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Background: The most common metastatic site of follicular variant of papillary thyroid carcinoma (FVPTC) is the central lymph nodes, which may be associated with the prognosis and survival of patients. In the present study, we establish a combined model based on preoperative clinical and ultrasound (US) features of FVPTC to predict the risk of central lymph node metastasis (CLNM). Methods: From January 2013 to December 2022, 315 patients with FVPTC were enrolled and randomly divided into the training and validation cohorts in a ratio of 7:3. The independent risk factors for CLNM in FVPTC were analysed using univariate and multivariate logistic regression analyses. Then, three different models were established based on clinical and US data. Subsequently, a nomogram was constructed to predict CLNM. Its predictive effect was evaluated via receiver operating characteristic and calibration curve analyses. Results: Backward multivariate regression analysis revealed that age (P=0.001), thyroid peroxidase antibody (TPOAb) (P=0.11), diameter (P=0.047), irregular/lobulated margin (P=0.15), extrathyroidal extension (P=0.001), nodules with macrocalcifications (P=0.009), nodules with microcalcification (P=0.003) and Thyroid Imaging Reporting and Data System (ACR-TI-RADS) category 5 (P=0.33) were independent risk factors for CLNM in FVPTC. The areas under the curve of the matching nomogram in the training (N=221) and validation cohorts (N=94) were 0.841 [95% confidence interval (CI): 0.788-0.895] and 0.735 (95% CI: 0.621-0.872), respectively. Conclusions: Preoperative thyroid US provides useful features for prediction of CLNM. The nomogram constructed based on combining US and clinical features can better predict the risk of CLNM and may facilitate decision-making in clinical settings.
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Immunoproteasomes are involved in various inflammatory diseases. Upon stimulation, standard constitutive proteasomes are partially replaced by newly formed immunoproteasomes that promote inflammatory responses. How the upregulated immunoproteasomes are cleared to constrain hyper-inflammation is unknown. Recently, our studies showed that the pan-FGFR inhibitor LY2874455 efficiently activates macroautophagy/autophagy in macrophages, leading to the degradation of the immunoproteasomes. Immunoproteasome subunits are ubiquitinated and recognized by the selective autophagy receptor SQSTM1/p62. LY2874455 suppresses inflammation induced by lipopolysaccharide both in vivo and in vitro through autophagic degradation of the immunoproteasomes. In summary, our work uncovers a mechanism of inflammation suppression by autophagy in macrophages.
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OBJECTIVE: Contrast-enhanced ultrasound (CEUS) is useful in mapping lymphatic vessels in upper limb lymphedema; this study was aimed to evaluate its efficiency in lower limb lymphedema and investigate whether magnetic resonance lymphangiography (MRL) enhance the efficiency of CEUS. METHODS: This retrospective study enrolled 48 patients with lymphedema undergoing lymphaticovenous anastomosis (LVA) surgery who received MRL and/or CEUS in addition to conventional indocyanine green (ICG) lymphangiography. The number of anastomotic sites and the duration per site (DPS) for LVA surgery were described and compared. RESULTS: Among the 48 patients subjected to analysis, it was observed that 12 (25%), 20 (41.67%), and 16 (33.33%) of them received ICG, ICG+CEUS, and ICG+CEUS+MRL, respectively. The ICG+CEUS group demonstrated a significant increase in the number of LVAs (median, 5; range, 4-7), compared with the ICG group (median, 2; range, 1-4) (P < .001). Moreover, the ICG+CEUS+MRL group exhibited a higher number of LVAs (median, 8; range, 7-8.25) compared with both the ICG+CEUS and ICG groups (P < .001). For lower limb lymphedema, the ICG+CEUS+MRL group displayed an elevated number of LVAs (median, 8; interquartile range, 7-9) (P = .003), in contrast to the ICG group (median, 3; interquartile range, 1.75-4.25). Furthermore, the DPS in the ICG+CEUS+MRL group (median, 50.56; interquartile range, 48.13-59.29) (P = .005) exhibited a remarkable decrease when compared with the ICG group (median, 131.25; interquartile range, 86.75-198.13]). CONCLUSIONS: MRL-CEUS fusion demonstrates superior performance in the identification of lymphatic vessels for lymphedema.
