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BACKGROUND: Triple-negative breast cancer (TNBC) is prone to relapse due to the lack of effective therapeutic targets. Macrophages are the most abundant immune cells in the tumor microenvironment (TME) of breast cancer. Targeting the cross-talk between macrophages and cancer cells provides a more efficient strategy for anti-tumor therapy. Toll-like receptors (TLRs) are important players involved in macrophage activation, and TLR agonists are known to play roles in cancer therapy. However, the combination strategy of TLR agonists with chemotherapy drugs is still not well characterized. METHODS: RT-PCR and Western blot were used to detect the expression of TLRs. The communication between breast cancer cells and macrophages were determined by co-culture in vitro. Tumor cells proliferation and migration were investigated by MTT assay and scratch wound assay. The effects of drug combinations and toxic side effects were assessed by immunohistochemistry and Hematoxylin & Eosin staining. RESULTS: Expression of TLR3 and TLR4 were lower in breast tumor tissues compared with adjacent normal tissues. Patients with higher TLR3 or TLR4 expression levels had a better prognosis than those with lower expression levels. TLR3/4 expression was significantly inhibited when breast cancer cells MDA-MB-231 and E0771 were conditioned-cultured with macrophages in vitro and was also inhibited by pirarubicin (THP). However, the combination of TLR agonists and THP could reverse this response and inhibit the proliferation and migration of breast cancer cells. Additionally, this combination significantly reduced the tumor volume and weight in the murine model, increased the expression of TLR3/4 in mouse breast tumors. CONCLUSIONS: Our results provide new ideas for the combination strategy of THP with TLR agonists which improves prognosis of breast cancer.

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Sclerotinia sclerotiorum (Lib.) de Bary is the causative agent of stem white mold disease which severely reduces major crop productivity including soybean and rapeseed worldwide. The current study aimed to explore plant growth-promoting traits and biocontrol of new isolated Bacillus subtilis BS-2301 to suppress S. sclerotiorum through various mechanisms. The results indicated that the BS-2301 exhibited strong biocontrol potential against S. sclerotiorum up to 74% both in dual culture and partition plate experiments. The BS-2301 and its crude extract significantly suppressed S. sclerotiorum growth involving excessive reactive oxygen species (ROS) production in mycelia for rapid death. Furthermore, the treated hyphae produced low oxalic acid (OA), a crucial pathogenicity factor of S. sclerotiorum. The SEM and TEM microscopy of S. sclerotiorum showed severe damage in terms of cell wall, cell membrane breakage, cytoplasm displacement, and organelles disintegration compared to control. The pathogenicity of S. sclerotiorum exposed to BS-2301 had less disease progression potential on soybean leaves in the detached leaf assay experiment. Remarkably, the strain also demonstrated broad-range antagonistic activity with 70%, and 68% inhibition rates against Phytophthora sojae and Fusarium oxysporum, respectively. Furthermore, the strain exhibits multiple plant growth-promoting and disease-prevention traits, including the production of indole-3-acetic acid (IAA), siderophores, amylases, cellulases and proteases as well as harboring calcium phosphate decomposition activity. In comparison to the control, the BS-2301 also showed great potential for enhancing soybean seedlings growth for different parameters, including shoot length 31.23%, root length 29.87%, total fresh weight 33.45%, and total dry weight 27.56%. The antioxidant enzymes like CAT, POD, SOD and APX under BS-2301 treatment were up-regulated in S. sclerotiorum infected plants along with the positive regulation of defense-related genes (PR1-2, PR10, PAL1, AOS, CHS, and PDF1.2). These findings demonstrate that the BS-2301 strain possesses a notable broad-spectrum biocontrol potential against different phytopathogens and provides new insight in suppressing S. sclerotiorum through various mechanisms. Therefore, BS-2301 will be helpful in the development of biofertilizers for sustainable agricultural practices.

