Impact of sarcopenia on postoperative outcomes after hepatectomy in older patients with intrahepatic cholangiocarcinoma: A multicentre cohort study.

BACKGROUND AND AIMS: Sarcopenia is associated with poor prognosis, but its role in older patients with intrahepatic cholangiocarcinoma (ICC) is unclear. We aimed to evaluate the impact of sarcopenia on the prognosis of older patients with ICC undergoing hepatectomy. METHODS: A total of 363 patients with ICC following hepatectomy from 2015 to 2021 were retrospectively reviewed at five institutions. Sarcopenia was evaluated using skeletal muscle index by computed tomography images. Patients were divided into four subgroups according to sarcopenia and age. Postoperative outcomes including complication, overall survival (OS) and recurrence-free survival (RFS) were evaluated. Risk factors were identified through univariate and multivariate Cox regression analyses. RESULTS: 302 patients were included in the analysis. The median age was 63 years and there were 128 patients (42.4%) aged over 65 years. 192 patients (63.6%) were diagnosed with sarcopenia, while 180 patients (59.6%) experienced myosteatosis. Older patients experienced a higher incidence of sarcopenia and myosteatosis, and worse postoperative outcomes than younger patients. In the subgroup of patients with sarcopenia, older patients experienced a significant shorter OS than younger patients, which was not observed in patients without sarcopenia. According to the multivariate Cox regression analysis, lymphatic metastasis (p < .001), blood transfusion (p = .004), low serum albumin (p = .051), sarcopenia (p = .024), and myosteatosis (p = .004) were identified as independent risk factors of OS in older patients, meanwhile tumour size (p = .013) and lymphatic metastasis (p < .001) were independent risk factors of RFS. CONCLUSIONS: Sarcopenia and myosteatosis have a significant adverse impact on postoperative outcomes in older patients with ICC undergoing hepatectomy.

Machine learning radiomics to predict the early recurrence of intrahepatic cholangiocarcinoma after curative resection: A multicentre cohort study.

PURPOSE: Postoperative early recurrence (ER) leads to a poor prognosis for intrahepatic cholangiocarcinoma (ICC). We aimed to develop machine learning (ML) radiomics models to predict ER in ICC after curative resection. METHODS: Patients with ICC undergoing curative surgery from three institutions were retrospectively recruited and assigned to training and external validation cohorts. Preoperative arterial and venous phase contrast-enhanced computed tomography (CECT) images were acquired and segmented. Radiomics features were extracted and ranked through their importance. Univariate and multivariate logistic regression analysis was used to identify clinical characteristics. Various ML algorithms were used to construct radiomics-based models, and the predictive performance was evaluated by receiver operating characteristic curves, calibration curves, and decision curve analysis. RESULTS: 127 patients were included for analysis: 90 patients in the training set and 37 patients in the validation set. Ninety-two patients (72.4%) experienced recurrence, including 71 patients exhibiting ER. Male sex, microvascular invasion, TNM stage, and serum CA19-9 were identified as independent risk factors for ER, with the corresponding clinical model having a poor predictive performance (AUC of 0.685). Fifty-seven differential radiomics features were identified, and the 10 most important features were utilized for modelling. Seven ML radiomics models were developed with a mean AUC of 0.87 ± 0.02, higher than the clinical model. Furthermore, the clinical-radiomics models showed similar predictive performance to the radiomics models (AUC of 0.87 ± 0.03). CONCLUSION: ML radiomics models based on CECT are valuable in predicting ER in ICC.

Up-regulation of PPAR-γ involved in the therapeutic effect of icariin on cigarette smoke-induced inflammation.

