adopted to combat ALI remains elusive. Using comparative genome-wide EC-pericyte crosstalk analysis of healthy and LPS-challenged lungs, we discovered that crosstalk between endothelial nitric oxide and pericyte soluble guanylate cyclase (NO-sGC) is impaired in ALI. Indeed, stimulating the NO-sGC pathway promotes vascular integrity and reduces lung edema and inflammation-induced lung injury, while pericyte-specific sGC knockout abolishes this protective effect. Mechanistically, sGC activation suppresses cytoskeleton rearrangement in pericytes through inhibiting VASP-dependent F-actin formation and MRTFA/SRF-dependent de novo synthesis of genes associated with cytoskeleton rearrangement, thereby leading to the stabilization of EC-pericyte interactions. Collectively, our data demonstrate that impaired NO-sGC crosstalk in the vascular niche results in elevated vascular permeability, and pharmacological activation of this crosstalk represents a promising translational therapy for ALI.


Assuntos
Lesão Pulmonar Aguda , Pericitos , Camundongos , Animais , Guanilil Ciclase Solúvel/genética , Guanilil Ciclase Solúvel/metabolismo , Óxido Nítrico/metabolismo , Lipopolissacarídeos/farmacologia , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/metabolismo
2.
Am J Obstet Gynecol ; 2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36403860

RESUMO

BACKGROUND: Previous studies have established the association between intertwin birthweight discordance and hypertensive disorders of pregnancy. However, longitudinal fetal size discordance in relation to gestational hypertension or preeclampsia remains unclear. OBJECTIVE: This study aimed to compare the patterns of estimated fetal weight (EFW) discordance throughout gestation among normotensive, gestational hypertension and preeclampsia, and to evaluate the association between crown-rump length (CRL) discordance at 11-14 weeks of gestation and hypertensive disorders of pregnancy. STUDY DESIGN: This was a retrospective cohort study of women with twin pregnancies who had antenatal care visits and delivered at a tertiary hospital between January 2013 and June 2021. CRL was measured at 11-14 weeks of gestation. EFW was calculated based on ultrasound examinations of fetal biometrics at 16-18, 20-24, 28-32, and ≥34 weeks of gestation, respectively. CRL and EFW discordances were calculated: (larger CRL-smaller CRL)/larger CRL×100% and (larger EFW-smaller EFW)/larger EFW ×100%, respectively. Multiple imputation was used to handle missing data and all models accounted for the imputation. Multilevel model analysis was used to compare the differences of EFW discordances throughout gestation among normotensive, gestational hypertension and preeclampsia. Generalized linear models was used to evaluate the association between CRL discordance and hypertensive disorders of pregnancy, assuming a Poisson distribution. The possible nonlinear relationship between continuous CRL discordance and hypertensive disorders of pregnancy was examined by generalized additive models. All the analyses were stratified by chorionicity. RESULTS: Of the 3280 twin pregnancies who met the inclusion criteria, 187 (5.7%) developed gestational hypertension and 436 (13.3%) developed preeclampsia, including 125 (3.8%) early-onset preeclampsia and 311 (9.5%) late-onset preeclampsia. In dichorionic twins, compared with normotensive women, a significant progression of EFW discordance throughout gestation was identified in women who developed preeclampsia, and a large progression of EFW discordance in late pregnancy was identified in women who developed gestational hypertension. In monochorionic twins, EFW discordances were more progressive from 20-24 weeks of gestation onwards in women who developed preeclampsia than in normotensive women. CRL discordance at 11-14 weeks of gestation was associated with increased risk of preeclampsia (relative risk [RR] 1.03, 95% confidence interval [CI] 1.00-1.05), particularly early-onset preeclampsia (RR 1.09, 95%CI 1.04-1.13). A CRL discordance of ≥10% had a 1.2 times increased risk of developing early-onset preeclampsia (RR 2.27, 95%CI 1.28-4.03). This association was identified in dichorionic twins, but not in monochorionic twins. CONCLUSION: Our study demonstrated distinct growth discordant patterns among normotensive, gestational hypertension and preeclampsia in twin pregnancies. Intertwin CRL discordance at 11-14 weeks of gestation was associated with increased risk of preeclampsia, especially early-onset preeclampsia in dichorionic twins, with a dose-response pattern.