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Anastomose Cirúrgica , Meios de Contraste , Verde de Indocianina , Vasos Linfáticos , Linfedema , Linfografia , Imageamento por Ressonância Magnética , Valor Preditivo dos Testes , Humanos , Feminino , Linfedema/cirurgia , Linfedema/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Vasos Linfáticos/cirurgia , Vasos Linfáticos/diagnóstico por imagem , Linfografia/métodos , Adulto , Meios de Contraste/administração & dosagem , Idoso , Verde de Indocianina/administração & dosagem , Resultado do Tratamento , Imagem Multimodal , Veias/cirurgia , Veias/diagnóstico por imagem , Ultrassonografia , Adulto JovemRESUMO
Defective autophagy is linked to proinflammatory diseases. However, the mechanisms by which autophagy limits inflammation remain elusive. Here, we found that the pan-FGFR inhibitor LY2874455 efficiently activated autophagy and suppressed expression of proinflammatory factors in macrophages stimulated by lipopolysaccharide (LPS). Multiplex proteomic profiling identified the immunoproteasome, which is a specific isoform of the 20s constitutive proteasome, as a substrate that is degraded by selective autophagy. SQSTM1/p62 was found to be a selective autophagy-related receptor that mediated this degradation. Autophagy deficiency or p62 knockdown blocked the effects of LY2874455, leading to the accumulation of immunoproteasomes and increases in inflammatory reactions. Expression of proinflammatory factors in autophagy-deficient macrophages could be reversed by immunoproteasome inhibitors, confirming the pivotal role of immunoproteasome turnover in the autophagy-mediated suppression on the expression of proinflammatory factors. In mice, LY2874455 protected against LPS-induced acute lung injury and dextran sulfate sodium (DSS)-induced colitis and caused low levels of proinflammatory cytokines and immunoproteasomes. These findings suggested that selective autophagy of the immunoproteasome was a key regulator of signaling via the innate immune system.
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Lipopolissacarídeos , Proteômica , Animais , Camundongos , Lipopolissacarídeos/farmacologia , Autofagia , Inflamação , Macrófagos , Complexo de Endopeptidases do ProteassomaRESUMO
Traumatic brain injury (TBI) leads to progressive neurodegeneration that may be caused by chronic traumatic encephalopathy (CTE). However, the precise mechanism remains unclear. Herein, the study identifies a crucial protein, axonemal dynein light intermediate polypeptide 1 (DNALI1), and elucidated its potential pathogenic role in post-TBI neurodegeneration. The DNALI1 gene is systematically screened through analyses of Aging, Dementia, and TBI studies, confirming its elevated expression both in vitro and in vivo. Moreover, it is observed that altered DNALI1 expression under normal conditions has no discernible effect. However, upon overexpression, DNALI1 inhibits autophagosome-lysosome fusion, reduces autophagic flux, and exacerbates cell death under pathological conditions. DNALI1 silencing significantly enhances autophagic flux and alleviates neurodegeneration in a CTE model. These findings highlight DNALI1 as a potential key target for preventing TBI-related neurodegeneration.
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Lesões Encefálicas Traumáticas , Encefalopatia Traumática Crônica , Humanos , Autofagossomos/metabolismo , Autofagossomos/patologia , Lesões Encefálicas Traumáticas/complicações , Encefalopatia Traumática Crônica/etiologia , Encefalopatia Traumática Crônica/patologia , Autofagia , Lisossomos/metabolismoRESUMO
Background: Lysosomes are known to have a significant impact on the development and recurrence of breast cancer. However, the association between lysosome-related genes (LRGs) and breast cancer remains unclear. This study aims to explore the potential role of LRGs in predicting the prognosis and treatment response of breast cancer. Methods: Breast cancer gene expression profile data and clinical information were downloaded from TCGA and GEO databases, and prognosis-related LRGs were screened for consensus clustering analysis. Lasso Cox regression analysis was used to construct risk features derived from LRGs, and immune cell infiltration, immune therapy response, drug sensitivity, and clinical pathological feature differences were evaluated for different molecular subtypes and risk groups. A nomogram based on risk features derived from LRGs was constructed and evaluated. Results: Our study identified 176 differentially expressed LRGs that are associated with breast cancer prognosis. Based on these genes, we divided breast cancer into two molecular subtypes with significant prognostic differences. We also found significant differences in immune cell infiltration between these subtypes. Furthermore, we constructed a prognostic risk model consisting of 7 LRGs, which effectively divides breast cancer patients into high-risk and low-risk groups. Patients in the low-risk group have better prognostic characteristics, respond better to immunotherapy, and have lower sensitivity to chemotherapy drugs, indicating that the low-risk group is more likely to benefit from immunotherapy and chemotherapy. Additionally, the risk score based on LRGs is significantly correlated with immune cell infiltration, including CD8 T cells and macrophages. This risk score model, along with age, chemotherapy, clinical stage, and N stage, is an independent prognostic factor for breast cancer. Finally, the nomogram composed of these factors has excellent performance in predicting overall survival of breast cancer. Conclusions: In conclusion, this study has constructed a novel LRG-derived breast cancer risk feature, which performs well in prognostic prediction when combined with clinical pathological features.
