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OBJECTIVE: Hyperthyroidism, a prevalent endocrine disorder, can lead to complications such as liver failure due to the liver's essential role in thyroid hormone metabolism. The study aimed to elucidate the respective contributions of 131I or/and ALSS in managing hyperthyroidism alongside liver failure. METHODS: A retrospective analysis was carried out on 74 patients diagnosed with severe liver failure in the context of Graves' disease. Patients were categorized into three groups: Group A (n=34) received 131I treatment, group B (n=17) underwent 131I and ALSS treatment, and group C (n=24) received ALSS treatment alone. RESULTS: Throughout the treatment period, the liver function indexes in all groups exhibited a decline trend. The thyroid function of group A and group B treated with 131I was significantly improved compared with that before treatment. There was no significant change in thyroid function in group C. After the correction of hyperthyroidism, significant improvements were observed in the liver function of individuals in group A and B, particularly with more noticeable amelioration compared to group C. After two months of treatment, the efficacy rates for the three groups were 79.41%, 82.35%, and 60.87% respectively. Mortality rates of the three groups were 5.88%,17.65% and 36% (p<0.01). Group B, receiving both 131I and ALSS treatments, exhibited a lower mortality rate than group C. CONCLUSION: In cases of severe liver failure accompanied by hyperthyroidism, prompt administration of 131I is recommended to alleviate the adverse effects of hyperthyroidism on liver function and facilitate a conducive environment for the recovery of liver functionality.

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Neoadjuvant chemoradiotherapy (NACRT) was the standard treatment for patients with locally advanced rectal cancer (LARC) with proficient mismatch repair (pMMR) proteins. In this randomized phase 2 trial (ClinicalTrial.gov: NCT04304209), 134 pMMR LARC patients were randomly (1:1) assigned to receive NACRT or NACRT and the programmed cell death protein 1 (PD-1) antibody sintilimab. As the primary endpoint, the total complete response (CR) rate is 26.9% (18/67, 95% confidence interval [CI] 16.0%-37.8%) and 44.8% (30/67, 95% CI 32.6%-57.0%) in the control and experimental arm, respectively, with significant difference (p = 0.031 for chi-squared test). Response ratio is 1.667 (95% CI 1.035-2.683). Immunohistochemistry shows PD-1 ligand 1 (PD-L1) combined positive score is associated with the synergistic effect. The safety profile is similar between the arms. Adding the PD-1 antibody sintilimab to NACRT significantly increases the CR rate in pMMR LARC, with a manageable safety profile. PD-L1 positivity may help identify patients who might benefit most from the combination therapy.

Asunto(s)

Anticuerpos Monoclonales Humanizados , Terapia Neoadyuvante , Neoplasias del Recto , Humanos , Neoplasias del Recto/terapia , Neoplasias del Recto/inmunología , Neoplasias del Recto/patología , Neoplasias del Recto/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Femenino , Terapia Neoadyuvante/métodos , Masculino , Persona de Mediana Edad , Anciano , Adulto , Reparación de la Incompatibilidad de ADN , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Quimioradioterapia/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico

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Osteosarcoma (OS) is the most common primary malignant tumour of the bone with high mortality. Here, we comprehensively analysed the hypoxia signalling in OS and further constructed novel hypoxia-related gene signatures for OS prediction and prognosis. This study employed Gene Set Enrichment Analysis (GSEA), Weighted correlation network analysis (WGCNA) and Least absolute shrinkage and selection operator (LASSO) analyses to identify Stanniocalcin 2 (STC2) and Transmembrane Protein 45A (TMEM45A) as the diagnostic biomarkers, which further assessed by Receiver Operating Characteristic (ROC), decision curve analysis (DCA), and calibration curves in training and test dataset. Univariate and multivariate Cox regression analyses were used to construct the prognostic model. STC2 and metastasis were devised to forge the OS risk model. The nomogram, risk score, Kaplan Meier plot, ROC, DCA, and calibration curves results certified the excellent performance of the prognostic model. The expression level of STC2 and TMEM45A was validated in external datasets and cell lines. In immune cell infiltration analysis, cancer-associated fibroblasts (CAFs) were significantly higher in the low-risk group. And the immune infiltration of CAFs was negatively associated with the expression of STC2 (P < 0.05). Pan-cancer analysis revealed that the expression level of STC2 was significantly higher in Esophageal carcinoma (ESCA), Head and Neck squamous cell carcinoma (HNSC), Kidney renal clear cell carcinoma (KIRC), Lung squamous cell carcinoma (LUSC), and Stomach adenocarcinoma (STAD). Additionally, the higher expression of STC2 was associated with the poor outcome in those cancers. In summary, this study identified STC2 and TMEM45A as novel markers for the diagnosis and prognosis of osteosarcoma, and STC2 was shown to correlate with immune infiltration of CAFs negatively.

