RESUMEN
BACKGROUND: The mitochondria and endoplasmic reticulum (ER) communicate via contact sites known as mitochondria associated membranes (MAMs). Many important cellular functions such as bioenergetics, mitophagy, apoptosis, and calcium signaling are regulated by MAMs, which are thought to be closely related to ischemic reperfusion injury (IRI). However, there exists a gap in systematic proteomic research addressing the relationship between these cellular processes. METHODS: A 4D label free mass spectrometry-based proteomic analysis of mitochondria associated membranes (MAMs) from the human renal proximal tubular epithelial cell line (HK-2 cells) was conducted under both normal (N) and hypoxia/reperfusion (HR) conditions. Subsequent differential proteins analysis aimed to characterize disease-relevant signaling molecules. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was applied to total proteins and differentially expressed proteins, encompassing Biological Process (BP), Cell Component (CC), Molecular Function (MF), and KEGG pathways. Further, Protein-Protein Interaction Network (PPI) exploration was carried out, leading to the identification of hub genes from differentially expressed proteins. Notably, Mitofusion 2 (MFN2) and BCL2/Adenovirus E1B 19-kDa interacting protein 3(BNIP3) were identified and subsequently validated both in vitro and in vivo. Finally, the impact of MFN2 on MAMs during hypoxia/reoxygenation was explored through regulation of gene expression. Subsequently, a comparative proteomics analysis was conducted between OE-MFN2 and normal HK-2 cells, providing further insights into the underlying mechanisms. RESULTS: A total of 4489 proteins were identified, with 3531 successfully quantified. GO/KEGG analysis revealed that MAM proteins were primarily associated with mitochondrial function and energy metabolism. Differential analysis between the two groups showed that 688 proteins in HR HK-2 cells exhibited significant changes in expression level with P-value < 0.05 and HR/N > 1.5 or HR/N < 0.66 set as the threshold criteria. Enrichment analysis of differentially expressed proteins unveiled biological processes such as mRNA splicing, apoptosis regulation, and cell division, while molecular functions were predominantly associated with energy metabolic activity. These proteins play key roles in the cellular responses during HR, offering insights into the IRI mechanisms and potential therapeutic targets. The validation of hub genes MFN2 and BNIP3 both in vitro and vivo was consistent with the proteomic findings. MFN2 demonstrated a protective role in maintaining the integrity of mitochondria associated membranes (MAMs) and mitigating mitochondrial damage following hypoxia/reoxygenation injury, this protective effect may be associated with the activation of the PI3K/AKT pathway. CONCLUSIONS: The proteins located in mitochondria associated membranes (MAMs) are implicated in crucial roles during renal ischemic reperfusion injury (IRI), with MFN2 playing a pivotal regulatory role in this context.
Asunto(s)
Membranas Asociadas a Mitocondrias , Daño por Reperfusión , Humanos , Fosfatidilinositol 3-Quinasas , Proteómica , HipoxiaRESUMEN
OBJECTIVES: To explore the relationship between different types of physical activity and female infertility. METHODS: This study analyzed data from 2,796 female participants aged 18-44 years in the United States, obtained from the National Health and Nutrition Examination Survey (NHANES) database spanning the years 2013 to 2020. Multiple logistic regression analyses and generalized linear models were used to explore the relationship between different types of physical activity and infertility after adjusting for potential confounding factors. RESULTS: We found a non-linear relationship between recreational activities and infertility with an inflection point of 5.83 h/week (moderate intensity), while work activities and traffic-related activities did not. On the left side of the inflection point, there was no significant association between recreational activity time and infertility (OR = 0.93, 95% CI: 0.86 to 1.02, P = 0.1146), but on the right side of the inflection point, there was a positive association between recreational activity time and the risk of infertility (OR = 1.04, 95% CI: 1.02 to 1.06, P = 0.0008). CONCLUSIONS: The relationship between different types of physical activity and female infertility varies. We acknowledge the potential influence of confounding variables on this relationship. However, we have already adjusted for these potential variables in our analysis. Therefore, our findings suggest that appropriate recreational activity programs are essential for promoting reproductive health in women of reproductive age. Nevertheless, it is important to note that the observed association does not imply causality. Given the limitations of cross-sectional studies, further prospective cohort studies are needed to explore the causal relationship while accounting for additional confounding factors.