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BACKGROUND: Triple-negative breast cancer (TNBC) is a unique breast cancer subtype with a high risk of metastasis and recurrence and a poor prognosis. Epithelial-mesenchymal transition (EMT) endows epithelial cells with the ability to move to distant sites, which is essential for the metastasis of TNBC to organs, including the lung. Autophagy, an intracellular degradation process that involves formation of double-layered lipid autophagosomes that transport cytosolic cargoes into lysosomes via autophagosome-lysosome fusion, is involved in various diseases, including cancer and neurodegenerative, metabolic, cardiovascular, and infectious diseases. The relationship between autophagy and cancer has become relatively clear. However, research on pharmacological drugs that block cancer EMT by targeting autophagy is still in the initial stages. Therefore, the re-evaluation of old drugs for their potential in blocking both autophagy and EMT was conducted. METHODS: More than 2000 small molecule chemicals were screened for dual autophagy/EMT inhibitors, and FRAX486 was identified as the best candidate inhibitor of autophagy/EMT. The functions of FRAX486 in TNBC metastasis were detected by CCK-8, migration and wound healing assays. The effects of FRAX486 on autophagy and its target PAK2 were determined by immunoblotting, immunofluorescence, immunoprecipitation analysis and transmission electron microscopy. The findings were validated in mouse models. RESULTS: Here, we report that FRAX486, a potent P21-activated kinase 2 (PAK2) inhibitor, facilitates TNBC suppression both in vitro and in vivo by blocking autophagy. Mechanistically, FRAX486 inhibits autophagy in TNBC cells by targeting PAK2, leading to the ubiquitination and proteasomal degradation of STX17, which mediates autophagosome-lysosome fusion. The inhibition of autophagy by FRAX486 causes upregulation of the epithelial marker protein E-cadherin and thus suppresses the migration and metastasis of TNBC cells. CONCLUSIONS: The effects of FRAX486 on TNBC metastasis suppression were verified to be dependent on PAK2 and autophagy inhibition. Together, our results provide a molecular basis for the application of FRAX486 as a potential treatment for inhibiting the metastasis of TNBC.
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Piridonas , Neoplasias de Mama Triplo Negativas , Camundongos , Humanos , Animais , Neoplasias de Mama Triplo Negativas/patologia , Linhagem Celular Tumoral , Pirimidinas/farmacologia , Movimento Celular , Autofagia , Transição Epitelial-Mesenquimal , Proliferação de CélulasRESUMO
Massive GGGGCC (G4C2) repeat expansion in C9orf72 and the resulting loss of C9orf72 function are the key features of ~50% of inherited amyotrophic lateral sclerosis and frontotemporal dementia cases. However, the biological function of C9orf72 remains unclear. We previously found that C9orf72 can form a stable GTPase activating protein (GAP) complex with SMCR8 (Smith-Magenis chromosome region 8). Herein, we report that the C9orf72-SMCR8 complex is a major negative regulator of primary ciliogenesis, abnormalities in which lead to ciliopathies. Mechanistically, the C9orf72-SMCR8 complex suppresses the primary cilium as a RAB8A GAP. Moreover, based on biochemical analysis, we found that C9orf72 is the RAB8A binding subunit and that SMCR8 is the GAP subunit in the complex. We further found that the C9orf72-SMCR8 complex suppressed the primary cilium in multiple tissues from mice, including but not limited to the brain, kidney, and spleen. Importantly, cells with C9orf72 or SMCR8 knocked out were more sensitive to hedgehog signaling. These results reveal the unexpected impact of C9orf72 on primary ciliogenesis and elucidate the pathogenesis of diseases caused by the loss of C9orf72 function.
