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BACKGROUND: Invasive deep brain stimulation (DBS) has been shown to be effective in treating patients with Parkinson's disease (PD), yet its clinical use is limited to patients at the advanced stage of the disease. Transcranial temporal interference stimulation (tTIS) may be a novel nonneurosurgical and safer alternative, yet its therapeutic potential remains unexplored. OBJECTIVE: This pilot study aims to examine the feasibility and safety of tTIS targeting the right globus pallidus internus (GPi) for motor symptoms in patients with PD. METHODS: Twelve participants with mild PD completed this randomized, double-blind, and sham-controlled experiment. Each of them received either 20-minute or sham tTIS of the right GPi. Before and immediately after the stimulation, participants completed the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS-III) in the "medication-on" state to assess the motor symptoms. The blinding efficacy and side effects were also assessed. RESULTS: tTIS was well tolerated by participants, with only mild, transient adverse effects reported. tTIS significantly reduced MDS-UPDRS-III scores by 6.64 points (14.7%), particularly in bradykinesia (23.5%) and tremor (15.3%). The left side showed more significant alleviation in motor symptoms, particularly bradykinesia, compared to the right side. Participants with severer bradykinesia and tremor before stimulation experienced greater improvement after tTIS. CONCLUSION: This pilot study suggests that the tTIS, as a novel noninvasive DBS approach, is feasible and safe for alleviating motor symptoms in mild PD, especially bradykinesia and tremor. Future larger-scale and more definitive studies are needed to confirm the benefits. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Background: This study investigated the correlation in parameters of arterial stiffness and cardiovascular disease (CVD) risk on age and body mass index (BMI) in Chinese females. Methods: This cross-sectional study enrolled 2220 females. Arterial stiffness was assessed by the measurement of arterial velocity pulse index (AVI) and arterial pressure volume index (API). Individual 10-year cardiovascular risk was calculated for each patient using the Framingham cardiovascular risk score (FCVRS). Results: API and AVI had a significant J-shaped relationship with age. Beginning at the age of 30 years, the API started to increase, while after 49 years, the increase in API was even steeper. AVI increased from the age of 32 years, and increased more rapidly after 56 years. The linear association between API and BMI following adjustment for age was significant ( ß = 0.324, 95% CI 0.247-0.400, p < 0.001). In the total study cohort, FCVRS scores increased by 0.16 scores for every 1 kg/ m 2 increase in BMI and by 0.11 scores for each 1 value increase in API in the age adjusted model. Conclusions: API and BMI correlate with 10-year cardiovascular risk at various ages in females. Regardless of age, overweight females have a higher risk of increased API. Therefore API can be used for the early detection of CVD so that preventive therapy can be instituted in these high risk patients. Clinical Trial Registration: Registered on the official website of the China Clinical Trial Registration Center (20/08/2020, ChiCTR2000035937).
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Hepatic ischemia-reperfusion injury (HIRI) is of common occurrence during liver surgery and transplantation. Pinocembrin (PIN) is a kind of flavonoid monomer extracted from the local traditional Chinese medicine Penthorum chinense Pursh (P. chinense). However, the effect of PIN on HIRI has not determined. We investigated the protective effect and potential mechanism of PIN against HIRI. Model mice were subjected to partial liver ischemia for 60 min, experimental mice were pretreated with PIN orally for 7 days, and H2 O2 -induced oxidative damage model in AML12 hepatic cells was established in vitro. Histopathologic analysis and serum biochemical levels revealed that PIN had hepatoprotective activities against HIRI. The variation of GSH, SOD, MDA, and ROS levels indicated that PIN treatments attenuated oxidative stress in tissue. PIN pretreatment obviously ameliorated apoptosis, and restrained the expression of HMGB1 and TLR4 in vivo. In vitro, compared with H2 O2 group, the contents of ROS, mitochondrial membrane potential, apoptotic cells, and Bcl-2 protein were decreased, while the Bax protein expression was increased. Moreover, HMGB-1 small interfering RNA test and western blotting showed that PIN pretreatment reduced HMGB1 and TLR4 protein levels. In conclusion, PIN pretreatment effectively protected hepatocytes from HIRI and inhibited the HMGB1/TLR4 signaling pathway.
