First-Generation Radiolabeled Cyclic Peptides for Molecular Imaging of Platelet-Derived Growth Factor Receptor α.

Occult nodal spread and metastatic disease require longstanding imaging and biochemical assessments for thyroid cancer, a disease that has a propensity for diffuse, small-volume disease. We have developed a 64Cu-labeled platelet-derived growth factor receptor α (PDGFRA) antibody for immuno-PET of PDGFRA in metastatic papillary thyroid cancer (PTC). The present work describes the discovery of small cyclic PDGFRA-targeting peptides, their binding features, and radiolabeling with positron emitter gallium-68 (68Ga) for in vitro and in vivo characterization in thyroid cancer models. Phage-display technology with two separate libraries and seven different cell lines was used through three rounds of biopanning as well as flow cytometry and comparative analysis with recombinant protein to select specific peptide sequences. Phenotypic binding analysis was completed by using phosphorylation and cell migration assays. In vitro protein binding was analyzed with thermophoresis and flow cytometry using the fluorescent-labeled PDGFRA peptide. Peptide candidates were modified with the NOTA chelator for radiolabeling with 68Ga. In vitro cell uptake was studied in various thyroid cancer cell lines. In vivo studies of 68Ga-labeled peptides included metabolic stability and PET imaging. From the original library (1013 compounds), five different peptide groups were identified based on biopanning experiments with and without the α subunit of PDGFR, leading to ∼50 peptides. Subsequent phenotypic screening revealed two core peptide sequences (CP16 and CP18) that demonstrated significant changes in the level of PDGFRA phosphorylation and cell migration. Alanine scan sublibraries were created from these two lead peptide sequences, and peptides were radiolabeled using 68Ga-GaCl3 at pH 4.5, resulting in RCP > 95% within 34-40 min, including SPE purification. Cyclic peptide CP18.5 showed the strongest effects on cell migration, flow cytometry, and binding by visual interference color assay. 68Ga-labeled PDGFRA-targeting peptides showed elevated cell and tumor uptake in models of thyroid cancer, with 68Ga-NOTA-CP18.5 being the lead candidate. However, metabolic stability in vivo was compromised for 68Ga-NOTA-CP18.5 vs 68Ga-NOTA-CP18 but without impacting tumor uptake or clearance profiles. First-generation radiolabeled cyclic peptides have been developed as novel radiotracers, particularly 68Ga-NOTA-CP18.5, for the molecular imaging of PDGFRA in thyroid cancer.

A Novel Polymer Nanoparticle Polydimethyl Diallyl Ammonium Chloride as An Adjuvant Enhances the Immune Response of SARS-CoV-2 Subunit Vaccine.

The Coronavirus Disease 2019 (COVID-19) pandemic caused by SARS-CoV-2 has a significant impact on global health and the economy. It has underscored the urgent need for a stable, easily produced and effective vaccine. This study presents a novel approach using SARS-CoV-2 spike (S) protein-conjugated nanoparticles (NPs) in combination with cyclic GMP-AMP (cGAMP) (S-NPs-cGAMP) as a subunit vaccine. When mice are immunized, the antiserum of S-NPs-cGAMP group exhibits a 16-fold increase in neutralizing activity against a pseudovirus, compared to S protein group. Additionally, S-NPs-cGAMP induces even higher levels of neutralizing antibodies. Remarkably, the vaccine also triggers a robust humoral immune response, as evidenced by a notable elevation in virus-specific IgG and IgM antibodies. Furthermore, after 42 days of immunization, there is an observed increase in specific immune cell populations in the spleen. CD3+CD4+ and CD3+CD8+T lymphocytes, as well as B220+CD19+ and CD3-CD49b+ NK lymphocytes, show an upward trend, indicating a positive cellular immune response. Moreover, the S-NPs-cGAMP demonstrates promising results against the Delta strain and exhibits good cross-neutralization potential against other variants. These findings suggest that pDMDAAC NPs is potential adjuvant and could serve as a versatile platform for future vaccine development.

Emerging applications of single-cell profiling in precision medicine of atherosclerosis.

Atherosclerosis is a chronic, progressive, inflammatory disease that occurs in the arterial wall. Despite recent advancements in treatment aimed at improving efficacy and prolonging survival, atherosclerosis remains largely incurable. In this review, we discuss emerging single-cell sequencing techniques and their novel insights into atherosclerosis. We provide examples of single-cell profiling studies that reveal phenotypic characteristics of atherosclerosis plaques, blood, liver, and the intestinal tract. Additionally, we highlight the potential clinical applications of single-cell analysis and propose that combining this approach with other techniques can facilitate early diagnosis and treatment, leading to more accurate medical interventions.

