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1.
Stem Cell Res Ther ; 13(1): 9, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35012650

RESUMO

Coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory coronavirus 2 is currently spreading throughout the world with a high rate of infection and mortality and poses a huge threat to global public health. COVID-19 primarily manifests as hypoxic respiratory failure and acute respiratory distress syndrome, which can lead to multiple organ failure. Despite advances in the supportive care approaches, there is still a lack of clinically effective therapies, and there is an urgent need to develop novel strategies to fight this disease. Currently, stem cell therapy and stem cell-derived organoid models have received extensive attention as a new treatment and research method for COVID-19. Here, we discuss how stem cells play a role in the battle against COVID-19 and present a systematic review and prospective of the study on stem cell treatment and organoid models of COVID-19, which provides a reference for the effective control of the COVID-19 pandemic worldwide.


Assuntos
COVID-19 , Pandemias , Humanos , Estudos Prospectivos , SARS-CoV-2 , Células-Tronco
2.
J Integr Plant Biol ; 2022 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-35029016

RESUMO

The root microbiome refers to the community of microbes living in association with a plant's roots, and includes mutualists, pathogens, and commensals. Here we focus on recent advances in the study of root commensal community which is the major research object of microbiome related researches. With the rapid development of new technologies, plant-commensal interactions can be explored with unprecedented breadth and depth. Both the soil environment and the host plant drive commensal community assembly. The bulk soil is the seed bank of potential commensals, and plants use root exudates and immune responses to build healthy microbial communities from the available microbes. The plant microbiome extends the functional system of plants by participating in a variety of processes, including nutrient absorption, growth promotion, and resistance to biotic and abiotic stresses. Plants and their microbiomes have evolved adaptation strategies over time. However, there is still a huge gap in our understanding of the regulatory mechanisms of plant-commensal interactions. In this review, we summarize recent research on the assembly of root microbial communities and the effects of these communities on plant growth and development, and look at the prospects for promoting sustainable agricultural development through the study of the root microbiome. This article is protected by copyright. All rights reserved.

3.
Free Radic Biol Med ; 178: 42-53, 2021 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-34848368

RESUMO

Insulin resistance (IR) promotes atherosclerosis and increases the risk of diabetes and cardiovascular diseases. Our previous studies have demonstrated that high uric acid (HUA) increased oxidative stress, leading to IR in cardiomyocytes and pancreatic ß cells. However, whether HUA can induce IR in monocytes/macrophages, which play critical roles in all stages of atherosclerosis, is unclear. Recent findings revealed that thioredoxin-interacting protein (TXNIP) negatively regulates insulin signaling; however, the roles and mechanisms of TXNIP in HUA-induced IR remain unclear. Therefore, in this study, we investigated the function of TXNIP in macrophages treated with UA. Transcriptomic profiling revealed TXNIP as one of the most upregulated genes, and subsequent RT-PCR and Western blot analyses confirmed that TXNIP was upregulated by HUA. HUA treatment significantly increased mitochondrial reactive oxygen species (MtROS) levels and decreased insulin-stimulated glucose uptake. Silencing TXNIP by RNA interference significantly diminished HUA-induced oxidative stress and IR. Mechanistically, silencing TXNIP reversed the inhibition of the phosphorylation of insulin receptor substrate 2 (IRS2)/protein kinase B (AKT) pathway induced by HUA. Additional study revealed that HUA induced the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) signaling pathway, but silencing TXNIP abolished it. Moreover, Nrf2 inhibitor (ML385) ameliorated HUA-induced IR independent of IRS2/AKT signaling. Probenecid, a well-known UA-lowering drug, significantly suppressed the activation of TXNIP and Nrf2/HO-1 signaling. Furthermore, RNA-seq revealed that activation of the TXNIP-related redox pathway may be a key regulator in patients with asymptomatic hyperuricemia. These data suggest that silencing TXNIP could ameliorate HUA-induced IR via the IRS2/AKT and Nrf2/HO-1 pathways in macrophages. Additionally, TXNIP might be a promising therapeutic target for preventing and treating oxidative stress and IR induced by HUA.

