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1.
Signal Transduct Target Ther ; 8(1): 51, 2023 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-36732502

RESUMO

As a terpenoids natural product isolated from the plant Thunder God Vine, Celastrol is widely studied for its pharmacological activities, including anti-tumor activities. The clinical application of Celastrol is strictly limited due to its severe side effects, whereas previously revealed targets and mechanism of Celastrol seldom reduce its in vivo toxicity via structural optimization. Target identification has a far-reaching influence on the development of innovative drugs, and omics data has been widely used for unbiased target prediction. However, it is difficult to enrich target of specific phenotype from thousands of genes or proteins, especially for natural products with broad promising activities. Here, we developed a text-mining-based web-server tool to enrich targets from omics data of inquired compounds. Then peroxiredoxin 1 (PRDX1) was identified as the ROS-manipulating target protein of Celastrol in colorectal cancer. Our solved high-resolution crystal structure revealed the unique covalent binding mode of Celastrol with PRDX1. New derivative compound 19-048 with improved potency against PRDX1 and selectivity towards PRDX2~PRDX6 were synthesized based on crystal structure analysis. Both Celastrol and 19-048 effectively suppressed the proliferation of colorectal cancer cells. The anti-tumor efficacy of Celastrol and 19-048 was significantly diminished on xenograft nude mice bearing PRDX1 knock-down colorectal cancer cells. Several downstream genes of p53 signaling pathway were dramatically up-regulated with Celastrol or 19-048 treatment. Our findings reveal that the side effects of Celastrol could be reduced via structural modification, and PRDX1 inhibition is promising for the treatment of colorectal cancer.

2.
EMBO Mol Med ; : e16235, 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36652375

RESUMO

Poly-ADP-ribose polymerase (PARP) inhibitors (PARPi) have shown great promise for treating BRCA-deficient tumors. However, over 40% of BRCA-deficient patients fail to respond to PARPi. Here, we report that thioparib, a next-generation PARPi with high affinity against multiple PARPs, including PARP1, PARP2, and PARP7, displays high antitumor activities against PARPi-sensitive and -resistant cells with homologous recombination (HR) deficiency both in vitro and in vivo. Thioparib treatment elicited PARP1-dependent DNA damage and replication stress, causing S-phase arrest and apoptosis. Conversely, thioparib strongly inhibited HR-mediated DNA repair while increasing RAD51 foci formation. Notably, the on-target inhibition of PARP7 by thioparib-activated STING/TBK1-dependent phosphorylation of STAT1, triggered a strong induction of type I interferons (IFNs), and resulted in tumor growth retardation in an immunocompetent mouse model. However, the inhibitory effect of thioparib on tumor growth was more pronounced in PARP1 knockout mice, suggesting that a specific PARP7 inhibitor, rather than a pan inhibitor such as thioparib, would be more relevant for clinical applications. Finally, genome-scale CRISPR screening identified PARP1 and MCRS1 as genes capable of modulating thioparib sensitivity. Taken together, thioparib, a next-generation PARPi acting on both DNA damage response and antitumor immunity, serves as a therapeutic potential for treating hyperactive HR tumors, including those resistant to earlier-generation PARPi.

