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1.
J Neurosci ; 2021 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-34848499

RESUMO

Mutations in some cell adhesion molecules (CAMs) cause abnormal synapse formation and maturation, and serve as one of the potential mechanisms of autism spectrum disorders (ASDs). Recently, DSCAM (Down syndrome cell adhesion molecule) was found to be a high-risk gene for autism. However, it is still unclear how DSCAM contributes to ASD. Here, we show that DSCAM expression was downregulated following synapse maturation, and that DSCAM deficiency caused accelerated dendritic spine maturation during early postnatal development. Mechanistically, the extracellular domain (ECD) of DSCAM interacts with neuroligin1 (NLGN1) to block the NLGN1-neurexin1ß (NRXN1ß) interaction. DSCAM-ECD was able to rescue spine overmaturation in DSCAM knockdown neurons. Precocious spines in DSCAM-deficient mice showed increased glutamatergic transmission in the developing cortex and induced autism-like behaviors such as social novelty deficits and repetitive behaviors. Thus, DSCAM might be a repressor that prevents premature spine maturation and excessive glutamatergic transmission, and its deficiency could lead to autism-like behaviors. Our study provides new insight into the potential pathophysiological mechanisms of ASDs.SIGNIFICANCE STATEMENT DSCAM is not only associated with Down syndrome but is also a strong autism risk gene based on large-scale sequencing analysis. However, it remains unknown exactly how DSCAM contributes to autism. In mice, either neuron- and astrocyte-specific or pyramidal neuron-specific DSCAM deficiencies resulted in autism-like behaviors and enhanced spatial memory. In addition, DSCAM knockout or knockdown in pyramidal neurons led to increased dendritic spine maturation. Mechanistically, the extracellular domain of DSCAM binds to NLGN1 and inhibits NLGN1-NRXN1ß interaction, which can rescue abnormal spine maturation induced by DSCAM deficiency. Our research demonstrates that DSCAM negatively modulates spine maturation, and that DSCAM deficiency leads to excessive spine maturation and autism-like behaviors, thus providing new insight into a potential pathophysiological mechanism of autism.

2.
Front Aging Neurosci ; 13: 769506, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34803660

RESUMO

Parkinson's disease (PD) is a neurodegenerative disorder closely related to immunity. An important aspect of the pathogenesis of PD is the interaction between α-synuclein and a series of immune cells. Studies have shown that accumulation of α-synuclein can induce an autoimmune response that accelerates the progression of PD. This study discusses the mechanisms underlying the interaction between α-synuclein and the immune system. During the development of PD, abnormally accumulated α-synuclein becomes an autoimmune antigen that binds to Toll-like receptors (TLRs) that activate microglia, which differentiate into the microglia type 1 (M1) subtype. The microglia activate intracellular inflammatory pathways, induce the release of proinflammatory cytokines, and promote the differentiation of cluster of differentiation 4 + (CD4 +) T cells into proinflammatory T helper type 1 (Th1) and T helper type 17 (Th17) subtypes. Given the important role of α-synuclein in the immune system of the patients with PD, identifying potential targets of immunotherapy related to α-synuclein is critical for slowing disease progression. An enhanced understanding of immune-associated mechanisms in PD can guide the development of associated therapeutic strategies in the future.

3.
Front Endocrinol (Lausanne) ; 12: 759049, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34803921

RESUMO

Purpose: To investigate the prognostic significance of extranodal extension (ENE) in papillary thyroid cancer (PTC). Methods: Seven hundred forty-three PTC patients were enrolled in the study from January 2014 to December 2017. The patients were dichotomized according to the presence of ENE. Logistic analysis was used to compare differences between the two groups. Kaplan-Meier (K-M) curve and propensity score matching (PSM) analyses were used for recurrence-free survival (RFS) comparisons. Cox regression was performed to analyze the effects of ENE on RFS in PTC. Results: Thirty-four patients (4.58%) had ENE. Univariate analysis showed that age, tumor size, extrathyroidal extension, and nodal stage were associated with ENE. Further logistic regression analysis showed that age, extrathyroidal extension, and nodal stage remained statistically significant. Evaluation of K-M curves showed a statistically significant difference between the two groups before and after PSM. Cox regression showed that tumor size and ENE were independent risk factors for RFS. Conclusions: Age ≥55 years, extrathyroidal extension, and lateral cervical lymph node metastasis were identified as independent risk factors for ENE. ENE is an independent prognostic factor in PTC.

