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1.
Antioxidants (Basel) ; 10(3)2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33809627

RESUMO

Oxidative stress is increasingly being recognized as a player in the pathogenesis of intestinal pathologies, and probiotics are becoming an attractive means of addressing it. The present study investigated the effects of dietary supplementation with Lactobacillus delbrueckii (LAB) on intestinal integrity and oxidative damage in lipopolysaccharide (LPS)-challenged piglets. A total of 36 crossbred weaned piglets (Duroc × Landrace × Large Yorkshire) were randomly divided into three groups: (1) non-challenged controls (CON), (2) LPS-challenged controls (LPS), and (3) 0.2% LAB (2.01 × 1010 CFU/g) + LPS treatment (LAB + LPS). On the 29th day of the experiment, the LPS and CON groups were injected intraperitoneally with LPS and saline at 100 ug/kg body weight, respectively. The results show that the LPS-induced elevation of the serum diamine oxidase (DAO) level and small intestinal crypt depth (CD) were reversed by the dietary addition of LAB, which also markedly increased the ileal expression of tight junction proteins (occludin, ZO-1, and claudin-1) in the LPS-challenged piglets. Furthermore, LAB supplementation normalized other LPS-induced changes, such as by decreasing malondialdehyde (MDA) in both the serum and intestinal mucosa and 8-hydroxy-2-deoxyguanosine (8-OHdG) in the jejunal mucosa, increasing glutathione reductase (GR) and glutathione peroxidase (GSH-Px) in both the serum and intestinal mucosa, and increasing glutathione (GSH) and superoxide dismutase (SOD) in the jejunal mucosa. LAB also activated Toll-like receptor (TLR)-Bruton's tyrosine kinase (Btk)-nuclear factor erythroid 2-related factor 2(Nrf2) signaling pathways in the intestine, suggesting that it plays a vital role in the ameliorative antioxidant capacity of weaned piglets. In summary, LAB increased intestinal integrity by improving the intestinal structure and tight junctions while enhancing antioxidant functions via the activation of the TLR-Btk-Nrf2 signaling pathway.

2.
J Agric Food Chem ; 2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33787254

RESUMO

The overuse of chemical nitrogen (N) and phosphorus (P) fertilizers in tomato cultivation is common for high fruit yields to meet the ever-increasing industrial needs, resulting in poor fruit quality, fertilizer waste, and environmental pollution. Nutrient-mobilizing microbes increase soil nutrient supply and decrease fertilizer use without yield sacrifices. Thus, the influence of a new white-rot fungus Ceriporia lacerata HG2011 was studied on soil N and P mobilization in lab and ketchup tomato performances in field. Compared with noninoculation, soil pH decreased, while ammonia (NH4+-N), available P, microbial biomass N and P, and activities of protease and phosphatase in the inoculated soil increased as the fungus grew on and in the sterile soil. Protease activity was positively correlated with NH4+-N and phosphatase activity was with water-soluble P and Olsen P in the sterile soil. Soil pH showed an inverse correlation with available P. In the field experiment, the treatments included a blank control, C. lacerata, chemical fertilizers, and chemical fertilizers plus C. lacerata. Fungal inoculation enhanced the available N and P and the activities of protease and phosphatase in both fertilized and unfertilized soils, leading to the increment of plant nutrient uptake. Fungal application increased the fruit yield by 18.18-20.16%, soluble solids by 3.17-6.30%, soluble sugar by 10.67-43.33%, sugar-acid ratio 20.19-52.91%, and vitamin C by 8.83-34.90%. Therefore, our results first demonstrated the new functions of C. lacerata HG2011 in the mobilization of soil N and P and the improvement of plant nutrient uptake, yield, and quality, showing a potential use as biofertilizers in ketchup-processing tomato cultivation.