4.
Front Plant Sci ; 12: 719706, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34868106

RESUMO

The continued improvement of crop yield is a fundamental driver in agriculture and is the goal of both plant breeders and researchers. Plant breeders have been remarkably successful in improving crop yield, as demonstrated by the continued release of varieties with improved yield potential. This has largely been accomplished through performance-based selection, without specific knowledge of the molecular mechanisms underpinning these improvements. Insight into molecular mechanisms has been provided by plant molecular, genetic, and biochemical research through elucidation of the function of genes and pathways that underlie many of the physiological processes that contribute to yield potential. Despite this knowledge, the impact of most genes and pathways on yield components have not been tested in key crops or in a field environment for yield assessment. This gap is difficult to bridge, but field-based physiological knowledge offers a starting point for leveraging molecular targets to successfully apply precision breeding technologies such as genome editing. A better understanding of both the molecular mechanisms underlying crop yield physiology and yield limiting processes under field conditions is essential for elucidating which combinations of favorable alleles are required for yield improvement. Consequently, one goal in plant biology should be to more fully integrate crop physiology, breeding, genetics, and molecular knowledge to identify impactful precision breeding targets for relevant yield traits. The foundation for this is an understanding of yield formation physiology. Here, using soybean as an example, we provide a top-down review of yield physiology, starting with the fact that yield is derived from a population of plants growing together in a community. We review yield and yield-related components to provide a basic overview of yield physiology, synthesizing these concepts to highlight how such knowledge can be leveraged for soybean improvement. Using genome editing as an example, we discuss why multiple disciplines must be brought together to fully realize the promise of precision breeding-based crop improvement.

5.
Angew Chem Int Ed Engl ; : e202116296, 2021 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-34921501

RESUMO

Building blocks with multiple components are promising for the synthesis of complex molecular assemblies, but are rarely available. Herein, we report a modification procedure for a multi-component building block [Ln3 Ti(HSA)6 (SA)4 (H2 O)]- ({Ln3 Ti-SA}, H2 SA=salicylic acid, Ln=Eu/Gd) to form new building blocks {Ln3 Tix -MSA} (H2 MSA=5-methoxysalicylic acid, x=1, 2, 3) by constructing [Ti(MSA)3 ]2- units. The obtained {Ln3 Tix -MSA} can further assemble into a chiral Ln22 Ti14 ring with the formulae [Eu22 Ti14 (MSA)48 (HMSA)22 (CH3 COO)4 (H2 O)10 (iPrOH)] and [Gd22 Ti14 (MSA)46 (HMSA)26 (CH3 COO)4 (H2 O)8 ]. Parallel experiments without Ti4+ result in linear Ln chains. Detailed analysis shows that the [Ti(MSA)4 ]4- unit makes the originally variable Ln chains become available building blocks and the modified [Ti(MSA)3 ]2- further triggers interesting chiral-sorting behavior. Finally, the electronic adsorption and magneto-optic responses of these molecular rings are investigated.

6.
Endoscopy ; 2021 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-34963146

RESUMO

BACKGROUND AND STUDY AIMS: The effectiveness of endoscopic screening on gastric cancer (GC) is less investigated and screening interval of repeated screening is yet to be optimized in China. PATIENTS AND METHODS: In a population-based prospective study, we included 375,800 subjects based on the Upper Gastrointestinal Cancer Early Detection Program in Linqu, a GC high-risk area in China, 14,670 of which underwent endoscopic screening(2012-2018). We assessed the associations of the risk of incident GC and GC-specific deaths with endoscopic screening and examined the changes in overall survival (OS) and disease-specific survival (DSS) of GCs by endoscopic screening. The optimal screening interval of repeated endoscopy for early detection of GC was explored. RESULTS: Ever receiving endoscopic screening significantly decreased the risk of invasive GC(age and sex-adjusted RR=0.69, 95%CI:0.52-0.92) and GC-specific deaths(RR=0.33, 95%CI: 0.20-0.56), particularly for non-cardia GC. Repeated screening strengthened the beneficial effect on invasive GC-specific deaths by one-time screening. Among invasive GCs, screening-detected cases had significantly better OS(RR=0.18, 95%CI: 0.13-0.25) and DSS(RR=0.18, 95%CI: 0.13-0.25) than cases in the unscreened group, particularly for those receiving repeated endoscopy. For individuals with intestinal metaplasia or low-grade intraepithelial neoplasia, repeated endoscopy at an interval of less than two years, particularly within one year, significantly enhanced the detection of early GC, compared with repeated screening after two years(P-trend=0.02). CONCLUSION: Endoscopic screening prevented GC occurrence and death and improved its prognosis in a population-based study. Repeated endoscopy enhanced the effectiveness, for which screening interval needs to be defined in conformity with the severity of gastric lesions.