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Banana Fusarium wilt, caused by Fusarium oxysporum f. sp. cubense tropical race 4 (Foc TR4), is a major disease of banana plants worldwide. Effector proteins play critical roles in banana-Foc TR4 interaction. Our previous studies highlighted a ribonuclease protein belonging to the T2 family (named as FocRnt2) in the Foc TR4 secretome, which was predicted to be an effector. However, its biological function in Foc TR4 infection is still unclear. Herein, we observed significant expression of FocRnt2 during the early stage of fungal infection in planta. A yeast signal sequence trap assay showed that FocRnt2 contained a functional signal peptide for secretion. FocRnt2 possessed ribonuclease activity that could degrade the banana total RNA in vitro. Subcellular localization showed that FocRnt2 was localized in the nucleus and cytoplasm of Nicotiana benthamiana leaves. Transient expression of FocRnt2 suppressed the expression of salicylic acid- and jasmonic acid-signalling marker genes, reactive oxygen species accumulation, and BAX-mediated cell death in N. benthamiana. FocRnt2 deletion limited fungal penetration, reduced fusaric acid biosynthesis in Foc TR4, and attenuated fungal virulence against banana plants, but had little effect on Foc TR4 growth and sensitivity to various stresses. Furthermore, FocRnt2 deletion mutants induced higher expression of the defence-related genes in banana plants. These results suggest that FocRnt2 plays an important role in full virulence of Foc TR4, further improving our understanding of effector-mediated Foc TR4 pathogenesis.

Asunto(s)

Fusarium , Musa , Nicotiana , Enfermedades de las Plantas , Fusarium/patogenicidad , Virulencia , Enfermedades de las Plantas/microbiología , Musa/microbiología , Nicotiana/microbiología , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/genética , Ribonucleasas/metabolismo , Ribonucleasas/genética , Especies Reactivas de Oxígeno/metabolismo , Endorribonucleasas

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Diabetic kidney disease (DKD) is a common microvascular complication of diabetes, inflammation and fibrosis play an important role in its progression. Histone lysine crotonylation (Kcr) was first identified as a new type of post-translational modification in 2011. In recent years, prominent progress has been made in the study of sodium crotonate (NaCr) and histone Kcr in kidney diseases. However, the effects of NaCr and NaCr-induced Kcr on DKD remain unclear. In this study, db/db mice and high glucose-induced human tubular epithelial cells (HK-2) were used respectively, and exogenous NaCr and crotonoyl-coenzyme A (Cr-CoA) as intervention reagents, histone Kcr and DKD-related indicators were detected. The results confirmed that NaCr had an antidiabetic effect and decreased blood glucose and serum lipid levels and alleviated renal function and DKD-related inflammatory and fibrotic damage. NaCr also induced histone Kcr and histone H3K18 crotonylation (H3K18cr). However, NaCr and Cr-CoA-induced histone Kcr and protective effects were reversed by inhibiting the activity of Acyl-CoA synthetase short-chain family member 2 (ACSS2) or histone acyltransferase P300 in vitro. In summary, our data reveal that NaCr may mitigate DKD via an antidiabetic effect as well as through ACSS2 and P300-induced histone Kcr, suggesting that Kcr may be the potential molecular mechanism and prevention target of DKD.

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BACKGROUND: Neuronal guanine nucleotide exchange factor (NGEF) plays a key role in several cancers; however, its role in lung adenocarcinoma (LUAD) remains unclear. The aim of this study was to evaluate the efficacy of NGEF as a prognostic biomarker and potential therapeutic target for LUAD. METHODS: NGEF expression data for multiple cancers and LUAD were downloaded from multiple databases. The high- and low-NGEF expression groups were constructed based on median NGEF expression in LUAD samples, and then performed Kaplan-Meier survival analysis. Differentially expressed genes (DEGs) from the two NGEF expression groups were screened and applied to construct a protein-protein interaction network. The primary pathways were obtained using gene set enrichment analysis. The associations between NGEF expression and clinical characteristics, immune infiltration, immune checkpoint inhibitors (ICIs), sensitivity to chemotherapy, and tumor mutation burden (TMB) were investigated using R. Levels of NGEF expression in the lung tissue was validated using single-cell RNA sequencing, quantitative polymerase chain reaction (qPCR), immunohistochemical staining, and western blot analysis. RESULTS: The expression of NGEF mRNA was upregulated in multiple cancers. mRNA and protein expression levels of NGEF were higher in patients with LUAD than in controls, as validated using qPCR and western blot. High NGEF expression was an independent prognostic factor for LUAD and was associated with advanced tumor stage, large tumor size, more lymph node metastasis, and worse overall survival (OS). A total of 182 overlapping DEGs were screened between The Cancer Genome Atlas and GSE31210, among which the top 20 hub genes were identified. NGEF expression was mainly enriched in the pathways of apoptosis, cell cycle, and DNA replication. Moreover, elevated NGEF expression were associated with a high fraction of activated memory CD4+ T cells and M0 macrophages; elevated expression levels of the ICIs: programmed cell death 1 and programmed cell death 1 ligand 1 expression; higher TMB; and better sensitivity to bortezomib, docetaxel, paclitaxel, and parthenolide, but less sensitivity to axitinib and metformin. CONCLUSION: NGEF expression is upregulated in LUAD and is significantly associated with tumor stages, OS probability, immune infiltration, immunotherapy response, and chemotherapy response. NGEF may be a potential diagnostic and prognostic biomarker and therapeutic target in LUAD.