3.
Health Phys ; 120(5): 541-551, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33760770

RESUMO

ABSTRACT: The impact of long-term low-dose radiation on human health has always been a concern. Long-term low-dose gamma radiation causes cells continuous injury and causes chromosomal mutations to greatly increase the chance of cancer. Because it is significant to identify biomarkers for long-term low-dose gamma radiation, we investigate the influence of low dose rate on the gene expressions in the AHH-1 lymphocytes cell line (AHH-1 cells) for long-term irradiation. Different dose rates (7, 14, 26, 34, and 43 µGy h-1) of irradiation from gamma radiation in uranium tailings powder were used to irradiate AHH-1 lymphocytes. We used flow cytometry to test the apoptosis of AHH-1 lymphocytes at different dose rates and irradiation times (7-84 d). It was found that 14 µGy h-1 is the most sensitive dose rate of AHH-1 lymphocyte irradiation. The 7-, 14-, and 21-d (2.4, 4.8, and 7.2 mGy) irradiation groups were sensitive, and the 84-d (28.8 mGy) irradiation group was insensitive to low dose gamma radiation. Microarray analysis was conducted on the significantly differentially expressed genes (p<0.05) in the 2.4, 4.8, 7.2, and 28.8 mGy irradiation groups. We found that TFRC1, SLC3A2, SLC39A8, FTH1, ACSL4, and GPX4 are significant genes with low-dose radiation and were constituents of the ferroptosis signaling pathway. In the range of 0-4.8 mGy radiation dose, the expressions of these genes were downregulated with increasing radiation dose, while in the range of 4.8-28.8 mGy, its expression increased with increasing radiation dose. RT-PCR and Western blot were used to detect the mRNA and protein expression of these genes. The results were consistent with those from microarray analysis. Our findings indicate that expression of the TFRC, SLC3A2, SLC39A, FTH1, ACSL4, and GPX4 genes is sensitive to low-dose radiation, and they are main members of the ferroptosis signaling pathway. Therefore, there is a very important connection between ferroptosis and low-dose radiation, which has become a hot topic in international research. These results can provide reference to the effect of ferroptosis on human health with low-dose radiation.

4.
Commun Biol ; 4(1): 266, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33649486

RESUMO

Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown. It can lead to severe visual morbidity in children and young adults and is a common indication for corneal transplantation worldwide. Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls. We have identified significant association with 36 genomic loci that, for the first time, implicate both dysregulation of corneal collagen matrix integrity and cell differentiation pathways as primary disease-causing mechanisms. The results also suggest pleiotropy, with some disease mechanisms shared with other corneal diseases, such as Fuchs endothelial corneal dystrophy. The common variants associated with keratoconus explain 12.5% of the genetic variance, which shows potential for the future development of a diagnostic test to detect susceptibility to disease.

5.
Biomed Res Int ; 2021: 6530298, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33748270

RESUMO

DUOX2 has been reported to highly express in several types of cancers. However, the prognostic significance and the biological function of DUOX2 expression with pancreatic cancer (PC) still remain unclear. The present study is aimed at investigating whether DUOX2 could act as a novel biomarker of prognosis and evaluating its effect on PC cell progression. The mRNA and protein expression of DUOX2 in PC cells and tissues were assessed by quantitative real-time PCR (RT-qPCR) and immunohistochemistry. The effect of DUOX2 expression on PC cell motility and proliferation was evaluated in vitro. The correlation between DUOX2 mRNA expression and clinicopathological features and its prognostic significance were analyzed according to the Gene Expression Profiling Interactive Analysis (GEPIA) website based on The Cancer Genome Atlas (TCGA) and the GTEx databases combined with our clinical information. According to bioinformatics analysis, we forecasted the upstream transcription factors (TFs) and microRNA (miRNA) regulatory mechanism of DUOX2 in PC. The expression of DUOX2 at transcriptional and protein level was dramatically increased in PC specimens when compared to adjacent nontumor specimens. Functionally, DUOX2 knockdown inhibited cell motility and proliferation activities. Our clinical data revealed that the patients had better postoperative overall survival (OS) with lower expression of DUOX2, which is consistent with GEPIA data. Multivariate analysis revealed that high DUOX2 expression was considered as an independent prognostic indicator for OS (P = 0.031). Based on Cistrome database, the top 5 TFs of each positively and negatively association with DUOX2 were predicted. hsa-miR-5193 and hsa-miR-1343-3p targeting DUOX2 were forecasted from TargetScan, miRDB, and DIANA-TarBase databases, which were negatively correlated with OS (P = 0.043 and P = 0.0088, respectively) and DUOX2 expression (P = 0.0093 and P = 0.0032, respectively) in PC from TCGA data. These findings suggest that DUOX2 acts as a promising predictive biomarker and an oncogene in PC, which could be a therapeutic target for PC.

