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1.
Gene ; 851: 146962, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36272651

RESUMO

We investigated the role of the STING1-CXCR3 axis using database data and verified it in a mouse model bearing Lewis lung carcinoma (LLC) cells exposed to hydrogen peroxide (H2O2). Mice were treated with STING agonist liposomes (STING-Lip), anti-programmed death-ligand 1 (PD-L1), or STING-Lip + anti-PD-L1. The database data revealed that immune response pathways were enriched in patients with lung adenocarcinoma with upregulated STING1 signaling. Upregulated STING1 signaling was associated with a high abundance of immunoregulatory and effector molecules, cytokines, activated CD8+ T cells, and M1 macrophages in patients with lung adenocarcinoma. In this study, H2O2-treated LLC cells promoted an immunosuppressive microenvironment and enhanced tumor growth in mice. STING-Lip inhibited distant, untreated, and H2O2-induced LLC growth by activating systemic immunity. STING-Lip + anti-PD-L1 failed to slow distant and untreated LLC growth, whereas STING-Lip + anti-PD-L1 + CXCR3 antagonist inhibited distant tumor growth in mice. The combination of STING1 activation and CXCR3 inhibition may be a novel immunotherapeutic strategy to overcome immune checkpoint inhibitor resistance in lung adenocarcinoma by activating systemic immunity in the tumor microenvironment under oxidative stress.

2.
Neural Regen Res ; 18(3): 657-663, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36018191

RESUMO

A hyaluronic acid granular hydrogel can promote neuronal and astrocyte colony formation and axonal extension in vitro, suggesting that the hydrogel can simulate an extracellular matrix structure to promote neural regeneration. However, in vivo experiments have not been conducted. In this study, we transplanted a hyaluronic acid granular hydrogel nerve guidance conduit to repair a 10-mm long sciatic nerve gap. The Basso, Beattie, and Bresnahan locomotor rating scale, sciatic nerve compound muscle action potential recording, Fluoro-Gold retrograde tracing, growth related protein 43/S100 immunofluorescence staining, transmission electron microscopy, gastrocnemius muscle dry/wet weight ratio, and Masson's trichrome staining results showed that the nerve guidance conduit exhibited similar regeneration of sciatic nerve axons and myelin sheath, and recovery of the electrophysiological function and motor function as autologous nerve transplantation. The conduit results were superior to those of a bulk hydrogel or silicone tube transplant. These findings suggest that tissue-engineered nerve conduits containing hyaluronic acid granular hydrogels effectively promote the morphological and functional recovery of the injured sciatic nerve. The nerve conduits have the potential as a material for repairing peripheral nerve defects.

3.
DNA Cell Biol ; 41(11): 924-934, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36356165

RESUMO

Endoplasmic reticulum (ER) stress and oxidative stress (OS) are often related states in cells as part of normal physiology but more frequently manifested in the pathophysiology of many diseases, particularly diseases involving acute or chronic inflammation. In this study, we reviewed recent findings about the role of ER stress and OS in the pathogenesis of inflammatory diseases.


Assuntos
Estresse do Retículo Endoplasmático , Estresse Oxidativo , Humanos , Estresse do Retículo Endoplasmático/fisiologia , Estresse Oxidativo/fisiologia , Inflamação , Espécies Reativas de Oxigênio
4.
J Fungi (Basel) ; 8(11)2022 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-36422049

