Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 308
Filtrar
1.
J Am Chem Soc ; 146(28): 18841-18847, 2024 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-38975938

RESUMO

An asymmetric intramolecular spiro-amination to high steric hindering α-C-H bond of 1,3-dicarbonyl via nitrene transfer using inactive aryl azides has been carried out by developing a novel Cp*Ir(III)-SPDO (spiro-pyrrolidine oxazoline) catalyst, thereby enabling the first successful construction of structurally rigid spiro-quaternary indolinone cores with moderate to high yields and excellent enantioselectivities. DFT computations support the presence of double bridging H-F bonds between [SbF6]- and both the ligand and substrate, which favors the plane-differentiation of the enol π-bond for nitrenoid attacking. These findings open up numerous opportunities for the development of new asymmetric nitrene transfer systems.

2.
Exp Eye Res ; 244: 109919, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38729254

RESUMO

Age-related macular degeneration (AMD) is the leading cause of vision loss among the elderly, which is primarily attributed to oxidative stress-induced damage to the retinal pigment epithelium (RPE). Human amniotic mesenchymal stem cells (hAMSC) were considered to be one of the most promising stem cells for clinical application due to their low immunogenicity, tissue repair ability, pluripotent potential and potent paracrine effects. The conditional medium (hAMSC-CM) and exosomes (hAMSC-exo) derived from hAMSC, as mediators of intercellular communication, play an important role in the treatment of retinal diseases, but their effect and mechanism on oxidative stress-induced retinal degeneration are not explored. Here, we reported that hAMSC-CM alleviated H2O2-induced ARPE-19 cell death through inhibiting mitochondrial-mediated apoptosis pathway in vitro. The overproduction of reactive oxygen species (ROS), alteration in mitochondrial morphology, loss of mitochondrial membrane potential and elevation of Bax/Bcl2 ratio in ARPE-19 cells under oxidative stress were efficiently reversed by hAMSC-CM. Moreover, it was found that hAMSC-CM protected cells against oxidative injury via PI3K/Akt/FoxO3 signaling. Intriguingly, exosome inhibitor GW4869 alleviated the inhibitory effect of hAMSC-CM on H2O2-induced decrease in cell viability of ARPE-19 cells. We further demonstrated that hAMSC-exo exerted the similar protective effect on ARPE-19 cells against oxidative damage as hAMSC-CM. Additionally, both hAMSC-CM and hAMSC-exo ameliorated sodium iodate-induced deterioration of RPE and retinal damage in vivo. These results first indicate that hAMSC-CM and hAMSC-exo protect RPE cells from oxidative damage by regulating PI3K/Akt/FoxO3 pathway, suggesting hAMSC-CM and hAMSC-exo will be a promising cell-free therapy for the treatment of AMD in the future.


Assuntos
Âmnio , Exossomos , Proteína Forkhead Box O3 , Células-Tronco Mesenquimais , Estresse Oxidativo , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Degeneração Retiniana , Epitélio Pigmentado da Retina , Transdução de Sinais , Humanos , Células-Tronco Mesenquimais/metabolismo , Exossomos/metabolismo , Âmnio/citologia , Meios de Cultivo Condicionados/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Degeneração Retiniana/metabolismo , Degeneração Retiniana/patologia , Degeneração Retiniana/etiologia , Proteína Forkhead Box O3/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Apoptose , Células Cultivadas , Espécies Reativas de Oxigênio/metabolismo , Potencial da Membrana Mitocondrial , Western Blotting , Animais , Sobrevivência Celular , Peróxido de Hidrogênio/toxicidade
3.
Pediatr Res ; 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38438553

