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1.
Cell ; 185(3): 414-416, 2022 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-35120661

RESUMO

The factors and mechanisms that shape the composition and function of closely related members in a complex microbial community are largely unknown. The study by Park and colleagues reveals that the fitness of various Bacteroidales species and strains in the gut microbiome is regulated by butyrate in a glycan-dependent manner.


Assuntos
Butiratos , Microbioma Gastrointestinal , Bacteroidetes , Instinto , Açúcares
2.
Cell ; 183(3): 666-683.e17, 2020 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-32991841

RESUMO

A mysterious feature of Crohn's disease (CD) is the extra-intestinal manifestation of "creeping fat" (CrF), defined as expansion of mesenteric adipose tissue around the inflamed and fibrotic intestine. In the current study, we explore whether microbial translocation in CD serves as a central cue for CrF development. We discovered a subset of mucosal-associated gut bacteria that consistently translocated and remained viable in CrF in CD ileal surgical resections, and identified Clostridium innocuum as a signature of this consortium with strain variation between mucosal and adipose isolates, suggesting preference for lipid-rich environments. Single-cell RNA sequencing characterized CrF as both pro-fibrotic and pro-adipogenic with a rich milieu of activated immune cells responding to microbial stimuli, which we confirm in gnotobiotic mice colonized with C. innocuum. Ex vivo validation of expression patterns suggests C. innocuum stimulates tissue remodeling via M2 macrophages, leading to an adipose tissue barrier that serves to prevent systemic dissemination of bacteria.


Assuntos
Tecido Adiposo/microbiologia , Translocação Bacteriana , Microbioma Gastrointestinal , Mesentério/microbiologia , Tecido Adiposo/patologia , Animais , Biodiversidade , Biomarcadores/metabolismo , Polaridade Celular , Células Cultivadas , Colite Ulcerativa/patologia , Doença de Crohn/microbiologia , Doença de Crohn/patologia , Microbioma Gastrointestinal/genética , Regulação da Expressão Gênica , Vida Livre de Germes , Humanos , Íleo/microbiologia , Íleo/patologia , Lipopolissacarídeos/metabolismo , Macrófagos/metabolismo , Metagenoma , Metagenômica , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , RNA Ribossômico 16S/genética , Células-Tronco/metabolismo
3.
Biochemistry ; 63(6): 788-796, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38417024

RESUMO

In our efforts to develop inhibitors selective for neuronal nitric oxide synthase (nNOS) over endothelial nitric oxide synthase (eNOS), we found that nNOS can undergo conformational changes in response to inhibitor binding that does not readily occur in eNOS. One change involves movement of a conserved tyrosine, which hydrogen bonds to one of the heme propionates, but in the presence of an inhibitor, changes conformation, enabling part of the inhibitor to hydrogen bond with the heme propionate. This movement does not occur as readily in eNOS and may account for the reason why these inhibitors bind more tightly to nNOS. A second structural change occurs upon the binding of a second inhibitor molecule to nNOS, displacing the pterin cofactor. Binding of this second site inhibitor requires structural changes at the dimer interface, which also occurs more readily in nNOS than in eNOS. Here, we used a combination of crystallography, mutagenesis, and computational methods to better understand the structural basis for these differences in NOS inhibitor binding. Computational results show that a conserved tyrosine near the primary inhibitor binding site is anchored more tightly in eNOS than in nNOS, allowing for less flexibility of this residue. We also find that the inefficiency of eNOS to bind a second inhibitor molecule is likely due to the tighter dimer interface in eNOS compared with nNOS. This study provides a better understanding of how subtle structural differences in NOS isoforms can result in substantial dynamic differences that can be exploited in the development of isoform-selective inhibitors.


Assuntos
Óxido Nítrico Sintase Tipo III , Óxido Nítrico Sintase , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/química , Óxido Nítrico Sintase Tipo I , Isoformas de Proteínas/química , Cristalografia por Raios X , Inibidores Enzimáticos/farmacologia , Heme/química , Tirosina , Óxido Nítrico
4.
Glob Chang Biol ; 30(6): e17361, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38822568

RESUMO

Our current planetary crisis, including multiple jointly acting factors of global change, moves the need for effective ecosystem restoration center stage and compels us to explore unusual options. We here propose exploring combinatorial approaches to restoration practices: management practices are drawn at random and combined from a locally relevant pool of possible management interventions, thus creating an experimental gradient in the number of interventions. This will move the current degree of interventions to higher dimensionality, opening new opportunities for unlocking unknown synergistic effects. Thus, the high dimensionality of global change (multiple jointly acting factors) would be more effectively countered by similar high-dimensionality in solutions. In this concept, regional restoration hubs play an important role as guardians of locally relevant information and sites of experimental exploration. Data collected from such studies could feed into a global database, which could be used to learn about general principles of combined restoration practices, helping to refine future experiments. Such combinatorial approaches to exploring restoration intervention options may be our best hope yet to achieve decisive progress in ecological restoration at the timescale needed to mitigate and reverse the most severe losses caused by global environmental change.