Asunto(s)
Ejercicio Físico , Infertilidad Femenina , Encuestas Nutricionales , Humanos , Femenino , Adulto , Infertilidad Femenina/epidemiología , Infertilidad Femenina/etiología , Ejercicio Físico/fisiología , Adulto Joven , Adolescente , Estados Unidos/epidemiología , Estudios TransversalesRESUMEN
The practical application of lithium-sulfur batteries with high theoretical energy density and readily available cathode active materials is hampered by problems such as sulfur insulation, dramatic volume changes, and polysulfide shuttling. The targeted development of novel binders is the most industrialized solution to the problem of sulfur cathodes. Herein, an aqueous conductive emulsion binder with the sulfonate-containing hard elastic copolymer core and the conjugate polymer shell, which is capable of forming a bicontinuous mesoscopic interpenetrating polymer network, is synthesized and investigated. Not only can the elastic skeleton formed by the copolymer bind the active substance under drastic volume changes, but also the rich ester and cyanide groups in it can effectively capture lithium polysulfide. Meanwhile, the conducting skeleton consisting of poly(3,4-ethylenedioxythiophene) both provides the additional charge conduction pathways and acts as the redox intermediates, significantly accelerating the kinetic process of lithium polysulfide conversion. Based on the synergistic effect of the above mechanisms, the use of the prepared binder on the sulfur carbon cathode significantly improves the rate performance and cycle stability of lithium sulfur batteries.
RESUMEN
Legionella pneumophila aspartate aminotransferase (Lpg0070) is a member of the transaminase and belongs to the pyridoxal 5'-phosphate (PLP)-dependent superfamily. It is responsible for the transfer of α-amino between aspartate and α-ketoglutarate to form glutamate and oxaloacetate. Here, we report the crystal structure of Lpg0070 at the resolution of 2.14 Å and 1.7 Å, in apo-form and PLP-bound, respectively. Our structural analysis revealed the specific residues involved in the PLP binding and free form against PLP-bound supported conformational changes before substrate recognition. In vitro enzyme activity proves that the absence of the N-terminal arm reduces the enzyme activity of Lpg0070. These data provide further evidence to support the N-terminal arm plays a crucial role in catalytic activity.
Asunto(s)
Legionella pneumophila , Aspartato Aminotransferasas/metabolismo , Legionella pneumophila/metabolismo , Sitios de Unión , Modelos Moleculares , Fosfato de Piridoxal/metabolismo , Ácido Glutámico/metabolismo , Cristalografía por Rayos XRESUMEN
The downregulation of adhesion molecule catenin alpha-like 1 (CTNNAL1) in airway epithelial cells of asthma patients and house dust mite (HDM)-induced asthma animal models was illustrated in our previous study. It is assumed to contribute to airway inflammation and mucus hypersecretion. In this work, we further explore the underlying mechanism of CTNNAL1 in asthma. CTNNAL1-silenced female mice exhibit a decreased level of cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated and ATP-gated Cl - channel that correlates with mucus hypersecretion. Our previous study demonstrated that ROCK1 expression decreases but ROCK2 expression increases in the lungs of a CTNNAL1-silenced mouse model. Inhibition of ROCK1 leads to a reduction in CFTR expression in CTNNAL1-overexpressing and CTNNAL1-silenced human bronchial epithelial (HBE) cells. It has been reported that ROCK1 is a downstream target of RhoA and that activation of RhoA increases CFTR expression after CTNNAL1 deficiency in vitro and in vivo. The above results indicate that CTNNAL1 regulates CFTR expression through the ROCK1 pathway. In addition, the expression of CFTR-associated ligand (CAL) is increased after CTNNAL1 silencing, and immunoprecipitation results confirm the interaction between ROCK1 and CAL. Inhibition of CAL does not influence ROCK1 expression but increases CFTR expression in CTNNAL1-silenced HBE cells. These data suggest that CTNNAL1 deficiency decreases CFTR expression in the HDM-induced asthma mouse model through the ROCK1-CAL signaling pathway.