6.
Animals (Basel) ; 11(3)2021 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-33673705

RESUMO

The current study aimed to investigate the evolution of gut microbiota and its influencing factors for NXP in youth. The results showed that Shannon index increased from d 21 to d 28 whereas the ACE index increased from d 21 until d 60. Firmicutes, mainly Lactobacillus dominated on d 21. The Bacteroides and Spirochetes showed highest relative abundance on d 28. Fiber-degrading bacteria, mainly Prevotellaceae, Lachnospiraceae, Ruminococcaceae, Muribaculaceae, and Oscillospiraceae_UCG-002, dominated the microbial communities at d 28 and d 35. The microbial communities at d 60 and d 75 contained more Clostridium_sensu_stricto_1, Terrisporobacter and Oscillospiraceae_UCG-005 than other ages, which had significantly positive correlations with acetate and total SCFAs concentration. In conclusion, the evolution of gut microbiota was mainly adapted to the change of dietary factors during NXP growth. The response of fiber-degrading bacteria at different stages may help NXP better adapt to plant-derived feeds.

7.
Clin Exp Med ; 2021 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-33677646

RESUMO

REC8 is a member of the cohesin family, and its abnormal activation has been detected in cancer cells. This study explored the role and possible mechanism of REC8 in hepatocellular carcinoma (HCC). A total of 40 pairs of HCC and adjacent tissues were collected, and the clinical significance of REC8 expression in HCC was evaluated. REC8 expression in human HCC tissues and HCC cell lines was investigated by quantitative real-time PCR, Western blotting, immunohistochemistry and immunofluorescence staining. The biological functions of REC8 in HCC cell lines were detected by wound-healing assay, Matrigel invasion assay and tube formation assay. The proteins interacting with REC8 were identified by mass spectrometry after immunoprecipitation screening. There was a correlation between the high expression of REC8 and positive alpha-fetoprotein levels. The expression level of REC8 protein in HCC tissues was higher than that in adjacent tissues. REC8 has mainly located in the nucleus of HCC tissue cells and HCC cell lines, but it was expressed in the cytoplasm of adjacent normal tissue cells and hepatocytes. The results of wound healing, transwell invasion and tubular formation assays indicated that the overexpression of REC8 accelerated the metastasis of HCC in vitro; however, metastasis was suppressed after REC8 was silenced by small interference RNA. A total of 57 differentially expressed proteins were identified by mass spectrometry, and it was found that REC8 and PKA RII-α staining was colocalized in the nucleus. The expression levels of MMP-9 and VEGF-C were decreased after treatment with the PKA inhibitor H89. Overall, REC8 promotes the migration, invasion and angiogenesis of HCC cells through the PKA pathway.

8.
Signal Transduct Target Ther ; 6(1): 117, 2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33692331

RESUMO

The Myc proto-oncogene family consists of three members, C-MYC, MYCN, and MYCL, which encodes the transcription factor c-Myc (hereafter Myc), N-Myc, and L-Myc, respectively. Myc protein orchestrates diverse physiological processes, including cell proliferation, differentiation, survival, and apoptosis. Myc modulates about 15% of the global transcriptome, and its deregulation rewires the cellular signaling modules inside tumor cells, thereby acquiring selective advantages. The deregulation of Myc occurs in >70% of human cancers, and is related to poor prognosis; hence, hyperactivated Myc oncoprotein has been proposed as an ideal drug target for decades. Nevertheless, no specific drug is currently available to directly target Myc, mainly because of its "undruggable" properties: lack of enzymatic pocket for conventional small molecules to bind; inaccessibility for antibody due to the predominant nucleus localization of Myc. Although the topic of targeting Myc has actively been reviewed in the past decades, exciting new progresses in this field keep emerging. In this review, after a comprehensive summarization of valuable sources for potential druggable targets of Myc-driven cancer, we also peer into the promising future of utilizing macropinocytosis to deliver peptides like Omomyc or antibody agents to intracellular compartment for cancer treatment.