4.
Appl Environ Microbiol ; : AEM0165521, 2021 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-34731046

RESUMO

The type VI secretion system (T6SS) is an important translocation apparatus that is widely employed by Gram-negative bacteria to deliver toxic effectors into eukaryotic and prokaryotic target cells, causing host damage and providing competitive advantages in polymicrobial environments. The genome of P. aeruginosa harbors three T6SS clusters (H1-T6SS, H2-T6SS, H3-T6SS). Activities of these systems are tightly regulated by a complicated signaling network which remains largely elusive. In this study, we focused on a previously characterized two-component system FleS/FleR and performed comparative transcriptome analysis between the PAO1 wild-type strain and its isogenic ΔfleR mutant, which revealed the important role of FleS/FleR in regulating multiple physiological pathways including T6SS. Gene expression and bacterial killing assays showed that the expression and activity of H1-T6SS are repressed in the wild-type strain owing to the high intracellular c-di-GMP content. Further explorations demonstrated that c-di-GMP relies on the transcription factor FleQ to repress H1-T6SS and its synthesis is controlled by a global regulator AmrZ which is induced by the active FleS/FleR. Interestingly, FleS/FleR regulates H1-T6SS in PAO1 is independent of RetS which is known to regulate H1-T6SS by controlling the central post-transcriptional factor RsmA. Together, our results identified a novel regulator of H1-T6SS and provided detailed mechanisms of this signaling pathway in PAO1. IMPORTANCE P. aeruginosa is an opportunistic human pathogen distributed widely in the environment. The genome of this pathogen contains three T6SS clusters which contribute significantly to its virulence. Understanding the complex regulatory network that controls the activity of T6SS is essential for the development of effective therapeutic treatments for P. aeruginosa infections. In this study, transcriptome analysis led to the identification of a novel regulator FleS/FleR which inversely regulates H1-T6SS and H2-T6SS in P. aeruginosa PAO1. We further revealed a detailed FleS/FleR-mediated regulatory pathway of H1-T6SS in PAO1 which involves two additional transcriptional regulators AmrZ and FleQ and the second messenger c-di-GMP, providing important implications to develop novel anti-infective strategies and antimicrobial drugs.

5.
Opt Express ; 29(15): 23461-23476, 2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34614611

RESUMO

Accurate identification of aerosols and cloud from remote sensing observations is of importance for quantitatively evaluating their radiative forcing and related impacts. Even though polarization lidar has exhibited a unique advantage of classifying atmospheric aerosols and clouds over the past several decades, polarization measurements are often achieved at one wavelength (UV or VIS) using laser remote sensing. To better identify the types of aerosols and clouds, we developed a ground-based dual-polarization lidar system that can simultaneously detect polarization measurements at wavelengths of 355 nm and 532 nm. Our results show that the volume depolarization ratios (VDRs) at 355 nm and 532 nm markedly differ for typical types of aerosols and clouds in the atmosphere. For non-spherical particles, the ratio of VDRs at 532 nm and 355 nm are 2.87 ± 1.35 for ice cloud and 1.51 ± 0.29 for dust-dominated aerosols, respectively. However, for spherical particles, the ratios are 0.43 ± 0.26 for water cloud and 0.56 ± 0.05 for air pollutants. Consequently, we proposed a simple reliable method for classifying atmospheric aerosols and clouds from polarization measurements observed by the developed lidar system. The proposed method first distinguishes clouds from aerosols using a combination of the color ratio (CR, 532 nm/355 nm) and attenuated backscattering coefficients (ABC) at 532 nm. Then, subtypes of clouds and aerosols are identified based on the ratio of VDRs at 532 nm and 355 nm. The results showed that dual-polarization lidar measurements can remarkably improve the classification of atmospheric aerosols and clouds, compared with results using a traditional method. This study illustrates that more information on atmospheric aerosols and clouds can be obtained from polarization measurements at multiple wavelengths by active remote sensing.

