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There is a relative scarcity of large-scale population studies investigating the relationship between the insulin resistance index of homeostasis model assessment (HOMA-IR) and vascular damage. Therefore, we assessed the association between HOMA-IR and vascular damage in adults aged 18 years and older in China. A total of 17,985 research subjects were included. Vascular damage markers and relevant laboratory tests were measured. HOMA-IR was calculated as (fasting insulin * fasting blood glucose)/22.5. Vascular damage included arteriosclerosis (ba-PWV > 1800 cm/s), peripheral artery disease (ABI < 0.9), and microalbuminuria (UACR > 30 mg/g). The relationship between HOMA-IR and vascular damage was analyzed using the RCS. The restricted cubic spline (RCS) analysis suggested that HOMA-IR was nonlinearly associated with arteriosclerosis (P for no-liner < 0.01), peripheral artery disease (P for no-liner < 0.01), and microalbuminuria (P for no-liner < 0.01). Further segmented regression analyses revealed that in study subjects with HOMA-IR < 5, we found that HOMA-IR was associated with an increased OR for arteriosclerosis (OR: 1.36, 95% CI (1.28, 1.45), P < 0.01), peripheral artery disease (OR: 1.33, 95% CI (1.10, 1.60), P < 0.01) and microalbuminuria (OR: 1.59, 95% CI (1.49, 1.70), P < 0.01). HOMA-IR is an independent risk factor for vascular damage, both macrovascular and microvascular. The phenomenon of saturation of HOMA-IR with vascular damage needs further investigation.
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Resistência à Insulina , Humanos , Masculino , China/epidemiologia , Feminino , Estudos Transversais , Pessoa de Meia-Idade , Adulto , Idoso , Albuminúria , Fatores de Risco , Doença Arterial Periférica/epidemiologia , Doença Arterial Periférica/etiologia , Glicemia/metabolismo , Arteriosclerose/patologia , Arteriosclerose/epidemiologia , Insulina/sangue , Insulina/metabolismoRESUMO
INTRODUCTION: Metabolic syndrome is a serious public health concern across the globe. However, the typical metabolites and mechanisms underlying the decreased fertility related to metabolic syndrome is still elusive. OBJECTIVES: The aim of the present study was to explore the typical metabolites and mechanisms underlying the decreased fertility related with metabolic syndrome. METHODS: Utilizing metabolomics, a comparative analysis was conducted on fatty acid compositions in various tissues of sows with high and low reproductive performance. Additionally, serum fatty acid compositions in a metabolic syndrome model (obese mice) induced by a high-fat diet (HFD) were investigated to elucidate the lipid metabolites associated with metabolic syndrome. Furthermore, the impact of nervonic acid (NA) on ovarian function was examined using rodent animal models (rats and mice). Through biological techniques such as transcriptomics, CUT&Tag, and analysis of post-translational protein modifications, the molecular mechanisms underlying NA mediated ovarian inflammation were further elucidated based on models utilizing ovarian granulosa cells from pigs, humans, and mice. Finally, validation was performed on ovaries from patients diagnosed with polycystic ovary syndrome. RESULTS: In vitro, targeted serum lipidomic analysis revealed that sows with low embryo survival rates exhibited abnormal lipid metabolism characterized by abnormal accumulation of NA in the liver, ovary, and adipose tissue. Additionally, elevated NA levels trigger ovarian inflammation to cause ovarian dysfunction in both sows and rats. Mechanistically, NA induce mitochondrial oxidative stress through inhibiting respiratory chain proteins CYTB and NDFUB8 to activate NLRP3 inflammasome, which triggers procaspase-1 into active caspase-1, and convert the cytokine precursors pro-IL-1ß into biologically active IL-1ß in ovarian granulosa cells. Notably, we evidenced that NA promotes IL-1ß activities by increasing H3K9ac modification level of IL-1ß promoter regions and regulating the expression of the transcription factor AP-1. Finally, we found that the decreased expression of CerS2 in ovaries and the increased level of chemokine CXCL14 may be the cause of abnormal NA accumulation. Surprisingly, individuals with polycystic ovary syndrome, obesity, non-alcoholic fatty liver or gestational diabetes mellitus exhibit a high level of serum NA. CONCLUSION: Collectively, our current study suggests that NA is a typical metabolite of metabolic syndrome, which strongly influences the ovarian function and embryo survival and also provides that interfering with mitochondrial ROS production is a potential strong strategy for target solving abnormal NA accumulation.
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Recent studies indicate that Glypican 1 (GPC-1) is aberrantly expressed and plays a key role in certain cancers, but little is known in the hepatocellular carcinoma. Raw data from TCGA, GTEx and TIMER databases were utilized to comprehensively analyze GPC-1 expression landscape in pan-cancer, and the biological function of GPC-1 was investigated in liver cancer cells. The results revealed that GPC-1 is highly expressed in HCC, negatively correlated with survival, and also positively correlated with immune infiltration and clinical stage. Furthermore, GPC-1 promoted cell proliferation and inhibited apoptosis in the HCC cell lines. WGCNA analysis and HCCDB database revealed that Akt acted as a key molecule related to GPC-1, influencing biological functions and regulating cell malignant behaviors via the AKT signaling pathway. In conclusion, our findings provide a relatively comprehensive understanding of the oncogenic role of GPC-1 in HCC, implying that GPC-1 could serve as an innovative therapeutic target.