Icariin (ICA) might be a potential anti-inflammatory medication in a variety of diseases including COPD, and previous studies showed that ICA could attenuate cigarette smoke (CS)-induced inflammation by inhibiting nuclear factor (NF)-κB. Peroxisome proliferator-activated receptor (PPAR) γ, a nuclear hormone receptor, has been reported to play a critical role in the inflammatory process in COPD. Whether PPAR-γ is involved in the anti-inflammatory effect of icariin on COPD has scarcely been explored. This study aimed at investigating the role of ICA in PPAR-γ expression in the CS-induced model, and then elucidating the therapeutic effects of ICA on COPD based on the PPARγ-NF-κB signaling pathway. The Beas-2B cells and H292 cells were induced with cigarette smoke extract (CSE) for 8 h after treatment with ICA for 16 h. The PPARγ expression and NF-κB pathway-related indicators were detected by western blotting, cellular immunofluorescence, and Real-time PCR. The PPARγ knock down or T0070907-treated Beas-2B cells were constructed to further investigate the relationship between the inhibition of NF-κB by ICA and PPARγ. A COPD model was established by CS exposure for 6 months, and ICA (40 mg/kg) was administrated by gastric perfusion. Then, the pulmonary function, lung histology, inflammatory cytokine levels, and protein expressions were detected. We found ICA up-regulated PPARγ protein expression in both Beas-2B cells and H292 cells, and it improved CSE-induced PPARγ down regulation and NF-κB activation. Furthermore, the inhibition of NF-κB pathway by ICA was partially dependent on PPARγ in the PPARγ knock down or T0070907-treated Beas-2B cells, suggesting that ICA attenuated CSE-induced inflammatory responses were associated with modulating the PPARγ-NF-κB pathway. Moreover, ICA showed similar effects on PPARγ and NF-κB expressions in the COPD model, and it effectively ameliorated the pulmonary function and lung inflammatory infiltration in the COPD rat model. Conclusively, the therapeutic effect of ICA on COPD was indirectly achieved by reducing airway inflammation, which was partially associated with modulating the PPARγ-NF-κB signaling pathway.

Inhibitor of Differentiation 1 (Id1) in Cancer and Cancer Therapy.

The inhibitor of DNA binding (Id) proteins are regulators of cell cycle and cell differentiation. Of all Id family proteins, Id1 is mostly linked to tumorigenesis, cellular senescence as well as cell proliferation and survival. Id1 is a stem cell-like gene more than a classical oncogene. Id1 is overexpressed in numerous types of cancers and exerts its promotion effect to these tumors through different pathways. Briefly, Id1 was found significantly correlated with EMT-related proteins, K-Ras signaling, EGFR signaling, BMP signaling, PI3K/Akt signaling, WNT and SHH signaling, c-Myc signaling, STAT3 signaling, RK1/2 MAPK/Egr1 pathway and TGF-ß pathway, etc. Id1 has potent effect on facilitating tumorous angiogenesis and metastasis. Moreover, high expression of Id1 plays a facilitating role in the development of drug resistance, including chemoresistance, radiation resistance and resistance to drugs targeting angiogenesis. However, controversial results were also obtained. Overall, Id1 represent a promising target of anti-tumor therapeutics based on its potent promotion effect to cancer. Numerous drugs were found exerting their anti-tumor function through Id1-related signaling pathways, such as fucoidan, berberine, tetramethylpyrazine, crizotinib, cannabidiol and vinblastine.

Baicalein enhances the antitumor efficacy of docetaxel on nonsmall cell lung cancer in a ß-catenin-dependent manner.

The side effects of docetaxel have limited its antitumor performances in the treatment of nonsmall cell lung cancer (NSCLC). To address the problem, baicalein, a bioactive flavone that exhibits antitumor activity, was combined with docetaxel so as to achieve better efficacy and lower toxicity. The combination treatment enhanced the stabilization of microtubules and halted the cell-cycle progression, thus synergistically inhibiting the proliferation and inducing the apoptosis of A549 cells and Lewis lung carcinoma cells. The decreased expression of Cyclin-dependent kinase 6 and Cyclin B1 confirmed its regulation in cell cycle, with ß-catenin being an important upstream effector, as evidenced by the decreased expression in the cytoplasm and nucleus as well as the attenuated aggregation in the nucleus. Furthermore, baicalein plus docetaxel evinced better antitumor efficacy by the suppressed tumor growth, increased apoptosis, and decreased tumor angiogenesis in vivo, with no increased toxicity discovered in both tumor-bearing and non-tumor-bearing mice, and an improvement in therapeutic index. This study has demonstrated that baicalein plus docetaxel is an appropriate combination simultaneously with augmented antitumor efficacy and acceptable safety, which might be a promising strategy for patients with advanced NSCLC.

