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AIM: To investigate whether oral microbiome diversity is associated with all-cause mortality in the general US population and in individuals with chronic diseases. MATERIALS AND METHODS: We included 8224 individuals with oral microbiome diversity data from the National Health and Nutrition Examination Survey (2009-2012), representing 164,000,205 US adults, using a survey-weighted analysis method. Cox regression analyses were performed to identify the association between oral microbiome diversity and all-cause mortality. RESULTS: During a survey-weighted mean follow-up period of 8.86 years, 429 all-cause deaths (survey-weighted number: 7,124,920) occurred in 8224 participants. Cox regression analysis revealed that higher oral microbiome diversity was significantly associated with a lower all-cause mortality risk. Significant differences in all-cause mortality risk were observed among the different clusters based on oral microbiome ß-diversity (log-rank p < 0.001). Subgroup analyses revealed that the oral microbiome diversity was independently associated with all-cause mortality in individuals with diabetes mellitus and hypertension. A multivariate logistic regression model showed that current smoking and antibiotic use were significantly associated with lower oral microbiome α diversity. CONCLUSIONS: Higher oral microbiome diversity was significantly associated with a lower all-cause mortality risk in the general US population and in individuals with diabetes mellitus and hypertension.
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BACKGROUND: Addressing hypertrophic scars and keloids poses a significant challenge in the realm of preventive and curative medicine. Combination corticosteroid with 5-fluorouracil (5-FU) is presumed to enhance the treatment of hypertrophic scars and keloids, although supportive evidence is lacking. This study is aimed at comparing the efficacy and safety profile of a combined corticosteroid and 5-FU regimen in treating hypertrophic scars and keloids. METHODS: A comprehensive search was conducted for pertinent studies across various databases, including Web of Science, PubMed, Google Scholar, Cochrane Library, and Medline. The calculation of weighted mean difference (WMD), risk ratios (RR), odds ratios (OR), and 95% confidence intervals (CIs) was executed. Additionally, the Cochrane Collaboration's Risk of Bias Tool was utilized to evaluate potential bias risks. RESULTS: A total of 15 studies were involved. The effectiveness based on patient self-assessment and the effectiveness based on observer assessment were significantly higher in the corticosteroid+5-FU group compared to those treated with control. A meta-analysis of scar height showed that the corticosteroid+5-FU group performed better than the control group (WMD = -0.38, 95% CI -0.58 to -0.18). There was no significant difference between the corticosteroid+5-FU group and the control group in improving scar vascularity, pliability and pigmentation. The result revealed that the corticosteroid+5-FU group of patients had less adverse effect of hypopigmentation, skin atrophy and telangiectasia than the control group. CONCLUSION: The combined use of corticosteroids and 5-FU appears to be a more effective strategy for the treatment and prevention of hypertrophic scars and keloids, as evidenced by greater improvements in scar height and overall effectiveness, coupled with a reduced incidence of side effects. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
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Microglia are the most important immune cells in the central nervous system (CNS), which can defend against external pathogens and stimuli. Dysregulation of microglia releases excessive proinflammatory cytokines and leads to neuroinflammation, which is fundamental to the pathophysiology of multiple neurological diseases. However, the molecular mechanisms underlying the regulation of proinflammatory cytokines in microglia are still not well-understood. Here, we identified that inhibitor of DNA binding protein 2 (Id2) was a negative regulator of tumor necrosis factor-α (TNFα) in cultured microglia. Knockdown of Id2 significantly increased the expression of TNFα in microglia, while overexpression of Id2 inhibited TNFα expression. Furthermore, by interacting with the p65 subunit of nuclear factor kappa-B (NF-κB), Id2 suppressed the transcription activation of NF-κB and inhibited TNFα expression. Interestingly, in lipopolysaccharides (LPS)-treated microglia, Id2 increased and underwent a cytoplasmic relocation. Immunoprecipitation and immunostaining results showed that by binding to the LIM domain of Id2, a scaffold protein PDZ and LIM 5 (PDLIM5) involved in the Id2 cytoplasmic relocation, which inactivated Id2 and resulted in higher TNFα expression in LPS-treated microglia. Collectively, our data delineate a novel effect of Id2 on TNFα regulation in microglia, which may shed a light on the proinflammatory cytokines regulating in microglia associated neuroimmune disorders.