3.
Environ Res ; 222: 115344, 2023 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-36693460

RESUMO

BACKGROUND: Numerous studies have demonstrated that greenspace(GS) exposure is associated with health improvements in individuals with hypertension and diabetes. However, studies examining the associations between multiple GS exposures and chronic health conditions in developing countries are limited. METHODS: Geospatial data and spatial analysis were employed to objectively measure the total neighbourhood vegetative cover (mean value of normalised difference vegetation index [NDVI] within specific buffer zone) and proximity to park-based GS (network distance from home to the entrance of park-based GS). Street view imagery and machine learning techniques were used to measure the subjective perceptions of street GS quality. A multiple linear regression model was applied to examine the associations between multiple GS exposures and the prevalence of hypertension and diabetes in neighbourhoods located in Qingdao, China. RESULTS: The model explained 29.8% and 28.2% of the prevalence of hypertension and diabetes, respectively. The results suggested that: 1) the total vegetative cover of the neighbourhood was inversely correlated with the prevalence of hypertension (ß = -0.272, p = 0.013, 95% confidence interval (CI): [-1.332, -0.162]) and diabetes (ß = -0.230, p = 0.037, 95% CI: [-0.720, -0.008]). 2) The street GS quality was negatively correlated with the prevalence of hypertension (ß = -0.303, p = 0.007, 95% CI: [-2.981, -0.491]) and diabetes (ß = -0.309, p = 0.006, 95% CI: [-1.839, -0.314]). 3) Proximity to park-based GS and the prevalence of hypertension and diabetes mellitus were not significantly correlated. CONCLUSIONS: This study used subjective and objective methods to comprehensively assess the greenspace exposure from overhead to eye level, from quantity, proximity to quality. The results demonstrated the beneficial relationships between street GS quality, total vegetative cover, and chronic health in a rapidly urbanising Chinese city. Furthermore. the effect of street GS quality was more pronounced in potentially mitigating chronic health problems, and improving the quality of street GS might be an efficient and effective intervention pathway for addressing chronic health issues in densely populated cities.

4.
Biomed Res Int ; 2023: 3626776, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36714031

RESUMO

Biodegradable iron alloy implants have become one of the most ideal possible candidates because of their biocompatibility and comprehensive mechanical properties. Iron alloy's impact on chondrocytes is still unknown, though. This investigation looked at the biocompatibility and degradation of the Fe30Mn0.6N alloy as well as how it affected bone formation and chondrocyte autophagy. In vivo implantation of Fe30Mn0.6N and Ti6Al4V rods into rabbit femoral cartilage and femoral shaft was carried out to evaluate the degradation of the alloy and the cartilage and bone response at different intervals. After 8 weeks of implantation, the cross-sectional area of the Fe30Mn0.6N alloys lowered by 50.79 ± 9.59%. More Ca and P element deposition was found on the surface Fe30Mn0.6N rods by using energy dispersive spectroscopy (EDS) and scanning electron microscopy (P < 0.05). After 2, 4, and 8 weeks of implantation, no evident inflammatory infiltration was seen in peri-implant cartilage and bone tissue of Fe30Mn0.6N and Ti6Al4V alloys. Also, implantation of Fe30Mn0.6N alloy promoted autophagy in cartilage by detecting expression of LC3-II compared with Ti6Al4V after implantation (P < 0.05). Fe30Mn0.6N alloy also stimulated early osteogenesis at the peri-implant interface compared with Ti6Al4V after implantation (P < 0.05). In the in vitro test, we found that low concentrations of Fe30Mn0.6N extracts had no influence on cell viability. 15% and 30% extracts of Fe30Mn0.6N could upregulate autophagy compared to the control group by detecting beclin-1, LC3, Atg3, and P62 on the basis of WB and IHC (P < 0.05). Also, the PI3K-AKT-mTOR signaling pathway mediated in the upregulation of autophagy of chondrocytes resulting in exposure to extract of Fe30Mn0.6N alloy. It is concluded that Fe30Mn0.6N showed degradability and biocompatibility in vivo and upregulated autophagy activity in chondrocytes.


Assuntos
Osteogênese , Fosfatidilinositol 3-Quinases , Animais , Coelhos , Fêmur/metabolismo , Ligas/química , Implantes Absorvíveis , Cartilagem/metabolismo
5.
Plants (Basel) ; 12(2)2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36679015

RESUMO

Sweet corn and waxy corn has a better taste and higher accumulated nutritional value than regular maize, and is widely planted and popularly consumed throughout the world. Plant height (PH), ear height (EH), and tassel branch number (TBN) are key plant architecture traits, which play an important role in improving grain yield in maize. In this study, a genome-wide association study (GWAS) and genomic prediction analysis were conducted on plant architecture traits of PH, EH, and TBN in a fresh edible maize population consisting of 190 sweet corn inbred lines and 287 waxy corn inbred lines. Phenotypic data from two locations showed high heritability for all three traits, with significant differences observed between sweet corn and waxy corn for both PH and EH. The differences between the three subgroups of sweet corn were not obvious for all three traits. Population structure and PCA analysis results divided the whole population into three subgroups, i.e., sweet corn, waxy corn, and the subgroup mixed with sweet and waxy corn. Analysis of GWAS was conducted with 278,592 SNPs obtained from resequencing data; 184, 45, and 68 significantly associated SNPs were detected for PH, EH, and TBN, respectively. The phenotypic variance explained (PVE) values of these significant SNPs ranged from 3.50% to 7.0%. The results of this study lay the foundation for further understanding the genetic basis of plant architecture traits in sweet corn and waxy corn. Genomic selection (GS) is a new approach for improving quantitative traits in large plant breeding populations that uses whole-genome molecular markers. The marker number and marker quality are essential for the application of GS in maize breeding. GWAS can choose the most related markers with the traits, so it can be used to improve the predictive accuracy of GS.