Dual role of autophagy/mitophagy in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a common lung disease characterised by progressive, irreversible airflow limitation. Multiple regulatory pathways are involved in COPD pathogenesis. Emerging evidence from clinical and basic medical research has suggested that autophagy-a highly conserved catabolic process mediated under various cellular stress conditions-plays a role in the development and prognosis of COPD. Nevertheless, precise function of autophagy remains debatable owing to its beneficial as well as detrimental consequences. In this review, we summarised the 'double-edged sword' functions of autophagy in COPD and aimed to distinguish and classify these functions on the basis of various factors, such as different airway cell types and autophagy stimulators and modulators. Moreover, we determined the biological-functional consequences of autophagy. In particular, we discussed mitophagy-also termed mitochondrial autophagy-which is a critical process in cellular energy homeostasis. We hope that our findings will shed new light on future therapeutic strategies for COPD.

Development of sarcopenia-based nomograms predicting postoperative complications of benign liver diseases undergoing hepatectomy: A multicenter cohort study.

Background: Sarcopenia has a remarkable negative impact on patients with liver diseases. We aimed to evaluate the impact of preoperative sarcopenia on the short-term outcomes after hepatectomy in patients with benign liver diseases. Methods: A total of 558 patients with benign liver diseases undergoing hepatectomy were prospectively reviewed. Both the muscle mass and strength were measured to define sarcopenia. Postoperative outcomes including complications, major complications and comprehensive complication index (CCI) were compared among four subgroups classified by muscle mass and strength. Predictors of complications, major complications and high CCI were identified by univariate and multivariate logistic regression analysis. Nomograms based on predictors were constructed and calibration cures were performed to verify the performance. Results: 120 patients were involved for analysis after exclusion. 33 patients were men (27.5%) and the median age was 54.0 years. The median grip strength was 26.5 kg and the median skeletal muscle index (SMI) was 44.4 cm2/m2. Forty-six patients (38.3%) had complications, 19 patients (15.8%) had major complications and 27 patients (22.5%) had a CCI ≥ 26.2. Age (p = 0.005), SMI (p = 0.005), grip strength (p = 0.018), surgical approach (p = 0.036), and operation time (p = 0.049) were predictors of overall complications. Child-Pugh score (p = 0.037), grip strength (p = 0.004) and surgical approach (p = 0.006) were predictors of major complications. SMI (p = 0.047), grip strength (p < 0.001) and surgical approach (p = 0.014) were predictors of high CCI. Among the four subgroups, patients with reduced muscle mass and strength showed the worst short-term outcomes. The nomograms for complications and major complications were validated by calibration curves and showed satisfactory performance. Conclusion: Sarcopenia has an adverse impact on the short-term outcomes after hepatectomy in patients with benign liver diseases and valuable sarcopenia-based nomograms were constructed to predict postoperative complications and major complications.

Machine Learning to Predict the Response to Lenvatinib Combined with Transarterial Chemoembolization for Unresectable Hepatocellular Carcinoma.