9.
Bioorg Chem ; 109: 104693, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33609914

RESUMO

Colorectal cancer (CRC) is the third commonly diagnosed malignancy and the second leading cause of cancer death worldwide. Development of novel chemotherapeutics is crucial. Natural products are the main source of drug discovery, and epipolythiodioxopiperazine (ETP) alkaloids are one kind of them have been reported to have potent biological activities. In the present study, we first isolated Chaetocochin J (CJ), an ETP alkaloid from the secondary metabolites of Chaetomium sp, and studied the anti-CRC activity and mechanism of it. The results showed that CJ exhibits potent proliferation inhibition effect, its IC50 to CRC cells are around 0.5 µM. CJ also induces apoptosis of CRC cells in a dose-dependent manner, and this effect is stronger than topotecan. In addition, CJ treatment triggers autophagic flux in CRC cells, inhibition of autophagy by chloroquine didn't affect CJ-induced apoptosis and growth inhibition, suggesting CJ may simultaneously induced apoptosis and autophagy in CRC cells. We further explored the mechanism of action, and found that CJ exerts its anti-CRC function via AMPK and PI3K/AKT/mTOR pathways and further regulation of their downstream signaling cascade in CRC cells, including apoptosis and autophagy. These data potently suggest that CJ may be a potential drug candidate for CRC treatment.

10.
Artigo em Inglês | MEDLINE | ID: mdl-33562586

RESUMO

Lockdown aiming at slowing COVID-19 transmission has altered nature accessibility patterns, creating quasi-experimental conditions to assess if retracted nature contact and perceived nature deprivation influence physical and emotional wellbeing. We measure through on-line survey methods (n = 529) how pandemic mandates limiting personal movement and outdoor nature access within the United States affect self-assessed nature exposure, perceived nature deprivation, and subsequent flourishing as measured by the Harvard Flourishing Index. Results indicate that perceived nature deprivation strongly associates with local nature contact, time in nature, and access to municipal nature during the pandemic, after controlling for lockdown mandates, job status, household composition, and sociodemographic variables. Our hypothesis is that individuals with strong perceived nature deprivation under COVID-19 leads to diminished wellbeing proved true. Interaction models of flourishing showed positive modification of nature affinity with age and qualitative modification of nature deprivation with race. Our results demonstrate the potential of local nature contact to support individual wellbeing in a background context of emotional distress and social isolation, important in guiding public health policies beyond pandemics.


Assuntos
/psicologia , Saúde Mental/tendências , Natureza , Pandemias , Cidades , Controle de Doenças Transmissíveis , Humanos , Angústia Psicológica , Inquéritos e Questionários , Estados Unidos
11.
Int Immunopharmacol ; 93: 107393, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33529914

RESUMO

BACKGROUND: B cells play a key role in the pathogenesis of immune thrombocytopenia (ITP) by producing platelet autoantibodies. Accumulating evidence suggest that microRNA (miRNA) is a critical regulator in B cells. The contribution of miRNA to B cell dysfunction in ITP has not been described. The aim of this study was to examine the expression of miRNA let-7b-5p in B cells of ITP patients and investigate its possible association with B cell function in ITP. METHODS: The CD19+ cells were isolated from peripheral mononuclear cells of ITP patients and healthy controls using immunomagnetic microbeads. B cell survival in vitro was evaluated by cell counting. The level of let-7b-5p was quantified by quantitative PCR. The surface expression of B cell activating factor receptor (BAFF-R) was detected by flow cytometry. The role of let-7b-5p was examined in isolated B cells by transfecting miRNA mimics or inhibitors. RESULTS: The results showed that let-7b-5p in B cells was elevated, and B cell survival was enhanced in ITP patients compared with healthy controls. BAFF and B cell receptor stimulation can induce the expression of let-7b-5p in vitro. Overexpression of let-7b-5p in B cells enhanced the expression of surface BAFF-R and promoted B cell survival. Moreover, let-7b-5p enhanced the phosphorylation of NF-κB2 p100 and upregulated the expression of survival factor Bcl-xL after BAFF induction. CONCLUSION: Let-7b-5p is a pro-survival miRNA in B cells and increased let-7b-5p is associated with enhanced surface BAFF-R in ITP.