6.
J Med Chem ; 66(2): 1634-1651, 2023 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-36642961

RESUMO

The histone lysine methyltransferase NSD2 is overexpressed, translocated, or mutated in multiple types of cancers and has emerged as an attractive therapeutic target. However, the development of small-molecule NSD2 inhibitors is still in its infancy, and selective and efficacious NSD2 inhibitors are highly desirable. Here, in view of the structural novelty of the reported NSD2 inhibitor DA3003-1, we conducted a comprehensive structural optimization based on the quinoline-5,8-dione scaffold. Compound 15a was identified possessing both high NSD2 inhibitory activity and potent anti-proliferative effects in the cell. Meanwhile, compound 15a has an excellent pharmacokinetic profile with high oral bioavailability. Further, this compound was found to display significant antitumor efficacy with desirable safety profile in the multiple myeloma xenograft mice models, thus warranting it as a promising candidate for further investigation.


Assuntos
Quinolinas , Proteínas Repressoras , Humanos , Animais , Camundongos , Quinolinas/farmacologia , Quinolinas/uso terapêutico
7.
Transplant Cell Ther ; 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36634739

RESUMO

Heart failure (HF) is an uncommon but serious cardiovascular complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Unfortunately, knowledge about early mortality prognostic factors in patients with HF after allo-HSCT is limited, and an easy-to-use prognostic model is not available. This study aimed to develop and validate a clinical-biomarker prognostic model capable of predicting HF mortality following allo-HSCT that uses a combination of variables readily available in clinical practice. To investigate this issue, we conducted a retrospective analysis at our center with 154 HF patients who underwent allo-HSCT between 2008 and 2021. The patients were separated according to the time of transplantation, with 100 patients composing the derivation cohort and the other 54 patients composing the external validation cohort. We first calculated the univariable association for each variable with 2-month mortality in the derivation cohort. We then included the variables with a P value <.1 in univariate analysis as candidate predictors in the multivariate analysis using a backward stepwise logistic regression model. Variables remaining in the final model were identified as independent prognostic factors. To predict the prognosis of HF, a scoring system was established, and scores were assigned to the prognostic factors based on the regression coefficient. Finally, 4 strongly significant independent prognostic factors for 2-month mortality from HF were identified using multivariable logistic regression methods with stepwise variable selection: pulmonary infection (P = .005), grade III to IV acute graft-versus-host disease (severe aGVHD; P = .033), lactate dehydrogenase (LDH) >426 U/L (P = .049), and brain natriuretic peptide (BNP) >1799 pg/mL (P = .026). A risk grading model termed the BLIPS score (for BNP, LDH, cardiac troponin I, pulmonary infection, and severe aGVHD) was constructed according to the regression coefficients. The validated internal C-statistic was .870 (95% confidence interval [CI], .798 to .942), and the external C-statistic was .882 (95% CI, .791-.973). According to the calibration plots, the model-predicted probability correlated well with the actual observed frequencies. The clinical use of the prognostic model, according to decision curve analysis, could benefit HF patients. The BLIPS model in our study can serve to identify HF patients at higher risk for mortality early, which might aid designing timely targeted therapies and eventually improving patients' survival and prognosis. © 2023 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

