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BACKGROUND: Pulmonary arterial hypertension (PAH) and the consequent right heart dysfunction persist with high morbidity and mortality, and the mechanisms and pharmacologic interventions for chronic right-sided heart failure (RHF) have not been adequately investigated. Research has shown that prolonged inflammation is critical in precipitating the progression of PAH-associated right heart pathology. Some research demonstrated that Lingguizhugan decoction (LGZGD), as a classical Chinese medicine formula, had beneficial effects in alleviating PAH and RHF, while its underlying mechanisms involved are not fully elucidated. PURPOSE: Based on that, this study aims to investigate the effects and underlying mechanisms of LGZGD on PAH-induced RHF. STUDY DESIGN: In this study, we identified the serum constituents and deciphered the potential anti-inflammatory mechanism and crucial components of LGZGD using combined approaches of UPLC-HRMS, transcriptomic analysis, and molecular docking techniques. Finally, we used in vivo experiments to verify the expression of key targets in the monocrotaline (MCT)-induced RHF model and the intervene effect of LGZGD. RESULTS: Integrated strategies based on UPLC-HRMS and systems biology approach combined with in vivo experimental validation showed that LGZGD could improve right heart fibrosis and dysfunction via regulating diverse inflammatory signaling pathways and the activity of immune cells, including chemokine family CCL2, CXCR4, leukocyte integrins family ITGAL, ITGB2, and M2 macrophage infiltration, as well as lipid peroxidation-associated HMOX1, NOX4, and 4-HNE. CONCLUSION: The present research demonstrated for the first time that LGZGD might improve PAH-induced RHF through multiple anti-inflammatory signaling and inhibition of ferroptosis, which could provide certain directions for future research in related fields.
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Medicamentos de Ervas Chinesas , Hipertensão Arterial Pulmonar , Biologia de Sistemas , Remodelação Ventricular , Animais , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/química , Hipertensão Arterial Pulmonar/tratamento farmacológico , Masculino , Remodelação Ventricular/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Simulação de Acoplamento Molecular , Ratos Sprague-Dawley , Ratos , Insuficiência Cardíaca/tratamento farmacológico , Modelos Animais de Doenças , Cromatografia Líquida de Alta PressãoRESUMO
BACKGROUND: Type 2 cardiorenal syndrome (CRS) is a progressive renal insufficiency in patients with chronic heart failure, but its pathophysiology is still unclear. The Chinese medicine Zhenwu Decoction plays an important role in the prevention and treatment of 2-CRS, however, its mechanism of action remains unknown. PURPOSE: The aim of this study was to investigate whether the ameliorative effect of ZWD on 2-CRS renal fibrosis is related to the modulation of miR-451 expression and thus mediating the TLR4/NF-κB/HIF-1α loop. STUDY DESIGN AND METHODS: A type 2 CRS rat model was constructed using ligation of the left anterior descending branch of the coronary artery + 3/4 nephrectomy, and randomly divided into Control, Sham, Model, Captopril, ZWD-L, ZWD-M and ZWD-H groups.After 4 weeks of ZWD intervention, its effects on cardiac and renal functions of type 2 CRS rats were observed by hematuria and cardiac ultrasonography. Changes in kidney tissue morphology were observed by HE, Masson and PASM staining. The protein and mRNA expression of TLR4, NF-κB, HIF-1α and IκBα in kidney tissues were detected by immunohistochemistry and qPCR. Immunofluorescence was used to detect the protein expression of NF-κB and HIF-1α in renal tissues. Western blot and qPCR were used to detect the protein expression of MCP-1, ICAM-1, IL-1ß, IL-6, TGF-ß, α-SMA, FN, Smad2, Smad3, and E-cadherin in renal tissues. PCR was used to detect the protein expression of miR-451mRNA expression level in kidney tissues. RESULTS: In this study, we found that ZWD was able to reduce the expression of Scr, BUN, NT-proBNP, and 24-hour quantitative urine protein, elevate LVEF, FS, CO, and reduce the level of LVIDS in type 2 CRS rats, as well as attenuate renal interstitial fibrosis and improve tubular swelling. In addition, Zhenwu Decoction up-regulated the expression of miR-451 in renal tissues and inhibited the expression of TLR4, NF-κB, and HIF-1α proteins and genes, which in turn inhibited the expression of inflammatory factors and fibrosis-related factors. CONCLUSION: ZWD was able to up-regulate the expression of miR-451 in renal tissues, inhibit the TLR4/NF-κB/HIF-1α response loop, and then inhibit the expression of inflammatory factors and fibrosis-related factors, improve renal fibrosis, and delay the pathological process of type 2 CRS.