7.
Artigo em Inglês | MEDLINE | ID: mdl-34831695

RESUMO

The fatigue of air traffic controllers (ATCOs) on duty seriously threatens air traffic safety and needs to be managed. ATCOs perform several different types of work, with each type of work having different characteristics. Nonetheless, the influence of work type on an ATCO's fatigue has yet to be demonstrated. Here, we present a field study in which the fatigue of ATCOs working in two types of work was compared based on an optimized data-driven method that was employed to detect the percentage of eyelid closure over the pupil over time (PERCLOS). Sixty-seven ATCOs working within two typical jobs (i.e., from the terminal control unit (TCU) and area control unit (ACU)) were recruited, and their fatigue was detected immediately before and after shift work using PERCLOS. Using a Spearman correlation test analysis, the results showed that the influence of work type on an ATCO's fatigue had interesting trends. Specifically, the ATCOs at the TCU who handle departures and arrivals, which include converging with and maneuvering around conflicts, retain normal circadian rhythms. Their fatigue was significantly influenced by the various demands from tasks focusing on sequencing and conflict resolution and by the time phase of a normal circadian rhythm. At the ACU, ATCOs manage flights that are mainly on route, causing monotonous monitoring and routine reporting tasks, and the ATCOs generally have frequent night shifts to handle overflights. Their fatigue was significantly influenced by the demand characteristics from tasks, but changes in fatigue rule were not consistent with a normal circadian rhythm, revealing that the ATCOs' circadian rhythms may have already been slightly disturbed. Furthermore, the interactions between task demand and circadian rhythm with an ATCO's fatigue were significantly observed in ATCOs working in the TCU but not in those in the ACU. This study provides first evidence that an ATCO's work type influences his or her fatigue. This discovery may incite stakeholders to consider work type in the management of employee fatigue, not only in the civil aviation industry but also in other transport industries.

8.
EBioMedicine ; 74: 103714, 2021 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-34818622

RESUMO

BACKGROUND: Molecular features underlining the multistage progression of gastric lesions and development of early gastric cancer (GC) are poorly understood, restricting the ability to GC prevention and management. METHODS: We portrayed proteomic landscape and explored proteomic signatures associated with progression of gastric lesions and risk of early GC. Tissue proteomic profiling was conducted for a total of 324 subjects. A case-control study was performed in the discovery stage (n=169) based on populations from Linqu, a known high-risk area for GC in China. We then conducted two-stage validation, including a cohort study from Linqu (n = 56), with prospective follow-up for progression of gastric lesions (280-473 days), and an independent case-control study from Beijing (n = 99). FINDINGS: There was a clear distinction in proteomic features for precancerous gastric lesions and GC. We derived four molecular subtypes of gastric lesions and identified subtype-S4 with the highest progression risk. We found 104 positively-associated and 113 inversely-associated proteins for early GC, with APOA1BP, PGC, HPX and DDT associated with the risk of gastric lesion progression. Integrating these proteomic signatures, the ability to predict progression of gastric lesions was significantly strengthened (areas-under-the-curve=0.88 (95%CI: 0.78-0.99) vs. 0.56 (0.36-0.76), Delong's P = 0.002). Immunohistochemistry assays and examination at mRNA level validated the findings for four proteins. INTERPRETATION: We defined proteomic signatures for progression of gastric lesions and risk of early GC, which may have translational significance for identifying particularly high-risk population and detecting GC at an early stage, improving potential for targeted GC prevention. FUNDING: The funders are listed in the Acknowledgement.

9.
iScience ; 24(11): 103249, 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34755091

RESUMO

Diffuse glioma is the most prevalent and malignant brain tumor. The function and significance of CD37 in diffuse gliomas remain largely unknown. Here, we showed CD37 was abnormally expressed in diverse cancers, especially glioma by pan-cancer differential expression analysis. In addition, we found CD37 was upregulated in higher grade and IDH or IDH1-wildtype gliomas, which was further validated by qPCR and IHC. Survival analysis revealed CD37 served as an independent indicator for unfavorable prognosis of patients with diffuse gliomas. Functional enrichment analysis revealed CD37 was associated with immunological processes. Moreover, immune infiltration analyses suggested gliomas with high-expression CD37 had greater infiltration of M2 macrophages and neutrophils, and lower NK cell abundance. CD37 was closely correlated to immune checkpoint molecules, including CD276, CD80, CD86, and PD-L2. Our results indicated CD37 is an independent prognostic factor and plays an immunosuppressive role in diffuse gliomas. Targeting CD37 could be a promising immunotherapeutic strategy for diffuse gliomas.