8.
Nat Microbiol ; 8(1): 107-120, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36593296

RESUMO

Staphylococcus aureus invades cells and persists intracellularly, causing persistent inflammation that is notoriously difficult to treat. Here we investigated host-pathogen interactions underlying intracellular S. aureus infection in macrophages and discovered that the endoplasmic reticulum (ER) is an important cellular compartment for intracellular S. aureus infection. Using CRISPR-Cas9 guide RNA library screening, we determined that the autocrine motility factor receptor (AMFR), an ER-resident E3 ubiquitin ligase, played an essential role in mediating intracellular S. aureus-induced inflammation. AMFR directly interacted with TAK1-binding protein 3 (TAB3) in the ER, inducing K27-linked polyubiquitination of TAB3 on lysine 649 and promoting TAK1 activation. Moreover, the virulence factor γ-haemolysin B (HIgB) of S. aureus bound to the AMFR and regulated TAB3. Our findings highlight an unknown role of AMFR in intracellular S. aureus infection-induced pneumonia and suggest that pharmacological interruption of AMFR-mediated TAB3 signalling cascades and HIgB targeting may prevent invasive staphylococci-mediated pneumonia.


Assuntos
Pneumonia , Ubiquitina-Proteína Ligases , Humanos , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático , Inflamação/metabolismo , Receptores do Fator Autócrino de Motilidade/metabolismo , Staphylococcus aureus/genética , Staphylococcus aureus/metabolismo , Ubiquitina-Proteína Ligases/genética , Fatores de Virulência/metabolismo
9.
ACS Nano ; 17(1): 322-336, 2023 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-36525314

RESUMO

The limited lymphocyte infiltration and exhaustion of tumoricidal functions in solid tumors remain a formidable obstacle to cancer immunotherapy. Herein, we designed a macrophage membrane-coated nano-gemcitabine system (MNGs) to promote lymphocyte infiltration and then synergized anti-programmed death ligand 1 (antiPD-L1) to reinvigorate the exhausted lymphocytes. MNGs exhibited effective intratumor-permeating and responsive drug-releasing capacity, produced notable elimination of versatile immunosuppressive cells, and promoted lymphocyte infiltration into cancer cell regions in tumors, but over 50% of these infiltrated lymphocytes were in the exhausted state. Compared with MNG monotherapy, the MNGs+antiPD-L1 combination produced 31.77% and 30.63% reduction of exhausted CD3+CD8+ T cells and natural killer (NK) cells and 2.83- and 3.17-fold increases of interferon-γ (IFN-γ)-positive subtypes, respectively, thereby resulting in considerable therapeutic benefits in several tumor models. Thus, MNGs provide an encouraging strategy to promote lymphocyte infiltration and synergize antiPD-L1 to restore their tumoricidal function for cancer immunotherapy.


Assuntos
Linfócitos T CD8-Positivos , Neoplasias , Humanos , Imunoterapia , Interferon gama/farmacologia , Macrófagos , Microambiente Tumoral , Nanoestruturas , Antígeno B7-H1/metabolismo
10.
J Cell Mol Med ; 27(2): 189-203, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36541023

RESUMO

Circular RNAs (circRNAs) are often found in eukaryocyte and have a role in the pathogenesis of a variety of human disorders. Our related research has shown the differential expression of circRNAs in periprosthetic osteolysis (PPOL). However, the involvement of circRNAs in the exact process is yet unknown. CircSLC8A1 expression was evaluated in clinical samples and human bone marrow mesenchymal stem cells (hBMSCs) in this investigation using quantitative real-time PCR. In vitro and in vivo studies were conducted to explicate its functional role and pathway. We demonstrated CircSLC8A1 is involved in PPOL using gain- and loss-of-function methods. The association of CircSLC8A1 and miR-144-3p, along with miR-144-3p and RUNX1, was predicted using bioinformatics. RNA pull-down and luciferase assays confirmed it. The impact of CircSLC8A1 in the PPOL-mouse model was also investigated using adeno-associated virus. CircSLC8A1 was found to be downregulated in PPOL patients' periprosthetic tissues. Overexpression of CircSLC8A1 promoted osteogenic differentiation (OD) and inhibited apoptosis of hBMSCs in vitro. The osteogenic markers of RUNX1, osteopontin (OPN) and osteocalcin (OCN) were significantly upregulated in hBMSCs after miR-144-3p inhibitor was transferred. Mechanistic analysis demonstrated that CircSLC8A1 directly bound to miR-144-3p and participated in PPOL through the miR-144-3p/RUNX1 pathway in hBMSCs. Micro-CT and quantitative analysis showed that CircSLC8A1 markedly inhibited PPOL, and osteogenic markers (RUNX1, OPN and OCN) were significantly increased (P<0.05) in the mice model. Our findings prove that CircSLC8A1 exerted a regulatory role in promoting osteogenic differentiation in hBMSCs, and CircSLC8A1/miR-144-3p/RUNX1 pathway may provide a potential target for prevention of PPOL.


