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1.
J Enzyme Inhib Med Chem ; 38(1): 2159957, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36728713

RESUMO

To discover novel multifunctional agents for the treatment of Parkinson's disease, a series of 2-(4-(benzyloxy)-5-(hydroxyl) phenyl) benzothiazole derivatives was designed, synthesized and evaluated. The results revealed that representative compound 3h possessed potent and selective MAO-B inhibitory activity (IC50 = 0.062 µM), and its inhibitory mode was competitive and reversible. Additionally, 3h also displayed excellent anti-oxidative effect (ORAC = 2.27 Trolox equivalent), significant metal chelating ability and appropriate BBB permeability. Moreover, 3h exhibited good neuroprotective effect and anti-neuroinflammtory ability. These results indicated that compound 3h was a promising candidate for further development against PD.

2.
Sci Rep ; 13(1): 1948, 2023 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-36732554

RESUMO

Because of the steep subduction of a highly concave slab, researchers have characterized megathrusts under the Marianas as among the coldest and curviest plate coupling interfaces in various circum-Pacific subduction zones. Seismic tomography indicates that the heterogeneous underlying plate varies markedly in its subduction angle, velocity, and flexure along the strike and dip, while their effects on the thermal structure and intraslab earthquake occurrence remain enigmatic. By incorporating the 3-D MORVEL velocity and state-of-the-art slab geometry into thermomechanical modeling, we estimated the 3-D subduction thermal state and hydrothermal regime below the Marianas. We find that (1) the concave slab geometry and the complexity of the intraslab velocity variation in the Marianas are associated with a heterogeneous along-strike thermal regime and a cold mantle wedge beneath the central Marianas; (2) amphibolitization and eclogitization of subducted oceanic crust cause variations in fluid pressure and fluid release from the subduction interface, which may influence the distribution of interface seismicity in the Mariana system; (3) the concentration of active hydrothermal vents in the trench > 8 km deep is accompanied by a large temperature gradient and subsequent remarkable slab dehydration in the southern Marianas; and (4) slab dehydration (> 0.02 wt%/km) from 30 to 80 km indicates notable fluid release and potential fluid migration in subduction channels, which may correspond to the large water flux at depth beneath the Marianas.

3.
ChemSusChem ; 2023 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-36737418

RESUMO

The carbonylation of alkynes using CO2 to generate aurones is unknown. Here, we report palladium-catalyzed carbonylation of terminal aromatic alkynes and the waste hydrosilane, poly(methylhydrosiloxane) (PMHS) with 2-iodophenol using CO2 to produce aurones. A variety of terminal alkynes and the substituted 2-iodophenols are transformed into aurones in good yields. Preliminary mechanistic studies indicate that silyl formate generated from CO2 and PMHS play a crucial role in carbonylation reaction.

4.
Artigo em Inglês | MEDLINE | ID: mdl-36683109

RESUMO

Traditional asphalt rubber (AR) has a high viscosity and poor fluidity, which makes its construction very difficult. Reducing viscosity has been identified as one of the effective way of solving these problems. Meanwhile, the mass production and improper discharge of waste engine oil (WEO) have a serious impact on the ecological environment, and its rational reuse needs to be addressed. In this paper, molecular models of AR and WEO-modified asphalt rubber (WEOMAR) was established by molecular dynamics (MD) simulations. The influence of WEO on asphalt component's behavior was studied by radial distribution function (RDF) and diffusion coefficient (D). Then, the microscopic mechanism of viscosity reduction was evaluated. Furthermore, the viscosity reduction behavior of WEO in AR was analyzed and verified by basic properties and low field nuclear magnetic resonance (LF-NMR) laboratory tests. The results showed that the RDF peak value of rubber molecules in WEOMAR is 14.07 higher than that of AR, at r = 2.16 Å. The D of saturated and aromatic components in WEOMAR obviously increased by 140% and 67.9%, respectively. The light component molecules increased after adding WEO into AR. The rubber molecule reduces the contact with asphaltene and resin, and the viscosity of AR is significantly reduced, which is confirmed by the macro tests.

