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BACKGROUND: The gastrointestinal tract is a well-known extranodal site of lymphoma. B-cell lymphoma is the most common type, while T-cell lymphoma is uncommon. Primary gastrointestinal lymphoma mainly occurs in the stomach and small intestine, and the colon is less frequently involved, especially in females. CASE SUMMARY: A 45-year-old woman was admitted to our hospital for physical examination. Gastroenteroscopy revealed a visible pedunculated polyp in the transverse colon, for which endoscopic submucosal dissection (ESD) was performed. Pathology suggested highly active proliferation of T lymphocytes with atypical hyperplasia. CONCLUSION: A middle-aged female patient was found to have colonic T-cell lymphoma by endoscopy. The lesion was successfully removed by ESD, and the surgical margin was negative. It is essential to raise awareness of colonic T-cell lymphoma and choose the appropriate treatment.
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BACKGROUND: Ubiquitination is a targeted protein modification process mediated by intracellular molecules. UBR1 encodes a protein that binds to unstable N-terminal residues of substrate proteins and contributes to the formation of substrate-linked polyubiquitin chains. However, the function and cellular pathways of UBR1 in tumors have received inadequate attention. This study aimed to investigate the potential of UBR1 as a prognostic biomarker and immunotherapy target for stomach adenocarcinoma (STAD) as well as its biological function and molecular mechanism in relation to the disease. METHODS: Differential expression and pan-cancer gene set enrichment analysis (GSEA) were conducted using The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Genotype-Tissue Expression (GTEx) datasets. The Human Protein Atlas (HPA) database was utilized to identify UBR1-enriched pathways in AGS cells and to compare immunohistochemical differences between cancerous and adjacent non-cancerous tissues in gastric cancer. Quantitative Polymerase Chain Reaction (QPCR) and Western blot (WB) analyses were employed to validate these findings in both cancerous and adjacent non-cancerous tissues of gastric cancer. UBR1 expression in GES-1 and four gastric cancer cell lines was assessed using QPCR and WB. Kaplan-Meier curves, univariate and multivariate Cox regression analyses, and receiver operating characteristic (ROC) curve analyses were performed to evaluate the prognostic and diagnostic roles of UBR1. Additionally, the correlation between UBR1 expression and clinical parameters was analyzed using TCGA and GEO databases. UBR1 mutation data were obtained from the cBioPortal database. The mutation landscape, mutation-associated genes, protein structure, tumor mutation burden (TMB), and microsatellite instability (MSI) correlations were analyzed and illustrated. The biological functions of UBR1 were investigated using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The correlation between UBR1 and immune infiltration was assessed using TIMER and EPIC computational methods. Protein expression levels of UBR1 in gastric cancer cell lines were determined by immunohistochemistry (IHC) and WB analysis. Quantitative real-time PCR (qRT-PCR) was employed to analyze mRNA expression. Immunoprecipitation (IP) assays were conducted to detect protein-protein interactions between UBR1 and PDL1, while cellular immunofluorescence was used to observe the co-localization of these proteins. Cell proliferation was evaluated using CCK8 and colony formation assays. Cell migration was assessed using Transwell and wound healing assays. Finally, apoptosis was analyzed using flow cytometry, and WB was used to detect changes in apoptotic proteins and NF-κB P65 pathway proteins. RESULTS: UBR1 was upregulated in 28 cancer types, including STAD, and its overexpression was validated in gastric cancer cell lines and tissues. UBR1 expression was associated with advanced pathological characteristics. High UBR1 expression was linked to poor prognostic outcomes, including overall survival (OS), progression-free interval (PFI), disease-specific survival (DSS), as well as responses to surgery, chemotherapy, and HER2 expression. UBR1 expression showed significant correlations with clinical parameters such as age, gender, TNM stage, pathological stage, tumor resection, and anti-reflux therapy. Amplifications and deletions were the most frequent genetic alterations associated with UBR1. According to KEGG and GSEA analyses, UBR1 was significantly associated with several cancer pathways, oxidative phosphorylation, and the TNF-NFκB pathway. UBR1 also exhibited a significant correlation with immune cell infiltration and immunotherapy, including a direct interaction with PDL1. Knockdown of UBR1 inhibited the proliferation, migration, and invasion of STAD cells and promoted apoptosis. CONCLUSIONS: UBR1 is overexpressed in STAD, promoting its progression and positively correlating with immune cell infiltration and immunotherapeutic responses. Therefore, UBR1 could be a promising biomarker for the prognosis and immunotherapy of STAD.