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Esclerose Lateral Amiotrófica , Proteína C9orf72 , Cílios , Demência Frontotemporal , Animais , Camundongos , Esclerose Lateral Amiotrófica/metabolismo , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Cílios/metabolismo , Expansão das Repetições de DNA , Demência Frontotemporal/metabolismo , Proteínas Ativadoras de GTPase/metabolismo , Humanos , Células HEK293RESUMO
Septin proteins are involved in diverse physiological functions, including the formation of specialized cytoskeletal structures. Septin 8 (Sept8) is implicated in spine morphogenesis and dendritic branching through palmitoylation. We explored the role and regulation of a Sept8 variant in human neural-like cells and in the mouse brain. We identified Sept8-204 as a brain-specific variant of Sept8 that was abundant in neurons and modified by palmitoylation, specifically at Cys469, Cys470, and Cys472. Sept8-204 palmitoylation was mediated by the palmitoyltransferase ZDHHC7 and was removed by the depalmitoylase PPT1. Palmitoylation of Sept8-204 bound to F-actin and induced cytoskeletal dynamics to promote the outgrowth of filopodia in N2a cells and the arborization of neurites in hippocampal neurons. In contrast, a Sept8-204 variant that could not be palmitoylated because of mutation of all three Cys residues (Sept8-204-3CA) lost its ability to bind F-actin, and expression of this mutant did not promote morphological changes. Genetic deletion of Sept8, Sept8-204, or Zdhhc7 caused deficits in learning and memory and promoted anxiety-like behaviors in mice. Our findings provide greater insight into the regulation of Sept8-204 by palmitoylation and its role in neuronal morphology and function in relation to cognition.
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Actinas , Septinas , Animais , Humanos , Camundongos , Actinas/genética , Ansiedade/genética , Neurônios/fisiologia , Pseudópodes/genética , Septinas/genética , Septinas/metabolismo , AprendizagemRESUMO
Calcium is involved in a variety of cellular processes. As the crucial components of cell membranes, sphingolipids also play important roles as signaling molecules. Intracellular calcium homeostasis, autophagy initiation and sphingolipid synthesis are associated with the endoplasmic reticulum (ER). Recently, through genetic screening and lipidomics analysis in Saccharomyces cerevisiae, we found that the ER calcium channel Csg2 converts sphingolipid metabolism into macroautophagy/autophagy regulation by controlling ER calcium homeostasis. The results showed that Csg2 acts as a calcium channel to mediate ER calcium efflux into the cytoplasm, and deletion of CSG2 causes a distinct increase of ER calcium concentration, thereby disrupting the stability of the sphingolipid synthase Aur1, leading to the accumulation of the bioactive sphingolipid phytosphingosine (PHS), which specifically and completely blocks autophagy. In summary, our work links calcium homeostasis, sphingolipid metabolism, and autophagy initiation via the ER calcium channel Csg2.
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Autofagia , Cálcio , Cálcio/metabolismo , Esfingolipídeos , Saccharomyces cerevisiae/metabolismo , Retículo Endoplasmático/metabolismo , Canais de Cálcio/metabolismo , HomeostaseRESUMO
Sphingolipids are ubiquitous components of membranes and function as bioactive lipid signaling molecules. Here, through genetic screening and lipidomics analyses, we find that the endoplasmic reticulum (ER) calcium channel Csg2 integrates sphingolipid metabolism with autophagy by regulating ER calcium homeostasis in the yeast Saccharomyces cerevisiae. Csg2 functions as a calcium release channel and maintains calcium homeostasis in the ER, which enables normal functioning of the essential sphingolipid synthase Aur1. Under starvation conditions, deletion of Csg2 causes increases in calcium levels in the ER and then disturbs Aur1 stability, leading to accumulation of the bioactive sphingolipid phytosphingosine, which specifically and completely blocks autophagy and induces loss of starvation resistance in cells. Our findings indicate that calcium homeostasis in the ER mediated by the channel Csg2 translates sphingolipid metabolism into autophagy regulation, further supporting the role of the ER as a signaling hub for calcium homeostasis, sphingolipid metabolism and autophagy.