3.
Ann Med ; 54(1): 3177-3188, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36351877

RESUMO

Objective: An increasing number of studies suggest that sleep disordered breathing (SDB) may be associated with postoperative atrial fibrillation (POAF), but these studies present discrepant results. Thus, this meta-analysis aimed to synthesize the data associating SDB with POAF in patients who underwent cardiac surgery.Methods: A literature search was performed in the Scopus, PubMed, Web of Science, EMBASE, CENTRAL, Weipu, Wanfang Data, and China National Knowledge Infrastructure databases before August 2022. Data were extracted, and the strength of the relationship between SDB and the risk of POAF was evaluated using odds ratio (OR) and 95% confidence intervals (CIs). All statistical analysis was carried out using the Stata 12.0 software.Results: A total of 24 studies with 660,685 subjects were included in current meta-analysis. SDB was significantly associated with the risk of POAF in the patients who underwent cardiac surgery (OR = 1.49; 95% CI, 1.30-1.70; p < .001). Next subgroup analysis revealed that such association may be increased in the group with medical equipment-measured SDB (OR = 2.27; 95% CI, 1.59-3.23; p < .001), prospective studies (OR = 2.17; 95% CI, 1.55-3.03; p < .001), patients without a previous history of atrial fibrillation (OR = 2.04; 95% CI, 1.47-2.82; p < .001), and patients who received a coronary artery bypass graft (OR = 2.10; 95% CI, 1.45-3.05; p < .001). No publication bias was identified.Conclusion: The results of meta-analysis support that SDB may be associated with an increased risk of POAF in patients who had undergone cardiac surgery, and these results should be confirmed in more rigorously designed studies.KEY MESSAGESPatients with SDB who underwent cardiac surgery showed increased risk of POAF.The relationship between SDB and POAF should be explained with caution with the consideration of various covariate.The effect of pre-treatment of SDB on POAF should be examined in future.


Assuntos
Fibrilação Atrial , Procedimentos Cirúrgicos Cardíacos , Síndromes da Apneia do Sono , Humanos , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/etiologia , Estudos Prospectivos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Síndromes da Apneia do Sono/complicações , Síndromes da Apneia do Sono/epidemiologia , Fatores de Risco
4.
Water Sci Technol ; 86(5): 950-967, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36358039

RESUMO

The removal of low concentration ammonia-nitrogen in industrial wastewater is necessary before discharged into the environment. In this study, vacuum plate membrane distillation (VPMD) technology was utilized and operating parameters such as pH, feed temperature, vacuum degree, feed flow and time were investigated. Based on the experimental data, the heat and mass transfer mechanism and mathematic model were studied. The experimental results show that low solution pH was significantly beneficial to ammonia-nitrogen removal but permeate flux was nearly changeless. At pH = 4, a removal rate up to 93.33% was achieved. Ammonia-nitrogen mainly exists with NH4+ ions in acidic solution, so only water molecules pass through the membrane to acquire the water product in the permeate side. Increasing the temperature of the solution was disadvantageous to the ammonia-nitrogen removal due to membrane pores expanding and the mass transfer coefficient of NH3 molecules increasing; therefore a low temperature was chosen if possible. Because vapor pressure of the feed solution increases exponentially with temperature and results in membrane surface pressure difference increases, therefore increasing the temperature enhances the permeate flux. Raising the vacuum degree enhanced ammonia removal rate and permeate flux obviously, a vacuum degree of 0.09 MPa was chosen for the experiment. The effect of feed flow rate on ammonia-nitrogen removal instead of permeate flux is weak, the reason is that the boundary layer wears thin when the feed flow rate is increased, which is conducive to permeate flux increasing. In a two-parameter model of Knudsen diffusion, Poiseuille flow was chosen to demonstrate the heat and mass transfers in the process of VPMD in the study. Based on the experimental values of permeate flux, two parameters CK and CP in the model were calculated using a nonlinear fitting method software, which indicated that the Knudsen diffusion model more than the Poiseuille flow model was suitable. The maximum values of the relative average deviation (RAD) and root mean square difference (RMSD) of experimental and calculated values with model equations of the permeate flux at the different temperature, vacuum degree and feed flow rate were no more than 8.7% and 3.20 kg · (m2 · h)-1, respectively.