RESUMO

This paper aims to understand the species diversity, taxonomy, and phylogeny of Cystostereaceae (Agaricales), which is based primarily on material from East and Southeast Asia. Cystostereaceae is a small, understudied family of saprobes of woody plants with a worldwide distribution. Phylogenetic analyses of the LSU and ITS sequences revealed four distinct clades in the Cystostereaceae, representing the genera Crustomyces, Cystostereum, Effusomyces gen. nov., and Parvodontia. In addition, phylogenetic analyses showed that Cystidiodontia and Rigidotubus are synonyms of Crustomyces for their type of species nested within the Crustomyces clade. The new monotypic genus Effusomyces, based on specimens from Thailand, lacks any distinctive morphological features. Parvodontia, originally erected for a species from South America, is reported for the first time from Asia. The widely distributed and morphologically well-characterized Cystostereum is represented in East Asia by two new species: Cystostereum crassisporum and C. submurrayi. In addition, three new species, viz., Crustomyces albidus, Effusomyces thailandicus, and Parvodontia austrosinensis, are described and illustrated. Finally, three new combinations are proposed: Crustomyces isabellinus, C. laminiferus, and C. tephroleucus. A key to the genera and species of Cystostereaceae is provided. Our results proved that the species diversity of wood-decaying fungi in East and Southeast Asia is rich and suggested that more investigations and studies should be carried out in the future.

5.
Infection ; 2022 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-36260281

RESUMO

BACKGROUND: Syphilis is a chronic sexually transmitted disease caused by Treponema pallidum subspecies pallidum (T. pallidum), which is a public health problem that seriously affects human health worldwide. T. pallidum is characterized by early transmission and immune escape and is therefore termed an "invisible pathogen". METHODS: This review systematically summarizes the host's innate and adaptive immune responses to T. pallidum infection as well as the escape mechanisms of T. pallidum. PURPOSE: To lay the foundation for assessing the pathogenic mechanism and the systematic prevention and treatment of syphilis. CONCLUSION: The immune escape mechanism of T. pallidum plays an important role in its survival. Exploring the occurrence and development of these mechanisms has laid the foundation for the development of syphilis vaccine.

6.
PLoS One ; 17(10): e0276004, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36315512

RESUMO

It is deemed that meat quality of kids' is better than that of adults' for Hainan black goat. Generally, meat quality is affected by many indicators, such as intramuscular fat (IMF) content, muscle fiber diameter and shear force. It is indicated that long non-coding RNAs (lncRNAs) play essential roles in meat quality of goats. However, it is unclear whether and how lncRNAs and genes play their roles in meat quality of Hainan Black goats. Here, we firstly compared the meat quality between two-month-old kids (kids) and adult goats (adults). Then, the lncRNA-seq and RNA-seq data were integrated and analyzed to explore the potential functions of lncRNAs and genes. The results showed that adults' IMF content and muscle fiber diameter were extremely significantly higher than that of kids (P<0.01). For the sequenced data, average 84,970,398, and 83,691,250 clean reads were obtained respectively for Kids and adults, among which ~96% were mapped to the reference genome of goats. Through analyzing, 18,242 goat annotated genes, 1,429 goat annotated lncRNAs and 2,967 novel lncRNAs were obtained. Analysis of differential expression genes (DEGs) and lncRNAs (DELs) showed that 328 DEGs and 98 DELs existed between kids and adults. Furthermore, functional enrichment analysis revealed that a number of DEGs and DELs were mainly associated with IMF. Primarily, DGAT2 expressed higher in adults than that in kids and CPT1A expressed higher in kids than that in adults. Both of them were overlapped by DEGs and targets of DELs, suggesting the two DEGs and the DELs targeted by the two DEGs might be the potential regulators of goat IMF deposition. Taken together, our results provide basic support for further understanding the function and mechanism of lncRNAs and genes in meat quality of Hainan black goats.


Assuntos
Cabras , RNA Longo não Codificante , Animais , Cabras/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Carne/análise , Músculo Esquelético/metabolismo , Expressão Gênica
7.
Front Pharmacol ; 13: 1005702, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36313375