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Background: It had been shown that selective cardiac vagal activation holds great potential for heart regeneration. Optogenetics has clinical translation potential as a novel means of modulating targeted neurons. This study aimed to investigate whether cardiac vagal activation via optogenetics could improve heart regenerative repair after myocardial infarction (MI) and to identify the underlying mechanism. Methods: We used an adeno-associated virus (AAV) as the vector to deliver ChR2, a light-sensitive protein, to the left nodose ganglion (LNG). To assess the effects of the cardiac vagus nerve on cardiomyocyte (CM) proliferation and myocardial regeneration in vivo, the light-emitting diode illumination (470 nm) was applied for optogenetic stimulation to perform the gain-of-function experiment and the vagotomy was used as a loss-of-function assay. Finally, sequencing data and molecular biology experiments were analyzed to determine the possible mechanisms by which the cardiac vagus nerve affects myocardial regenerative repair after MI. Results: Absence of cardiac surface vagus nerve after MI was more common in adult hearts with low proliferative capacity, causing a poor prognosis. Gain- and loss-of-function experiments further demonstrated that optogenetic stimulation of the cardiac vagus nerve positively regulated cardiomyocyte (CM) proliferation and myocardial regeneration in vivo. More importantly, optogenetic stimulation attenuated ventricular remodeling and improved cardiac function after MI. Further analysis of sequencing results and flow cytometry revealed that cardiac vagal stimulation activated the IL-10/STAT3 pathway and promoted the polarization of cardiac macrophages to the M2 type, resulting in beneficial cardiac regenerative repair after MI. Conclusions: Targeting the cardiac vagus nerve by optogenetic stimulation induced macrophage M2 polarization by activating the IL-10/STAT3 signaling pathway, which obviously optimized the regenerative microenvironment and then improved cardiac function after MI.
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Interleucina-10 , Infarto do Miocárdio , Adulto , Humanos , Interleucina-10/genética , Optogenética , Infarto do Miocárdio/terapia , Nervo Vago , Miócitos CardíacosRESUMO
Colorectal cancer (CRC) is well known as a prevalent malignancy affecting the digestive tract, yet its precise etiological determinants remain to be elusive. Accordingly, identifying specific molecular targets for colorectal cancer and predicting potential malignant tumor behavior are potential strategies for therapeutic interventions. Of note, apoptosis (type I programmed cell death) has been widely reported to play a pivotal role in tumorigenesis by exerting a suppressive effect on cancer development. Moreover, autophagy-dependent cell death (type II programmed cell death) has been implicated in different types of human cancers. Thus, investigating the molecular mechanisms underlying apoptosis and autophagy-dependent cell death is paramount in treatment modalities of colorectal cancer. In this study, we uncovered that a new small-molecule activator of SIRT3, named MY-13, triggered both autophagy-dependent cell death and apoptosis by modulating the SIRT3/Hsp90/AKT signaling pathway. Consequently, this compound inhibited tumor cell proliferation and migration in RKO and HCT-116 cell lines. Moreover, we further demonstrated that the small-molecule activator significantly suppressed tumor growth in vivo. In conclusion, these findings demonstrate that the novel small-molecule activator of SIRT3 may hold a therapeutic potential as a drug candidate in colorectal cancer.