Assuntos
Destilação , Purificação da Água , Destilação/métodos , Águas Residuárias/química , Amônia , Vácuo , Membranas Artificiais , Purificação da Água/métodos , Nitrogênio , Água , Tecnologia
5.
Circ Heart Fail ; : e009772, 2022 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-36373549

RESUMO

BACKGROUND: Patients with cancer (patients with a history of cancer) with advanced heart failure are increasing, but unlikely to be transplanted, and left ventricular assist device (LVAD) is an alternative strategy. This study investigates the characteristics and outcomes of patients with cancer undergoing durable LVAD. METHODS: Adult patients with a history of cancer who received LVADs were identified from INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) registry: 2008 and 2017. Characteristics and outcomes between patients with cancer and those without cancer were compared, and subgroup analyses of cancer therapy-induced cardiomyopathy (CCM) and non-CCM were also conducted. RESULTS: Overall, 1273 (6.5%) patients had a history of cancer, including 289 (22.7%) with CCM and 984 (77.3%) with non-CCM as the primary reason for heart failure. Patients with cancer had shorter median survival (3.72 versus 3.97 years, log-rank P=0.002), and multivariable Cox and competing risk regressions revealed that a history of cancer was associated with reduced survival (hazard ratio, 1.14 [95% CI, 1.04-1.26]; P=0.005; subdistribution hazard ratio, 1.24 [95% CI, 1.13-1.36]; P<0.001) and decreased incidence of heart transplantation. There was no significant difference in mortality between patients with CCM-induced heart failure and patients without cancer. Patients with cancer experienced an increased risk of bleeding, and age, INTERMACS profile, albumin, dialysis, and blood urea nitrogen were associated with mortality in these patients. CONCLUSIONS: A history of cancer is associated with mildly reduced survival, lower incidence of heart transplantation, and increased risk of bleeding after LVAD, whereas the survival in patients with cancer with CCM-induced heart failure is similar to those without cancer. LVAD implantation in patients with cancer is very well possible.

6.
Front Pediatr ; 10: 982179, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36324821

RESUMO

Objectives: To assess and summarize current evidence on the effectiveness and safety of ertapenem for treatment of childhood infections, in consideration of high infection prevalence in children and wide use of ertapenem. Methods: The following 8 databases were searched on 13th May 2021: Web of Science, Embase via Ovid SP, PubMed, The Cochrane Library (CENTRAL), Chinese BioMedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), VIP and Wanfang. The primary outcome was treatment success rate. Risk ratios (RRs) and 95% confidence interval (CI) were estimated using random-effect models. Subgroup analysis was conducted where heterogeneity was found. Results: Fifteen studies (8 randomized controlled trials, 1 observational comparative study, and 6 before and after studies) involving 2,528 patients were included in the final review. Ertapenem had similar treatment success rates with ß-lactam antibiotics [relative risk (RR) = 1.08, 95% CI: 0.99-1.19]. In a subgroup analysis, similar efficacy (RR = 1.08, 95% CI: 0.97-1.20) between ertapenem and other carbapenems. Compared with ß-lactam antibiotics, ertapenem did not increase the risk of any adverse events (RR = 1.02, 95%CI: 0.71-1.48), drug-related diarrhea (all non-Asian children, RR = 0.62, 95%CI: 0.31-1.25), or injection site pain (all non-Asian children, RR = 1.66, 95%CI: 0.59-4.68). Subgroup analysis showed no obvious difference between ertapenem group and carbapenems or non-carbapenems group on risk of adverse events. Conclusion: Our findings suggest that ertapenem is effective and safe in treatment for children with infection. Further comparative real-world data is needed to supplement clinical evidence on the overall benefits of ertapenem in this population.