RESUMO

Treatment-resistant schizophrenia (TRS) often results in severe disability and functional impairment. Currently, the diagnosis of TRS is largely exclusionary and emphasizes the improvement of symptoms that may not be detected early and treated according to TRS guideline. As the gold standard, clozapine is the most prescribed selection for TRS. Therefore, how to predict TRS in advance is critical for forming subsequent treatment strategy especially clozapine is used during the early stage of TRS. Although mounting studies have identified certain clinical factors and neuroimaging characteristics associated with treatment response in schizophrenia, the predictors for TRS remain to be explored. Biomarkers, particularly for peripheral biomarkers, show great potential in predicting TRS in view of their predictive validity, noninvasiveness, ease of testing and low cost that would enable their widespread use. Recent evidence supports that the pathogenesis of TRS may be involved in abnormal neurotransmitter systems, inflammation and stress. Due to the heterogeneity of TRS and the lack of consensus in diagnostic criteria, it is difficult to compare extensive results among different studies. Based on the reported neurobiological mechanisms that may be associated with TRS, this paper narratively reviews the updates of peripheral biomarkers of TRS, from genetic and other related perspectives. Although current evidence regarding biomarkers in TRS remains fragmentary, when taken together, it can help to better understand the neurobiological interface of clinical phenotypes and psychiatric symptoms, which will enable individualized prediction and therapy for TRS in the long run.

8.
Artigo em Inglês | MEDLINE | ID: mdl-36114959

RESUMO

Bisphenol A (BPA) is regarded as a hazardous pollutant that exists widely in aquatic environments, posing a severe threat to human health. In this study, a vacuum ultraviolet (VUV) lamp emitting a hybrid of 254 nm and 185 nm light was used to degrade BPA. Results indicated that photolysis via 254 nm wavelength accounted for 24.93% for BPA decay, while indirect oxidation was responsible for 52.27% of decay. Results confirmed that the degradation of BPA under VUV illumination mainly occurred via photo-excited degradation and ·OH electrophilic addition reactions based on average local ionization energy (ALIE) calculation and density functional theory (DFT) calculations. Therefore, only light with a wavelength of 254 nm was able to induce the first three excited states of BPA, forming the electron transition type of n → π* from O atom to a single benzene ring and π → π* in the single benzene ring. Indirect oxidation by ·OH occurred as it preferentially attacked the C6 atom in BPA ring A. Moreover, the energy required for photo-excited degradation was about twofold than that of ·OH electrophilic addition reactions.

9.
Adv Healthc Mater ; 11(21): e2200782, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36101484

RESUMO

Impaired diabetic wound healing is associated with the persistence of chronic inflammation and excessive oxidative stress, which has become one of the most serious clinical challenges. Wound dressings with anti-inflammatory and reactive oxygen species (ROS)-scavenging properties are desirable for diabetic wound treatment. In this study, a shape-adaptable, biodegradable, biocompatible, antioxidant, and immunomodulatory interleukin-33 (IL-33)-cytogel is developed by encapsulating IL-33 into physically cross-linked DNA hydrogels and used as wound dressings to promote diabetic wound healing. The porous microstructures and biodegradable properties of the IL-33-cytogel ensure the local sustained-release of IL-33 in the wound area, where the sustained-release of IL-33 is maintained for at least 7 days. IL-33-cytogel can induce local accumulation of group 2 innate lymphoid cells (ILC2s) and regulatory T cells (Tregs), as well as M1-to-M2 transition at the wound sites. Additionally, the antioxidant and biocompatible characteristics of DNA hydrogels promote the scavenging of intracellular ROS without affecting cell viability. As a result, local inflammation in the diabetic wound area is resolved upon IL-33-cytogel treatment, which is accompanied by improved granulation tissue regeneration and accelerated wound closure. This study demonstrates a promising strategy in tissue engineering and regenerative medicine by incorporating DNA hydrogels and cytokine immunotherapy for promoting diabetic wound healing.