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Morte Celular Autofágica , Neoplasias Colorretais , Sirtuína 3 , Humanos , Neoplasias Colorretais/metabolismo , Autofagia , Proliferação de Células , Apoptose , Linhagem Celular TumoralRESUMO
Objective: At present, the structure of knowledge in the field of childhood thyroid cancer is not clear enough, and scholars lack a sufficient understanding of the developing trends in this field, which has led to a shortage of forward-looking outputs. The purpose of this research is to help scholars construct a complete knowledge framework and identify current challenges, opportunities, and development trends. Methods: We searched the literature in the Web of Science Core Collection database on August 7, 2023 and extracted key information from the top 100 most cited articles, such as the countries, institutions, authors, themes, and keywords. We used bibliometric tools such as bibliometrix, VOSviewer, and CiteSpace for a visualization analysis and Excel for statistical descriptions. Results: The top 100 most cited articles fluctuated over time, and the research was concentrated in European countries, the United States, and Japan, among which scientific research institutions and scholars from the United States made outstanding contributions. Keyword analysis revealed that research has shifted from simple treatment methods for pediatric thyroid cancer (total thyroidectomy) and inducing factors (the Chernobyl power station accident) to the clinical applications of genetic mutations (such as the BRAF and RET genes) and larger-scale genetic changes (mutation studies of the DICER1 gene). The thematic strategy analysis showed an increasing trend towards the popularity of fusion oncogenes, while the popularity of research on traditional treatments and diagnostics has gradually declined. Conclusion: Extensive research has been conducted on the basic problems of pediatric thyroid cancer, and there has been significant outputs in the follow-up and cohort analysis of conventional diagnostic and treatment methods. However, these methods still have certain limitations. Therefore, scholars should focus on exploring fusion genes, the clinical applications of molecular targets, and novel treatment methods. This study provides a strong reference for scholars in this field.
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Background: Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4)-mediated reactive oxygen species (ROS) has been reported to induce cardiomyocyte apoptosis, but its effect on pyroptosis of cardiomyocytes has been rarely reported. This paper aimed to explore the effects of NOX4-mediated ROS production on doxorubicin (DOX)-induced myocardial injury and pyroptosis through nucleotide-binding and oligomerization domain-like receptor protein 3 (NLRP3) inflammasome. Methods: HL-1 cells were treated with DOX or mice (30 mice were divided into five groups with six mice/group) underwent intraperitoneal injection with DOX (5 mg/kg, once a week, five times) to induce myocardial injury, followed by assessment of NOX4 and NLRP3 expression in cell supernatant and myocardial tissues. In cardiomyocyte HL-1 cells, cell proliferation was tested by MTT assay and the activity of ROS by probes. The superoxide dismutase (SOD) activity, malondialdehyde (MDA) content, and glutathione (GSH) activity were evaluated by kits. The expression of pyroptosis proteins was assessed by western blotting. Subsequently, the expression of NOX4 or NLRP3 was altered to determine the effect of NOX4 or NLRP3 expression on cardiomyocyte injury and pyroptosis. The animal models were utilized to evaluate the changes in the cardiac function of mice using an echocardiographic system, with these parameters measured including left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), and left ventricular end-diastolic diameter (LVEDD). Furthermore, the content of myocardial injury markers and the protein expression of pyroptosis proteins were determined to evaluate myocardial injury in the mice. Results: DOX treatment led to cardiomyocyte injury and pyroptosis, as evidenced by weakened LVEF, LVFS, and cell proliferation (P<0.05), elevated LVEDD, ROS, and MDA (P<0.05), increased expression of pyroptosis proteins (P<0.05), and decreased SOD and GSH (P<0.05). Additionally, NOX4 and NLRP3 were highly-expressed (P<0.05) in cell supernatant and myocardial tissues. In DOX-induced HL-1 cells, the overexpression of NOX4 intensified ROS levels to aggravate cardiomyocyte injury and pyroptosis, which was reversed by treatment of the ROS scavenger N-acetyl-cysteine. Furthermore, it was revealed that the combination of short hairpin RNA (sh)-NOX4 and overexpressed (oe)-NLRP3 reversed the cardioprotective effects of sh-NOX4 and increased myocardial tissue or cell injury and pyroptosis in vitro and in vivo. No mice died during the animal experiments, and only two were ruled out due to a weight loss greater than 20%. Conclusions: NOX4-mediated ROS production activated NLRP3 inflammasome, thereby aggravating DOX-induced myocardial injury in vitro and in vivo.