8.
Microbiol Spectr ; : e0324722, 2022 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-36326495

RESUMO

Phosphopantetheinyl transferases (PPTases) play important roles in activating apo-acyl carrier proteins (apo-ACPs) and apo-peptidyl carrier proteins (apo-PCPs) in both primary and secondary metabolism. PPTases catalyze the posttranslational modifications of those carrier proteins by covalent attachment of the 4'-phosphopantetheine group to a conserved serine residue. The protein-protein interactions between a PPTase and a cognate acyl or peptidyl carrier protein have important regulatory functions in microbial biosynthesis, but the molecular mechanism underlying their specific recognition remains elusive. In this study, we identified a new rishirilide biosynthetic gene cluster with a rare in-cluster PPTase from Streptomyces xanthophaeus no2. The function of this Sfp-type PPTase, SxrX, in rishirilide production was confirmed using genetic mutagenesis and biochemical characterization. We applied molecular modeling and site-directed mutagenesis to identify key residues mediating the protein-protein interaction between SxrX and its cognate ACP. In addition, six natural products were isolated from wild-type S. xanthophaeus no2 and the ΔsxrX mutant, including rishirilide A and lupinacidin A, that exhibited antimicrobial and anticancer activities, respectively. SxrX is the first Sfp-type PPTase identified from an aromatic polyketide biosynthetic gene cluster and shown to be responsible for high-level production of rishirilide derivatives. IMPORTANCE Genome mining has been a vital means for natural product drug discovery in the postgenomic era. The rishirilide-type polyketides have attracted attention due to their potent bioactivity, but the poor robustness of production hosts has limited further research and development. This study not only identifies a hyperproducer of rishirilides but also reveals a rare, in-cluster PPTase SxrX that plays an important role in boosting rishirilide biosynthesis. Experimental and computational investigations revealed new insights on the protein-protein interaction between SxrX and its cognate ACP with wide implications for understanding polyketide biosynthesis.

9.
Foods ; 11(21)2022 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-36359948

RESUMO

The detection of food safety and quality is very significant throughout the food supply. Stable dual-emission copper-modified fluorescent carbon dots (Cu-CDs) were successfully synthesized by a simple and environment-friendly hydrothermal, which was used for the real-time detection of pesticide residues in agricultural products. By optimizing the reaction conditions, Cu-CDs showed two emission peaks, with the highest fluorescence intensities at 375 and 450 nm. The structure, chemical composition and optical properties of Cu-CDs were investigated by XRD, TEM and IR. The results showed that thiophanate methyl (TM) could induce fluorescence quenching of Cu-CDs with no other ligands by the electron transfer through π-π stacking. The synchronous response of the dual-emission sensor enhanced the specificity of TM, which showed remarkable anti-interference capability. The fluorescence quenching degree of Cu-CDs had a good linear relationship with the TM concentration; the low detection limit for a pear was 0.75 µM, and for an apple, 0.78 µM. The recoveries in the fruit samples were 79.70-91.15% and 81.20-93.55%, respectively, and the relative standard deviations (RSDs) were less than 4.23% for the pear and less than 3.78% for the apple. Thus, our results indicate the feasibility and reliability of our methods in detecting pesticide residues in agricultural products.

10.
Int J Mol Sci ; 23(21)2022 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-36361934

RESUMO

Carbon monoxide (CO), a product of organic oxidation processes, arises in vivo principally from the enzymatic reaction of heme oxygenase (HO, transcription gene named HMX1). HO/CO has been found to exert many salutary effects in multiple biological processes, including the stress response. However, whether HO/CO is involved in the regulation of the heat-stress (HS) response of Ganoderma lucidum (G. lucidum) is still poorly understood. In this paper, we reported that under heat stress, the HMX1 transcription level, HO enzyme activity, and CO content increased by 5.2-fold, 6.5-fold and 2-fold, respectively. HMX1 silenced strains showed a 12% increase in ganoderic acid (GA) content under HS as analyzed by HPLC. Furthermore, according to Western blot analysis of the protein phosphorylation levels, HMX1 attenuated the increase in phosphorylation levels of slt2, but the phosphorylation levels were prolonged over a 3 h HS time period. The chitin and glucan content in HMX1 silenced strains increased by 108% and 75%, respectively. In summary, these findings showed that the HO/CO system responds to heat stress and then regulates the HS-induced GA biosynthesis and the cell-wall integrity mediated by the Slt-MAPK phosphorylation level in G. lucidum.