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Proteínas de Saccharomyces cerevisiae , Autofagia , Cálcio/metabolismo , Retículo Endoplasmático/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Esfingolipídeos/metabolismoRESUMO
This study aimed to evaluate the performance of traditional-deep learning combination model based on Doppler ultrasound for diagnosing malignant complex cystic and solid breast nodules. A conventional statistical prediction model based on the ultrasound features and basic clinical information was established. A deep learning prediction model was used to train the training group images and derive the deep learning prediction model. The two models were validated, and their accuracy rates were compared using the data and images of the test group, respectively. A logistic regression method was used to combine the two models to derive a combination diagnostic model and validate it in the test group. The diagnostic performance of each model was represented by the receiver operating characteristic curve and the area under the curve. In the test cohort, the diagnostic efficacy of the deep learning model was better than traditional statistical model, and the combined diagnostic model was better and outperformed the other two models (combination model vs traditional statistical model: AUC: 0.95 > 0.70, P = 0.001; combination model vs deep learning model: AUC: 0.95 > 0.87, P = 0.04). A combination model based on deep learning and ultrasound features has good diagnostic value.
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Aprendizado Profundo , Neoplasias , Humanos , Ultrassonografia , Angiografia , Testes de Função CardíacaRESUMO
PURPOSE: To develop an ultrasound predictive model to differentiate between benign and malignant complex cystic and solid nodules (C-SNs). METHODS: A total of 211 patients with complex C-SNs rated as American College of Radiology Breast Imaging Reporting and Data System (ACR BI-RADS) category 4 or 5 on the ultrasound reports were included in the study, from June 2018-2021. Multivariate stepwise logistic regression analysis was used to establish a predictive model, based on clinical and ultrasound features. The diagnostic performance of the model was evaluated by the area under the curve (AUC) of the receiver operating characteristic curve. RESULTS: A total of 109 breast nodules, including 74 benign nodules (67.89%) and 35 malignant nodules (32.11%), were detected by surgical pathology or puncture biopsy. Multivariate analysis showed that the blood flow (BF) of complex C-SNs (p = 0.03), cystic fluid transmission (p = 0.02), longitudinal diameter (p < 0.001), and age (p = 0.03) were independent risk factors for malignant complex cystic and solid breast nodules. The ultrasound model equation was Z=-12.14+2.24×X12+1.97×X20+0.40×X7+0.11×X0; M=ez1+ez (M is the malignancy score, e = 2.72). The area under the curve (AUC) was 0.89, which indicated good predictive utility for the model. CONCLUSIONS: A prediction model incorporating major risk factors can predict the malignant C-SNs with accuracy.
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Mama , Humanos , Estudos Retrospectivos , Ultrassonografia/métodos , Curva ROC , Fatores de RiscoRESUMO
BACKGROUND: There are few reported cases of intracranial large artery embolism due to carotid thrombosis caused by a neck massager. Herein we report such a case. CASE SUMMARY: A 49-year-old woman presented with left limb weakness and dysarthria after a history of neck massage for 1 mo. Neurological examination showed left central facial paralysis and left hemiparesis with a National Institutes of Health Stroke Scale score of 12. Brain magnetic resonance imaging revealed restricted diffusion on diffusion-weighted imaging in the right parietal and temporal lobes. Computed tomography angiography (CTA) indicated M3 segment embolism of the right middle cerebral artery. Neck CTA revealed thrombosis of the bilateral common carotid arteries. Carotid ultrasound showed thrombosis in the bilateral common carotid arteries (approximately 2 cm below the proximal end of the carotid sinus), and contrast-enhanced ultrasound did not suggest enhancement. No hypertension, diabetes, heart disease, vasculitis, or thrombophilia was found after admission. After 1 wk of treatment with aspirin 200 mg and atorvastatin 40 mg, a carotid ultrasound reexamination showed that the thrombosis had significantly reduced. CONCLUSION: Neck massager may cause carotid artery thrombosis.