Assuntos
Conservação dos Recursos Naturais , Ecossistema , Conservação dos Recursos Naturais/métodos , Recuperação e Remediação Ambiental/métodos , Ecologia/métodos , Mudança Climática
5.
BMC Public Health ; 24(1): 212, 2024 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-38233775

RESUMO

OBJECTIVE: In view of the high incidence and mortality of esophageal cancer, the latest statistical data on the disease burden of esophageal cancer can provide strategies for cancer screening, early detection and treatment, and help to rationally allocate health resources. This study provides an analysis of the global disease burden and risk factors of esophageal cancer from 1990 to 2019. METHODS: Using the 2019 Global Burden of Disease, Injury and Risk Factor (GBD) data, we present the incidence, mortality and disability-adjusted life years (DALY) of esophageal cancer in 21 regions and 204 countries and different sociodemographic index (SDI) regions from 1990 to 2019. The age-period-cohort model was used to estimate the age, period, and cohort trend of esophageal cancer in different SDI regions. The estimated proportion of DALY attributable to each risk factor from 1990 to 2019. RESULTS: From 1990 to 2019, the number of new cases of esophageal cancer, the number of deaths and DALY increased by 67.07%, 55.97% and 42.13%, respectively, but age standardized incidence rate (ASIR), age standardized mortality rate (ASMR) and age standardized DALY rate (ASDR) decreased by 19.28%, 25.32% and 88.22%, respectively. Overall, the results of the age-period-cohort model showed that the incidence, mortality, and DALY rates in countries and regions with higher SDI levels showed a downward trend over time and with the passage of time. Conversely, there were no significant changes in incidence and mortality in countries and regions with low SDI levels. In the past 30 years, the incidence and death of esophageal cancer in the world has gradually changed to people over 80 years old, but the population aged 60-79 still accounts for the largest proportion. The global DALY in esophageal cancer is mainly attributable to smoking, followed by alcohol consumption and occupational exposure. CONCLUSIONS: Although ASIR, ASMR and ASDR have decreased significantly, esophageal cancer is still the main factor causing the disease burden worldwide. Public health administrators in low SDI and low-middle SDI countries are high-risk areas for esophageal cancer, and preventive control measures should be implemented to raise awareness, screening, and treatment of esophageal cancer in these areas. Tobacco and alcohol control and reduction of occupational hazards are key steps in reducing the burden of esophageal cancer.


Assuntos
Anos de Vida Ajustados por Deficiência , Neoplasias Esofágicas , Humanos , Idoso de 80 Anos ou mais , Incidência , Anos de Vida Ajustados por Qualidade de Vida , Neoplasias Esofágicas/epidemiologia , Carga Global da Doença , Saúde Global , Estudos de Coortes
6.
Anim Biotechnol ; 35(1): 2349625, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-38733367

RESUMO

This study aimed to evaluate the genetic diversity and structure within the Dengchuan cattle population and effectively protect and utilize their germplasm resources. Herein, the single-nucleotide polymorphisms (SNPs) of 100 Dengchuan cattle (46 bulls and 54 cows) were determined using the GGP Bovine 100K SNP Beadchip. The results showed that among the Dengchuan cattle, a total of 101,220 SNPs were detected, and there were 83,534 SNPs that passed quality control, of which 85.7% were polymorphic. The average genetic distance based on identity-by-state (IBS) within the conservation population of Dengchuan cattle was 0.26 ± 0.02. A total of 3,999 genome-length runs of homozygosity (ROHs) were detected in the Dengchuan cattle, with ROH lengths primarily concentrated in the range of 1-5 Mb, accounting for 87.02% of the total. The average inbreeding coefficient based on ROHs was 4.6%, within the conservation population of Dengchuan cattle, whereas it was 4.9% for bulls, and the Wright inbreeding coefficient (FIS) value was 2.4%, demonstrating a low level of inbreeding within the Dengchuan cattle population. Based on neighbor-joining tree analysis, the Dengchuan cattle could be divided into 16 families. In summary, the conservation population of Dengchuan cattle displays relatively abundant diversity and a moderate genetic relationship. Inbreeding was observed among a few individuals, but the overall inbreeding level of the population remained low. It is important to maintain this low level of inbreeding when introducing purebred bloodlines to expand the core group. This approach will ensure the long-term conservation of Dengchuan cattle germplasm resources and prevent loss of genetic diversity.