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Adenocarcinoma del Pulmón , Biomarcadores de Tumor , Factores de Intercambio de Guanina Nucleótido , Inmunoterapia , Neoplasias Pulmonares , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Regulación Neoplásica de la Expresión Génica , Factores de Intercambio de Guanina Nucleótido/genética , Factores de Intercambio de Guanina Nucleótido/metabolismo , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia/métodos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Pronóstico , Mapas de Interacción de Proteínas

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Acinetobacter , Asma , Modelos Animales de Enfermedad , Interleucina-6 , Animales , Ratones , Asma/inmunología , Asma/etiología , Asma/microbiología , Interleucina-6/metabolismo , Administración Intranasal , Ciego/microbiología , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/inmunología , Microbiota

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Earthen sites are the important cultural heritage that carriers of human civilization and contains abundant history information. Microorganisms are one of important factors causing the deterioration of cultural heritage. However, little attention has been paid to the role of biological factors on the deterioration of earthen sites at present. In this study, microbial communities of Jinsha earthen site soils with different deterioration types and degrees as well as related to environmental factors were analyzed. The results showed that the concentrations of Mg2+ and SO42- were higher in the severe deterioration degree soils than in the minor deterioration degree soils. The Chao1 richness and Shannon diversity indices of bacteria in different type deterioration were higher in the summer than in the winter; the Chao1 and Shannon indices of fungi were lower in the summer. The differences in bacterial and fungal communities were associated with differences in Na+, K+, Mg2+ and Ca2+ contents. Based on both the relative abundances in amplicon sequencing and isolated strains, the bacterial phyla Actinobacteria, Firmicutes and Proteobacteria, and the Ascomycota genera Aspergillus, Cladosporium and Penicillium were common in all soils. The OTUs enriched in the severe deterioration degree soils were mostly assigned to Actinobacteria and Proteobacteria, whereas the Firmicutes OTUs differentially abundant in the severe deterioration degree were all depleted. All bacterial isolates produced alkali, implying that the deterioration on Jinsha earthen site may be accelerated through alkali production. The fungal isolates included both alkali and acid producing strains. The fungi with strong ability to produce acid were mainly from the severe deterioration degree samples and were likely to contribute to the deterioration. Taken together, the interaction between soil microbial communities and environment may affect the soil deterioration, accelerate the deterioration process and threaten the long-term preservation of Jinsha earthen site.

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Microbiota , Humanos , Bacterias/genética , Suelo , Álcalis , Microbiología del Suelo

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Epigenetics, specifically histone post-translational modification (HPTM) induced by environmental factors, plays a crucial role in the development of diabetes. Sodium benzoate (NAB) is a widely used additive, however, its potential contribution to diabetes has been largely overlooked. In 2018, a novel HPTM called benzoylation (Kbz) induced by NAB was discovered. This modification can be catalyzed by ACSS2 (acyl-CoA synthetase short-chain member 2) and acyltransferase P300/CBP, and can be reversed by erase enzymes SIRT2. Studies have indicated that Kbz may regulate insulin secretion, although the exact molecular mechanism remains unclear. In our study, C57BL/6J mice were divided into two groups: the NC group and the 1g/kg NAB water feeding group. In vivo experiments were conducted using ß-TC-6 cells, with 6 mM NAB or 100 µM benzoyl-CoA as stimuli, and 10 µM A485 (P300 inhibitor), 5 µM ACSS2 inhibitor (inhibiting benzoyl-CoA synthesis), or 5 µM AGK2 (SIRT2 inhibitor) as intervention factors. Our study found that, although the experimental concentration of NAB is below the maximum allowable concentration in food, it still damaged the insulin secretion function of C57BL/6J mice and induced inflammation and apoptosis of islet ß cells. We observed significant differences in serum benzoyl-CoA levels between healthy individuals and patients with type 2 diabetes. Furthermore, NAB concentration-dependently increases benzoyl-CoA and Kbz levels. When Kbz is down-regulated using A485 and ACSS2 inhibitor, we observed a reduction in ß cell inflammation, apoptosis, and insulin secretion damage. Conversely, up-regulating Kbz using AGK2 resulted in increased levels of ß cell inflammation and apoptosis. In conclusion, our data suggest that NAB, despite being within the safe dose range, may be an overlooked environmental risk factor contributing to the pathogenesis of diabetes through its impact on Kbz.