Asunto(s)
Asma , Regulador de Conductancia de Transmembrana de Fibrosis Quística , Animales , Femenino , Humanos , Ratones , alfa Catenina/metabolismo , Asma/inducido químicamente , Asma/genética , Asma/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Modelos Animales de Enfermedad , Células Epiteliales/metabolismo , Pyroglyphidae/metabolismo , Quinasas Asociadas a rho/genética , Quinasas Asociadas a rho/metabolismo , Transducción de SeñalRESUMEN
Mycobacterium tuberculosis (Mtb) remains the deadliest pathogenic bacteria worldwide. The search for new antibiotics to treat drug-sensitive as well as drug-resistant tuberculosis has become a priority. The essential enzyme phenylalanyl-tRNA synthetase (PheRS) is an antibacterial drug target because of the large differences between bacterial and human PheRS counterparts. In a high-throughput screening of 2148 bioactive compounds, PF-3845, which is a known inhibitor of human fatty acid amide hydrolase, was identified inhibiting Mtb PheRS at Ki â¼ 0.73 ± 0.06 µM. The inhibition mechanism was studied with enzyme kinetics, protein structural modeling, and crystallography, in comparison to a PheRS inhibitor of the noted phenyl-thiazolylurea-sulfonamide class. The 2.3-Å crystal structure of Mtb PheRS in complex with PF-3845 revealed its novel binding mode, in which a trifluoromethyl-pyridinylphenyl group occupies the phenylalanine pocket, whereas a piperidine-piperazine urea group binds into the ATP pocket through an interaction network enforced by a sulfate ion. It represents the first non-nucleoside bisubstrate competitive inhibitor of bacterial PheRS. PF-3845 inhibits the in vitro growth of Mtb H37Rv at â¼24 µM, and the potency of PF-3845 increased against an engineered strain Mtb pheS-FDAS, suggesting on target activity in mycobacterial whole cells. PF-3845 does not inhibit human cytoplasmic or mitochondrial PheRS in biochemical assay, which can be explained from the crystal structures. Further medicinal chemistry efforts focused on the piperidine-piperazine urea moiety may result in the identification of a selective antibacterial lead compound.