10.
Theranostics ; 11(20): 9775-9790, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34815785

RESUMO

Rationale: Diffuse glioma patients have high mortality and recurrence despite multimodal therapies. This study aims to identify the potential tumor antigens for mRNA vaccines and subtypes suitable for the immunotherapy of patients with diffuse glioma. Methods: Gene expression profiles and corresponding clinical information were obtained from the Chinese Glioma Genome Atlas (CGGA) and the Cancer Genome Atlas (TCGA) databases. Genetic alterations were extracted from cBioPortal. Differential gene analysis, survival analysis, correlation analysis, consensus clustering analysis, and immune cell infiltration analysis were conducted based on the various databases. Finally, the hub genes, the modules related to tumor antigens, and the immune subtypes were identified using WGCNA method. Results: Three over-expressed, amplified, and mutated tumor antigens, including KDR, COL1A2, and SAMD9, were associated with clinical outcomes. The expression of the three genes had a positive correlation with the abundance of antigen-presenting cells (APCs) and APC marker expression. Subsequently, three immune subtypes (Ims1, Ims2, and Ims3) were distinguished in the TCGA cohort, which exhibited distinct molecular, cellular, and clinical characteristics consistent with the CGGA cohort. Diffuse gliomas with subtype Ims1 were more malignant with immunosuppressive phenotypes and more associated with poor prognosis than the other two subtypes. The three antigens and the immune checkpoints were differentially expressed among the three immune subtypes. Finally, functional enrichment analysis of the genes related to tumor antigens and immune subtypes suggested that they are enriched in many immune-associated processes. Conclusions: KDR, COL1A2, and SAMD9 are potential antigens for developing mRNA vaccines against diffuse glioma. The results suggest that immunotherapy targeting these three antigens is more suitable for patients with subtype Ims1. This study provides insights into immunotherapy for diffuse glioma.

12.
World J Surg Oncol ; 19(1): 326, 2021 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-34781983

RESUMO

BACKGROUND: Src-related kinase lacking C-terminal regulatory tyrosine and N-terminal myristoylation sites (SRMS) is a non-receptor tyrosine kinase that has been found to be overexpressed in various tumors. However, the role of SRMS in colorectal cancer (CRC) has not been well established. METHODS: We evaluated the expression levels of SRMS in CRC using GEPIA, Oncomine, and HPA datasets. Survival information and gene expression data of CRC were obtained from The Cancer Genome Atlas (TCGA). Then, the association between SRMS and clinicopathological features was analyzed using UALCAN dataset. LinkedOmics was used to determine co-expression and functional networks associated with SRMS. Besides, we used TISIDB to assess the correlation between SRMS and immune signatures, including tumor-infiltrating immune cells and immunomodulators. Lastly, protein-protein interaction network (PPI) was established and the function enrichment analysis of the SRMS-associated immunomodulators and immune cell marker genes were performed using the STRING portal. RESULTS: Compared to normal colorectal tissues, SRMS was found to be overexpressed in CRC tissues, which was correlated with a poor prognosis. In colon adenocarcinoma (COAD), the expression levels of SRMS are significantly correlated with pathological stages and nodal metastasis status. Functional network analysis suggested that SRMS regulates intermediate filament-based processes, protein autophosphorylation, translational initiation, and elongation signaling through pathways involving ribosomes, proteasomes, oxidative phosphorylation, and DNA replication. In addition, SRMS expression was correlated with infiltrating levels of CD4+ T cells, CD56dim, MEM B, Neutrophils, Th2, Th17, and Act DC. The gene ontology (GO) analysis of SRMS-associated immunomodulators and immune cell marker genes showed that they were mainly enriched in the immune microenvironment molecule-related signals. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of these genes indicated that they are involved in multiple cancer-related pathways. CONCLUSIONS: SRMS is a promising prognostic biomarker and potential therapeutic target for CRC patients. In particular, SRMS regulates CRC progression by modulating cytokine-cytokine receptor interaction, chemokines, IL-17, and intestinal immune networks for IgA production signaling pathways among others. However, more studies are needed to validate these findings.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Colorretais/genética , Biologia Computacional , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Humanos , Prognóstico , Mapas de Interação de Proteínas , Microambiente Tumoral
13.
Sheng Wu Gong Cheng Xue Bao ; 37(9): 3268-3275, 2021 Sep 25.
Artigo em Chinês | MEDLINE | ID: mdl-34622634