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Approximately one-third of the patients with diabetes worldwide suffer from neuropathic pain, mainly categorized by spontaneous and stimulus-induced pain. Microglia are a class of immune effector cells residing in the central nervous system and play a pivotal role in diabetic neuropathic pain (DNP). Microglia specifically respond to hyperglycemia along with inflammatory cytokines and adenosine triphosphate produced during hyperglycemic damage to nerve fibers. Because of the presence of multiple receptors on the microglial surface, microglia are dynamically and highly responsive to their immediate environment. Following peripheral sensitization caused by hyperglycemia, microglia are affected by the cascade of inflammatory factors and other substances and respond accordingly, resulting in a change in their functional state for DNP pathogenesis. Inhibition of receptors such as P2X reporters, reducing cytokine expression levels in the microglial reactivity mechanisms, and inhibiting their intracellular signaling pathways can effectively alleviate DNP. A variety of drugs attenuate DNP by inhibiting the aforementioned processes induced by microglial reactivity. In this review, we summarize the pathological mechanisms by which microglia promote and maintain DNP, the drugs and therapeutic techniques available, and the latest advances in this field.
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This case report aims to highlight the importance of considering lymphoma as a potential differential diagnosis in patients presenting with laryngeal mass and associated cervical lymphadenopathy, particularly those with a history of chronic tonsillitis. A case of a 63-year-old male patient who underwent bilateral tonsillectomy for tumor in the left tonsil was presented. Two months after the procedure, he developed throat discomfort, dysphagia, neck swelling, and other symptoms. The patient was initially diagnosed with "tongue base mass" and chronic lymphadenitis. Partial excision of the tongue base mass was performed twice in another hospital, revealing chronic inflammation of the epithelial mucosa. Further evaluations, including electron laryngoscopy and imaging studies, were conducted to investigate the condition. A computed tomography (CT) scan showed irregular soft tissue density in the oropharyngeal region, along with multiple lymph nodes in the neck. Subsequent histopathological examination of the lingual base biopsy revealed peripheral T-cell lymphoma with a follicular T-helper cell phenotype. Immunohistochemical staining confirmed specific markers while ruling out other markers. In situ hybridization testing demonstrated positivity for Epstein-Barr virus-encoded RNA, and TCRG clonality was confirmed. The duration from symptom onset to diagnosis was 2 months. This case emphasizes the importance of considering lymphoma in patients with laryngeal mass and associated cervical lymphadenopathy, especially when a history of chronic tonsillitis is present. Accurate diagnosis and early intervention are crucial for effective management and improved patient outcomes.
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The novel gelling polysaccharides (NPGP) were extracted and characterized from Nicandra physalodes (Linn.) Gaertn. seeds, while properties and potential application of NPGP gels with tea polyphenols were further explored. NPGP was composed of GalA, Glc, Rha, Gal, Xyl, Ara, and Man at a molar ratio of 71.87:17.13:3.10:2.55:2.19:1.64:1.52, with molecular weight of 6.32 × 104 Da and low methoxylation degree of 45.21%. The gelling properties of NPGP gel induced by tea polyphenols showed that tea polyphenols significantly improved the structural and rheological properties of NPGP gel, due to the formation of dense network by hydrogen bonds and the increase of crystalline degree of NPGP. NPGP gels with tea polyphenols could significantly ameliorated the texture, water-holding capacity, aggregation, leading force, and moisture distribution of surimi during freeze-thaw cycles. All results suggest that NPGP gels with tea polyphenols has fine properties and show potential to be applied as natural additives in food industry.
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The medial prefrontal cortex (mPFC) has been identified as a key brain region involved in the modulation of chronic pain. Our recent study demonstrated that unilateral anterior crossbite (UAC) developed the comorbidity model of temporomandibular disorders (TMD) and fibromyalgia syndrome (FMS), which was characterized by both orofacial and somatic hyperalgesia. In the present study, UAC rats exhibited significant changes in gene expression in the mPFC. Enrichment analysis revealed that the significantly involved pathways were cytokines-cytokine receptor interaction and immune response. The expression of group III secretory phospholipase A2 (sPLA2-III) was significantly increased in the mPFC of UAC rats. Silencing sPLA2-III expression in the mPFC blocked the orofacial and somatic hyperalgesia. Immunofluorescence showed that sPLA2-III was mainly localized in neurons. The expression of interleukin-1ß (IL-1ß) in the mPFC significantly increased after UAC. Injection of IL-1ß antibody into the mPFC blocked orofacial and somatic hyperalgesia. IL-1ß was mainly localized in microglia cells. Furthermore, injection of IL-1ß antibody significantly reduced the expression of sPLA2-III. These results indicate that neuroinflammatory cascade responses induced by glial-neuron crosstalk in the mPFC may contribute to the development of TMD and FMS comorbidity, and IL-1ß and sPLA2-III are identified as novel potential therapeutic targets for the treatment of chronic pain in the comorbidity of TMD and FMS.