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SARS-CoV-2 and its variants, with the Omicron subvariant XBB currently prevailing the global infections, continue to pose threats on public health worldwide. This non-segmented positive-stranded RNA virus encodes the multi-functional nucleocapsid protein (N) that plays key roles in viral infection, replication, genome packaging and budding. N protein consists of two structural domains, NTD and CTD, and three intrinsically disordered regions (IDRs) including the NIDR, the serine/arginine rich motif (SRIDR), and the CIDR. Previous studies revealed functions of N protein in RNA binding, oligomerization, and liquid-liquid phase separation (LLPS), however, characterizations of individual domains and their dissected contributions to N protein functions remain incomplete. In particular, little is known about N protein assembly that may play essential roles in viral replication and genome packing. Here, we present a modular approach to dissect functional roles of individual domains in SARS-CoV-2 N protein that reveals inhibitory or augmented modulations of protein assembly and LLPS in the presence of viral RNAs. Intriguingly, full-length N protein (NFL) assembles into ring-like architecture whereas the truncated SRIDR-CTD-CIDR (N182-419) promotes filamentous assembly. Moreover, LLPS droplets of NFL and N182-419 are significantly enlarged in the presence of viral RNAs, and we observed filamentous structures in the N182-419 droplets using correlative light and electron microscopy (CLEM), suggesting that the formation of LLPS droplets may promote higher-order assembly of N protein for transcription, replication and packaging. Together this study expands our understanding of the multiple functions of N protein in SARS-CoV-2.
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BACKGROUND: Severe lymphedema presents a challenge in terms of treatment due to the significant formation of scar tissue that accompanies it. The aim of this study was to identify intraoperative and preoperative risk factors of severe lymphedema and to develop a nomogram for estimating the risk of severe lymphedema within 3 years of surgery. METHOD: Data was collected from a retrospective cohort of 326 patients with BCRL at the Zhejiang Cancer Hospital from November 2015 to November 2018. Univariate and multivariate logistic regression analysis was conducted to identify predictive indicators of severe lymphedema. A nomogram was developed to further improve the clinical applicability. RESULTS: In the retrospective cohort, the ratio of severe/non-severe lymphedema within 3 years of surgery was 1:3. Independent risk factors for severe lymphedema were determined to be age, positive lymph nodes, interpectoral (Rotter's) lymph nodes (IPNs) dissection, and educational level. IPNs dissection was found to contribute greatly to the development of severe lymphedema with a higher odds ratio (7.76; 95% CI: 3.87-15.54) than other risk factors. A nomogram was developed by integrating age, positive lymph nodes, IPNs dissection, and educational level, which yielded a C-index of 0.810 and 0.681 in the training and validation cohort, respectively. This suggested a moderate performance of the nomogram in predicting the risk of severe lymphedema within 3 years of surgery. The cut-off values of the low-, medium- and high-risk probabilities were 0.0876 and 0.3498, and the severe lymphedema exhibited a significantly higher risk probability as compared with the non-severe lymphedema. CONCLUSION: This study identified the risk factors of severe lymphedema and highlighted the substantial contribution of IPNs dissection to the severity of lymphedema.
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Linfedema Relacionado a Câncer de Mama , Neoplasias da Mama , Linfedema , Humanos , Feminino , Estudos Retrospectivos , Excisão de Linfonodo/efeitos adversos , Neoplasias da Mama/complicações , Neoplasias da Mama/cirurgia , Fatores de Risco , Linfedema Relacionado a Câncer de Mama/epidemiologia , Linfedema Relacionado a Câncer de Mama/etiologia , Linfedema/epidemiologia , Linfedema/etiologia , Linfonodos , AxilaRESUMO
Phosphatidylinositol lipids play vital roles in lipid signal transduction, membrane recognition, vesicle transport, and viral replication. Previous studies have revealed that SAC1-like phosphatidylinositol phosphatase (SACM1L/SAC1), which uses phosphatidylinositol-4-phosphate (PI4P) as its substrate, greatly affects the replication of certain bacteria and viruses in vitro. However, it remains unclear whether and how SAC1 modulates hepatitis B virus (HBV) replication in vitro and in vivo. In the present study, we observed that SAC1 silencing significantly increased HBV DNA replication, subviral particle (SVP) expression, and secretion of HBV virions, whereas SAC1 overexpression exerted the opposite effects. Moreover, SAC1 overexpression inhibited HBV DNA replication and SVP expression in a hydrodynamic injection-based HBV-persistent replicating mouse model. Mechanistically, SAC1 silencing increased the number of HBV-containing autophagosomes as well as PI4P levels on the autophagosome membrane. Moreover, SAC1 silencing blocked autophagosome-lysosome fusion by inhibiting the interaction between synaptosomal-associated protein 29 and vesicle-associated membrane protein 8. Collectively, our data indicate that SAC1 significantly inhibits HBV replication by promoting the autophagic degradation of HBV virions. Our findings support that SAC1-mediated phospholipid metabolism greatly modulates certain steps of the HBV life-cycle and provide a new theoretical basis for antiviral therapy.