Assuntos
Diabetes Mellitus , Hidrogéis , Humanos , Hidrogéis/química , Antioxidantes , Interleucina-33 , Imunidade Inata , Preparações de Ação Retardada , Espécies Reativas de Oxigênio , Citocinas , Linfócitos , Cicatrização , Inflamação , DNA
10.
Cells ; 11(17)2022 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-36078054

RESUMO

Müller glial cells (MGCs) are a group of glial cells in the retina that provide essential support to retinal neurons; however, the understanding of MGC apoptosis and autophagy remains limited. This study was aimed at investigating the role of autophagy in MGCs under normal and oxidative conditions, and identifying the underlying mechanisms. In addition, the sirtuin 4 (SIRT4)-mediated signaling pathway was observed to regulate the autophagic process in MGCs. To assess the effect of autophagy on MGC mitochondrial function and survival, we treated rMC-1 cells-rat-derived Müller glial cells-with rapamycin and 3-methyladenine (3-MA), and found that MGC death was not induced by such treatment, while autophagic dysfunction could increase MGC apoptosis under oxidative stress, as reflected by the expression level of cleaved caspase 3 and PI staining. In addition, the downregulation of autophagy by 3-MA could influence the morphology of the mitochondrial network structure, the mitochondrial membrane potential, and generation of reactive oxygen species (ROS) under oxidative stress. Moreover, SIRT4 depletion enhanced autophagosome formation, as verified by an increase in the LC3 II/I ratio and a decrease in the expression of SQSTM1/p62, and vice versa. The inhibition of AMPK phosphorylation by compound C could reverse these changes in LC3 II/I and SQSTM1/p62 caused by SIRT4 knockdown. Our research concludes that MGCs can endure autophagic dysfunction in the absence of oxidative stress, while the downregulation of autophagy can cause MGCs to become more sensitized to oxidative stress. Simultaneous exposure to oxidative stress and autophagic dysfunction in MGCs can result in a pronounced impairment of cell survival. Mechanically, SIRT4 depletion can activate the autophagic process in MGCs by regulating the AMPK-mTOR signaling pathway.


Assuntos
Proteínas Quinases Ativadas por AMP , Sirtuínas , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Apoptose , Autofagia , Células Ependimogliais/metabolismo , Estresse Oxidativo , Ratos , Proteína Sequestossoma-1/metabolismo , Sirtuínas/metabolismo , Serina-Treonina Quinases TOR/metabolismo
11.
J Gastrointest Oncol ; 13(4): 1782-1792, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36092349

RESUMO

Background: Colon adenocarcinoma (COAD) is an incurable malignancy and the third most common tumor worldwide. Advances in biomarkers screening have greatly contributed to explore the new diagnostic and prognostic biomarkers for the early detection and prognostic of COAD. However, the heterogeneity-specific nature of COAD in patients of different cancer stages, different races, genders and age are still the major challenge to clinical treatment. Methods: Gene expression, copy number (CN), and dependency score (DS) data were obtained from the Cancer Cell Line Encyclopedia (CCLE), and linear regression analyses were performed using R language. We conducted receiver operating characteristic (ROC) curve analysis and compared the area under the ROC curve area under the curve (AUC) values to evaluate the sensitivity and specificity of nuclear cap binding protein subunit 2 (NCBP2) for the diagnosis of COAD in The Cancer Genome Atlas (TCGA) database. Survival analysis was performed in the distinct NCBP2 expression groups. In vitro experiments and bioinformatics analysis were used to investigate the molecular mechanisms of NCBP2 in COAD and its biological roles. A Connectivity Map (Cmap) was used to identify potential small molecule targeted drugs for NCBP2 in COAD. Results: Through the linear regression analysis of DS, CN, and gene expression, we determined that NCBP2 met our criteria. The mean AUC of the ROC curve of NCBP2 was 0.940±0.050. Survival analysis showed that high NCBP2 expression was associated with a worse prognosis [hazard ratio (HR) =1.98, P<0.007]. NCBP2 knockdown inhibited COAD cell proliferation and caused G0/G1 phase arrest in COAD cells. Conclusions: NCBP2 was the novel diagnostic and prognostic biomarker of in COAD. Our research had implications for the treatment of colon cancer.