RESUMO

Polyethylene terephthalate (PET) is a synthetic polymer consisting of ester bond-linked terephthalate and ethylene glycol. Tremendous amounts of PET have been produced and majority of them enters terrestrial and marine environment as wastes, posing serious threats to the global ecosystems. In 2016, a PET hydrolase from a PET-assimilating bacterium Ideonalla sakaiensis was reported and termed as IsPETase. This enzyme outperforms other PET-hydrolyzing enzymes in terms of its PET hydrolytic activity at ambient temperature, thus holds a great promise for PET biodegradation. In order to improve IsPETase activity, we conducted structure-based engineering to modify the putative substrate-binding tunnel. Among the several variants to the N233 residue of IsPETase, we discovered that the substitution of N233 with alanine increases its PET hydrolytic activity, which can be further enhanced when combined with a R280A mutation. We also determined the X-ray crystal structure of the IsPETase N233A variant, which shares nearly identical fold to the WT protein, except for an open end of subsite Ⅱ. We hypothesized that the smaller side chain of N233A variant might lead to an extended subsite Ⅱ for PET binding, which subsequently increases the enzymatic activity. Thus, this study provides new clues for further structure-based engineering of PETase.


Assuntos
Burkholderiales , Hidrolases , Polietilenotereftalatos/metabolismo , Burkholderiales/enzimologia , Hidrolases/genética , Engenharia de Proteínas
14.
Artigo em Inglês | MEDLINE | ID: mdl-34658118

RESUMO

Protein stability and evolvability influence each other. Although protein dynamics play essential roles in various catalytically important properties, their high flexibility and diversity makes it difficult to incorporate such properties into rational engineering. Therefore, how to unlock the potential evolvability in a user-friendly rational design process remains a challenge. In this endeavor, we describe a method for engineering an enantioselective alcohol dehydrogenase. It enables synthetically important substrate acceptance for 4-chlorophenyl pyridine-2-yl ketone, and perfect stereocontrol of both (S)- and (R)-configured products. Thermodynamic analysis unveiled the subtle interaction between enzyme stability and evolvability, while computational studies provided insights into the origin of selectivity and substrate recognition. Preparative-scale synthesis of the (S)-product (73 % yield; >99 % ee) was performed on a gram-scale. This proof-of-principle study demonstrates that interfaced proline residues can be rationally engineered to unlock evolvability and thus provide access to new biocatalysts with highly improved catalytic performance.

15.
Exp Brain Res ; 239(11): 3397-3404, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34499186

RESUMO

Our objective of this study is to determine the molecular mechanism of MAPKs (mitogen activated protein kinase systems) on TRPV4 (transient receptor potential vanilloid 4)-mediated trigeminal neuralgia (TN). Partial chronic constriction injury of the infraorbital nerve (CCI-ION) ligation model was used in this research. When treated with antagonists of p38, JNK or ERK, the mechanical hyperalgesia threshold, nerve fiber disorder, myelinoclasis, and Schwann cells proliferation could be reversed. RT-PCR (real-time quantitative polymerase chain reaction), Western blot and IHC (immunohistochemistry) showed that TRPV4 mRNA and protein levels, TRPV4-positive cells and small positive neurons decreased remarkably in TN group treated with antagonists of p38, JNK or ERK. ELISA (enzyme-linked immunosorbent assay) was performed to discover inhibition of MAPK pathway can down-regulate the expression of HATs (histone acetyltransferases), and up-regulate the expression of HDACs (histone deacetylases) in TN, thus inhibiting histone acetylation. Finally, Western blot was performed to identify the phosphorylation status of p38, JNK and ERK, finding decreased phosphorylation forms in antagonists treated TN groups compared with TN groups. Based on the above investigation method, on a whole, our study showed that down-regulation of MAPK pathway could alleviate TRPV4-mediated trigeminal neuralgia, via inhibiting the activation of histone acetylation.