IGF­1 inhibits palmitic acid­induced mitochondrial apoptosis in macrophages.

Insulin growth factor­1 (IGF­1) is an endocrine regulator that plays an important role in normal growth and development. IGF­1 mediated effects may result in protecting macrophages from immunometabolic response. However, it is unclear whether IGF­1 has a protective effect on fatty acid­induced macrophages damage. In the present study, THP­1 cells were differentiated into macrophages and stimulated with palmitic acid (PA) in the absence or presence of IGF­1. Macrophages apoptosis was measured by Cell Counting Kit­8 assay, flow cytometry, Hoechst 33342 staining and western blotting. The mitochondrial damage was evaluated using JC­1 staining and mitochondrial reactive oxygen species detection. The activation of mitophagy was assessed using immunofluorescence and western blotting. As a result, IGF­1 significantly restored the survival rate in macrophages, while the apoptosis was inhibited through mitochondrial pathway. In addition, IGF­1 protected the mitochondrial damage induced by PA. Furthermore, PA induced mitophagy via phosphatase and tensin homolog­induced putative kinase protein 1/Parkin, which was reversed by IGF­1. Taken together, the present study demonstrated the protective effect of IGF­1 on PA­induced mitochondrial apoptosis in macrophages, which might provide a potential therapeutic strategy for treatment of lipotoxicity.

The Role of Circular RNAs in Ischemic Stroke.

Ischemic stroke (IS), a devastating condition characterized by intracranial artery stenosis and middle cerebral artery occlusion leading to insufficient oxygen supply to the brain, is a major cause of death and physical disability worldwide. Recent research has demonstrated the critical role of circular RNAs (circRNAs), a class of covalently enclosed noncoding RNAs that are widespread in eukaryotic cells, in regulating various physiological and pathophysiological cellular processes, including cell apoptosis, autophagy, synaptic plasticity, and neuroinflammation. In the past few years, circRNAs have attracted extensive attention in the field of IS research. This review summarizes the current understanding of the mechanisms underlying the involvement of circRNAs in IS development. A better understanding of circRNA-mediated pathogenic mechanisms in IS may pave the way for translating circRNA research into clinical practice, ultimately improving the clinical outcomes of IS patients.

Association between interpersonal relations and anxiety, depression symptoms, and suicidal ideation among middle school students.

Objective: This study aimed to explore the relationship between different types of interpersonal relationships and anxiety symptoms, depressive symptoms, and suicidal ideation and discusses the impact of different grades among middle school students. Methods: The Patient Health Questionnaire Depression Scale, the Chinese version of the Generalized Anxiety Scale, suicidal ideation questions, and interpersonal relations items were used to measure the depression symptoms, anxiety symptoms, suicidal ideation, and interpersonal relations of the participants. The variables of anxiety symptoms, depressive symptoms, suicidal ideation, and interpersonal relations were screened using the Chi-square test and principal component analysis. AMOS17.0 constructs the path of the association between interpersonal relations and depressive symptoms, anxiety symptoms, and suicidal ideation. Results: The mother-child relationship had direct impacts of -0.06, -0.07, and -0.06 on anxiety symptoms, depressive symptoms, and suicidal ideation. On anxiety symptoms, depressive symptoms, and suicidal ideation, the direct impacts of the father-child relationship were -0.09, -0.03, and -0.08. Moreover, the direct effects of peer relationships on depressive symptoms were -0.04, whereas the direct impact of teacher-student relationships on anxiety and depressive symptoms were -0.10 and -0.09. Further pathway analysis based on grade level showed that in the junior high school model, the direct effect of the mother-child relationship on anxiety and depressive symptoms was -0.18 and -0.16. The direct impact of the father-child relationship on depressive symptoms and suicidal ideation was -0.08 and 0.09. The direct effect of peer relationships on depressive symptoms was -0.08, and the direct impact of the teacher-student relationship on anxiety symptoms was -0.06. In the high school model, the direct effect of the mother-child relationship on suicidal ideation was -0.07, while the direct impact of the father-child relationship on anxiety, depression, and suicidal ideation was -0.10, -0.07, and -0.12, respectively. In addition, the direct effects of peer relationships on anxiety and depression were -0.06 and -0.05, and the direct impact of teacher-student relationships on anxiety and depression was -0.10 and -0.11. Conclusion: The father-child relationship affects suicidal ideation and depression the most, followed by the mother-child relationship, the teacher-student interaction, and the peer relationship. The teacher-student relationship influences anxiety symptoms the most, followed by the father-child and mother-child relationships. The association between interpersonal interactions and anxiety, depressive symptoms, and suicidal ideation varied significantly across grade levels.