Assuntos
Polimorfismo de Nucleotídeo Único , Animais , Bovinos/genética , Polimorfismo de Nucleotídeo Único/genética , Variação Genética , Espécies em Perigo de Extinção , Masculino , Endogamia , Feminino , Genética Populacional , China
7.
J Dairy Sci ; 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38490542

RESUMO

The development of new drug therapies for Alzheimer's disease (AD) is an important research topic today, but the pathogenesis of AD has not been thoroughly studied, and there are still several shortcomings in existing drug therapies. Therefore, this study aims to explore the molecular mechanism of lactoferrin in the treatments of AD and ulcerative colitis (UC) which are susceptible to AD, starting from the principle of "one drug, two diseases, and the same treatment." This study used pathological staining and specific indicators staining to preliminarily evaluate the interventions of lactoferrin on UC injury and AD progression. And 16s RNA full-length sequencing was used to investigate the effect of lactoferrin on the abundance of intestinal microbiota in AD mice. Then, intestinal tissue and brain tissue metabolomics analysis were used to screen specific metabolic pathways and preliminarily verify the metabolic mechanism of lactoferrin in alleviating 2 diseases by regulating certain specific metabolites. Moreover, lactoferrin significantly changed the types and abundance of gut microbiota in AD mice complicated by UC. To conclude, this study proved the clinical phenomenon of AD susceptibility to UC, and verified the therapeutic effect of lactoferrin on 2 diseases. More importantly, we revealed the possible molecular mechanism of LF, not only does it enrich the cognitive level of lactoferrin in alleviating AD by regulating the gut microbiota through the brain gut axis from the perspective of the theory of "food nutrition promoting human health," but it also provides a practical basis for the subsequent research and development of lactoferrin and drug validation from the perspective of "drug food homology."

8.
BMC Genomics ; 24(1): 282, 2023 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-37231368

RESUMO

BACKGROUND: The genus Acidithiobacillus has been widely concerned due to its superior survival and oxidation ability in acid mine drainage (AMD). However, the contribution of insertion sequence (IS) to their biological evolution and environmental adaptation is very limited. ISs are the simplest kinds of mobile genetic elements (MGEs), capable of interrupting genes, operons, or regulating the expression of genes through transposition activity. ISs could be classified into different families with their own members, possessing different copies. RESULTS: In this study, the distribution and evolution of ISs, as well as the functions of the genes around ISs in 36 Acidithiobacillus genomes, were analyzed. The results showed that 248 members belonging to 23 IS families with a total of 10,652 copies were identified within the target genomes. The IS families and copy numbers among each species were significantly different, indicating that the IS distribution of Acidithiobacillus were not even. A. ferrooxidans had 166 IS members, which may develop more gene transposition strategies compared with other Acidithiobacillus spp. What's more, A. thiooxidans harbored the most IS copies, suggesting that their ISs were the most active and more likely to transpose. The ISs clustered in the phylogenetic tree approximately according to the family, which were mostly different from the evolutionary trends of their host genomes. Thus, it was suggested that the recent activity of ISs of Acidithiobacillus was not only determined by their genetic characteristics, but related with the environmental pressure. In addition, many ISs especially Tn3 and IS110 families were inserted around the regions whose functions were As/Hg/Cu/Co/Zn/Cd translocation and sulfur oxidation, implying that ISs could improve the adaptive capacities of Acidithiobacillus to the extremely acidic environment by enhancing their resistance to heavy metals and utilization of sulfur. CONCLUSIONS: This study provided the genomic evidence for the contribution of IS to evolution and adaptation of Acidithiobacillus, opening novel sights into the genome plasticity of those acidophiles.