5.
J Cosmet Dermatol ; 2023 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-36683314

RESUMO

BACKGROUND: Silver sulfadiazine is commonly used to treat local burn wounds. Aquacel-Ag is a hydrogen fiber dressing containing ionic silver that reduces burn wound infection and promotes antimicrobial activity. It is necessary to compare the efficacy of the two in the healing of burns. AIMS: The aim of this study was to systematically evaluate the effect of Aquacel-Ag on burn wound healing. METHODS: A computerized search of CNKI, VIP, Wanfang, SinoMed, PubMed, Cochrane Library, EMbase, Science Direct, Web of Science, Wiley Online Library, and Open Access Library databases was performed from January 1, 2000 to December 31, 2021 for randomized controlled clinical trials. The trials on Aquacel-Ag dressing and silver sulfadiazine in the treatment of burns were selected. Meta-analysis was performed using Review Manager 5.0 software. RESULTS: Eleven articles were finally included, with 794 burn patients. Meta-analysis results showed that compared with patients treated with silver sulfadiazine, burn patients treated with Aquacel-Ag dressing had shorter wound healing time [MD = -2.49, 95% CI (-5.64-0.65), p = 0.12], significantly lower tumor necrosis factor-α (TNF-α) level [MD = -0.52, 95% CI (-0.82-0.22), p = 0.0008], higher wound healing rate [MD = 8.41, 95% CI (3.39-13.43), p = 0.001], fewer dressing changes [MD = -3.27, 95% CI (-4.90-1.63), p < 0.0001]. CONCLUSION: Aquacel-Ag dressing can shorten wound healing time and effectively reduce inflammatory reactions in burn patients compared with silver sulfadiazine, but their safety still needs further exploration and analysis.

6.
Artigo em Inglês | MEDLINE | ID: mdl-36652095

RESUMO

Metformin (Metf), a biguanide widely used to manage type 2 diabetes mellitus, has recently entered the spotlight as a hopeful anti-tumor agent. In this work, because of the hyaluronic acid (HA) capability to specifically target CD44 receptors over-expressed on the surface of non-small lung cancer cells, a tumor-targeted drug delivery nanocarrier-based HA-coated mesoporous silica nanoparticles (MSNs) have been used for active targeting and efficient delivery of Metf. For this purpose, the synthesized MSNs-HA were characterized using BET, FE-EM, DLS, and FTIR. Confocal microscopy was applied to show the enhanced cellular uptake of the FITC-labelled MSNs-HA compared to MSNs without HA coating. MTT and qPCR results also revealed superior cytotoxicity and pro-apoptotic effects of Metf-loaded MSNs-HA (Metf@MSNs-HA) against the A549 lung cancer cells compared to the free Metf and MSNs@Metf due to the efficient CD44-targeting capability and delivery of Metf@MSNs-HA. Besides, it was demonstrated that Metf@MSNs-HA could effectively trigger the AMP-activated protein kinase α (AMPKα) pathway and inhibit the mammalian target rapamycin (mTOR), increasing the growth suppression. In conclusion, this preliminary work disclosed the great potential of Metf@MSNs-HA in targeted therapy of lung cancer cells.

7.
Exp Dermatol ; 2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36620869

RESUMO

Keratinocytes regulate melanogenesis in a paracrine manner. Previous studies have shown that melatonin can directly inhibit melanin production in the melanocytes. However, it is unclear whether melatonin can also indirectly regulate melanogenesis through the keratinocytes. In this study, we explored the role of melatonin in regulating keratinocyte-mediated melanogenesis using reconstructed human epidermis (RHE). Melatonin showed an inhibitory effect on melanin synthesis in this model. Furthermore, the conditioned media from melatonin-treated HaCaT cells downregulated melanogenesis-related genes, including MITF, TYR, TYRP1, DCT and RAB27A in the pigment MNT1 cells, and decreased levels of phosphorylated ERK, JNK and p38. RNA sequencing further showed that mitochondrial functions and oxidative stress pathway in the MNT1 cells were inhibited by the conditioned medium from melatonin-treated HaCaT cells. Furthermore, melatonin reduced the secretion of ET-1 and PTGS2 from HaCaT cells by inhibiting the JAK2/STAT3 signalling pathway. In conclusion, melatonin downregulates the paracrine factors ET-1 and PTGS2 in the keratinocytes by inhibiting the JAK2/STAT3 pathway, which reduces melanin production in pigment cells. Thus, melatonin has a potential therapeutic effect on skin pigmentation disorders.