6.
J Coll Physicians Surg Pak ; 31(10): 1207-1213, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34601843

RESUMO

This study aimed to explore the diagnostic performance of urinary microRNAs (miRNAs) in bladder cancer (BC) in the Asian population. PubMed, Embase, Web of Science and Cochrane Library were searched for relevant literature on the diagnostic performance of miRNAs for BC in the Asian population. Subsequently, quality assessment on diagnostic accuracy studies-2 (QUADAS-2) was used for evaluating the quality of the included literature, and Stata version 15.0 for statistical analysis. Eleven published studies, including 1,220 BC patients, met the inclusion and exclusion criteria and, therefore, were investigated in this meta-analysis. The pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of urinary miRNAs in the diagnosis of BC were 0.80 (95%CI: 0.74-0.85), 0.76 (95%CI: 0.69-0.81), 3.28 (95%CI: 2.63-4.10), 0.26(95%CI: 0.21-0.33), respectively. Additionally, the area under the curve (AUC) was 0.85 in the summary receiver operating characteristic (SROC) curve, and the diagnostic odds ratio (DOR) was 12.39 (95%CI: 9.00-17.07). In conclusion, urinary miRNAs show good performance in diagnosing BC in Asia, and, therefore, can serve as effective biomarkers for early clinical screening and auxiliary diagnosis of BC. Key Words: MicroRNAs, Bladder cancer, Diagnostic value, Meta-analysis.


Assuntos
MicroRNAs , Neoplasias da Bexiga Urinária , Ásia , Grupo com Ancestrais do Continente Asiático , Humanos , MicroRNAs/genética , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/genética
7.
Front Cardiovasc Med ; 8: 736854, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34660739

RESUMO

Background: Several cardiovascular risk factors have been suggested to be associated with anthracycline-induced cardiotoxicity, but their quantitative effects have not reached a consensus. Methods: We searched PubMed, EMBASE, and Cochrane Library databases for manuscripts published from inception to February 2021, which reported the results of cardiotoxicity due to anthracycline chemotherapy without trastuzumab. Cardiotoxicity defined by any reduction of left ventricular eject fraction (LVEF) to below 50% or a >10% reduction from baseline was defined as the primary endpoint. Odd ratios (OR) with 95% confidence intervals (CI) were calculated using a random-effects model meta-analysis. Results: A total of 7,488 patients receiving anthracycline chemotherapy without trastuzumab were included, who had at least one risk factor at baseline. Hypertension (OR: 1.99; 95% CI: 1.43-2.76), diabetes mellitus (OR: 1.74; 95% CI: 1.11-2.74), and obesity (OR: 1.72; 95% CI: 1.13-2.61) were associated with increased risk of cardiotoxicity. In addition, the relative reduction of global longitudinal strain (GLS) from baseline after anthracycline treatment could significantly improve the detection ability of cardiotoxicity (28.5%, 95% CI: 22.1-35.8% vs. 16.4%, 95% CI: 13.4-19.9%) compared with LVEF. The early detection rate of anthracycline-induced cardiotoxicity (3 months after chemotherapy) by GLS was 30.2% (95% CI: 24.9-36.1%), which is similar with the overall result of GLS. Conclusions: Hypertension, diabetes mellitus, and obesity are associated with increased risk of anthracycline-induced cardiotoxicity, which indicates that corresponding protective strategies should be used during and after anthracycline treatment. The findings of higher detection rate and better early detection ability for cardiotoxicity than LVEF added new proofs for the advantages of GLS in detection of AIC.