Asunto(s)

Biomarcadores de Tumor , Neoplasias Óseas , Péptidos y Proteínas de Señalización Intercelular , Aprendizaje Automático , Osteosarcoma , Osteosarcoma/genética , Osteosarcoma/diagnóstico , Osteosarcoma/patología , Humanos , Pronóstico , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Biomarcadores de Tumor/genética , Neoplasias Óseas/genética , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/patología , Regulación Neoplásica de la Expresión Génica , Glicoproteínas/genética , Glicoproteínas/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Perfilación de la Expresión Génica , Nomogramas , Transcriptoma , Curva ROC , Femenino , Hipoxia/genética , Masculino

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Freckle is a prevalent pigmentary dermatosis with an obvious hereditary component. Dozens of freckles risk loci have been discovered through research on multiple traits or other diseases, rather than as an independent trait. To discover novel variants associated with freckles, we performed GWAS and meta-analysis in 4813 Chinese individuals. We conducted GWAS and meta-analysis of two cohorts: 197 patients and 1603 controls (Cohort I), and 336 patients and 2677 controls (Cohort II), both from China. Then we performed linkage disequilibrium (LD) analysis, eQTL study, and enrichment analysis with association results for functional implications. Finally, we discovered 59 new SNPs and 13 novel susceptibility genes associated with freckles (Pmeta <5 × 10-8), which has enriched the genetic research on freckles.

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In this paper, a novel study on the way inter-individual information interacts in meta-heuristic algorithms (MHAs) is carried out using a scheme known as population interaction networks (PIN). Specifically, three representative MHAs, including the differential evolutionary algorithm (DE), the particle swarm optimization algorithm (PSO), the gravitational search algorithm (GSA), and four classical variations of the gravitational search algorithm, are analyzed in terms of inter-individual information interactions and the differences in the performance of each of the algorithms on IEEE Congress on Evolutionary Computation 2017 benchmark functions. The cumulative distribution function (CDF) of the node degree obtained by the algorithm on the benchmark function is fitted to the seven distribution models by using PIN. The results show that among the seven compared algorithms, the more powerful DE is more skewed towards the Poisson distribution, and the weaker PSO, GSA, and GSA variants are more skewed towards the Logistic distribution. The more deviation from Logistic distribution GSA variants conform, the stronger their performance. From the point of view of the CDF, deviating from the Logistic distribution facilitates the improvement of the GSA. Our findings suggest that the population interaction network is a powerful tool for characterizing and comparing the performance of different MHAs in a more comprehensive and meaningful way.

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Fiber optical tweezers (FOTs) provide a functionality for micro-/nanoparticle manipulation with a slim and flexible optical fiber setup. An added in situ spectroscopic functionality can achieve characterization of the trapped particle, potentially useful for endoscopic, in-vivo studies in an inherently heterogeneous environment if the applicator end is all-fiber-built. Here, we demonstrate all-fiber optical tweezers (a-FOTs) for the trapping and in situ spectral measurement of a single, cell-sized microparticle. The key to ensure the simultaneous bifunctionality is a high numerical aperture (NA) Fresnel lens fabricated by two-photon direct laser writing (DLW) corrected by grid-correction methods. We demonstrate trapping and time-resolved, in situ spectroscopy of a single upconversion particle (UCP), a common fluorescent biomarker in biophotonics. The system achieves a 0.5-s time resolution in the in situ spectral measurement of a trapped UCP. The all-fiber designed system preserves the advantages of flexibility and robustness of the fiber, potentially useful for in-vivo biomedical studies such as cell-to-cell interactions, pH and temperature detection, and nucleic acids detection.