Assuntos
Acidithiobacillus , Metais Pesados , Humanos , Elementos de DNA Transponíveis/genética , Filogenia , Enxofre/metabolismo
9.
Small ; 19(12): e2206461, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36587969

RESUMO

Structurally-colored photonic hydrogels which are fabricated by introducing hydrogels into thin films or photonic crystal structures are promising candidates for biosensing. Generally, the design of photonic hydrogel biosensors is based on the sensor-analyte interactions induced charge variation within the hydrogel matrix, or chemically grafting binding sites onto the polymer chains, to achieve significant volume change and color variation of the photonic hydrogel. However, relatively low anti-interference capability or complicated synthesis hinder the facile and low-cost fabrication of high-performance photonic hydrogel biosensors. Here, a facilely prepared supramolecular photonic hydrogel biosensor is developed for high-sensitivity detection of alkaline phosphatase (ALP), which is an extensively considered clinical biomarker for a variety of diseases. Responding to ALP results in the broken supramolecular crosslinking and thus increased lattice distancing of the photonic hydrogel driven by synergistic repulsive force between nanoparticles embedded in photonic crystal structure and osmotic swelling pressure. The biosensor shows sensitivity of 7.3 nm spectral shift per mU mL-1 ALP, with detection limit of 0.52 mU mL-1 . High-accuracy colorimetric detection can be realized via a smartphone, promoting point-of-care sensing and timely diagnosis of related pathological conditions.


Assuntos
Técnicas Biossensoriais , Hidrogéis , Hidrogéis/química , Fosfatase Alcalina , Polímeros/química , Pressão Osmótica , Técnicas Biossensoriais/métodos
10.
Biol Chem ; 404(6): 585-599, 2023 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-36420535

RESUMO

The dysregulation of the translation elongation factor families which are responsible for reprogramming of mRNA translation has been shown to contribute to tumor progression. Here, we report that the acetylation of eukaryotic Elongation Factor 1 Alpha 1 (eEF1A1/EF1A1) is required for genotoxic stress response and maintaining the malignancy of colorectal cancer (CRC) cells. The evolutionarily conserved site K439 is identified as the key acetylation site. Tissue expression analysis demonstrates that the acetylation level of eEF1A1 K439 is higher than paired normal tissues. Most importantly, hyperacetylation of eEF1A1 at K439 negatively correlates with CRC patient survival. Mechanistically, CBP and SIRT1 are the major acetyltransferase and deacetylase of eEF1A1. Hyperacetylation of eEF1A1 at K439 shows a significant tumor-promoting effect by increasing the capacity of proliferation, migration, and invasion of CRC cells. Our findings identify the altered post-translational modification at the translation machines as a critical factor in stress response and susceptibility to colorectal carcinogenesis.


Assuntos
Neoplasias Colorretais , Fator 1 de Elongação de Peptídeos , Humanos , Fator 1 de Elongação de Peptídeos/genética , Fator 1 de Elongação de Peptídeos/metabolismo , Acetilação , Processamento de Proteína Pós-Traducional , Carcinogênese
11.
J Transl Med ; 21(1): 156, 2023 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-36855062

RESUMO

BACKGROUND: Although the relationship between type 2 diabetes (T2D) and the increased risk of colorectal carcinogenesis is widely defined in clinical studies, the therapeutic methods and molecular mechanism of T2D-induced colon cancer and how does hyperglycemia affect the progression is still unknown. Here, we studied the function of lactoferrin (LF) in suppressing the progression of colon cancer in T2D mice, and uncovered the related molecular mechanisms in DNA 5mC and RNA m6A levels. METHODS: We examined the effects of LF (50% iron saturation) on the migration and invasion of colon tumor cells under high concentration of glucose. Then, transcriptomics and DNA methylation profilings of colon tumor cells was co-analyzed to screen out the special gene (NT5DC3), and the expression level of NT5DC3 in 75 clinical blood samples was detected by q-PCR and western blot, to investigate whether NT5DC3 was a biomarker to distinguish T2D patients and T2D-induced colon cancer patients from healthy volunteers. Futhermore, in T2D mouse with xenografted colon tumor models, the inhibitory effects of LF and NT5DC3 protein on colon tumors were investigated. In addition, epigenetic alterations were measured to examine the 5mC/m6A modification sites of NT5DC3 regulated by LF. Utilizing siRNA fragments of eight m6A-related genes, the special gene (WTAP) regulating m6A of NT5DC was proved, and the effect of LF on WTAP/NT5DC3/HKDC1 axis was finally evaluated. RESULTS: A special gene NT5DC3 was screened out through co-analysis of transcriptomics and DNA methylation profiling, and HKDC1 might be a downstream sensor of NT5DC3. Mechanistically, LF-dependent cellular DNA 5mC and RNA m6A profiling remodeling transcriptionally regulate NT5DC3 expression. WTAP plays a key role in regulating NT5DC3 m6A modification and subsequently controls NT5DC3 downstream target HKDC1 expression. Moreover, co-treatment of lactoferrin and NT5DC3 protein restrains the growth of colon tumors by altering the aberrant epigenetic markers. Strikingly, clinical blood samples analysis demonstrates NT5DC3 protein expression is required to direct the distinction of T2D or T2D-induced colon cancer with healthy humans. CONCLUSIONS: Together, this study reveals that lactoferrin acts as a major factor to repress the progression of colon cancer under hyperglycemia, thus, significantly expanding the landscape of natural dietary mediated tumor suppression.