8.
Med Image Anal ; 85: 102759, 2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36706638

RESUMO

Diffusion MRI tractography is an advanced imaging technique that enables in vivo mapping of the brain's white matter connections. White matter parcellation classifies tractography streamlines into clusters or anatomically meaningful tracts. It enables quantification and visualization of whole-brain tractography. Currently, most parcellation methods focus on the deep white matter (DWM), whereas fewer methods address the superficial white matter (SWM) due to its complexity. We propose a novel two-stage deep-learning-based framework, Superficial White Matter Analysis (SupWMA), that performs an efficient and consistent parcellation of 198 SWM clusters from whole-brain tractography. A point-cloud-based network is adapted to our SWM parcellation task, and supervised contrastive learning enables more discriminative representations between plausible streamlines and outliers for SWM. We train our model on a large-scale tractography dataset including streamline samples from labeled long- and medium-range (over 40 mm) SWM clusters and anatomically implausible streamline samples, and we perform testing on six independently acquired datasets of different ages and health conditions (including neonates and patients with space-occupying brain tumors). Compared to several state-of-the-art methods, SupWMA obtains highly consistent and accurate SWM parcellation results on all datasets, showing good generalization across the lifespan in health and disease. In addition, the computational speed of SupWMA is much faster than other methods.

9.
iScience ; 26(2): 105932, 2023 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-36698722

RESUMO

A better understanding of the molecular mechanism involving the lncRNA-miRNA-mRNA network underlying radiation damage can be beneficial for radioprotection. This study was designed to investigate the potential role of lncRNA NEAT1, miR-147 and Phosphoinositide Dependent Protein Kinase 1 (PDPK1) interaction in radioprotection by troxerutin (TRT). We first demonstrated that NEAT1 sponged miR-147, and PDPK1 mRNA was the primary target of miR-147. In the cells, the NEAT1 and PDPK1 levels were downregulated after the radiation but increased after the treatment with TRT. The miR-147 level was significantly induced by radiation and inhibited by TRT. NEAT1 negatively regulated the expression of miR-147, whereas miR-47 targeted PDPK1 to downregulate its expression. In radioprotection, TRT effectively upregulated NEAT1 to inhibit miR-147 and to upregulate PDPK1. We concluded that TRT could promote radioprotection by stimulating NEAT1 to upregulate PDPK1 expression by suppressing miR-147. NEAT1 could be a critical therapeutic target of radiation damage.

10.
Oncogene ; 2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36611121

RESUMO

The androgen receptor (AR) plays an important role in PCa metabolism, with androgen receptor pathway inhibition (ARPI) subjecting PCa cells to acute metabolic stress caused by reduced biosynthesis and energy production. Defining acute stress response mechanisms that alleviate ARPI stress and therefore mediate prostate cancer (PCa) treatment resistance will help improve therapeutic outcomes of patients treated with ARPI. We identified the up-regulation of chaperone-mediated autophagy (CMA) in response to acute ARPI stress, which persisted in castration-resistant PCa (CRPC); previously undefined in PCa. CMA is a selective protein degradation pathway and a key stress response mechanism up-regulated under several stress stimuli, including metabolic stress. Through selective protein degradation, CMA orchestrates the cellular stress response by regulating cellular pathways through selective proteome remodeling. Through broad-spectrum proteomic analysis, CMA coordinates metabolic reprogramming of PCa cells to sustain PCa growth and survival during ARPI; through the upregulation of mTORC1 signaling and pathways associated with PCa biosynthesis and energetics. This not only promoted PCa growth during ARPI, but also promoted the emergence of CRPC in-vivo. During CMA inhibition, PCa metabolism is compromised, leading to ATP depletion, resulting in a profound anti-proliferative effect on PCa cells, and is enhanced when combined with ARPI. Furthermore, CMA inhibition prevented in-vivo tumour formation, and also re-sensitized enzalutamide-resistant cell lines in-vitro. The profound anti-proliferative effect of CMA inhibition was attributed to cell cycle arrest mediated through p53 transcriptional repression of E2F target genes. In summary, CMA is an acute ARPI stress response mechanism, essential in alleviating ARPI induced metabolic stress, essential for ensuring PCa growth and survival. CMA plays a critical role in the development of ARPI resistance in PCa.

