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1.
Heliyon ; 10(14): e34246, 2024 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-39100460

RESUMO

Despite China's building into a leading sporting nation and sport-tourism integration high-quality development strategy in the 20th National Congress of the Communist Party of China, existing tourism studies seldom concern sport-tourism integration, especially their spatial hot spots and evolutional trend based on geospatial big data. This study aims to probe into the spatiality and the underlying mechanism of sport tourism through internet attention data in 2015, 2018, and 2021 by social network analysis, with a specific focus on aero-sports tourism. Shaanxi Province is chosen as the study site given its advantages of rich aero-sports tourism resources and various aero-sports modes (e.g., sky diving, paragliding, etc.). The results are concluded: (1) At the provincial scale, the aero-sports tourism internet attention shows a pattern of "strong in the middle and weak in the north and south". (2) At the regional scale, the sub-group clusters within the three specific regions (Shanbei, Guanzhong, and Shannan) of Shaanxi Province turn to be inter-regional clusters. Guanzhong region, especially with Xi'an as the core, is dominant in connecting its peripheral area. Since 2016, the radiation effects of the Guanzhong Region have shown a homogeneous trend of yearly growth and effect strengthening, yet become loosely connected with a heterogeneous trend in 2021 due to the COVID-19 epidemic. (3) At the city scale, the core area of aero-sports tourism internet attention expanded from Xi'an and Xianyang to Yulin and Baoji from 2015 to 2021, resulting from urban economic strength and aviation flight camp club development. (4) The number of general aviation manufacturers, tourist attendance, and tourism revenue significantly affect aero-sports tourism internet attention.

2.
J Transl Med ; 22(1): 729, 2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-39103909

RESUMO

BACKGROUND: Metabolic syndrome (MetS) is highly prevalent in individuals with schizophrenia (SZ), leading to negative consequences like premature mortality. Gut dysbiosis, which refers to an imbalance of the microbiota, and chronic inflammation are associated with both SZ and MetS. However, the relationship between gut dysbiosis, host immunological dysfunction, and SZ comorbid with MetS (SZ-MetS) remains unclear. This study aims to explore alterations in gut microbiota and their correlation with immune dysfunction in SZ-MetS, offering new insights into its pathogenesis. METHODS AND RESULTS: We enrolled 114 Chinese patients with SZ-MetS and 111 age-matched healthy controls from Zhejiang, China, to investigate fecal microbiota using Illumina MiSeq sequencing targeting 16 S rRNA gene V3-V4 hypervariable regions. Host immune responses were assessed using the Bio-Plex Pro Human Cytokine 27-Plex Assay to examine cytokine profiles. In SZ-MetS, we observed decreased bacterial α-diversity and significant differences in ß-diversity. LEfSe analysis identified enriched acetate-producing genera (Megamonas and Lactobacillus), and decreased butyrate-producing bacteria (Subdoligranulum, and Faecalibacterium) in SZ-MetS. These altered genera correlated with body mass index, the severity of symptoms (as measured by the Scale for Assessment of Positive Symptoms and Scale for Assessment of Negative Symptoms), and triglyceride levels. Altered bacterial metabolic pathways related to lipopolysaccharide biosynthesis, lipid metabolism, and various amino acid metabolism were also found. Additionally, SZ-MetS exhibited immunological dysfunction with increased pro-inflammatory cytokines, which correlated with the differential genera. CONCLUSION: These findings suggested that gut microbiota dysbiosis and immune dysfunction play a vital role in SZ-MetS development, highlighting potential therapeutic approaches targeting the gut microbiota. While these therapies show promise, further mechanistic studies are needed to fully understand their efficacy and safety before clinical implementation.


Assuntos
Microbioma Gastrointestinal , Síndrome Metabólica , Esquizofrenia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos de Casos e Controles , China , Comorbidade , Citocinas/metabolismo , Disbiose/microbiologia , Disbiose/imunologia , Disbiose/complicações , População do Leste Asiático , Fezes/microbiologia , Imunidade , Síndrome Metabólica/microbiologia , Síndrome Metabólica/imunologia , Síndrome Metabólica/complicações , Esquizofrenia/microbiologia , Esquizofrenia/imunologia , Esquizofrenia/complicações
3.
Commun Biol ; 7(1): 960, 2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-39117859