Asunto(s)

Diabetes Mellitus Tipo 2 , Benzoato de Sodio , Humanos , Ratones , Animales , Benzoato de Sodio/toxicidad , Benzoato de Sodio/metabolismo , Sirtuina 2/metabolismo , Diabetes Mellitus Tipo 2/inducido químicamente , Ratones Endogámicos C57BL , Histonas , Inflamación/inducido químicamente , Apoptosis

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Purpose: Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer cases. Immediate early response 5 like (IER5L) plays crucial roles in progression and prognosis for several tumors, but its role in NSCLC remains unclear. Patients and Methods: Gene expression and mutation profiles, DNA methylation data, and clinical information for cancers were downloaded from multiple databases. Relative expression, prognostic value, and correlation with disease progression of IER5L were analyzed in multiple cancers, including NSCLC. Upstream mechanisms were explored using a transcriptional network. Functional enrichment analysis, protein-protein interaction network, and gene set enrichment analysis were applied to study downstream mechanisms. Correlations of IER5L with immune infiltration, immune molecules, methylation status, and tumor mutation burden (TMB) were analyzed using R language. Finally, quantitative polymerase chain reaction (qPCR) and single-cell RNA sequencing (scRNA seq) analysis were performed to validate IER5L expression in NSCLC. Results: Pan-cancer analysis displayed that IER5L expression was upregulated in multiple cancers and was associated with disease prognosis and progression, including NSCLC, which was validated using qPCR. scRNA seq analysis showed that multiple cells had increased IER5L expression. An EGR1-hsa-miR-8075-IER5L network was constructed for NSCLC. A total of 191 DEGs were identified between the two IER5L groups, which were significantly enriched in biological process of action potential, sodium ion transport, and regulation of membrane potential. Increased IER5L expression was primarily enriched in cell cycle, NOTCH signaling pathway, and oxidative phosphorylation pathway, and was correlated with increased regulatory T cells and neutrophils, elevated levels of immune molecules, and higher TMB. Conclusion: Our findings show that increased IER5L expression was correlated with progression and prognosis in multiple cancers as well as with immune infiltration and immune molecules in NSCLC. Thus, IER5L is a prognostic biomarker in multiple cancers and may correlate with immunotherapeutic response in NSCLC.

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Previous studies have found that ß-Hydroxybutyrate (BHB), the main component of ketone bodies, is of physiological importance as a backup energy source during starvation or induces diabetic ketoacidosis when insulin deficiency occurs. Ketogenic diets (KD) have been used as metabolic therapy for over a hundred years, it is well known that ketone bodies and BHB not only serve as ancillary fuel substituting for glucose but also induce anti-oxidative, anti-inflammatory, and cardioprotective features via binding to several target proteins, including histone deacetylase (HDAC), or G protein-coupled receptors (GPCRs). Recent advances in epigenetics, especially novel histone post-translational modifications (HPTMs), have continuously updated our understanding of BHB, which also acts as a signal transduction molecule and modification substrate to regulate a series of epigenetic phenomena, such as histone acetylation, histone ß-hydroxybutyrylation, histone methylation, DNA methylation, and microRNAs. These epigenetic events alter the activity of genes without changing the DNA structure and further participate in the pathogenesis of related diseases. This review focuses on the metabolic process of BHB and BHB-mediated epigenetics in cardiovascular diseases, diabetes and complications of diabetes, neuropsychiatric diseases, cancers, osteoporosis, liver and kidney injury, embryonic and fetal development, and intestinal homeostasis, and discusses potential molecular mechanisms, drug targets, and application prospects.