RESUMO

BACKGROUND: To facilitate the identification of less common clinical phenotypes of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) in children. METHODS: We retrospectively reviewed medical records of 236 patients with MOGAD. The following phenotypes were considered to be typical for MOGAD: ADEM, ON, TM, and NMOSD. Less common onset clinical phenotypes were screened out; their clinical and magnetic resonance imaging (MRI), diagnosis, treatment, and prognosis were summarized and analyzed. RESULTS: 16 cases (6.8%) presented as cortical encephalitis, with convulsions, headache, and fever as the main symptoms. 15 cases were misdiagnosed in the early period. 13 cases (5.5%) showed the overlapping syndrome of MOGAD and anti-N-methyl-D aspartate receptor encephalitis (MNOS), with seizures (92.3%) being the most common clinical symptom. 11 cases (84.6%) showed relapses. The cerebral leukodystrophy-like phenotype was present in seven cases (3.0%), with a recurrence rate of 50%. Isolated seizures without any findings on MRI phenotype was present in three cases (1.3%), with the only clinical symptom being seizures of focal origin. Three cases (1.3%) of aseptic meningitis phenotype presented with prolonged fever. CONCLUSION: 40/236 (16.9%) of children with MOGAD had less common phenotypes. Less common clinical phenotypes of pediatric MOGAD are susceptible to misdiagnosis and deserve more attention. IMPACT: This is the first comprehensive analysis and summary of all less commonl clinical phenotypes of MOGAD in children, while previous studies have only focused on a specific phenotype or case reports. We analyzed the characteristics of MOGAD in children and further revealed the reasons why these less common clinical phenotypes are prone to misdiagnosis and deserve more attention. Our research on treatment has shown that early detection of MOG antibodies and early treatment are of great significance for improving the prognosis of these patients.

4.
J Pineal Res ; 76(5): e12987, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38975671

RESUMO

Sleep deprivation (SD) has been associated with a plethora of severe pathophysiological syndromes, including gut damage, which recently has been elucidated as an outcome of the accumulation of reactive oxygen species (ROS). However, the spatiotemporal analysis conducted in this study has intriguingly shown that specific events cause harmful damage to the gut, particularly to goblet cells, before the accumulation of lethal ROS. Transcriptomic and metabolomic analyses have identified significant enrichment of metabolites related to ferroptosis in mice suffering from SD. Further analysis revealed that melatonin could rescue the ferroptotic damage in mice by suppressing lipid peroxidation associated with ALOX15 signaling. ALOX15 knockout protected the mice from the serious damage caused by SD-associated ferroptosis. These findings suggest that melatonin and ferroptosis could be targets to prevent devastating gut damage in animals exposed to SD. To sum up, this study is the first report that proposes a noncanonical modulation in SD-induced gut damage via ferroptosis with a clearly elucidated mechanism and highlights the active role of melatonin as a potential target to maximally sustain the state during SD.


Assuntos
Ferroptose , Melatonina , Camundongos Knockout , Privação do Sono , Animais , Camundongos , Melatonina/metabolismo , Melatonina/farmacologia , Privação do Sono/metabolismo , Masculino , Espécies Reativas de Oxigênio/metabolismo , Camundongos Endogâmicos C57BL , Peroxidação de Lipídeos , Araquidonato 15-Lipoxigenase/metabolismo , Araquidonato 15-Lipoxigenase/genética , Araquidonato 12-Lipoxigenase
5.
J Immunol ; 209(6): 1059-1070, 2022 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-36002233

RESUMO

The BCR-associated protein 31 (BAP31), a transmembrane protein in the endoplasmic reticulum, participates in the regulation of immune cells, such as microglia and T cells, and has potential functions in macrophages that remain to be unexplored. In this study, we designed and bred macrophage-specific BAP31 knockdown mice to detect the polarization and functions of macrophages. The results revealed that M2 macrophage-associated genes were suppressed in mouse bone marrow-derived macrophages of Lyz2 Cre-BAP31flox/flox mice. Multiple macrophage-associated transcription factors were demonstrated to be able to be regulated by BAP31. Among these factors, C/EBPß was the most significantly decreased and was regulated by early growth response 2. BAP31 could also affect C/EBPß via modulating IL-4Rα ubiquitination and proteasome degradation in IL-4-stimulated macrophages. Furthermore, we found that BAP31 affects macrophages functions, including angiogenesis and skin fibrosis, during the wound healing process through IL-4Rα, as confirmed by infection with adeno-associated virus-short hairpin (sh)-IL-4Rα in Lyz2 Cre-BAP31flox/flox mice. Our findings indicate a novel mechanism of BAP31 in regulating macrophages and provide potential solutions for the prevention and treatment of chronic wounds.


