Reinforced Nacre-Like MXene/Sodium Alginate Composite Films for Bioinspired Actuators Driven by Moisture and Sunlight.

MXene-based soft actuators have attracted increasing attention and shown competitive performance in various intelligent devices such as supercapacitors, bionic robots and artificial muscles. However, the development of robust MXene-based actuators with multi-stimuli responsiveness remains challenging. In this study, a nacre-like structure soft actuator based on MXene and sodium alginate (SA) composite films is prepared using a straightforward solvent casting self-assembly method, which not only enhances the mechanical performance (tensile strength of 72 MPa) but also diversifies the stimuli responsiveness of the material. The composite actuators can be powered by external stimuli from renewable energy sources, from moisture inducing a maximum bending angle of 190 degrees at a relative humidity (RH) of 91%, and sunlight irradiation generating a maximum curvature of 1.45 cm-1 under 100 mW cm-2. The feasibility of practical applications, including moisture-responsive flowers and walkers, sunlight-responsive oscillators, and smart switches, is demonstrated through comprehensive experimental characterization and performance evaluation. The work presented here provides insight into the design of robust actuators via the utilization and conversion of environmentally renewable energy sources.

Insights into multilevel tissue-level collateral status using ColorViz maps from dual data sources in acute ischemic cerebrovascular diseases: A STARD-compliant retrospective study.

This study aims to explore the utility of ColorViz mapping from dual data sources for assessing arterial collateral circulation and predicting cerebral tissue-level collateral (TLC) in patients with acute ischemic cerebrovascular diseases. A retrospective study was conducted at a single center on a cohort of 79 patients diagnosed with acute ischemic cerebrovascular diseases between November 2021 and April 2022, who had undergone both multi-phase CT angiography (mCTA) and computed tomography perfusion (CTP). The quality of images and arterial collateral status depicted on ColorViz maps from dual data-sets (mCTA and CTP) were assessed using a "5-point scale" and a "10-point scale," respectively. The status of TLC was evaluated by analyzing multilevel hypoperfusion volume and the hypoperfusion intensity ratio (HIR). The Spearman correlation coefficient was employed to examine the association between arterial collateral status derived from dual data sources and TLC. Receiver operating characteristic curve analysis was used to determine the diagnostic efficacy in detecting large vessel occlusive acute ischemic stroke (LVO-AIS). The ColorViz maps derived from dual data sources facilitated comparable image quality, with over 95% of cases meeting diagnostic criteria, for the evaluation of arterial level collateral circulation. Patients with robust arterial collateral circulation, as determined by dual data sources, were more likely to exhibit favorable TLC status, as evidenced by reductions in hypoperfusion volume (Tmax > 4 seconds, Tmax > 6 seconds, Tmax > 8 seconds, and Tmax > 10 seconds, P < .05) and HIR (Tmax > 6 seconds/4 seconds, Tmax > 8 seconds/4 seconds, Tmax > 10 seconds/4 seconds, and Tmax > 8 seconds/6 seconds, P < .05). The sensitivity and specificity in detecting LVO-AIS was 60.00% and 97.73% for mCTA source maps, while 74.29% and 72.73% for CTP source maps (P > .05 based on De-Long test). In conclusion, this study indicates that ColorViz maps derived from both data sources are equally important in evaluating arterial collateral circulation and enhancing diagnostic efficiency in patients with LVO-AIS, as well as offering insights into the TLC status based on hypoperfusion volume and HIR.

Functional role of carbohydrate-binding modules in multi-modular chitinase OfChtII.

The primary distinction between insect and bacterial chitin degradation systems lies in the presence of a multi-modular endo-acting chitinase ChtII, in contrast to a processive exo-acting chitinase. Although the essential role of ChtII during insect development and its synergistic action with processive chitinase during chitin degradation has been established, the mechanistic understanding of how it deconstructs chitin remains largely elusive. Here OfChtII from the insect Ostrinia furnacalis was investigated employing comprehensive approaches encompassing biochemical and microscopic analyses. The results demonstrated that OfChtII truncations with more carbohydrate-binding modules (CBMs) exhibited enhanced hydrolysis activity, effectively yielding a greater proportion of fibrillary fractions from the compacted chitin substrate. At the single-molecule level, the CBMs in these OfChtII truncations have been shown to primarily facilitate chitin substrate association rather than dissociation. Furthermore, a greater number of CBMs was demonstrated to be essential for the enzyme to effectively bind to chitin substrates with high crystallinity. Through real-time imaging by high-speed atomic force microscopy, the OfChtII-B4C1 truncation with three CBMs was observed to shear chitin fibers, thereby generating fibrillary fragments and deconstructing the compacted chitin structure. This work pioneers in revealing the nanoscale mechanism of endo-acting multi-modular chitinase involved in chitin degradation, which provides an important reference for the rational design of chitinases or other glycoside hydrolases.