12.
Front Immunol ; 13: 947755, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36091059

RESUMO

The intestine is the largest digestive and immune organ in the human body, with an intact intestinal mucosal barrier. Bifidobacterium longum is the specific gut commensals colonized in the human gut for boosting intestinal immunity to defend against intestinal mucosal immune injury. In the LPS-induced intestinal injury model, the Bifidobacterium longum BL-10 was suggested to boost the intestinal immune. Detailly, compared with the LPS-induced mice, the BL10 group significantly reduced intestine (jejunum, ileum, and colon) tissue injury, pro-inflammatory cytokines (TNF-α, IFN-γ, IL-2, IL-6, IL-17, IL-22, and IL-12) levels and myeloperoxidase activities. Moreover, the B. longum BL-10 significantly increased the number of immunocytes (CD4+ T cells, IgA plasma cells) and the expression of tight junction protein (Claudin1 and Occludin). B. longum BL-10 regulated the body's immune function by regulating the Th1/Th2 and Th17/Treg balance, which showed a greater impact on the Th1/Th2 balance. Moreover, the results also showed that B. longum BL-10 significantly down-regulated the intestinal protein expression of TLR4, p-IκB, and NF-κB p65. The B. longum BL-10 increased the relative abundance of the genera, including Lachnospiraceae_NK4A136_group and Clostridia_UCG-014, which were related to declining the levels of intestinal injury. Overall, these results indicated that the B. longum BL-10 had great functionality in reducing LPS-induced intestinal mucosal immune injury.


Assuntos
Bifidobacterium longum , Animais , Humanos , Imunidade , Imunomodulação , Mucosa Intestinal , Lipopolissacarídeos/farmacologia , Camundongos
13.
ACS Appl Mater Interfaces ; 14(35): 39866-39872, 2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-36018586

RESUMO

DNAzyme-based signal amplification circuits promote the advances in low-abundant miRNA imaging in living cells. However, due to the insufficient cofactor in living cells and unsustainable target utilization, self-powered and self-feedback DNAzyme amplification circuits have rarely been achieved. Here, a MnO2 nanosheet-mediated self-powered and self-feedback entropy-driven catalyst (EDC)-DNAzyme nanoprobe (MnPFEDz) was demonstrated for sensitive imaging of intracellular microRNA (miRNA). In this strategy, MnPFEDz was formed by adsorbing EDC modules and substrate probes on MnO2 nanosheets. The MnO2 nanosheets acted not only as glutathione (GSH)-responsive nanocarriers for efficient delivery of DNA probes but also as a DNAzyme cofactor supplier to power the DNAzyme biocatalysis and promote signal transduction in a feedback way. When entering the cells, GSH could decompose MnO2 nanosheets to generate numerous Mn2+ ion cofactors, leading to the release of DNA probes. Subsequently, the target miRNA initiated EDC cycles to generate amplified fluorescence signals and exposed the complete DNAzyme. Meanwhile, each of the exposed DNAzyme then cleaved the substrate probes with the help of Mn2+ ion cofactors and released a new trigger analogue for the next round of EDC cycles, initiating additional fluorescence signals in a feedback way. As a multiple signal amplification strategy, the MnPFEDz nanoprobe facilitated the effective detection of intracellular molecules with enhanced sensitivity and provided a versatile strategy for the construction of self-powered and self-feedback DNA circuits in living cells.


Assuntos
DNA Catalítico , MicroRNAs , DNA Catalítico/química , Entropia , Retroalimentação , Compostos de Manganês/química , MicroRNAs/genética , Óxidos/química
14.
Psychiatry Res ; 316: 114762, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35940088