12.
Transl Psychiatry ; 11(1): 120, 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33633108

RESUMO

Cigarette smoking contributes to numerous diseases and is one of the leading causes of death in the United States. Smoking behaviors vary widely across race/ethnicity, but it is not clear why. Here, we examine the contribution of genetic ancestry to variation in two smoking-related traits in 43,485 individuals from four race/ethnicity groups (non-Hispanic white, Hispanic/Latino, East Asian, and African American) from a single U.S. healthcare plan. Smoking prevalence was the lowest among East Asians (22.7%) and the highest among non-Hispanic whites (38.5%). We observed significant associations between genetic ancestry and smoking-related traits. Within East Asians, we observed higher smoking prevalence with greater European (versus Asian) ancestry (P = 9.95 × 10-12). Within Hispanic/Latinos, higher cigarettes per day (CPD) was associated with greater European ancestry (P = 3.34 × 10-25). Within non-Hispanic whites, the lowest number of CPD was observed for individuals of southeastern European ancestry (P = 9.06 × 10-5). These associations remained after considering known smoking-associated loci, education, socioeconomic factors, and marital status. Our findings support the role of genetic ancestry and socioeconomic factors in cigarette smoking behaviors in non-Hispanic whites, Hispanic/Latinos, and East Asians.

13.
Artigo em Inglês | MEDLINE | ID: mdl-33544571

RESUMO

The piezoelectric constant (d33) and converse piezoelectric coefficient (d33*) of a piezoelectric material are critically important parameters for sensors and actuators. Here, we simultaneously achieve a high d33 of 595 ± 10 pC/N and a large d33* of ∼776 ± 20 pm/V in (K,Na)NbO3 (KNN)-based ceramics, which exceed those of PZT5H and PZT4 ceramics, presenting good potential for practical piezoelectric applications. Moreover, the ceramic exhibits a relaxor-like and diffuse dielectric behavior due to the occurrence of local heterogeneity. According to the experiments and atomic resolution polarization mapping by Z-contrast imaging, hierarchical architecture of nanodomains and even smaller polar nanoregions with multiphase coexistence caused by compositional modification is the structural origin of the enhanced piezoelectric properties in this work. This work would pave a practical way to future applications of lead-free KNN-based ceramics.

14.
Ear Nose Throat J ; : 145561321991338, 2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33530739

RESUMO

Solitary fibrous tumor/hemangiopericytoma (SFT/HPC) is extremely rare, and most of them are immediately treated for radical resection. However, the information concerning its natural history remains unclear. In this report, we presented a patient with parapharyngeal SFT/HPC, who was not immediately treated with surgical resection at first diagnosis. After approximately 3 years, the tumor volume doubling time (TVDT) and specific growth rate (SGR) could be measured through 3 serial magnetic resonance imagings. The TVDTs in the early and late pretreatment stages were 350 and 180 days, respectively, while the SGRs were 0.002 and 0.003, respectively. The growth rate of this disease entity is generally slow and may accelerate in the disease process.

15.
Nano Lett ; 2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33596083

RESUMO

It is quite challenging to prepare subnanometer porous materials from traditional porous precursors, and use of supramolecules as carbon sources was seldom reported due to the complex preparation and purification processes. We explore a facile one-pot method to fabricate supramolecular coordination compounds as carbon sources. The resultant CB[6]-derived carbons (CBC) have a high N content of 7.0-22.0%, surface area of 552-861 m2 g-1, and subnano/mesopores. The CBC electrodes have a narrow size distribution at 5.9 Å, and the supercapacitor exhibits an energy density of 117.1 Wh kg-1 and a potential window of over 3.8 V in a two-electrode system in the ionic liquid (MMIMBF4) electrolyte with appropriate cationic (5.8 Å) and anionic (2.3 Å) diameter. This work presents the facile fabrication of novel supermolecule cucurbituril subnanoporous carbon materials and the smart design of "pores and balls" for high-performance energy storage systems.