Assuntos
Neuralgia do Trigêmeo , Acetilação , Animais , Regulação para Baixo , Histonas , Hiperalgesia , Ratos , Ratos Sprague-Dawley , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo , Neuralgia do Trigêmeo/tratamento farmacológico
16.
Biochem Biophys Res Commun ; 579: 54-61, 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34587555

RESUMO

1,2-ß-Mannobiose phosphorylases (1,2-ß-MBPs) from glycoside hydrolase 130 (GH130) family are important bio-catalysts in glycochemistry applications owing to their ability in synthesizing oligomannans. Here, we report the crystal structure of a thermostable 1,2-ß-MBP from Thermoanaerobacter sp. X-514 termed Teth514_1789 to reveal the molecular basis of its higher thermostability and mechanism of action. We also solved the enzyme complexes of mannose, mannose-1-phosphate (M1P) and 1,4-ß-mannobiose to manifest the enzyme-substrate interaction networks of three main subsites. Notably, a Zn ion that should be derived from crystallization buffer was found in the active site and coordinates the phosphate moiety of M1P. Nonetheless, this Zn-coordination should reflect an inhibitory status as supplementing Zn severely impairs the enzyme activity. These results indicate that the effects of metal ions should be taken into consideration when applying Teth514_1789 and other related enzymes. Based on the structure, a reliable model of Teth514_1788 that shares 61.7% sequence identity to Teth514_1789 but displays a different substrate preference was built. Analyzing the structural features of these two closely related enzymes, we hypothesized that the length of a loop fragment that covers the entrance of the catalytic center might regulate the substrate selectivity. In conclusion, these information provide in-depth understanding of GH130 1,2-ß-MBPs and should serve as an important guidance for enzyme engineering for further applications.

17.
Clin Infect Dis ; 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34487151

RESUMO

OBJECTIVES: Pradefovir is a liver-targeted prodrug of adefovir, a nucleotide analog with antiviral activity against hepatitis B virus (HBV) DNA polymerase. This phase 2 study compared the efficacy and safety of oral pradefovir (30mg, 45mg, 60mg, and 75mg) versus tenofovir disoproxil fumarate (TDF; 300mg) and aimed to identify the most appropriate dose of pradefovir for the forthcoming phase 3 study. METHODS: Treatment-naive and experienced (not on treatment >6 months) patients with chronic hepatitis B were eligible. RESULTS: A total of 240 participants were randomized and treated in the study (48 per group). Approximately 80% were HBeAg positive and 10% had liver cirrhosis. The reductions from baseline in HBV DNA levels achieved at week 24 were 5.40, 5.34, 5.33, and 5.40 log10 IU/ml with pradefovir doses of 30mg, 45mg, 60mg, and 75mg, respectively, compared to 5.12 log10 IU/ml with TDF. However, HBeAg loss was attained by more participants who received 45mg, 60mg or 75mg pradefovir than those receiving TDF (12%, 6%, 9% vs. 3%). The TDF group exhibited a more significant increase in serum creatinine than the pradefovir 30mg or 45mg groups, and serum phosphate levels were comparable among all groups. Most adverse events were mild (grade 1). No treatment-related severe adverse events were reported. Overall, adverse events and laboratory abnormalities were comparable to the TDF group. CONCLUSIONS: Pradefovir exhibited comparable reductions in HBV DNA levels to TDF. All treatments were safe and well tolerated.

18.
Mamm Genome ; 32(6): 495-502, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34480205

RESUMO

Numerous studies have suggested that the abnormal expression of circular RNAs plays an essential role in the pathological progression of numerous tumors. Nonetheless, the functions and underlying mechanisms of the circular RNA circCRIM1 in osteosarcoma (OS) are still not fully understood. In this study, 47 classes of OS tissues and adjoining normal tissues were obtained from patients. Real-time PCR was employed to measure circCRIM1 expression levels in both OS tissues and cell lines. The proliferation, migration, and invasion ability in OS cell lines were measured by MTT assays, EDU assays, transwell migration experiments, and transwell invasion assays. The results demonstrated that the expression of circCRIM1 was notably decreased both in OS tissues and cell lines. Depressed circCRIM1 expression was correlated with lymph node metastasis, advanced FIGO stage, and low overall survival of OS patients. In addition, the results indicated that circCRIM1 could decrease the migration, invasion, and growth of OS cells. Further mechanistic studies indicated that circCRIM1 served as a competing endogenous RNA (ceRNA) of miR-513, leading to decreases in the proliferation, migration, and invasion of OS cells. Taken together, our data uncovered a significant role of the circCRIM1/miR-513 pathway in the proliferation, migration, and invasion of OS cell lines and suggested that circCRIM1 may serve as a possible therapeutic target for OS treatment.