Spectral CT for preoperative diagnosis of N2 station lymph node metastasis in solid T1 non-small cell lung cancer.

PURPOSE: To evaluate the diagnostic value of spectral CT for the preoperative diagnosis of N2 station lymph nodes metastasis in solid T1 non-small cell lung cancer (NSCLC). METHOD: For this retrospective study, dual-phase contrast agent-enhanced CT was performed in patients with NSCLC from September 2019 to June 2023. Quantitative spectral CT parameters measurements were performed by 2 radiologists independently. Logistic regression analysis and Delong test were performed. RESULTS: 60 NSCLC patients (mean age, 62.85 years ± 8.49, 44men) were evaluated. A total of 121 lymph nodes (38 with metastasis) were enrolled. There was no significant difference in the slope of the spectral Hounsfield unit curve (λHu) on arterial phase (AP) or venous phase (VP) between primary lesions and metastatic lymph nodes (P > 0.05), but significant difference in VP λHu between primary lesions and non-metastatic lymph nodes (P < 0.001). The CT40KeV, λHu, normalized iodine concentration (nIC), normalized effective atomic number (nZeff) measured during both AP and VP were lower in metastatic lymph nodes than in non-metastatic lymph nodes (all P < 0.05). Short-axis diameter (S) of metastatic lymph nodes was higher than non-metastatic lymph nodes (P < 0.001). Area under the curve (AUC) for S performed the highest (0.788) in diagnosing metastatic lymph nodes. When combined with VP λHu, VP nZeff, AUC increased to 0.871. CONCLUSION: Spectral CT is a complementary means for the preoperative diagnosis of N2 station lymph nodes metastasis in solid T1 NSCLC. The combined parameters have higher diagnostic efficiency.

Therapeutic potential of CB1R activation by Qingyangshen glycoside M1 for seizure relief.

ETHNOPHARMACOLOGICAL RELEVANCE: Cynanchum otophyllum C.K.Schneid.PI.Wilson, commonly referred as ''Qingyangshen'' (QYS), is a traditional folk medicine from Yunnan, renowned for its efficacy in neurological and psychiatric disorders. Glycosides isolated from QYS have shown promise in alleviating epilepsy, however, mechanisms of action and specific molecular targets remain to be elucidated. AIM OF THE STUDY: The study aimed to evaluate the anticonvulsant effects of Qingyangshen glycosides M1 (M1), a C21 steroidal glycoside from QYS, on pentylenetetrazol (PTZ)-induced convulsions in zebrafish (Danio rerio), and its neuroprotective effect on Glutamate (Glu)-induced damage to PC12 cells, and importantly to identify its potential molecular targets. MATERIALS AND METHODS: To evaluate anticonvulsant activity of M1, 7 days-post-fertilization (7-dpf) animals were pretreated (by immersion) and then exposed to PTZ (10 mM) solution. Furthermore, Glu-induced PC12 cell damage was employed to investigate the neuroprotective and anti-apoptotic capacity. Cells were pretreated with various concentrations of M1 (0-10 µM) for 12 h and then co-treated with Glu (15 mM) for an additional 24 h. The cell viability, apoptosis rate and apoptosis-related proteins (p-PI3K, PI3K, Akt, p-Akt, CREB, p-CREB, BDNF, Bax and Bcl-2) were measured using CCK-8, annexin V/PI and Western blot assays. To model the expected interaction between M1 and candidate cannabinoid receptor type 1 (CB1R), ERK phosphorylation, molecular docking, and drug affinity responsive target stability (DARTS) techniques were employed. Finally, CB1R antagonist Rimonabant (Rim) was validated by co-administration in both zebrafish and cells to confirm the requirement of CB1R for M1 efficacy. RESULTS: At a concentration of 400 µM, M1 dramatically reversed PTZ-induced convulsive-like behaviors in zebrafish, as evidenced by a significant reduction in locomotor activity. In the context of Glu-induced cytotoxicity, M1 (10 µM) demonstrated a notable increase in cell viability and suppressed apoptosis through modulation of the Bax/Bcl-2 ratio and activation of the PI3K/Akt/CREB/BDNF signaling axis. These effects were facilitated through CB1R activation. In contrast, Rim dampened the beneficial activities of M1 as a cannabinoid agonist. CONCLUSIONS: These results demonstrated that M1 as a potential CB1R activator, exhibiting anticonvulsive effects in a PTZ-induced zebrafish model and neuroprotective properties via the PI3K/Akt/CREB/BDNF signaling axis in a Glu-induced PC12 cell injury model. Notably, the observed seizure relief attenuated by CB1R chemical antagonism.