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Síndrome Cardiorrenal , Medicamentos de Ervas Chinesas , Fibrose , Subunidade alfa do Fator 1 Induzível por Hipóxia , Rim , MicroRNAs , NF-kappa B , Ratos Sprague-Dawley , Receptor 4 Toll-Like , Animais , Receptor 4 Toll-Like/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , NF-kappa B/metabolismo , MicroRNAs/metabolismo , MicroRNAs/genética , Masculino , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Síndrome Cardiorrenal/tratamento farmacológico , Ratos , Modelos Animais de DoençasRESUMO
The inhibition of hepatic macrophage and Kupfer cell recruitment and activation is a potential strategy for treating insulin resistance and nonalcoholic steatohepatitis (NASH). Cenicriviroc (CVC), a dual C-C chemokine receptor 2 (CCR2) and CCR5 antagonist, has shown antifibrotic activity in murine models of NASH and has been evaluated in clinical trials on patients with NASH. This study investigated the effects of CVC on macrophage infiltration and polarization in a lipotoxic model of NASH. C57BL/6 mice were fed a high-cholesterol, high-fat (CL) diet or a CL diet containing 0.015% CVC (CL + CVC) for 12 weeks. Macrophage recruitment and activation were assayed by immunohistochemistry and flow cytometry. CVC supplementation attenuated excessive hepatic lipid accumulation and peroxidation and alleviated glucose intolerance and hyperinsulinemia in the mice that were fed the CL diet. Flow cytometry analysis revealed that compared with the CL group, mice fed the CL + CVC diet had fewer M1-like macrophages, more M2-like macrophages, and fewer T cell counts, indicating that CVC caused an M2-dominant shift of macrophages in the liver. Similarly, CVC decreased lipopolysaccharide-stimulated M1-like macrophage activation, whereas it increased interleukin-4-induced M2-type macrophage polarization in vitro. In addition, CVC attenuated hepatic fibrosis by repressing hepatic stellate cell activation. Lastly, CVC reversed insulin resistance as well as steatosis, inflammation, and fibrosis of the liver in mice with pre-existing NASH. In conclusion, CVC prevented and reversed hepatic steatosis, insulin resistance, inflammation, and fibrogenesis in the liver of NASH mice via M2 macrophage polarization.
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Fígado , Macrófagos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica , Animais , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/patologia , Masculino , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/metabolismo , Dieta Hiperlipídica/efeitos adversos , Receptores CCR2/metabolismo , Sulfóxidos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Antagonistas dos Receptores CCR5/farmacologia , Antagonistas dos Receptores CCR5/uso terapêutico , Resistência à Insulina , ImidazóisRESUMO
Fusarium pseudograminearum causes destructive crown disease in wheat. The velvet protein family is a crucial regulator in development, virulence, and secondary metabolism of fungi. We conducted a functional analysis of FpVelB using a gene replacement strategy. The deletion of FpVelB decreased radial growth and enhanced conidial production compared to that of wild type. Furthermore, FpVelB modulates the fungal responses to abiotic stress through diverse mechanisms. Significantly, virulence decreased after the deletion of FpVelB in both the stem base and head of wheat. Genome-wide gene expression profiling revealed that the regulation of genes by FpVelB is associated with several processes related to the aforementioned phenotype, including "immune", "membrane", and "antioxidant activity", particularly with regard to secondary metabolites. Most importantly, we demonstrated that FpVelB regulates pathogen virulence by influencing deoxynivalenol production and modulating the expression of the PKS11 gene. In conclusion, FpVelB is crucial for plant growth, asexual development, and abiotic stress response and is essential for full virulence via secondary metabolism in F. pseudograminearum.