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Histone lysine crotonylation was first identified as a new type of post-translational modification in 2011. In recent years, prominent progress has been made in the study of histone and nonhistone crotonylation in reproduction, development, and disease. Although the regulatory enzyme systems and targets of crotonylation partially overlap with those of acetylation, the peculiar CC bond structure of crotonylation suggests that crotonylation may have specific biological functions. In this review, we summarize the latest research progress regarding crotonylation, especially its regulatory factors and relationship with diseases, which suggest further research directions for crotonylation and provide new ideas for developing disease intervention and treatment regimens.

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Histonas , Lisina , Histonas/metabolismo , Lisina/metabolismo , Acetilación , Procesamiento Proteico-Postraduccional

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Magnaporthe oryzae is the causal agent of rice blast, one of the most serious diseases of rice worldwide. Secreted proteins play essential roles during a M. oryzae-rice interaction. Although much progress has been made in recent decades, it is still necessary to systematically explore M. oryzae-secreted proteins and to analyze their functions. This study employs a shotgun-based proteomic analysis to investigate the in vitro secretome of M. oryzae by spraying fungus conidia onto the PVDF membrane to mimic the early stages of infection, during which 3315 non-redundant secreted proteins were identified. Among these proteins, 9.6% (319) and 24.7% (818) are classified as classically or non-classically secreted proteins, while the remaining 1988 proteins (60.0%) are secreted through currently unknown secretory pathway. Functional characteristics analysis show that 257 (7.8%) and 90 (2.7%) secreted proteins are annotated as CAZymes and candidate effectors, respectively. Eighteen candidate effectors are selected for further experimental validation. All 18 genes encoding candidate effectors are significantly up- or down-regulated during the early infection process. Sixteen of the eighteen candidate effectors cause the suppression of BAX-mediated cell death in Nicotiana benthamiana by using an Agrobacterium-mediated transient expression assay, suggesting their involvement in pathogenicity related to secretion effectors. Our results provide high-quality experimental secretome data of M. oryzae and will expand our knowledge on the molecular mechanisms of M. oryzae pathogenesis.

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Ascomicetos , Magnaporthe , Oryza , Magnaporthe/fisiología , Proteómica , Proteínas Fúngicas/metabolismo , Ascomicetos/metabolismo , Oryza/metabolismo , Enfermedades de las Plantas/microbiología

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BACKGROUND: Acute pancreatitis (AP) is a common digestive disease with increased incidence globally but without internationally licenced pharmacological therapy. Moderately severe and severe acute pancreatitis (MSAP/SAP) contributes predominately for its morbidities and mortality and has been managed in West China Hospital for decades using the traditional Chinese medicinal formula chaiqin chengqi decoction (CQCQD). The current study tests whether the early administration of CQCQD will result in improved clinical outcomes in predicted MSAP/SAP patients. METHODS: This is a single-centre, randomised, controlled, double-blind pragmatic clinical trial. AP patients aged 18-75 admitted within 72 h of onset will be assessed at admission for enrolment. We excluded the predicted mild acute pancreatitis (Harmless Acute Pancreatitis Score > 2 at admission) and severe organ failure (Sequential Organ Failure Assessment [SOFA] score of respiratory, cardiovascular, or renal systems > 3) at admission. Eligible patients will be randomly allocated on a 1:1 basis to CQCQD or placebo control administration based on conventional therapy. The administration of CQCQD and placebo is guided by the Acute Gastrointestinal Injury grade-based algorithm. The primary outcome measure will be the duration of respiratory failure (SOFA score of respiratory system ≥ 2) within 28 days after onset. Secondary outcome measures include occurrence of new-onset any organ failure (SOFA score of respiratory, cardiovascular, or renal system ≥ 2) and new-onset persistent organ failure (organ failure lasts > 48 h), dynamic surrogate biochemical markers and clinical severity scores, gut-centred treatment modalities, local complications status, intensive care need and duration, surgical interventions, mortality, and length of hospital stay. Follow-up will be scheduled on 6, 12, and 26 weeks after enrolment to assess AP recurrence, local complications, the requirement for surgical interventions, all-cause mortality, and patient-reported outcomes. DISCUSSION: The results of this study will provide high-quality evidence to appraise the efficacy of CQCQD for the early management of AP patients. TRIAL REGISTRATION: Chictr.org.cn Registry ( ChiCTR2000034325 ). Registered on 2 July, 2020.