RESUMEN

BACKGROUND & AIMS: Our previous study has demonstrated that Telomeric repeat-binding factor 2-interacting protein 1(Terf2ip), played an important role in hepatic ischemia reperfusion injury. This study is aimed to explore the function and mechanism of Terf2ip in non-alcoholic steatohepatitis (NASH). METHODS: The expression of Terf2ip was detected in liver tissue samples obtained from patients diagnosed with NASH. Mice NASH models were constructed by fed with high-fat diet (HFD) or methionine/choline deficient diet (MCD) in Terf2ip knockout and wild type (WT) mice. To further investigate the role of Terf2ip in NASH, adeno-associated viruses (AAV)-Terf2ip was administrated to mice. RESULTS: We observed a significant down-regulation of Terf2ip levels in the livers of NASH patients and mice NASH models. Terf2ip deficiency was associated with an exacerbation of hepatic steatosis in mice under HFD or MCD. Additionally, Terf2ip deficiency impaired lipophagy and fatty acid oxidation (FAO) in NASH models. Mechanically, we discovered that Terf2ip bound to the promoter region of Sirt1 to regulate Sirt1/AMPK pathway activation. As a result, Terf2ip deficiency was shown to inhibit lipophagy through the AMPK pathway, while the activation of Sirt1 alleviated steatohepatitis in the livers of mice. Finally, re-expression of Terf2ip in hepatocyes alleviated liver steatosis, inflammation, and restored lipophagy. CONCLUSIONS: These results revealed that Terf2ip played a protective role in the progression of NASH through regulating lipophagy and FAO by binding to Sirt1 promoter. Our findings provided a potential therapeutic target for the treatment of NASH.

Asunto(s)

Ácidos Grasos , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico , Oxidación-Reducción , Sirtuina 1 , Animales , Humanos , Masculino , Ratones , Proteínas Quinasas Activadas por AMP/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Ácidos Grasos/metabolismo , Metabolismo de los Lípidos/genética , Hígado/metabolismo , Hígado/patología , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/etiología , Transducción de Señal , Sirtuina 1/metabolismo , Sirtuina 1/genética

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BACKGROUND: Metastasis driven by epithelial-mesenchymal transition (EMT) remains a significant contributor to the poor prognosis of colorectal cancer (CRC), and requires more effective interventions. GPR81 signaling has been linked to tumor metastasis, while lacks an efficient specific inhibitor. PURPOSE: Our study aimed to investigate the effect and mechanism of Gentisic acid on colorectal cancer (CRC) metastasis. STUDY DESIGN: A lung metastasis mouse model induced by tail vein injection and a subcutaneous graft tumor model were used. Gentisic acid (GA) was administered by an intraperitoneal injection. HCT116 was treated with lactate to establish an in vitro model. METHODS: MC38 cells with mCherry fluorescent protein were injected into tail vein to investigate lung metastasis ability in vivo. GA was administered by intraperitoneal injection for 3 weeks. The therapeutic effect was evaluated by survival rates, histochemical analysis, RT-qPCR and live imaging. The mechanism was explored using small interfering RNA (siRNA), Western blotting, RT-qPCR and immunofluorescence. RESULTS: GA had a therapeutic effect on CRC metastasis and improved survival rates and pathological changes in dose-dependent manner. GA emerged as an GPR81 inhibitor, effectively suppressed EMT and mTOR signaling in CRC induced by lactate both in vivo and in vitro. Mechanistically, GA halted lactate-induce degradation of DEPDC5 through impeding the activation of Chaperone-mediated autophagy (CMA). CONCLUSION: CMA-mediated DEPDC5 degradation is crucial for lactate/GPR81-induced CRC metastasis, and GA may be a promising candidate for metastasis by inhibiting GPR81 signaling.

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Neoplasias Colorrectales , Transición Epitelial-Mesenquimal , Neoplasias Pulmonares , Receptores Acoplados a Proteínas G , Animales , Receptores Acoplados a Proteínas G/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/tratamiento farmacológico , Humanos , Ratones , Transición Epitelial-Mesenquimal/efectos de los fármacos , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/tratamiento farmacológico , Células HCT116 , Transducción de Señal/efectos de los fármacos , Línea Celular Tumoral , Masculino , Serina-Treonina Quinasas TOR/metabolismo