8.
Exp Ther Med ; 22(5): 1286, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34630641

RESUMO

Oxidative stress plays an important role in the pathogenesis of cataracts. Under oxidative stress, apoptosis of lens epithelial cells (LECs) is activated, which may cause lens opacity and accelerate the development of cataracts. Long non-coding RNA (lncRNA) and microRNA (miRNA/miR) are involved in cataracts. Previous studies have demonstrated that lncRNA taurine upregulated 1 (TUG1) promotes cell apoptosis induced by ultraviolet radiation by downregulating the expression of miR-421. However, the mechanism underlying TUG1 in age-related cataract remains to be elucidated. The present study aimed to investigate the effect of TUG1 in age-related cataracts and to determine the related underlying molecular mechanism. In the present study, the association between TUG1 and microRNA (miR)-196a-5p was predicted using StarBase and verified using a dual luciferase reporter assay in 293 cells. The LEC line SRA01/04 was exposed to 200 µM hydrogen peroxide (H2O2) for 24 h to establish an in vitro oxidative stress model. The mRNA expression levels of TUG1 and miR-196a-5p were analyzed using reverse transcription-quantitative PCR, whilst cell viability and apoptosis were determined using MTT and flow cytometry assays, respectively. The protein expression levels of cleaved caspase-3 and caspase-3 in SRA01/04 cells were determined using western blotting. The results of the present study revealed that TUG1 directly targeted miR-196a-5p expression. In addition, the expression levels of miR-196a-5p were downregulated in SRA01/04 cells following oxidative stress, whilst TUG1 expression was upregulated. Cell transfection with TUG1-small interfering RNA (siRNA) upregulated miR-196a-5p expression levels in SRA01/04 cells, which was reversed following co-transfection with the miR-196a-5p inhibitor. Transfection with TUG1-siRNA also reduced the levels of H2O2-induced oxidative damage in SRA01/04 cells, which was demonstrated by increased cell viability, reduced levels of apoptosis and downregulated cleaved caspase-3 levels. Conversely, transfection with the miR-196a-5p inhibitor reversed these effects aforementioned. Overexpression of miR-196a-5p reduced H2O2-induced oxidative damage in SRA01/04 cells. In conclusion, findings from the present study suggested that knocking down TUG1 expression may protect LECs from oxidative stress-induced apoptosis by upregulating the expression of miR-196a-5p.

9.
J Control Release ; 339: 14-26, 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34547257

RESUMO

Ferroptosis is a type of programmed cell death caused by the iron-dependent lipid hydroperoxide pathway and has attracted significant interest. However, Fenton reaction-dependent ferroptosis has shown unsatisfactory therapeutic effects in tumor therapy, mainly due to inadequate reaction conditions in the tumor microenvironment. Here, we report a new strategy for Fenton-independent pathway by employing photothermal nanozyme to overcome limitations of the low efficiency of Fenton reaction. Specifically, we used iron redox pair (Fe2+/Fe3+)-containing hollow mesoporous Prussian blue (HMPB) nanocubes as the iron sources to fabricate iron-loaded liposome (HMPB@Lip). HMPB@Lip not only exerts the photothermal therapy, but also functions as nanozyme catalyzing lipid peroxidation for ferroptosis therapy. Importantly, Fenton reaction-independent ferroptosis triggered by photothermal nanozyme achieved effective tumor ablation. Therefore, HMPB@Lip can be used as a potential multifunctional nanozyme for effective Fenton reaction-independent ferroptosis therapy.