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Lymphocyte-specific protein tyrosine kinase (LCK), a member of the Src family of tyrosine kinases, is implicated in the pathogenesis of almost all types of leukemia via T cells activation and signal transduction. LCK is highly expressed in acute lymphoblastic leukemia (ALL), and knockdown of the LCK gene can significantly inhibit the proliferation of leukemia cell lines. Here, we designed and synthesized a series of benzothiazole derivatives as novel LCK inhibitors using both docking-based virtual screening and activity assays for structural optimization. Among these compounds, 7 m showed a strong inhibitory activity in the proliferation of leukemia cell lines and LCK kinase activity. Moreover, we found that compound 7 m could induce apoptosis while simultaneously blocking cell cycle via decreasing its phosphorylation at Tyr394 of the LCK. Collectively, these findings shed new light on compound 7 m that would be utilized as a promising drug candidate with apoptosis-triggered and cell cycle arrest activities for the future ALL therapy.
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Proteína Tirosina Quinase p56(lck) Linfócito-Específica , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/genética , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/metabolismo , Fosforilação , Transdução de Sinais , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Benzotiazóis/farmacologiaRESUMO
MicroRNAs (miRNAs) are important biomacromolecules used as biomarkers for the diagnosis of several diseases. However, current detection strategies are limited by expensive equipment and complicated procedures. Here, we develop a portable, sensitive, and stable (Eu-MOF)-based sensing platform to detect miRNA via smartphone. The Eu-MOF absorbs the carboxyfluorescein (FAM)-tagged probe DNA (pDNA) to generate hybrid pDNA@Eu-MOF, which can efficiently quench the fluorescence of FAM through a photoinduced electron transfer (PET) process. When integrated with a smartphone, the nonemissive pDNA@ Eu-MOF hybrid could be utilized as a portable and sensitive platform to sense miRNA (miR-892b) with a detection limit of 0.32 pM, which could be even distinguished by the naked eye. Moreover, this system demonstrates high selectivity for identifying miRNA family members with single-base mismatches. Furthermore, the expression levels of miRNA in cancer cell samples could be analyzed accurately. Therefore, the proposed method offers a promising guideline for the design of MOF-based sensing strategies and expands their potential applications for diagnostic purposes.
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Estruturas Metalorgânicas , MicroRNAs , MicroRNAs/genética , Luminescência , Sondas de DNA/genética , Fluorescência , Limite de DetecçãoRESUMO
RAS/RAF/MEK/ERK signaling pathway is one of the most important pathways of Mitogen-activated protein kinases (MAPK), which widely participate in regulating cell proliferation, differentiation, apoptosis and signaling transduction. Autophagy is an essential mechanism that maintains cellular homeostasis by degrading aged and damaged organelles. Recently, some studies revealed RAS/RAF/MEK/ERK signaling pathway is closely related to autophagy regulation and has a dual effect in tumor cells. However, the specific mechanism by which RAS/RAF/MEK/ERK signaling pathway participates in autophagy regulation is not fully understood. This article provides a comprehensive review of the research progress with regard to the RAS/RAF/MEK/ERK signaling pathway and autophagy, as well as their interplay in cancer therapy. The impact of small molecule inhibitors that target the RAS/RAF/MEK/ERK signaling pathway on autophagy is discussed in this study. The advantages and limitations of the clinical combination of these small molecule inhibitors with autophagy inhibitors are also explored. The findings from this study may provide additional perspectives for future cancer treatment strategies.