Assuntos
Macrófagos , Proteínas de Membrana , Complexo de Endopeptidases do Proteassoma , Cicatrização , Animais , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Proteína 2 de Resposta de Crescimento Precoce/metabolismo , Macrófagos/citologia , Proteínas de Membrana/metabolismo , Camundongos , Complexo de Endopeptidases do Proteassoma/metabolismo , Receptores de Superfície Celular/metabolismo
6.
Acta Pharmacol Sin ; 2024 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-39284878

RESUMO

Chronic itch is a maladaptive and debilitating symptom in patients with allergic contact dermatitis (ACD), adversely affecting their quality of life. There is a lack of effective treatments for ACD-associated uncontrollable itch. In this study, we explored the antipruritic effects of baicalein (BE), a bioactive flavonoid extracted from the root of Scutellaria baicalensis Georgi, and the underlying mechanisms in alleviating chronic itch triggered by diphenylcyclopropenone (DCP) in a mouse model of ACD. The ACD mice were intraperitoneally injected with BE (5, 30, and 60 mg·kg-1·d-1) for 7 days during the DCP challenge phase. The results showed that DCP-treated mice exhibited severe spontaneous scratching behaviors that was reduced after BE injections in a dose-dependent manner accompanied by inhibition of spinal astrocyte activation. We observed that the spinal astrocytic STAT3-LCN2 cascade plays a crucial role in controlling the activation of astrocytes in chronic itch. Intrathecal injection of the STAT3 inhibitor AG490 or Lcn2 siRNA significantly reduced scratching behavior and astrocyte activation in ACD mice. Moreover, BE markedly attenuated the increased phosphorylation of STAT3 (p-STAT3) and LCN2 expression in the spinal cords of ACD mice and in lipopolysaccharide-stimulated primary spinal astrocytes. Altogether, BE relieved chronic itch by suppressing the spinal astrocytic STAT3-LCN2 cascade. These findings provide a potential avenue for the management of chronic itch. Schematic summary of the main findings illustrating that BE alleviates chronic itch through suppressing the spinal astrocytic STAT3-LCN2 cascade. Specifically, BE suppresses the expression of p-STAT3 to inhibit the reactive state of astrocytes in spinal dorsal horn, and then decreases the expression of astrocytic LCN2 to alleviate chronic itch in ACD mice.

7.
Lipids Health Dis ; 23(1): 164, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38831466

RESUMO

OBJECTIVE: Although blood urea nitrogen (BUN) has a crucial impact on many diseases, its effect on outcomes in patients with hyperlipidemia remains unknown. The study aimed to investigate the relationships between BUN levels and all-cause and cardiovascular disease (CVD) mortality in individuals with hyperlipidemia. METHODS: This analysis comprised 28,122 subjects with hyperlipidemia from the National Health and Nutrition Examination Survey (NHANES) spanning 1999 to 2018. The risk of BUN on mortality was evaluated using weighted Cox regression models. Additionally, to illustrate the dose-response association, the restricted cubic spline (RCS) was used. RESULTS: During the observation period, 4276 participant deaths were recorded, of which 1206 were due to CVD. Compared to patients with hyperlipidemia in the third BUN quintile, the hazard ratios (HRs) for all-cause mortality were 1.26 (95% CIs: 1.09, 1.45) and 1.22 (95% CIs: 1.09, 1.37) for patients in the first and fifth quintiles of BUN, respectively. The HRs for CVD mortality among patients in the fifth quintile of BUN were 1.48 (95% CIs: 1.14, 1.93). BUN levels were found to have a U-shaped association with all-cause mortality and a linear association with CVD mortality using restricted triple spline analysis. CONCLUSIONS: This study revealed that both low and high BUN levels in patients with hyperlipidemia are associated with heightened all-cause mortality. Furthermore, elevated BUN levels are also associated with increased CVD mortality. The findings indicate that patients with hyperlipidemia may face an elevated risk of death if they have abnormal BUN levels.


Assuntos
Nitrogênio da Ureia Sanguínea , Doenças Cardiovasculares , Hiperlipidemias , Inquéritos Nutricionais , Humanos , Hiperlipidemias/sangue , Hiperlipidemias/mortalidade , Masculino , Feminino , Pessoa de Meia-Idade , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/sangue , Modelos de Riscos Proporcionais , Idoso , Adulto , Fatores de Risco
8.
Am J Perinatol ; 2024 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-39209304