Assuntos
Células-Tronco Mesenquimais , MicroRNAs , Osteólise , Animais , Camundongos , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , Osteogênese/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Osteólise/genética , Osteólise/metabolismo , Diferenciação Celular/genética , Células-Tronco Mesenquimais/metabolismo , Osteocalcina/metabolismo , Células Cultivadas
11.
Artigo em Inglês | MEDLINE | ID: mdl-36471477

RESUMO

Additional sex combs-like 1 (ASXL1) mutations, a hotspot in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), have been frequently reported for their potential prognostic value, but the results are controversial. Therefore, a meta-analysis was performed. Databases, including PubMed, Embase, and Cochrane Library, were searched for relevant studies published up to January 13, 2022. STATA v16.0 software was used to calculate the combined hazard ratios (HRs) and their 95% confidence intervals (CIs) for overall survival (OS) and AML transformation. Subgroup analysis was used to explore the effects of the grouping factors on heterogeneity.Ten studies on ASXL1 mutations and the prognosis of MDS were selected. Our results indicate that ASXL1 mutations have an adverse prognostic impact on OS (HR = 1.68,95%CI:1.45-1.94, p < .0001) and AML transformation (HR = 2.20,95% CI:1.68-2.87, p < .0001). The results for different age groups were not significantly different (HR = 1.87,95% CI: 1.31-2.67; HR = 1.62,95% CI:1.35-2.07). Ten studies covering 5816 patients with AML were included. The pooled HR for OS was 1.37 (95% CI:1.20-1.56, p < .0001). ASXL1 mutations were especially associated with a poorer OS in the subgroup aged ≥60 years (HR = 2.86, 95% CI:1.34-6.08, p = .006); when considering cytogenetically normal AML (CN-AML), the HR was 1.78(95% CI:1.27-2.49, p = .001). This meta-analysis indicates an independent, adverse prognostic impact of ASXL1 mutations in patients with MDS and AML, which also applies to patients with CN-AML. Age was a risk factor for patients with AML and ASXL1 mutations but not for patients with MDS.

12.
Front Immunol ; 13: 1006395, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36569928

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic caused by the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has cast a notorious damage to the public health and global economy. The Stimulator of Interferon Genes (STING) is a crucial element of the host antiviral pathway and plays a pivotal but complex role in the infection and development of COVID-19. Herein, we discussed the antagonistic mechanism of viral proteins to the STING pathway as well as its activation induced by host cells. Specifically, we highlighted that the persistent activation of STING by SARS-CoV-2 led to abnormal inflammation, and STING inhibitors could reduce the excessive inflammation. In addition, we also emphasized that STING agonists possessed antiviral potency against diverse coronavirus and showed adjuvant efficacy in SARS-CoV-2 vaccines by inducing IFN responses.


Assuntos
COVID-19 , Humanos , SARS-CoV-2 , Vacinas contra COVID-19 , Antivirais/farmacologia , Inflamação
14.
Vaccines (Basel) ; 10(12)2022 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-36560428