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Proteína HMGB1 , Traumatismo por Reperfusão , Camundongos , Animais , Espécies Reativas de Oxigênio/metabolismo , Receptor 4 Toll-Like/metabolismo , Fígado , Transdução de Sinais , Traumatismo por Reperfusão/tratamento farmacológico , ApoptoseRESUMO
Nonalcoholic steatohepatitis (NASH) is a severely inflammatory subtype of nonalcoholic fatty liver. Endoplasmic reticulum stress (ERS) and oxidative stress (OS) cause metabolic abnormalities, promote liver steatosis and inflammation, and are central to the development of NASH. Dihydroartemisinin (DHA) is a compound extracted from Artemisia annua that is often used in the treatment of malaria. Recent studies have shown that DHA also has a wide range of pharmacological effects, acting on various organs throughout the body to exert anti-inflammatory, antioxidant, and anti-fibrotic effects. In this study, we demonstrated in vitro that the anti-inflammatory effect of DHA is effective against NASH and reduces liver steatosis. DHA treatment decreased the synthesis of lipids, such as cholesterol and free fatty acids, and the expression of nuclear factor kappa-B. This is accomplished by inhibiting the unfolded protein response and reducing the production of reactive oxygen species, thereby inhibiting OS and ERS. This study reveals DHA's therapeutic effect and potential mechanism in NASH, implying that DHA could be a new and promising candidate for NASH therapy.
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Hepatopatia Gordurosa não Alcoólica , Artemisininas , Estresse do Retículo Endoplasmático , Humanos , Inflamação/tratamento farmacológico , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Estresse OxidativoRESUMO
BACKGROUND: Although liver fibrosis is a key pathologic process in many liver diseases, therapeutic approaches for inhibiting liver fibrosis are still very limited. N-Acetyl-l-tryptophan (l-NAT) has a hepatoprotective effect via inhibiting the destruction of liver cells, enhancing cell viability and reducing the inflammation. However, the effect of l-NAT on liver fibrosis is not determined. PURPOSE: The present study investigated the effect of l-NAT on liver fibrosis and explored it potential molecular mechanism. METHODS: To address this concern, this study was carried out via fibrotic mice model induced by CCl4 and many approaches such as various histological staining methods, western blot assay, etc. RESULT: l-NAT decreased the levels of alanine aminotransferase (ALT) and aspartate transaminase (AST) in fibrotic mice model induced by carbon tetrachloride (CCl4). Histological staining showed that l-NAT ameliorated liver injury and fibrosis, and reduced the expression of α-smooth muscle actin (α-SMA) and Collagen I protein. l-NAT also attenuated apoptosis by down-regulating the level of pro-apoptotic protein Bax and up-regulating that of anti-apoptotic protein Bcl-2. Moreover, l-NAT inhibited the expressions of TGF-ß1/SMAD and matrix metalloproteinase 9 (MMP9) proteins, and reversed the expression of YAP1 protein in CCl4-induced liver fibrosis. CONCLUSION: These results clearly demonstrated that l-NAT attenuated CCl4-induced liver fibrosis in mice, and this protective mechanism might relate to TGF-ß1/SMAD and Hippo/YAP1 signaling pathway. Thus, this study provided data basis for the prevention and treatment of liver fibrosis.
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Proteínas Smad , Fator de Crescimento Transformador beta1 , Animais , Tetracloreto de Carbono , Via de Sinalização Hippo , Fígado , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Camundongos , Transdução de Sinais , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Triptofano/metabolismo , Proteínas de Sinalização YAP/metabolismoRESUMO
Chronic pancreatitis (CP), characterized by pancreatic fibrosis, is a recurrent, progressive and irreversible disease. Activation of the pancreatic stellate cells (PSCs) is considered a core event in pancreatic fibrosis. In this study, we investigated the role of hydrogen peroxide-inducible clone-5 (Hic-5) in CP. Analysis of the human pancreatic tissue samples revealed that Hic-5 was overexpressed in patients with CP and was extremely low in healthy pancreas. Hic-5 was significant up-regulated in the activated primary PSCs independently from transforming growth factor beta stimulation. CP induced by cerulein injection was ameliorated in Hic-5 knockout (KO) mice, as shown by staining of tissue level. Simultaneously, the activation ability of the primary PSCs from Hic-5 KO mice was significantly attenuated. We also found that the Hic-5 up-regulation by cerulein activated the NF-κB (p65)/IL-6 signalling pathway and regulated the downstream extracellular matrix (ECM) genes such as α-SMA and Col1a1. Therefore, we determined whether suppressing NF-κB/p65 alleviated CP by treating mice with the NF-κB/p65 inhibitor triptolide in the cerulein-induced CP model and found that pancreatic fibrosis was alleviated by NF-κB/p65 inhibition. These findings provide evidence for Hic-5 as a therapeutic target that plays a crucial role in regulating PSCs activation and pancreatic fibrosis.