Asunto(s)

Medicamentos Herbarios Chinos , Pancreatitis , Humanos , Enfermedad Aguda , Medicamentos Herbarios Chinos/efectos adversos , Pulmón , Pancreatitis/diagnóstico , Pancreatitis/tratamiento farmacológico , Pancreatitis/complicaciones , Ensayos Clínicos Controlados Aleatorios como Asunto , Ensayos Clínicos Pragmáticos como Asunto

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Diabetes is a group of global epidemic diseases with high prevalence and morbidity. The pathophysiological changes of diabetes can be affected by genes, environmental factors, and several socioeconomic factors. Histone post-translational modification is the central epigenetic mechanism regulated by genetic and environmental factors. Histone methylation and acetylation have been thoroughly studied in various pathological processes of diabetes, such as the metabolic memory phenomenon, inflammation, and endothelial dysfunction. In recent years, an increasing number of novel histone acylation modifications have been identified by mass spectrometry. The level of any novel histone modification depends on the relative concentration of its respective acyl-CoA, which can be generated through various intermediate metabolic pathways. Although studies have shown that these novel modifications and metabolic regulation of histone acylation have a close connection with diabetes, investigations on this connection have lagged. Moreover, the locations of acylation modification sites and how enzymatic reactions regulate diabetes and its complications remain largely unknown. This review summarizes the relationship between novel histone modifications and diabetes, mainly focusing on ß-hydroxybutyrylation, propionylation, butyrylation, malonylation, and succinylation. We aim to highlight the typical characteristics of novel acylation modifications and provide a new perspective for further research on the pathogenesis and treatment of diabetes and its complications.

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Complicaciones de la Diabetes , Diabetes Mellitus , Humanos , Histonas/metabolismo , Procesamiento Proteico-Postraduccional , Código de Histonas

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Histone post-translational modifications (HPTMs) are essential epigenetic mechanisms that affect chromatin-associated nuclear processes without altering the DNA sequence. With the application of mass spectrometry-based proteomics, novel histone lysine acylation, such as propionylation, butyrylation, crotonylation, malonylation, succinylation, glutarylation, and lactoylation have been successively discovered. The emerging diversity of the lysine acylation landscape prompted us to investigate the function and mechanism of these novel HPTMs in health and disease. Recently, it has been reported that ß-hydroxybutyrate (BHB), the main component of the ketone body, has various protective roles beyond alternative fuel provision during starvation. Histone lysine ß-hydroxybutyrylation (Kbhb) is a novel HPTMs identified by mass spectrometry, which regulates gene transcription in response to carbohydrate restriction or elevated BHB levels in vivo and vitro. Recent studies have shown that histone Kbhb is strongly associated with the pathogenesis of metabolic cardiovascular diseases, kidney diseases, tumors, neuropsychiatric disorders, and metabolic diseases suggesting it has different functions from histone acetylation and methylation. This review focuses on the writers, erasers, sites, and underlying functions of histone Kbhb, providing a glimpse into their complex regulation mechanism.

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Histonas , Lisina , Ácido 3-Hidroxibutírico/metabolismo , Carbohidratos , Cromatina , Histonas/metabolismo , Lisina/metabolismo