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Carcinoma Hepatocelular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Glipicanas , Neoplasias Hepáticas , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Glipicanas/metabolismo , Glipicanas/genética , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/genética , Linhagem Celular Tumoral , Apoptose/genética , Transdução de Sinais , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
OBJECTIVE: There is a lack of effective biomarkers for predicting the distant metastasis in nasopharyngeal carcinoma (NPC). We aimed to explore the expression of FAP+Cancer-associated fibroblasts (CAFs) derived CXCL1 in NPC and its predictive values for distant metastasis and correlation with PD-L1 expression. MATERIALS AND METHODS: A total of 345 patients with locoregionally advanced NPC were retrospectively enrolled (the training cohort: the validation cohort = 160:185). Co-expression of CXCL1 and FAP and the expression of PD-L1 were detected by multi-immunofluorescence staining and immunohistochemistry, respectively. The primary end-point was distant metastasis-free survival (DMFS). The Kaplan-Meier method was used to calculate the survival. The Cox proportional hazards model was used to assess prognostic risk factors. RESULTS: A novel CXCL1+_FAP+ phenotype in CAFs was identified in NPC and then used to divide patients into low and high risk groups. Both in the training cohort and validation cohort, patients in the high risk group had poorer DMFS, overall survival (OS), progression-free survival (PFS) and locoregional relapse-free survival (LRFS) than patients in the low risk group. Multivariate analysis revealed CXCL1+_FAP+ phenotype was an independent prognostic factor for DMFS, OS, PFS and LRFS. Further results showed patients in the high risk group had higher PD-L1 expression than those in the low risk group. CONCLUSION: Our study showed CXCL1+_FAP+ phenotype in CAFs could effectively classified locoregionally advanced NPC patients into different risk groups for distant metastasis and might be a potential biomarker for anti-PD-1/PD-L1 immunotherapy.
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Antígeno B7-H1 , Fibroblastos Associados a Câncer , Quimiocina CXCL1 , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Humanos , Antígeno B7-H1/metabolismo , Masculino , Feminino , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/mortalidade , Pessoa de Meia-Idade , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/mortalidade , Quimiocina CXCL1/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Adulto , Estudos Retrospectivos , Metástase Neoplásica , Prognóstico , Fenótipo , Biomarcadores Tumorais/metabolismo , Idoso , Serina Endopeptidases/metabolismo , Endopeptidases/metabolismo , Proteínas de Membrana/metabolismoRESUMO
The intrinsic resistance of MRSA coupled with biofilm antibiotic tolerance challenges the antibiotic treatment of MRSA biofilm infections. Phytochemical-based nanoplatform is a promising emerging approach for treatment of biofilm infection. However, their therapeutic efficacy was restricted by the low drug loading capacity and lack of selectivity. Herein, we constructed a surface charge adaptive phytochemical-based nanoparticle with high isoliquiritigenin (ISL) loading content for effective treatment of MRSA biofilm. A dimeric ISL prodrug (ISL-G2) bearing a lipase responsive ester bond was synthesized, and then encapsulated into the amphiphilic quaternized oligochitosan. The obtained ISL-G2 loaded NPs possessed positively charged surface, which allowed cis-aconityl-d-tyrosine (CA-Tyr) binding via electrostatic interaction to obtain ISL-G2@TMDCOS-Tyr NPs. The NPs maintained their negatively charged surface, thus prolonging the blood circulation time. In response to low pH in the biofilms, the fast removal of CA-Tyr led to a shift in their surface charge from negative to positive, which enhanced the accumulation and penetration of NPs in the biofilms. Sequentially, the pH-triggered release of d-tyrosine dispersed the biofilm and lipase-triggered released of ISL effectively kill biofilm MRSA. An in vivo study was performed on a MRSA biofilm infected wound model. This phytochemical-based system led to â¼2 log CFU (>99 %) reduction of biofilm MRSA as compared to untreated wound (P < 0.001) with negligible biotoxicity in mice. This phytochemical dimer nanoplatform shows great potential for long-term treatment of resistant bacterial infections.