BACKGROUND: Lenvatinib and transarterial chemoembolization (TACE) are first-line treatments for unresectable hepatocellular carcinoma (HCC), but the objective response rate (ORR) is not satisfactory. We aimed to predict the response to lenvatinib combined with TACE before treatment for unresectable HCC using machine learning (ML) algorithms based on clinical data. METHODS: Patients with unresectable HCC receiving the combination therapy of lenvatinib combined with TACE from two medical centers were retrospectively collected from January 2020 to December 2021. The response to the combination therapy was evaluated over the following 4-12 weeks. Five types of ML algorithms were applied to develop the predictive models, including classification and regression tree (CART), adaptive boosting (AdaBoost), extreme gradient boosting (XGBoost), random forest (RF), and support vector machine (SVM). The performance of the models was assessed by the receiver operating characteristic (ROC) curve and area under the receiver operating characteristic curve (AUC). The Shapley Additive exPlanation (SHAP) method was applied to explain the model. RESULTS: A total of 125 unresectable HCC patients were included in the analysis after the inclusion and exclusion criteria, among which 42 (33.6%) patients showed progression disease (PD), 49 (39.2%) showed stable disease (SD), and 34 (27.2%) achieved partial response (PR). The nonresponse group (PD + SD) included 91 patients, while the response group (PR) included 34 patients. The top 40 most important features from all 64 clinical features were selected using the recursive feature elimination (RFE) algorithm to develop the predictive models. The predictive power was satisfactory, with AUCs of 0.74 to 0.91. The SVM model and RF model showed the highest accuracy (86.5%), and the RF model showed the largest AUC (0.91, 95% confidence interval (CI): 0.61-0.95). The SHAP summary plot and decision plot illustrated the impact of the top 40 features on the efficacy of the combination therapy, and the SHAP force plot successfully predicted the efficacy at the individualized level. CONCLUSIONS: A new predictive model based on clinical data was developed using ML algorithms, which showed favorable performance in predicting the response to lenvatinib combined with TACE for unresectable HCC. Combining ML with SHAP could provide an explicit explanation of the efficacy prediction.

Predicting very early recurrence in intrahepatic cholangiocarcinoma after curative hepatectomy using machine learning radiomics based on CECT: A multi-institutional study.

BACKGROUND: Even after curative resection, the prognosis for patients with intrahepatic cholangiocarcinoma (iCCA) remains disappointing due to the extremely high incidence of postoperative recurrence. METHODS: A total of 280 iCCA patients following curative hepatectomy from three independent institutions were recruited to establish the retrospective multicenter cohort study. The very early recurrence (VER) of iCCA was defined as the appearance of recurrence within 6 months. The 3D tumor region of interest (ROI) derived from contrast-enhanced CT (CECT) was used for radiomics analysis. The independent clinical predictors for VER were histological stage, AJCC stage, and CA199 levels. We implemented K-means clustering algorithm to investigate novel radiomics-based subtypes of iCCA. Six types of machine learning (ML) algorithms were performed for VER prediction, including logistic, random forest (RF), neural network, bayes, support vector machine (SVM), and eXtreme Gradient Boosting (XGBoost). Additionally, six clinical ML (CML) models and six radiomics-clinical ML (RCML) models were developed to predict VER. Predictive performance was internally validated by 10-fold cross-validation in the training cohort, and further evaluated in the external validation cohort. RESULTS: Approximately 30 % of patients with iCCA experienced VER with extremely discouraging outcome (Hazard ratio (HR) = 5.77, 95 % Confidence Interval (CI) = 3.73-8.93, P < 0.001). Two distinct iCCA subtypes based on radiomics features were identified, and subtype 2 harbored a higher proportion of VER (47.62 % Vs 25.53 %) and significant shorter survival time than subtype 1. The average AUC values of the CML and RCML models were 0.744 ± 0.018, and 0.900 ± 0.014 in the training cohort, and 0.769 ± 0.065 and 0.929 ± 0.027 in the external validation cohort, respectively. CONCLUSION: Two radiomics-based iCCA subtypes were identified, and six RCML models were developed to predict VER of iCCA, which can be used as valid tools to guide individualized management in clinical practice.

Prediction of Response to Lenvatinib Monotherapy for Unresectable Hepatocellular Carcinoma by Machine Learning Radiomics: A Multicenter Cohort Study.

PURPOSE: We aimed to construct machine learning (ML) radiomics models to predict response to lenvatinib monotherapy for unresectable hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: Patients with HCC receiving lenvatinib monotherapy at three institutions were retrospectively identified and assigned to training and external validation cohorts. Tumor response after initiation of lenvatinib was evaluated. Radiomics features were extracted from contrast-enhanced CT images. The K-means clustering algorithm was used to distinguish radiomics-based subtypes. Ten ML radiomics models were constructed and internally validated by 10-fold cross-validation. These models were subsequently verified in an external validation cohort. RESULTS: A total of 109 patients were identified for analysis, namely, 74 in the training cohort and 35 in the external validation cohort. Thirty-two patients showed partial response, 33 showed stable disease, and 44 showed progressive disease. The overall response rate (ORR) was 29.4%, and the disease control rate was 59.6%. A total of 224 radiomics features were extracted, and 25 significant features were identified for further analysis. Two distant radiomics-based subtypes were identified by K-means clustering, and subtype 1 was associated with a higher ORR and longer progression-free survival (PFS). Among the 10 ML algorithms, AutoGluon displayed the highest predictive performance (AUC = 0.97), which was relatively stable in the validation cohort (AUC = 0.93). Kaplan-Meier analysis showed that responders had a better overall survival [HR = 0.21; 95% confidence interval (CI): 0.12-0.36; P < 0.001] and PFS (HR = 0.14; 95% CI: 0.09-0.22; P < 0.001) than nonresponders. CONCLUSIONS: Valuable ML radiomics models were constructed, with favorable performance in predicting the response to lenvatinib monotherapy for unresectable HCC.