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Background: An imbalance in the redox homeostasis has been reported in multiple cancers and is associated with a poor prognosis of disease. However, the prognostic value of redox-related genes in non-small-cell lung cancer (NSCLC) remains unclear. Methods: RNA sequencing data, DNA methylation data, mutation, and clinical data of NSCLC patients were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus databases. Redox-related differentially expressed genes (DEGs) were used to construct the prognostic signature using least absolute shrinkage and selection operator (LASSO) regression analysis. Kaplan-Meier survival curve and receiver operator characteristic (ROC) curve analyses were applied to validate the accuracy of the gene signature. Nomogram and calibration plots of the nomogram were constructed to predict prognosis. Pathway analysis was performed using gene set enrichment analysis. The correlations of risk score with tumor stage, immune infiltration, DNA methylation, tumor mutation burden (TMB), and chemotherapy sensitivity were evaluated. The prognostic signature was validated using GSE31210, GSE26939, and GSE68465 datasets. Real-time polymerase chain reaction (PCR) was used to validate dysregulated genes in NSCLC. Results: A prognostic signature was constructed using the LASSO regression analysis and was represented as a risk score. The high-risk group was significantly correlated with worse overall survival (OS) (p < 0.001). The area under the ROC curve (AUC) at the 5-year stage was 0.657. The risk score was precisely correlated with the tumor stage and was an independent prognostic factor for NSCLC. The constructed nomogram accurately predicted the OS of patients after 1-, 3-, and 5-year periods. DNA replication, cell cycle, and ECM receptor interaction were the main pathways enriched in the high-risk group. In addition, the high-risk score was correlated with higher TMB, lower methylation levels, increased infiltrating macrophages, activated memory CD4+ T cells, and a higher sensitivity to chemotherapy. The signature was validated in GSE31210, GSE26939, and GSE68465 datasets. Real-time PCR validated dysregulated mRNA expression levels in NSCLC. Conclusions: A prognostic redox-related gene signature was successfully established in NSCLC, with potential applications in the clinical setting.

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Agricultural emission reduction is a key objective associated with sustainable agricultural development and a meaningful way to slow down global warming. Based on the comprehensive estimation of agricultural carbon emissions, this study applied the traditional spatial Durbin model (SDM) to analyze the type of regional emission reduction interaction and explore whether it is a direct or an indirect interaction caused by technology spillovers. Moreover, geographic, economic, and technical weights were used to discuss the channels of emission reduction interactions. The partitioned spatial Durbin model was applied to explore the realization conditions of regional emission reduction interactions. We found that: (1) comprehensive emission reduction interactions were identified in various regions of China, including direct and indirect interactions, in which geographic and technical channels were the major pathways for direct and indirect emission reduction interactions, respectively; (2) regions with similar economic development levels are more likely to have direct interactions, whereas regions with low technical levels are more willing to follow the high-tech regions, and the benchmarking effect is noticeable; (3) emission reduction results promoted by economic cooperation may be offset by vicious economic competition between regions, and more emission reduction intervention measures should be given to regions with high economic development levels; (4) to achieve better technological cooperation, regions must have similar technology absorption capabilities and should provide full play to the driving force of technical benchmarks.

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Dióxido de Carbono , Carbono , Agricultura , Carbono/análisis , Dióxido de Carbono/análisis , China , Desarrollo Económico , Calentamiento Global

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Inflammation and fibrosis are the important pathophysiologic processes in diabetic kidney disease (DKD), which is induced by epigenetics, especially histone posttranslational modification (HPTMs). Recent reports highlighted that butyrate, one of the short-chain fatty acids (SCFAs) primarily originated from the fermentation of dietary fiber in the gut, attenuates inflammation and fibrosis in the prevention and treatment of DKD; however, the molecular mechanisms are still unclear. Histone lysine butyrylation (Kbu), a novel histone modification marker induced by butyrate, has been found to be involved in the regulation of pathophysiological processes. To reveal the mechanisms of butyrate-induced histone (Kbu), in the prevention and treatment of DKD, both DKD models in vivo and in vitro were treated with sodium butyrate (NaB). Our results confirmed that exogenous NaB improved the disorder of glucose and lipid metabolism, prevented proteinuria and renal failure, and inhibited renal inflammation and fibrosis. Meanwhile, NaB also induced histone Kbu and H3K9 butyrylation (H3K9bu) in vivo and in vitro; however, inhibition of histone Kbu with the histone modification enzyme p300 inhibitor A485 reversed the anti-inflammatory and anti-fibrosis effects of NaB. In conclusion, our data reveal that NaB antagonizes renal inflammatory and fibrosis injury and attenuates DKD possibly via histone Kbu, suggesting that butyrate-induced histone Kbu or H3K9bu may be an important molecular mechanism in the pathogenesis and treatment of DKD.