Optimized Morphology Enables High-Efficiency Nonfullerene Ternary Organic Solar Cells.

Tuning the three-dimensional morphology in the active layer is an effective method to improve the performance of bulk heterojunction organic solar cells (OSCs). In this work, an acceptor-donor-acceptor structured small molecule ST10-CN-1 was synthesized and employed as the guest donor to fabricate ternary OSCs based on a PBDB-T:IT-M host binary system. The incorporation of ST10-CN-1 could broaden the active layer's absorption range of solar light thereby leading to a promotional short-circuit current. Moreover, adding an appropriate amount of ST10-CN-1 could effectively regulate the morphology of the active layer in both the lateral direction and vertical stratification. All of these morphological alterations helped to speed up the exciton dissociation, charge transit, and charge collecting processes, which in turn increased the power conversion efficiency. As a result, an excellent PCE of 11.5% for the ternary device based on PBDB-T:IT-M:ST10-CN-1 was obtained. The enhanced PCE was also linked to the formation of an alloylike state between PBDB-T and ST10-CN-1, as evidenced by the fact that the open circuit voltage of ternary OSCs lay between those for PBDB-T:IT-M (0.925 V) and ST10-CN-1:IT-M (1.064 V). This work illustrates that refining the morphology of the active layer by incorporating an appropriate third component is an effective way to further enhance the device's performance.

Long-term disability in common mental disorders in Chinese community: evidence from a five-year follow-up study.

BACKGROUND: Common mental disorders are general term for mental disorders with high disability rates and significant social burden. The purpose of this study was to determine the degree of long-term disability associated with common mental disorders and to interpret the relationship between common mental disorders and long-term disability. METHODS: Participants in the 2013 China Mental Health Survey were followed up by telephone between April and June 2018. This study evaluated long-term disability over a five-year period using the World Health Organization's Disability Assessment Schedule 2.0. Poisson regression was used to analyze the relationship between common mental disorders and long-term disability. RESULTS: A total of 6269 patients were followed up by telephone. In patients with common mental disorders, the prevalence of disability ranged from 7.62% to 43.94%. The long-term disabilities were significantly associated with dysthymic disorder (DD, RR:2.40; 95% CI:1.87-3.03), major depressive disorder (MDD, RR:1.63; 95% CI:1.34-1.98), generalized anxiety disorder (GAD, RR:1.95; 95% CI:1.15-3.09), obsessive-compulsive disorder (OCD, RR:1.68; 95% CI:1.24-2.22) and alcohol use disorder (AUD, RR: 1.42; 95% CI:0.99-1.96). CONCLUSIONS: In China, common mental disorders raise the risk of long-term disability, and there is a critical need for monitoring patients with DD, MDD, GAD, OCD, and AUD. For improved quality of life and reduced disability levels, more resources need to be dedicated to mental health in the future.

A multilevel model of the help-seeking behaviors among adolescents with mental health problems.

Objective: Mental health problems are highly prevalent among adolescents yet the utilization of mental health services among such a population is very low. This study was conducted to examine mental health problems and related help-seeking behaviors among a Chinese sample of adolescents. Methods: A total of 3,480 students were recruited from four middle- and high schools in Changsha City, Hunan province, and completed an online questionnaire that assessed their general information, mental health problems including depression, anxiety, self-harm, and suicide ideation, as well as their help-seeking behaviors from both formal (including psychological teachers and mental health professionals) and informal sources (including family, friends, and teachers). Results: The participants had a prevalence of 13.7% for depression, 11.5% for anxiety, 9.8% for self-harm, and 9.1% for suicide ideation. Although a high rate of help-seeking behaviors was observed (73.0%), most were concentrated in informal sources (99.3%), while only a small portion of participants resorted to formal sources (13.9%). Being female (OR: 1.45, 95% CI: 1.15-1.83), higher grade (OR: 1.32, 95% CI: 1.01-1.73), school mental health resources not available (OR: 1.39, 95% CI: 1.02-1.88), without suicide ideation (OR: 2.03, 95% CI: 1.42-2.90) were all associated with increased likelihood of formal help-seeking behaviors. On the other hand, complete middle school (OR: 0.36, 95% CI: 0.22-0.59), the middle level of academic ranking (OR: 0.64, 95% CI: 0.42-0.97), and higher father education levels (OR: 0.54-0.56, 95% CI: 0.33-0.90) were all associated with a decreased likelihood of formal help-seeking behaviors. Conclusion: Our results showed a higher prevalence of help-seeking behavior for emotional or psychological problems during the past year. Compared to the high rate of informal help-seeking behaviors, students showed a lower propensity to seek formal help for their mental health problems, which may be explained by individual-level, family-level, and school-level factors. Our findings provide important implications for the development and popularization of targeted, needs-based mental health promotion and education programs in the future.