RESUMEN

BACKGROUND: Cholangiocarcinoma (CCA) comprises a heterogeneous group of biliary tract cancer. Our previous CCA mutation pattern study focused on genes in the post-transcription modification process, among which the alternative splicing factor RBM10 captured our attention. However, the roles of RBM10 wild type and mutations in CCA remain unclear. METHODS: RBM10 mutation spectrum in CCA was clarified using our initial data and other CCA genomic datasets from domestic and international sources. Real-time PCR and tissue microarray were used to detect RBM10 clinical association. Function assays were conducted to investigate the effects of RBM10 wild type and mutations on CCA. RNA sequencing was to investigate the changes in alternative splicing events in the mutation group compared to the wild-type group. Minigene splicing reporter and interaction assays were performed to elucidate the mechanism of mutation influence on alternative splicing events. RESULTS: RBM10 mutations were more common in Chinese CCA populations and exhibited more protein truncation variants. RBM10 exerted a tumor suppressive effect in CCA and correlated with favorable prognosis of CCA patients. The overexpression of wild-type RBM10 enhanced the ASPM exon18 exon skipping event interacting with SRSF2. The C761Y mutation in the C2H2-type zinc finger domain impaired its interaction with SRSF2, resulting in a loss-of-function mutation. Elevated ASPM203 stabilized DVL2 and enhanced ß-catenin signaling, which promoted CCA progression. CONCLUSIONS: Our results showed that RBM10C761Y-modulated ASPM203 promoted CCA progression in a Wnt/ß-catenin signaling-dependent manner. This study may enhance the understanding of the regulatory mechanisms that link mutation-altering splicing variants to CCA.

Asunto(s)

Neoplasias de los Conductos Biliares , Colangiocarcinoma , Humanos , beta Catenina/genética , beta Catenina/metabolismo , Mutación , Colangiocarcinoma/genética , Colangiocarcinoma/patología , Vía de Señalización Wnt , Conductos Biliares Intrahepáticos/metabolismo , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/patología , Isoformas de Proteínas , Proteínas del Tejido Nervioso/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo

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Cutaneous sympathetic nerve is a crucial part of neuropsychiatric factors contributing to skin immune response, but its role in the psoriasis pathogenesis remains unclear. It is found that cutaneous calcium/calmodulin-dependent protein kinase II-γ (CAMK2γ), expressed mainly in sympathetic nerves, is activated by stress and imiquimod in mouse skin. Camk2g-deficient mice exhibits attenuated imiquimod-induced psoriasis-like manifestations and skin inflammation. CaMK2γ regulates dermal γδT-cell interleukin-17 production in imiquimod-treated mice, dependent on norepinephrine production following cutaneous sympathetic nerve activation. Adrenoceptor ß1, the primary skin norepinephrine receptor, colocalises with γδT cells. CaMK2γ aggravates psoriasiform inflammation via sympathetic nerve-norepinephrine-γδT cell-adrenoceptor ß1-nuclear factor-κB and -p38 axis activation. Application of alcaftadine, a small-molecule CaMK2γ inhibitor, relieves imiquimod-induced psoriasis-like manifestations in mice. This study reveals the mechanisms of sympathetic-nervous-system regulation of γδT-cell interleukin-17 secretion, and provides insight into neuropsychiatric factors dictating psoriasis pathogenesis and new potential targets for clinical psoriasis treatment.

Asunto(s)

Modelos Animales de Enfermedad , Norepinefrina , Psoriasis , Sistema Nervioso Simpático , Animales , Ratones , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/genética , Imiquimod , Interleucina-17/metabolismo , Ratones Endogámicos C57BL , Norepinefrina/metabolismo , Psoriasis/metabolismo , Piel/metabolismo , Piel/inervación , Sistema Nervioso Simpático/metabolismo

RESUMEN

The damage of integrated epithelial epithelium is a key pathogenic factor and closely associated with the recurrence of ulcerative colitis (UC). Here, we reported that vanillic acid (VA) exerted potent therapeutic effects on DSS-induced colitis by restoring intestinal epithelium homeostasis via the inhibition of ferroptosis. By the CETSA assay and DARTS assay, we identified carbonic anhydrase IX (CAIX, CA9) as the direct target of VA. The binding of VA to CA9 causes insulin-induced gene-2 (INSIG2) to interact with stromal interaction molecule 1 (STIM1), rather than SREBP cleavage-activating protein (SCAP), leading to the translocation of SCAP-SREBP1 from the endoplasmic reticulum (ER) to the Golgi apparatus for cleavage into mature SREBP1. The activation of SREBP1 induced by VA then significantly facilitated the transcription of stearoyl-CoA desaturase 1 (SCD1) to exert an inhibitory effect on ferroptosis. By inhibiting the excessive death of intestinal epithelial cells caused by ferroptosis, VA effectively preserved the integrity of intestinal barrier and prevented the progression of unresolved inflammation. In conclusion, our study demonstrated that VA could alleviate colitis by restoring intestinal epithelium homeostasis through CA9/STIM1-mediated inhibition of ferroptosis, providing a promising therapeutic candidate for UC.