Study on effects of zhi zi (fructus gardeniae) on non-alcoholic fatty liver disease in the rat.

OBJECTIVE: To investigate the effects of Zhi Zi (Fructus Gardeniae) on non-alcoholic fatty liver disease (NAFLD) induced by a high-fat diet in the rat. METHODS: A rat model of NAFLD was established using a high-fat diet. Twenty one rats were randomly divided into a normal group, a model group and a Zhi Zi treatment group, 7 rats per group. Drinking water and the drug were intragastrically administrated for 5 weeks. Samples were then taken to observe pathological changes of the liver tissue (HE staining); changes in the fat metabolism pathway e. g. triglyceride (TG) and free fatty acid (FFA) content; alterations in liver function, i.e. serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity; and differences in tumor necrosis factor alpha (TNF-alpha) and P-IkB protein expression in the liver tissue. RESULTS: Fatty degeneration and vacuole-like changes of different degrees occurred in hepatic cells of the model group. Markers for fat metabolism, serum ALT and AST activities, and expression of TNF-alpha and P-IkB proteins in liver tissue significantly increased. Fat metabolism in the Zhi Zi group significantly reduced, as shown by a drop in marker levels. Serum ALT and AST activities, and expression of TNF-alpha, P-IkB proteins in liver tissue were also significantly decreased in this group. CONCLUSION: Zhi Zi has a very strong inhibitory action on lipidosis and inflammatory injury in the rat model of NAFLD. This mechanism may possibly be related to the inhibition of the free fatty acid metabolism pathway.

Icaritin inhibited cigarette smoke extract-induced CD8+ T cell chemotaxis enhancement by targeting the CXCL10/CXCR3 axis and TGF-ß/Smad2 signaling.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a disabling/fatal disease characterized by progressive pulmonary function decline, and there are currently few drugs that can effectively reverse the decline in lung function; therefore, it is necessary to find novel drug targets. CD8+ T cells might be a new therapeutic target for alleviating lung tissue destruction and improving pulmonary function in COPD. The CXCL10/CXCR3 axis is a pivotal chemotactic axis involved in the abnormal infiltration of CD8+ T cells into the lung tissue of COPD; thus, inhibition of this axis might be a potential method to suppress CD8+ T cell-mediated lung tissue destruction in COPD. However, few drugs have been reported to target CD8+ T cells and the CXCL10/CXCR3 axis. Icaritin (ICT), one of the major components of Epimedii Folium, has been reported to have antioxidative effects in a COPD model in vitro. Whether ICT also has effects on CD8+ T cells and the CXCL10/CXCR3 axis in COPD has never been investigated. PURPOSE: This study aimed to investigate the effects of ICT on CD8+ T cell chemotaxis and the CXCL10/CXCR3 axis in interferon (IFN)-γ + cigarette smoke extract (CSE)-stimulated THP-1-derived macrophages, which simulated the pulmonary microenvironment of COPD, and then to determine the mechanisms. METHODS: The effects of ICT on the expression and secretion of CXCL9, CXCL10, and CXCL11 in THP-1-derived macrophages were measured by qRT-PCR and ELISA, and the effects of the supernatant of THP-1-derived macrophages treated with or without ICT on CD8+ T cell chemotaxis were also evaluated. Subsequently, the effects of ICT on the apoptosis and proliferation of CD8+ T cells were also assessed by EdU-488 assays and Annexin V/PI staining, respectively. Moreover, the mechanisms by which ICT inhibits the CXCL10/CXCR3 axis were investigated by RNA sequencing (RNA-seq) and KEGG pathway enrichment analysis. RESULTS: The present study showed that ICT (5 µM) significantly suppressed the expression and secretion of CXCL9, CXCL10, and CXCL11 in THP-1-derived macrophages after stimulation with IFN-γ + CSE and indirectly inhibited CD8+ T cell chemotaxis by reducing the secretion of the above chemokines. In addition, this study found that ICT had no significant effect on the proliferation of CD8+ T cells, and neither led to apoptosis. The results of the RNA-seq analysis illustrated that the transforming growth factor (TGF)-ß signaling pathway was significantly downregulated after ICT intervention, and subsequent qRT-PCR and western blotting showed that ICT could significantly downregulate the TGF-ß-Smad2 signaling pathway. CONCLUSIONS: ICT reduced CD8+ T cell chemotaxis by inhibiting the CXCL10/CXCR3 axis, and these effects might be achieved by suppressing the TGF-ß-Smad2 signaling pathway.