10.
Front Endocrinol (Lausanne) ; 12: 738138, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34531829

RESUMO

Objective: Our goal was to investigate the correlation between papillary thyroid carcinoma (PTC) characteristics on ultrasonography and metastases of lymph nodes posterior to the right recurrent laryngeal nerve (LN-prRLN). There is still no good method for clinicians to judge whether a patient needs LN-prRLN resection before surgery, and we also wanted to establish a new scoring system to determine whether patients with papillary thyroid carcinoma require LN-prRLN resection before surgery. Patients and Methods: There were 482 patients with right or bilateral PTC who underwent thyroid gland resection from December 2015 to December 2017 recruited as study subjects. The relationship between the PTC characteristics on ultrasonography and the metastases of LN-prRLN was analyzed by univariate and logistic regression analyses. Based on the risk factors identified in univariate and logistic regression analysis, a nomogram-based LN-prRLN prediction model was established. Result: LN-prRLN were removed from all patients, of which 79 had LN-prRLN metastasis, with a metastasis rate of 16.39%. Multivariate logistic regression analysis revealed that LN-prRLN metastasis was closely related to sex, age, blood supply, larger tumors (> 1 cm) and capsular invasion. A risk prediction model has been established and fully verified. The calibration curve used to evaluate the nomogram shows that the consistency index was 0.75 ± 0.065. Conclusion: Preoperative clinical data, such as sex, age, abundant blood supply, larger tumor (> 1 cm) and capsular invasion, are positively correlated with LN-prRLN metastasis. Our scoring system can help surgeons non-invasively determine which patients should undergo LN-prRLN resection before surgery. We recommend that LN-prRLN resection should be performed when the score is above 103.1.

11.
Eur J Pharmacol ; 910: 174441, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34474028

RESUMO

Gefitinib, a tyrosine kinase inhibitor, was the first targeted therapy for non-small cell lung cancer (NSCLC). Gefitinib could block human Ether-à-go-go-Related Gene (hERG) channel, an important target in drug-induced long QT syndrome. However, it is unclear whether gefitinib could induce QT interval prolongation. Here, whole-cell patch-clamp technique was used for evaluating the effect of gefitinib on rapidly-activating delayed rectifier K+ current (IKr), slowly-activating delayed rectifier K+ current (IKs), transient outward potassium current (Ito), inward rectifier K+ current (IK1) and on action potentials in guinea pig ventricular myocytes. The Langendorff heart perfusion technique was used to determine drug effect on the ECG. Gefitinib depressed IKr by binding to open and closed hERG channels in a concentration-dependent way (IC50: 1.91 µM). The inhibitory effect of gefitinib on wildtype hERG channels was reduced at the hERG mutants Y652A, S636A, F656V and S631A (IC50: 8.51, 13.97, 18.86, 32.99 µM), indicating that gefitinib is a pore inhibitor of hERG channels. In addition, gefitinib accelerated hERG channel inactivation and decreased channel steady-state inactivation. Gefitinib also decreased IKs with IC50 of 23.8 µM. Moreover, gefitinib increased action potential duration (APD) in guinea pig ventricular myocytes and the corrected QT interval (QTc) in isolated perfused guinea pig hearts in a concentration-dependent way (1-30 µM). These findings indicate that gefitinib could prolong QTc interval by potently blocking hERG channel, modulating kinetic properties of hERG channel. Partial block of KCNQ1/KCNE1 could also contribute to delayed repolarization and prolonged QT interval. Thus, caution should be taken when gefitinib is used for NSCLC treatment.

12.
Int J Mol Sci ; 22(18)2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34576026

RESUMO

Quorum sensing (QS) is a microbial cell-cell communication mechanism and plays an important role in bacterial infections. QS-mediated bacterial infections can be blocked through quorum quenching (QQ), which hampers signal accumulation, recognition, and communication. The pathogenicity of numerous bacteria, including Xanthomonas campestris pv. campestris (Xcc), is regulated by diffusible signal factor (DSF), a well-known fatty acid signaling molecule of QS. Cupriavidus pinatubonensis HN-2 could substantially attenuate the infection of XCC through QQ by degrading DSF. The QQ mechanism in strain HN-2, on the other hand, is yet to be known. To understand the molecular mechanism of QQ in strain HN-2, we used whole-genome sequencing and comparative genomics studies. We discovered that the fadT gene encodes acyl-CoA dehydrogenase as a novel QQ enzyme. The results of site-directed mutagenesis demonstrated the requirement of fadT gene for DSF degradation in strain HN-2. Purified FadT exhibited high enzymatic activity and outstanding stability over a broad pH and temperature range with maximal activity at pH 7.0 and 35 °C. No cofactors were required for FadT enzyme activity. The enzyme showed a strong ability to degrade DSF. Furthermore, the expression of fadT in Xcc results in a significant reduction in the pathogenicity in host plants, such as Chinese cabbage, radish, and pakchoi. Taken together, our results identified a novel DSF-degrading enzyme, FadT, in C. pinatubonensis HN-2, which suggests its potential use in the biological control of DSF-mediated pathogens.