RESUMO

OBJECTIVES: The current study aims to survey the willingness of parents to vaccinate their children, who are childhood acute lymphoblastic leukemia survivors (CALLS), and identify factors associated with vaccine acceptance. METHODS: Parents of CALLS on/off treatment, with the general condition of being amendable to vaccination, were recruited for interviews with attending oncologists about COVID-19 vaccination acceptance from July to November 2021 in China. After controlling for socioeconomic factors, the Association of Oncologists' recommendations and parent-oncologist alliance with acceptance status were investigated. For validation, propensity score-matched (PSM) analysis was used. RESULTS: A total of 424 families were included in the study, with CALLS mean remission age of 5.99 ± 3.40 years. Among them, 91 (21.4%) agreed, 168 (39.6%) hesitated, and 165 (38.9%) parents disagreed with the vaccination. The most common reason that kept parents from vaccinating their children was lack of recommendations from professional personnel (84/165, 50.9%), and massive amounts of internet information (78/175, 44.6%) was the main nonhealthcare resource against vaccination. Logistic regression analysis showed that only the recommendation from the oncologist was associated with parents' vaccine acceptance (OR = 3.17, 95% CI = 1.93-5.20), as demonstrated by PSM comparison (42 in recommendation group vs. 18 in nonrecommendation group among 114 pairs, p < 0.001). An exploratory analysis revealed that parents with a better patient-oncologist alliance had a significantly higher level of acceptance (65.6% in alliance group vs. 15.6% in nonalliance group among 32 pairs, p < 0.001). CONCLUSIONS: Due to a lack of professional recommendation resources and the potential for serious consequences, parents were generally reluctant to vaccinate their CALLS. The recommendation of oncologists, which was influenced by the parent-oncologist alliance, significantly increased acceptance. This study emphasizes the critical role of oncologists in vaccinating cancer survivors and can be used to promote COVID-19 vaccines among vulnerable populations.

15.
Int J Mol Sci ; 23(24)2022 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-36555340

RESUMO

The imbalance in polyunsaturated fatty acid (PUFA) composition in human food is ubiquitous and closely related to obesity and cardiovascular diseases. The development of n-3 PUFA-enriched poultry products is of great significance for optimizing fatty acid composition. This study aimed to improve our understanding of the effects of dietary linseed oil on hepatic metabolism using untargeted metabolomics and 4D label-free proteome analysis. A total of 91 metabolites and 63 proteins showed differences in abundance in duck livers between the high linseed oil and control groups. Pathway analysis revealed that the biosynthesis of unsaturated fatty acids, linoleic acid, glycerophospholipid, and pyrimidine metabolisms were significantly enriched in ducks fed with linseed oil. Meanwhile, dietary linseed oil changed liver fatty acid composition, which was reflected in the increase in the abundance of downstream metabolites, such as α-linolenic acid (ALA; 18:3n-3) as a substrate, including n-3 PUFA and its related glycerophospholipids, and a decrease in downstream n-6 PUFA synthesis using linoleic acid (LA; 18:2n-6) as a substrate. Moreover, the anabolism of PUFA in duck livers showed substrate-dependent effects, and the expression of related proteins in the process of fatty acid anabolism, such as FADS2, LPIN2, and PLA2G4A, were significantly regulated by linseed oil. Collectively, our work highlights the ALA substrate dependence during n-3 PUFA synthesis in duck livers. The present study expands our knowledge of the process products of PUFA metabolism and provides some potential biomarkers for liver health.


Assuntos
Gorduras Insaturadas na Dieta , Ácidos Graxos Ômega-3 , Linho , Animais , Humanos , Óleo de Semente do Linho/metabolismo , Gorduras Insaturadas na Dieta/metabolismo , Patos , Linho/metabolismo , Proteômica , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Insaturados/metabolismo , Ácidos Graxos/metabolismo , Fígado/metabolismo , Ácido Linoleico/metabolismo
16.
Eur Urol Oncol ; 2022 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-36517406