RESUMO

Social determinants of health (SDOH) are the conditions in which people are born, grow, work, live, and age. SDOH are systemic factors that may explain, perpetuate, and exacerbate disparities in health outcomes for different populations and can be measured at both an individual and neighborhood or community level (iSDOH, nSDOH). In pregnancy, increasing evidence shows that adverse iSDOH and/or nSDOH are associated with a greater likelihood that diabetes develops, and that when it develops, there is worse glycemic control and a greater frequency of adverse pregnancy outcomes. Future research should not only continue to examine the relationships between SDOH and adverse pregnancy outcomes with diabetes but should determine whether multi-level interventions that seek to mitigate adverse SDOH result in equitable maternal care and improved patient health outcomes for pregnant individuals living with diabetes. KEY POINTS: · SDOH are conditions in which people are born, grow, work, live, and age.. · SDOH are systemic factors that may explain, perpetuate, and exacerbate disparities in health outcomes.. · SDOH can be measured at the individual and neighborhood level.. · Adverse SDOH are associated with worse outcomes for pregnant individuals living with diabetes.. · Interventions that mitigate adverse SDOH to improve maternal health equity and outcomes are needed..

9.
Int J Mol Sci ; 25(8)2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38673941

RESUMO

Abdominal aortic aneurysm (AAA) is a serious vascular disease which is associated with vascular remodeling. CD38 is a main NAD+-consuming enzyme in mammals, and our previous results showed that CD38 plays the important roles in many cardiovascular diseases. However, the role of CD38 in AAA has not been explored. Here, we report that smooth-muscle-cell-specific deletion of CD38 (CD38SKO) significantly reduced the morbidity of AngII-induced AAA in CD38SKOApoe-/- mice, which was accompanied with a increases in the aortic diameter, medial thickness, collagen deposition, and elastin degradation of aortas. In addition, CD38SKO significantly suppressed the AngII-induced decreases in α-SMA, SM22α, and MYH11 expression; the increase in Vimentin expression in VSMCs; and the increase in VCAM-1 expression in smooth muscle cells and macrophage infiltration. Furthermore, we demonstrated that the role of CD38SKO in attenuating AAA was associated with the activation of sirtuin signaling pathways. Therefore, we concluded that CD38 plays a pivotal role in AngII-induced AAA through promoting vascular remodeling, suggesting that CD38 may serve as a potential therapeutic target for the prevention of AAA.


Assuntos
ADP-Ribosil Ciclase 1 , Angiotensina II , Aneurisma da Aorta Abdominal , Camundongos Knockout , Miócitos de Músculo Liso , Remodelação Vascular , Animais , Masculino , Camundongos , ADP-Ribosil Ciclase 1/metabolismo , ADP-Ribosil Ciclase 1/genética , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/patologia , Modelos Animais de Doenças , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Cadeias Pesadas de Miosina/metabolismo , Cadeias Pesadas de Miosina/genética , Transdução de Sinais , Remodelação Vascular/genética
10.
Molecules ; 29(14)2024 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-39065007

RESUMO

The oxidation of benzylic alcohols is an important transformation in modern organic synthesis. A plethora of photoredox protocols have been developed to achieve the aerobic oxidation of alcohols into carbonyls. Recently, several groups described that ultraviolet (UV) or purple light can initiate the aerobic oxidation of benzylic alcohols in the absence of an external catalyst, and depicted different mechanisms involving the photoinduction of •O2- as a critical reactive oxygen species (ROS). However, based on comprehensive mechanistic investigations, including control experiments, radical quenching experiments, EPR studies, UV-vis spectroscopy, kinetics studies, and density functional theory calculations (DFT), we elucidate here that HOO•, which is released via the H2O2 elimination of α-hydroxyl peroxyl radicals [ArCR(OH)OO•], serves as the real chain carrier for the autocatalytic photooxidation of benzylic alcohols. The mechanistic ambiguities depicted in the precedent literature are clarified, in terms of the crucial ROS and its evolution, the rate-limiting step, and the primary radical cascade. This work highlights the necessity of stricter mechanistic analyses on UV-driven oxidative reactions that involve aldehydes' (or ketones) generation.