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BACKGROUND: The status of dental caries is closely related to changes in the oral microbiome. In this study, we compared the diversity and structure of the dental plaque microbiome in children with severe early childhood caries (S-ECC) before and after general anaesthesia and outpatient treatment. METHODS: Forty children aged 3 to 5 years with S-ECC who had completed whole-mouth dental treatment under general anaesthesia (C1) or in outpatient settings (C2) were selected, 20 in each group. The basic information and oral health status of the children were recorded, and the microbial community structure and diversity of dental plaque before treatment (C1, C2), the day after treatment(C2_0D), 7 days after treatment (C1_7D, C2_7D), 1 month after treatment (C1_1M, C2_1M), and 3 months after treatment (C1_3M, C2_3M) were analysed via 16 S rRNA high-throughput sequencing technology. RESULTS: (1) The alpha diversity test showed that the flora richness in the multiappointment group was significantly greater at posttreatment than at pretreatment (P < 0.05), and the remaining alpha diversity index did not significantly differ between the 2 groups (P > 0.05). The beta diversity analysis revealed that the flora structures of the C1_7D group and the C2_3M group were significantly different from those of the other time points within the respective groups (P < 0.05). (2) The core flora existed in both the pre- and posttreatment groups, and the proportion of their flora abundance could be altered depending on the caries status of the children in both groups. Leptotrichia abundance was significantly (P < 0.05) lower at 7 days posttreatment in both the single- and multiappointment groups. Corynebacterium and Corynebacterium_matruchotii were significantly more abundant in the C1_1M and C1_3M groups than in the C1 and C1_7D groups (P < 0.05). Streptococcus, Haemophilus and Haemophilus_parainfluenzae were significantly more abundant in the C1_7D group than in the other groups (P < 0.05). CONCLUSION: A single session of treatment under general anaesthesia can cause dramatic changes in the microbial community structure and composition within 7 days after treatment, whereas treatment over multiple appointments may cause slow changes in oral flora diversity.
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Cárie Dentária , Placa Dentária , Humanos , Placa Dentária/microbiologia , Cárie Dentária/microbiologia , Cárie Dentária/terapia , Pré-Escolar , Masculino , Feminino , Microbiota , Anestesia Geral , RNA Ribossômico 16SRESUMO
INTRODUCTION: Acute kidney injury (AKI) is a common complication after on-pump cardiac surgery, and previous studies have suggested that blood glucose is associated with postoperative AKI. However, limited evidence is available regarding intraoperative glycemic thresholds in cardiac surgery. The aim of this study was to explore the association between peak intraoperative blood glucose and postoperative AKI, and determine the cut-off values for intraoperative glucose concentration associated with an increased risk of AKI. METHODS: The study was retrospective and single-centered. Adult patients in West China Hospital of Sichuan University who underwent on-pump cardiac surgery (n = 3375) were included. The primary outcome was the incidence of AKI. Multivariable logistic analysis using restricted cubic spline was performed to explore the association between intraoperative blood glucose and postoperative AKI. RESULTS: The incidence of AKI in the study population was 18.0% (607 of 3375). Patients who developed AKI had a significantly higher peak intraoperative glucose during the surgery compared to those without AKI. After adjustment for confounders, the incidence of AKI increased with peak intraoperative blood glucose (adjusted odds ratio, 1.08, 95% confidence interval 1.03, 1.12). Furthermore, it was demonstrated that the possibility of AKI was relatively ï¬at till 127.8 mg/dL (7.1 mmol/L) glucose levels which started to rapidly increase afterward. CONCLUSIONS: Increased intraoperative blood glucose was associated with an increased risk of AKI. Among patients undergoing on-pump cardiac surgery, avoiding a high glucose peak (i.e., below 127.8 mg/dL [7.1 mmol/L]) may reduce the risk of postoperative AKI.
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Injúria Renal Aguda , Glicemia , Procedimentos Cirúrgicos Cardíacos , Complicações Pós-Operatórias , Humanos , Estudos Retrospectivos , Masculino , Feminino , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/sangue , Injúria Renal Aguda/diagnóstico , Pessoa de Meia-Idade , Glicemia/análise , Idoso , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/sangue , Incidência , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , China/epidemiologia , Fatores de Risco , Período Intraoperatório , AdultoRESUMO
As the second most common malignant tumor in the urinary system, renal cell carcinoma (RCC) is imperative to explore its early diagnostic markers and therapeutic targets. Numerous studies have shown that AURKB promotes tumor development by phosphorylating downstream substrates. However, the functional effects and regulatory mechanisms of AURKB on clear cell renal cell carcinoma (ccRCC) progression remain largely unknown. In the current study, we identified AURKB as a novel key gene in ccRCC progression based on bioinformatics analysis. Meanwhile, we observed that AURKB was highly expressed in ccRCC tissue and cell lines and knockdown AURKB in ccRCC cells inhibit cell proliferation and migration in vitro and in vivo. Identified CDC37 as a kinase molecular chaperone for AURKB, which phenocopy AURKB in ccRCC. AURKB/CDC37 complex mediate the stabilization of MYC protein by directly phosphorylating MYC at S67 and S373 to promote ccRCC development. At the same time, we demonstrated that the AURKB/CDC37 complex activates MYC to transcribe CCND1, enhances Rb phosphorylation, and promotes E2F1 release, which in turn activates AURKB transcription and forms a positive feedforward loop in ccRCC. Collectively, our study identified AURKB as a novel marker of ccRCC, revealed a new mechanism by which the AURKB/CDC37 complex promotes ccRCC by directly phosphorylating MYC to enhance its stability, and first proposed AURKB/E2F1-positive feedforward loop, highlighting AURKB may be a promising therapeutic target for ccRCC.