RESUMO

BACKGROUND: A renal mass in a solitary kidney (RMSK) has traditionally been managed with partial nephrectomy (PN), although radical nephrectomy (RN) is occasionally required. Most RMSK studies have focused on patients for whom PN was achieved. OBJECTIVE: To provide a comprehensive analysis of the management strategies/outcomes for an RMSK and address knowledge deficits regarding this challenging disorder. DESIGN, SETTING, AND PARTICIPANTS: A total of 1024 patients diagnosed with an RMSK (1975-2022) were retrospectively evaluated. Baseline characteristics and pathologic/functional/survival outcomes were analyzed. INTERVENTION: PN/RN/cryoablation (CA)/active surveillance (AS). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Functional outcomes, perioperative morbidity/mortality, and 5-yr recurrence-free survival (RFS) were evaluated. Kruskal-Wallis and chi-square tests were used to compare cohorts, and log-rank test and Cox proportional hazard model were used for survival analysis. RESULTS AND LIMITATIONS: Of 1024 patients, 842 underwent PN (82%), 102 CA (10%), 54 RN (5%), and 26 AS (3%). The median tumor size and RENAL([R]adius [tumor size as maximal diameter], [E]xophytic/endophytic properties of tumor, [N]earness of tumor deepest portion to collecting system or sinus, [A]nterior [a]/posterior [p] descriptor, and [L]ocation relative to polar lines) score were 3.7 cm and 8, respectively. The median follow-up was 53 mo. For PN, 95% were clamped, and the median warm and cold ischemia times were 22 and 45 min, respectively. For PN, the median preoperative glomerular filtration rate (GFR) was 57 ml/min/1.73 m2, and the median new baseline and 5-yr GFRs were 47 and 48 ml/min/1.73 m2, respectively. Dialysis-free survival for PN was 97% at 5 yr. Twenty-two (2.1%) patients with clear-cell renal cell carcinoma and RENAL score ≥10 (median = 11) received tyrosine kinase inhibitors (TKIs) to facilitate PN, leading to 57% median decrease of tumor volume; PN was accomplished in 20 (91%). Forty-one patients had planned RN (4.0%), most often due to severe pre-existing chronic kidney disease (CKD), and 13 were converted from PN to RN (1.5%). Clavien III-V perioperative complications were observed in 80 (8%) patients and 90-d mortality was 0.6%. Five-year RFS for PN, CA, and RN were 83%, 80%, and 72%, respectively (p = 0.03 for PN vs RN). CONCLUSIONS: Nephron-sparing approaches are feasible and successful in most RMSK patients. PN for an RMSK is often challenging but can be facilitated by selective use of TKIs. RN is occasionally required due to severe CKD, over-riding oncologic concerns, or conversion from PN. This is the first large RMSK study to provide a comprehensive analysis of all management strategies/outcomes. PATIENT SUMMARY: Kidney cancer in a solitary kidney is a major challenge for achieving cancer-free status and avoiding dialysis. Although partial nephrectomy is the principal treatment for a renal mass in a solitary kidney, other options are occasionally required to optimize outcomes.

17.
Front Nutr ; 9: 1030712, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36386908

RESUMO

Linseed oil, an important source of dietary α-linolenic acid, is used to provide meat enriched in n-3 PUFA. We investigated the effects of dietary linseed oil (0, 0.5, 1, and 2%) on growth performance, meat quality, tissue fatty acid (FA), and transcriptome profiles in ducks. The result showed that dietary linseed oil had no effect on growth performance. Increasing dietary linseed oil enrichment raised n-3 PUFA and linoleic acid (LA) levels in both the liver and breast muscle, but decreased dihomo-gamma-linolenic acid (DGLA) and arachidonic acid (ARA) levels in the liver. The liver n-3 PUFA content was negatively correlated with duck body weight. Transcriptome analysis showed that dietary linseed oil caused hepatic changes in genes (SCD, FADS1, FADS2, and ACOT6) related to the biosynthesis of unsaturated fatty acids. Besides, dietary linseed oil also affected the expression of genes related to PUFAs and downstream metabolites (such as linoleic acid, steroid hormone, progesterone, etc.) metabolic pathways in both liver and breast muscle. Key genes involved in PUFA synthesis and transport pathways were examined by RT-qPCR, and the results verified that hepatic expression levels of FADS1 and FADS2 decreased, and those of FABP4 and FABP5 increased when 2% linseed oil was added. CD36 expression level increased in breast muscle when 2% linseed oil was added. Thus, 2% dietary linseed oil supplementation produces n-3 PUFA-enriched duck products by regulating the PUFA metabolic pathways, which could be advantageous for health-conscious consumers.

18.
Mar Genomics ; 66: 100995, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36400548

RESUMO

Pseudomonas sp. strain DNDY-54, a denitrifying bacterium, was isolated from a deep-sea sediment sample from Ninety East Ridge in the Indian Ocean. Here, we show that the complete genome of DNDY-54 has one circular chromosome of 4,412,895 bp with mean 60.57% GC content. The complete genome contains 4111 predicted protein-coding genes, 59 tRNAs, and 4 rRNA operons as 16S-23S-5S rRNA. On the basis of the annotation results, we identified genes that encode 27 proteins related to nitrogen metabolism, including enzymes that make up a complete denitrifying pathway. This work will improve the understanding of nitrogen cycling in the deep biosphere and provides a new candidate for protection of the environment and applications in waste water disposal.