Icariin and icaritin ameliorated hippocampus neuroinflammation via mediating HMGB1 expression in social defeat model in mice.

Depression is a chronic, severe, and often life-threatening disease accompanied with impaired neurogenesis. Evidence showed that neuroinflammation played a key role in the process of depression. High mobility group protein box 1 (HMGB1) has been proved to function as a pro-inflammatory cytokine. In this study, we used a social defeat (SD) stress to induce inflammatory response, aiming to explore the relationship between HMGB1 and neuroinflammation. We found that the expression of HMGB1 decreased in mice exposure to SD stress, but showed a high expression of cytoplasmic HMGB1 and a high expression of RAGE, which could be rescued by ICA and ICT. So, we speculated that the translocation of HMGB1 from the nucleus to the cytoplasm might play an important role in neuroinflammatory process, and HMGB1-RAGE signaling was involved in this process. Furthermore, we also found that TLR4-XBP1s-ER stress related NF-κB signaling activation was also involved in HMGB1-related neuroinflammation. However, ICA and ICT treatment activated NF-κB signaling, and we also observed the translocation of HMGB1 into the nucleus and the increased number of neurons in mice hippocampus, indicating that the activation of NF-κB signaling might be related to neuroregeneration. Moreover, recombinant human HMGB1 protein (rHMGB1) pretreatment could suppress HMGB1-RAGE signaling and TLR4-XBP1s-ER stress related NF-κB signaling, resulted in a suppressed microglia activation in mice hippocampus. We supposed that ICA and ICT could ameliorate neuroinflammation in hippocampus via suppressing HMGB1-RAGE signaling and show neuroprotective effects via activating TLR4- NF-κB signaling at the same time, resulting in improving depressive behaviors in mice.

Icariin and icaritin ameliorated hippocampus neuroinflammation via inhibiting HMGB1-related pro-inflammatory signals in lipopolysaccharide-induced inflammation model in C57BL/6 J mice.

Inflammation is a defensive response of the body and is at the center of many diseases' process like depression. High mobility group protein box 1 (HMGB1), has been proved to function as a pro-inflammatory cytokine. We aim to explore the role of HMGB1 played in the neuroinflammation here. In this study, we used LPS to induce an acute inflammatory response, and to measure the anti-neuroinflammation effect of icariin (ICA) and icaritin (ICT). We found that LPS could increase the expression of HMGB1 in serum and hippocampus, along with a high expression of HMGB1 in the cytoplasm and a high expression of RAGE, which could be rescued by ICA and ICT, and ethyl pyruvate (EP) pretreatment showed similar effects here. We speculated that the translocation of HMGB1 from the nucleus to the cytoplasm played an important role in neuroinflammatory process, and HMGB1-RAGE signal was involved in this process. Furthermore, we found that ICA and ICT treatment activated TLR4-XBP1s related NF-κB signal, which we thought was relevant with the neuroprotective effect of ICA and ICT. However, EP pretreatment suppressed TLR4-XBP1s- endoplasmic reticulum stress related NF-κB signal to anti-inflammatory response, which was almost absolutely opposite with ICA and ICT treatment. We speculated that it might be caused by the duration of inflammation. We supposed that ICA and ICT could ameliorate neuroinflammation in hippocampus via suppressing HMGB1-RAGE signaling and might show a neuroprotective effect via activating TLR4-XBP1s related NF-κB signal at the same time, making it possible to act as an anti-neuroinflammatory drugs.