Asunto(s)
Mycobacterium tuberculosis/enzimología , Fenilalanina-ARNt Ligasa/ultraestructura , Conformación Proteica , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Amidohidrolasas/antagonistas & inhibidores , Amidohidrolasas/química , Secuencia de Aminoácidos/genética , Antibacterianos/química , Sitios de Unión/efectos de los fármacos , Cristalografía por Rayos X , Humanos , Cinética , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/patogenicidad , Fenilalanina-ARNt Ligasa/antagonistas & inhibidores , Fenilalanina-ARNt Ligasa/química , Piperidinas/química , Piperidinas/farmacología , Piridinas/química , Piridinas/farmacología , Tuberculosis Resistente a Múltiples Medicamentos/enzimología , Tuberculosis Resistente a Múltiples Medicamentos/genéticaRESUMEN
Mycobacteria tuberculosis (Mtb) remains the deadliest pathogenic bacteria worldwide. The search for new antibiotics to treat drug-sensitive as well as drug-resistant tuberculosis has become a priority. The essential enzyme phenylalanyl-tRNA synthetase (PheRS) is an antibacterial drug target because of the large differences between bacterial and human PheRS counterparts. In a high-throughput screening of 2148 bioactive compounds, PF-3845, which is a known inhibitor of human fatty acid amide hydrolase (FAAH), was identified inhibiting Mtb PheRS at Ki ~0.73 ± 0.06 µM. The inhibition mechanism was studied with enzyme kinetics, protein structural modelling and crystallography, in comparison to a PheRS inhibitor of the noted phenyl-thiazolylurea-sulfonamide class. The 2.3-Å crystal structure of Mtb PheRS in complex with PF-3845 revealed its novel binding mode, in which a trifluoromethyl-pyridinylphenyl group occupies the Phe pocket while a piperidine-piperazine urea group binds into the ATP pocket through an interaction network enforced by a sulfate ion. It represents the first non-nucleoside bi-substrate competitive inhibitor of bacterial PheRS. PF-3845 inhibits the in vitro growth of Mtb H37Rv at ~24 µM, and the potency of PF-3845 increased against Mtb pheS-FDAS, suggesting on target activity in mycobacterial whole cells. PF-3845 does not inhibit human cytoplasmic or mitochondrial PheRS in biochemical assay, which can be explained from the crystal structures. Further medicinal chemistry efforts focused on the piperidine-piperazine urea moiety may result in the identification of a selective antibacterial lead compound.
RESUMEN
Nucleotide analogs targeting viral RNA polymerase have been proved to be an effective strategy for antiviral treatment and are promising antiviral drugs to combat the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. In this study, we developed a robust in vitro nonradioactive primer extension assay to quantitatively evaluate the efficiency of incorporation of nucleotide analogs by SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). Our results show that many nucleotide analogs can be incorporated into RNA by SARS-CoV-2 RdRp and that the incorporation of some of them leads to chain termination. The discrimination values of nucleotide analogs over those of natural nucleotides were measured to evaluate the incorporation efficiency of nucleotide analog by SARS-CoV-2 RdRp. In agreement with the data published in the literature, we found that the incorporation efficiency of remdesivir-TP is higher than that of ATP and incorporation of remdesivir-TP caused delayed chain termination, which can be overcome by higher concentrations of the next nucleotide to be incorporated. Our data also showed that the delayed chain termination pattern caused by remdesivir-TP incorporation is different for different template sequences. Multiple incorporations of remdesivir-TP caused chain termination under our assay conditions. Incorporation of sofosbuvir-TP is very low, suggesting that sofosbuvir may not be very effective in treating SARS-CoV-2 infection. As a comparison, 2'-C-methyl-GTP can be incorporated into RNA efficiently, and the derivative of 2'-C-methyl-GTP may have therapeutic application in treating SARS-CoV-2 infection. This report provides a simple screening method that should be useful for evaluating nucleotide-based drugs targeting SARS-CoV-2 RdRp and for studying the mechanism of action of selected nucleotide analogs.