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MAP Quinases Reguladas por Sinal Extracelular , Neoplasias , Idoso , Humanos , Autofagia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Sistema de Sinalização das MAP Quinases , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Neoplasias/tratamento farmacológico , Quinases raf/metabolismo , Transdução de Sinais , Proteínas Proto-Oncogênicas p21(ras)/metabolismoRESUMO
Anomanolide C (AC), a natural withanolide isolated from Tubocapsicum anomalum, has been reported to have exhibits remarkable anti-tumour activities in several types of human cancers, particularly triple-negative breast cancer (TNBC). However, its intricate mechanisms still remain need to be clarified. Here, we evaluated whether AC could inhibit cell proliferation and the role of AC in ferroptosis induction and autophagy activation. Subsequently, the anti-migration potential of AC was found via autophagy-dependent ferroptosis. Additionally, we found that AC reduced the expression of GPX4 by ubiquitination and inhibited TNBC proliferation and metastasis in vitro and in vivo. Moreover, we demonstrated that AC induced autophagy-dependent ferroptosis, and led to Fe2+ accumulation via ubiquitinating GPX4. Moreover, AC was shown to induce autophagy-dependent ferroptosis as well as to inhibit TNBC proliferation and migration via GPX4 ubiquitination. Together, these results demonstrated that AC inhibited the progression and metastasis of TNBC by inducing autophagy-dependent ferroptosis via ubiquitinating GPX4, which might shed light on exploiting AC as a new drug candidate for the future TNBC therapy.
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Ferroptose , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , AutofagiaRESUMO
BACKGROUND: The salt-inducible kinase 1 (SIK1)-CREB-regulated transcription co-activator 1 (CRTC1) system in the paraventricular nucleus (PVN) of the hypothalamus has been demonstrated to participate in not only depression neurobiology but also the antidepressant mechanisms of fluoxetine, paroxetine, venlafaxine, and duloxetine. Like fluoxetine and paroxetine, escitalopram is also a well-known selective serotonin (5-HT) reuptake inhibitor (SSRI). However, recently it has been found that escitalopram can modulate a lot of targets other than the 5-HT system. Here, we speculate that escitalopram produces effects on the SIK1-CRTC1 system in the PVN. METHODS: Two mice models of depression (chronic social defeat stress (CSDS) and chronic unpredictable mild stress (CUMS)), various behavioral tests, enzyme linked immunosorbent assay (ELISA), western blotting, co-immunoprecipitation (Co-IP), quantitative real-time reverse transcription PCR (qRT-PCR), immunofluorescence, and adeno-associated virus (AAV)-mediated gene transfer were used together in the present study. RESULTS: It was found that escitalopram administration not only significantly prevented the hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis induced by CSDS and CUMS, but also notably reversed the effects of CSDS and CUMS on SIK1, CRTC1, and CRTC1-CREB binding in the PVN of mice. AAV-based genetic knock-down of SIK1 in PVN neurons evidently abolished the antidepressant-like effects of escitalopram in mice. LIMITATION: A shortage of this study is that only rodent models of depression were used, while human samples were not included. CONCLUSIONS: In summary, regulating the SIK1-CRTC1 system in the PVN participates in the antidepressant mechanism of escitalopram, which extends the knowledge of the pharmacological actions of escitalopram.
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Escitalopram , Núcleo Hipotalâmico Paraventricular , Camundongos , Humanos , Animais , Paroxetina , Fluoxetina , Serotonina , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Depressão/tratamento farmacológico , Depressão/genética , Depressão/metabolismoRESUMO
Distant metastasis (DM) is relatively uncommon in T1 stage gastric cancer (GC). The aim of this study was to develop and validate a predictive model for DM in stage T1 GC using machine learning (ML) algorithms. Patients with stage T1 GC from 2010 to 2017 were screened from the public Surveillance, Epidemiology and End Results (SEER) database. Meanwhile, we collected patients with stage T1 GC admitted to the Department of Gastrointestinal Surgery of the Second Affiliated Hospital of Nanchang University from 2015 to 2017. We applied seven ML algorithms: logistic regression, random forest (RF), LASSO, support vector machine, k-Nearest Neighbor, Naive Bayesian Model, Artificial Neural Network. Finally, a RF model for DM of T1 GC was developed. The AUC, sensitivity, specificity, F1-score and accuracy were used to evaluate and compare the predictive performance of the RF model with other models. Finally, we performed a prognostic analysis of patients who developed distant metastases. Independent risk factors for prognosis were analysed by univariate and multifactorial regression. K-M curves were used to express differences in survival prognosis for each variable and subvariable. A total of 2698 cases were included in the SEER dataset, 314 with DM, and 107 hospital patients were included, 14 with DM. Age, T-stage, N-stage, tumour size, grade and tumour location were independent risk factors for the development of DM in stage T1 GC. A combined analysis of seven ML algorithms in the training and test sets found that the RF prediction model had the best prediction performance (AUC: 0.941, Accuracy: 0.917, Recall: 0.841, Specificity: 0.927, F1-score: 0.877). The external validation set ROCAUC was 0.750. Meanwhile, survival prognostic analysis showed that surgery (HR = 3.620, 95% CI 2.164-6.065) and adjuvant chemotherapy (HR = 2.637, 95% CI 2.067-3.365) were independent risk factors for survival prognosis in patients with DM from stage T1 GC. Age, T-stage, N-stage, tumour size, grade and tumour location were independent risk factors for the development of DM in stage T1 GC. ML algorithms had shown that RF prediction models had the best predictive efficacy to accurately screen at-risk populations for further clinical screening for metastases. At the same time, aggressive surgery and adjuvant chemotherapy can improve the survival rate of patients with DM.