Assuntos
Reishi , Triterpenos , Reishi/genética , Reishi/metabolismo , Monóxido de Carbono/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Triterpenos/farmacologia , Resposta ao Choque Térmico
11.
Mol Biol Rep ; 2022 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-36376538

RESUMO

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a liver metabolic syndrome and still lacks effective treatments because the molecular mechanism underlying the development of NAFLD is not completely understood. We investigated the role of Hydroxyl CoA dehydrogenase alpha subunit (HADHA) in the pathogenesis of NAFLD. METHODS: HADHA expression was detected both in NAFLD cell and mice, and knockdown of HADHA in free fatty acids (FFA)-treated L02 or overexpression of HADHA in high fat diet (HFD)-fed mice was used to detected the influence of HADHA on hepatic steatosis, mitochondrial dysfunction, and oxidative stress by regulating of MKK3/MAPK signaling. RESULTS: Our data revealed that HADHA expression was decreased in FFA-treated L02 cells and in HFD-fed mice. Knockdown of HADHA markedly aggravated hepatic steatosis, inflammation and oxidative stress in FFA-treated L02 cells, which was associated with the activation of MKK3/MAPK signalling pathways. Moreover, oxidative stress and liver lesions were improved in NAFLD mice by upregulation of HADHA. Importantly, we demonstrated that overexpression of HADHA inhibited the expression of p-MAPK in NAFLD mice, reducing lipid accumulation and steatosis. CONCLUSION: HADHA may function as a protective factor in the progression of NAFLD by alleviating abnormal metabolism and oxidative stress by suppressing MKK3/MAPK signalling pathway activation, providing a new target for the treatment of NAFLD.

12.
Appl Environ Microbiol ; 88(22): e0132222, 2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36342130

RESUMO

Fungi utilize a wide range of nitrogen to adapt their metabolism. The transcription factor GCN4 has a pivotal role in nitrogen metabolism. However, the mechanism by which GCN4 regulates nitrogen utilization in Ganoderma lucidum is not well understood. In this study, we found that GCN4 physically interacts with SKO1, a bZIP (basic leucine zipper) transcription factor. GCN4 cooperated with SKO1 to positively regulate nitrogen utilization, especially for the expression of areA. Electrophoretic mobility shift assays (EMSA) indicate that GCN4 directly binds to the areA promoter region. Further affinity analysis through biolayer interferometry (BLI) experiments and surface plasmon resonance (SPR) confirmed that GCN4 specifically binds to the promoter region of areA with a strong binding affinity to activate the transcription of areA. In contrast, SKO1 showed no specified binding effect on the areA promoter. However, SKO1 activates the expression of the areA by forming a complex with GCN4, which exhibits a 14.2-fold-higher affinity than GCN4 alone. Furthermore, the presence of SKO1 promotes the stability of GCN4 protein. Accordingly, our study found that the transcription factor SKO1 enhances the transcriptional activity of GCN4 on its target gene areA by interacting with GCN4. Our study illustrates a specific regulatory mechanism for the involvement of GCN4 and SKO1 in nitrogen utilization, which provides innovative insight into the regulation of nitrogen utilization in fungi. IMPORTANCE Nitrogen is an essential nutrient for cell growth and proliferation. Limitations of nitrogen availability in organisms elicit a series of rapid transcriptional reprogramming mechanisms, which involve the participation of many transcription factors. However, the specific mechanism of coordination between different transcription factors regulating nitrogen metabolism has not been explored. Our study revealed that GCN4 interacts with SKO1 and that they are both involved in regulating nitrogen utilization by affecting the transcription level of areA. We also found that GCN4 activates transcription by directly binding to the promoter recognition region of areA. SKO1 facilitates the transcription of areA by GCN4 by forming a more stable complex with GCN4. Our study deepens our understanding of the regulatory network of nitrogen metabolism and demonstrates a further level of regulation for transcription factors.