16.
Chemistry ; 27(18): 5810-5816, 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33501668

RESUMO

Wrinkles and photo-oxidation reactions are widely found in soft materials, which are intimately associated with the failure of materials and structures. It is expected that the photo-oxidation process could also have a positive effect on the material and its surface. Here, we report the photo-oxidation of 2-(4-dietheylaminophenyl)-4,5-bis(4-methoxyphenyl) imidazole (DEA-TAI) into a wrinkled bilayer system to control surface wrinkle and fluorescent patterns, in which a supramolecular polymer network composed of carboxylic acid-containing copolymer (PS-BA-AA; PS=poly(styrene), BA=butyl acrylate; AA=acrylic acid) and DEA-TAI were used as the skin layer. Ultraviolet (UV) irradiation can induce photo-oxidation of the imidazole ring of DEA-TAI to weaken the intermolecular hydrogen bonding between PS-BA-AA and DEA-TAI, resulting in the release of stress in the bilayer system. The wrinkled morphology and fluorescence of the surface can be simultaneously regulated by photo-oxidation of DEA-TAI under UV light, and the resulting wrinkles are extremely sensitive to the pH value, which can be quickly and reversibly erased by NH3 gas. Smart surfaces with specific hierarchical wrinkles and fluorescence can be achieved by selective irradiation with photomasks, which may find potential applications in smart displays and multi-code information storage.

17.
Clin Biomech (Bristol, Avon) ; 82: 105256, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33508562

RESUMO

BACKGROUND: This study aimed to adopt computational fluid dynamics to simulate the blood flow dynamics in inferior vena cava stenosis based on time-dependent patient-specific models of Budd-Chiari syndrome as well as a normal model. It could offer valuable references for a retrospective insight into the underlying mechanisms of Budd-Chiari syndrome pathogenesis as well as more accurate evaluation of postoperative efficacy. METHODS: Three-dimensional inferior vena cava models of Budd-Chiari syndrome patient-specific (preoperative and postoperative) and normal morphology model were reconstructed as per magnetic resonance images using Simpleware. Moreover, computational fluid dynamics of time-resolved inferior vena cava blood flow were simulated using actual patient-specific measurements to reflect time-dependent flow rates. FINDINGS: The assessment of the preoperative model revealed the dramatic variations of hemodynamic parameters of the stenotic inferior vena cava. Moreover, the comparison of the preoperative and postoperative models with the normal model as benchmark showed that postoperative hemodynamic parameters were markedly ameliorated via stenting, with the attenuation of overall velocity and wall shear stress, and the increase of pressure. However, the comparative analysis of the patient-specific simulations revealed that some postoperative hemodynamic profiles still bore some resemblance to the preoperative ones, indicating potential risks of restenosis. INTERPRETATION: Computational fluid dynamics simulation of time-resolved blood flow could reveal the tight correlation between the hemodynamic characteristics and the pathological mechanisms of inferior vena cava stenosis. Furthermore, such time-resolved hemodynamic profiles could provide a quantitative approach to diagnosis, operative regimen and postoperative evaluation of Budd-Chiari syndrome with inferior vena cava stenosis.