11.
Angew Chem Int Ed Engl ; 63(2): e202314304, 2024 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-38009446

RESUMO

Bridged benzazepine scaffolds, possessing unique structural and physicochemical activities, are widespread in various natural products and drugs. The construction of these skeletons often requires elaborate synthetic effort with low efficiency. Herein, we develop a simple and divergent approach for constructing various bridged benzazepines by a photocatalytic intermolecular dearomatization of naphthalene derivatives with readily available α-amino acids. The bridged motif is created via a cascade sequence involving photocatalytic 1,4-hydroaminoalkylation, alkene isomerization and cyclization. Interestingly, the diastereoselectivity can be regulated through different reaction modes in the cyclization step. Moreover, aminohydroxylation and its further bromination have also been demonstrated to access highly functionalized bridged benzazepines. Preliminary mechanistic studies have been performed to get insights into the mechanism. This method provides a divergent synthetic approach for construction of highly functionalized bridged benzazepines, which have been otherwise difficult to access.

12.
Angew Chem Int Ed Engl ; : e202412337, 2024 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-39106111

RESUMO

A cascade Nazarov cyclization/dicycloexpansions reaction was developed for the precise synthesis of the angularly fused M/5/N (M = 5, 6; N = 4-9, 13) tricyclic skeletons. The prioritized expansion of the first ring played a critical role in the transformations, due to the release of ring strain, and the nature of the substituents present on the substrate is another influencing factor. This pioneering cascade reaction features broad substrates scope (33 examples), short reaction time, exceptional yields (up to 95%), and remarkable regioselectivities (> 20:1). Exploiting the synthetic application of this cascade reaction, we successfully executed a succinct total synthesis of nominal madreporanone for the first time.

13.
Biomed Chromatogr ; 37(1): e5509, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36097410

RESUMO

Hyperlipidemia has been highlighted as one of the most prominent and global chronic conditions nowadays. Bidens bipinnata L. (BBL), a folk medicine in contemporary China, has efficacy in the treatment of hyperlipidemia (HLP) in China. Although some physiological and pathological function parameters of hyperlipidemia have been investigated, little information about the changes in small metabolites in biofluids has been reported. In the present study, global metabolic profiling with high-performance liquid chromatography-linear ion trap/Orbitrap high-resolution mass spectrometry (HPLC-LTQ/Orbitrap MS) combined with a pattern recognition method was performed to discover the underlying lipid-regulating mechanisms of BBL on hyperlipidemic rats induced by high-fat diet (HFD). The total of four metabolites, up- or down-regulated (p < 0.05 or 0.01), were identified and contributed to the progression of hyperlipidemia. These promising identified biomarkers underpin the metabolic pathway, including glyoxylate and dicarboxylate metabolism, the TCA cycle, sphingolipid metabolism and purine metabolism. They are disturbed in hyperlipidemic rats, and are identified using pathway analysis with MetPA. The altered metabolite indices could be regulated closer to normal levels after BBL intervention. The results demonstrated that urinary metabolomics is a powerful tool in the clinical diagnosis and treatment of hyperlipidemia to provide information on changes in metabolite pathways.


Assuntos
Bidens , Hiperlipidemias , Ratos , Animais , Ratos Sprague-Dawley , Metabolômica/métodos , Redes e Vias Metabólicas , Hiperlipidemias/metabolismo , Cromatografia Líquida de Alta Pressão
14.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 54(1): 108-113, 2023 Jan.
Artigo em Zh | MEDLINE | ID: mdl-36647652

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused an ongoing global pandemic of coronavirus disease 2019 (COVID-19). Proper nutritional support helps boost the immunity of the human body, strengthen the high-risk populations' defense against SARS-CoV-2, reduce the prevalence of COVID-19, prevent mild cases from developing into severe cases, and reduce the occurrence of adverse symptoms during recovery. Nutritional support is an important guarantee to provide protection against virus infection, promote patient recovery, and improve patient prognosis. Whole nutritional food formulas designed according to the characteristic clinical symptoms of COVID-19 provide patients with comprehensive nutritional support of appropriate nutritional content, which effectively improves the nutritional status of patients and provides strong technical support to improve their quality of survival. During the critical period of COVID-19 prevention and control, more emphasis should be placed on the essential role of nutritional support and the clinical efficacy of nutritional support should be given full play.