Assuntos
Neoplasias do Colo , Diabetes Mellitus Tipo 2 , Hiperglicemia , Humanos , Animais , Camundongos , Lactoferrina/genética , Neoplasias do Colo/genética , Hiperglicemia/complicações , Hiperglicemia/genética , Modelos Animais de Doenças , Fatores de Processamento de RNA , Proteínas de Ciclo Celular , Hexoquinase
12.
Virol J ; 20(1): 135, 2023 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-37349792

RESUMO

OBJECTIVE: To isolate a prevalent G9P[8] group A rotavirus (RVA) (N4006) in China and investigate its genomic and evolutionary characteristics, with the goal of facilitating the development of a new rotavirus vaccine. METHODS: The RVA G9P[8] genotype from a diarrhea sample was passaged in MA104 cells. The virus was evaluated by TEM, polyacrylamide gel electrophoresis, and indirect immunofluorescence assay. The complete genome of virus was obtained by RT-PCR and sequencing. The genomic and evolutionary characteristics of the virus were evaluated by nucleic acid sequence analysis with MEGA ver. 5.0.5 and DNASTAR software. The neutralizing epitopes of VP7 and VP4 (VP5* and VP8*) were analyzed using BioEdit ver. 7.0.9.0 and PyMOL ver. 2.5.2. RESULTS: The RVA N4006 (G9P[8] genotype) was adapted in MA104 cells with a high titer (105.5 PFU/mL). Whole-genome sequence analysis showed N4006 to be a reassortant rotavirus of Wa-like G9P[8] RVA and the NSP4 gene of DS-1-like G2P[4] RVA, with the genotype constellation G9-P[8]-I1-R1-C1-M1-A1-N1-T1-E2-H1 (G9P[8]-E2). Phylogenetic analysis indicated that N4006 had a common ancestor with Japanese G9P[8]-E2 rotavirus. Neutralizing epitope analysis showed that VP7, VP5*, and VP8* of N4006 had low homology with vaccine viruses of the same genotype and marked differences with vaccine viruses of other genotypes. CONCLUSION: The RVA G9P[8] genotype with the G9-P[8]-I1-R1-C1-M1-A1-N1-T1-E2-H1 (G9P[8]-E2) constellation predominates in China and may originate from reassortment between Japanese G9P[8] with Japanese DS-1-like G2P[4] rotaviruses. The antigenic variation of N4006 with the vaccine virus necessitates an evaluation of the effect of the rotavirus vaccine on G9P[8]-E2 genotype rotavirus.


Assuntos
Infecções por Rotavirus , Vacinas contra Rotavirus , Rotavirus , Humanos , Infecções por Rotavirus/epidemiologia , Filogenia , Genoma Viral , Genômica , Genótipo
13.
Gastric Cancer ; 26(6): 863-877, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37344705