Asunto(s)
Antivirales/farmacología , ARN Polimerasa Dependiente de ARN de Coronavirus/genética , Evaluación Preclínica de Medicamentos/métodos , Nucleótidos/farmacología , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/química , Adenosina Monofosfato/genética , Adenosina Monofosfato/farmacología , Alanina/análogos & derivados , Alanina/química , Alanina/genética , Alanina/farmacología , Antivirales/química , ARN Polimerasa Dependiente de ARN de Coronavirus/antagonistas & inhibidores , ARN Polimerasa Dependiente de ARN de Coronavirus/metabolismo , Nucleótidos/química , ARN , ARN Viral/biosíntesis , Proteínas no Estructurales ViralesRESUMEN
OBJECTIVE: To establish the reference value of high sensitive cardiac troponin T (hs-cTnT) and the efficiency of reference value in the diagnosis of chest pain. METHODS: Volunteers from eight independent communities in Chengdu,Sichuan were selected with detailed records of physical examination,electrocardiogram,ultrasound examination. The level of hs-cTnT for healthy volunteers was tested to determine ninety-ninth percentile references according to sex and ages. 2 249 patients with chest pain in the emergency department of Western China Hospital from July 2009 to July 2014 were enrolled to measure the efficiency of reference value for diagnosing acute myocardial infarction (AMI). RESULTS: There were 1 305 volunteers included finally. Among them,the mean hs-cTnT level of male was 4.3 (3.2-5.9) ng/L,which was significantly higher than that of female 3.0 (3.0-3.1) ng/L ( P<0.01) . The correlation coefficient between age and hs-cTnT level was 0.43 (male) and 0.29 (female),and the P-value was less than 0.01. The 99th percentile values of male were 10.8 ng/L,15.4 ng/L and 19.7 ng/L for <45 yr.,45-<60 yr. and ≥60 yr.,respectively. Those values of female were 4.6 ng/L,8.9 ng/L,18.8 ng/L,respectively. There was no difference in sensitivity and specificity between the value we figured out and manufactures provided (14.0 ng/L) for those<60 yr.. For the patients ≥60 yr.,the sensitivity and negative predictive value did not show diversity ( P>0.05) but the specificity and positive predictive value showed significant difference (male: 0.67 vs. 0.56 and 0.83 vs. 0.79, P<0.05;female:0.75 vs. 0.68 and 0.74 vs. 0.69, P<0.05). CONCLUSION: We recommends that the ninety-ninth percentile reference value of patients<60 yr. should be 14.0 ng/L,while 20.0 ng/L for those patients≥60 yr.
Asunto(s)
Dolor en el Pecho/diagnóstico , Infarto del Miocardio/diagnóstico , Troponina T/sangre , Adulto , Biomarcadores/sangre , Dolor en el Pecho/sangre , China , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/sangre , Valores de ReferenciaRESUMEN
BACKGROUND: In clinical work, patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) often have high-sensitivity cardiac troponin T (hs-cTnT) levels that surpass the 99th percentile of the normal reference population, a cutoff used to screen patients for acute myocardial infarction (AMI). However, a large proportion of these patients prove not to have AMI and are frequently misdiagnosed and overtreated. We analyzed whether the cutoff value of hs-cTnT for diagnosing AMI in AECOPD patients should be adjusted. METHODS: This was a prospective study of 873 consecutive patients with AECOPD who presented at the emergency department of West China Hospital of Sichuan University from January 2010 to December 2013. Conventional cardiac troponin (cTnT) was measured in patients' blood samples taken at presentation, and values were compared with their final diagnoses. RESULTS: Among patients with a final diagnosis other than AMI, 64.64% had a plasma hs-cTnT concentration above the 99th percentile of a normal reference population (14 ng/L). The median level of hs-cTnT in AECOPD patients without AMI was 16 ng/L. The area under the receiver-operating characteristic curve (AUC) of hs-cTnT for diagnosis of AMI was 0.92 (0.85 - 0.99, p < 0.001) with a cutoff value of 60.5 ng/L. CONCLUSIONS: The baseline levels of hs-cTnT were relatively high in AECOPD patients, and the optimal cutoff value of hs-cTnT for AMI diagnosis (60.5 ng/L) was also higher than that for non-AECOPD patients.