11.
Molecules ; 28(2)2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36677723

RESUMO

Genetic improvement of milk fatty acid content traits in dairy cattle is of great significance. However, chromatography-based methods to measure milk fatty acid content have several disadvantages. Thus, quick and accurate predictions of various milk fatty acid contents based on the mid-infrared spectrum (MIRS) from dairy herd improvement (DHI) data are essential and meaningful to expand the amount of phenotypic data available. In this study, 24 kinds of milk fatty acid concentrations were measured from the milk samples of 336 Holstein cows in Shandong Province, China, using the gas chromatography (GC) technique, which simultaneously produced MIRS values for the prediction of fatty acids. After quantification by the GC technique, milk fatty acid contents expressed as g/100 g of milk (milk-basis) and g/100 g of fat (fat-basis) were processed by five spectral pre-processing algorithms: first-order derivative (DER1), second-order derivative (DER2), multiple scattering correction (MSC), standard normal transform (SNV), and Savitzky-Golsy convolution smoothing (SG), and four regression models: random forest regression (RFR), partial least square regression (PLSR), least absolute shrinkage and selection operator regression (LassoR), and ridge regression (RidgeR). Two ranges of wavebands (4000~400 cm-1 and 3017~2823 cm-1/1805~1734 cm-1) were also used in the above analysis. The prediction accuracy was evaluated using a 10-fold cross validation procedure, with the ratio of the training set and the test set as 3:1, where the determination coefficient (R2) and residual predictive deviation (RPD) were used for evaluations. The results showed that 17 out of 31 milk fatty acids were accurately predicted using MIRS, with RPD values higher than 2 and R2 values higher than 0.75. In addition, 16 out of 31 fatty acids were accurately predicted by RFR, indicating that the ensemble learning model potentially resulted in a higher prediction accuracy. Meanwhile, DER1, DER2 and SG pre-processing algorithms led to high prediction accuracy for most fatty acids. In summary, these results imply that the application of MIRS to predict the fatty acid contents of milk is feasible.


Assuntos
Lactação , Leite , Animais , Feminino , Bovinos , Leite/química , Ácidos Graxos/análise , Espectrofotometria Infravermelho/métodos , Análise dos Mínimos Quadrados
12.
bioRxiv ; 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36711592

RESUMO

Degradation of most yeast mRNAs involves decapping by Dcp1/Dcp2. DEAD-box protein Dhh1 has been implicated as an activator of decapping, in coupling codon non-optimality to enhanced degradation, and as a translational repressor, but its functions in cells are incompletely understood. RNA-Seq analyses coupled with CAGE sequencing of all capped mRNAs revealed increased abundance of hundreds of mRNAs in dcp2 Δ cells that appears to result directly from impaired decapping rather than elevated transcription, which was confirmed by ChIP-Seq analysis of RNA Polymerase II occupancies genome-wide. Interestingly, only a subset of mRNAs requires Dhh1 for targeting by Dcp2, and also generally requires the other decapping activators Pat1, Lsm2, Edc3 or Scd6; whereas most of the remaining transcripts utilize NMD factors for Dcp2-mediated turnover. Neither inefficient translation initiation nor stalled elongation appears to be a major driver of Dhh1-enhanced mRNA degradation. Surprisingly, ribosome profiling revealed that dcp2 Δ confers widespread changes in relative TEs that generally favor well-translated mRNAs. Because ribosome biogenesis is reduced while capped mRNA abundance is increased by dcp2 Δ, we propose that an increased ratio of mRNA to ribosomes increases competition among mRNAs for limiting ribosomes to favor efficiently translated mRNAs in dcp2 Δ cells. Interestingly, genes involved in respiration or utilization of alternative carbon or nitrogen sources are derepressed, and both mitochondrial function and cell filamentation (a strategy for nutrient foraging) are elevated by dcp2 Δ, suggesting that mRNA decapping sculpts gene expression post-transcriptionally to fine-tune metabolic pathways and morphological transitions according to nutrient availability.