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Proteínas Fúngicas , Fusarium , Regulação Fúngica da Expressão Gênica , Metabolismo Secundário , Fusarium/patogenicidade , Fusarium/genética , Fusarium/metabolismo , Metabolismo Secundário/genética , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/genética , Virulência/genética , Doenças das Plantas/microbiologia , Triticum/microbiologia , Estresse Fisiológico , Tricotecenos/metabolismo , Esporos Fúngicos/metabolismoRESUMO
Bipolaris maydis partitivirus 36 (BmPV36) is a mycovirus that can significantly reduce the virulence of the host Bipolaris maydis, but its hypovirulence mechanism is not clear. To investigate the response of B. maydis to BmPV36, the effects of BmPV36 on host cell structure and gene expression were studied via transmission electron microscopy and transcriptome sequencing using BmPV36-carrying and virus-free mycelium on the second and fifth culture. The results of transmission electron microscopy showed that the cell wall microfibrils of B. maydis were shortened, the cell membrane was broken, and membrane-bound vesicles and vacuoles appeared in the cells after carrying BmPV36. Transcriptome sequencing results showed that after carrying BmPV36, B. maydis membrane-related genes were significantly up-regulated, but membrane transport-related genes were significantly down-regulated. Genes related to carbohydrate macromolecule polysaccharide metabolic and catabolic processes were significantly down-regulated, as were genes related to the synthesis of toxins and cell wall degrading enzymes. Therefore, we speculated that BmPV36 reduces the virulence of B. maydis by destroying the host's cell structure, inhibiting the synthesis of toxins and cell wall degrading enzymes, and reducing cell metabolism. Gaining insights into the hypovirulence mechanism of mycoviruses will provide environmentally friendly strategies for the control of fungal diseases.
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BACKGROUND: Cancer-related fatigue is one of the most common symptoms in cancer patients, usually accompanied by anxiety, depression and insomnia, which seriously affect patients' quality of life. Progressive muscle relaxation training is widely used for cancer-related fatigue, but the overall effect is unclear. OBJECTIVES: The aim of this study was to summarize the evidence on the effects of progressive muscle relaxation training on cancer-related fatigue and quality of life in cancer patients. DESIGN: Systematic review and meta-analysis. METHODS: Nine electronic databases (PubMed, Excerpta Medica Database (Embase), The Cochrane Library (Cochrane Central Register of Controlled Trials, CENTRAL), Web of Science, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Chinese Biomedical Literature Database (CBM), Chinese National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP) and Wanfang Database) were explored for randomized controlled trials (RCTs) published before February 2023. This study was reported based on the PRISMA 2020 statement. The Cochrane Collaboration's risk of bias assessment tool was used for methodological assessment, and the GRADE pro online assessment tool was used for evidence evaluation. The data were analyzed with the Review Manager 5.4 software. RESULTS: Twelve studies involving 1047 patients were included. Meta-analysis showed that progressive muscle relaxation training plus routine nursing produced more positive effects than routine nursing in improving cancer-related fatigue [SMDâ¯=â¯-1.06, 95â¯% CI -1.49, -0.62, Pâ¯<â¯0.00001], anxiety [SMDâ¯=â¯-1.09, 95â¯% CI -1.40, -0.77, Pâ¯<â¯0.00001], depression [SMDâ¯=â¯-1.43, 95â¯% CI -1.76, -1.10, Pâ¯<â¯0.00001], and quality of sleep [MDâ¯=â¯-1.41, 95â¯% CI -1.74, -1.08, Pâ¯<â¯0.00001]. However, there was no significant difference in improving quality of life [SMDâ¯=â¯0.27, 95â¯% CI -0.62, 1.15, Pâ¯=â¯0.55]. Progressive resistance exercise plus routine nursing improved cancer-related fatigue more than progressive muscle relaxation training plus routine nursing [SMDâ¯=â¯1.11, 95â¯% CI 0.43, 1.78, Pâ¯=â¯0.001]. There was low certainty of evidence that progressive muscle relaxation training improved cancer-related fatigue and quality of sleep, and the evidence that improved quality of life, anxiety and depression was very low. CONCLUSION: Current evidence suggested that progressive muscle relaxation training has the potential to improve cancer-related fatigue, anxiety, depression and quality of sleep in patients with cancer and is a low-load, simple exercise worthy of recommendation for cancer patients in fatigue state. Future research should focus on improving the methodological quality of randomized controlled trials to enhance the persuasive evidence of progressive muscle relaxation training efficacy.