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Aurora Quinase B , Carcinoma de Células Renais , Proteínas de Ciclo Celular , Progressão da Doença , Fator de Transcrição E2F1 , Neoplasias Renais , Proteínas Proto-Oncogênicas c-myc , Humanos , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/metabolismo , Fator de Transcrição E2F1/metabolismo , Fator de Transcrição E2F1/genética , Neoplasias Renais/patologia , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Fosforilação , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Aurora Quinase B/metabolismo , Aurora Quinase B/genética , Proliferação de Células , Animais , Regulação Neoplásica da Expressão Gênica , Camundongos Nus , Camundongos , Movimento Celular/genética , ChaperoninasRESUMO
SET domain containing 7(SETD7), a member of histone methyltransferases, is abnormally expressed in multiple tumor types. However, the biological function and underlying molecular mechanism of SETD7 in clear cell renal cell carcinoma (ccRCC) remain unclear. Here, we explored the biological effects of SETD7-TAF7-CCNA2 axis on proliferation and metastasis in ccRCC. We identified both SETD7 and TAF7 were up-regulated and significantly promoted the proliferation and migration of ccRCC cells. Concurrently, there was a significant positive correlation between the expression of SETD7 and TAF7, and the two were colocalized in the nucleus. Mechanistically, SETD7 methylates TAF7 at K5 and K300 sites, resulting in the deubiquitination and stabilization of TAF7. Furthermore, re-expression of TAF7 could partially restore SETD7 knockdown inhibited ccRCC cells proliferation and migration. In addition, TAF7 transcriptionally activated to drive the expression of cyclin A2 (CCNA2). And more importantly, the methylation of TAF7 at K5 and K300 sites exhibited higher transcriptional activity of CCNA2, which promotes formation and progression of ccRCC. Our findings reveal a unique mechanism that SETD7 mediated TAF7 methylation in regulating transcriptional activation of CCNA2 in ccRCC progression and provide a basis for developing effective therapeutic strategies by targeting members of SETD7-TAF7-CCNA2 axis.
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Carcinoma de Células Renais , Movimento Celular , Proliferação de Células , Histona-Lisina N-Metiltransferase , Neoplasias Renais , Humanos , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Proliferação de Células/genética , Histona-Lisina N-Metiltransferase/metabolismo , Histona-Lisina N-Metiltransferase/genética , Movimento Celular/genética , Neoplasias Renais/metabolismo , Neoplasias Renais/genética , Neoplasias Renais/patologia , Linhagem Celular Tumoral , Fatores Associados à Proteína de Ligação a TATA/metabolismo , Fatores Associados à Proteína de Ligação a TATA/genética , Metilação , Fator de Transcrição TFIID/metabolismo , Fator de Transcrição TFIID/genética , Regulação Neoplásica da Expressão GênicaRESUMO
BACKGROUND: The host-microbiota interaction plays a crucial role in maintaining homeostasis and disease susceptibility, and microbial tryptophan metabolites are potent modulators of host physiology. However, whether and how these metabolites mediate host-microbiota interactions, particularly in terms of inter-microbial communication, remains unclear. RESULTS: Here, we have demonstrated that indole-3-lactic acid (ILA) is a key molecule produced by Lactobacillus in protecting against intestinal inflammation and correcting microbial dysbiosis. Specifically, Lactobacillus metabolizes tryptophan into ILA, thereby augmenting the expression of key bacterial enzymes implicated in tryptophan metabolism, leading to the synthesis of other indole derivatives including indole-3-propionic acid (IPA) and indole-3-acetic acid (IAA). Notably, ILA, IPA, and IAA possess the ability to mitigate intestinal inflammation and modulate the gut microbiota in both DSS-induced and IL-10-/- spontaneous colitis models. ILA increases the abundance of tryptophan-metabolizing bacteria (e.g., Clostridium), as well as the mRNA expression of acyl-CoA dehydrogenase and indolelactate dehydrogenase in vivo and in vitro, resulting in an augmented production of IPA and IAA. Furthermore, a mutant strain of Lactobacillus fails to protect against inflammation and producing other derivatives. ILA-mediated microbial cross-feeding was microbiota-dependent and specifically enhanced indole derivatives production under conditions of dysbiosis induced by Citrobacter rodentium or DSS, but not of microbiota disruption with antibiotics. CONCLUSION: Taken together, we highlight mechanisms by which microbiome-host crosstalk cooperatively control intestinal homoeostasis through microbiota-derived indoles mediating the inter-microbial communication. These findings may contribute to the development of microbiota-derived metabolites or targeted "postbiotic" as potential interventions for the treatment or prevention of dysbiosis-driven diseases. Video Abstract.
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Microbiota , Triptofano , Humanos , Triptofano/metabolismo , Disbiose/microbiologia , Indóis/farmacologia , Bactérias/genética , Bactérias/metabolismo , InflamaçãoRESUMO
Gastric cancer (GC) is a tumor characterized by high incidence and mortality, with metastasis being the primary cause of poor prognosis. Extracellular vesicles (EVs) are an important intercellular communication medium. They contain bioactive substances such as proteins, nucleic acids, and lipids. EVs play a crucial biological role in the process of GC metastasis. Through mechanisms such as remodeling the tumor microenvironment (TME), immune suppression, promoting angiogenesis, and facilitating epithelial-mesenchymal transition (EMT) and mesothelial-mesenchymal transition (MMT), EVs promote invasion and metastasis in GC. Further exploration of the biological roles of EVs will contribute to our understanding of the mechanisms underlying GC metastasis and may provide novel targets and strategies for the diagnosis and treatment of GC. In this review, we summarize the mechanisms by which EVs influence GC metastasis from four aspects: remodeling the TME, modulating the immune system, influencing angiogenesis, and modulating the processes of EMT and MMT. Finally, we briefly summarized the organotropism of GC metastasis as well as the potential and limitations of EVs in GC.
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Mirizzi syndrome is a serious complication of gallstone disease. It is caused by the impacted stones in the gallbladder neck or cystic duct. One of the features of Mirizzi syndrome is severe inflammation or dense fibrosis at the Calot's triangle. In our clinical practice, bile duct, branches of right hepatic artery and right portal vein clinging to gallbladder infundibulum are often observed due to gallbladder infundibulum adhered to right hepatic hilum. The intraoperative damage of branches of right hepatic artery occurs more easily than that of bile duct, all of which are hidden pitfalls for surgeons. Magnetic resonance cholangiopancreatography (MRCP) and endoscopic retrograde cholangiopancreatography (ERCP) are the preferable tools for the diagnosis of Mirizzi syndrome. Anterograde cholecystectomy in Mirizzi syndrome is easy to damage branches of right hepatic artery and bile duct due to gallbladder infundibulum adhered to right hepatic hilum. Subtotal cholecystectomy is an easy, safe and definitive approach to Mirizzi syndrome. When combined with the application of ERCP, a laparoscopic management of Mirizzi syndrome by well-trained surgeons is feasible and safe. The objective of this review was to highlight its existing problems: (1) low preoperative diagnostic rate, (2) easy to damage bile duct and branches of right hepatic artery, and (3) high concomitant gallbladder carcinoma. Meanwhile, the review aimed to discuss the possible therapeutic strategies: (1) to enhance its preoperative recognition by imaging findings, and (2) to avoid potential pitfalls during surgery.
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Colelitíase , Síndrome de Mirizzi , Humanos , Síndrome de Mirizzi/diagnóstico por imagem , Síndrome de Mirizzi/cirurgia , Colangiopancreatografia Retrógrada Endoscópica , Colelitíase/cirurgia , Colecistectomia , Ductos BiliaresRESUMO
OBJECTIVE: To investigate the role of eye signs in predicting poor outcomes in systemic lupus erythematosus (SLE) patients with pulmonary arterial hypertension (PAH). METHODS: This prospective observational study recruited patients diagnosed with SLE-PAH from Jan. 2021 to Dec. 2021 at the First Affiliated Hospital of Nanchang University; those with other potential causes of PAH were excluded. The evaluation of various parameters, such as N-terminal prohormone of brain natriuretic peptide (NT-proBNP), 6-minute walking distance (6MWD), World Health Organization functional class (WHO-FC), echocardiography, and risk stratification based on the 2015 European Society of Cardiology (ESC)/European Respiratory Society (ERS) Guidelines, was conducted at intervals of every 1-3 months, and a 6-month follow-up period was observed. The primary outcome measure considered improvement if there was a decline in the risk stratification grade at the end point and unimproved if there was no decline. Conjunctival microvascular images were observed and recorded. RESULTS: A total of 29 SLE-PAH patients were enrolled, comprising 12 in the improved group and 17 in the nonimproved group. All SLE-PAH patients showed various manifestations of eye signs, including vessel twisting, dilation, ischaemic areas, haemorrhages, reticulum deformity, and wound spots. The nonimproved group exhibited significantly lower vessel density (VD) and microvascular flow index (MFI) of conjunctival microvascular images than the improved group. Correlation analysis revealed that VD displayed a negative correlation with the WHO-FC (r = -0.413, p = 0.026) and NT-proBNP (r = -0.472, p = 0.010), as well as a positive correlation with the 6MWD (r = 0.561, p = 0.002). Similarly, MFI exhibited a negative correlation with WHO-FC (r = -0.408, p = 0.028) and NT-proBNP (r = -0.472, p = 0.010) and a positive correlation with 6MWD (r = 0.157, p = 0.004). Multivariate logistic regression analysis indicated that VD (OR 10.11, 95% CI 1.95-52.36), MFI (OR 7.85, 95% CI 1.73-35.67), NT-proBNP, and 6MWD were influential factors in predicting the prognostic improvement of SLE-PAH patients. ROC curve analysis demonstrated that VD, MFI, 6MWD, and NT-proBNP (with respective AUC values of 0.83, 0.83, 0.76, and 0.90, respectively) possessed a sensitivity and specificity of 75 and 100%, as well as 83 and 100%, respectively. Regarding prognostic prediction, VD and MFI exhibited higher sensitivity than 6MWD, whereas MFI displayed higher sensitivity and specificity than NT-proBNP. CONCLUSION: SLE-PAH can lead to various conjunctival microvascular manifestations in which vascular density and microvascular flow index can be used to assess cardiopulmonary function and predict therapeutic efficacy and prognosis in SLE-PAH patients.
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Lúpus Eritematoso Sistêmico , Hipertensão Arterial Pulmonar , Humanos , Lúpus Eritematoso Sistêmico/complicações , Prognóstico , Hipertensão Arterial Pulmonar/etiologia , Curva ROC , Sensibilidade e Especificidade , Estudos ProspectivosRESUMO
BACKGROUND: Pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) is an aggressive disease with an overall poor prognosis. Pancreatitis is a major risk factor for the development of PDAC. Due to the lack of reliable and accurate biomarkers, the diagnosis, treatment, and prognosis of PDAC face great challenges. It is of great significance to elucidate the pathogenesis of PDAC and explore novel inflammatory biomarkers. METHODS: We identified E3 ubiquitin ligases associated with pancreatic inflammation by combining multiple GEO datasets and UbiNet 2.0, and integrating the WGCNA algorithm and Limma R package. A risk score model for PDAC patients was established by using LASSO regression. We investigated the correlation between FBXW11 and immune cell infiltration using CIBERSORT, mMCP-counter, ImmuCellAI-mouse, QUANTISEQ, and TIMER algorithms, based on GEO, ArrayExpress, and TCGA datasets. We used Ubibrowser 2.0 to predict potential substrates for FBXW11. WikiPathway, MSigDB Hallmark, and Elsevier pathway analysis of FBXW11 key substrates were also performed using the EnrichR database. We detected protein expression through IHC, immunofluorescence, and western blot in the cerulein-induced acute pancreatitis mouse model. RESULTS: We first identified that FBXW11 exhibited a clear tendency to gradually increase in normal, pancreatitis, and PDAC patients. The validation analysis revealed that the FBXW11 protein exhibited significantly high expression in cerulein-induced acute pancreatitis mice, with its distribution primarily observed in the cytoplasm. Simultaneously, we developed a risk model utilizing the genes associated with FBXW11 to forecast the outcome of patients with PDAC and the likelihood of pancreatitis advancing to pancreatic cancer. Functional analysis showed that FBXW11, as a novel inflammatory biomarker, had a significant positive correlation with macrophage infiltration and the NF-κB signaling pathway. Finally, the western blot assay of the NF-κB signaling pathway in pancreatic tissues demonstrated that high activation of NF-κB was correlated with high expression of FBXW11. CONCLUSIONS: Our research not only provides evidence for FBXW11 as a novel inflammatory biomarker but also provides new insights into the research and clinical treatment of pancreatic cancer.
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Neoplasias Pancreáticas , Pancreatite , Animais , Humanos , Camundongos , Doença Aguda , Proteínas Contendo Repetições de beta-Transducina , Biomarcadores , Ceruletídeo , NF-kappa B , Transdução de Sinais , Ubiquitina-Proteína LigasesRESUMO
INTRODUCTION: Ovarian steroidogenesis not only affects the embryonic development and pregnancy outcome, but also associates with many diseases in mammals and women. Exploring the nutrients and mechanisms influencing ovarian steroidogenesis is critical to maintaining the optimal reproductive performance, as well as guaranteeing body health. OBJECTIVES: This research aimed to explore the effect of retinol metabolism on ovarian steroidogenesis and the underlying mechanisms. METHODS: Comparative transcriptomic analysis of ovaries from normal and low reproductive performance sows were performed to identify the main causes leading to low fertility. The metabolites regulating steroid hormones synthesis were investigated in ovarian granulosa cells. Gene interference, overexpression, dual-luciferase reporter assays, chromatin immunoprecipitation and transcriptome analysis were further conducted to explore the underlying mechanisms of Aldh1a1 mediating ovarian steroidogenesis. RESULTS: Transcriptome analysis of ovaries from normal and low reproductive performance sows showed the significant differences in both retinol metabolism and steroid hormones synthesis, indicating retinol metabolism probably influenced steroid hormones synthesis. The related metabolite retinoic acid was furtherly proven a highly active and potent substance strengthening estrogen and progesterone synthesis in ovarian granulosa cells. For the first time, we revealed that retinoic acid synthesis in porcine and human ovarian granulosa cells was dominated by Aldh1a1, and required the assistance of Aldh1a2. Importantly, we demonstrated that Aldh1a1 enhanced the proliferation of ovarian granulosa cells by activating PI3K-Akt-hedgehog signaling pathways. In addition, Aldh1a1 regulated the expression of transcription factor MESP2, which targeted the transcription of Star and Cyp11a1 through binding to corresponding promoter regions. CONCLUSION: Our data identified Aldh1a1 modulates ovarian steroidogenesis through enhancing granulosa cell proliferation and MESP2/STAR/CYP11A1 pathway. These findings provide valuable clues for improving ovarian health in mammals.
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Enzima de Clivagem da Cadeia Lateral do Colesterol , Ovário , Feminino , Suínos , Animais , Gravidez , Humanos , Ovário/metabolismo , Tretinoína , Fosfatidilinositol 3-Quinases , Vitamina A , Proteínas Hedgehog , Progesterona , Proliferação de Células , Mamíferos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice BásicosRESUMO
Embryo development exerts far-reaching influence on pregnancy outcome, postnatal development and lifelong health. Thereafter, to select functional nutrients to improve embryo development is of great importance. Herein, a stable porcine trophectoderm cell line expressing a luciferase reporter gene driven by a 1,009 bp PCNA gene promoter was constructed through lentiviral transduction and G418 selection. A high throughput screening assay was subsequently developed using the stable reporter cell line to screen a library of 225 nutrients. Seven nutrients with a minimum Z-score of 2.0 were initially identified to be capable of enhancing embryonic development. Among these nutrients, resveratrol, apigenin, and retinol palmitate were furtherly confirmed the beneficial effects for embryo development. Resveratrol significantly increased the expression of key genes involved in pTr cell proliferation and the number of S-phase cells. Resveratrol was furtherly confirmed to promote the expression of key genes in trophoblast development and increase embryo adhesion rate in vitro. Similarly, dietary 0.05% resveratrol supplementation significantly increased the number of embryo attachment and serum level of P4 and E2 in rats. Resveratrol could also improve maternal antioxidant levels and reduce intracellular ROS. Collectively, a high throughput screening cell model for nutrient regulation of embryonic development was established, which can be used to highly effectively select the potential candidates for embryo development. These findings have great implications for exploring optimal functional nutrients to improve embryo development, ultimately beneficial for pregnancy outcome, offspring postnatal development and lifelong health for human beings and mammalian animals.
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Desenvolvimento Embrionário , Ensaios de Triagem em Larga Escala , Feminino , Suínos , Gravidez , Ratos , Humanos , Animais , Resveratrol/farmacologia , Desenvolvimento Embrionário/genética , Antioxidantes/farmacologia , Nutrientes , MamíferosRESUMO
Extracting vanadium (V) from vanadium slag (VS) by the traditional roasting-leaching process has disadvantages of high energy consumption and high poisonous gases emission. In this work, a green and efficient route was developed to extract V from VS without roasting by electro-oxidation combined with ultrasound cavitation (EOUC) intensification in sulfuric acid solution. The leaching parameters (e.g., leaching temperature, sulfuric acid concentration, anodic current density, ultrasound power, liquid to solid ratio, leaching time and particle size) were optimized. The leaching mechanism was explored by comparing the leaching behavior and mineralogical evolution of the direct sulfuric acidic leaching (DSL), electro-oxidation-assisted sulfuric acidic leaching (EOSL), ultrasound cavitation-assisted sulfuric acidic leaching (UCSL) and EOUC methods. The results show that introducing electric field strengthens the ultrasound cavitation effect on slag particles in sulfuric acid solution. Under the optimum parameter of EOUC method, the leaching rate of V from VS is as high as 94.64 %. Using EOUC method can open the silicate-wrapped structure of the spinel, increase pore volume of VS from 0.00127 cm3 g-1 to 0.01124 cm3 g-1, decrease slag particle size from 26.8 µm to 16.4 µm and improve specific surface area from 0.508 m2 g-1 to 10.855 m2 g-1, which significantly accelerate V leaching process. The exposed spinel was oxidized by both electrochemical route and chemical route, forming a mixture of V3+ ion and VO2+ ion after leaching.
RESUMO
The follicle is an important unit for the synthesis of steroid hormones and the oocyte development and maturation in mammals. However, the effect of methionine supply on follicle development and its regulatory mechanism are still unclear. In the present study, we found that dietary methionine supplementation during the estrous cycle significantly increased the number of embryo implantation sites, as well as serum contents of a variety of amino acids and methionine metabolic enzymes in rats. Additionally, methionine supplementation markedly enhanced the expression of rat ovarian neutral amino acid transporters, DNA methyltransferases (DNMTs), and cystathionine gamma-lyase (CSE); meanwhile, it significantly increased the ovarian concentrations of the metabolite S-adenosylmethionine (SAM) and glutathione (GSH). In vitro data showed that methionine supply promotes rat follicle development through enhancing the expression of critical gene growth differentiation factor 9 and bone morphogenetic protein 15. Furthermore, methionine enhanced the relative protein and mRNA expression of critical genes related to estrogen synthesis, ultimately increasing estrogen synthesis in primary ovarian granulosa cells. Taken together, our results suggested that methionine promoted follicular growth and estrogen synthesis in rats during the estrus cycle, which improved embryo implantation during early pregnancy. These findings provided a potential nutritional strategy to improve the reproductive performance of animals.
Assuntos
Metionina , Folículo Ovariano , Gravidez , Feminino , Ratos , Animais , Metionina/metabolismo , Folículo Ovariano/metabolismo , Ciclo Estral , S-Adenosilmetionina/metabolismo , S-Adenosilmetionina/farmacologia , Glutationa/metabolismo , Racemetionina/metabolismo , Racemetionina/farmacologia , Suplementos Nutricionais , Estrogênios/metabolismo , Mamíferos/metabolismoRESUMO
BACKGROUND: Tibial artery calcification (TAC) is correlated with an increased risk of amputation and mortality in patients with chronic limb-threatening ischemia (CLTI). The association between calcification characteristics and adverse limb events of CLTI. However, it has not been assessed. This study aims to assess the relationship between the characteristics of TAC based on computed tomography angiography (CTA) scans and postoperative outcomes in patients with CLTI undergoing infrapopliteal endovascular therapy. METHODS: This was a retrospective study of patients who underwent infrapopliteal endovascular revascularization for CLTI and had a preoperative CTA scan. Based on CTA, TAC was divided into the following categories: annularity, thickness, continuity and severity. Cox regression models using generalized estimating equations were performed to assess the relationship between calcification characteristics and postoperative outcomes. The outcomes evaluated were the occurrence of all cause mortality (ACM) and unplanned amputation. RESULTS: Among the 148 patients undergoing endovascular, there were 50 (33.8%) patients died and 26 (17.6%) patients underwent unplanned amputation. Annular calcification was more common in the ACM group than in the non-ACM group. No significant differences were found between the two groups with regard to the probability of calcification in the thickness and the continuity (P>0.05). Patients in the unplanned amputation group had significantly annular, thin and continuity calcifications (P<0.05) than those in the non-unplanned amputation group. The presence of annular calcification was an independent predictor of ACM (hazard ratio (HR), 3.186; 95% confidence interval (CI), 1.781-5.702; P<0.001) and unplanned amputation (HR, 3.739; 95% CI, 1.707-8.191; P<0.05). CONCLUSIONS: Among patients with CLTI, the occurrence of annular calcification in the tibial artery are related to a greater chance of ACM and unplanned amputation in the postoperative period. The circumferential degree of TAC of the operated limb can be considered as a marker of clinical prognosis in this group of patients.
Assuntos
Procedimentos Endovasculares , Doença Arterial Periférica , Humanos , Isquemia Crônica Crítica de Membro , Artérias da Tíbia/diagnóstico por imagem , Artérias da Tíbia/cirurgia , Procedimentos Endovasculares/métodos , Fatores de Risco , Estudos Retrospectivos , Doença Arterial Periférica/diagnóstico por imagem , Doença Arterial Periférica/cirurgia , Resultado do Tratamento , Isquemia/diagnóstico por imagem , Isquemia/cirurgia , Salvamento de Membro/efeitos adversos , Salvamento de Membro/métodos , Doença CrônicaRESUMO
Background: Despite the long-lasting notion about the substantial contribution of intraoperative un-stabilization of homeostasis factors on the incidence on acute kidney injury (AKI), the possible influence of intraoperative glucose or lactate management, as a modifiable factor, on the development of AKI remains inconclusive. Objectives: To investigated the relationship between intraoperative hyperglycemia, hyperlactatemia, and postoperative AKI in cardiac surgery. Methods: A retrospective cohort study was conducted among 4,435 adult patients who underwent on-pump cardiac surgery from July 2019 to March 2022. Intraoperative hyperglycemia and hyperlactatemia were defined as blood glucose levels >10â mmol/L and lactate levels >2â mmol/L, respectively. The primary outcome was the incidence of AKI. All statistical analyses, including t tests, Wilcoxon rank sum tests, chi-square tests, Fisher's exact test, Kolmogorov-Smirnov test, logistic regression models, subgroup analyses, collinearity analysis, and receiver operating characteristic analysis, were performed using the statistical software program R version 4.1.1. Results: Among the 4,435 patients in the ï¬nal analysis, a total of 734 (16.55%) patients developed AKI after on-pump cardiac surgery. All studied intraoperative metabolic disorders was associated with increased AKI risk, with most pronounced odds ratio (OR) noted for both hyperglycemia and hyperlactatemia were present intraoperatively [adjusted OR 3.69, 95% confidence intervals (CI) 2.68-5.13, p < 0.001]. Even when hyperglycemia or hyperlactatemia was present alone, the risk of postoperative AKI remained elevated (adjusted OR 1.97, 95% CI 1.50-2.60, p < 0.001). Conclusion: The presence of intraoperative hyperglycemia and hyperlactatemia may be associated with postoperative acute kidney injury (AKI) in patients undergoing on-pump cardiac surgery. Proper and timely interventions for these metabolic disorders are crucially important in mitigating the risk of AKI.