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Proteínas do Citoesqueleto/deficiência , Proteínas de Ligação a DNA/deficiência , Regulação para Baixo , Interleucina-6/metabolismo , Proteínas com Domínio LIM/deficiência , NF-kappa B/metabolismo , Pancreatite Crônica/induzido quimicamente , Pancreatite Crônica/prevenção & controle , Transdução de Sinais , Animais , Células Cultivadas , Ceruletídeo , Proteínas do Citoesqueleto/metabolismo , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Diterpenos/farmacologia , Regulação para Baixo/efeitos dos fármacos , Compostos de Epóxi/farmacologia , Fibrose , Proteínas com Domínio LIM/metabolismo , Camundongos Knockout , Pâncreas/metabolismo , Pâncreas/patologia , Células Estreladas do Pâncreas/efeitos dos fármacos , Células Estreladas do Pâncreas/metabolismo , Células Estreladas do Pâncreas/patologia , Pancreatite Crônica/genética , Pancreatite Crônica/patologia , Fenantrenos/farmacologia , Fator de Transcrição RelA/metabolismo , Fator de Crescimento Transformador beta/farmacologiaRESUMO
Pancreatic stellate cells (PSCs) have been recognized as key mediators of pancreatic fibrosis, a characteristic feature of chronic pancreatitis (CP). As a cullin-based E3 ubiquitin ligase, speckle-type POZ protein (SPOP) has been identified to participate in tumorigenesis and organ development. However, its biological role in CP remains unknown. Therefore, this study sought to investigate the changed expression of SPOP in CP and to examine the effect on mice PSCs activation of SPOP. We found that SPOP was downregulated in the pancreatic tissues of cerulein-induced CP mice. siRNA-mediated knockdown of SPOP led to significant promotion in primary PSCs activity by activating the nuclear factor-kappaB (NF-κB)/interleukin-6 (IL-6) signaling pathway. In addition, we examined the effects of Fas-associated death domain (FADD), a proven SPOP substrate that activates NF-κB, on the regulation of PSCs activation. We found that FADD was downregulated by SPOP via interaction-mediated degradation, and was upregulated during PSCs activation. The promotion of PSCs activation in knocking down SPOP with siSPOP-1 were counteracted by knocking down FADD. The results suggest that the SPOP-induced inhibition of PSCs activation partially depended on FADD. These results highlight the importance of SPOP in CP and provide a potential target for therapeutic intervention.
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Ceruletídeo/farmacologia , Proteína de Domínio de Morte Associada a Fas/metabolismo , Pâncreas/metabolismo , Células Estreladas do Pâncreas/metabolismo , Células Estreladas do Pâncreas/fisiologia , Pancreatite Crônica/induzido quimicamente , Pancreatite Crônica/metabolismo , Animais , Células Cultivadas , Domínio de Morte/efeitos dos fármacos , Domínio de Morte/fisiologia , Regulação para Baixo/efeitos dos fármacos , Fibrose/metabolismo , Interleucina-6/metabolismo , Camundongos , NF-kappa B/metabolismo , Pâncreas/fisiologia , Células Estreladas do Pâncreas/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacosRESUMO
BACKGROUND: Accurate and early prognosis of disease is essential to clinical decision making, particularly in diseases, such as HCC, that are typically diagnosed at a late stage in the course of disease and therefore carry a poor prognosis. CDCA5 is a cell cycle regulatory protein that has shown prognostic value in several cancers. METHODS: We retrospectively evaluated 178 patients with HCC treated with curative liver resection between September 2009 and September 2012 at Nanchong Central Hospital in Nanchong, Sichuan Province, China. Patients were screened for their CDCA5 expression levels and assigned to either the high or low expression group. Patient demographics, comorbidities, clinicopathologic data, such as tumor microvascular invasion status and size, and long-term outcomes were compared between the two groups. The effect of CDCA5 on the proliferation of liver cancer cells was analyzed using in vitro and in vivo assays. RESULTS: The present study found that increased CDCA5 expression was associated with increased tumor diameter and microvascular invasion in HCC. It was also found that CDCA5 overexpression may be associated with liver cancer cells. Additionally, this study confirmed that CDCA5 expression was increased in HCC tissue versus normal liver tissue, that CDCA5 expression was associated with decreased survival and that CDCA5 knockdown using shRNA led to cell cycle arrest in the G2/M phase. CONCLUSIONS: These findings suggest that CDCA5 expression is associated with poor prognosis in patients with hepatocellular carcinoma.