RESUMO

Previous studies in small samples have identified inconsistent cortical abnormalities in major depressive disorder (MDD). Despite genetic influences on MDD and the brain, it is unclear how genetic risk for MDD is translated into spatially patterned cortical vulnerability. Here, we initially examined voxel-wise differences in cortical function and structure using the largest multi-modal MRI data from 1660 MDD patients and 1341 controls. Combined with the Allen Human Brain Atlas, we then adopted transcription-neuroimaging spatial correlation and the newly developed ensemble-based gene category enrichment analysis to identify gene categories with expression related to cortical changes in MDD. Results showed that patients had relatively circumscribed impairments in local functional properties and broadly distributed disruptions in global functional connectivity, consistently characterized by hyper-function in associative areas and hypo-function in primary regions. Moreover, the local functional alterations were correlated with genes enriched for biological functions related to MDD in general (e.g., endoplasmic reticulum stress, mitogen-activated protein kinase, histone acetylation, and DNA methylation); and the global functional connectivity changes were associated with not only MDD-general, but also brain-relevant genes (e.g., neuron, synapse, axon, glial cell, and neurotransmitters). Our findings may provide important insights into the transcriptomic signatures of regional cortical vulnerability to MDD.


Assuntos
Transtorno Depressivo Maior , Transcriptoma , Humanos , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/fisiopatologia , Feminino , Masculino , Adulto , Córtex Cerebral/fisiopatologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Pessoa de Meia-Idade , Imageamento por Ressonância Magnética , Perfilação da Expressão Gênica
4.
Sci Adv ; 10(32): eadl2842, 2024 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-39121226

RESUMO

The 2022 eruption of the Hunga submarine volcano injected an unprecedented volume of water vapor into the stratosphere, presenting a unique, natural experiment for ascertaining the influence of stratospheric water vapor within the global radiation budget. This study examines the radiative forcings of the Hunga stratospheric water vapor enhancement, comparing stratosphere-adjusted radiative forcing derived from offline methods to an effective radiative forcing derived from Earth System Model simulations. Assuming a uniform 2 parts per million mass mixing ratio increase of water vapor in the Southern Hemisphere stratosphere, we estimated the instantaneous, stratosphere-adjusted, and overall effective radiative forcing to be -0.04, 0.08, and 0.05 W m-2, respectively. The lower magnitude of the positive volcanic stratospheric water vapor effective radiative forcing is due to compensating effects from atmospheric adjustments. Ensemble simulations of a coupled atmosphere-ocean model suggest a surface warming of 0.05 K, affirming a limited influence on global mean surface temperature from the volcanic stratospheric water vapor injection.

5.
Food Chem ; 460(Pt 2): 140623, 2024 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-39096798

RESUMO

Milk alternative attracts more attention due to nutrition benefits, but the low solubility and the calcium deficiency of plant protein hinder the development of milk alternatives. Therefore, pH shifting was optimized to improve chickpea protein solubility and calcium fortification while ensuring good digestibility. The results showed that pH shifting reduced the particle size from 2197.67 ± 178.2 nm to 80.2 ± 2 nm, and increased the net ζ potential from -0.48 ± 0.24 to -21.27 ± 0.65 due to the unfolding of secondary protein structure, by which chickpea protein bring better solution stability. Additionally, the whiteness of the solution with chickpea protein increased. The calcium addition kept the solution stable with small particle size despite a slight increase. The microstructure of chickpea protein during digestion was well disrupted even with fortifying calcium. This study provides proof of the positive effect of pH shifting on chickpea protein stability and calcium fortification.

6.
Front Pharmacol ; 15: 1412938, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38948471

RESUMO

Background: Capecitabine has been reported to be associated with severe gastrointestinal (GI) adverse drug reactions (gastrointestinal ulceration, haemorrhage, and obstruction). However, statistical correlations have not been demonstrated, and specific GI adverse drug reactions, such as GI obstruction, are not listed on its label. Aim: We aimed to determine the associations between capecitabine and GI ulceration, haemorrhage, or obstruction among patients with breast cancer by examining data from the United States Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: We performed disproportionality analysis of GI ulceration, haemorrhage, and obstruction by evaluating the reporting odds ratio (ROR) and the information component (IC) with their 95% confidence intervals (CIs). Results: We identified 279 patients with capecitabine-associated GI ulceration, haemorrhage, or obstruction reported between 1 January 2004 and 31 December 2020. One-fourth of the cases of GI ulceration, haemorrhage, or obstruction resulted in death. Capecitabine as a drug class had disproportionately high reporting rates for GI ulceration [ROR 1.94 (1.71-2.21); IC 0.80 (0.60-0.99)], haemorrhage [ROR 2.27 (1.86-2.76); IC 0.99 (0.69-1.28)], and obstruction [ROR 2.19 (1.63-2.95); IC 0.96 (0.51-1.40)]. Conclusion: Pharmacovigilance research on the FAERS has revealed a slight increase in reports of GI ulceration, haemorrhage, and obstruction in capecitabine users, which may cause serious or deadly consequences. In addition to the adverse reactions described in the package insert, close attention should be paid to GI obstruction to avoid discontinuation or life-threatening outcomes.