Asunto(s)

Diabetes Mellitus , Nefropatías Diabéticas , Ácido Butírico/farmacología , Ácido Butírico/uso terapéutico , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/metabolismo , Histonas/metabolismo , Humanos , Inflamación/tratamiento farmacológico , Procesamiento Proteico-Postraduccional

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Background: Acute pancreatitis (AP) is an inflammatory disorder of the exocrine pancreas without specific treatment. Shenmai injection (SMI) was reported to eliminate the severity of experimental AP. This study aimed to explore the mechanisms underlying the synergistic protective effects of SMI on AP based on network pharmacology and experimental validation. Methods: Network pharmacology analysis and molecular docking based on identified components were performed to construct the potential therapeutic targets and pathways. The principal components of SMI were detected via ultra-high-performance liquid chromatography-coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF/MS). Effect of SMI and the identified components on cellular injury and IL6/STAT3 signaling was assessed on mouse pancreatic acinar cell line 266-6 cells. Finally, 4% sodium taurocholate (NaT) was used to induce AP model to assess the effects of SMI in treating AP and validate the potential molecular mechanisms. Results: By searching the TCMSP and ETCM databases, 119 candidate components of SMI were obtained. UHPLC-QTOF/MS analysis successfully determined the representative components of SMI: ginsenoside Rb1, ginsenoside Rg1, ginsenoside Re, and ophiopogonin D. Fifteen hub targets and eight related pathways were obtained to establish the main pharmacology network. Subnetwork analysis and molecular docking indicated that the effects of these four main SMI components were mostly related to the interleukin (IL) 6/STAT3 pathway. In vitro, SMI, ginsenoside Rb1, ginsenoside Rg1, ginsenoside Re, and ophiopogonin D increased the cell viability of NaT-stimulated mouse pancreatic acinar 266-6 cells and decreased IL6 and STAT3 expression. In vivo, 10 mL/kg SMI significantly alleviated the pancreatic histopathological changes and the expression of IL6 and STAT3 in the AP mice. Conclusion: This study demonstrated SMI may exert anti-inflammatory effects against AP by suppressing IL6/STAT3 activation, thus providing a basis for its potential use in clinical practice and further study in treating AP.

Asunto(s)

Medicamentos Herbarios Chinos , Pancreatitis , Enfermedad Aguda , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Combinación de Medicamentos , Interleucina-6 , Ratones , Simulación del Acoplamiento Molecular , Farmacología en Red , Pancreatitis/metabolismo

RESUMEN

Background: Hydromorphone patient-controlled analgesia (PCA) provides satisfactory postoperative pain therapy, but its effect has not been assessed in acute pancreatitis (AP). Aim: To assess the safety and efficacy of intravenous hydromorphone PCA for pain relief in AP. Methods: This open-label trial included AP patients admitted within 72 h of symptom onset, aged 18-70 years old, and with Visual Analog Scale (VAS) for pain intensity ≥5. They were randomized to receive intravenous hydromorphone PCA (0.05 mg/h with 0.2 mg on-demand) or intramuscular pethidine (50 mg as required) for three consecutive days. Intramuscular dezocine (5 mg on demand) was the rescue analgesia. The primary outcome was the change of VAS score recorded every 4 h for 3 days. Interim analysis was conducted by an Independent Data and Safety Monitoring Committee (IDSMC). Results: From 26 July 2019 to 15 January 2020, 77 patients were eligible for the intention-to-treat analysis in the interim analysis (39 in the hydromorphone group and 38 in the pethidine group). Baseline parameters were comparable between groups. No difference in VAS between the two groups was found. Hydromorphone PCA was associated with higher moderately severe to severe cases (82.1% vs. 55.3%, p = 0.011), acute peripancreatic fluid collections (53.9% vs. 28.9%, p = 0.027), more cumulative opioid consumption (median 46.7 vs. 5 mg, p < 0.001), higher analgesia costs (median 85.5 vs. 0.5 $, p < 0.001) and hospitalization costs (median 3,778 vs. 2,273 $, p = 0.007), and more adverse events (20.5% vs. 2.6%, p = 0.087). The per-protocol analysis did not change the results. Although a sample size of 122 patients was planned, the IDSMC halted further recruitment as disease worsening or worse clinical outcomes between the groups in the interim analysis. Conclusion: Hydromorphone PCA was not superior to pethidine in relieving pain in AP patients and might have worse clinical outcomes. Therefore, its use is not recommended. Clinical Trial Registration: Chictr.org.cn. ChiCTR1900025971.