Asunto(s)
Infarto del Miocardio/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Troponina T/sangre , Anciano , Área Bajo la Curva , Biomarcadores/sangre , China , Errores Diagnósticos , Progresión de la Enfermedad , Servicio de Urgencia en Hospital , Femenino , Humanos , Masculino , Infarto del Miocardio/sangre , Valor Predictivo de las Pruebas , Estudios Prospectivos , Enfermedad Pulmonar Obstructiva Crónica/sangre , Curva ROC , Valores de Referencia , Reproducibilidad de los ResultadosRESUMEN
With the rapid urbanization and aging population, depression has become a severe public health issue globally, affecting millions of individuals and significantly impacting their quality of life and healthcare costs. Urban resilience refers to a city's ability to absorb, recover, and prepare for future shocks, ensuring sustainable development despite challenges. This study aims to explore the impact of urban resilience on depressive symptoms among middle-aged and elderly adults. Using data from the China Health and Retirement Longitudinal Study (CHARLS), we analyzed five dimensions of urban resilience: economic, social, ecological, institutional, and infrastructural resilience. The results of cox proportional hazards model indicate that high levels of urban resilience significantly reduce the risk of depressive symptoms (HR = 0.875, 95% CI: 0.832-0.920, P < 0.001). Specifically, economic resilience (HR = 0.883, 95% CI: 0.846-0.921, P < 0.001), social resilience (HR = 0.916, 95% CI: 0.876-0.958, P < 0.001), ecological resilience (HR = 0.670, 95% CI: 0.516-0.869, P = 0.003), institutional resilience (HR = 0.922, 95% CI: 0.886-0.960, P < 0.001), and infrastructural resilience (HR = 0.875, 95% CI: 0.826-0.926, P < 0.001) all show significant negative correlations with depressive symptoms. Furthermore, the mitigation of depressive symptoms risk resulting from improved urban resilience disproportionately benefits vulnerable groups and those with healthy living habits. These findings provide scientific evidence for urban planning and policy formulation, contributing to the promotion of mental health and healthy aging among middle-aged and elderly populations.
RESUMEN
This study investigated the impacts of various culture temperatures and light regimes on growth and biochemical constituents of Chlamydomonas reinhardtii under carbon-supply and nitrogen-limited conditions to improve oil production in algal cells. Results displayed that under a 30 â and 150 µE/m2/s regime, there was a significant increase in biomass, total lipids, and lipid productivity. Specifically, these parameters reached 1.83 g/L, 36.25 %, and 130.73 mg/L/d, respectively. Remarkably, prolonging the photoperiod further enhanced the aforementioned three parameters, reaching peak levels of 1.92 g/L, 41.10 %, and 157.54 mg/L/d, respectively, recorded at a 24/0h photoperiod. Compared with cultures grown under normal conditions, these values displayed increments of 1.21-fold, 74.88 %, and 3.01-fold, respectively. Additionally, under optimal conditions, the soluble sugar content reached 79.72 mg/g, and the biodiesel properties were improved. These findings indicate that moderately increasing temperature, light intensity, and photoperiod could achieve the co-production of biomass, lipids, and sugars in C. reinhardtii.
Asunto(s)
Chlamydomonas reinhardtii , Microalgas , Lípidos , Temperatura , Biomasa , Carbono , Luz , NitrógenoRESUMEN
S-Adenosyl-l-homocysteine hydrolase (SAHH) is a crucial enzyme that governs S-adenosyl methionine (SAM)-dependent methylation reactions within cells and regulates the intracellular concentration of SAH. Legionella pneumophila, the causative pathogen of Legionnaires' disease, encodes Lpg2021, which is the first identified dimeric SAHH in bacteria and is a promising target for drug development. Here, we report the structure of Lpg2021 in its ligand-free state and in complexes with adenine (ADE), adenosine (ADO), and 3-Deazaneplanocin A (DZNep). X-ray crystallography, isothermal titration calorimetry (ITC), and molecular docking were used to elucidate the binding mechanisms of Lpg2021 to its substrates and inhibitors. Virtual screening was performed to identify potential Lpg2021 inhibitors. This study contributes a novel perspective to the understanding of SAHH evolution and establishes a structural framework for designing specific inhibitors targeting pathogenic Legionella pneumophila SAHH.