RESUMO

BACKGROUND: It is vital to screen or develop alternative therapeutic drugs with higher curative characteristics and fewer side effects for the clinical treatment of gastric cancer. METHODS: Gastric cancer cells were exposed to different auramycin G doses while determining the impact on cell viability, migration, and invasion. Then the antitumor effects of auramycin G, 5-fluorouracil (5-Fu) and their combination were evaluated. Furthermore, the molecular mechanisms of angiogenesis and lymphangiogenesis regulated by auramycin G and its analogs were investigated. RESULTS: Auramycin G inhibited cell viability in a dose-dependent manner, with a 50% inhibitory concentration of 23.72 ± 6.36 mg/L and 32.54 ± 5.91 mg/L for AGS and MGC803 cells, respectively. The migration and invasion of gastric cancer cells were significantly inhibited by 10 mg/L auramycin G, which was consistent with the down-regulation of the VEGFR2-VEGFA-pPI3K-pAkt-pErk1 and VEGFR3-VEGFC-pPI3K-pAkt-pmTOR proteins. Notably, the average tumor weights were significantly reduced in both the auramycin G (2.21 ± 0.45 g) of 50 mg/kg body weight and auramycin G + 5-fluorouracil (5-Fu) groups (1.33 ± 0.28 g), compared with the control (3.73 ± 0.56 g). Considering that auramycin G decreased the growth of blood and lymphatic vessels while reducing the degree of tumor malignancy, it effectively suppressed tumors by regulating the angiogenic and lymphangiogenic pathways. CONCLUSION: The present study confirmed that auramycin G displayed a prominent antitumor activity in gastric tumor models, both in vitro and in vivo. Moreover, it was confirmed that auramycin G played a specific role in certain gastric cancer cell types, while the mechanism was validated to be associated with angiogenesis- and lymphangiogenesis-related pathway suppression.


Assuntos
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patologia , Linfangiogênese , Linhagem Celular Tumoral , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Antraciclinas
14.
BMC Geriatr ; 23(1): 360, 2023 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-37296410

RESUMO

BACKGROUND: The allostatic load (AL) refers to the cumulative weakening of multiple physiological systems caused by repeated adaptation of the body to stressors There are still no studies have focused on the association between AL and the prognosis of patients with heart failure with preserved ejection fraction (HFpEF). The present study aimed to investigate the association between AL and adverse outcomes, including mortality and HF admission, among elderly male patients with HFpEF. METHODS: We conducted a prospective cohort study of 1111 elderly male patients with HFpEF, diagnosed between 2015 and 2019 and followed up through 2021. We constructed an AL measure using a combination of 12 biomarkers. The diagnosis of HFpEF was made according to the 2021 European Society of Cardiology guidelines. A Cox proportional hazards model was used to determine the associations between AL and adverse outcomes. RESULTS: In multivariate analysis, AL was significantly associated with increased risk of all-cause mortality (medium AL: adjusted hazard ratio [HR] = 2.53; 95% confidence interval [CI] 1.37-4.68; high AL: HR = 4.21; 95% CI 2.27-7.83; per-score increase: HR = 1.31; 95% CI 1.18-1.46), cardiovascular mortality (medium AL: HR = 2.67; 95% CI 1.07-6.68; high AL: HR = 3.13; 95% CI 1.23-7.97; per-score increase: HR = 1.20; 95% CI 1.03-1.40), non-cardiovascular mortality (medium AL: HR = 2.45; 95% CI 1.06-5.63; high AL: HR = 5.81; 95% CI 2.55-10.28; per-score increase: HR = 1.46; 95% CI 1.26-1.69), and HF admission (medium AL: HR = 2.68; 95% CI 1.43-5.01; high AL: HR = 3.24; 95% CI 1.69-6.23; per-score increase: HR = 1.24; 95% CI 1.11-1.39). Consistent results were found in multiple subgroup analyses. CONCLUSIONS: A higher AL was associated with poor prognosis in elderly men with HFpEF. AL relies on information that is easily obtained in physical examinations and laboratory parameters and can be assessed in various care and clinical settings to help risk stratification of HFpEF patients.


Assuntos
Alostase , Insuficiência Cardíaca , Humanos , Masculino , Idoso , Insuficiência Cardíaca/diagnóstico , Volume Sistólico/fisiologia , Estudos Prospectivos , Prognóstico
15.
Proc Natl Acad Sci U S A ; 117(52): 33426-33435, 2020 12 29.
Artigo em Inglês | MEDLINE | ID: mdl-33318209

RESUMO

Precise genetic engineering in specific cell types within an intact organism is intriguing yet challenging, especially in a spatiotemporal manner without the interference caused by chemical inducers. Here we engineered a photoactivatable Dre recombinase based on the identification of an optimal split site and demonstrated that it efficiently regulated transgene expression in mouse tissues spatiotemporally upon blue light illumination. Moreover, through a double-floxed inverted open reading frame strategy, we developed a Cre-activated light-inducible Dre (CALID) system. Taking advantage of well-defined cell-type-specific promoters or a well-established Cre transgenic mouse strain, we demonstrated that the CALID system was able to activate endogenous reporter expression for either bulk or sparse labeling of CaMKIIα-positive excitatory neurons and parvalbumin interneurons in the brain. This flexible and tunable system could be a powerful tool for the dissection and modulation of developmental and genetic complexity in a wide range of biological systems.