Assuntos
Proteínas Fúngicas , Reishi , Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Regulação Fúngica da Expressão Gênica , Nitrogênio/metabolismo , Reishi/genética , Reishi/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
13.
Sci Total Environ ; 859(Pt 1): 159923, 2022 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-36356761

RESUMO

Global DNA methylation levels in peripheral blood leukocytes can be a biomarker for cancer risk; however, levels can be changed by various factors such as environmental pollutants. We investigated the association between serum concentrations of perfluoroalkyl substances (PFASs) and global DNA methylation levels of leukocytes in a cross-sectional study using the control group of a Japanese breast cancer case-control study [397 women with a mean age of 54.1 (SD 10.1) years]. Importantly, our analysis distinguished branched PFAS isomers as different from linear isomers. The serum concentrations of 20 PFASs were measured by in-port arylation gas-chromatography negative chemical ionization mass spectrometry. Global DNA methylation levels in peripheral blood leukocytes were measured using a luminometric methylation assay. Associations between log10-transformed serum PFAS concentrations and global DNA methylation levels were evaluated by regression coefficients in multivariable robust linear regression analyses. Serum concentrations of 13 PFASs were significantly associated with increased global DNA methylation levels in leukocytes. Global DNA methylation was significantly increased by 1.45 %-3.96 % per log10-unit increase of serum PFAS concentration. Our results indicate that exposure to PFASs may increase global DNA methylation levels in peripheral blood leukocytes of Japanese women.

14.
Front Microbiol ; 13: 931431, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36329847

RESUMO

Objective: Rheumatoid arthritis (RA) is a chronic inflammatory joint disease, which is associated with progressive disability, systemic complications, and early death. But its etiology and pathogenesis are not fully understood. We aimed to investigate the alterations in plasma metabolite profiles, gut bacteria, and fungi and their role of them in the pathogenesis of RA. Methods: Metabolomics profiling of plasma from 363 participants including RA (n = 244), systemic lupus erythematosus (SLE, n = 50), and healthy control (HC, n = 69) were performed using the ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry. The differentially expressed metabolites were selected among groups and used to explore important metabolic pathways. Gut microbial diversity analysis was performed by 16S rRNA sequencing and ITS sequencing (RA = 195, HC = 269), and the specific microbial floras were identified afterward. The diagnosis models were established based on significant differential metabolites and microbial floras, respectively. Results: There were 63 differential metabolites discovered between RA and HC groups, mainly significantly enriched in the arginine and proline metabolism, glycine, serine, and threonine metabolism, and glycerophospholipid metabolism between RA and HC groups. The core differential metabolites included L-arginine, creatine, D-proline, ornithine, choline, betaine, L-threonine, LysoPC (18:0), phosphorylcholine, and glycerophosphocholine. The L-arginine and phosphorylcholine were increased in the RA group. The AUC of the predictive model was 0.992, based on the combination of the 10 differential metabolites. Compared with the SLE group, 23 metabolites increased and 61 metabolites decreased in the RA group. However, no significant metabolic pathways were enriched between RA and SLE groups. On the genus level, a total of 117 differential bacteria genera and 531 differential fungal genera were identified between RA and HC groups. The results indicated that three bacteria genera (Eubacterium_hallii_group, Escherichia-Shigella, Streptococcus) and two fungal genera (Candida and Debaryomyces) significantly increased in RA patients. The AUC was 0.80 based on a combination of six differential bacterial genera and the AUC was 0.812 based on a combination of seven differential fungal genera. Functional predictive analysis displayed that differential bacterial and differential fungus both were associated with KEGG pathways involving superpathway of L-serine and glycine biosynthesis I, arginine, ornithine, and proline interconversion. Conclusion: The plasma metabolism profile and gut microbe profile changed markedly in RA. The glycine, serine, and threonine metabolism and arginine and proline metabolism played an important role in RA.