Assuntos
Genoma Bacteriano , Pseudomonas , Pseudomonas/genética , Poliéster Sulfúrico de Pentosana , Análise de Sequência de DNA , RNA Ribossômico 16S/genética , Nitrogênio
19.
Medicine (Baltimore) ; 101(46): e31823, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36401496

RESUMO

BACKGROUND: There is a close and causative correlation between stroke and diabetes, and the complication of the 2 diseases seriously harms human health and currently becomes a topic of clinical importance. To date, the common methods of treating diabetic stroke include acupuncture and pharmacological interventions. However, there is no high-quality or direct evidence of their comparative effectiveness. This review aims to provide a network meta-analysis to compare the efficacy of acupuncture and pharmacological interventions in treating diabetic stroke. METHODS: Databases such as PubMed, Cochrane Central Register of Controlled Trials, EMBASE, China National Knowledge Infrastructure, China Biology Medicine Disc will be searched for relevant randomized controlled trials to obtain literatures on the treatment of diabetic stroke, and clinical randomized controlled trials will be screened out from their inception to December 30, 2022. The participant intervention comparator outcomes of this study are as flowing: P, patients with diabetic stroke; I, acupuncture and pharmacological interventions; C, no treatment, pharmacological placebo, or sham acupuncture groups; O, primary outcome will be blood glucose levels, glycosylated hemoglobin levels, and the rate of stroke recurrence; secondary outcomes will include fasting and post-load blood glucose levels, cholesterol, triglycerides, and quality of life scale scores. Cochrane Risk of Bias Tool will be used in assessing literature's quality. Review Manager software 5.3 and Stata 15.1 will be used in data analysis. RESULT: This systematic review and network meta-analysis will provide evidence of the efficacy of different therapeutic methods in treating diabetic stroke, to show which forms of therapy are more commonly used with higher effectiveness. CONCLUSION: The results will systematically provide suggestions for medical practitioners to choose the effective, time-saving and economical therapeutic strategy for diabetic stroke.


Assuntos
Terapia por Acupuntura , Diabetes Mellitus , Acidente Vascular Cerebral , Humanos , Metanálise em Rede , Glicemia , Qualidade de Vida , Terapia por Acupuntura/métodos , Acidente Vascular Cerebral/terapia , Acidente Vascular Cerebral/complicações , Revisões Sistemáticas como Assunto , Metanálise como Assunto
20.
Innovation (Camb) ; 3(6): 100343, 2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36353676

RESUMO

Dirac semimetal is a phase of matter whose elementary excitation is described by the relativistic Dirac equation. In the limit of zero mass, its parity-time symmetry enforces the Dirac fermion in the momentum space, which is composed of two Weyl fermions with opposite chirality, to be non-chiral. Inspired by the flavor symmetry in particle physics, we theoretically propose a massless Dirac-like equation yet linking two Weyl fields with the identical chirality by assuming SU ( 2 ) isospin symmetry, independent of the space-time rotation exchanging the two fields. Dramatically, such symmetry is hidden in certain solid-state spin-1/2 systems with negligible spin-orbit coupling, where the spin degree of freedom is decoupled with the lattice. Therefore, the existence of the corresponding quasiparticle, dubbed as flavor Weyl fermion, cannot be explained by the conventional (magnetic) space group framework. The 4-fold degenerate flavor Weyl fermion manifests linear dispersion and a Chern number of ± 2, leading to a robust network of topologically protected Fermi arcs throughout the Brillouin zone. For material realization, we show that the transition-metal chalcogenide CoNb3S6 with experimentally confirmed collinear antiferromagnetic order is ideal for flavor Weyl semimetal under the approximation of vanishing spin-orbit coupling. Our work reveals a counterpart of the flavor symmetry in magnetic electronic systems, leading to further possibilities of emergent phenomena in quantum materials.

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