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The dorsal root ganglion (DRG) is the primary neuron responsible for transmitting peripheral pain signals to the central nervous system and plays a crucial role in pain transduction. Modulation of DRG excitability is considered a viable approach for pain management. Neuronal excitability is intricately linked to the ion channels on the neurons. The small and medium-sized DRG neurons are chiefly engaged in pain conduction and have high levels of TTX-S sodium channels, with Nav1.7 accounting for approximately 80% of the current. Voltage-gated sodium channel (VGSC or Nav) blockers are vital targets for the management of central nervous system diseases, particularly chronic pain. VGSCs play a key role in controlling cellular excitability. Clinical research has shown that Nav1.7 plays a crucial role in pain sensation, and there is strong genetic evidence linking Nav1.7 and its encoding gene SCN9A gene to painful disorders in humans. Many studies have shown that Nav1.7 plays an important role in pain management. The role of Nav1.7 in pain signaling pathways makes it an attractive target for the potential development of new pain drugs. Meanwhile, understanding the architecture of Nav1.7 may help to develop the next generation of painkillers. This review provides updates on the recently reported molecular inhibitors targeting the Nav1.7 pathway, summarizes their structure-activity relationships (SARs), and discusses their therapeutic effects on painful diseases. Pharmaceutical chemists are working to improve the therapeutic index of Nav1.7 inhibitors, achieve better analgesic effects, and reduce side effects. We hope that this review will contribute to the development of novel Nav1.7 inhibitors as potential drugs.
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Canal de Sódio Disparado por Voltagem NAV1.7 , Bloqueadores do Canal de Sódio Disparado por Voltagem , Humanos , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêutico , Dor do Câncer/tratamento farmacológico , Dor do Câncer/metabolismo , Analgésicos/química , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Relação Estrutura-Atividade , Manejo da Dor/métodos , Estrutura Molecular , Neoplasias/tratamento farmacológico , Bloqueadores dos Canais de Sódio/farmacologia , Bloqueadores dos Canais de Sódio/química , Bloqueadores dos Canais de Sódio/uso terapêuticoRESUMO
OBJECTIVE: This study investigated sex-specific pathogenesis mechanisms in Alzheimer's disease (AD) using single-nucleus RNA sequencing (snRNA-seq) data. METHODS: Data from the Gene Expression Omnibus (GEO) were searched using terms "Alzheimer's Disease", "single cell", and "Homo sapiens". Studies excluding APOE E4 and including comprehensive gender information with 10× sequencing methods were selected, resulting in GSE157827 and GSE174367 datasets from human prefrontal cortex samples. Sex-stratified analyses were conducted on these datasets, and the outcomes of the analysis for GSE157827 were compared with those of GSE174367. The findings were validated using expression profiling from the mouse dataset GSE85162. Furthermore, real-time PCR experiments in mice further confirmed these findings. The Seurat R package was used to identify cell types, and batch effects were mitigated using the Harmony R package. Cell proportions by sex were compared using the Mann-Whitney-Wilcoxon test, and gene expression variability was displayed with an empirical cumulative distribution plot. Differentially expressed genes were identified using the FindMarkers function with the MAST test. Transcription factors were analyzed using the RcisTarget R package. RESULTS: Seven cell types were identified: astrocytes, endothelial cells, excitatory neurons, inhibitory neurons, microglia, oligodendrocytes, and oligodendrocyte progenitor cells. Additionally, five distinct subpopulations of both endothelial and microglial cells were also identified, respectively. Key findings included: (1) In endothelial cells, genes involved in synapse organization, such as Insulin Like Growth Factor 1 Receptor (IGF1R) and Fms Related Receptor Tyrosine Kinase 1(FLT1), showed higher expression in females with AD. (2) In microglial cells, genes in the ribosome pathway exhibited higher expression in males without AD compared to females (with or without AD) and males with AD. (3) Chromodomain Helicase DNA Binding Protein 2 (CHD2) negatively regulated gene expression in the ribosome pathway in male microglia, suppressing AD, this finding was further validated in mice. (4) Differences between Asians and Caucasians were observed based on sex and disease status stratification. CONCLUSIONS: IGF1R and FLT1 in endothelial cells contribute to AD in females, while CHD2 negatively regulates ribosome pathway gene expression in male microglia, suppressing AD in humans and mice.
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Doença de Alzheimer , Células Endoteliais , Microglia , Receptor IGF Tipo 1 , Receptor 1 de Fatores de Crescimento do Endotélio Vascular , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Feminino , Animais , Masculino , Microglia/metabolismo , Humanos , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Camundongos , Células Endoteliais/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Fatores Sexuais , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Córtex Pré-Frontal/metabolismo , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Helicobacter pylori (HP), the most common pathogenic microorganism in the stomach, can induce inflammatory reactions in the gastric mucosa, causing chronic gastritis and even gastric cancer. HP infection affects over 4.4 billion people globally, with a worldwide infection rate of up to 50%. The multidrug resistance of HP poses a serious challenge to eradication. It has been de-monstrated that compared to bismuth quadruple therapy, Qingre Huashi decoction (QHD) combined with triple therapy exhibits comparable eradication rates but with a lower incidence of adverse reactions; in addition, QHD can directly inhibit and kill HP in vitro. AIM: To explore the effect and mechanism of QHD on clinically multidrug-resistant and strong biofilm-forming HP. METHODS: In this study, 12 HP strains were isolated in vitro after biopsy during gastroscopy of HP-infected patients. In vitro, the minimum inhibitory concentration (MIC) values for clinical HP strains and biofilm quantification were determined through the E-test method and crystal violet staining, respectively. The most robust biofilm-forming strain of HP was selected, and QHD was evaluated for its inhibitory and bactericidal effects on the strain with strong biofilm formation. This assessment was performed using agar dilution, E-test, killing dynamics, and transmission electron microscopy (TEM). The study also explored the impact of QHD on antibiotic resistance in these HP strains with strong biofilm formation. Crystalline violet method, scanning electron microscopy, laser confocal scanning microscopy, and (p)ppGpp chromatographic identification were employed to evaluate the effect of QHD on biofilm in strong biofilm-forming HP strains. The effect of QHD on biofilm and efflux pump-related gene expression was evaluated by quantitative polymerase chain reaction. Non-targeted metabolomics with UHPLC-MS/MS was used to identify potential metabolic pathways and biomarkers which were different between the NC and QHD groups. RESULTS: HP could form biofilms of different degrees in vitro, and the intensity of formation was associated with the drug resistance of the strain. QHD had strong bacteriostatic and bactericidal effects on HP, with MICs of 32-64 mg/mL. QHD could inhibit the biofilm formation of the strong biofilm-forming HP strains, disrupt the biofilm structure, lower the accumulation of (p)ppGpp, decrease the expression of biofilm-related genes including LuxS, Spot, glup (HP1174), NapA, and CagE, and reduce the expression of efflux pump-related genes such as HP0605, HP0971, HP1327, and HP1489. Based on metabolomic analysis, QHD induced oxidative stress in HP, enhanced metabolism, and potentially inhibited relevant signaling pathways by upregulating adenosine monophosphate (AMP), thereby affecting HP growth, metabolism, and protein synthesis. CONCLUSION: QHD exerts bacteriostatic and bactericidal effects on HP, and reduces HP drug resistance by inhibiting HP biofilm formation, destroying its biofilm structure, inhibiting the expression of biofilm-related genes and efflux pump-related genes, enhancing HP metabolism, and activating AMP in HP.
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Antibacterianos , Biofilmes , Medicamentos de Ervas Chinesas , Infecções por Helicobacter , Helicobacter pylori , Testes de Sensibilidade Microbiana , Helicobacter pylori/efeitos dos fármacos , Helicobacter pylori/isolamento & purificação , Biofilmes/efeitos dos fármacos , Humanos , Medicamentos de Ervas Chinesas/farmacologia , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/microbiologia , Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , GastroscopiaRESUMO
AIM: Rhodojaponin VI (R-VI) is the key compound of Rhododendron molle G. Don (Ericaceae) (RM) with effective clinical application in rheumatoid arthritis and chronic glomerulonephritis. In our study, we tried to explore the effect of R-VI on the rat model of membranous nephropathy. METHODS: The rat model of passive heymann nephritis (PHN) was established by injecting sheep anti-rat Fx1A serum at a single dose through the tail. The rats were orally administered R-VI (0.02 mg/kg) or FK506 (1 mg/kg) 1 day before PHN induction, which was kept for 4 weeks. Urine and blood samples as well as kidney tissue were collected for analysis. C5b-9-induced human podocyte cell (HPC) was employed for experiments in vitro. RESULTS: R-VI could alleviate glomerulonephritis progression and podocyte injury in PHN rats, as indicated by the decreased proteinuria and the elevated level of albumin, accompanied with reduced immune deposits, reversed podocyte injury in the kidneys. Furthermore, R-VI suppressed murine double minute 2 (MDM2) expression without the alteration in the protein level of p53 and decreased Notch1 expression independent of Numb regulation. Pre-treatment with R-VI in C5b-9-induced HPC blocked MDM2/Notch1 signalling pathway. CONCLUSION: Thus, R-VI ameliorates podocyte injury in rats with PHN, which was probably related with MDM2/Notch1 signalling pathway.
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Modelos Animais de Doenças , Glomerulonefrite Membranosa , Podócitos , Proteínas Proto-Oncogênicas c-mdm2 , Receptor Notch1 , Saponinas , Transdução de Sinais , Animais , Glomerulonefrite Membranosa/tratamento farmacológico , Glomerulonefrite Membranosa/patologia , Glomerulonefrite Membranosa/metabolismo , Podócitos/efeitos dos fármacos , Podócitos/patologia , Podócitos/metabolismo , Receptor Notch1/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Humanos , Saponinas/farmacologia , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
In eukaryotes, the nucleolus is the critical non-membranous organelle within nuclei that is responsible for ribosomal DNA (rDNA) transcription and ribosome biogenesis. The transcription of rDNA, a rate-limiting step for ribosome biogenesis, is tightly regulated to meet the demand for global protein synthesis in response to cell physiology, especially in neurons, which undergo rapid changes in morphology and protein composition during development and synaptic plasticity. However, it is unknown how the pre-initiation complex for rDNA transcription is efficiently assembled within the nucleolus in neurons. Here, we report that the nucleolar protein, coronin 2B, regulates rDNA transcription and maintains nucleolar function through direct interaction with upstream binding factor (UBF), an activator of RNA polymerase I transcriptional machinery. We show that coronin 2B knockdown impairs the formation of the transcription initiation complex, inhibits rDNA transcription, destroys nucleolar integrity, and ultimately induces nucleolar stress. In turn, coronin 2B-mediated nucleolar stress leads to p53 stabilization and activation, eventually resulting in neuronal apoptosis. Thus, we identified that coronin 2B coordinates with UBF to regulate rDNA transcription and maintain proper nucleolar function in neurons.
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Apoptose , Nucléolo Celular , Neurônios , Proteínas Pol1 do Complexo de Iniciação de Transcrição , Apoptose/genética , Nucléolo Celular/metabolismo , Neurônios/metabolismo , Animais , Proteínas Pol1 do Complexo de Iniciação de Transcrição/metabolismo , Proteínas Pol1 do Complexo de Iniciação de Transcrição/genética , Humanos , DNA Ribossômico/metabolismo , DNA Ribossômico/genética , Proteínas dos Microfilamentos/metabolismo , Proteínas dos Microfilamentos/genética , Transcrição Gênica , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Camundongos , Estresse FisiológicoRESUMO
BACKGROUND: The prognostic significance of metastasis-associated in colon cancer-1 (MACC1) has been explored in a variety of malignancies. However, its clinical relevance in patients with gastric cancer (GC) is limited, also remains controversial. METHOD: In this study, we retrospectively evaluated the prognostic value of lesion MACC1 expression in 347 GC patients. Lesion MACC1 expression was analyzed with immunohistochemistry and grouped as MACC1low (n = 172) and MACC1high (n = 175) cases. RESULTS: Data revealed that the degree of MACC1 expression is not related to patient sex, age and disease stage (all p > 0.05). Survival analysis showed that only post-operation advanced pT (p = 0.018), pN (p < 0.001), pM (p = 0.001) and AJCC stages (p < 0.001) are significantly associated with shorter survival, while no obvious difference was observed between MACC1low and MACC1high cases (p = 0.158). However, we found that survival for female (p = 0.032), older (p = 0.028), and early disease stage (pT stage I + II, p = 0.033) patients with MACC1high are remarkably worse than those with MACC1low. CONCLUSION: In summary, our findings revealed that, though MACC1 expression is not associated with the survival of the whole cohort, the prognostic risk stratification value of lesion MACC1 expression in subgroups of patients with gastric cancer should be noted.
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Background: Although the importance and benefit of heme oxygenase-1 (HO-1) in diabetes rodent models has been known, the contribution of HO-1 in the pre-diabetic patients with hyperlipidemia risk still remains unclear. This cross-sectional study aims to evaluate whether HO-1 is associated with hyperlipidemia in pre-diabetes. Methods: Serum level of HO-1 was detected using commercially available ELISA kit among 1,425 participants aged 49.3-63.9 with pre-diabetes in a multicenter Risk Evaluation of cAncers in Chinese diabeTic Individuals: A lONgitudinal (REACTION) prospective observational study. Levels of total cholesterol (TC) and triglyceride (TG) were measured and used to defined hyperlipidemia. The association between HO-1 and hyperlipidemia was explored in different subgroups. Result: The level of HO-1 in pre-diabetic patients with hyperlipidemia (181.72 ± 309.57 pg/ml) was obviously lower than that in pre-diabetic patients without hyperlipidemia (322.95 ± 456.37 pg/ml). High level of HO-1 [(210.18,1,746.18) pg/ml] was negatively associated with hyperlipidemia (OR, 0.60; 95% CI, 0.37-0.97; p = 0.0367) after we adjusted potential confounding factors. In subgroup analysis, high level of HO-1 was negatively associated with hyperlipidemia in overweight pre-diabetic patients (OR, 0.50; 95% CI, 0.3-0.9; p = 0.034), especially in overweight women (OR, 0.42; 95% CI, 0.21-0.84; p = 0.014). Conclusions: In conclusion, elevated HO-1 level was negatively associated with risk of hyperlipidemia in overweight pre-diabetic patients, especially in female ones. Our findings provide information on the exploratory study of the mechanism of HO-1 in hyperlipidemia, while also suggesting that its mechanism may be influenced by body weight and gender.
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Heme Oxigenase-1 , Hiperlipidemias , Estado Pré-Diabético , Humanos , Hiperlipidemias/sangue , Hiperlipidemias/epidemiologia , Feminino , Masculino , Estudos Transversais , Pessoa de Meia-Idade , Heme Oxigenase-1/sangue , Estado Pré-Diabético/sangue , Estado Pré-Diabético/epidemiologia , Estudos Prospectivos , Estudos Longitudinais , Fatores de Risco , China/epidemiologiaRESUMO
Therapy resistance poses a significant obstacle to effective cancer treatment. Recent insights into cell plasticity as a new paradigm for understanding resistance to treatment: as cancer progresses, cancer cells experience phenotypic and molecular alterations, corporately known as cell plasticity. These alterations are caused by microenvironment factors, stochastic genetic and epigenetic changes, and/or selective pressure engendered by treatment, resulting in tumor heterogeneity and therapy resistance. Increasing evidence suggests that cancer cells display remarkable intrinsic plasticity and reversibly adapt to dynamic microenvironment conditions. Dynamic interactions between cell states and with the surrounding microenvironment form a flexible tumor ecosystem, which is able to quickly adapt to external pressure, especially treatment. Here, this review delineates the formation of cancer cell plasticity (CCP) as well as its manipulation of cancer escape from treatment. Furthermore, the intrinsic and extrinsic mechanisms driving CCP that promote the development of therapy resistance is summarized. Novel treatment strategies, e.g., inhibiting or reversing CCP is also proposed. Moreover, the review discusses the multiple lines of ongoing clinical trials globally aimed at ameliorating therapy resistance. Such advances provide directions for the development of new treatment modalities and combination therapies against CCP in the context of therapy resistance.
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Antineoplásicos , Plasticidade Celular , Resistencia a Medicamentos Antineoplásicos , Neoplasias , Microambiente Tumoral , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Neoplasias/patologia , Neoplasias/genética , Microambiente Tumoral/efeitos dos fármacos , Plasticidade Celular/efeitos dos fármacos , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Animais , Epigênese GenéticaRESUMO
The accumulation of protein aggregates is a hallmark of many diseases, including Alzheimer's disease. As a major pillar of the proteostasis network, autophagy mediates the degradation of protein aggregates. The autophagy cargo receptor p62 recognizes ubiquitin on proteins and cooperates with TAX1BP1 to recruit the autophagy machinery. Paradoxically, protein aggregates are not degraded in various diseases despite p62 association. Here, we reconstituted the recognition by the autophagy receptors of physiological and pathological Tau forms. Monomeric Tau recruits p62 and TAX1BP1 via the sequential actions of the chaperone and ubiquitylation machineries. In contrast, Tau fibrils from Alzheimer's disease brains are recognized by p62 but fail to recruit TAX1BP1. This failure is due to the masking of fibrils ubiquitin moieties by p62. Tau fibrils are resistant to deubiquitylation, and, thus, this nonproductive interaction of p62 with the fibrils is irreversible. Our results shed light on the mechanism underlying autophagy evasion by protein aggregates and their consequent accumulation in disease.
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Autofagia , Proteína Sequestossoma-1 , Ubiquitinação , Proteínas tau , Humanos , Proteínas tau/metabolismo , Proteínas tau/química , Proteína Sequestossoma-1/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Ligação Proteica , Agregados Proteicos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ubiquitina/metabolismo , Proteínas de NeoplasiasRESUMO
BACKGROUND: No reliable clinical tools exist to predict acute kidney injury (AKI) progression. We aim to explore a scoring system for predicting the composite outcome of progression to severe AKI or death within seven days among early AKI patients after cardiac surgery. METHODS: In this study, we used two independent cohorts, and patients who experienced mild/moderate AKI within 48 h after cardiac surgery were enrolled. Eventually, 3188 patients from the MIMIC-IV database were used as the derivation cohort, while 499 patients from the Zhongshan cohort were used as external validation. The primary outcome was defined by the composite outcome of progression to severe AKI or death within seven days after enrollment. The variables identified by LASSO regression analysis were entered into logistic regression models and were used to construct the risk score. RESULTS: The composite outcome accounted for 3.7% (n = 119) and 7.6% (n = 38) of the derivation and validation cohorts, respectively. Six predictors were assembled into a risk score (AKI-Pro score), including female, baseline eGFR, aortic surgery, modified furosemide responsiveness index (mFRI), SOFA, and AKI stage. And we stratified the risk score into four groups: low, moderate, high, and very high risk. The risk score displayed satisfied predictive discrimination and calibration in the derivation and validation cohort. The AKI-Pro score discriminated the composite outcome better than CRATE score, Cleveland score, AKICS score, Simplified renal index, and SRI risk score (all P < 0.05). CONCLUSIONS: The AKI-Pro score is a new clinical tool that could assist clinicians to identify early AKI patients at high risk for AKI progression or death.
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Injúria Renal Aguda , Procedimentos Cirúrgicos Cardíacos , Progressão da Doença , Humanos , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/diagnóstico , Feminino , Masculino , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Pessoa de Meia-Idade , Idoso , Fatores de Risco , Estudos de Coortes , Índice de Gravidade de Doença , Curva ROC , Medição de Risco , PrognósticoRESUMO
Two new species of Polyporales, Cerrenacaulinicystidiata and Polyporusminutissimus, are illustrated and described on the basis of morphological studies and phylogenetic analyses from southern China and Vietnam. C.caulinicystidiata is characterized by annual, resupinate, sometimes effused-reflexed basidiocarps, greyish orange to brownish orange pore surface, irregular pores (3-8 per mm), a trimitic hyphal system, pyriform to ventricose cystidia, and subglobose basidiospores 3.2-4.5 × 2.8-3.5 µm in size. P.minutissimus is characterized by annual, solitary, fan-shaped with a depressed center or infundibuliform basidiocarps, obvious black stipe, cream to buff yellow pileal surface with glabrous, occasionally zonate and radially aligned stripes, angular pores (6-9 per mm), a dimitic hyphal system, and cylindrical basidiospores, 5-9.2 × 2.2-4 µm. Detailed descriptions and illustrations of the two new species are provided. The differences between the two new species and their morphologically similar and phylogenetically related species are discussed.
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BACKGROUND AND HYPOTHESIS: This study investigated the role of the medial prefrontal cortex (mPFC)-basolateral amygdala (BLA) pathway in schizophrenia (SCZ)-related cognitive impairments using various techniques. STUDY DESIGN: This study utilized clinical scales, magnetic resonance imaging, single-cell RNA sequencing, and optogenetics to investigate the mPFC-BLA pathway in SCZ patients. In the mouse model, 6-week-old methylazoxymethanol acetate-induced mice demonstrated significant cognitive deficits, which were addressed through stereotaxic injections of an adeno-associated viral vector to unveil the neural connection between the mPFC and BLA. STUDY RESULTS: Significant disparities in brain volume and neural activity, particularly in the dorsolateral prefrontal cortex (DLPFC) and BLA regions, were found between SCZ patients and healthy controls. Additionally, we observed correlations indicating that reduced volumes of the DLPFC and BLA were associated with lower cognitive function scores. Activation of the mPFC-BLA pathway notably improved cognitive performance in the SCZ model mice, with the targeting of excitatory or inhibitory neurons alone failing to replicate this effect. Single-cell transcriptomic profiling revealed gene expression differences in excitatory and inhibitory neurons in the BLA of SCZ model mice. Notably, genes differentially expressed in the BLA of these model mice were also found in the blood exosomes of SCZ patients. CONCLUSIONS: Our research provides a comprehensive understanding of the role of the PFC-BLA pathway in SCZ, underscoring its significance in cognitive impairment and offering novel diagnostic and therapeutic avenues. Additionally, our research highlights the potential of blood exosomal mRNAs as noninvasive biomarkers for SCZ diagnosis, underscoring the clinical feasibility and utility of this method.
Assuntos
Complexo Nuclear Basolateral da Amígdala , Disfunção Cognitiva , Modelos Animais de Doenças , Imageamento por Ressonância Magnética , Córtex Pré-Frontal , Esquizofrenia , Animais , Esquizofrenia/fisiopatologia , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/metabolismo , Camundongos , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/diagnóstico por imagem , Córtex Pré-Frontal/fisiopatologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/diagnóstico por imagem , Masculino , Humanos , Complexo Nuclear Basolateral da Amígdala/fisiopatologia , Complexo Nuclear Basolateral da Amígdala/metabolismo , Complexo Nuclear Basolateral da Amígdala/diagnóstico por imagem , Feminino , Adulto , Vias Neurais/fisiopatologia , Pessoa de Meia-Idade , Optogenética , Camundongos Endogâmicos C57BLRESUMO
OBJECTIVES: To evaluate signal enhancement ratio (SER) for tissue characterization and prognosis stratification in pancreatic adenocarcinoma (PDAC), with quantitative histopathological analysis (QHA) as the reference standard. METHODS: This retrospective study included 277 PDAC patients who underwent multi-phase contrast-enhanced (CE) MRI and whole-slide imaging (WSI) from three centers (2015-2021). SER is defined as (SIlt - SIpre)/(SIea - SIpre), where SIpre, SIea, and SIlt represent the signal intensity of the tumor in pre-contrast, early-, and late post-contrast images, respectively. Deep-learning algorithms were implemented to quantify the stroma, epithelium, and lumen of PDAC on WSIs. Correlation, regression, and Bland-Altman analyses were utilized to investigate the associations between SER and QHA. The prognostic significance of SER on overall survival (OS) was evaluated using Cox regression analysis and Kaplan-Meier curves. RESULTS: The internal dataset comprised 159 patients, which was further divided into training, validation, and internal test datasets (n = 60, 41, and 58, respectively). Sixty-five and 53 patients were included in two external test datasets. Excluding lumen, SER demonstrated significant correlations with stroma (r = 0.29-0.74, all p < 0.001) and epithelium (r = -0.23 to -0.71, all p < 0.001) across a wide post-injection time window (range, 25-300 s). Bland-Altman analysis revealed a small bias between SER and QHA for quantifying stroma/epithelium in individual training, validation (all within ± 2%), and three test datasets (all within ± 4%). Moreover, SER-predicted low stromal proportion was independently associated with worse OS (HR = 1.84 (1.17-2.91), p = 0.009) in training and validation datasets, which remained significant across three combined test datasets (HR = 1.73 (1.25-2.41), p = 0.001). CONCLUSION: SER of multi-phase CE-MRI allows for tissue characterization and prognosis stratification in PDAC. CLINICAL RELEVANCE STATEMENT: The signal enhancement ratio of multi-phase CE-MRI can serve as a novel imaging biomarker for characterizing tissue composition and holds the potential for improving patient stratification and therapy in PDAC. KEY POINTS: Imaging biomarkers are needed to better characterize tumor tissue in pancreatic adenocarcinoma. Signal enhancement ratio (SER)-predicted stromal/epithelial proportion showed good agreement with histopathology measurements across three distinct centers. Signal enhancement ratio (SER)-predicted stromal proportion was demonstrated to be an independent prognostic factor for OS in PDAC.
RESUMO
Soft tissue sarcoma (STS) incidence, progression, and metastasis are tightly linked to the tumor microenvironment (TME). The modification patterns mediated by pyroptosis-related genes (PRGs) in STS are unknown regarding the immune cell infiltration landscape of TME, immunotherapy effect, and prognostic value. First, we downloaded STS samples from the Cancer Genome Atlas (TCGA) and gene-expression omnibus (GEO) databases. Based on 52 PRGs, 2 pyroptosis modification patterns were analyzed, and the associations of pyroptosis modification patterns with immune cell infiltration in the TME were elucidated systematically. To quantify PRG modification patterns in STS patients, we generated a pyroptosis scoring system using principal component analysis (PCA). We identified 2 distinct pyroptosis modification patterns in STS. Compared to PRG cluster A, the prognosis of cluster B was better. These 2 pyroptosis modification patterns corresponded to different characteristics of immune cell infiltration in the TME and biological behaviors. In the pyroptosis scoring system, a high pyroptosis score was connected to higher immune cell infiltration, stronger immune surveillance, immune-killing effects on tumor cells, and better clinical benefits. The results from 3 anti-PD1/PD-L1-treated immune cohorts demonstrated that higher pyroptosis scores are also closely connected to better immunotherapy results. We demonstrated that pyroptosis modification is essential to the STS microenvironment. Moreover, the pyroptosis score is a reliable and independent prognostic factor in STS patients, enabling a richer understanding of the STS microenvironment and the screening of immunotherapy candidates, predicting the immunotherapeutic effects for individual STS patients, and guiding the use of chemotherapy drugs.