Assuntos
Acil-CoA Desidrogenase/genética , Infecções Bacterianas/genética , Ácidos Graxos/genética , Doenças das Plantas/genética , Xanthomonas campestris/genética , Acil-CoA Desidrogenase/química , Acil-CoA Desidrogenase/isolamento & purificação , Infecções Bacterianas/microbiologia , Brassica/crescimento & desenvolvimento , Brassica/microbiologia , Comunicação Celular/genética , Ácidos Graxos/metabolismo , Regulação Enzimológica da Expressão Gênica , Genoma Bacteriano/genética , Genômica , Mutagênese Sítio-Dirigida , Doenças das Plantas/microbiologia , Percepção de Quorum/genética , Raphanus/genética , Raphanus/microbiologia , Transdução de Sinais/genética , Fatores de Virulência/genética , Sequenciamento Completo do Genoma , Xanthomonas campestris/enzimologia
13.
Mol Plant ; 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34562666

RESUMO

Phosphorous (P) and iron (Fe), two essential nutrients for plant growth and development, are highly abundant elements in the earth's crust but often display low availability to plants. Due to the ability to form insoluble complexes, the antagonistic interaction between P and Fe nutrition in plants has been noticed for decades. However, the underlying molecular mechanism modulating the signaling and homeostasis between them remains obscure. Here, we show that the possible iron sensors HRZs, the iron deficiency-induced E3 ligases, could interact with the central regulator of phosphate (Pi) signaling, PHR2, and prompt its ubiquitination at lysine residues K319 and K328, leading to its degradation in rice. Consistent with this, the hrzs mutants displayed a high Pi accumulation phenotype. Furthermore, we found that iron deficiency could attenuate Pi starvation signaling by inducing the expression of HRZs, which in turn trigger PHR2 protein degradation. Interestingly, on the other hand, rice PHRs could negatively regulate the expression of HRZs to modulate iron deficiency responses. Therefore, PHR2 and HRZs form a reciprocal inhibitory module to coordinate Pi and iron signaling and homeostasis in rice. Taken together, our results uncover a molecular link between Pi and iron master regulators, which fine-tunes plant adaptation to Pi and iron availability in rice.

14.
Biomaterials ; 277: 121108, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34478929

RESUMO

Rare monogenic disorders are a group of single-gene-mutated diseases that have a low incidence rate (less than 0.5‰) and eventually lead to patient disability and even death. Due to the relatively low number of people affected, these diseases typically fail to attract a great deal of commercial investment and research interest, and the affected patients thus have unmet medical needs. Advances in genomics biology, gene editing, and gene delivery can now offer potentially effective options for treating rare monogenic diseases. Herein, we review the application of gene therapy strategies (traditional gene therapy and gene editing) against various rare monogenic diseases with nuclear or mitochondrial gene mutations, including eye, central nervous system, pulmonary, systemic, and blood cell diseases. We summarize their pathologic features, address the barriers to gene delivery for these diseases, discuss available therapies in the clinic and in clinical trials, and sum up in-development gene delivery systems for various rare monogenic disorders. Finally, we elaborate the possible directions and outlook of gene therapy for rare monogenic disorders.