7.
Cancer Cell Int ; 24(1): 249, 2024 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-39020371

RESUMO

BACKGROUND: Microtubule polymerization is usually considered as the upstream of apoptotic cell death induced by taxanes, but recently published studies provide more insights into the mechanisms responsible for the antineoplastic effect of taxanes. In this study, we figure out the role of the stress-related PERK/eIF2α axis in tumor cell death upon taxane treatment along with paclitaxel resistance. METHODS: Utilizing immunoblot assay, the activation status of PERK-eIF2α signaling was detected in a panel of cancer cell lines after the treatment of taxanes. The causal role of PERK-eIF2α signaling in the cancer cell apoptosis induced by taxanes was examined via pharmacological and genetic inhibitions of PERK. The relationship between microtubule polymerization and PERK-eIF2α activation was explored by immunofluorescent and immunoblotting assays. Eventaually, the combined therapeutic effect of paclitaxel (PTX) and CCT020312, a PERK agonist, was investigated in PTX-resistant breast cancer cells in vitro and in vivo. RESULTS: PERK-eIF2α axis was dramatically activated by taxanes in several cancer cell types. Pharmacological or genetic inhibition of PERK efficiently impaired taxane-induced apoptotic cell death, independent of the cellular microtubule polymerization status. Moreover, PTX was able to activate the PERK/eIF2α axis in a very low concentration without triggering microtubule polymerization. In PTX-resistant breast cancer cells, the PERK/eIF2α axis was attenuated in comparison with the PTX-sensitive counterparts. Reactivation of the PERK/eIF2α axis in the PTX-resistant breast cancer cells with PERK agonist sensitized them to PTX in vitro. Combination treatment of the xenografted PTX-resistant breast tumors with PERK agonist and PTX validated the synergic effect of PTX and PERK activation in vivo. CONCLUSION: Activation of the PERK/eIF2α axis is a pivotal prerequisite of taxanes to initiate cancer cell apoptosis, which is independent of the well-known microtubule polymerization-dependent manner. Simultaneous activation of PERK-eIF2α signaling would be a promising therapeutic strategy to overcome PTX resistance in breast cancer or other cancers.

8.
Cytokine ; 182: 156717, 2024 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-39067394

RESUMO

PURPOSE: Aspergillus fumigatus (A. fumigatus) keratitis is a type of infectious corneal disease that significantly impairs vision. The objective of this study is to evaluate the therapeutic potential of chelerythrine (CHE) on A. fumigatus keratitis. METHODS: The antifungal activity of CHE was assessed through various tests including the minimum inhibitory concentration test, scanning electron microscopy, transmission electron microscopy, propidium iodide uptake test and plate count. Neutrophil infiltration and activity were assessed using immunofluorescence staining and the myeloperoxidase test. RT-PCR, western blotting assay, and ELISA were performed to measure the expression levels of proinflammatory cytokines (IL-1ß and IL-6), NF-E2-related factor (Nrf2), heme oxygenase-1 (HO-1), and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), as well as to determine the ratio of phosphorylated-p38 (p-p38) mitogen-activated protein kinase (MAPK) to p38 MAPK. RESULTS: In vitro, CHE inhibited the growth of A. fumigatus conidia, reduced fungal hyphae survival, and prevented fungal biofilm formation. In vivo, CHE reduced the severity of A. fumigatus keratitis and exhibited an excellent anti-inflammatory effect by blocking neutrophil infiltration. Furthermore, CHE decreased the expression levels of proinflammatory cytokines and LOX-1 at both mRNA and protein levels, while also decreasing the p-p38 MAPK/p38 MAPK ratio. Additionally, CHE increased the expression levels of Nrf2 and HO-1. CONCLUSION: CHE provides protection against A. fumigatus keratitis through multiple mechanisms, including reducing fungal survival, inducing anti-inflammatory effects, enhancing Nrf2 and HO-1 expression, and suppressing the signaling pathway of LOX-1/p38 MAPK.