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Treinamento Autógeno , Neoplasias , Humanos , Exercício Físico , Fadiga/etiologia , Fadiga/terapia , Neoplasias/complicações , Qualidade de VidaRESUMO
Community assembly describes how different ecological processes shape microbial community composition and structure. How environmental factors impact community assembly remains elusive. Here we sampled microbial communities and >200 biogeochemical variables in groundwater at the Oak Ridge Field Research Center, a former nuclear waste disposal site, and developed a theoretical framework to conceptualize the relationships between community assembly processes and environmental stresses. We found that stochastic assembly processes were critical (>60% on average) in shaping community structure, but their relative importance decreased as stress increased. Dispersal limitation and 'drift' related to random birth and death had negative correlations with stresses, whereas the selection processes leading to dissimilar communities increased with stresses, primarily related to pH, cobalt and molybdenum. Assembly mechanisms also varied greatly among different phylogenetic groups. Our findings highlight the importance of microbial dispersal limitation and environmental heterogeneity in ecosystem restoration and management.
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Água Subterrânea , Microbiota , Filogenia , Processos EstocásticosRESUMO
BACKGROUND AND AIMS: Chemokine (CC motif) receptor 1 (CCR1) promotes liver fibrosis in mice. However, its effects on nonalcoholic steatohepatitis (NASH) remain unclear. Therefore, the present study aimed to investigate the role of CCR1 in the progression of NASH. METHODS: Human serum and liver tissues were obtained from patients with NASH and controls. Systemic (Ccr1-/-) and liver macrophage-knockout Ccr1 (Ccr1LKD) mice were fed a high-cholesterol and high-fat (CL) diet for 12 weeks or a methionine/choline-deficient (MCD) diet for 4 weeks. BX471 was used to pharmacologically inhibit CCR1 in CL-fed mice. RESULTS: CCR1 was significantly upregulated in liver samples from patients with NASH and in animal models of dietary-induced NASH. In the livers of mice fed a CL diet for 12 weeks, the CCR1 protein colocalized with F4/80+ macrophages rather than with hepatic stellate cells. Compared to their wild-type littermates, Ccr1-/- mice fed with the CL or MCD diet showed inhibition of NASH-associated hepatic steatosis, inflammation, and fibrosis. Mechanistically, Ccr1 deficiency suppressed macrophage infiltration and activation by attenuating the mechanistic target of rapamycin complex 1 (mTORC1) signaling. Similar results were observed in Ccr1LKD mice administered the CL diet. Moreover, CCR1 inhibition by BX471 effectively suppressed NASH progression in CL-fed mice. CONCLUSIONS: Ccr1 deficiency mitigated macrophage activity by inhibiting mTORC1 signaling, thereby preventing the development of NASH. Notably, the CCR1 inhibitor BX471 protected against NASH. These findings would help in developing novel strategies for the treatment of NASH.
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Hepatopatia Gordurosa não Alcoólica , Compostos de Fenilureia , Piperidinas , Animais , Humanos , Camundongos , Colina/metabolismo , Colina/farmacologia , Modelos Animais de Doenças , Fígado/metabolismo , Cirrose Hepática/patologia , Ativação de Macrófagos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Metionina/metabolismo , Metionina/farmacologia , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptores CCR1/genética , Receptores CCR1/metabolismo , Receptores de Quimiocinas/metabolismoRESUMO
OBJECTIVES: To explore the correlation between Blood urea nitrogen to creatinine ratio (BUN/Scr ratio) and prognosis of patients with chronic heart failure complicated with renal injury. METHODS: A retrospective analysis of 504 patients hospitalized in Guang 'anmen Hospital, Chinese Academy of Traditional Chinese Medicine from March 2006 to June 2014 was conducted. The baseline data were analyzed, and the cutoff value was obtained by receiver operator characteristic curve (ROC) analysis, according to the cutoff value, all the participants were divided into two groups, BUN/Scr < 19.37 group (280 cases) and BUN/Scr ≥ 19.37 group (224 cases). The main end point was defined as all-cause death. The long-term mortality of the two groups was evaluated, and Kaplan-Meier survival curve was drawn. Univariate analysis was performed on all the variables affecting the patient's prognosis, and the variables with P < 0.05 were put into Cox regression model, and subgroup analysis was performed on the variables that might affect the patient's prognosis. RESULTS: The baseline data of 504 patients were analyzed and found that the median follow up was 683. Through ROC analysis of 504 subjects, the cutoff value of BUN/Scr was 19.37. The results of Kaplan-Meier survival curve showed that the mortality rate of patients with ratio ≥ 19.37 was higher than that of patients with ratio < 19.37. After multivariate analysis, COX regression model showed that the mortality of patients with BUN/Scr ≥ 19.37 was 1.885 times that of patients with BUN/Scr < 19.37 [HR = 1.885 (1.298-2.737), P = 0.001]. Subgroup analysis showed that the relationship between BUN/Scr and the prognosis of CHF was influenced by NYHA and eGRF (P < 0.05). CONCLUSIONS: BUN/Scr ratio is related to the poor prognosis of patients with CHF, and is an independent predictor of all-cause death.