Aqueous Electroreduction of Nitric Oxide to Ammonia at Low Concentration via Vacancy Engineered FeOCl.

Electroreduction of nitric oxide (NO) to NH3 (NORR) has gained extensive attention for the sake of low carbon emission and air pollutant treatment. Unfortunately, NORR is greatly hindered by its sluggish kinetics, especially under low concentrations of NO. Herein, we developed a chlorine (Cl) vacancy strategy to overcome this limitation over FeOCl nanosheets (FeOCl-VCl ). Density functional theory (DFT) calculations revealed that the Cl vacancy resulted in defective Fe with sharp d-states characteristics in FeOCl-VCl to enhance the absorption and activation of NO. In situ X-ray absorption near-edge structure (XANES) and attenuated total reflection-infrared spectroscopy (ATR-IR) verified the lower average oxidation state of defective Fe to enhance the electron transfer for NO adsorption/activation and facilitate the generation of key NHO and NHx intermediates. As a result, the FeOCl-VCl exhibited superior NORR activities with the NH3 Faradaic efficiency up to 91.1 % while maintaining a high NH3 yield rate of 455.4 µg cm-2 h-1 under 1.0 vol % NO concentration, competitive with those of previously reported literatures under higher NO concentration. Further, the assembled Zn-NO battery utilizing FeOCl-VCl as cathode delivered a record peak power density of 6.2 mW cm-2 , offering a new route for simultaneous NO removal, NH3 production, and energy supply.

Correlations between iodine uptake, invasive CT features and pleural invasion in adenocarcinomas with pleural contact.

Pleural contact in lung cancers does not always imply pleural invasion (PI). This study was designed to determine whether specific invasive CT characteristics or iodine uptake can aid in the prediction of PI. The sample population comprised patients with resected solid lung adenocarcinomas between April 2019 and May 2022. All participants underwent a contrast enhanced spectral CT scan. Two proficient radiologists independently evaluated the CT features and iodine uptake. Logistic regression analyses were employed to identify predictors for PI, via CT features and iodine uptake. To validate the improved diagnostic efficiency, accuracy analysis and ROC curves were subsequently used. A two-tailed P value of less than 0.05 was considered statistically significant. We enrolled 97 consecutive patients (mean age, 61.8 years ± 10; 48 females) in our study. The binomial logistic regression model revealed that a contact length > 10 mm (OR 4.80, 95% CI 1.92, 11.99, p = 0.001), and spiculation sign (OR 2.71, 95% CI 1.08, 6.79, p = 0.033) were independent predictors of PI, while iodine uptake was not. Enhanced sensitivity (90%) and a greater area under the curve (0.73) were achieved by integrating the two aforementioned CT features in predicting PI. We concluded that the combination of contact length > 10 mm and spiculation sign can enhance the diagnostic performance of PI.

Stressors in university life and anxiety symptoms among international students: a sequential mediation model.

BACKGROUND: Anxiety is a common mental health problem among university students, and identification of its risk or associated factors and revelation of the underlying mechanism will be useful for making proper intervention strategies. The aim of our study is to test the sequential mediation of self-efficacy and perceived stress in the association between stressors in university life and anxiety symptoms. METHODS: A cross-sectional study design was adopted and a sample of 512 international students from a medical university of China completed the survey with measurements of stressors in university life, self-efficacy, perceived stress and anxiety symptoms. RESULTS: We found that 28.71% of the international students had anxiety symptoms, and stressors in university life were positively associated with anxiety symptoms (ß = 0.23, t = 5.83, p < 0.01). Moreover, sequential mediating role of self-efficacy and perceived stress in the association between the stressors and anxiety symptoms was revealed. CONCLUSIONS: Our study provided a new perspective on how to maintain the mental health, which suggested that self-efficacy improvement and stress reduction strategies should be incorporated in the training programs to support students.