RESUMO

There is a paucity of biomarkers for the prediction of treatment response in schizophrenia. In this study, we aimed to investigate whether diminished antipsychotic treatment response in relapsed versus first-episode schizophrenia can be revealed and predicted by a panel of blood-based biomarkers. A cross-sectional cohort consisting of 655 schizophrenia patients at different episodes and 606 healthy controls, and a longitudinal cohort including 52 first-episode antipsychotic-naïve schizophrenia patients treated with the same antipsychotic drugs during the 5-year follow-up of their first three episodes were enrolled. Plasma biomarker changes and symptom improvement were compared between the drug-free phase of psychosis onset and after 4 weeks of atypical antipsychotic drug (AAPD) treatment. In response to treatment, the extent of changes in the biomarkers of bioenergetic, purinergic, phospholipid and neurosteroid metabolisms dwindled down as number of episode and illness duration increased in relapsed schizophrenia. The changes of creatine, inosine, progesterone, allopregnanolone, cortisol and PE(16:0/22:6) were significantly correlated with the improvement of symptomatology. Inosine and progesterone at baseline were shown to be strong predictive biomarkers of treatment response. The results suggest that AAPD treatment response is diminished in the context of relapse, and our findings open new avenues for understanding the pathophysiology of treatment-resistance schizophrenia.


Assuntos
Antipsicóticos , Esquizofrenia , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Biomarcadores , Estudos Transversais , Humanos , Inosina/uso terapêutico , Estudos Longitudinais , Progesterona , Esquizofrenia/diagnóstico
15.
Front Psychol ; 13: 948740, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35936344

RESUMO

Purpose: The purpose of this study was to perform the translation and adaption of the Cognitive Reserve Index questionnaire into Chinese and assess the reliability of the Chinese version. Materials and Methods: The Chinese version of the Cognitive Reserve Index questionnaire was created from a standard forward-backward translation. A total of 371 volunteers, aged between 20 and 89 years, participated in this survey. Participants were divided into three age-groups (Young, Middle-aged, and Elderly), and subgroup differences were examined by independent samples t-tests, ANOVA analysis as well as post-hoc analysis. Pearson correlation analysis was applied to test the association between the total scores and each subscore (CRI-Education, CRI-WorkingActivity, and CRI-LeisureTime). The internal consistency and test-retest reliability of the Cognitive Reserve Index questionnaire were assessed. The test-retest reliability was measured among 40 participants with a 2-week interval using intraclass correlation coefficient. Results: Strong correlations were observed between the total scores and each subscore (CRI-Education, CRI-WorkingActivity, and CRI-LeisureTime: r = 0.65, 0.79, and 0.70, respectively). In contrast, it was found low to moderate correlations among three subscores. The internal consistency was acceptable (Cronbach's alpha coefficient = 0.68). The intraclass correlation coefficient for total scores of the Chinese version of the Cognitive Reserve Index questionnaire was 0.87 (95% CI 0.74-0.93). Conclusion: The Chinese version of the Cognitive Reserve Index questionnaire was a potentially reliable and practical tool for evaluating cognitive reserve accumulated through a person's life span.

16.
J Bone Miner Metab ; 2022 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-36036835

RESUMO

BACKGROUND AND AIM: Apolipoprotein D (ApoD) is a 25-30 kDa glycoprotein, as a distinct component of the human plasma lipoprotein system. Its known biological functions are mainly related to lipid metabolism. The purpose of this study was to explore the potential role of ApoD concentration in knee osteoarthritis (KOA). METHODS: This study was performed in a population of 113 KOA subjects and 97 healthy controls. Serum ApoD was detected using the commercial ELISA kit (Cusabio, Wu Han, China, Cat No. CSB-EL001935HU). Radiographic progression was evaluated using Kellgren-Lawrence (KL) classification. The clinical severity of KOA was assessed by visual analog score (VAS), Hospital for special surgery (HSS) knee score disease duration and TNF-α. Receiver-operating characteristic (ROC) curve was performed to test the potential diagnostic value of ApoD in radiographic progression. RESULTS: The serum ApoD level of patients with KOA was significantly lower than that of healthy controls. The serum ApoD level was negatively correlated with KL grades, VAS score, disease duration, TNF-α concentrations. On the contrary, it was positively correlated with HSS score. However, there was no correlation between this serological indicator and which side was affected. ROC curve analysis indicated that attenuated serum ApoD could serve as an appropriate biomarker concerning the diagnosis of KOA. CONCLUSIONS: Serum ApoD concentration was correlated with the presence and severity of KOA.