9.
Transl Vis Sci Technol ; 13(7): 16, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-39042048

RESUMO

Purpose: The purpose of this study was to investigate the ocular morphological characteristics of Col4a3-/- mice as a model of Alport syndrome (AS) and the potential pathogenesis. Methods: The expression of collagen IV at 8, 12, and 21 weeks of age was evaluated by immunohistochemistry in wild-type (WT) and Col4a3-/- mice. Hematoxylin and eosin (H&E) staining and thickness measurements were performed to assess the thickness of anterior lens capsule and retina. Ultrastructure analysis of corneal epithelial basement membrane, anterior lens capsule, internal limiting membrane (ILM), and retinal pigment epithelium (RPE) basement membrane was performed using transmission electron microscopy. Finally, Müller cell activation was evaluated by glial fibrillary acidic protein (GFAP) expression. Results: Collagen IV was downregulated in the corneal epithelial basement membrane and ILM of Col4a3-/- mice. The hemidesmosomes of Col4a3-/- mice corneal epithelium became flat and less electron-dense than those of the WT group. Compared with those of the WT mice, the anterior lens capsules of Col4a3-/- mice were thinner. Abnormal structure was detected at the ILM Col4a3-/- mice, and the basal folds of the RPE basement membrane in Col4a3-/- mice were thicker and shorter. The retinas of Col4a3-/- mice were thinner than those of WT mice, especially within 1000 µm away from the optic nerve. GFAP expression enhanced in each age group of Col4a3-/- mice. Conclusions: Our results suggested that Col4a3-/- mice exhibit ocular anomalies similar to patients with AS. Additionally, Müller cells may be involved in AS retinal anomalies. Translational Relevance: This animal model could provide an opportunity to understand the underlying mechanisms of AS ocular disorders and to investigate potential new treatments.


Assuntos
Membrana Basal , Colágeno Tipo IV , Modelos Animais de Doenças , Camundongos Knockout , Nefrite Hereditária , Animais , Nefrite Hereditária/patologia , Nefrite Hereditária/genética , Nefrite Hereditária/metabolismo , Colágeno Tipo IV/genética , Colágeno Tipo IV/metabolismo , Colágeno Tipo IV/deficiência , Camundongos , Membrana Basal/metabolismo , Membrana Basal/patologia , Membrana Basal/ultraestrutura , Epitélio Pigmentado da Retina/patologia , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/ultraestrutura , Microscopia Eletrônica de Transmissão , Camundongos Endogâmicos C57BL , Cápsula do Cristalino/metabolismo , Cápsula do Cristalino/patologia , Cápsula do Cristalino/ultraestrutura , Epitélio Corneano/patologia , Epitélio Corneano/ultraestrutura , Epitélio Corneano/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Proteína Glial Fibrilar Ácida/genética , Retina/patologia , Retina/metabolismo , Retina/ultraestrutura , Autoantígenos/genética , Autoantígenos/metabolismo , Células Ependimogliais/patologia , Células Ependimogliais/metabolismo , Células Ependimogliais/ultraestrutura , Imuno-Histoquímica , Masculino
10.
BMJ Open ; 14(7): e083730, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-39009458