Asunto(s)
Adenosilhomocisteinasa , Legionella pneumophila , Simulación del Acoplamiento Molecular , Legionella pneumophila/enzimología , Especificidad por Sustrato , Adenosilhomocisteinasa/metabolismo , Adenosilhomocisteinasa/antagonistas & inhibidores , Adenosilhomocisteinasa/química , Cristalografía por Rayos X , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/química , Adenina/química , Adenina/metabolismo , Adenina/análogos & derivados , Unión Proteica , Proteínas Bacterianas/química , Proteínas Bacterianas/metabolismo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , N-Glicosil HidrolasasRESUMEN
The objective of this meta-analysis is to determine the beneficial effect of recombinant-luteinizing Hormone (r-LH) addition in women undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) with gonadotropin-releasing hormone (GnRH) antagonist protocol and whether an optimal time of Recombinant-Luteinizing Hormone (r-LH) supplementation exist during the controlled of stimulation (COS). The primary outcomes are clinical Pregnancy rate and the number of oocytes retrieved. Secondary outcomes are the number of metaphase II oocytes, miscarriage rate and live birth rate. Results show that supplementation of LH generated a greater number of oocytes retrieved than patients who did not receive LH supplementation, but it did not help with other pregnancy outcomes. Furthermore, the result of the subgroup analysis revealed no significant difference in the outcomes with different LH addition times.
Asunto(s)
Hormona Liberadora de Gonadotropina , Inyecciones de Esperma Intracitoplasmáticas , Embarazo , Humanos , Femenino , Masculino , Inducción de la Ovulación/métodos , Semen , Hormona Luteinizante , Fertilización In Vitro/métodos , Índice de Embarazo , Antagonistas de Hormonas/uso terapéutico , Suplementos Dietéticos , Metaanálisis como Asunto , Revisiones Sistemáticas como AsuntoRESUMEN
Maternal hypercholesterolemia during pregnancy is associated with an increased risk of preterm birth which is defined as <37 weeks of complete gestation. However, the underlying mechanism for the association between hypercholesterolemia and preterm birth is not fully understood. Macrophage, as one of the largest cell types in the placenta, plays a very critical role in mediating inflammation and triggers labor initiation. Here, we hypothesize that macrophages can uptake maternal excessive cholesterol leading to its accumulation, resulting in a breach of the immune tolerance and precipitating labor.
RESUMEN
NAMPT is the rate-limiting enzyme in the NAD salvage pathway, which makes it an attractive target for the treatment of many diseases associated with NAD exhaustion such as neurodegenerative diseases. Herein, we present the systematic optimization of NAT, an initial hit of NAMPT activator discovered by us through high-throughput screening, based on the co-crystal structure of the NAMPT-NAT complex. Over 80 NAT derivatives have been designed and synthesized, among which compound 72 showed notably improved potency as NAMPT activator and effectively protected cultured cells from FK866-mediated toxicity. Moreover, compound 72 exhibited strong neuroprotective efficacy in a mouse model of chemotherapy-induced peripheral neuropathy (CIPN) without any overt toxicity, which renders it a promising candidate for the development of novel neuroprotective agents.