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Insuficiência Cardíaca , Humanos , Nitrogênio da Ureia Sanguínea , Creatinina , Estudos Retrospectivos , Doença CrônicaRESUMO
BACKGROUND: Atrial fibrillation (AF) is one of the most common arrhythmias encountered in clinical settings. Currently, the pathophysiology of AF remains unclear, which severely limits the effectiveness and safety of medical therapies. The Chinese herbal formula Qi-Po-Sheng-Mai Granule (QPSM) has been widely used in China to treat AF. However, its pharmacological and molecular mechanisms remain unknown. PURPOSE: The purpose of this study was to investigate the molecular mechanisms and potential targets of QPSM for AF. STUDY DESIGN AND METHODS: The AF model was induced by Ach (66 µg/ml) and CaCl2 (10 mg/kg), and the dose of 0.1 ml/100 g was injected into the tail vein for 5 weeks. QPSM was administered daily at doses of 4.42 and 8.84 g/kg, and amiodarone (0.18 g/kg) was used as the positive control. The effect of QPSM on AF was assessed by electrocardiogram, echocardiography, and histopathological analysis. Then, we employed network pharmacology with single nucleus RNA sequencing (snRNA-Seq) to investigate the molecular mechanisms and potential targets of QPSM for AF. Furthermore, high performance liquid chromatography (HPLC) method was used for component analysis of QPSM, and molecular docking was used to verify the potential targets. Using the IonOptix single cell contraction and ion synchronization test equipment, single myocyte length and calcium ion variations were observed in real time. The expression levels of calcium Transporter-related proteins were detected by western blot and immunohistochemistry. RESULTS: Based on an Ach-CaCl2-induced AF model, we found that QPSM treatment significantly reduced atrial electrical remodeling-related markers, such as AF inducibility and duration, and attenuated atrial dilation and fibrosis. Network pharmacology identified 52 active ingredients and 119 potential targets for QPSM in the treatment of AF, and 45 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were enriched, among which calcium pathway had the greatest impact. Using single nucleus sequencing (snRNA-seq), we identified cardiomyocytes as the most differentially expressed in response to drug treatment, with nine differentially expressed genes enriched in calcium signaling pathways. High performance liquid chromatography and molecular docking confirmed that the core components of QPSM strongly bind to the key factors in the calcium signaling pathway. Additional experiments have shown that QPSM increases calcium transients (CaT) and contractility in the individual cardiomyocyte. This was accomplished by increasing the expression of CACNA1C and SERCA2a and decreasing the expression of CAMK2B and NCX1. CONCLUSION: The present study has systematically elucidated the role of QPSM in maintaining calcium homeostasis in cardiomyocytes through the regulation of calcium transporters, which could lead to new drug development ideas for AF.