Asunto(s)

Colitis , Ferroptosis , Humanos , Animales , Ratones , Ácido Vanílico , Molécula de Interacción Estromal 1 , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Homeostasis , Mucosa Intestinal , Sulfato de Dextran , Ratones Endogámicos C57BL , Anhidrasa Carbónica IX , Antígenos de Neoplasias , Proteínas de Neoplasias

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BACKGROUND: Previous research has indicated the inverse association between physical activity (PA) and gestational diabetes mellitus (GDM). However, the dose-response relationship currently remains undetermined. This study aims to explore the dose-response relationship between PA during the first and second trimesters of pregnancy and GDM risk. METHODS: Studies on the relationship between PA during pregnancy and GDM risk published before April 25, 2023, were searched for in six databases. According to the inclusion and exclusion criteria, all literature was screened for eligibility. The Newcastle-Ottawa Scale (NOS) was used to assess risk of bias. Publication bias was examined using funnel plots, Begg's and Egger's tests, as well as trim-and-fill analysis. We harmonized exposure estimates of PA during pregnancy to the common unit of the metabolic equivalent of task (MET)-h/week. Restricted cubic splines were used to model the dose-response relationship. The criteria from the World Cancer Research Fund were used to assess the certainty of evidence across outcomes. All analyses were performed using Stata 15.1. RESULTS: The results indicated that in contrast with the lowest level of PA, promoting the highest PA level lowers the risk of GDM by 36% (RR = 0.64, 95%CI: 0.53 ~ 0.78). We found a curvilinear dose-response association between PA during the first trimester and incident GDM (Pnonlinearity = 0.012). Compared to inactive pregnant women, for those who achieved the guidelines-suggested minimum level (10 MET-h/week) of PA during the first trimester, the GDM risk was decreased by 13% (RR = 0.87, 95%CI: 0.79 ~ 0.96). A linear relationship was found between PA during the second trimester and the GDM risk (Pnonlinearity = 0.276). The results with a restricted cubic spline model suggested that pregnant women who accumulate 10 MET-h/week have a 1% reduced risk of GDM compared to completely inactive individuals. Twice (20 MET-h/week) or a higher amount of PA (50 MET-h/week) contributed to further reductions in GDM risk. CONCLUSION: There is a dose-response relationship between higher levels of PA in both the first and second trimesters and reduced risk of GDM; the relationship is stronger in the first trimester. Increasing PA during pregnancy can prevent the development of GDM. PROSPERO REGISTRATION NUMBER: CRD42023420564.

Asunto(s)

Diabetes Gestacional , Ejercicio Físico , Humanos , Embarazo , Diabetes Gestacional/epidemiología , Femenino , Factores de Riesgo , Primer Trimestre del Embarazo , Segundo Trimestre del Embarazo

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Deubiquitylating enzymes (DUBs) play an essential role in targeted protein degradation and represent an emerging therapeutic paradigm in cancer. However, their therapeutic potential in cholangiocarcinoma (CCA) has not been explored. Herein, based on The Cancer Genome Atlas (TCGA) and The Gene Expression Omnibus (GEO) databases, we found that ubiquitin-specific protease 21 (USP21) was upregulated in CCA, high USP21 level was associated with poor prognosis. In vivo and in vitro, we identified USP21 as a master regulator of CCA growth and maintenance, which directly interacted with deubiquitinates and stabilized the heat shock protein 90 (HSP90) through K48-linked deubiquitination, and in turn, this stabilization increased HIF1A expression, thus upregulating key glycolytic enzyme genes ENO2, ENO3, ALDOC, ACSS2, and then promoted aerobic glycolysis, which provided energy for CCA cell proliferation. In addition, USP21 could directly stabilize alpha-Enolase 1 (ENO1) to promote aerobic glycolysis. Furthermore, increased USP21 level enhanced chemotherapy resistance to the gemcitabine-based regimen. Taken together, we identify a USP21-regulated aerobic glycolysis mechanism that involves the USP21/HSP90/HIF1A axis and USP21/ENO1 axis in CCA tumorigenesis, which could serve as a potential target for the treatment of CCA.