13.
Sci Rep ; 13(1): 1617, 2023 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-36709392

RESUMO

Segmentation of white matter tracts in diffusion magnetic resonance images is an important first step in many imaging studies of the brain in health and disease. Similar to medical image segmentation in general, a popular approach to white matter tract segmentation is to use U-Net based artificial neural network architectures. Despite many suggested improvements to the U-Net architecture in recent years, there is a lack of systematic comparison of architectural variants for white matter tract segmentation. In this paper, we evaluate multiple U-Net based architectures specifically for this purpose. We compare the results of these networks to those achieved by our own various architecture changes, as well as to new U-Net architectures designed automatically via neural architecture search (NAS). To the best of our knowledge, this is the first study to systematically compare multiple U-Net based architectures for white matter tract segmentation, and the first to use NAS. We find that the recently proposed medical imaging segmentation network UNet3+ slightly outperforms the current state of the art for white matter tract segmentation, and achieves a notably better mean Dice score for segmentation of the fornix (+ 0.01 and + 0.006 mean Dice increase for left and right fornix respectively), a tract that the current state of the art model struggles to segment. UNet3+ also outperforms the current state of the art when little training data is available. Additionally, manual architecture search found that a minor segmentation improvement is observed when an additional, deeper layer is added to the U-shape of UNet3+. However, all networks, including those designed via NAS, achieve similar results, suggesting that there may be benefit in exploring networks that deviate from the general U-Net paradigm.


Assuntos
Fenômenos Biológicos , Substância Branca , Substância Branca/diagnóstico por imagem , Redes Neurais de Computação , Encéfalo/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Processamento de Imagem Assistida por Computador/métodos
14.
Oxid Med Cell Longev ; 2023: 4463063, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36713031

RESUMO

Visceral pain caused by inflammatory bowel disease (IBD) greatly diminishes the quality of life in affected patients. Yet, the mechanism of how IBD causes visceral pain is currently not fully understood. Previous studies have suggested that the central nervous system (CNS) and gut-brain axis (GBA) play an important role in IBD-inducing visceral pain. As one of the treatments for IBD, electroacupuncture (EA) has been used to treat various types of pain and gastrointestinal diseases in clinical practice. However, whether EA relieves the visceral pain of IBD through the gut-brain axis has not been confirmed. To verify the relationship between visceral pain and CNS, the following experiments were conducted. 1H-NMR analysis was performed on the prefrontal cortex (PFC) tissue obtained from IBD rat models to determine the link between the metabolites and their role in EA treatment against visceral pain. Western blot assay was employed for detecting the contents of glutamate transporter excitatory amino acid transporters 2 (EAAT2) and the glutamate receptor N-methyl-D-aspartate (NMDA) to verify whether EA treatment can alleviate neurotoxic symptoms induced by abnormal increases of glutamate. Study results showed that the glutamate content was significantly increased in the PFC of TNBS-induced IBD rats. This change was reversed after EA treatment. This process was associated with increased EAAT2 expression and decreased expression of NMDA receptors in the PFC. In addition, an increase in intestinal glutamic-metabolizing bacteria was observed. In conclusion, this study suggests that EA treatment can relieve visceral pain by reducing glutamine toxicity in the PFC, and serves an alternative clinical utility.


Assuntos
Eletroacupuntura , Doenças Inflamatórias Intestinais , Dor Visceral , Ratos , Animais , Ratos Sprague-Dawley , Dor Visceral/terapia , Dor Visceral/etiologia , Dor Visceral/metabolismo , Eletroacupuntura/métodos , Ácido Trinitrobenzenossulfônico , Qualidade de Vida , Doenças Inflamatórias Intestinais/complicações , Córtex Pré-Frontal/metabolismo , Glutamatos
15.
Small ; : e2207029, 2023 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-36703529