Permeability Prediction of Nanoscale Porous Materials Using Discrete Cosine Transform-Based Artificial Neural Networks.

The permeability of porous materials determines the fluid flow rate and aids in the prediction of their mechanical properties. This study developed a novel approach that combines the discrete cosine transform (DCT) and artificial neural networks (ANN) for permeability analysis and prediction in digital rock images, focusing on nanoscale porous materials in shale formations. The DCT effectively captured the morphology and spatial distribution of material structure at the nanoscale and enhanced the computational efficiency, which was crucial for handling the complexity and high dimensionality of the digital rock images. The ANN model, trained using the Levenberg-Marquardt algorithm, preserved essential features and demonstrated exceptional accuracy for permeability prediction from the DCT-processed rock images. Our approach offers versatility and efficiency in handling diverse rock samples, from nanoscale shale to microscale sandstone. This work contributes to the comprehension and exploitation of unconventional resources, especially those preserved in nanoscale pore structures.

Constructing imine groups on the surface of Cu1/Pd(111) as a novel strategy for CO2 hydrogenation to methanol.

Developing a promising strategy to improve the limited selectivity and activity of traditional Pd-Cu bimetallic catalysts for CO2 hydrogenation to methanol (CH3OH) remains a grand challenge. By using density functional theory calculations, we discovered that introducing imine groups on the Cu1/Pd(111) surface through a condensation reaction of aldehydes and amines is an intriguing approach for simultaneously enhancing the selectivity and activity of Cu1/Pd(111) for CO2 hydrogenation to CH3OH. The imine groups formed by amino reactions with acrolein on the Cu1/Pd(111) surface (C3H4O@NH2-Cu1/Pd(111)) improved the turnover frequency (TOF). The imine group optimized the electronic structure of active sites and increased electron transfer to the anti-bonding orbital of CO2, facilitating the activity of C3H4O@NH2-Cu1/Pd(111) for CO2 hydrogenation to CH3OH. Besides, the inhibition of CO by-products and the low desorption energy of CH3OH were responsible for the high selectivity of C3H4O@NH2-Cu1/Pd(111) for CH3OH. This work advances our understanding of the role of imines in catalysis and provides a new strategy for designing excellent functional group-modified catalysts for the hydrogenation of CO2 to CH3OH.

Challenges and Perspectives in Target Identification and Mechanism Illustration for Chinese Medicine.

Chinese medicine (CM) is an important resource for human life understanding and discovery of drugs. However, due to the unclear pharmacological mechanism caused by unclear target, research and international promotion of many active components have made little progress in the past decades of years. CM is mainly composed of multi-ingredients with multi-targets. The identification of targets of multiple active components and the weight analysis of multiple targets in a specific pathological environment, that is, the determination of the most important target is the main obstacle to the mechanism clarification and thus hinders its internationalization. In this review, the main approach to target identification and network pharmacology were summarized. And BIBm (Bayesian inference modeling), a powerful method for drug target identification and key pathway determination was introduced. We aim to provide a new scientific basis and ideas for the development and international promotion of new drugs based on CM.

AA15 lytic polysaccharide monooxygenase is required for efficient chitinous cuticle turnover during insect molting.

Microbial lytic polysaccharide monooxygenases (LPMOs) catalyze the oxidative cleavage of crystalline polysaccharides including chitin and cellulose. The discovery of a large assortment of LPMO-like proteins widely distributed in insect genomes suggests that they could be involved in assisting chitin degradation in the exoskeleton, tracheae and peritrophic matrix during development. However, the physiological functions of insect LPMO-like proteins are still undetermined. To investigate the functions of insect LPMO15 subgroup I-like proteins (LPMO15-1s), two evolutionarily distant species, Tribolium castaneum and Locusta migratoria, were chosen. Depletion by RNAi of T. castaneum TcLPMO15-1 caused molting arrest at all developmental stages, whereas depletion of the L. migratoria LmLPMO15-1, prevented only adult eclosion. In both species, LPMO15-1-deficient animals were unable to shed their exuviae and died. TEM analysis revealed failure of turnover of the chitinous cuticle, which is critical for completion of molting. Purified recombinant LPMO15-1-like protein from Ostrinia furnacalis (rOfLPMO15-1) exhibited oxidative cleavage activity and substrate preference for chitin. These results reveal the physiological importance of catalytically active LPMO15-1-like proteins from distant insect species and provide new insight into the enzymatic mechanism of cuticular chitin turnover during molting.