RESUMO

INTRODUCTION: Patients with non-ST segment elevation acute coronary syndrome (NSTE-ACS) and concomitant multivessel coronary artery disease (CAD) are considered patients with extremely high-risk atherosclerotic cardiovascular disease (ASCVD), and current guidelines specify a lower low-density lipoprotein cholesterol (LDL-C) target for this population. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to effectively reduce LDL-C levels on a statin background. Additionally, several studies have confirmed the role of PCSK9 inhibitors in plaque regression and reducing residual cardiovascular risk in patients with ACS. However, those studies included coronary lesions with a degree of stenosis <50%. Whether the application of PCSK9 inhibitors in patients with NSTE-ACS with non-culprit artery critical lesions (stenosis degree between 50% and 75%) has a similar effect on plaque regression and improvement of cardiovascular outcomes remains unknown, with a lack of relevant research. This study aims to further investigate the safety and efficacy of evolocumab in patients with NSTE-ACS and concomitant multivessel CAD (non-culprit artery stenosis between 50% and 75%). METHODS AND ANALYSIS: In this single-centre clinical randomised controlled trial, 122 patients with NSTE-ACS and concomitant multivessel CAD (non-culprit artery stenosis between 50% and 75%) will be randomly assigned to either the evolocumab treatment group or the standard treatment group after completing culprit vessel revascularisation. The evolocumab treatment group will receive evolocumab in addition to statin therapy, while the standard treatment group will receive standard statin therapy. At baseline and week 50, patients in the evolocumab treatment group will undergo coronary angiography and OCT imaging to visualise pre-existing non-lesional vessels. The primary end point is the absolute change in average minimum fibrous cap thickness (FCT) from baseline to week 50. Secondary end points include changes in plaque lipid arc, lipid length, macrophage grading, lipid levels and major adverse cardiovascular events during the 1-year follow-up period. ETHICS AND DISSEMINATION: Ethics: this study will adhere to the principles outlined in the Helsinki Declaration and other applicable ethical guidelines. This study protocol has received approval from the Medical Research Ethics Committee of the First Affiliated Hospital of the University of Science and Technology of China (Anhui Provincial Hospital), with approval number 2022-ky214. DISSEMINATION: we plan to disseminate the findings of this study through various channels. This includes publication in peer-reviewed academic journals, presentation at relevant academic conferences and communication to the public, policymakers and healthcare professionals. We will also share updates on the research progress through social media and other online platforms to facilitate the exchange and application of scientific knowledge. Efforts will be made to ensure widespread dissemination of the research results and to have a positive impact on society. TRIAL REGISTRATION NUMBER: ChiCTR2200066675.


Assuntos
Síndrome Coronariana Aguda , Anticorpos Monoclonais Humanizados , Doença da Artéria Coronariana , Inibidores de PCSK9 , Humanos , Síndrome Coronariana Aguda/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Doença da Artéria Coronariana/tratamento farmacológico , LDL-Colesterol/sangue , Ensaios Clínicos Controlados Aleatórios como Assunto , Anticolesterolemiantes/uso terapêutico , Anticolesterolemiantes/efeitos adversos , Placa Aterosclerótica/tratamento farmacológico , Placa Aterosclerótica/diagnóstico por imagem , Feminino , Masculino , Resultado do Tratamento , Pessoa de Meia-Idade , Pró-Proteína Convertase 9
11.
Sensors (Basel) ; 24(13)2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-39001164

RESUMO

Hyperspectral detection of the change rate of organic matter content in agricultural remote sensing requires a high signal-to-noise ratio (SNR). However, due to the large number and efficiency limitation of the components, it is difficult to improve the SNR. This study uses high-efficiency convex grating with a diffraction efficiency exceeding 50% across the 360-850 nm range, a back-illuminated Complementary Metal Oxide Semiconductor (CMOS) detector with a 95% efficiency in peak wavelength, and silver-coated mirrors to develop an imaging spectrometer for detecting soil organic matter (SOM). The designed system meets the spectral resolution of 10 nm in the 360-850 nm range and achieves a swath of 100 km and a spatial resolution of 100 m at an orbital height of 648.2 km. This study also uses the basic structure of Offner with fewer components in the design and sets the mirrors of the Offner structure to have the same sphere, which can achieve the rapid adjustment of the co-standard. This study performs a theoretical analysis of the developed Offner imaging spectrometer based on the classical Rowland circular structure, with a 21.8 mm slit length; simulates its capacity for suppressing the +2nd-order diffraction stray light with the filter; and analyzes the imaging quality after meeting the tolerance requirements, which is combined with the surface shape characteristics of the high-efficiency grating. After this test, the grating has a diffraction efficiency above 50%, and the silver-coated mirrors have a reflection value above 95% on average. Finally, the laboratory tests show that the SNR over the waveband exceeds 300 and reaches 800 at 550 nm, which is higher than some current instruments in orbit for soil observation. The proposed imaging spectrometer has a spectral resolution of 10 nm, and its modulation transfer function (MTF) is greater than 0.23 at the Nyquist frequency, making it suitable for remote sensing observation of SOM change rate. The manufacture of such a high-efficiency broadband grating and the development of the proposed instrument with high energy transmission efficiency can provide a feasible technical solution for observing faint targets with a high SNR.