18.
Signal Transduct Target Ther ; 6(1): 28, 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33479196

RESUMO

The immune system initiates robust immune responses to defend against invading pathogens or tumor cells and protect the body from damage, thus acting as a fortress of the body. However, excessive responses cause detrimental effects, such as inflammation and autoimmune diseases. To balance the immune responses and maintain immune homeostasis, there are immune checkpoints to terminate overwhelmed immune responses. Pathogens and tumor cells can also exploit immune checkpoint pathways to suppress immune responses, thus escaping immune surveillance. As a consequence, therapeutic antibodies that target immune checkpoints have made great breakthroughs, in particular for cancer treatment. While the overall efficacy of immune checkpoint blockade (ICB) is unsatisfactory since only a small group of patients benefited from ICB treatment. Hence, there is a strong need to search for other targets that improve the efficacy of ICB. Ubiquitination is a highly conserved process which participates in numerous biological activities, including innate and adaptive immunity. A growing body of evidence emphasizes the importance of ubiquitination and its reverse process, deubiquitination, on the regulation of immune responses, providing the rational of simultaneous targeting of immune checkpoints and ubiquitination/deubiquitination pathways to enhance the therapeutic efficacy. Our review will summarize the latest findings of ubiquitination/deubiquitination pathways for anti-tumor immunity, and discuss therapeutic significance of targeting ubiquitination/deubiquitination pathways in the future of immunotherapy.

19.
Mol Ther ; 2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33484966

RESUMO

Growing evidence indicates that N6-methyladenosine (m6A) is the most pervasive RNA modification in eukaryotic cells. However, the specific role of METTL3 in papillary thyroid carcinoma (PTC) initiation and development remains elusive. Here we found that downregulation of METTL3 was correlated with malignant progression and poor prognosis in PTC. A variety of gain- and loss-of-function studies clarified the effect of METTL3 on regulation of growth and metastasis of PTC cells in vitro and in vivo. By combining RNA sequencing (RNA-seq) and methylated RNA immunoprecipitation sequencing (meRIP-seq), our mechanistic studies pinpointed c-Rel and RelA as downstream m6A targets of METTL3. Disruption of METTL3 elicited secretion of interleukin-8 (IL-8), and elevated concentrations of IL-8 promoted recruitment of tumor-associated neutrophils (TANs) in chemotaxis assays and mouse models. Administration of the IL-8 antagonist SB225002 substantially retarded tumor growth and abolished TAN accumulation in immunodeficient mice. Our findings revealed that METTL3 played a pivotal tumor-suppressor role in PTC carcinogenesis through c-Rel and RelA inactivation of the nuclear factor κB (NF-κB) pathway by cooperating with YTHDF2 and altered TAN infiltration to regulate tumor growth, which extends our understanding of the relationship between m6A modification and plasticity of the tumor microenvironment.

20.
Hepatol Int ; 15(1): 155-165, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33385299

RESUMO

BACKGROUND AND AIMS: Rifaximin has been recommended as a prophylactic drug for hepatic encephalopathy (HE) and spontaneous bacterial peritonitis (SBP). This study aims to explore whether low-dose rifaximin can prevent overall complications and prolong survival in cirrhotic patients. METHODS: In this multi-centre randomized open-labelled prospective study, 200 patients with decompensated cirrhosis were randomly assigned at a ratio of 1:1. Patients in rifaximin group were administered 400 mg rifaximin twice daily for 6 months, and all other therapeutic strategies were kept unchanged in both groups as long as possible. The primary efficacy endpoints were the incidence of overall complications and liver transplantation-free survival. The secondary endspoints were the incidence of each major cirrhosis-related complication, as well as the Child-Pugh score and class. RESULTS: The major baseline characteristics were similar in the two groups except for HE. The cumulative incidence and frequency of overall complications were significantly lower in rifaximin group than in the control group (p < 0.001). Though liver transplantation-free survival was not significantly different between the two groups, subgroup analysis showed rifaximin markedly prolonged liver transplantation-free survival in patients with Child-Pugh score ≥ 9 (p = 0.007). Moreover, rifaximin markedly reduced the episodes of ascites exacerbation (p < 0.001), HE (p < 0.001) and gastric variceal bleeding (EGVB, p = 0.031). The incidence of adverse events was similar in the two groups. CONCLUSION: Low-dose rifaximin significantly decreases the occurrence of overall complications, leading to prolonged survival in patients with advanced stages of cirrhosis in this trail. Further study should be carried out to compare the effect of this low-dose rifaximin with normal dose (1200 mg/day) rifaximin in preventing cirrhosis-related complications. CLINICAL TRIAL NUMBER: NCT02190357.

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