A midgut-specific lytic polysaccharide monooxygenase of Locusta migratoria is indispensable for the deconstruction of the peritrophic matrix.

Lytic polysaccharide monooxygenases (LPMOs) are important enzymes that boost the hydrolysis of recalcitrant polysaccharides, such as chitin. They are found extensively in different insect species and are classified as auxiliary activities family 15 (AA15) LPMOs (LPMO15). Some of them were identified from the insect midgut and proven to act on chitin. However, knowledge about their physiological roles during insect growth and development remains limited. Here, we found that midgut-specific LPMO15s are widely distributed in different insect orders, such as the orthopteran Locusta migratoria and the lepidopteran Bombyx mori. Using L. migratoria as a model insect, the function of midgut-specific LmLPMO15-3 during development was investigated. Double-stranded RNA-mediated downregulation of LmLPMO15-3 expression at the 4th or 5th instar nymph stage severely decreased the survival rate and resulted in lethal phenotypes. Hematoxylin and eosin staining results indicated that the deficient individuals exhibited incompletely digested peritrophic matrix (PM), which suggested that LmLPMO15-3 is essential for the deconstruction of the PM during molting. This study provides direct evidence of the physiological importance of a midgut-specific LPMO15 during insect development. As L. migratoria is one of the most destructive agricultural pests, LmLPMO15-3 is a potential target for pest management.

Association of Covid-19 pandemic-related stress and depressive symptoms among international medical students.

BACKGROUND: The outbreak of Covid-19 had negative impacts on the mental stress and induced psychological distress among university students worldwide. This study proposed a moderated mediation model, and hypothesized that the Covid-19 pandemic-related stress was positively related to depressive symptoms among international medical students. METHODS: An online survey on stress and depressive symptoms of international students was conducted in a medical university. Questions on Covid-19 pandemic-related stress, Patient Health Quesionnaire-9, Simplified Coping Style Questionnaire and the Perceived Social Support Scale were used as measurements, and model analyses were conducted using Hayes' PROCESS macro for SPSS. RESULTS: It was found that 9.83%, 3.08% and 2.12% students had mild, moderate and severe depressive symptoms, respectively, and the positive association between Covid-19 pandemic-related stress and depressive symptoms was significant (ß = 0.27, t = 6.87, P < 0.01). Negative coping was also significantly correlated to depressive symptoms (ß = 0.26, t = 6.60, P < 0.01), and partially mediated the association between Covid-19 pandemic-related stress and depressive symptoms. Perceived social support had a negative association with depressive symptoms (ß=-0.26, t=-6.25, P < 0.01), played a negative moderating role in the relationship between negative coping and depressive symptoms, and moderated the indirect effect of Covid-19 pandemic-related stress on depressive symptoms via negative coping. CONCLUSIONS: Results of the study suggested that under the background of continuing pandemic, intervention or prevention of mental health problem is urgently needed for the international students, and depression may be alleviated through reducing negative coping and increasing perceived social support.

Dictamnine, a novel c-Met inhibitor, suppresses the proliferation of lung cancer cells by downregulating the PI3K/AKT/mTOR and MAPK signaling pathways.

Dictamnine (Dic), a naturally occurring small-molecule furoquinoline alkaloid isolated from the root bark of Dictamnus dasycarpus Turcz., is reported to display anticancer properties. However, little is known about the direct target proteins and anticancer mechanisms of Dic. In the current study, Dic was found to suppress the growth of lung cancer cells in vitro and in vivo, and to attenuate the activation of PI3K/AKT/mTOR and mitogen-activated protein kinase (MAPK) signaling pathways by inhibiting the phosphorylation and activation of receptor tyrosine kinase c-Met. Moreover, the binding of Dic to c-Met was confirmed by using cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) assay. Among all cancer cell lines tested, Dic inhibited the proliferation of c-Met-dependent EBC-1 cells with the greatest potency (IC50 = 2.811 µM). Notably, Dic was shown to synergistically improve the chemo-sensitivity of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-resistant lung cancer cells to gefitinib and osimertinib. These results suggest that Dic is a c-Met inhibitor that can serve as a potential therapeutic agent in the treatment of lung cancer, especially against EGFR TKI-resistant and c-Met-dependent lung cancer.