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Neoplasias Gástricas , Humanos , Neoplasias Gástricas/diagnóstico , Teorema de Bayes , Algoritmos , Algoritmo Florestas Aleatórias , Aprendizado de MáquinaRESUMO
OBJECTIVES: Doxorubicin (DOX) can contribute to severe myocardial injury, and bone marrow stromal cells (BMSC)-exosomes (Exos) improves acute myocardial infarction. Hence, this research investigated whether BMSC-Exos alleviated DOX-induced myocardial injury. METHODS: BMSC-derived Exos were isolated and identified, and the optimal concentration of DOX was confirmed. H9C2 cells were treated with DOX and BMSC-Exos or in combination with the protein kinase B (AKT) inhibitor. Reactive oxygen species (ROS) and JC-1 were detected to assess oxidative stress (OS) and mitochondrial membrane damage, respectively. In addition, the expression of pyroptosis-related molecules was measured. The expression of phosphatidylinositol 3 kinase (PI3K)-AKT pathway-related proteins and the phosphorylation and acetylation of forkhead box O1 (Foxo1) in the cell nucleus and cytoplasm were tested. Last, interactions between Foxo1 and gasdermin D (GSDMD) were assessed. RESULTS: BMSC-Exo treatment increased viability and mitochondrial membrane potential and reduced lactic dehydrogenase release and ROS levels in DOX-treated H9C2 cells. Furthermore, the addition of BMSC-Exos suppressed DOX-induced activation and upregulation of NLRP3 and apoptosis-associated speck-like protein containing A CARD (ASC) and in vitro cleavage of caspase-1, GSDMD, interleukin (IL)-1ß, and IL-18 proteins. Additionally, BMSC-Exo treatment enhanced the expression of phosphorylated (p)-PI3K, p-AKT, and p-mTOR in DOX-treated H9C2 cells and the levels of phosphorylated Foxo1 in the cytoplasm of DOX-treated H9C2 cells. Foxo1 was enriched in the promoter region of GSDMD. Moreover, the AKT inhibitor API-2 annulled the effects of BMSC-Exos on OS, pyroptosis, and Foxo1 phosphorylation in DOX-treated H9C2 cells. CONCLUSIONS: BMSC-Exos phosphorylated Foxo1 and inactivated Foxo1 transcription via the PI3K-AKT pathway to diminish GSDMD expression, thus restraining DOX-induced pyroptosis and OS of myocardial cells.