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Fibrilação Atrial , Conservadores da Densidade Óssea , Humanos , Fibrilação Atrial/induzido quimicamente , Fibrilação Atrial/tratamento farmacológico , Miócitos Cardíacos , Cálcio , Cloreto de Cálcio , Simulação de Acoplamento Molecular , Qi , Aminoácidos , HomeostaseRESUMO
Cardiorenal syndrome (CRS) is a state of coexisting heart failure and renal insufficiency in which acute or chronic dysfunction of the heart or kidney lead to acute or chronic dysfunction of the other organ.It was found that renal fibrosis is an important pathological process in the progression of type 2 CRS to end-stage renal disease, and progressive renal impairment accelerates the deterioration of cardiac function and significantly increases the hospitalization and mortality rates of patients. Previous studies have found that Hemodynamic Aiteration, RAAS Overactivation, SNS Dysfunction, Endothelial Dysfunction and Imbalance of natriuretic peptide system contribute to the development of renal disease in the decompensated phase of heart failure, but the exact mechanisms is not clear. Therefore, in this review, we focus on the molecular pathways involved in the development of renal fibrosis due to heart failure and identify the canonical and non-canonical TGF-ß signaling pathways and hypoxia-sensing pathways, oxidative stress, endoplasmic reticulum stress, pro-inflammatory cytokines and chemokines as important triggers and regulators of fibrosis development, and summarize the therapeutic approaches for the above signaling pathways, including SB-525334 Sfrp1, DKK1, IMC, rosarostat, 4-PBA, etc. In addition, some potential natural drugs for this disease are also summarized, including SQD4S2, Wogonin, Astragaloside, etc.
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Síndrome Cardiorrenal , Insuficiência Cardíaca , Humanos , Síndrome Cardiorrenal/metabolismo , Insuficiência Cardíaca/tratamento farmacológico , Rim/patologia , Coração , FibroseRESUMO
Excessive fertilization is associated with nutrient loss, soil compaction, and weak plant resistance. Straw returning can increase soil fertility with a consequent reduction in fertilizer, but the effects of fertilizer reduction coupled with straw returning on crop endophytic microbes and crop disease are poorly understood. Therefore, using metagenomic sequencing methods we investigated the responses of soil fertility, diversity, the function of root endophytic bacteria, and the occurrence of wheat crown rot due to the application of fertilizer (no, moderate and excessive fertilizer) coupled with or without straw returning after 7 years of treatments. The results showed that, after excessive fertilization, the wheat crown rot became severe, registering a disease index of 23. Compared with excessive fertilization, moderate fertilization coupled with straw returning significantly reduced the incidence of wheat crown rot, the disease index was reduced by 38.50%, and the richness and diversity of endophytic bacteria were increased by 61.20 and 11.93%, respectively, but the soil fertility was not significantly affected. In addition, moderate fertilization coupled with straw returning changed the community structure of endophytic bacteria and increased the relative abundance of carbohydrate metabolism and nitrogen fixation-related genes by 4.72 and 9.32%, respectively. Our results indicated that fertilizer reduction coupled with straw returning reduced the occurrence of wheat crown rot, increased the diversity of endophytic bacteria, and changed the community structure and function of endophytic bacteria, which will provide a better understanding of the interaction of fertilization coupled with straw returning, endophytic bacteria and wheat crown rot.
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Fusarium pseudograminearum is a soil-borne pathogen that is capable of causing a highly destructive crown disease in wheat. Secondary metabolites (SMs), especially deoxynivalenol (DON), are the primary virulence factors during infection. Here, we characterised the global regulator FpLaeB, an orthologue of LaeB protein function, to regulate the SM in Aspergillus nidulans. Through the utility of the gene targeting approach, we found that the vegetative growth of the FpLaeB deletion mutant was drastically reduced compared to that of the wild type. FpLaeB was also important for conidiation because the FpLaeB deletion mutant formed fewer conidia in induced medium. In addition, the sensitivity of the FpLaeB deletion mutant to the cell wall integrity inhibitor was decreased, while its growth was more severely inhibited by the cell membrane inhibitor sodium dodecyl sulfate (SDS) than that of the wild type. More importantly, the virulence was decreased when the FpLaeB deletion mutant was inoculated onto the wheat stem base or head. Through genome-wide gene expression profiling, FpLaeB was found to regulate several processes related to the above phenotypes such as the carbohydrate metabolic process, which is an integral and intrinsic component of membranes, especially SMs. Furthermore, the generation of DON was impaired in the FpLaeB deletion mutant via ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) assay. These results showed that FpLaeB plays an important role in the growth, development, and maintenance of the cell wall, and in membrane integrity. More importantly, FpLaeB is required for SMs and full virulence in F. pseudograminearum.