12.
ACS Infect Dis ; 10(8): 2991-2998, 2024 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-39083647

RESUMO

Purpose: to explore the anti-inflammatory effects of a nanobody (Nb) specific to ß-glucan on fungal keratitis (FK). Methods: in order to verify the therapeutic and anti-inflammatory efficacy of Nb in FK, the severity of inflammation was assessed with inflammatory scores, hematoxylin-eosin (HE) staining, and myeloperoxidase (MPO) assays. In corneas of mice of FK model and human corneal epithelial cells stimulated by fungal hyphae, real-time reverse transcriptase polymerase chain reaction, Western blot, and enzyme-linked immunosorbent assay were used to detect the expression levels of inflammatory cytokines and pattern recognition receptors (PRRs). In vivo, macrophages and neutrophils infiltration in the cornea stroma was detected by immunofluorescence (IFS) staining. Results: In murine models infected with Aspergillus fumigatus (A. fumigatus), Nb treatment could reduce the inflammatory scores. HE staining and MPO results showed Nb significantly alleviated corneal edema and reduced inflammatory cell infiltration 3 days post-infection. In addition, the expression levels of LOX-1 and Dectin-1 were significantly decreased in the Nb group in vivo. The expression of chemokines CCL2 and CXCL2 also decreased in the Nb group. Compared with the PBS group, the number of macrophages and neutrophils in the Nb group was significantly decreased, which was shown in IFS results. Moreover, Nb attenuated the expression of Dectin-1, LOX-1, and inflammatory mediators, including IL-6 and IL-8 in vitro. Conclusion: our study showed that Nb could alleviate FK by downregulating the expression of PRRs and inflammatory factors as well as reducing the infiltration of macrophages and neutrophils.


Assuntos
Anti-Inflamatórios , Aspergillus fumigatus , Modelos Animais de Doenças , Ceratite , Anticorpos de Domínio Único , beta-Glucanas , Animais , Ceratite/tratamento farmacológico , Ceratite/microbiologia , Camundongos , beta-Glucanas/farmacologia , Anti-Inflamatórios/farmacologia , Humanos , Anticorpos de Domínio Único/farmacologia , Parede Celular/química , Aspergilose/tratamento farmacológico , Aspergilose/microbiologia , Aspergilose/imunologia , Córnea/efeitos dos fármacos , Citocinas/metabolismo , Macrófagos/efeitos dos fármacos , Infecções Oculares Fúngicas/tratamento farmacológico , Infecções Oculares Fúngicas/microbiologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia
13.
J Affect Disord ; 362: 391-403, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-38986877

RESUMO

BACKGROUND: Considering the high comorbidity, shared risk factors, and genetic pathways between irritable bowel syndrome (IBS) and major depressive disorder (MDD), we hypothesized that there would be both shared and disorder-specific alterations in brain function. METHODS: A total of 39 IBS patients, 39 MDD patients, and 40 healthy controls (HCs) were enrolled and matched for sex, age, and educational level. All subjects underwent resting-state functional MRI. The clinical variables of anxiety, depression, gastrointestinal symptoms and alexithymia were recorded. The 12 subregions of the striatum were employed as seeds to assess their functional connectivity (FC) with every voxel throughout the whole brain. RESULTS: Compared to HC, IBS and MDD patients exhibited aberrant frontal-striatal circuitry. We observed a common decrease in FC between the dorsal striatum and regions of the hippocampus, sensorimotor cortex, and prefrontal cortex (PFC) in both IBS and MDD patients. Patients with IBS exhibited disorder-specific decreases in FC within the striatum, along with reduced connectivity between the ventral striatum and sensorimotor cortex. In contrast, MDD patients showed disorder-specific hyperconnectivity in the medial PFC-limbic system. Receiver operating characteristic curve analysis showed that frontal-striatal FC values could serve as transdiagnostic markers of IBS and MDD. Within the IBS group, striatal connectivity was not only negatively associated with weekly abdominal pain days but also negatively correlated with the levels of anxiety and alexithymia. CONCLUSIONS: This exploratory analysis indicated that patients with IBS and MDD exhibited both shared and disorder-specific frontal-striatal circuit impairments, potentially explaining both comorbidity and distinct phenotypes.


Assuntos
Corpo Estriado , Transtorno Depressivo Maior , Síndrome do Intestino Irritável , Imageamento por Ressonância Magnética , Humanos , Transtorno Depressivo Maior/fisiopatologia , Feminino , Masculino , Síndrome do Intestino Irritável/fisiopatologia , Síndrome do Intestino Irritável/psicologia , Adulto , Corpo Estriado/fisiopatologia , Corpo Estriado/diagnóstico por imagem , Córtex Pré-Frontal/fisiopatologia , Córtex Pré-Frontal/diagnóstico por imagem , Lobo Frontal/fisiopatologia , Lobo Frontal/diagnóstico por imagem , Pessoa de Meia-Idade , Vias Neurais/fisiopatologia , Estudos de Casos e Controles , Adulto Jovem
14.
Int J Mol Sci ; 25(13)2024 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-39000539