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Exossomos , Gasderminas , Células-Tronco Mesenquimais , Doxorrubicina/toxicidade , Exossomos/metabolismo , Estresse Oxidativo , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt , Piroptose , Espécies Reativas de Oxigênio/metabolismo , Ratos , Animais , Gasderminas/genéticaRESUMO
Regulated cell death (RCD) refers to programmed cell death regulated by various protein molecules, such as apoptosis, autophagy-dependent cell death, and necroptosis. Accumulating evidence has recently revealed that RCD subroutines have several links to many types of human cancer; therefore, targeting RCD with pharmacological small-molecule compounds would be a promising therapeutic strategy. Moreover, plant natural compounds, small-molecule compounds synthesized from plant sources, and their derivatives have been widely reported to regulate different RCD subroutines to improve potential cancer therapy. Thus, in this review, we focus on updating the intricate mechanisms of apoptosis, autophagy-dependent cell death, and necroptosis in cancer. Moreover, we further discuss several representative plant natural compounds and their derivatives that regulate the above-mentioned three subroutines of RCD, and their potential as candidate small-molecule drugs for the future cancer treatment.
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Morte Celular Autofágica , Neoplasias , Morte Celular Regulada , Humanos , Necroptose , Apoptose , Neoplasias/tratamento farmacológicoRESUMO
Methods capable of manipulating bacterial colonization are of great significance for modulating host-microbiota relationships. Here, we describe a strategy of in-situ chemical reaction-mediated covalent localization of bacteria. Through a simple one-step imidoester reaction, primary amino groups on bacterial surface can be converted to free thiols under cytocompatible conditions. Surface thiolation is applicable to modify diverse strains and the number of introduced thiols per bacterium can be easily tuned by varying feed ratios. These chemically reactive bacteria are able to spontaneously bond with mucous layer by catalyst-free thiol-disulfide exchange between mucin-associated disulfides and newly converted thiols on bacterial surface and show thiolation level-dependent attachment. Bacteria optimized with 9.3 × 107 thiols per cell achieve 170-fold higher attachment in mucin-enriched jejunum, a challenging location for gut microbiota to colonize. As a proof-of-concept application for microbiota transplantation, covalent bonding-assisted localization of an oral probiotic in the jejunum generates an improved remission of jejunal mucositis. Our findings demonstrate that transforming bacteria with a reactive surface provides an approach to chemically control bacterial localization, which is highly desirable for developing next-generation bacterial living bioagents.
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Dissulfetos , Probióticos , Dissulfetos/química , Compostos de Sulfidrila/química , Mucinas , BactériasRESUMO
Kynurenine-3-monooxygenase (KMO) is a mitochondrial enzyme involved in the eukaryotic kynurenine pathway (KP), which is the major catabolic route of tryptophan. KMO can convert the substrate kynurenine into the neurotoxin 3-hydroxykynurenine and quinolinic acid, which promote the production of toxic metabolites and formation of free radical in the blood, while decrease the neuroprotective metabolite kynurenic acid. As a result of branch point, KMO is predicted as an attractive drug target for several diseases, especially neurodegenerative diseases, psychosis, and cancer. This review mainly pays attention to KMO structure and the research of mechanisms and functions, with a particular emphasis on the roles of KMO in the pathogenesis of various conditions. Furthermore, we also summarized important KMO inhibitors to supporting their effects on these diseases, indicating the prospect to find novel KMO inhibitors for diseases therapy.
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Quinurenina 3-Mono-Oxigenase , Doenças Neurodegenerativas , Humanos , Progressão da Doença , Ácido Cinurênico/metabolismo , Cinurenina/metabolismo , Quinurenina 3-Mono-Oxigenase/química , Quinurenina 3-Mono-Oxigenase/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Triptofano/metabolismoRESUMO
AIMS: Metabolic switching during heart development contributes to postnatal cardiomyocyte (CM) cell cycle exit and loss of regenerative capacity in the mammalian heart. Metabolic control has potential for developing effective CM proliferation strategies. We sought to determine whether lactate dehydrogenase A (LDHA) regulated CM proliferation by inducing metabolic reprogramming. METHODS AND RESULTS: LDHA expression was high in P1 hearts and significantly decreased during postnatal heart development. CM-specific LDHA knockout mice were generated using CRISPR/Cas9 technology. CM-specific LDHA knockout inhibited CM proliferation, leading to worse cardiac function and a lower survival rate in the neonatal apical resection model. In contrast, CM-specific overexpression of LDHA promoted CM proliferation and cardiac repair post-MI. The α-MHC-H2B-mCh/CAG-eGFP-anillin system was used to confirm the proliferative effect triggered by LDHA on P7 CMs and adult hearts. Metabolomics, proteomics and Co-IP experiments indicated that LDHA-mediated succinyl coenzyme A reduction inhibited succinylation-dependent ubiquitination of thioredoxin reductase 1 (Txnrd1), which alleviated ROS and thereby promoted CM proliferation. In addition, flow cytometry and western blotting showed that LDHA-driven lactate production created a beneficial cardiac regenerative microenvironment by inducing M2 macrophage polarization. CONCLUSIONS: LDHA-mediated metabolic reprogramming promoted CM proliferation by alleviating ROS and inducing M2 macrophage polarization, indicating that LDHA might be an effective target for promoting cardiac repair post-MI.