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Neoadjuvant therapy (NAT) for advanced colorectal cancer (ACRC) is a kind of well-evidenced therapy, yet a portion of ACRC patients have poor therapeutic response. To date, no suitable biomarker used for assessing NAT efficacy has been reported. Here, we collect 72 colonoscopy biopsy tissue specimens from ACRC patients before undergoing NAT and investigate the relationship between HOXA13 expression and NAT efficacy. The results show that HOXA13 expression in pretreated tumor specimens is negatively associated with tumor regression ( P<0.001) and progression-free survival ( P<0.05) in ACRC patients who underwent NAT. Silencing of HOXA13 or its regulator HOTTIP significantly enhances the chemosensitivity of colorectal cancer (CRC) cells, leading to an increase in cell apoptosis and the DNA damage response (DDR) to chemotherapeutic drug treatment. In contrast, HOXA13 overexpression causes a significant increase in chemoresistance in CRC cells. In summary, we find that the HOTTIP/HOXA13 axis is involved in regulating chemotherapeutic sensitivity in CRC cells by modulating the DDR and that HOXA13 serves as a promising marker for NAT efficacy prediction in ACRC patients.
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Neoplasias Colorretais , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , Regulação Neoplásica da Expressão Gênica , Terapia Neoadjuvante , Linhagem Celular Tumoral , Proliferação de Células/genética , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , BiomarcadoresRESUMO
BACKGROUNDS/OBJECTIVES: Melatonin promotes brown adipose tissue (BAT) activity, leading to body mass reduction and energy expenditure. However, the mechanisms governing these beneficial effects are not well-established. This study aimed to assess the effects of (1) melatonin on BAT and energy metabolism, and (2) fibroblast growth factor 21 (FGF21) in BAT-mediated thermogenesis. METHODS: Male C57BL/6 J mice received a high-fat diet (HFD) or normal chow, accompanied by intraperitoneal injection of 20 mg/kg melatonin for 12 weeks. FGF21-/- mice consumed an HFD with or without melatonin for 8 weeks. RESULTS: Melatonin attenuated weight gain, insulin resistance, adipocyte hypertrophy, inflammation, and hepatic steatosis induced by the HFD and increased energy expenditure. Furthermore, melatonin improved cold tolerance by increasing BAT uncoupling protein 1 (UCP1) expression and producing heat. Notably, melatonin resulted in a shift in energy metabolism favouring the utilization of fat, and it increased FGF21 in circulating and metabolic tissues and skeletal muscle phosphorylation of AMP-activated protein kinase. However, melatonin did not protect against obesity, insulin resistance, and energy expenditure in HFD-fed FGF21-/- mice. CONCLUSIONS: Melatonin suppressed obesity and insulin resistance resulting from the HFD by enhancing BAT activity and energy expenditure, and these effects were dependent on FGF21.
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Resistência à Insulina , Melatonina , Proteínas Quinases Ativadas por AMP/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Dieta Hiperlipídica , Metabolismo Energético/fisiologia , Lipólise , Masculino , Melatonina/metabolismo , Melatonina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Proteína Desacopladora 1/metabolismoRESUMO
Obesity is a risk factor for many metabolic diseases. Efficient therapeutic strategies are urgently needed. Swertiamarin (STM) prevents obesity and the associated insulin resistance and inflammation. However, the therapeutic effects of STM on preexisting obesity remain unclear. Therefore, in this study we aim to investigate the effects of STM on energy expenditure and fat browning in mice with preexisting obesity. C57BL/6J mice are fed with a high-fat diet (HFD) for 8 weeks to induce obesity and then gavaged (or not) with STM for 10 weeks. The whole-body energy metabolism of mice is examined by indirect calorimetry. The results show that after 10 weeks of treatment, STM markedly prevents HFD-induced weight gain, chronic inflammation, insulin resistance, and hepatic steatosis. STM promotes oxygen consumption and energy expenditure. The level of uncoupling protein 1 is enhanced in the brown and white adipose tissues of STM-treated mice. STM increases the phosphorylation of AMP-activated protein kinase and the expressions of genes involved in fat oxidation, reducing fat deposition in skeletal muscles. Meanwhile, STM does not affect the intestinal microbiotic composition. Overall, STM supplementation may serve as a potential therapy for obesity.
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Resistência à Insulina , Camundongos , Animais , Camundongos Obesos , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Tecido Adiposo/metabolismo , Metabolismo Energético , Dieta Hiperlipídica/efeitos adversos , Inflamação/metabolismo , Estresse Oxidativo , Tecido Adiposo Marrom/metabolismoRESUMO
Hydrogenotrophic denitrification (HD) is a promising autotrophic biological process for advanced nitrogen removal, while sludge granulation was seldom reported. This study aimed to cultivate granular sludge to improve capacity and stability of HD process. The resulting HD granular sludge performed high nitrogen removal rate (NRR) of 0.42 ± 0.0.4 kgN/(m3·d) with low accumulation of nitrite and nitrous oxide emission. HD granular sludge reactor performed over 3 times higher NRR compared to that in HD fixed-bed biofilm reactor (0.13 ± 0.01 kgN/(m3·d). Besides, granular sludge reactor could treat groundwater well even at the low temperature of 15 °C. The dominant genera were Hydrogenophaga and Comamonas in granular sludge, and Dechloromonas in biofilm. Noticeably, sulfate in the groundwater stimulated the growth of sulfur converting microbes with increasing abundances of sulfite reductase gene and sulfate-reducing bacteria Desulfovibrio. This study highlights the potential implementation of HD process in granular sludge reactor for advance nitrogen removal from impaired groundwater.
Assuntos
Desnitrificação , Esgotos , Reatores Biológicos , Nitritos , Nitrogênio , Óxido Nitroso , Oxirredutases atuantes sobre Doadores de Grupo Enxofre , Esgotos/microbiologia , Sulfatos , EnxofreRESUMO
Bacillus cereus strain CPT56D-587-MTF (CPTF) was isolated from the highly contaminated Oak Ridge Reservation (ORR) subsurface. This site is contaminated with high levels of nitric acid and multiple heavy metals. Amplicon sequencing of the 16S rRNA genes (V4 region) in sediment from this area revealed an amplicon sequence variant (ASV) with 100% identity to the CPTF 16S rRNA sequence. Notably, this CPTF-matching ASV had the highest relative abundance in this community survey, with a median relative abundance of 3.77% and comprised 20%-40% of reads in some samples. Pangenomic analysis revealed that strain CPTF has expanded genomic content compared to other B. cereus species-largely due to plasmid acquisition and expansion of transposable elements. This suggests that these features are important for rapid adaptation to native environmental stressors. We connected genotype to phenotype in the context of the unique geochemistry of the site. These analyses revealed that certain genes (e.g. nitrate reductase, heavy metal efflux pumps) that allow this strain to successfully occupy the geochemically heterogenous microniches of its native site are characteristic of the B. cereus species while others such as acid tolerance are mobile genetic element associated and are generally unique to strain CPTF.
Assuntos
Bacillus cereus , Metais Pesados , RNA Ribossômico 16S/genética , Bacillus cereus/genética , Genômica , FilogeniaRESUMO
Cardiovascular disease (CVD) refers to a group of diseases involving the heart or blood vessels and is currently the leading cause of morbidity and mortality in many countries around the world and poses a serious economic burden. Macrophages are key effectors of inflammatory and innate immune responses, and their aberrant expression contributes to the development of various types of CVD.This study retrieved articles published from 1990-2022 on macrophages in CVD from the Web of Science core collection, based on CiteSpace and VOSviewer on these literature The annual output, countries and regions, institutions, authors, core journals, keywords and co-cited literature were analyzed. A total of 7,197 articles and reviews were retrieved, with a general upward trend despite slight fluctuations in annual publications. Europe, the United States and Asia are the main countries and regions publishing articles, especially the United States, with the highest number of articles (2,581), citations (173,692) and H-index (197), which also has the world's largest number of elite institutions, professional The country also has the world's largest number of elite institutions, professional researchers and high-impact journals, and is the leading country in this field of research. Keywords "inflammation", "immunology", "autophagy", "lipid-peroxidation" are the main pathogenesis of CVD caused by macrophages. "NLRP3", "nf kappa b" and "TNF-α" are the most frequently studied signalling pathways. Atherosclerosis, myocarditis and myocardial injury are the most studied disease types in this field. In addition, the study of macrophage-related CVD induced by COVID-19 seems to be a recent hot topic, and the mechanisms involved are mainly macrophage polarization, inflammatory factor storm, ACE2 and so on. The present study reveals hot spots and new trends in research on macrophages in CVD, which can provide scholars with key information in this field of research and help further explore new research directions.