RESUMO

Isocitrate dehydrogenase 1 (IDH1) is a necessary enzyme for cellular respiration in the tricarboxylic acid cycle. Mutant isocitrate dehydrogenase 1 (mIDH1) has been detected overexpressed in a variety of cancers. mIDH1 inhibitor ivosidenib (AG-120) was only approved by the Food and Drug Administration (FDA) for marketing, nevertheless, a range of resistance has been frequently reported. In this study, several mIDH1 inhibitors with the common backbone pyridin-2-one were explored using the three-dimensional structure-activity relationship (3D-QSAR), scaffold hopping, absorption, distribution, metabolism, excretion (ADME) prediction, and molecular dynamics (MD) simulations. Comparative molecular field analysis (CoMFA, R2 = 0.980, Q2 = 0.765) and comparative molecular similarity index analysis (CoMSIA, R2 = 0.997, Q2 = 0.770) were used to build 3D-QSAR models, which yielded notably decent predictive ability. A series of novel structures was designed through scaffold hopping. The predicted pIC50 values of C3, C6, and C9 were higher in the model of 3D-QSAR. Additionally, MD simulations culminated in the identification of potent mIDH1 inhibitors, exhibiting strong binding interactions, while the analyzed parameters were free energy landscape (FEL), radius of gyration (Rg), solvent accessible surface area (SASA), and polar surface area (PSA). Binding free energy demonstrated that C2 exhibited the highest binding free energy with IDH1, which was -93.25 ± 5.20 kcal/mol. This research offers theoretical guidance for the rational design of novel mIDH1 inhibitors.


Assuntos
Isocitrato Desidrogenase , Simulação de Dinâmica Molecular , Relação Quantitativa Estrutura-Atividade , Isocitrato Desidrogenase/antagonistas & inibidores , Isocitrato Desidrogenase/química , Isocitrato Desidrogenase/metabolismo , Isocitrato Desidrogenase/genética , Humanos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Piridonas/química , Piridonas/farmacologia
15.
J Med Chem ; 2024 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-39084610

RESUMO

HPK1, a well-known negative regulator of T cell receptors, can cause T cell dysfunction when abnormally activated. In this study, a PROTAC C3 was designed and synthesized by optimizing the physicochemical properties of the warhead, linker, and CRBN ligand. C3 demonstrated significant HPK1 degradation with a DC50 of 21.26 nM, excellent oral absorption with a Cmax of 10,899.92 ng/mL, and a bioavailability (F %) of 81.7%. C3 also showed degradation selectivity and potent immune activation effects. Proteomic and WB analyses revealed that immune-activating effect of C3 is attributed to the inhibition of SLP76 and NF-κB signaling pathways, as well as the enhancement of MAPK signaling pathway transduction. In vivo efficacy study demonstrated that oral administration of C3 in combination with anti-PDL1 antibody significantly inhibited tumor growth (tumor growth inhibition = 65.58%). These findings suggest that C3, a novel HPK1 PROTAC, holds promise as a therapeutic agent for tumor immunotherapy.

17.
Environ Sci Pollut Res Int ; 31(30): 42766-42778, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38878240

RESUMO

Homoacetogenesis is an important pathway for bio-utilization of CO2; however, oxygen is a key environmental influencing factor. This study explored the impact of different initial oxygen partial pressures (OPPs) on homoacetogenesis, while implementing low pH regulation enhanced acetic acid (HAc) accumulation under microaerobic conditions. Results indicated that cumulative HAc production increased by 18.2% in 5% OPP group, whereas decreases of 31.3% and 56.0% were observed in 10% and 20% OPP groups, respectively, compared to the control group. However, hydrogenotrophic methanogens adapted to microaerobic environment and competed with homoacetogens for CO2, thus limiting homoacetogenesis. Controlling influent pH 5.0 per cycle increased cumulative HAc production by 18.3% and 18.2% in 5% and 10% OPP groups, respectively, compared with the control group. Consequently, regulating low pH effectively inhibited methanogenic activity under microaerobic conditions, thus increasing HAc production. This study was expected to expand the practical application of homoacetogenesis in bio-utilization of CO2.