Assuntos
Proteínas de Escherichia coli/metabolismo , Engenharia Genética , Genoma , Luz , Recombinases/metabolismo , Animais , Encéfalo/metabolismo , Dependovirus/metabolismo , Expressão Gênica , Genes Reporter , Vetores Genéticos/metabolismo , Células HEK293 , Humanos , Integrases/metabolismo , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/metabolismo , Fatores de Tempo
16.
Ecotoxicol Environ Saf ; 262: 115186, 2023 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-37393821

RESUMO

Rotenone, an insecticide that inhibits mitochondrial complex I and generates oxidative stress, is responsible for neurological disorders and affects the female reproductive system. However, the underlying mechanism is not fully understood. Melatonin, a potential free-radical scavenger, has been shown to protect the reproductive system from oxidative damage. In this study, we investigated the impact of rotenone on mouse oocyte quality and evaluated the protective effect of melatonin on oocytes exposed to rotenone. Our results showed that rotenone impaired mouse oocyte maturation and early embryo cleavage. However, melatonin prevented these negative effects by ameliorating rotenone-induced mitochondrial dysfunction and dynamic imbalance, intracellular Ca2+ homeostasis damage, ER stress, early apoptosis, meiotic spindle formation disruption, and aneuploidy in oocytes. Additionally, RNA sequencing analysis showed that rotenone exposure changed the expression of multiple genes involved in histone methylation and acetylation modifications that result in mouse meiotic defects. However, melatonin partially rescued these defects. These findings suggest that melatonin has protective effects against rotenone-induced mouse oocyte defects.

17.
Ecotoxicol Environ Saf ; 255: 114725, 2023 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-36924558

RESUMO

Tributyltin chloride (TBTCL) is a widely used fungicide and heat stabilizer in compositions of PVC. TBTCL has been detected in human bodies and potentially causes harmful effects on humans' thyroid, cardiovascular and other organs. As one of the first examples of endocrine disruptors, the toxicity effects of TBTCL on the male reproduction system have aroused concerns. However, the potential cellular mechanisms are not fully explored. In the current study, by using Sertoli cells, a critical regulator of spermatogenesis as a cell model, we showed that with 200 nM exposure for 24 h, TBTCL causes apoptosis and cell cycle arrest. RNA sequencing analyses suggested that TBTCL probably activates endoplasmic reticulum (ER) stress, and disrupts autophagy. Biochemical analysis showed that TBTCL indeed induces ER stress and the dysregulation of autophagy. Interestingly, activation of ER stress and inhibition of autophagy is responsible for TBTCL-induced apoptosis and cell cycle arrest. Our results thus uncovered a novel insight into the cellular mechanisms for TBTCL-induced toxicology in Sertoli cells.


Assuntos
Células de Sertoli , Compostos de Trialquitina , Masculino , Humanos , Compostos de Trialquitina/toxicidade , Glândula Tireoide , Espermatogênese , Apoptose , Estresse do Retículo Endoplasmático , Autofagia
18.
Int J Mol Sci ; 24(2)2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36674819

RESUMO

Salmonella Typhimurium is a Gram-negative intestinal pathogen that can infect humans and a variety of animals, causing gastroenteritis or serious systemic infection. Replication within host macrophages is essential for S. Typhimurium to cause systemic infection. By analyzing transcriptome data, the expression of yhjC gene, which encodes a putative regulator in S. Typhimurium, was found to be significantly up-regulated after the internalization of Salmonella by macrophages. Whether yhjC gene is involved in S. Typhimurium systemic infection and the related mechanisms were investigated in this study. The deletion of yhjC reduced the replication ability of S. Typhimurium in macrophages and decreased the colonization of S. Typhimurium in mouse systemic organs (liver and spleen), while increasing the survival rate of the infected mice, suggesting that YhjC protein promotes systemic infection by S. Typhimurium. Furthermore, by using transcriptome sequencing and RT-qPCR assay, the transcription of several virulence genes, including spvD, iroCDE and zraP, was found to be down-regulated after the deletion of yhjC. Electrophoretic mobility shift assay showed that YhjC protein can directly bind to the promoter region of spvD and zraP to promote their transcription. These findings suggest that YhjC contributes to the systemic virulence of S. Typhimurium via the regulation of multiple virulence genes and YhjC could represent a promising target to control S. Typhimurium infection.