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Infarto do Miocárdio , Miócitos Cardíacos , Animais , Proliferação de Células , Coenzima A/farmacologia , Lactato Desidrogenase 5 , Lactatos/metabolismo , Lactatos/farmacologia , Macrófagos/metabolismo , Mamíferos , Camundongos , Camundongos Knockout , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Tiorredoxina Redutase 1/metabolismoRESUMO
Understanding immune cell phenotypes in the tumor microenvironment (TME) is essential for explaining and predicting progression of non-small cell lung cancer (NSCLC) and its response to immunotherapy. Here we describe the single-cell transcriptomics of CD45+ immune cells from tumors, normal tissues and blood of NSCLC patients. We identified three clusters of immune cells exerting immunosuppressive effects: CD8+ T cells with exhausted phenotype, tumor-associated macrophages (TAMs) with a pro-inflammatory M2 phenotype, and regulatory B cells (B regs) with tumor-promoting characteristics. We identified genes that may be mediating T cell phenotypes, including the transcription factors ONECUT2 and ETV4 in exhausted CD8+ T cells, TIGIT and CTL4 high expression in regulatory T cells. Our results highlight the heterogeneity of CD45+ immune cells in the TME and provide testable hypotheses about the cell types and genes that define the TME.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Linfócitos T CD8-Positivos , Proteínas de Homeodomínio/genética , Humanos , Fatores de Transcrição/genética , Transcriptoma , Microambiente Tumoral/genéticaRESUMO
Depression is a very prevalent psychiatric disorder which threats nearly one in six of the population in this world. To date, the pathogenesis of depression remains elusive and is thought to depend on multiple factors in which chronic stress is critical. Currently, it has been demonstrated that besides monoaminergic dysfunction, depression is accompanied by several other important pathological phenomena such as impaired neurogenesis and decreased brain-derived neurotrophic factor (BDNF)-cAMP response element binding protein (CREB) signaling cascade in the hippocampus. F3/Contactin is a cell-adhesion molecule which has been reported to correlate with hippocampal neurogenesis and BDNF-CREB signaling. Here we assumed that F3/Contactin may be implicated in depression, and various methods including western blotting, immunofluorescence, virus-mediated gene transfer and chronic stress models of depression were adopted together. It was found that both chronic restraint stress (CRS) and chronic social defeat stress (CSDS) significantly decreased the expression of F3/Contactin in the hippocampus. Adeno-associated virus (AAV)-mediated over-expression of hippocampal F3/Contactin notably prevented the CRS-induced and CSDS-induced depressive-like behaviors in mice. Moreover, hippocampal F3/Contactin over-expression also fully reversed the CRS-induced and CSDS-induced dysfunction in the hippocampal BDNF-CREB signaling and neurogenesis of mice. Furthermore, administration of vortioxetine, a multimodal-acting antidepressant, fully ameliorated the inhibitory actions of both CRS and CSDS on the hippocampal F3/Contactin expression. In contrast, AAV-mediated knockdown of hippocampal F3/Contactin significantly abolished the protecting effects of vortioxetine against CRS and CSDS. Collectively, hippocampal F3/Contactin is implicated in depression and could be a novel antidepressant target.