Assuntos
Genes Mitocondriais , Terapia Genética , Edição de Genes , Técnicas de Transferência de Genes , Humanos , Mutação
15.
Front Microbiol ; 12: 707711, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34367113

RESUMO

Pseudomonas aeruginosa, a major cause of nosocomial infection, can survive under diverse environmental conditions. Its great adaptive ability is dependent on its multiple signaling systems such as the two-component system (TCS). A TCS FleS/FleR has been previously identified to positively regulate a variety of virulence-related traits in P. aeruginosa PAO1 including motility and biofilm formation which are involved in the acute and chronic infections, respectively. However, the molecular mechanisms underlying these regulations are still unclear. In this study, we first analyzed the regulatory roles of each domains in FleS/FleR and characterized key residues in the FleS-HisKA, FleR-REC and FleR-AAA domains that are essential for the signaling. Next, we revealed that FleS/FleR regulates biofilm formation in a c-di-GMP and FleQ dependent manner. Lastly, we demonstrated that FleR can regulate flagellum biosynthesis independently without FleS, which explains the discrepant regulation of swimming motility by FleS and FleR.

16.
Cancer Med ; 10(18): 6384-6401, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34382349

RESUMO

With the widespread use of PD-1/PD-L1 monoclonal antibodies (mAbs) in the treatment of multiple malignant tumors, they were also gradually applied to advanced renal cell carcinoma (aRCC). Nowadays, multiple PD-1/PD-L1 mAbs, such as nivolumab, avelumab, and pembrolizumab, have achieved considerable efficacy in clinical trials. However, due to the primary, adaptive, and acquired resistance to these mAbs, the efficacy of this immunotherapy is not satisfactory. Theories also vary as to why the difference in efficacy occurs. The alterations of PD-L1 expression and the interference of cellular immunity may affect the efficacy. These mechanisms demand to be revealed to achieve a sustained and complete objective response in patients with aRCC. Tyrosine kinase inhibitors have been proven to have synergistic mechanisms with PD-1/PD-L1 mAb in the treatment of aRCC, and CTLA-4 mAb has been shown to have a non-redundant effect with PD-1/PD-L1 mAb to enhance efficacy. Although combinations with targeted agents or other checkpoint mAbs have yielded enhanced clinical outcomes in multiple clinical trials nowadays, the potential of PD-1/PD-L1 mAbs still has a large development space. More potential mechanisms that affect the efficacy demand to be developed and transformed into the clinical treatment of aRCC to search for possible combination regimens. We elucidate these mechanisms in RCC and present existing combination therapies applied in clinical trials. This may help physicians' select treatment options for patients with refractory kidney cancer.

17.
Glia ; 69(11): 2644-2657, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34288126

RESUMO

Activation of microglia and inflammation-mediated vascular damages are suggested to play a decisive role in the pathogenesis of various retinopathies. The inducible nitric oxide synthase (iNOS) was required for activated microglia-mediated injuries. However, the induction mechanism of microglia activation during retinal vascular diseases is still elusive. Here we showed that IL-17 induced microglia activation with high expression of iNOS and promoted the development of retinal vascular diseases. IL-17-dependent activation of the STAT3-iNOS pathway was essentially required for microglia activation, which promoted endothelial cell growth and accelerated vascular leakage and leukostasis via IL-6 in vitro and in vivo. Taken together, our data provide novel mechanistic insights on microglia activation-mediated retinopathy, unveil the specific role of IL-17 on microglia, and define novel therapeutic targets for treating retinal vascular diseases.

18.
Oxid Med Cell Longev ; 2021: 6617345, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34239692

RESUMO

Hepatic ischemia-reperfusion injury (IRI) is the most common cause of liver damage leading to surgical failures in hepatectomy and liver transplantation. Extensive inflammatory reactions and oxidative responses are reported to be the major processes exacerbating IRI. The involvement of Yes-associated protein (YAP) in either process has been suggested, but the role and mechanism of YAP in IRI remain unclear. In this study, we constructed hepatocyte-specific YAP knockout (YAP-HKO) mice and induced a hepatic IRI model. Surprisingly, the amount of serum EVs decreased in YAP-HKO compared to WT mice during hepatic IRI. Then, we found that the activation of YAP increased EV secretion through F-actin by increasing membrane formation, while inhibiting the fusion of multivesicular body (MVB) and lysosomes in hepatocytes. Further, to explore the essential elements of YAP-induced EVs, we applied mass spectrometry and noticed CD47 was among the top targets highly expressed on hepatocyte-derived EVs. Thus, we enriched CD47+ EVs by microbeads and applied the isolated CD47+ EVs on IRI mice. We found ameliorated IRI symptoms after CD47+ EV treatment in these mice, and CD47+ EVs bound to CD172α on the surface of dendritic cells (DCs), which inhibited DC activation and the cascade of inflammatory responses. Our data showed that CD47-enriched EVs were released in a YAP-dependent manner by hepatocytes, which could inhibit DC activation and contribute to the amelioration of hepatic IRI. CD47+ EVs could be a potential strategy for treating hepatic IRI.