Assuntos
Ácido Acético , Oxigênio , Concentração de Íons de Hidrogênio , Ácido Acético/metabolismo , Oxigênio/metabolismo , Pressão Parcial , Dióxido de Carbono
18.
ACS Appl Mater Interfaces ; 16(26): 33723-33732, 2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38913623

RESUMO

LiFePO4 is widely used because of its high safety and cycle stability, but its inefficient electronic conductivity combined with sluggish Li+ diffusivity restricts its performance. To overcome this obstacle, applying a layer of conductive carbon onto the surface of LiFePO4 has the greatest improvement in electronic conductivity and Li+ diffusivity. However, the rate performance of carbon-coated LiFePO4 makes it difficult to meet the application requirements. Although nitrogen doping improves electrochemical performance by providing active sites and electronic conductivity, the N-doped carbon coating is prone to agglomeration, which causes a sharp decrease in capacity when the current rate increases. In this work, a synergistic N, Mn codoping strategy is implemented to overcome the aforementioned drawbacks by disrupting the large agglomeration of C-N bonds, improving the uniformity of the surface coating layer to enhance the completeness of the conductive network and increasing the number of Li+ diffusion channels, and thus accelerating the mass transfer rate under high-rate current. Consequently, this strategy effectively improves the rate capability (119 mA h g-1 at 10 C) while maintaining excellent cycling performance (88% capacity retention over 600 cycles at 5 C). This work improves the rate of ion diffusion and the rate capability of micrometer-sized LiFePO4, thus, enabling its wider application.

19.
Eur J Med Chem ; 275: 116539, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-38878515

RESUMO

AML is an aggressive malignancy of immature myeloid progenitor cells. Discovering effective treatments for AML through cell differentiation and anti-proliferation remains a significant challenge. Building on previous studies on CDK2 PROTACs with differentiation-inducing properties, this research aims to enhance CDKs degradation through structural optimization to facilitate the differentiation and inhibit the proliferation of AML cells. Compound C3, featuring a 4-methylpiperidine ring linker, effectively degraded CDK2 with a DC50 value of 18.73 ± 10.78 nM, and stimulated 72.77 ± 3.51 % cell differentiation at 6.25 nM in HL-60 cells. Moreover, C3 exhibited potent anti-proliferative activity against various AML cell types. Degradation selectivity analysis indicated that C3 could be endowed with efficient degradation of CDK2/4/6/9 and FLT3, especially FLT3-ITD in MV4-11 cells. These findings propose that C3 combined targeting CDK2/4/6/9 and FLT3 with enhanced differentiation and proliferation inhibition, which holds promise as a potential treatment for AML.


Assuntos
Antineoplásicos , Quinases Ciclina-Dependentes , Descoberta de Drogas , Leucemia Mieloide Aguda , Inibidores de Proteínas Quinases , Quimera de Direcionamento de Proteólise , Proteólise , Tirosina Quinase 3 Semelhante a fms , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Relação Estrutura-Atividade , Quimera de Direcionamento de Proteólise/química , Quimera de Direcionamento de Proteólise/farmacologia , Quimera de Direcionamento de Proteólise/uso terapêutico
20.
Sensors (Basel) ; 24(12)2024 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-38931517

RESUMO

This study integrates hollow microneedle arrays (HMNA) with a novel jellyfish-shaped electrochemical sensor for the detection of key biomarkers, including uric acid (UA), glucose, and pH, in artificial interstitial fluid. The jellyfish-shaped sensor displayed linear responses in detecting UA and glucose via differential pulse voltammetry (DPV) and chronoamperometry, respectively. Notably, the open circuit potential (OCP) of the system showed a linear variation with pH changes, validating its pH-sensing capability. The sensor system demonstrates exceptional electrochemical responsiveness within the physiological concentration ranges of these biomarkers in simulated epidermis sensing applications. The detection linear ranges of UA, glucose, and pH were 0~0.8 mM, 0~7 mM, and 4.0~8.0, respectively. These findings highlight the potential of the HMNA-integrated jellyfish-shaped sensors in real-world epidermal applications for comprehensive disease diagnosis and health monitoring.


Assuntos
Biomarcadores , Técnicas Biossensoriais , Técnicas Eletroquímicas , Líquido Extracelular , Agulhas , Líquido Extracelular/química , Biomarcadores/análise , Técnicas Biossensoriais/instrumentação , Técnicas Biossensoriais/métodos , Técnicas Eletroquímicas/instrumentação , Técnicas Eletroquímicas/métodos , Concentração de Íons de Hidrogênio , Glucose/análise , Ácido Úrico/análise , Animais , Humanos
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