Asunto(s)
NAD , Fármacos Neuroprotectores , Animales , Línea Celular , Citocinas/metabolismo , Modelos Animales de Enfermedad , Ratones , NAD/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Nicotinamida Fosforribosiltransferasa/metabolismoRESUMEN
The speciation of heavy metals was analyzed using modified BCR four-step extraction methods to analyze the pollution of heavy metals in surface sediments collected from the mangrove wetland in Jiulong River Estuary. Subsequently, the pollution degree and the ecological risk of heavy metals were evaluated by using the ratio of secondary phase to primary phase (RSP), risk assessment code (RAC), and modified potential ecological risk index (MRI) assessment methods. The results of BCR four-step extraction showed that Cd (52.55%) and Mn (47.71%) mainly existed in weak-acid extractable fractions. Pb, Y, and Cu mainly existed in reducible and oxidizable fractions. Ba, Tl, V, Th, Cr, As, U, Hg, Ni, Zn, and Co mainly existed in residue fractions. The results of RSP showed that the sediments were heavily polluted by Cd and Mn and moderately polluted by Pb. Cu, Y, and Co were slightly polluted, whereas Zn, Hg, As, U, Ni, Cr, Th, V, Ba, and Tl were not polluted. The results of RAC showed that Cd and Mn were high risk, whereas Co and Zn were moderate risk. Ni, Cu, Hg, and Y were slight risk, and the other elements (U, As, Pb, Cr, V, Tl, Ba, and Th) presented no risk. The MRI results showed that the comprehensive potential ecological risk of heavy metals was serious in the surface sediments, whereas Hg and Cd were the main contribution factors. Hg was a serious potential hazard, followed by Cd. Tl was a medium potential hazard, and the other elements were low potential hazards. These results demonstrated that the mangroves were polluted by heavy metals in Jiulong River Estuary, and effective strategies should be employed to remediate the mangrove sediment in the future.
Asunto(s)
Mercurio , Metales Pesados , Contaminantes Químicos del Agua , Cadmio , China , Monitoreo del Ambiente/métodos , Estuarios , Sedimentos Geológicos/química , Plomo , Metales Pesados/análisis , Medición de Riesgo , Ríos/química , Contaminantes Químicos del Agua/análisisRESUMEN
The decline of nicotinamide adenine dinucleotide (NAD) occurs in a variety of human pathologies including neurodegeneration. NAD-boosting agents can provide neuroprotective benefits. Here, we report the discovery and development of a class of potent activators (NATs) of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD salvage pathway. We obtained the crystal structure of NAMPT in complex with the NAT, which defined the allosteric action of NAT near the enzyme active site. The optimization of NAT further revealed the critical role of K189 residue in boosting NAMPT activity. NATs effectively increased intracellular levels of NAD and induced subsequent metabolic and transcriptional reprogramming. Importantly, NATs exhibited strong neuroprotective efficacy in a mouse model of chemotherapy-induced peripheral neuropathy (CIPN) without any overt toxicity. These findings demonstrate the potential of NATs in the treatment of neurodegenerative diseases or conditions associated with NAD level decline.
Asunto(s)
NAD , Nicotinamida Fosforribosiltransferasa , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Ratones , NAD/metabolismo , Nicotinamida Fosforribosiltransferasa/metabolismo , Nicotinamida Fosforribosiltransferasa/uso terapéuticoRESUMEN
OBJECTIVE: To explore the effect of problematic mobile phone use on college students' physical activity and their relationships. METHODS: A cross-sectional study was conducted among 3980 college students from three universities in Jiangsu province by random cluster sampling. The International Physical Activity Questionnaire Short (IPAQ-SF) measured college students' physical activity. The Mobile Phone Addiction Tendency Scale for College Students (MPATS) measured problematic mobile phone use tendencies. College students' physical activity was measured by the International Physical Activity Questionnaire Short (IPAQ-SF), and the Mobile Phone Addiction Tendency Scale measured their mobile phone addiction tendency for College Students (MPATS). RESULTS: (1) The proportions of the low-, medium-, and high-intensity physical activity were 83.5%, 10.7%, and 5.8%, respectively, with gender differences; The score of problematic mobile phone use tendency was 38.725 ± 15.139. (2) There were significant differences in problematic mobile phone use tendency among college students with different physical activity intensity (F = 11.839, p < 0.001, η2 = 0.007). (3) The level of physical activity was significantly correlated with the tendency of problematic mobile phone use (r = -0.173, p < 0.001). (4) Physical activity of college students could significantly predict the tendency of problematic mobile phone use (F (3,3605) = 11.296, p < 0.001). CONCLUSIONS: The physical activity of college students was mainly moderate to low intensity, while the tendency of problematic mobile phone use was high. College students' physical activity level was one of the important constraints of problematic mobile phone use tendency.