RESUMO

The establishment of effective antitumor immune responses of vaccines is mainly limited by insufficient priming tumor infiltration of T cells and immunosuppressive tumor microenvironment (TME). Targeting ß-adrenergic receptor (ß-AR) signaling exerts promising benefits on reversing the suppressive effects directly on T cells, but it appears to have considerably limited antitumor performance when combined with vaccine-based immunotherapies. Herein, a tumor membrane-coated nanoplatform for codelivery of adjuvant CpG and propranolol (Pro), a ß-AR inhibitor is designed. The biomimetic nanovaccine displayed an improved accumulation in lymph nodes and sufficient drug release, thereby inducing dendritic cell maturation and antigen presentation. Meanwhile, the integration of vaccination and blockade of ß-AR signaling not only promoted the priming of the naive CD8+ T cells and effector T cell egress from lymph nodes, but also alleviated the immunosuppressive TME by decreasing the frequency of immunosuppressive cells and increasing the tumor infiltration of B cells and NK cells. Consequently, the biomimetic nanovaccines outperformed greater prophylactic and therapeutic efficacy than nanovaccines without Pro encapsulation in B16-F10 melanoma mice. Taken together, the work explored a biomimetic nanovaccine for priming tumor infiltration of T cells and immunosuppressive TME regulation, offering tremendous potential for a combined ß-AR signaling-targeting strategy in cancer immunotherapy.

16.
Microbiol Spectr ; : e0379722, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36629430

RESUMO

Phytophthora species are devastating filamentous plant pathogens that belong to oomycetes, a group of microorganisms similar to fungi in morphology but phylogenetically distinct. They are sterol auxotrophic, but nevertheless exploit exogenous sterols for growth and development. However, as for now the mechanisms underlying sterol utilization in Phytophthora are unknown. In this study, we identified four genes in Phytophthora capsici that encode proteins containing a sterol-sensing domain (SSD), a protein domain of around 180 amino acids comprising five transmembrane segments and known to feature in sterol signaling in animals. Using a modified CRISPR/Cas9 system, we successfully knocked out the four genes named PcSCP1 to PcSCP4 (for P. capsici SSD-containing protein 1 to 4), either individually or sequentially, thereby creating single, double, triple, and quadruple knockout transformants. Results showed that knocking out just one of the four PcSCPs was not sufficient to block sterol signaling. However, the quadruple "all-four" PcSCPs knockout transformants no longer responded to sterol treatment in asexual reproduction, in contrast to wild-type P. capsici that produced zoospores under sterol treatment. Apparently, the four PcSCPs play a key role in sterol signaling in P. capsici with functional redundancy. Transcriptome analysis indicated that the expression of a subset of genes is regulated by exogenous sterols via PcSCPs. Further investigations showed that sterols could stimulate zoospore differentiation via PcSCPs by controlling actin-mediated membrane trafficking. Moreover, the pathogenicity of the "all-four" PcSCPs knockout transformants was significantly decreased and many pathogenicity related genes were downregulated, implying that PcSCPs also contribute to plant-pathogen interaction. IMPORTANCE Phytophthora is an important genus of oomycetes that comprises many destructive plant pathogens. Due to the incompleteness of the sterol synthesis pathway, Phytophthora spp. do not possess the ability to produce sterols. Therefore, these sterol auxotrophic oomycetes need to recruit sterols from the environment such as host plants to support growth and development, which seems crucial during pathogen-plant interactions. However, the mechanisms underlying sterol utilization by Phytophthora spp. remain largely unknown. Here, we show that a family of sterol-sensing domain-containing proteins (SCPs) consisting of four members in P. capsici plays a key role in sterol signaling with functional redundancy. Moreover, these SCPs play a role in different biological processes, including asexual reproduction and pathogenicity. Our study overall revealed the multiple functions of PcSCPs and addressed the question of how exogenous sterols regulate the development of heterothallic Phytophthora spp. via SSD-containing proteins.

17.
Artigo em Inglês | MEDLINE | ID: mdl-36633744

RESUMO

Phthalate metabolites have been detected from urine in most of the US population and have become a public health problem. However, the association between phthalate metabolites and hyperuricemia has been scarcely studied so far. We aimed to evaluate if phthalate metabolites were associated with hyperuricemia in US adults. A total of 8816 participants of the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2018 were included in our study. We used multivariable logistic regression models and restricted cubic spline (RCS) models to explore the association between urinary phthalate metabolites and hyperuricemia. Then, stratified analyses were conducted by sex and age. The prevalence of hyperuricemia in the study sample was 20.35%. Compared to the lowest quantile, the odds ratios (ORs) and 95% confidence intervals (CIs) for hyperuricemia were all statistically significant in following phthalate metabolites: 1.34 (1.13-1.58) for the second quartile in Mono-isobutyl phthalate (MiBP), 1.21 (1.01-1.46) for the highest quartile in Mono-(carboxyoctyl) phthalate (MCOP), 0.66 (0.56-0.76) for the second quartile in Mono-(2-ethyl)-hexyl phthalate (MEHP), 1.22 (1.05-1.43) for quartile 2 in Benzyl butyl phthalate (ΣBBP), and 1.43 (1.22-1.66) for the third quartile in high molecular-weight phthalate (ΣHigh MWP), respectively. Our results indicate that several urinary phthalate metabolites are positively associated with the odds of hyperuricemia.