15.
Front Pharmacol ; 13: 996635, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36339559

RESUMO

Transdifferentiation of keratocytes into fibroblasts or further into myofibroblasts, which produced denser and more disorganized extracellular matrix, is the major cause of corneal fibrosis and scarring, leading to corneal blindness. TGF-ß1 is the critical cytokine for the myofibroblast's transdifferentiation and survival. Hypoxia Inducible Factor (HIF) was found to play an important role in promoting fibrosis in lung, kidney, and dermal tissues recently. Our preliminary study demonstrated that topical administration of the acriflavine (ACF), a drug inhibiting HIF dimerization, delayed corneal opacity and neovascularization after the alkali burn. To know whether ACF could prevent corneal fibrosis and improve corneal transparency, we created a mouse mechanical corneal injury model and found that topical administration of ACF significantly inhibited corneal fibrosis at day 14 post-injury. The reduction of myofibroblast marker α-SMA, and fibronectin, one of the disorganized extracellular matrix molecules, in the corneal stroma were confirmed by the examination of immunohistochemistry and real-time PCR. Furthermore, the ACF inhibited the expression of α-SMA and fibronectin in both TGF-ß1 stimulated or unstimulated fibroblasts in vitro. This effect was based on the inhibition of HIF signal pathways since the levels of the HIF-1α downstream genes including Slc2a1, Bnip3 and VEGFA were downregulated. To our knowledge, this is the first time to implicate that HIFs might be a new treatment target for controlling corneal fibrosis in mechanical corneal injuries.

16.
Free Radic Biol Med ; 193(Pt 2): 511-525, 2022 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-36336229

RESUMO

Sirtuin-3 (SIRT3), the main deacetylase in the mitochondria, maintains cellular energy metabolism and redox balance by deacetylating mitochondrial proteins in a NAD+-dependent manner. Growing evidence indicates that decreased Sirt3 expression is involved in various age-related maladies. However, the role of Sirt3 in ovarian and testicular senescence remains unclear. In this study, we observed that sirt3 expression showed age-dependent decreases in the ovary but not the testis. We generated Sirt3 null mice via CRISPR/Cas9-mediated genome editing. We observed that Sirt3 deletion accelerated ovarian aging, as shown by a decrease in offspring sizes, the follicle reserve and oocytes markers (Bmp15 and Gdf9) as well as increased expression of aging and inflammation-related genes (p16, p21, Il-1α, and Il-1ß). Sirt3 deficiency led to an accumulation of superoxide and disruption of spindle assembly accompanied by mitochondrial dysfunction (uneven mitochondria distribution, decreased mitochondrial potential as well as reduced mitochondrial DNA content) in aging oocytes. Meanwhile, in ovaries of Sirt3 null mice, the impaired mitochondrial functions were shown by decreases in mitochondrial respiratory complexes, along with lower levels of mitochondrial fusion (OPA1, MFN2) and fission (DRP1, FIS1) proteins. er levels of mitochondrial fusion (OPA1, MFN2) and fission (DRP1, FIS1) proteins. Interestingly, Sirt3-/- male mice exhibited no changes on the testicular histology, serum testosterone levels, germ-cell proliferation, and differentiation of spermatogonia. Meiotic prophase I spermatocytes were also normal. Levels of superoxide, mitochondrial potential as well as expression of mitochondrially-encoded genes were unaltered in Sirt3-/- testes. Collectively, the results indicated that SIRT3 plays a critical role in maintaining the ovarian follicle reserve and oocyte quality in aging mice, suggesting its important role in controlling ovarian senescence.