Prevalence and Predictors of Anxiety and Depressive Symptoms Among International Medical Students in China During COVID-19 Pandemic.

Background: The rapid spread of Coronavirus Disease-19 (COVID-19) infection has been the most important public health crisis across the globe since the end of 2019. Anxiety and depression are the most common mental health problems among people during the pandemic, and many studies have reported anxiety and depressive symptoms in college students. However, information on the mental health status of international medical students during this critical period of time has been scarce, which hinders the efforts in making proper policy or strategies to help these students. The present study aims to explore the prevalence of anxiety and depressive symptoms in international medical students in China and to find out the factors that have potential predictive value for anxiety and depressive symptoms. Method: A cross-sectional study was carried out for international medical students during November 2020 at China Medical University in Shenyang, China. Five hundred and nineteen international students were interviewed with questionnaires containing demographic variables, Stressors in school, Generalized Anxiety Disorder Assessment (GAD-7), Patient Health Questionnaire-9 (PHQ-9), Simplified Coping Style Questionnaire (SCSQ), Perceived Stress Scale (PSS-10), the Multidimensional Scale of Perceived Social Support (MSPSS), Revised Life Orientation Test (LOT-R) and Resilience Scale-14 (RS-14). Univariate logistic regression and stepwise multiple logistic regression analyses were conducted where appropriate to explore the predictive factors of anxiety symptoms and depressive symptoms. Results: The prevalence of anxiety symptoms and depressive symptoms in the sample population was 28.5% (148/519) and 31.6% (164/519), respectively. Stressors in school (ß = 0.176, OR = 1.192, CI: 1.102-1.289), negative coping style (ß = 0.639, OR = 1.894, CI: 1.287-2.788) and perceived stress (ß = 0.230, OR = 1.258, CI: 1.184-1.337) were found to be the predictors of anxiety symptoms among the international medical students; while gender (ß = -0.594, OR = 0.552, CI: 0.315-0.968), stay up late (ß = 0.828, OR = 2.288, CI: 1.182-4.431), current place of residence (ß = 1.082, OR = 2.951, CI: 1.256-6.931), stressors in the school (ß = 0.303, OR = 1.354, CI: 1.266-1.496), negative coping style (ß = 0.866, OR = 2.377, CI: 1.516-3.725), perceived stress (ß = 0.233, OR = 1.262, CI: 1.180-1.351) were found to be predictors of depressive symptoms. Conclusion: The prevalence of anxiety symptoms and depressive symptoms was moderate among international medical students in China. The communal predictors of anxiety and depressive symptoms were stressors in school, negative coping style and perceived stress; while demographic factors such as gender (male), stay up late at night and current place of residence were found associated with depressive symptoms. These results suggest that proper stress management and specific interventions are needed to help students maintain their mental health during the COVID-19 pandemic period.

A Novel 5-HT1B Receptor Agonist of Herbal Compounds and One of the Therapeutic Uses for Alzheimer's Disease.