18.
Cancers (Basel) ; 15(1)2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36612317

RESUMO

Due to the absence of hormone receptor (both estrogen receptors and progesterone receptors) along with human epidermal growth factor receptor 2 (HER-2) amplification, the treatment of triple-negative breast cancer (TNBC) cannot benefit from endocrine or anti-HER-2 therapy. For a long time, chemotherapy was the only systemic treatment for TNBC. Due to the lack of effective treatment options, the prognosis for TNBC is extremely poor. The successful application of immune checkpoint inhibitors (ICIs) launched the era of immunotherapy in TNBC. However, the current findings show modest efficacy of programmed cell death- (ligand) 1 (PD-(L)1) inhibitors monotherapy and only a small proportion of patients can benefit from this approach. Based on the basic principles of immunotherapy and the characteristics of the tumor immune microenvironment (TIME) in TNBC, immune combination therapy is expected to further enhance the efficacy and expand the beneficiary population of patients. Given the diversity of drugs that can be combined, it is important to select effective biomarkers to identify the target population. Moreover, the side effects associated with the combination of multiple drugs should also be considered.

19.
Cell Res ; 2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36650286

RESUMO

SARS-CoV-2 infection can trigger strong inflammatory responses and cause severe lung damage in COVID-19 patients with critical illness. However, the molecular mechanisms by which the infection induces excessive inflammatory responses are not fully understood. Here, we report that SARS-CoV-2 infection results in the formation of viral Z-RNA in the cytoplasm of infected cells and thereby activates the ZBP1-RIPK3 pathway. Pharmacological inhibition of RIPK3 by GSK872 or genetic deletion of MLKL reduced SARS-CoV-2-induced IL-1ß release. ZBP1 or RIPK3 deficiency leads to reduced production of both inflammatory cytokines and chemokines during SARS-CoV-2 infection both in vitro and in vivo. Furthermore, deletion of ZBP1 or RIPK3 alleviated SARS-CoV-2 infection-induced immune cell infiltration and lung damage in infected mouse models. These results suggest that the ZBP1-RIPK3 pathway plays a critical role in SARS-CoV-2-induced inflammatory responses and lung damage. Our study provides novel insights into how SARS-CoV-2 infection triggers inflammatory responses and lung pathology, and implicates the therapeutic potential of targeting ZBP1-RIPK3 axis in treating COVID-19.

20.
Artigo em Inglês | MEDLINE | ID: mdl-36651353

RESUMO

INTRODUCTION: The anatomical substrate for idiopathic left ventricular tachycardia (ILVT) remains speculative. Purkinje networks surrounding false tendons (FTs) might be involved in the reentrant circuit of ILVT. The objective was to evaluate the anatomical and electrophysiological features of false tendons FTs in relation to ILVT. METHODS: Intracardiac echocardiography (ICE) was conducted on patients with ILVT. The relationship of the FTs with ILVT was determined using electro-anatomical mapping. RESULTS: Electrophysiological evaluation and radiofrequency ablation were conducted in 23 consecutive patients with ILVT. FTs were identified in 19/23 cases (82.6%) with P1 potentials during VT recorded at the FT in 14 of these patients (73.7%). Three FT types were identified. In type 1, the FT attached the septum to the base of the posteromedial papillary muscle (PPM) (4/19); type 2 FTs ran between the septum and the PPM apex (3/19), while in type 3, the connection occurred between the septum and apex (11/19) or between the septum and the LV free wall (1/19). The effective ILVT ablation sites were situated at the FT-PPM (3/19) and the FT-septum (16/19) attachment sites. CONCLUSIONS: This series demonstrates the association between Purkinje fibers and FTs during catheter ablation of ILVT and verifies that left ventricular FTs are an important substrate in this type of tachycardia.

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