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Proteínas Adaptadoras de Transdução de Sinal/genética , Biomarcadores Tumorais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidade , Proteínas de Ciclo Celular/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Animais , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Ciclo Celular , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Xenoenxertos , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Masculino , Camundongos , Pessoa de Meia-IdadeRESUMO
The objective of this study was to evaluate the feasibility, safety, and effectiveness of intravenous stem cell delivery utilizing ultrasound-targeted microbubble destruction (UTMD) in a rat model of middle cerebral artery occlusion (MCAO), while investigating the underlying mechanisms. Acute cerebral infarction (ACI) was induced surgically in adult rats to create the MCAO rat model. Intravenous injection of SonoVue microbubbles and bone marrow-derived mesenchymal stem cells (BMSC) was performed concurrently, with or without ultrasound targeting the stroke. The animals were divided into four groups: sham-operated group, ACI-MCAO rats treated with phosphate-buffered saline (ACI+PBS), rats receiving intravenous delivery of BMSC expressing green fluorescent protein (GFP-BMSC; ACI+BMSC), and rats receiving intravenous GFP-BMSC with simultaneous UTMD exposure (ACI+BMSC+UTMD). The efficacy of the treatments was assessed by evaluating the animals' neurological function using the Longa score and examining histopathological changes such as cerebral infarct volume, cerebral edema, and cell apoptosis. A rat cytokine array was utilized to identify the potential cytokines that may be responsible for the therapeutic effect of UTMD-mediated BMSC treatment. Optimal UTMD parameters resulted in an increase in blood-brain barrier (BBB) permeability after 30 min, which returned to baseline 72 h later without causing any residual injury. UTMD application significantly increased the homing of intravenously delivered BMSC, resulting in a 2.2-fold increase in GFP-BMSC cell count on day 3 and a 2.6-fold increase on day 7 compared with intravenous delivery alone. This effect persisted for up to 6 weeks after injection. Intravenous BMSC delivery significantly reduced the volume of cerebral infarct and decreased cerebral edema, leading to a lower Longa score. Furthermore, this effect was further enhanced by UTMD. Acute cerebral infarction induced by MCAO led to elevated matrix metalloproteinase 8 (MMP8) levels in the cerebrospinal fluid, which were significantly reduced following UTMD-mediated BMSC treatment. Ultrasound-targeted microbubble destruction facilitates the migration and homing of BMSC into the brain, possibly by transiently increasing blood-brain barrier (BBB) permeability, thereby improving therapeutic outcomes in an ACI rat model. The observed effect may be partly attributed to modulation of MMP8 levels.Advances in knowledge: UTMD-mediated intravenously delivered BMSC transplantation led to a significant increase in cell homing and reduction of MMP8 levels, resulting in increased therapeutic effect in an acute ischemic cerebral infarction model.
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Edema Encefálico , Isquemia Encefálica , Acidente Vascular Cerebral , Animais , Ratos , Barreira Hematoencefálica , Metaloproteinase 8 da Matriz , Microbolhas , Acidente Vascular Cerebral/terapia , Infarto Cerebral , Células-TroncoRESUMO
Pancreatic cancer (PaCa) is a hypovascular type of tumor and is not very responsive to conventional chemotherapy due to the problem of low drug accumulation. Recent advancements in ultrasound targeted microbubble destruction (UTMD) have improved drug delivery into target tissues. UTMD operates via microbubble interaction with vascular endothelial cells; however, the molecular mechanism and interrelationship in the PaCa microenvironment remain enigmatic. Tumor-associated macrophages (TAMs) have different phenotypes and regulate tumorigenesis. Using a PaCa orthotopic model, we established that UTMD improved chemotherapy by redirecting TAM polarization from M2 macrophages to tumor-inhibiting M1 macrophages, remodeling vessel normalization, and inducing anti-tumor immune responses. Tumor vascular maturity and function were also improved, and an insignificant change in vascular density resulting in enhanced blood perfusion and inhibited tumor growth and metastasis were observed. Therefore, this research unveils the crucial role of TAM polarization on UTMD-induced tumor vessel normalization and inhibition of tumor progression. These findings offer a novel insight into UTMD-mediated drug delivery for anti-tumor and anti-angiogenic treatment.