Assuntos
Salmonelose Animal , Salmonella typhimurium , Fatores de Virulência , Animais , Humanos , Camundongos , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Salmonella typhimurium/metabolismo , Fatores de Transcrição/metabolismo , Virulência/genética , Fatores de Virulência/genética
19.
J Environ Manage ; 340: 117929, 2023 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-37086561

RESUMO

As an important means to address global climate change and land-use/land-cover (LULC) change, ecological restoration projects (ERPs) have a large effect on carbon storage functions and eco-environmental quality. However, the various ERPs carried out in the Yellow River Delta region have important implications for ecological security strategies in China. Therefore, based on land-use data and remote sensing image data, with the help of ArcGIS and Google Earth Engine (GEE) platforms, this study uses the Integrated Valuation of Ecosystem Services and Trade-offs (InVEST) model, an improved remote sensing ecological index (RSEI) model and other methods to deeply examine the evolutionary trends of eco-environmental quality and carbon storage during the implementation of ERPs in the Yellow River Delta and selects key implementation areas for in-depth analysis to determine the implementation effects of ERPs. Our findings suggested that the RSEI and carbon storage levels in the study area had opposite evolutionary trends from 2001 to 2020. Among them, the RSEI showed a fluctuating upwards trend (0.4461 (2001) and 0.5185 (2020)), while the total carbon stock showed a fluctuating downwards trend (30.67 Tg (2001) and 26.40 Tg (2020)). However, from 2015 to 2020, the RSEI and carbon storage were at a relatively stable level, which indirectly indicated that the ERPs carried out during the period from 2015 to 2020 had achieved a good comprehensive implementation effect. In addition, the areas with better improvement effects from 2015 to 2020 were primarily located in the mouth of the Yellow River Delta (Areas C and D), and their RSEI and the total carbon stock showed a certain upwards trend. This research can promote the formulation of the management strategy of ERPs in the Yellow River Delta, which is of tremendous importance to the ecological environmental preservation and high-quality development of the Yellow River Basin.


Assuntos
Ecossistema , Monitoramento Ambiental , Carbono , Tecnologia de Sensoriamento Remoto , China , Conservação dos Recursos Naturais
20.
J Environ Manage ; 344: 118416, 2023 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-37331315

RESUMO

Knowledge on relationship and determinants of water and carbon dioxide (CO2) exchange is crucial to land managers and policy makers especially for the desertified land restoration. However, there remains highly uncertain in terms of water use and carbon sequestration for artificial plantation in desert. Here, continuous water and carbon fluxes were measured using eddy covariance (EC) in conjunction with hydrometeorological measurements over an artificial C4 shrub, Haloxylon ammodendron (C. A. Mey.) Bunge, from July 2020 to 2021 in Tengger Desert, China. Throughout 2021, evapotranspiration (ET) was 189.5 mm, of which 85% (150 mm) occurred during growing season, that was comparable with the summation of precipitation (132.2 mm), dew (33.5 mm) and potential other sources (e.g. deep subsoil water). This ecosystem was a strong carbon sink with net ecosystem production (NEP) up to 446.4 g C m-2 yr-1, much higher than surrounding sites. Gross primary production (GPP, 598.7 g C m-2 yr-1) in this shrubland was comparable with that of other shrublands, whereas ecosystem respiration (Re, 152.3 g C m-2 yr-1) was lower. Random Forest showed that environmental factors can explain 71.56% and 80.07% variation of GPP and ET, respectively. Interestingly, environmental factors have divergent effect on water and carbon exchange, i.e., soil hydrothermic factors (soil moisture content and soil temperature) determine the magnitude and seasonal pattern of ET and Re, while aerodynamics factors (net radiation, atmospheric temperature and wind speed) determine GPP and NEP. As such, divergent response of abiotic factors resulted in the decoupling of water and carbon exchange. Our results suggest that H. ammodendron is a suitable species for large-scale afforestation in dryland given its low water use but high carbon sequestration. Therefore, we infer that artificial planting H. ammodendron in dryland could provide an opportunity for climate change mitigation, and the long-term time series data is needed to confirm its sustainable role of carbon sequestration in the future.


Assuntos
Ecossistema , Água , Ciclo do Carbono , Sequestro de Carbono , Solo , Estações do Ano , Dióxido de Carbono/análise
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