Assuntos
COVID-19 , Humanos , COVID-19/prevenção & controle , Estado Nutricional , Fatores de Risco , SARS-CoV-2 , Resultado do Tratamento
15.
Angew Chem Int Ed Engl ; 62(17): e202300036, 2023 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-36826223

RESUMO

The catalytic bis-allylation of alkynes is an important but challenging protocol to construct all-carbon tetra-substituted alkenes. Particularly, the catalytic unsymmetrical bis-allylation of alkynes remains as an underexplored task to date. We herein report an unprecedented unsymmetrical bis-allylation by simultaneously utilizing electrophilic trifluoromethyl alkene and nucleophilic allylboronate as the allylic reagents. With the aid of robust Ni0 /NHC catalysis, valuable skipped trienes can be obtained in high regio- and stereo-selectivities under mild conditions. Mechanistic studies indicate that the reaction may proceed through a ß-fluorine elimination of a nickelacycle followed by a transmetalation step with allylboronate. The present method exhibits a good tolerance of various functional groups. Besides, the skipped triene products can undergo an array of elaborate transformations, which highlights the potential applications of this strategy.

16.
Angew Chem Int Ed Engl ; 62(22): e202303656, 2023 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-37016511

RESUMO

Stable isotope chemical labeling methods have been widely used for high-throughput mass spectrometry (MS)-based quantitative proteomics in biological and clinical applications. However, the existing methods are far from meeting the requirements for high sensitivity detection. In the present study, a novel isobaric stable isotope N-phosphorylation labeling (iSIPL) strategy was developed for quantitative proteome analysis. The tryptic peptides were selectively labeled with iSIPL tag to generate the novel reporter ions containing phosphoramidate P-N bond with high intensities under lower collision energies. iSIPL strategy are suitable for peptide sequencing and quantitative analysis with high sensitivity and accuracy even for samples of limited quantity. Furthermore, iSIPL coupled with affinity purification and mass spectrometry was applied to measure the dynamics of cyclin dependent kinase 9 (CDK9) interactomes during transactivation of the HIV-1 provirus. The interaction of CDK9 with PARP13 was found to significantly decrease during Tat-induced activation of HIV-1 gene transcription, suggesting the effectiveness of iSIPL strategy in dynamic analysis of protein-protein interaction in vivo. More than that, the proposed iSIPL strategy would facilitate large-scale accurate quantitative proteomics by increasing multiplexing capability.


Assuntos
Proteoma , Espectrometria de Massas em Tandem , Proteoma/análise , Espectrometria de Massas em Tandem/métodos , Fosforilação , Peptídeos/química , Marcação por Isótopo/métodos , Isótopos
17.
Glia ; 70(1): 106-122, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34498776

RESUMO

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized primarily by impaired social communication and rigid, repetitive, and stereotyped behaviors. Many studies implicate abnormal synapse development and the resultant abnormalities in synaptic excitatory-inhibitory (E/I) balance may underlie many features of the disease, suggesting aberrant neuronal connections and networks are prone to occur in the developing autistic brain. Astrocytes are crucial for synaptic formation and function, and defects in astrocytic activation and function during a critical developmental period may also contribute to the pathogenesis of ASD. Here, we report that increasing hippocampal astrogenesis during development induces autistic-like behavior in mice and a concurrent decreased E/I ratio in the hippocampus that results from enhanced GABAergic transmission in CA1 pyramidal neurons. Suppressing the aberrantly elevated GABAergic synaptic transmission in hippocampal CA1 area rescues autistic-like behavior and restores the E/I balance. Thus, we provide direct evidence for a developmental role of astrocytes in driving the behavioral phenotypes of ASD, and our results support that targeting the altered GABAergic neurotransmission may represent a promising therapeutic strategy for ASD.


Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Animais , Transtorno do Espectro Autista/genética , Hipocampo/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Células Piramidais/fisiologia , Transmissão Sináptica
18.
Future Oncol ; 18(2): 149-161, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34643088

RESUMO

Background: Chemoresistance usually occurs in ovarian cancer. We aimed to explore the mechanisms of chemoresistance. Methods: Western blotting assay was used to detect the expression of GALNT14. Further cell function experiments were performed to investigate the effect of GALNT14 in ovarian cancer. Results: GALNT14 is significantly upregulated in ovarian cancer. Downregulation of GALNT14 significantly inhibits both apoptosis and ferroptosis of ovarian cancer cells. A further mechanism assay illustrated that downregulation of GALNT14 suppresses the activity of the mTOR pathway through modifying O-glycosylation of EGFR. Finally, an additive effect promoting cell death occurs with a combination of an mTOR inhibitor and cisplatin. Conclusion: Our study might provide a promising method to overcome cisplatin resistance for patients with ovarian cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , N-Acetilgalactosaminiltransferases/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/metabolismo , Feminino , Ferroptose/efeitos dos fármacos , Ferroptose/genética , Regulação Neoplásica da Expressão Gênica , Glicosilação/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Ovário/patologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Sirolimo/análogos & derivados , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Regulação para Cima
19.
J Nanobiotechnology ; 20(1): 54, 2022 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-35093074