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Células Endoteliais , Neoplasias Pancreáticas , Humanos , Microbolhas , Neoplasias Pancreáticas/tratamento farmacológico , Macrófagos , Microambiente Tumoral , Neoplasias PancreáticasRESUMO
Previous retrospective studies have suggested that surufatinib is effective for treating advanced solid tumors; however, the efficacy and safety of this drug needs to be investigated further via high-quality evidence or randomized controlled trials. In the present study, a meta-analysis was carried out to evaluate the safety and effectiveness of surufatinib for patients with advanced solid tumors. Systematic, electronic literature searches were conducted using PubMed, EMBASE, Cochrane Library and ClinicalTrials.gov. The disease control rate (DCR) of surufatinib in solid tumors was 86% [effect size (ES), 0.86; 95% confidence interval (CI), 0.82-0.90; I2=34%; P=0.208] and the objective response rate was 16% (ES, 0.16; 95% CI, 0.12-0.21; I2=48%; P=0.103), while the progressive disease rate was only 9% (ES, 0.09; 95% CI, 0.05-0.15; I2=68%, P=0.014). Surufatinib showed different degrees of adverse reactions during the treatment of solid tumors. Among these adverse events, the incidence of increased levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were 24% (ES, 0.24; 95% CI, 0.18-0.30; I2=45.1%; P=0.141) and 33% (ES, 0.33; 95%CI, 0.28-0.38; I2=63.9%; P=0.040), respectively. In the placebo-controlled trial, the relative risks (RRs) of elevated AST and ALT were 1.04 (95% CI, 0.54-2.02; I2=73.3%; P=0.053) and 0.84 (95% CI, 0.57-1.23; I2=0%; P=0.886), respectively. Overall, surufatinib was characterized by a high DCR and a low disease progression rate, thus indicating that it could exert a good therapeutic effect on solid tumors. Additionally, surufatinib showed a lower RR for adverse effects compared with other treatment modalities.
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Introduction: Glioma is the most common primary brain tumor and primary malignant tumor of the brain in clinical practice. Conventional treatment has not significantly altered the prognosis of patients with glioma. As research into immunotherapy continues, glioma immunotherapy has shown great potential. Methods: The clinical data were acquired from the Chinese Glioma Genome Atlas (CGGA) database and validated by the Gene Expression Omnibus (GEO) database, The Cancer Genome Atlas (TCGA) dataset, Clinical Proteomic Tumor Analysis Consortium (CPTAP) database, and Western blot (WB) analysis. By Cox regression analyses, we examined the association between different variables and overall survival (OS) and its potential as an independent prognostic factor. By constructing a nomogram that incorporates both clinicopathological variables and the expression of URB2, we provide a model for the prediction of prognosis. Moreover, we explored the relationship between immunity and URB2 and elucidated its underlying mechanism of action. Results: Our study shows that URB2 likely plays an oncogenic role in glioma and confirms that URB2 is a prognostic independent risk factor for glioma. Furthermore, we revealed a close relationship between immunity and URB2, which suggests a new approach for the immunotherapy of glioma. Conclusion: URB2 can be used for prognosis prediction and immunotherapy of glioma.