The serotonin receptor 5-HT1B is widely expressed in the central nervous system and has been considered a drug target in a variety of cognitive and psychiatric disorders. The anti-inflammatory effects of 5-HT1B agonists may present a promising approach for Alzheimer's disease (AD) treatment. Herbal antidepressants used in the treatment of AD have shown functional overlap between the active compounds and 5-HT1B receptor stimulation. Therefore, compounds in these medicinal plants that target and stimulate 5-HT1B deserve careful study. Molecular docking, drug affinity responsive target stability, cellular thermal shift assay, fluorescence resonance energy transfer (FRET), and extracellular regulated protein kinases (ERK) 1/2 phosphorylation tests were used to identify emodin-8-O-ß-d-glucopyranoside (EG), a compound from Chinese medicinal plants with cognitive deficit attenuating and antidepressant effects, as an agonist of 5-HT1B. EG selectively targeted 5-HT1B and activated the 5-HT1B-induced signaling pathway. The activated 5-HT1B pathway suppressed tumor necrosis factor (TNF)-α levels, thereby protecting neural cells against beta-amyloid (Aß)-induced death. Moreover, the agonist activity of EG towards 5-HT1B receptor, in FRET and ERK1/2 phosphorylation, was antagonized by SB 224289, a 5-HT1B antagonist. In addition, EG relieved AD symptoms in transgenic worm models. These results suggested that 5-HT1B receptor activation by EG positively affected Aß-related inflammatory process regulation and neural death resistance, which were reversed by antagonist SB 224289. The active compounds such as EG might act as potential therapeutic agents through targeting and stimulating 5-HT1B receptor for AD and other serotonin-related disorders. This study describes methods for identification of 5-HT1B agonists from herbal compounds and for evaluating agonists with biological functions, providing preliminary information on medicinal herbal pharmacology.

Akt scaffold proteins: the key to controlling specificity of Akt signaling.

The phosphatidylinositol 3-kinase-Akt signaling pathway plays an essential role in regulating cell proliferation and apoptosis. Akt kinase is at the center of this signaling pathway and interacts with a variety of proteins. Akt is overexpressed in almost 80% of tumors. However, inhibiting Akt has serious clinical side effects so is not a suitable treatment for cancer. During recent years, Akt scaffold proteins have received increasing attention for their ability to regulate Akt signaling and have emerged as potential targets for cancer therapy. In this paper, we categorize Akt kinase scaffold proteins into four groups based on their cellular location: membrane-bound activator and inhibitor, cytoplasm, and endosome. We describe how these scaffolds interact with Akt kinase, how they affect Akt activity, and how they regulate the specificity of Akt signaling. We also discuss the clinical application of Akt scaffold proteins as targets for cancer therapy.

IRS4 promotes the progression of non-small cell lung cancer and confers resistance to EGFR-TKI through the activation of PI3K/Akt and Ras-MAPK pathways.

IRS4 is a member of the insulin receptor substrate (IRS) protein family. It acts as a cytoplasmic adaptor protein, integrating and transmitting signals from receptor protein tyrosine kinases to the intracellular environment. IRS4 can induce mammary tumorigenesis and is usually overexpressed in non-small cell lung cancer (NSCLC). However, little is known about the role of IRS4 in the development and progression of lung cancer. In this study, we show that IRS4 knockout suppresses the proliferation, colony formation, migration, and invasion of A549 lung cancer cells, as well as tumor growth in a nude mouse xenograft model. In contrast, stable expression of IRS4 showed the opposite effects. As expected, IRS4 was found to activate the PI3K/Akt and Ras-MAPK pathways, and we also showed that IRS4 depletion significantly enhanced the sensitivity of EGFR tyrosine kinase inhibitor (EGFR-TKI)-resistant cells to gefitinib. Taken together, these results show that IRS4 promotes NSCLC progression and may represent a potential therapeutic target for EGFR-TKI-resistant NSCLC.

The C-terminal of the α1b-adreneroceptor is a key determinant for its structure integrity and biological functions.

The C-terminal of G protein-coupled receptors is now recognized as being important for G protein activation and signaling function. To detect the role of C-terminal tail in receptor activation, we used the α1b-AR, which has a long C-terminal of 164 amino acids. We constructed the intramolecular FRET sensors, in which the C-terminal was truncated to 10 (∆C-10), 20 (∆C-20), 30 (∆C-30), 50 (∆C-50), 70 (∆C-70), or 90 (∆C-90). The truncated mutants of ∆C-10, ∆C-20, or ∆C-30 cannot induce FRET signal changes and downstream ERK1/2 phosphorylation. However, the truncated mutants of ∆C-50, ∆C-70, or ∆C-90 induce significant FRET signal changes and downstream ERK1/2 phosphorylation, especially ∆C-90. This is particularly true in the case of the ∆C-90, ∆C-70, or ∆C-50 which retained the potential phosphorylation sites (Ser401, Ser404, Ser408, or Ser410). The ∆C-90 showed an increase in agonist-induced FRET signal changes and ERK1/2 phosphorylation in PKC- or endocytosis-dependent and EGFR-, src-, or ß-arrestin2-independent.