18.
Life Sci ; 309: 121043, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36206835

RESUMO

Tissue engineering holds great promise in the generation of cartilage analogues for cartilage injury repair and replacement. However, for a long time, a variety of issues have remained unsolved in articular cartilage tissue engineering concerning immunogenicity, stability, and mechanical strength, among others. One of the most remarkable reasons lies in the lack or insufficiency of recapitulating the chondrocyte biomechanical microenvironment (BME) in the articular cartilage tissue engineering. In recent years, an increasing number of studies have disclosed the crucial role of the BME in chondrocyte phenotype and cartilage functions, which has inspired more precise and individualized research in articular cartilage tissue engineering by engineering the chondrocyte BME. This review first takes an in-depth look into the chondrocyte BME and its crucial effects on chondrocytes and articular cartilage tissues. Then, as the core of this work, the principal strategies and their approaches of engineering the chondrocyte BME towards articular cartilage tissue engineering were comprehensively discussed, from the perspectives of simulating the main characteristics of chondrocyte BME including engineering the heterogeneous matrix and the dynamic mechanical stimulation. The current limitations in this emerging area and potential strategies were also proposed to shed some light on the future directions in this field. Although there are still challenges to obtaining engineered articular cartilages with desired performance, the road ahead is bright under the constant efforts in engineering the chondrocyte BME at higher levels towards articular cartilage tissue engineering.


Assuntos
Cartilagem Articular , Condrócitos , Condrócitos/fisiologia , Cartilagem Articular/fisiologia , Engenharia Tecidual , Fenótipo
19.
iScience ; 25(10): 105141, 2022 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-36204278

RESUMO

As a common complication of diabetes, the pathogenesis of diabetic peripheral neuropathy (DPN) is closely related to high glucose but has not been clarified. Exosomes can mediate crosstalk between Schwann cells (SC) and neurons in the peripheral nerve. Herein, we found that miR-21 in serum exosomes from DPN rats was decreased. SC proliferation was inhibited, cell apoptosis was increased, and the expression of miR-21 in cells and exosomes was downregulated when cultured in high glucose. Increasing miR-21 expression reversed these changes, while knockdown of miR-21 led to the opposite results. When co-cultured with exosomes derived from SC exposed to high glucose, neurite outgrowth was inhibited. On the contrary, neurite outgrowth was accelerated when incubated with exosomes rich in miR-21. We further demonstrated that the SC-derived exosomal miR-21 participates in neurite outgrowth probably through the AKT signaling pathway. Thus, SC-derived exosomal miR-21 contributes to high glucose regulation of neurite outgrowth.

20.
Immunol Invest ; : 1-13, 2022 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-36239661

RESUMO

BACKGROUND: Semaphorin 4A (Sema4A) is an immunoregulatory molecule that is closely related to the pathogenesis of some autoimmune diseases. However, the relationship between Sema4A and systemic lupus erythematosus (SLE) remains unknown. We therefore aimed to investigate the expression and clinical value of Sema4A in SLE patients. METHODS: Patients with SLE, rheumatoid arthritis (RA), and healthy controls (HC) were enrolled. The whole blood samples were collected from SLE (83), RA (29) and HC (85), and the expression of Sema4A on several types of leukocytes in peripheral blood was detected by flow cytometry. The serum samples were collected from SLE(77), RA (23) and HC (63), and the concentrations of soluble Sema4A in plasma were detected by ELISA. The diagnostic value of membrane-bound and soluble Sema4A in SLE patients was evaluated using a receiver operating characteristic (ROC) curve. RESULTS: The concentration of soluble Sema4A was significantly higher in plasma from SLE patients compared to that from HC and RA patients. In SLE patients, the ratio of CD4+CD11c+ myeloid dendritic cells (mDCs) expressing Sema4A increased significantly, and the levels of soluble Sema4A and membrane-bound Sema4A were negatively correlated with the levels of C3 and C4, respectively. The same result was observed for membrane-bound Sema4A on CD4+CD11c+ mDCs cells. In addition, the level of soluble Sema4A negatively correlated with the concentration of hemoglobin (Hb). Importantly, the expression ratio of membrane-bound Sema4A on CD4+CD11c+ mDCs was positively correlated with systemic lupus erythematosus disease activity index (SLEDAI). Finally, we revealed that soluble and membrane- bound Sema4A had high sensitivity and specificity for diagnosis of SLE, and had a greater ability to distinguish between SLE and RA. CONCLUSION: Sema4A has potential as a new diagnostic biomarker for SLE, and is promising for distinguishing between SLE and RA.

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