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Liver fibrosis refers to the excessive buildup of extracellular matrix (ECM) components in liver tissue. It is considered a pathological response to liver damage for which there is no effective treatment. Aloin, an anthraquinone compound isolated from the aloe plant, has shown good pharmacological effects in the treatment of gastric cancer, ulcerative colitis, myocardial hypertrophy, traumatic brain injury, and other diseases; however, its specific impact on liver fibrosis remains unclear. To address this gap, we conducted a study to explore the mechanisms underlying the potential antifibrotic effect of aloin. We constructed a mouse liver fibrosis model using carbon tetrachloride (CCl4) dissolved in olive oil as a modeling drug. Additionally, a cellular model was developed by using transforming growth factor ß1 (TGF-ß1) as a stimulus applied to hepatic stellate cells. After aloin intervention, serum alanine aminotransferase, hepatic hydroxyproline, and serum aspartate aminotransferase were reduced in mice after aloin intervention compared to CCl4-mediated liver injury without aloin intervention. Aloin relieved the oxidative stress caused by CCl4 via reducing hepatic malondialdehyde in liver tissue and increasing the level of superoxide dismutase. Aloin treatment decreased interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α and increased the expression of IL-10, which inhibited the inflammatory response in liver injury. In addition, aloin inhibited the activation of hepatic stellate cells and reduced the level of α-smooth muscle actin (α-SMA) and collagen type I. In cell and animal experiments, aloin attenuated liver fibrosis, acting through the TGF-ß/Smad2/3 signaling pathway, and mitigated CCl4- and TGF-ß1-induced inflammation. Thus, the findings of this study provided theoretical data support and a new possible treatment strategy for liver fibrosis.
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Proteínas Smad , Fator de Crescimento Transformador beta1 , Camundongos , Animais , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Proteínas Smad/genética , Proteínas Smad/metabolismo , Proteínas Smad/farmacologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/genética , Fígado/metabolismo , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/metabolismo , Estresse Oxidativo , Modelos Animais de Doenças , Tetracloreto de Carbono/efeitos adversos , Tetracloreto de Carbono/metabolismo , Células Estreladas do FígadoRESUMO
OBJECTIVE: To characterize non-mass breast lesions (NML) quantitatively by contrast-enhanced ultrasound (CEUS) and to evaluate its additional diagnostic value based on the Breast Imaging Reporting and Data System (BI-RADS) categories. METHODS: A prospective study was performed among consecutive patients with NMLs. All lesions were examined by grayscale ultrasound and CEUS and diagnosed on pathology. Standard mammograms were obtained in the patients over 30 years old. Three independent radiologists assessed the features on grayscale ultrasound and mammograms and classified NMLs according to BI-RADS categories. Combined with the quantitative analysis in CEUS, the BI-RADS categories were reassessed, and the sensitivity, specificity, positive-predictive value, negative-predictive value and area under the receiver operating characteristic curve (AUC) were calculated for the evaluation of the diagnostic performance. RESULTS: 30 benign and 24 malignant NMLs were finally enrolled in this study, with ductal carcinoma in situ being the majority of malignant (15/24). Average contrast signal intensity (AI), wash-in rate (WiR) and enhancement intensity at 40 s (I40) were found to be the most efficient kinetic parameters to diagnose malignant NMLs. Combined with the cut-off values of 205.2 for AI, 127.8 for WiR and 136.4 for I40, the diagnostic accuracy was improved (AUC = 0.904), with the sensitivity of 95.8% and the specificity of 70.0%. CONCLUSION: The results suggested that hyperenhancement and rapid wash-in and wash-out are the characteristics of malignant NMLs. The kinetic analysis using CEUS can reflect hypervascular nature of malignant NMLs, thus improving the diagnostic performance combined with grayscale ultrasound. ADVANCES IN KNOWLEDGE: In this study, we quantified the enhancement characteristics of non-mass breast lesions with CEUS. We revealed that the combination of CEUS and conventional ultrasound provided higher sensitivity for diagnosing malignant NMLs.