Scutellaria Flavonoids Effectively Inhibit the Malignant Phenotypes of Non-small Cell Lung Cancer in an Id1-dependent Manner.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death in the world. Inhibitor of differentiation 1 (Id1) is overexpressed in NSCLC and involved in promoting its progression and metastasis. Identifying natural compounds targeting Id1 may have utility in NSCLC treatment. Here, we sought to determine whether the anti-tumor activities of Scutellaria flavonoids (SFs) were related to Id1. We reported that three SFs (baicalin, baicalein and wogonin) exhibited strong antitumor activity in NSCLC cells in vitro and in vivo. Id1 played a pivotal role on blockage of migration and invasion by SFs. Abrogation of invasion and migration mediated by baicalin, baicalein and wogonin were totally abolished by ectopic overexpression of Id1. Mechanistically, baicalin, baicalein and wogonin activated Rap1-GTP binding and dephosphorylated Akt and Src by suppressing a7nAChR, consequently triggering inhibition of Id1. Then attenuation of its downstream mediators, VEGF-A, N-cadherin, vimentin, combined with augment of E-cadherin led to the blockage of proliferation, EMT and angiogenesis of NSCLC. Overall, our data shed light on heretofore-undescribed role of SFs as modulators of Id1, which may be a useful strategy in the treatment of NSCLC.

Baicalein Inhibits Orthotopic Human Non-Small Cell Lung Cancer Xenografts via Src/Id1 Pathway.

Non-small cell lung cancer (NSCLC) is one of the most lethal cancers worldwide. Inhibitor of differentiation 1 (Id1) is the member mostly linked to tumorigenesis in Id family and a potential molecular target in cancer therapy. In the current study, we established an orthotopic lung cancer model by injecting athymic nude mice with A549 cells and evaluated the antitumor effect of baicalein and expression of Id1-related proteins in vivo and in vitro. Micro-CT images showed that tumor volume in baicalein group was significantly reduced. Western blot analysis revealed that baicalein suppressed the expression of Id1 protein, epithelial-to-mesenchymal transition (EMT) related molecules (N-Cadherin, vimentin), and angiogenesis related protein (VEGF-A), accompanied by upregulation of epithelial markers (such as E-cadherin). In addition, phosphorylation of upstream molecular Src was significantly restrained after baicalein treatment. This study firstly demonstrates that baicalein inhibits tumor growth in orthotopic human NSCLC xenografts via targeting Src/Id1 pathway.

Kidney-Qi deficiency diagnosed by Deng's diagnosis standard was not correlated with aging based on clinical observation of 90 participants.

OBJECTIVE: To verify the Traditional Chinese Medicine (TCM) theory that kidney-Qi deficiency (KQD) is considered to be the main cause of aging using cross-sectional study. METHODS: Demographic and lifestyle characteristics of 90 healthy participants were collected with a self-administered questionnaire. KQD syndrome was diagnosed according to Deng's diagnosis standard. Creatinine-adjusted urinary 8-hydroxy-2'-deoxyguanosine (8-OH-dG) and 8-isomeric-prostaglandin2α (8-iso-PGF2α), salivary advanced oxidation protein products (AOPPs), malondialdehyde (MDA) and dehydroepiandrosterone-sulfate (DHEA-S) were selected as aging markers and measured using enzyme-linked immunosorbent assay. RESULTS: No significant differences were observed in participant characteristics between the KQD group and non-KQD (NKQD) group (P > 0.05). Levels of 8-OH-dG, 8-iso-PGF2α, AOPPs, and MDA increased with age, except for a slight decrease in 8-OH-dG in the older group. The increase in 8-iso-PGF2α was significant (P < 0.05). DHEA-S significantly decreased with increasing age (P < 0.01). 8-OH-dG levels were higher in the KQD group compared with the NKQD group. Levels of urinary 8-iso-PGF2α, salivary AOPPs, and MDA in the KQD group were lower than in the NKQD group. Salivary DHEA-S was higher in the KQD group compared with the NKQD group. However, differences between KQD group and NKQD group were not significant. CONCLUSION: The current results suggested that KQD syndrome, as diagnosed by Deng's standard, does not underlie the aging phenotype.