17.
Cardiovasc Diabetol ; 21(1): 165, 2022 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-36030201

RESUMO

BACKGROUND: Cardiomyocyte death contributes to cardiac pathology of diabetes. Studies have shown that the RIPK3/MLKL necroptosis signaling is activated in diabetic hearts. Deletion of RIPK3 was reported to attenuate myocardial injury and heart dysfunction in streptozocin (STZ)-induced diabetic mice, suggesting a potential role of necroptosis in diabetic cardiomyopathy. This study characterized cardiomyocyte necroptosis in diabetic hearts and investigated whether MLKL-mediated necroptosis is a target for cardiac protection in diabetes. METHODS: Type 1 diabetes was induced in RIPK3 knockout, MLKL knockout and wild-type mice. Akita Type-1 diabetic mice were injected with shRNA for MLKL. Myocardial function was assessed by echocardiography. Immuno-histological analyses determined cardiomyocyte death and fibrosis in the heart. Cultured adult mouse cardiomyocytes were incubated with high glucose in the presence of various drugs. Cell death and phosphorylation of RIPK3 and MLKL were analysed. RESULTS: We showed that the levels of phosphorylated RIPK3 and MLKL were higher in high glucose-stimulated cardiomyocytes and hearts of STZ-induced type-1 diabetic mice, akita mice and type-1 diabetic monkeys when compared to non-diabetic controls. Inhibition of RIPK3 by its pharmacological inhibitor or gene deletion, or MLKL deletion prevented high glucose-induced MLKL phosphorylation and attenuated necroptosis in cardiomyocytes. In STZ-induced type-1 diabetic mice, cardiomyocyte necroptosis was present along with elevated cardiac troponin I in serum and MLKL oligomerization, and co-localized with phosphorylated MLKL. Deletion of RIPK3 or MLKL prevented MLKL phosphorylation and cardiac necroptosis, attenuated serum cardiac troponin I levels, reduced myocardial collagen deposition and improved myocardial function in STZ-injected mice. Additionally, shRNA-mediated down-regulation of MLKL reduced cardiomyocyte necroptosis in akita mice. Interestingly, incubation with anti-diabetic drugs (empagliflozin and metformin) prevented phosphorylation of RIPK3 and MLKL, and reduced cell death in high glucose-induced cardiomyocytes. CONCLUSIONS: We have provided evidence that cardiomyocyte necroptosis is present in diabetic hearts and that MLKL-mediated cardiomyocyte necroptosis contributes to diabetic cardiomyopathy. These findings highlight MLKL-mediated necroptosis as a target for cardiac protection in diabetes.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Cardiomiopatias Diabéticas , Necroptose , Proteínas Quinases , Animais , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/patologia , Cardiomiopatias Diabéticas/patologia , Modelos Animais de Doenças , Glucose , Camundongos , Proteínas Quinases/metabolismo , RNA Interferente Pequeno , Troponina I
18.
Front Immunol ; 13: 923194, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35935940

RESUMO

Ovarian cancer is the most common and lethal gynecological tumor in women worldwide. High-grade serous ovarian carcinoma (HGSOC) is one of the histological subtypes of epithelial ovarian cancer, accounting for 70%. It often occurs at later stages associated with a more fatal prognosis than endometrioid carcinomas (EC), another subtype of epithelial ovarian cancer. However, the molecular mechanism and biology underlying the metastatic HGSOC (HG_M) immunophenotype remain poorly elusive. Here, we performed single-cell RNA sequencing analyses of primary HGSOC (HG_P) samples, metastatic HGSOC (HG_M) samples, and endometrioid carcinomas (EC) samples. We found that ERBB2 and HOXB-AS3 genes were more amplified in metastasis tumors than in primary tumors. Notably, high-grade serous ovarian cancer metastases are accompanied by dysregulation of multiple pathways. Malignant cells with features of epithelial-mesenchymal transition (EMT) affiliated with poor overall survival were identified. In addition, cancer-associated fibroblasts with EMT-program were enriched in HG_M, participating in angiogenesis and immune regulation, such as IL6/STAT3 pathway activity. Compared with ECs, HGSOCs exhibited higher T cell infiltration. PRDM1 regulators may be involved in T cell exhaustion in ovarian cancer. The CX3CR1_macro subpopulation may play a role in promoting tumor progression in ovarian cancer with high expression of BAG3, IL1B, and VEGFA. The new targets we discovered in this study will be useful in the future, providing guidance on the treatment of ovarian cancer.


Assuntos
Carcinoma Endometrioide , Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Carcinoma Endometrioide/metabolismo , Carcinoma Epitelial do Ovário , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Feminino , Humanos , Neoplasias Ovarianas/metabolismo , RNA , Microambiente Tumoral/genética
19.
Eur J Cancer Care (Engl) ; 31(6): e13688, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35971281

RESUMO

OBJECTIVE: Nurses' palliative care practice ability is the key to evaluating the quality of palliative care. This study aimed to identify the current situation of palliative care practices, competence and difficulties among nurses and determine whether difficulties play a mediating role between practices and competence. METHODS: A cross-sectional study was conducted. The online survey comprised demographics, the Palliative Care Self-Reported Practices Scale, the Palliative Care Nursing Self-competence Scale and the Palliative Care Difficulties Scale. Data were analysed by using descriptive statistics, univariate analysis, linear regression and mediation analysis. RESULTS: A total of 284 questionnaires were included for statistical analysis. The mean scores for practices, competence and difficulties were 67.81 (SD = 13.60), 124.28 (41.21) and 44.32 (12.68), respectively. There was a correlation between practices, competence and difficulties (p < 0.01). Competence and difficulties were independent predictors of practices (R2 adj  = 0.384, p < 0.001). Furthermore, difficulties mediated the relationship between practices and competence (b = 0.052, 95% confidence interval: 0.008-0.155). CONCLUSIONS: Continuous efforts should be made to enhance nurses' practices, competence and problem-solving abilities in palliative care. This study suggested further targeted education programmes, especially in special symptom management, interagency and multidisciplinary communication.

20.
J Dairy Sci ; 105(8): 6405-6421, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35840401

RESUMO

Infant formula is currently an important food to cope with insufficient breastfeeding. Although 1,3-olein-2-palmitin (OPO) has been used in infant formula, its effects on the immune system, gut microbiota, and metabolites for infants remain unclear. This study constructed a mouse model of colonizing healthy infant feces using antibiotic treatment and fecal microbial transplantation. Thus, the gap between the infant formula supplemented with OPO and human milk in mouse serum biochemistry, immune system, intestinal microbiota, short-chain fatty acid production, and metabolites was evaluated. Our results showed that regarding IL-9, IL-10 levels, fecal secretory IgA, and endotoxin, formula supplemented with OPO and human milk types had comparable levels. Additionally, OPO slightly increased the content of short-chain fatty acids. The 16S rRNA gene sequence analysis and metabonomics analysis demonstrated that feeding different foods affects the gut microbiota of mice; in particular, supplementing formula feeding with OPO enriched the abundance of bifidobacteria. Furthermore, feeding different foods leads to unique intestinal content of metabolites, and the gut microbiota regulates the metabolites' differences. Our results reveal a brand new perspective of OPO regarding gut microbiota and metabolites.


Assuntos
Microbioma Gastrointestinal , Fórmulas Infantis , Animais , Ácidos Graxos Voláteis/análise , Fezes/microbiologia , Microbioma Gastrointestinal/genética , Humanos , Fórmulas Infantis/química , Camundongos , Leite Humano/química , RNA Ribossômico 16S/análise
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