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Neoplasias da Mama , Ultrassonografia Mamária , Feminino , Humanos , Adulto , Ultrassonografia Mamária/métodos , Estudos Prospectivos , Cinética , Meios de Contraste , Mama/diagnóstico por imagem , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Sensibilidade e Especificidade , Estudos RetrospectivosRESUMO
Hepatocellular carcinoma (HCC) is a common malignancy that is driven by multiple genes and pathways. The aim of this study was to investigate the role and specific mechanism of the actin-interacting protein zyxin (ZYX) in HCC. We found that the expression of ZYX was significantly higher in HCC tissues compared to that in normal liver tissues. In addition, overexpression of ZYX in hepatoma cell lines (PLC/PRF/5, HCCLM3) enhanced their proliferation, migration and invasion, whereas ZYX knockdown had the opposite effects (SK HEP-1, Huh-7). Furthermore, the change in the expression levels of ZYX also altered that of proteins related to cell cycle, migration and invasion. Similar results were obtained with xenograft models. The AKT/mTOR signaling pathway is one of the key mediators of cancer development. While ZYX overexpression upregulated the levels of phosphorylated AKT/mTOR proteins, its knockdown had the opposite effect. In addition, the AKT inhibitor MK2206 neutralized the pro-oncogenic effects of ZYX on the HCC cells, whereas the AKT activator SC79 restored the proliferation, migration and invasion of HCC cells with ZYX knockdown. Taken together, ZYX promotes the malignant progression of HCC by activating AKT/mTOR signaling pathway, and is a potential therapeutic target in HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Zixina , Humanos , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Hepáticas/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/metabolismo , Zixina/metabolismoRESUMO
PURPOSE: Familial celiac disease syndrome (FCS) is a form of hypertriglyceridemia (HTG) caused by the accumulation of celiac particles. Currently, volanesorsen is considered to be used to treat patients with FCS and HTG to improve symptoms. To evaluate the effect of volanesorsen on lipid metabolism in patients with FCS, we performed a systematic evaluation and meta-analysis. METHODS: A systematic search of PubMed, Embase, ClinicalTrials.gov, and the Cochrane Library was conducted, and the bibliographies of original articles were checked manually. The quality of the studies was assessed using the Cochrane Risk of Bias tool. RESULTS: Four randomized, controlled trials involving 246 patients were analyzed in this study. Patients treated with volanesorsen showed (MD = -78.85%; 95% CI = -96.04 to -61.65, P = 0.67, I2 = 0%) decrease in TG and (MD = -80.08%; 95% CI = -90.02 to -71.54, P = 0.25, I2 = 29%) decrease in ApoC-III levels compared to patients in the placebo group showing a significant decrease. In addition, HDL-C increased (MD = 46.01% 95% CI = 41.03 to 50.99, P = 0.41, I2 = 0%), NHDL-C decreased (MD = -32.12%; 95% CI = -44.39 to -19.85, P = 0.11, I2 = 55%), VLDL-C decreased (MD = -65.88%; 95% CI = -83.97 to -47.79, P = 0.71, I2 = 0%), apo A1 increased (MD = 13.12%; 95% CI = 7.83 to 18.40, P = 0.72, I2 = 0%), and apoB increased (MD = 7.94 %; 95% CI = -1.90 to 17.78, P = 0.54, I2 = 0%) all suggest that volanesorsen has an overall FCS with a therapeutic effect. However, LDL-C increased (MD = 99.59%; 95% CI = 69.19 to 130.00, P = 0.61, I2 = 0%) and apo B48 decreased (MD = 82.89%; 95% CI = -100.88 to -64.91, P = 0.42, I2 = 0%), showing an inverse effect, suggesting that volanesorsen's did not target all proteins of lipid metabolism.
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Hipertrigliceridemia , Oligonucleotídeos , Apolipoproteína C-III/metabolismo , Humanos , Hipertrigliceridemia/tratamento farmacológico , Oligonucleotídeos/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , TriglicerídeosRESUMO
The purpose of this study is to investigate the protective effect of kaempferol (KAE), the main active monomer from Penthorum chinense Pursh, on hepatic ischemia/reperfusion injury (HI/RI) and its specific mechanism. HI/RI is a common complication closely related to the prognosis of liver surgery, and effective prevention and treatment methods are still unavailable. Ischemia/reperfusion (I/R) injury is caused by tissue damage during ischemia and sustained oxidative stress and inflammation during reperfusion. Penthorum chinense Pursh is a traditional Chinese medicine widely used to treat liver disease since ancient times. Kaempferol (KAE), a highly purified flavonoid active monomer isolated and extracted from Penthorum chinense Pursh, was investigated for its protective effect on HI/RI. Our study indicates that KAE pretreatment alleviated I/R-induced transaminase elevation and pathological changes. Further analysis revealed that KAE pretreatment attenuates I/R-induced oxidative stress (as measured by the content of MDA, SOD and GSH) in vivo and reduces hypoxia/reoxygenation (H/R) -induced reactive oxygen species (ROS) generation in vitro. Meanwhile, KAE inhibits activation of NF-κB/p65 and reduces the release of pro-inflammatory factors (TNF-α and IL-6) to protect the liver from I/R-induced inflammation. Nuclear erythroid 2-related factor 2 (Nrf2) is a crucial cytoprotection regulator because it induces anti-inflammatory, antioxidant, and cytoprotective genes. Therefore, we analyzed the protein levels of Nrf2 and its downstream heme oxygenase-1 (HO-1) in the liver of mice and hepatocytes of humankind, respectively, and discovered that KAE pretreatment activates the Nrf2/HO-1 signaling pathway. In summary, this study confirmed the hepatoprotective effect of KAE on HI/RI, which inhibits oxidative stress and inflammation by activating the Nrf2/HO-1 signaling pathway.