Asunto(s)

Neoplasias de los Conductos Biliares , Colangiocarcinoma , Humanos , Colangiocarcinoma/metabolismo , Proliferación Celular/genética , Fosfopiruvato Hidratasa/genética , Fosfopiruvato Hidratasa/metabolismo , Conductos Biliares Intrahepáticos/metabolismo , Neoplasias de los Conductos Biliares/genética , Glucólisis/genética , Línea Celular Tumoral , Proteínas de Unión al ADN/metabolismo , Biomarcadores de Tumor/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/metabolismo

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BACKGROUND: circular RNAs (circRNAs) have been reported to exert important effects in the progression of numerous cancers. However, the functions of circRNAs in intrahepatic cholangiocarcinoma (ICC) are still unclear. METHODS: circPCNXL2 (has_circ_0016956) were identified in paired ICC by circRNA microarray. Then, we assessed the biological functions of circPCNXL2 by CCK8, EdU, clone formation, transwell, wound healing assays, and xenograft models. RNA pull-down, mass spectrometry, and RNA immunoprecipitation (RIP) were applied to explore the interaction between cirrcPCNXL2 and serine-threonine kinase receptor-associated protein (STRAP). RNA pull-down, RIP and luciferase reporter assays were used to investigate the sponge functions of circPCNXL2. In the end, we explore the effects of circPCNXL2 and trametinib (a MEK1/2 inhibitor) in vivo. RESULTS: circPCNXL2 was upregulated in ICC tissues and cell lines, which promoted the proliferation and metastasis of ICC in vitro and in vivo. In terms of the mechanisms, circPCNXL2 could directly bind to STRAP and induce the interaction between STRAP and MEK1/2, resulting in the tumor promotion in ICC by activation of ERK/MAPK pathways. Besides, circPCNXL2 could regulate the expression of SRSF1 by sponging miR-766-3p and subsequently facilitated the growth of ICC. Finally, circPCNXL2 could partially inhibit the anti-tumor activity of trametinib in vivo. CONCLUSION: circPCNXL2 played a crucial role in the progression of ICC by interacting with STRAP to activate the ERK signaling pathway, as well as by modulating the miR-766-3p/SRSF1 axis. These findings suggest that circPCNXL2 may be a promising biomarker and therapeutic target for ICC.

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Neoplasias de los Conductos Biliares , Colangiocarcinoma , MicroARNs , Humanos , ARN Circular/genética , Proliferación Celular/genética , Colangiocarcinoma/metabolismo , Transducción de Señal , Conductos Biliares Intrahepáticos/metabolismo , Conductos Biliares Intrahepáticos/patología , Neoplasias de los Conductos Biliares/metabolismo , MicroARNs/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Factores de Empalme Serina-Arginina/metabolismo

RESUMEN

Vitiligo is an autoimmune disease involving loss of melanocytes. Although several genetic studies have confirmed that genetic factors play an important role, its pathogenesis remains incompletely characterized. In this study, a genome-wide meta-analysis was conducted to search for more susceptibility variants of vitiligo. Tang et al performed a GWAS for cohort I (1117 vitiligo cases and 1701 healthy controls) previously, and we conducted a GWAS for cohort II (3323 vitiligo cases and 7186 healthy controls) in this study, with the results subjected to a genome-wide meta-analysis and linkage disequilibrium analysis. We identify, to our knowledge, 11 previously unreported susceptibility variants, of which 6 variants are located in the intronic regions, and the remaining 5 variants are located within intergenic regions between genes. In addition, the results of polygenic risk score show that the best evaluated effect for target data is among significant SNVs of the base data. The susceptibility genes of vitiligo are mainly enriched in the immune-related functions and pathways. The susceptibility variants expand the role of genetic factors associated with vitiligo. The bioinformatics analysis for risk genes provides further insight into the pathogenesis of vitiligo.

Asunto(s)

Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Vitíligo , Femenino , Humanos , Masculino , Estudios de Casos y Controles , China/epidemiología , Pueblos del Este de Asia/genética , Desequilibrio de Ligamiento , Vitíligo/genética

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BACKGROUND: Spindle and kinetochore-associated complex subunit 3 (SKA3) plays an important role in cell proliferation by regulating the separation of chromosomes and their division into daughter cells. Previous studies demonstrated that SKA3 was strongly implicated in tumor development and progression. However, the roles of SKA3 in cholangiocarcinoma (CCA) and the underlying mechanisms remain unclear. METHODS: Next-generation sequencing (NGS) was performed with paired CCA tissues and normal adjacent tissues (NATs). SKA3 was chose to be the target gene because of its remarkably upregulation and unknown function in cholangiocarcinoma in TCGA datasets, GSE107943 datasets and our sequencing results. RT-PCR and immunohistochemistry staining were used to detect the expression of SKA3 in paired CCA tissues and normal adjacent tissues. The SKA3 knockdown and overexpression cell line were constructed by small interfering RNA and lentivirus vector transfection. The effect of SKA3 on the proliferation of cholangiocarcinoma under hypoxic conditions was detected by experiments in vitro and in vivo. RNA-seq was used to find out the differentially expressed pathways in cholangiocarcinoma proliferation under hypoxia regulated by SKA3. IP/MS analysis and Western blot assays were used to explore the specific mechanism of SKA3 in regulating the expression of HIF-1a under hypoxia. RESULTS: SKA3 was up-regulated in NGS, TCGA and GSE107943 databases and was associated with poor prognosis. Functional experiments in vitro and in vivo showed that hypoxia-induced SKA3 promoted cholangiocarcinoma cell proliferation. RNA-sequencing was performed and verified that SKA3 enhanced fatty acid synthesis by up-regulating the expression of key fatty acid synthase, thus promoting cholangiocarcinoma cell proliferation under hypoxic conditions. Further studies indicated that under hypoxic conditions, SKA3 recruited PARP1 to bind to HIF-1a, thus enhancing the poly ADP-ribosylation (PARylation) of HIF-1a. This PARylation enhanced the binding between HIF-1a and USP7, which triggered the deubiquitylation of HIF-1a under hypoxic conditions. Additionally, PARP1 and HIF-1a were upregulated in CCA and promoted CCA cell proliferation. SKA3 promoted CCA cell proliferation and fatty acid synthesis via the PARP1/HIF-1a axis under hypoxic conditions. High SKA3 and HIF-1a expression levels were associated with poor prognosis after surgery. CONCLUSION: Hypoxia-induced SKA3 promoted CCA progression by enhancing fatty acid synthesis via the regulation of PARylation-dependent HIF-1a deubiquitylation. Furthermore, increased SKA3 level enhanced chemotherapy-resistance to gemcitabine-based regimen under hypoxic conditions. SKA3 and HIF-1a could be potential oncogenes and significant biomarkers for the analysis of CCA patient prognosis.

Asunto(s)

Neoplasias de los Conductos Biliares , Colangiocarcinoma , Humanos , Resistencia a Antineoplásicos/genética , Colangiocarcinoma/patología , Proliferación Celular/genética , Conductos Biliares Intrahepáticos/metabolismo , Neoplasias de los Conductos Biliares/patología , Hipoxia/genética , Ácidos Grasos , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Peptidasa Específica de Ubiquitina 7/genética

RESUMEN

Psychological stress has long been considered to cause the aggravation and recurrence of psoriasis, but the underlying mechanism remains largely unknown. Here, we used a mouse model of restraint-induced stress and imiquimod (IMQ)-induced psoriasiform inflammation to investigate the crosstalk between stress and the skin immune system and their functions in the pathogenesis of psoriasis. We found that stress aggravated skin inflammation and elevated serum corticosterone (CORT) levels in mice. Stress also increased the number of macrophages and glucocorticoid receptor (GR) expression in IMQ-treated mouse skin. GR agonist CORT upregulated the phosphorylation of STAT1 to promote M1 macrophage polarization in vitro. Additionally, GR deletion in macrophages and pharmacologic inhibition of GR improved skin inflammation and reduced M1 macrophage polarization under stress. Taken together, these results indicate that stress aggravates psoriasiform inflammation by promoting CORT/GR signaling-induced M1 macrophage polarization, suggesting that blocking the GR signaling has great potential as an adjuvant treatment for psoriasis patients with chronic stress.