19.
Environ Int ; 157: 106793, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34332302

RESUMO

Pre-ozonation can reduce the formation of disinfection byproducts (DBPs) and related adverse effects during subsequent chlorination, but the change of each molecular weight (MW) fraction during each step of combined pre-ozonation and post-chlorination has not been well illustrated. In this study, it was investigated in terms of electron-donating-moieties (EDMs) and UVA254 for a representative natural organic matter from Suwanee river (SRNOM). Pre-ozonation suppressed the post-chlorination of SRNOM through oxidation of almost all EDMs (>85%) and UVA254 (>90%) in high MW fractions (HMW, >3.2 kDa) and moderate EDMs (43%) and UVA254 (72%) in medium MW fractions (MMW, 1.0-3.2 kDa). Furthermore, pre-ozonation led to comparable abatements of EDMs and UVA254 for HMW fractions, but lower abatement of EDMs than UVA254 for MMW fractions. However, when t-BuOH was used as an •OH-quencher, pre-ozonation led to a few instances in which there were higher abatements of EDMs than UVA254 for the MMW fraction. These findings suggested that the HMW fraction dominantly underwent ring-cleavage of phenols via O3- or •OH-oxidation. Differently, the MMW fraction underwent ring-cleavage of phenols and quinones-formation via O3-oxidation, but occasionally underwent hydroxylation and hydro-phenol formation via •OH-oxidation. Because of forehand elimination of reactive moieties (e.g. EDMs), pre-ozonation obviously inhibited the formation of representative DBPs (67%-84% inhibition), total organic chloride (51% inhibition) and cytotoxicity (31% inhibition), but may have promoted the formation of carbonyl-DBPs (trichloroacetone and chloral hydrate). When compared with UVA254, EDMs would better for surrogate of DBPs formation. EDM abatement surrogated the formation of total organic chlorine (TOCl) and cytotoxicity following a two-stage phase, possibly because the speciation of DBPs and transformation products varied with the abatement of EDMs.


Assuntos
Desinfetantes , Ozônio , Poluentes Químicos da Água , Purificação da Água , Desinfecção , Elétrons , Halogenação , Peso Molecular , Poluentes Químicos da Água/análise
20.
Front Bioeng Biotechnol ; 9: 630977, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34178953

RESUMO

Guided tissue regeneration (GTR) is a promising treatment for periodontal tissue defects, which generally uses a membrane to build a mechanical barrier from the gingival epithelium and hold space for the periodontal regeneration especially the tooth-supporting bone. However, existing membranes possess insufficient mechanical properties and limited bioactivity for periodontal bone regenerate. Herein, fish collagen and polyvinyl alcohol (Col/PVA) dual-layer membrane were developed via a combined freezing/thawing and layer coating method. This dual-layer membrane had a clear but contact boundary line between collagen and PVA layers, which were both hydrophilic. The dual membrane had an elongation at break of 193 ± 27% and would undergo an in vitro degradation duration of more than 17 days. Further cell experiments showed that compared with the PVA layer, the collagen layer not only presented good cytocompatibility with rat bone marrow-derived mesenchymal stem cells (BMSCs), but also promoted the osteogenic genes (RUNX2, ALP, OCN, and COL1) and protein (ALP) expression of BMSCs. Hence, the currently developed dual-layer membranes could be used as a stable barrier with a stable degradation rate and selectively favor the bone tissue to repopulate the periodontal defect. The membranes could meet the challenges encountered by GTR for superior defect repair, demonstrating great potential in clinical applications.

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