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Glioma is the most common malignant intracranial tumor and exhibits diffuse metastasis and a high recurrence rate. The invasive property of glioma results from cell detachment. Anoikis is a special form of apoptosis that is activated upon cell detachment. Resistance to anoikis has proven to be a protumor factor. Therefore, it is suggested that anoikis resistance commonly occurs in glioma and promotes diffuse invasion. Several factors, such as integrin, E-cadherin, EGFR, IGFR, Trk, TGF-ß, the Hippo pathway, NF-κB, eEF-2 kinase, MOB2, hypoxia, acidosis, ROS, Hsp and protective autophagy, have been shown to induce anoikis resistance in glioma. In our present review, we aim to summarize the underlying mechanism of resistance and the therapeutic potential of these molecules.
RESUMO
BACKGROUND: As a major metabolic site, the liver is an important target organ of endotoxemia. High serum lipopolysaccharide (LPS) levels can cause hepatocyte necrosis and produce cholestasis, which results in severe liver injury. Contrastingly, thiamine (THA) has shown anti-inflammatory effects against severe infections and may be indicated for systemic endotoxemia treatment. Therefore, the present study was conducted to investigate the effective treatment of endotoxemia-induced liver injury with THA and the possible molecular mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: in vivo, We established two models of endotoxemia-induced liver injury at the in vivo level using LPS and bile duct ligation (BDL) + LPS, administering prophylactic THA intraperitoneally to mice. In vitro, the effects of THA on RAW264.7 and THP-1 administration of LPS-induced inflammatory macrophage activation were observed. Metabolomic analysis screening and subsequent validation experiments were also performed. THA has different degrees of preventive therapeutic effects on different causes of endotoxemia-induced liver injury, as evidenced by a decreased alanine aminotransferase (ALT) and decreased inflammatory factors. This study aimed to clarify the specific mechanism. We subsequently found that THA reduced the inflammatory macrophages produced by RAW264.7 and THP-1 in response to LPS. Additionally, THA reduced galactose liver accumulation and improved glucose metabolism. Moreover, Galectin-3 (Gal-3), as a point of interaction between macrophage activation and galactose metabolism mechanisms, was observed to inhibit Gal-3 expression by THA at both in vivo and in vitro levels. CONCLUSIONS: This study revealed that THA may be a viable prophylactic treatment option for the prevention of liver injury occurring in endotoxemia, which is associated with its effects on the modulation of Gal-3 to improve the inflammatory response and the inhibition of galactose metabolism. Additional evidence is provided for its clinical application.
Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas , Colestase , Endotoxemia , Animais , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Colestase/complicações , Endotoxemia/tratamento farmacológico , Galactose/metabolismo , Lipopolissacarídeos/farmacologia , Fígado , Ativação de Macrófagos , Camundongos , Tiamina/metabolismo , Tiamina/farmacologia , Tiamina/uso terapêuticoRESUMO
The purpose of this study is to investigate the protective effect of γ-oryzanol (ORY) against hepatic ischemia reperfusion (HIR) injury and the potential protective mechanisms of ORY. ORY is an important biologically active ingredient isolated from rice bran oil, which has anti-inflammatory and antiapoptotic effects. However, it is still unknown whether ORY can protect the liver from the HIR damage. In this study, ORY was administered orally for seven days, after which the animals were subjected to liver ischemia for 60 minutes and reperfused for 6 hours. Related indicators were analyzed. The results showed that ORY pretreatment significantly reduced the levels of AST and ALT, relieved hepatocellular damage and apoptosis, and attenuated the exhaustion of SOD and GSH and accumulation of MDA and MPO. Interestingly, ORY treatment could significantly decreased ER stress. Furthermore, ORY pretreatment remarkably reduced the protein expressions of HMGB1, NLRP3, caspase-1 (p20), and IL-1ß to protect the liver from I/R-induced inflammasome activation and apoptosis. In conclusion, we demonstrated the potential effect of ORY in modulating oxidative stress, endoplasmic reticulum stress, and inflammasome activation during HIR.