RESUMEN

Spindle assembly checkpoint (SAC) plays an essential part in facilitating normal cell division. However, the clinicopathological and biological significance of mitotic arrest deficient 2 like 1 (MAD2/MAD2L1), a highly conserved member of SAC in cholangiocarcinoma (CCA) remain unclear. We aim to determine the role and mechanism of MAD2 in CCA progression. In the study, we found up-regulated MAD2 facilitated CCA progression and induced lymphatic metastasis dependent on USP44/LIMA1/PI3K/AKT pathway. MAD2 interfered the binding of USP44 to LIMA1 by sequestrating more USP44 in nuclei, causing impaired formation of USP44/LIMA1 complex and enhanced LIMA1 K48 (Lys48)-linked ubiquitination. In therapeutic perspective, the data combined eleven cases of CCA PDTX model showed that high-MAD2 inhibits tumor necrosis and diminishes the inhibition of cell viability after treated with gemcitabine-based regimens. Immunohistochemistry (IHC) analysis of tissue microarray (TMA) for CCA patients revealed that high-MAD2, low-USP44 or low-LIMA1 level are correlated with worse survival for patients. Together, MAD2 activates PI3K/AKT pathway, promotes cancer progression and induces gemcitabine chemo-resistance in CCA. These findings suggest that MAD2 might be an excellent indicator in prognosis analysis and chemotherapy guidance for CCA patients.

Asunto(s)

Neoplasias de los Conductos Biliares , Colangiocarcinoma , Humanos , Neoplasias de los Conductos Biliares/metabolismo , Conductos Biliares Intrahepáticos/patología , Colangiocarcinoma/patología , Proteínas del Citoesqueleto , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor IGF Tipo 1 , Ubiquitina Tiolesterasa/genética

RESUMEN

Intestinal stem cell (ISC) is a promising therapeutic target for inflammatory bowel disease. Cholesterol availability is critical for ISC stemness. Low plasma cholesterol is a typical feature of Crohn's disease (CD); however, its impact on mucosal healing remains unclear. Here, we identified an essential role of sorting nexin 10 (SNX10) in maintaining the stemness of ISCs. SNX10 expression in intestinal tissues positively correlates with the severity of human CD and mouse colitis. Conditional SNX10 knockout in intestinal epithelial cells or ISCs promotes intestinal mucosal repair by maintaining the ISC population associated with increased intracellular cholesterol synthesis. Disassociation of ERLIN2 with SCAP by SNX10 deletion enhances the activation of SREBP2, resulting in increased cholesterol biosynthesis. DC-SX029, a small-molecule inhibitor of SNX10, was used to verify the druggable potential of SNX10 for the treatment of patients with CD. Our study provides a strategy for mucosal healing through SREBP2-mediated stemness restoration of ISCs.

Asunto(s)

Enfermedades Inflamatorias del Intestino , Nexinas de Clasificación , Animales , Humanos , Ratones , Mucosa Intestinal , Intestinos , Nexinas de Clasificación/genética , Células Madre

RESUMEN

The vascular endothelial growth factor (VEGF) signal transduction pathway has been shown to be a potential target for the treatment of psoriasis. Ras guanyl-releasing protein 1 (RasGRP1), a downstream target gene of VEGF, regulates the development, homeostasis, and differentiation of T cells, but the contribution of RasGRP1 to psoriasis is limited. In this manuscript, we aimed to investigate the role of RasGRP1 in psoriasis. The RNA-Seq transcriptome sequencing data from the mouse model of psoriasis treated with IMQ (imiquimod) were analyzed. The effect of RasGRP1 was investigated through in vivo injection of activators or small molecular inhibitors, as well as adeno-associated virus injections. Gene knockout and NB-UVB (narrow-band ultraviolet B) treatments were utilized to interfere with the psoriatic mouse model. By transfection of lentivirus in vitro, the effect of RasGRP1 gene function on the secretion of psoriasis-related cytokines by T cells was confirmed. We showed that cutaneous VEGF and RasGRP1 were strongly activated in human psoriatic lesions and the skin of mice with IMQ-induced psoriasis. RasGRP1 deficiency and overexpression influence IMQ-induced psoriasis-like manifestations and skin inflammation in mice. VEGF, secreted mainly by epidermal cells, mediates psoriatic inflammation through the RasGRP1-AKT-NF-κB pathway. RasGRP1 is required for psoriasis development mediated by VEGF. These results confirmed the role of RasGRP1 in the pathogenesis of psoriasis and provided potential targets for clinical psoriasis treatment.

Asunto(s)

Psoriasis , Factor A de Crecimiento Endotelial Vascular , Humanos , Animales , Ratones , Imiquimod/farmacología , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Piel/patología , Psoriasis/inducido químicamente , Psoriasis/genética , Psoriasis/tratamiento farmacológico , Inflamación/metabolismo , Modelos Animales de Enfermedad , Ratones Endogámicos BALB C