RESUMO

BACKGROUND: Harnessing the immune system to fight cancer has led to prominent clinical successes. Strategies to stimulate innate immune effectors are attracting considerable interest in cancer therapy. Here, through conjugating multivalent Fc fragments onto the surface of mesoporous silica nanoparticles (MSN), we developed a nanoparticle-based innate immune system activator (NISA) for breast cancer immunotherapy. METHODS: NISA was prepared through conjugating mouse IgG3 Fc to MSN surface. Then, long-chain PEG5000, which was used to shield Fc to confer nanoparticle colloidal stability, was linked to the MSN surface via matrix metalloprotease-2 (MMP-2)-cleavable peptide (GPLGIAGQC). The activation of multiple components of innate immune system, including complement and the innate cells (macrophages and dendritic cells) and the associated anticancer effect were investigated. RESULTS: Fc fragments of NISA can be exposed through hydrolysis of long-chain PEG5000 by highly expressed MMP-2 in tumor microenvironment. Then, effective stimulation and activation of multiple components of innate immune system, including complement, macrophages, and dendritic cells were obtained, leading to efficient antitumor effect in 4T1 breast cancer cells and orthotopic breast tumor model in mice. CONCLUSIONS: The antitumor potency conferred by NISA highlights the significance of stimulating multiple innate immune elements in cancer immunotherapy.


Assuntos
Nanopartículas , Neoplasias , Animais , Linhagem Celular Tumoral , Imunoterapia , Macrófagos , Camundongos , Nanopartículas/uso terapêutico , Microambiente Tumoral
20.
Neurol Sci ; 43(4): 2449-2460, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34694512

RESUMO

BACKGROUND AND PURPOSE: We aimed to build a nomogram, based on patients with spontaneous intracerebral hemorrhage (SICH), to predict the probability of mortality and morbidity at 7 days and 90 days, respectively. METHODS: We performed a retrospective study, with patients at less than 6 h from ictus admitted to the department of neurosurgery in a single institute, from January 2011 to December 2018. A total of 1036 patients with SICH were included, 486 patients (46.9%) were 47-66 years old at diagnosis, and 711 patients (68.6%) were male. The least absolute shrinkage and section operator method was performed to identify the key adverse factors predicting the outcomes in patients with SICH, and multivariate logistic regression analysis was built on these variables, and then the results were visualized by a nomogram. The discrimination of the prognostic models was measured and compared by means of Harrell's concordance index (C-index), calibration curve, area under the curve (AUC), and decision curve analysis (DCA). RESULTS: Multivariate logistic regression analysis revealed that factors affecting 7-day mortality, including the following: age, therapy, Glasgow Coma Scale (GCS) admission, location, ventricle involved, hematoma volume, white blood cell (WBC), uric acid (UA), and L-lactic dehydrogenase (LDH); and factors affecting 90-day mortality, including temperature, therapy, GCS admission, ventricle involved, WBC, international normalized ratio, UA, LDH, and systolic blood pressure. The C-index for the 7-day mortality and 90-day mortality prediction nomogram was 0.9239 (95% CI = 0.9061-0.9416) and 0.9241 (95% CI = 0.9064-0.9418), respectively. The AUC of 7-day mortality was 92.4, as is true of 90-day mortality. The calibration curve and DCA indicated that nomograms in our study had a good prediction ability. For 90-day morbidity, age, marital status, and GCS at 7-day remained statistically significant in multivariate analysis. The C-index for the prediction nomogram was 0.6898 (95% CI = 0.6511-0.7285), and the calibration curve, AUC as well as DCA curve indicated that the nomogram for the prediction of good outcome demonstrated good agreement in this cohort. CONCLUSIONS: Nomograms in this study revealed many novel prognostic demographic and laboratory factors, and the individualized quantitative risk estimation by this model would be more practical for treatment management and patient counseling.


Assuntos
Hemorragias Intracranianas , Nomogramas , Adulto , Idoso , China/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Estudos Retrospectivos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA