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1.
Nat Commun ; 14(1): 8, 2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36596787

RESUMO

Despite neoadjuvant/conversion chemotherapy, the prognosis of cT4a/bN+ gastric cancer is poor. Immune checkpoint inhibitors (ICIs) and antiangiogenic agents have shown activity in late-stage gastric cancer, but their efficacy in the neoadjuvant/conversion setting is unclear. In this single-armed, phase II, exploratory trial (NCT03878472), we evaluate the efficacy of a combination of ICI (camrelizumab), antiangiogenesis (apatinib), and chemotherapy (S-1 ± oxaliplatin) for neoadjuvant/conversion treatment of cT4a/bN+ gastric cancer. The primary endpoints are pathological responses and their potential biomarkers. Secondary endpoints include safety, objective response, progression-free survival, and overall survival. Complete and major pathological response rates are 15.8% and 26.3%. Pathological responses correlate significantly with microsatellite instability status, PD-L1 expression, and tumor mutational burden. In addition, multi-omics examination reveals several putative biomarkers for pathological responses, including RREB1 and SSPO mutation, immune-related signatures, and a peripheral T cell expansion score. Multi-omics also demonstrates dynamic changes in dominant tumor subclones, immune microenvironments, and T cell receptor repertoires during neoadjuvant immunotherapy. The toxicity and post-surgery complications are limited. These data support further validation of ICI- and antiangiogenesis-based neoadjuvant/conversion therapy in large randomized trials and provide candidate biomarkers.


Assuntos
Inibidores de Checkpoint Imunológico , Neoplasias Gástricas , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia , Terapia Neoadjuvante , Intervalo Livre de Progressão , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Microambiente Tumoral
2.
Chem Biodivers ; : e202200308, 2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36621947

RESUMO

The therapeutic effect of apigenin (APG) on hyperlipidemia was investigated using network pharmacology combined with molecular docking strategy, and the potential targets of APG in the treatment of hyperlipidemia were explored. Genetic Ontology Biological Process (GOBP) and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway enrichment analysis of common targets were performed. Then, molecular docking was used to predict the binding mode of APG to the target. Finally, Sprague Dawley rats were used to establish a hyperlipidemia model. The expression levels of insulin (INS) and vascular endothelial growth factor A (VEGFA) mRNA in each group were detected by quantitative reverse transcription-polymerase chain reaction. Network pharmacological studies revealed that the role of APG in the treatment of hyperlipidemia was through the regulation of INS, VEGFA, tumor necrosis factor, epidermal growth factor receptor, matrix metalloprotein 9, and other targets, as well as through the regulation of the hypoxia-inducible factor 1 (HIF-1) signaling pathway, fluid shear stress, and atherosclerosis signaling pathways, vascular permeability; APG also participated in the regulation of glucose metabolism and lipid metabolism, and acted on vascular endothelial cells, and regulated vascular tone. Molecular docking showed that APG binds to the target with good efficiency. Experiments showed that after APG treatment, the expression levels of INS and VEGFA mRNA in the model group were significantly decreased (p<0.01). In conclusion, APG has multiple targets and affects pathways involved in the treatment of hyperlipidemia by regulating the HIF-1 signaling pathway, fluid shear stress, and the atherosclerosis pathway.

3.
Eur J Oncol Nurs ; 62: 102267, 2023 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-36716532

RESUMO

PURPOSE: To systematically collect published research in order to identify and quantify risk factors for delirium in advanced cancer patients. METHODS: The Cochrane Library, PubMed, Proquest, CINAHL, Web of Science, Ovid MEDLINE, Embase, Scopus, Chinese Wanfang Data, Chinese Periodical Full-text Database (VIP), Chinese Biomedical Literature Database (CBM), and Chinese National Knowledge Infrastructure (CNKI) were systematically searched for cohort or case-control studies reporting individual risk factors for delirium among advanced-stage cancer patients published prior to March 2022. The Newcastle-Ottawa Scale was used to assess the methodological quality of included studies. The pooled adjusted odds ratio (aOR) and its 95% confidence interval were calculated using the RevMan 5.4 software package. RESULTS: A total of 15 studies with data from 3106 advanced cancer patients were included in our analysis. Nine studies were high-quality and six were of moderate quality. Pooled analyses revealed that 11 risk factors were statistically significant. High-intensity risk factors included sleep disturbance, infection, cachexia and the Palliative Prognostic Index; medium-intensity risk factors included male sex, renal failure, dehydration and drowsiness; low-intensity risk factors included age, total bilirubin and opioid use. Antibiotic use was found to have been a protective factor. CONCLUSIONS: We identified 12 independent risk factors that were significantly associated with delirium in advanced cancer patients and provide an evidence-based foundation to implement appropriate preventive strategies.

4.
Mol Neurobiol ; 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36717479

RESUMO

Increasing evidence suggests that circadian dysfunction is related to Parkinson's disease (PD). However, the role of circadian clock genes in PD is still poorly understood. This study aimed to illustrate the association between genetic variants of circadian clock genes and PD in a large Chinese population cohort. Ten circadian clock genes were included in this study. Whole-exome sequencing (WES) was conducted in 1997 early-onset or familial PD patients and 1652 controls (WES cohort), and whole-genome sequencing (WGS) was conducted in 1962 sporadic late-onset PD patients and 1279 controls (WGS cohort). Analyses were completed using the optimized sequence kernel association test and regression analyses. In the burden analysis of the circadian clock gene set, we found suggestive significant associations between the circadian clock genes and PD in the WES cohort when considering missense, damaging missense (Dmis), and deleterious variants. Moreover, the burden analysis of single genes revealed suggestive significant associations between PD and the loss-of-function variants of the CRY1 gene, missense, Dmis, and deleterious variants of the PER1 gene, and Dmis and deleterious variants of the PER2 gene in the WES cohort. Rare variants in the WGS cohort and all common variants in the WGS and WES cohorts were unrelated to PD. Phenotypic analysis indicated that deleterious variants of the PER1 gene were associated with dyskinesia in the WES cohort. Our study provides evidence of a potential link between circadian clock genes and PD from a genetic perspective.

5.
Med Oncol ; 40(2): 73, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36607478

RESUMO

Colorectal cancer (CRC) is the third leading malignancy worldwide in both new cases and deaths. Neoadjuvant radiotherapy is the standard preoperative regimens for locally advanced patients. However, approximately 50% of patients develop recurrence and metastasis after radiotherapy, which is largely due to the radiation resistance properties of the tumor, and the internal mechanism has not been elucidated. Here we found that CEMIP expression is up-regulated in a variety of tumor types, particularly in CRC. Public databases and clinical samples revealed that CEMIP expression is significantly higher in tumor tissues than in adjacent normal tissues in patients with locally advanced CRC who received neoadjuvant chemoradiotherapy, and it is closely related to the poor prognosis. Functional characterization uncovered that downregulation of CEMIP expression can enhance the radiosensitivity of CRC cells, which is confirmed to be achieved by promoting DNA damage and apoptosis. In vivo studies further verified that CEMIP knockdown can significantly improve the radiosensitivity of subcutaneously implanted colorectal tumors in mice, suggesting that CEMIP may be a radiation-resistant gene in CRC. Mechanistically, EGFR/PI3K/Akt signaling pathway is hypothesized to play a key role in CEMIP mediating radiation resistance. These results provide a potential new strategy targeting CEMIP gene for the comprehensive treatment of locally advanced CRC patients.


Assuntos
Neoplasias Colorretais , Animais , Camundongos , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/radioterapia , Neoplasias Colorretais/metabolismo , Regulação para Baixo , Fosfatidilinositol 3-Quinases/metabolismo , Tolerância a Radiação/genética , Hialuronoglucosaminidase/genética
6.
J Funct Biomater ; 14(1)2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36662091

RESUMO

To explore the potential applicability of chitosan (CTS), we prepared aldehyde chitosan (CTS-CHO) with chitosan and sodium periodate via oxidation reaction and then a chitosan-based hydrophilic and antibacterial coating on the surface of poly (lactic acid) (PLA) film was developed and characterized. The oxidation degree was determined by Elemental analyser to be 12.53%, and a Fourier transform infrared spectroscopy was used to characterize the structure of CTS-CHO. It was evident that CTS-CHO is a biocompatible coating biomaterial with more than 80% cell viability obtained through the Live/Dead staining assay and the alamarBlue assay. The hydrophilic and antibacterial CTS-CHO coating on the PLA surface was prepared by ultrasonic atomization assisted LbL assembly technique due to Schiff's base reaction within and between layers. The CTS-CHO coating had better hydrophilicity and transparency, a more definite industrialization potential, and higher antibacterial activity at experimental concentrations than the CTS coating. All of the results demonstrated that the ultrasonic atomization-assisted LbL assembly CTS-CHO coating is a promising alternative for improving hydrophilicity and antibacterial activity on the PLA surface. The functional groups of CTS-CHO could react with active components with amino groups via dynamic Schiff's base reaction and provide the opportunity to create a drug releasing surface for biomedical applications.

7.
J Diabetes Complications ; 37(2): 108406, 2023 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-36682230

RESUMO

OBJECTIVES: The impacts of diabetic peripheral neuropathy (DPN) on clinical manifestations of left ventricular (LV) function in patients suffering from type 2 diabetes mellitus (T2DM) and the preserved LV ejection fraction (LVEF) lack a full evaluation. This study was carried out to investigate the correlation of peripheral neuropathy with subclinical LV systolic dysfunction, accompanied by the exploration of the relevant clinical features of peripheral neuropathy in these patients. METHODS: A retrospective analysis was conducted depending on the data of 101 consecutive inpatients with T2DM and preserved LVEF (all ≥ 50 %), without coronary artery disease and other histories of heart disease. All subjects received both a nerve conduction assessment and a speckle-tracking echocardiography examination. Global longitudinal strain (GLS) was conducted to assess the subclinical LV systolic function. RESULTS: Forty-six (46 %) patients were diagnosed as DPN according to electrophysiological examination and clinical assessment. A significant difference was revealed in GLS between patients with and without DPN (16.5 ± 2.8 vs. 19.3 ± 3.4, p < 0.001). Multiple logistic regression analysis indicated GLS as one of the independent determinative factors for DPN (odds ratio, 0.68; P < 0.001). In addition, motor-sensory nerve conduction exhibited a significant positive correlation with GLS, which may not be revealed between the types of peripheral nerve damage. CONCLUSIONS: Despite the preserved LVEF, the subclinical LV myocardial dysfunction may have occurred in T2DM patients with DPN. Peripheral nerve conduction was significantly correlated with GLS. An early assessment of nerve conduction may exert a dual warning significance for the progression of subclinical LV dysfunction in asymptomatic patients with T2DM.

8.
Cell Commun Signal ; 21(1): 14, 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36670446

RESUMO

BACKGROUND: Cellular communication network factor 3 (CCN3) has been implicated in the regulation of osteoblast differentiation. However, it is not known if CCN3 can regulate valvular calcification. While macrophages have been shown to regulate valvular calcification, the molecular and cellular mechanisms of this process remain poorly understood. In the present study, we investigated the role of macrophage-derived CCN3 in the progression of calcific aortic valve disease. METHODS: Myeloid-specific knockout of CCN3 (Mye-CCN3-KO) and control mice were subjected to a single tail intravenous injection of AAV encoding mutant mPCSK9 (rAAV8/D377Y-mPCSK9) to induce hyperlipidemia. AAV-injected mice were then fed a high fat diet for 40 weeks. At the conclusion of high fat diet feeding, tissues were harvested and subjected to histologic and pathologic analyses. In vitro, bone marrow-derived macrophages (BMDM) were obtained from Mye-CCN3-KO and control mice and the expression of bone morphogenic protein signaling related gene were verified via quantitative real-time PCR and Western blotting. The BMDM conditioned medium was cocultured with human valvular intersititial cells which was artificially induced calcification to test the effect of the conditioned medium via Western blotting and Alizarin red staining. RESULTS: Echocardiography revealed that both male and female Mye-CCN3-KO mice displayed compromised aortic valvular function accompanied by exacerbated valve thickness and cardiac dysfunction. Histologically, Alizarin-Red staining revealed a marked increase in aortic valve calcification in Mye-CCN3-KO mice when compared to the controls. In vitro, CCN3 deficiency augmented BMP2 production and secretion from bone marrow-derived macrophages. In addition, human valvular interstitial cells cultured with conditioned media from CCN3-deficient BMDMs resulted in exaggerated pro-calcifying gene expression and the consequent calcification. CONCLUSION: Our data uncovered a novel role of myeloid CCN3 in the regulation of aortic valve calcification. Modulation of BMP2 production and secretion in macrophages might serve as a key mechanism for macrophage-derived CCN3's anti-calcification function in the development of CAVD. Video Abstract.


Assuntos
Estenose da Valva Aórtica , Calcinose , Masculino , Feminino , Humanos , Camundongos , Animais , Valva Aórtica/metabolismo , Valva Aórtica/patologia , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/patologia , Meios de Cultivo Condicionados , Calcinose/metabolismo , Calcinose/patologia , Células Cultivadas
9.
Int J Mol Sci ; 24(2)2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36674552

RESUMO

Platelets are the second most abundant blood component after red blood cells and can participate in a variety of physiological and pathological functions. Beyond its traditional role in hemostasis and thrombosis, it also plays an indispensable role in inflammatory diseases. However, thrombocytopenia is a common hematologic problem in the clinic, and it presents a proportional relationship with the fatality of many diseases. Therefore, the prevention and treatment of thrombocytopenia is of great importance. The expression of Toll-like receptors (TLRs) is one of the most relevant characteristics of thrombopoiesis and the platelet inflammatory function. We know that the TLR family is found on the surface or inside almost all cells, where they perform many immune functions. Of those, TLR2 and TLR4 are the main stress-inducing members and play an integral role in inflammatory diseases and platelet production and function. Therefore, the aim of this review is to present and discuss the relationship between platelets, inflammation and the TLR family and extend recent research on the influence of the TLR2 and TLR4 pathways and the regulation of platelet production and function. Reviewing the interaction between TLRs and platelets in inflammation may be a research direction or program for the treatment of thrombocytopenia-related and inflammatory-related diseases.


Assuntos
Trombocitopenia , Trombopoese , Humanos , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Receptores Toll-Like , Trombocitopenia/metabolismo , Inflamação
10.
iScience ; 26(1): 105816, 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36636340

RESUMO

Obesity has become a global epidemic, associated with several chronic complications. The intestinal microbiome is a critical regulator of metabolic homeostasis and obesity. Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has putative anti-obesity effects. In this study, we used multi-omics analysis to determine whether empagliflozin regulates metabolism in an obese host through the intestinal microbiota. Compared with obese mice, the empagliflozin-treated mice had a higher species diversity of gut microbiota, characterized by a reduction in the Firmicutes/Bacteroides ratio. Metabolomic analysis unambiguously identified 1,065 small molecules with empagliflozin affecting metabolites mainly enriched in amino acid metabolism, such as tryptophan metabolism. RNA sequencing results showed that immunoglobulin A and peroxisome proliferator-activated receptor signaling pathways in the intestinal immune network were activated after empagliflozin treatment. This integrative analysis highlighted that empagliflozin maintains intestinal homeostasis by modulating gut microbiota diversity and tryptophan metabolism. This will inform the development of therapies for obesity based on host-microbe interactions.

11.
Oxid Med Cell Longev ; 2023: 5199810, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36644582

RESUMO

Atrial fibrillation (AF) is a major risk factor for ischemic stroke. We aimed to identify novel potential biomarkers with diagnostic value in patients with atrial fibrillation-related cardioembolic stroke (AF-CE).Publicly available gene expression profiles related to AF, cardioembolic stroke (CE), and large artery atherosclerosis (LAA) were downloaded from the Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) were identified and then functionally annotated. The support vector machine recursive feature elimination (SVM-RFE) and least absolute shrinkage and selection operator (LASSO) regression analysis were conducted to identify potential diagnostic AF-CE biomarkers. Furthermore, the results were validated by using external data sets, and discriminability was measured by the area under the ROC curve (AUC). In order to verify the predictive results, the blood samples of 13 healthy controls, 20 patients with CE, and 20 patients with LAA stroke were acquired for RT-qPCR, and the correlation between biomarkers and clinical features was further explored. Lastly, a nomogram and the companion website were developed to predict the CE-risk rate. Three feature genes (C1QC, VSIG4, and CFD) were selected and validated in the training and the external datasets. The qRT-PCR evaluation showed that the levels of blood biomarkers (C1QC, VSIG4, and CFD) in patients with AF-CE can be used to differentiate patients with AF-CE from normal controls (P < 0.05) and can effectively discriminate AF-CE from LAA stroke (P < 0.05). Immune cell infiltration analysis revealed that three feature genes were correlated with immune system such as neutrophils. Clinical impact curve, calibration curves, ROC, and DCAs of the nomogram indicate that the nomogram had good performance. Our findings showed that C1QC, VSIG4, and CFD can potentially serve as diagnostic blood biomarkers of AF-CE; novel nomogram and the companion website can help clinicians to identify high-risk individuals, thus helping to guide treatment decisions for stroke patients.


Assuntos
Aterosclerose , Fibrilação Atrial , AVC Embólico , Humanos , Aterosclerose/complicações , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/genética , Biomarcadores , AVC Embólico/diagnóstico , AVC Embólico/genética , AVC Embólico/complicações
12.
Nature ; 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36653448

RESUMO

The human microbiome is an integral component of the human body and a co-determinant of several health conditions1,2. However, the extent to which interpersonal relations shape the individual genetic makeup of the microbiome and its transmission within and across populations remains largely unknown3,4. Here, capitalizing on more than 9,700 human metagenomes and computational strain-level profiling, we detected extensive bacterial strain sharing across individuals (more than 10 million instances) with distinct mother-to-infant, intra-household and intra-population transmission patterns. Mother-to-infant gut microbiome transmission was considerable and stable during infancy (around 50% of the same strains among shared species (strain-sharing rate)) and remained detectable at older ages. By contrast, the transmission of the oral microbiome occurred largely horizontally and was enhanced by the duration of cohabitation. There was substantial strain sharing among cohabiting individuals, with 12% and 32% median strain-sharing rates for the gut and oral microbiomes, and time since cohabitation affected strain sharing more than age or genetics did. Bacterial strain sharing additionally recapitulated host population structures better than species-level profiles did. Finally, distinct taxa appeared as efficient spreaders across transmission modes and were associated with different predicted bacterial phenotypes linked with out-of-host survival capabilities. The extent of microorganism transmission that we describe underscores its relevance in human microbiome studies5, especially those on non-infectious, microbiome-associated diseases.

13.
J Transl Med ; 21(1): 27, 2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36647167

RESUMO

Mitochondria determine the physiological status of most eukaryotes. Mitochondrial dynamics plays an important role in maintaining mitochondrial homeostasis, and the disorder in mitochondrial dynamics could affect cellular energy metabolism leading to tumorigenesis. In recent years, disrupted mitochondrial dynamics has been found to influence the biological behaviors of gastrointestinal cancer with the potential to be a novel target for its individualized therapy. This review systematically introduced the role of mitochondrial dynamics in maintaining mitochondrial homeostasis, and further elaborated the effects of disrupted mitochondrial dynamics on the cellular biological behaviors of gastrointestinal cancer as well as its association with cancer progression. We aim to provide clues for elucidating the etiology and pathogenesis of gastrointestinal cancer from the perspective of mitochondrial homeostasis and disorder.


Assuntos
Neoplasias Gastrointestinais , Mitocôndrias , Humanos , Mitocôndrias/metabolismo , Dinâmica Mitocondrial , Neoplasias Gastrointestinais/metabolismo , Neoplasias Gastrointestinais/patologia , Homeostase , Carcinogênese/patologia
14.
JCI Insight ; 8(1)2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36625347

RESUMO

Vascular smooth muscle cell (SMC) phenotypic switching is widely recognized as a key mechanism responsible for the pathogenesis of several aortic diseases, such as aortic aneurysm. Cellular communication network factor 2 (CCN2), often upregulated in human pathologies and animal disease models, exerts myriad context-dependent biological functions. However, current understanding of the role of SMC-CCN2 in SMC phenotypic switching and its function in the pathology of abdominal aortic aneurysm (AAA) is lacking. Here, we show that SMC-restricted CCN2 deficiency causes AAA in the infrarenal aorta of angiotensin II-infused (Ang II-infused) hypercholesterolemic mice at a similar anatomic location to human AAA. Notably, the resistance of naive C57BL/6 WT mice to Ang II-induced AAA formation is lost upon silencing of CCN2 in SMC. Furthermore, the pro-AAA phenotype of SMC-CCN2-KO mice is recapitulated in a different model that involves the application of elastase-ß-aminopropionitrile. Mechanistically, our findings reveal that CCN2 intersects with TGF-ß signaling and regulates SMC marker expression. Deficiency of CCN2 triggers SMC reprograming associated with alterations in Krüppel-like factor 4 and contractile marker expression, and this reprograming likely contributes to the development of AAA in mice. These results identify SMC-CCN2 as potentially a novel regulator of SMC phenotypic switching and AA biology.


Assuntos
Aneurisma da Aorta Abdominal , Músculo Liso Vascular , Humanos , Camundongos , Animais , Músculo Liso Vascular/patologia , Reprogramação Celular , Camundongos Endogâmicos C57BL , Aneurisma da Aorta Abdominal/metabolismo , Miócitos de Músculo Liso/metabolismo
15.
BMC Med Genomics ; 16(1): 2, 2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36611208

RESUMO

BACKGROUND: Hepatocellular Carcinoma (HCC) is a common malignant neoplasm with limited treatment options and poor outcomes. Thus, there is an urgent need to find sensitive biomarkers for HCC. METHODS: Gene expression and clinicopathological information were obtained from public databases, based on which a pyroptosis-related gene signature was constructed by the least absolute shrinkage and selection operator Cox regression. The applicability of the signature was evaluated via Kaplan-Meier curve and time-dependent ROC curve. TIMER, QUANTISEQ, MCPCOUNTER, EPIC, CIBERSORT, ssGSEA, and ESTIMATE were employed to assess the immune status. Comparisons between groups were analyzed with Wilcoxon test. Pearson and Spearman correlation analyses were adopted for linear correlation analysis. Genetic knockdown was conducted using siRNA transfection and the mRNA expression levels of interest genes were measured using quantitative reverse transcription PCR. Finally, protein levels in 10 paired tumor tissues and adjacent non-tumor tissues from HCC patients were measured using immunohistochemistry. RESULTS: A pyroptosis-related gene signature was established successfully to calculate independent prognostic risk scores. It was found that survival outcomes varied significantly between different risk groups. In addition, an attenuated antitumor immune response was found in the high-risk group. Meanwhile, multiple immune checkpoints were up-regulated in high-risk score patients. Cell cycle-related genes, angiogenesis-related genes and tumor drug resistance genes were also markedly elevated. Knockdown of prognostic genes in the signature significantly inhibited the expression of immune checkpoint genes and angiogenesis-related genes. Besides, each prognostic gene was expressed at a higher level in HCC tissues than in adjacent normal tissues. CONCLUSIONS: We successfully established a novel pyroptosis-related gene signature which could help predict the overall survival and assess the immune status of HCC patients.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Piroptose/genética , Neoplasias Hepáticas/genética , Prognóstico , Bases de Dados Factuais , Biomarcadores Tumorais/genética
16.
Redox Biol ; 60: 102608, 2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36681047

RESUMO

BACKGROUND: We recently reported a novel IgG4-centered immune evasion mechanism in cancer, and this was achieved mostly through the Fc-Fc reaction of increased IgG4 to cancer-bound IgG in cancer microenvironment. The mechanism was suggested to be related to cancer hyperprogressive disease (HPD) which is a side-effect often associated to IgG4 subtype PD-1 antibody immunotherapy. HPD was reported to occur in cancers with certain mutated genes including KRAS and such mutations are often associated to glutathione (GSH) synthesis. Therefore, we hypothesize that IgG4 and GSH may play a synergistic role in local immunosuppression of cancer. METHODS: Quantitatively analyzed the distribution and abundance of GSH and IgG4 in human cancer samples with ELISA and immunohistochemistry. The interactions between GSH and IgG4 were examined with Electrophoresis and Western Blot. The synergistic effects of the two on classic immune responses were investigated in vitro. The combined effects were also tested in a lung cancer model and a skin graft model in mice. RESULTS: We detected significant increases of both GSH and IgG4 in the microenvironment of lung cancer, esophageal cancer, and colon cancer tissues. GSH disrupted the disulfide bond of IgG4 heavy chain and enhanced IgG4's ability of Fc-Fc reaction to immobilized IgG subtypes. Combined administration of IgG4 and GSH augmented the inhibitory effect of IgG4 on the classic ADCC, ADCP, and CDC reactions. Local administration of IgG4/GSH achieved the most obvious effect of accelerating cancer growth in the mouse lung cancer model. The same combination prolonged the survival of skin grafts between two different strains of mouse. In both models, immune cells and several cytokines were found to shift to the state of immune tolerance. CONCLUSION: Combined application of GSH and IgG4 can promote tumor growth and protect skin graft. The mechanism may be achieved through the effect of the Fc-Fc reaction between IgG4 and other tissue-bound IgG subtypes resulting in local immunosuppression. This reaction was facilitated by increased GSH to dissociate the two heavy chains of IgG4 Fc fragment at its disulfide bonds. Our findings unveiled the interaction between the redox system and the immune systems in cancer microenvironment. It offers a sensible explanation for HPD and provides new possibilities for manipulating this mechanism for cancer immunotherapy.

17.
Physiol Plant ; : e13861, 2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36690459

RESUMO

Expansins are cell-wall loosening proteins involved in plant cell expansion and elongation. Objectives of this study were to identify expansins related to leaf elongation in a perennial grass species and determine the relationship between the expression of expansin genes and leaf elongation. A total of 20 expansin genes were identified in tall fescue (Festuca arundinacea), out of which 9 genes belonged to the EXPA- and 11 to the EXPB subfamily. Two genotypes ('TF007' and 'TF116') with different growth rates were used to determine the correlation between expansins and leaf growth. Among the 20 expansins, 16 were differentially expressed in the leaf growth zone in 'TF007' and 'TF116'. The further analysis of gene expression in different leaf segments of 'TF007' and 'TF116' revealed that the expression level of FaEXPB16 was positively correlated with leaf elongation rate, and 'TF007' had a higher leaf elongation rate than 'TF116' due to the greater expression level of FaEXPB16. FaEXPA7 exhibited significantly higher expression level in leaves of the rapid-growing genotypes than the slow-growing genotypes, suggesting that FaEXPA7 acts as a positive regulator for leaf elongation. FaEXPA7 also exhibited its highest expression level in the cell division zone located in the leaf base. FaEXPB3, FaEXPB4-2, and FaEXPB11-2 showed a negative correlation with the leaf elongation rate in 'TF007' and 'TF116' and were highly expressed in leaves of the slow-growing genotypes. As promoting or repressing factors for leaf growth, these five expansins could be used as candidate genes in developing the rapid or slow-growing perennial grass species. This article is protected by copyright. All rights reserved.

18.
Exp Ther Med ; 25(1): 41, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36569432

RESUMO

Intestinal ischemia/reperfusion (I/R) injury is a common clinical problem with a high mortality rate, resulting from loss of blood flow to an intestinal segment. Adenosine serves a protective role in intestinal I/R injury; however, its potential mechanism is not completely understood. The present study aimed to investigate the protective effects of adenosine A1 receptor (A1R) agonists CPA and LUF6941 and whether their mechanisms are associated with the PI3K/Akt signaling pathway. To simulate intestinal I/R injury, a cell oxygen-glucose deprivation/reoxygenation (OGD/R) model was established and the human colon cancer cell line (Caco-2) was incubated with A1R agonists before OGD/R treatment. The viability of Caco-2 cells was detected by PI and Cell Counting Kit-8 assay, apoptosis was detected using flow cytometry and western blotting was used to analyze protein expression levels of PI3K, Akt and p53 in Caco-2 cells. A1R agonist pretreatment protected Caco-2 cells against OGD/R-induced cell damage and activated PI3K/Akt signaling. Additionally, apoptosis was inhibited by downregulating phosphorylation of p53 protein, as evidenced by increased cell viability. These findings suggested that A1R agonists decreased OGD/R damage in Caco-2 cells, which may be due to their anti-apoptotic effects and activation of the PI3K/Akt/p53 signal pathway.

19.
Biosens Bioelectron ; 222: 114990, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36495719

RESUMO

Neurotransmitter serotonin (5-HT) is involved in various physiological and pathological processes. Therefore, its highly sensitive and selective detection in human serum is of great significance for early diagnosis of disease. In this work, employing iron phthalocyanine as Fe source, ultrafine Fe3O4 nanoparticles anchored on carbon spheres (Fe3O4/CSs) have been prepared, which exhibits an excellent electrochemical sensing performance toward 5-HT. With carbonecous spheres turned into conductive carbon spheres under the heat treatment in N2 atmosphere, iron phthalocyanine absorbed on their surfaces are simultaneously pyrolysised and oxidized, and finally transformed into ultrafine Fe3O4 nanoparticles. Electrochemical results demonstrate a high sensitivity (5.503 µA µM-1) and a low detection limit (4 nM) toward 5-HT for as-prepared Fe3O4/CSs. In combination with the morphology and physicochemical property of Fe3O4/CSs, the enhanced sensing mechanism toward 5-HT is disscussed. In addition, the developed electrochemical sensor also displays a good sensing stability and an anti-interferent ability. Further applied in real human serum samples, a satisfactory recovery rate is achieved. Promisingly, the developed electrochemical sensor can be employed for the determination of 5-HT in actual samples.


Assuntos
Técnicas Biossensoriais , Nanopartículas , Humanos , Carbono/química , Serotonina , Limite de Detecção , Técnicas Biossensoriais/métodos , Técnicas Eletroquímicas/métodos , Eletrodos
20.
Biomed Pharmacother ; 158: 114106, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36535197

RESUMO

Heart failure (HF) is a complex clinical syndrome caused by various cardiovascular diseases. Its main pathogenesis includes cardiomyocyte loss, myocardial energy metabolism disorder, and activation of cardiac inflammation. Due to the clinically unsatisfactory treatment of heart failure, different mechanisms need to be explored to provide new targets for the treatment of this disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a gene mainly related to familial hypercholesterolemia, was discovered in 2003. Aside from regulating lipid metabolism, PCSK9 may be involved in other biological processes such as apoptosis, autophagy, pyroptosis, inflammation, and tumor immunity and related to diabetes and neurodegenerative diseases. Recently, clinical data have shown that the circulating PCSK9 level is significantly increased in patients with heart failure, and it is related to the prognosis for heart failure. Furthermore, in animal models and patients with myocardial infarction, PCSK9 in the infarct margin area was also found to be significantly increased, which further suggested that PCSK9 might be closely related to heart failure. However, the specific mechanism of how PCSK9 participates in heart failure remains to be further explored. The purpose of this review is to summarize the potential mechanism of PCSK9's involvement in heart failure, thereby providing a new treatment strategy for heart failure.


Assuntos
Insuficiência Cardíaca , Infarto do Miocárdio , Animais , Humanos , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo , Insuficiência Cardíaca/genética , Inflamação
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