Establishment and Evaluation of a Rat Model of Sidestream Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is a common cause of mortality worldwide. The current lack of an animal model that can be established within a certain time frame and imitate the unique features of the disease is a major limiting factor in its study. The present study established and evaluated an animal model of COPD that represents the early and advanced stage features using short-, middle-, and long-term sidestream cigarette smoke (CS) exposure. One hundred and nine Sprague-Dawley rats were randomly divided into 10 groups for different periods of sidestream CS exposure or no exposure (i.e., normal groups). The rats were exposed to CS from 3R4F cigarettes in an exposure chamber. Histological analysis was performed to determine pathological changes. We also conducted open-field tests, lung function evaluations, and cytokine analysis of the blood serum, bronchoalveolar lavage fluid, and lung tissue. The lung tissue protein levels, blood gases, and were also analyzed. As the CS exposure time increased, the indicators associated with oxidative stress, inflammatory responses, and airway remodeling were greater in the CS exposure groups than in the normal group. At 24 and 36 weeks, the COPD model rats displayed the middle- and advanced-stage features of COPD, respectively. In the 8-week CS exposure group, after the CS exposure was stopped for 4 weeks, inflammatory responses and oxidative responses were ameliorated and lung function exacerbation was reduced compared with the 12-week CS exposure group. Therefore, we established a more adequate rat model of sidestream CS induced COPD, which will have great significance for a better understanding of the pathogenesis of COPD and drug effectiveness evaluation.

Glucose transporter-1 as an independent prognostic marker for cancer: a meta-analysis.

OBJECTIVE: Glucose transporter-1 (GLUT-1) as the major glucose transporter present in human cells is found overexpressed in a proportion of human malignancies. This meta-analysis is attempted to assess the prognostic significance of GLUT-1 for survival in various cancers. MATERIALS AND METHODS: We conducted an electronic search using the databases PubMed, Embase and Web of Science, from inception to Oct 20th, 2016. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. RESULTS: Fourty-one studies with a total of 4794 patients were included. High GLUT-1 expression was significantly associated with poorer prognosis [overall survival: HR = 1.833 (95% CI: 1.597-2.069, P < 0.0001); disease-free survival: HR = 1.838 (95% CI: 1.264-2.673, P < 0.0001); progression-free survival: HR = 2.451 (95% CI: 1.668-3.233, P < 0.0001); disease specific survival: HR = 1.96 (95% CI: 1.05-2.871, P < 0.0001)]. CONCLUSIONS: High GLUT-1 expression may be an independent prognostic marker to predict poor survival in various types of cancers. Further clinical trials with high quality need to be conducted to confirm our conclusion.

Changes of the brain activities after chronic restraint stress in rats: A study based on 18F-FDG PET.

As a prevalent disease all over the world, changed functional activities and/or structures in many brain regions have been found in depression. In this study, 5-week chronic restraint stress (CRS) was performed to establish depression rat models, and 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) was used to detect brain functional activities. Our study found that CRS induced depressive behaviors and increased the expression of serum IL-6. After exposure to CRS, rats showed decreased glucose metabolism in the whole-brain and brain regions including left medial prefrontal and auditory cortices; right amygdala, cingulate cortex, olfactory and AcbCore/Shell; bilateral caudate putamen, dorsal hippocampi, insular and entorhinal cortices. Expression of serum IL-6 and glucose metabolism in most of the above brain regions were significantly correlated with the severity of some CRS-induced depressive behaviors. In conclusion, the increased peripheral inflammatory response and decreased brain functional activities might be the important pathogenesis of experimental depression induced by CRS, and could reflect the severity of depression to some extent.