19.
J Agric Food Chem ; 69(39): 11616-11625, 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34553918

RESUMO

Salicylic acid (SA) decarboxylase from Trichosporon moniliiforme (TmSdc), which reversibly catalyses the decarboxylation of SA to yield phenol, is of significant interest because of its potential for the production of benzoic acid derivatives under environmentally friendly reaction conditions. TmSdc showed a preference for C2 hydroxybenzoate derivatives, with kcat/Km of SA being 3.2 × 103 M-1 s-1. Here, we presented the first crystal structures of TmSdc, including a complex with SA. The three conserved residues of Glu8, His169, and Asp298 are the catalytic residues within the TIM-barrel domain of TmSdc. Trp239 forms a unique hydrophobic recognition site by interacting with the phenyl ring of SA, while Arg235 is responsible for recognizing the hydroxyl group at the C2 of SA via hydrogen bond interactions. Using a semi-rational combinatorial active-site saturation test, we obtained the TmSdc mutant MT3 (Y64T/P191G/F195V/E302D), which exhibited a 26.4-fold increase in kcat/Km with SA, reaching 8.4 × 104 M-1 s-1. Steered molecular dynamics simulations suggested that the structural changes in MT3 relieved the steric hindrance within the substrate access channel and enlarged the substrate-binding pocket, leading to the increased activity by improving substrate access. Our data elucidate the unique substrate recognition mode and the substrate entrance tunnel of SA decarboxylase.


Assuntos
Basidiomycota/enzimologia , Carboxiliases , Ácido Salicílico , Carboxiliases/genética , Carboxiliases/metabolismo , Catálise , Domínio Catalítico , Cristalografia por Raios X , Especificidade por Substrato
20.
Front Immunol ; 12: 547333, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34394068

RESUMO

Adenocarcinoma (AD) and squamous cell carcinoma (SCC) are both classified as major forms of non-small cell lung cancer, but differences in clinical prognoses and molecular mechanisms are remarkable. Recent studies have supported the importance of understanding immune status in that it influences clinical outcomes of cancer, and immunotherapies based on the theory of "immune editing" have had notable clinical success. Our study aimed to identify specific long non-coding (lnc) RNAs that control key immune-related genes and to use them to construct risk models for AD and SCC. Risk scores were used to separate patients into high- and low-risk groups, and we validated the prognostic significance of both risk scores with our own cohorts. A Gene Set Enrichment Analysis suggested that the immune responses of patients in the AD high-risk group and the SCC low-risk group tended to be weakened. Evaluation of immune infiltration revealed that the degree of infiltration of dendritic cells is of particular importance in AD. In addition, prediction of responses to immune checkpoint inhibitor (ICI) treatments, based on the T Cell Immune Dysfunction and Exclusion and immunophenoscore models, indicated that deterioration of the immune microenvironment is due mainly to T cell exclusion in AD patients and T cell dysfunction in SCC patients and that high-risk patients with SCC might benefit from ICI treatment. The prediction of downstream targets via The Cancer Proteome Atlas and RNA-seq analyses of a transfected lung cancer cell line indicated that the lncRNA LINC00996 is a potential therapeutic target in AD.


Assuntos
Adenocarcinoma/genética , Carcinoma de Células Escamosas/genética , Neoplasias Pulmonares/genética , Modelos Imunológicos , RNA Longo não Codificante/genética , Linfócitos T/imunologia , Células A549 , Adenocarcinoma/imunologia , Adenocarcinoma/mortalidade , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/mortalidade , Senescência Celular/genética , Estudos de Coortes , Humanos , Imunidade/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Terapia de Alvo Molecular , RNA Longo não Codificante/imunologia , Risco , Análise de Sobrevida , Microambiente Tumoral
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