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Vírus da Hepatite B , Hepatite B , Animais , Camundongos , Vírus da Hepatite B/genética , Replicação Viral , Hepatite B/metabolismo , Fosfatidilinositóis/farmacologia , Vírion/metabolismo , Monoéster Fosfórico Hidrolases/farmacologiaRESUMO
Macroautophagy/autophagy is a catabolic recycling pathway and is tightly regulated by upstream signals. Autophagy genes are quickly upregulated upon stimuli such as nutrition limitation in response to the external environment. However, how the transcriptional activation of autophagy genes occurs is not well understood. We recently found that in yeast, the RNA polymerase II subunit Rpb9 specifically and efficiently upregulates the transcription of the autophagy gene ATG1 with the mediation of Gcn4. Such regulation was shown to be essential for autophagic activities induced by starvation. Furthermore, the function of Rpb9 in autophagy and the activation of ATG1 transcription is conserved in mammalian cells. In conclusion, Rpb9 specifically and positively regulates ATG1 transcription as a key regulator of autophagy.
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RNA Polimerase II , Proteínas de Saccharomyces cerevisiae , Animais , RNA Polimerase II/genética , RNA Polimerase II/metabolismo , Autofagia/genética , Regulação da Expressão Gênica , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Mamíferos/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismoRESUMO
Colorectal cancer (CRC) raises concerns to people because of its high recurrence and metastasis rate, diagnosis challenges, and poor prognosis. Various studies have shown the association of altered autophagy with tumorigenesis, tumor-stroma interactions, and resistance to cancer therapy in CRC. Autophagy is a highly conserved cytosolic catabolic process in eukaryotes that plays distinct roles in CRC occurrence and progression. In early tumorigenesis, autophagy may inhibit tumor growth through diverse mechanisms, whereas it exhibits a tumor promoting function in CRC progression. This different functions of autophagy in CRC occurrence and progression make developing therapies targeting autophagy complicated. In this review, we discuss the classification and process of autophagy as well as its dual roles in CRC, functions in the tumor microenvironment, cross-talk with apoptosis, and potential usefulness as a CRC therapeutic target.
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Neoplasias Colorretais , Humanos , Neoplasias Colorretais/metabolismo , Apoptose , Carcinogênese , Transformação Celular Neoplásica , Autofagia , Microambiente TumoralRESUMO
Background: Carotid free-floating thrombus (CFFT) is a rare but sometimes emergent condition. There has been controversy over the optimal treatment strategy. Emerging evidence suggests that endovascular thrombectomy (EVT) may be an alternative to surgery. Accurate alignment of the aspiration catheter and thrombus during EVT is critical but has, so far, remained unresolved. Case summary: This is a rare case of CFFT presenting with acute right-sided facial droop and moderate dysarthria in a 77-year-old man. He was in sinus rhythm with a blood pressure of 110/82 mmHg. Both non-contrast CT (NCCT) and head CT angiography (CTA) were unremarkable, while whole-brain CT perfusion (WB-CTP) suggested left hemisphere core infarction. Delayed imaging of the left internal carotid system by 4D-CTA suggested severe proximal obstructive disease, as confirmed by carotid CTA and ultrasonography. The initial two aspirations under DSA were invalid due to the challenging anatomical angle between the thrombus and the catheter. The success of CFFT removal was achieved with a pressure-assisted ultrasound-guided approach that helps to compress the catheter tip toward the thrombus. Conclusion: We innovatively report a successful ultrasound-guided EVT for CFFT. Ultrasound assistance can provide quick and effective guidance and may guide tailored aspirations during EVT.