The association between sleep and suicidality in the presence and absence of depressive symptoms: A cross-sectional study in rural China.

This study aimed to explore the association between sleep and suicidality in the presence and absence of depressive symptoms in the rural Chinese population. The research involved a cross-sectional survey conducted in Liuyang, China, between November 2010 and August 2011. A total of 2052 participants were surveyed (987 males and 1065 females). To investigate the mediating effect of depressive symptoms in the correlation between sleep quality and suicidality. The association between sleep quality and suicidality in the absence of depressive symptoms was also explored. Suicide risk was measured using the Mini-International Neuropsychiatric Interview subscale. The visual analog scale was used to assess sleep quality. Patient Health Questionnaire-9 and Patient Health Questionnaire-2, avoiding the overlap in sleep and suicidality assessments, were used for detecting depressive symptoms in participants. Depressive symptoms partially mediated the association between sleep quality and suicidality among rural adults. Furthermore, some participants did not exhibit depressive symptoms in this study yet still exhibited a risk for suicidality, with poor sleep quality contributing significantly to their suicidality even after adjusting for cofounders. Poor sleep quality significantly increases the likelihood of suicidality in the presence and absence of depressive symptoms in the rural Chinese population. Poor sleep quality could correlate with increased suicide risk independently of depressive symptoms.

Histone Deacetylase 3: A Potential Therapeutic Target for Atherosclerosis.

Atherosclerosis, the pathological basis of most cardiovascular disease, is characterized by plaque formation in the intima. Secondary lesions include intraplaque hemorrhage, plaque rupture, and local thrombosis. Vascular endothelial function impairment and smooth muscle cell migration lead to vascular dysfunction, which is conducive to the formation of macrophage-derived foam cells and aggravates inflammatory response and lipid accumulation that cause atherosclerosis. Histone deacetylase (HDAC) is an epigenetic modifying enzyme closely related to chromatin structure and gene transcriptional regulation. Emerging studies have demonstrated that the Class I member HDAC3 of the HDAC super family has cell-specific functions in atherosclerosis, including 1) maintenance of endothelial integrity and functions, 2) regulation of vascular smooth muscle cell proliferation and migration, 3) modulation of macrophage phenotype, and 4) influence on foam cell formation. Although several studies have shown that HDAC3 may be a promising therapeutic target, only a few HDAC3-selective inhibitors have been thoroughly researched and reported. Here, we specifically summarize the impact of HDAC3 and its inhibitors on vascular function, inflammation, lipid accumulation, and plaque stability in the development of atherosclerosis with the hopes of opening up new opportunities for the treatment of cardiovascular diseases.

Future Trends in Disability and Its Determinants Among Chinese Community Patients With Anxiety Disorders: Evidence From a 5-Year Follow-Up Study.

Background: Anxiety disorders (ADs) are a group of disorders with a high disability rate and bring a huge social burden. In China, information on future trends in the disability among community ADs patients and its determinants are rare. The objectives of this study are to describe the future trends in the disability among ADs patients living in community and to investigate the determinants of the disability. Methods: Participants diagnosed with 12-month ADs in the China Mental Health Survey (CMHS) were followed up by telephone from April to June 2018 to assess the future trends in the disability in a 5-year interval using the World Health Organization's Disability Assessment Schedule 2.0. The disability rate was reported and its determinants were analyzed by complex sample design multivariate logistic regression. Results: Totally 271 patients were interviewed by telephone and 33 informants finished proxy interviews. The disability rates were 45.9% and 14.3% among ADs patients at baseline and during the follow-up. Patients with general anxiety disorder (GAD) or agoraphobia with/without panic disorder (AGP) had the lower decrease and higher disability during the follow-up than patients with other subtypes. Patients aged in middle age (aged 40-49 years old, OR = 11.12, 95% CI: 4.16-29.72), having disability at baseline (OR = 7.18, 95% CI: 1.37-37.73), having comorbidity with three or more physical diseases (OR = 9.27, 95% CI: 2.48-34.71), and having comorbidity with other mental disorders (OR = 3.97, 95% CI: 1.13-13.96) had higher disability during the follow-up. Conclusions: The disability rate tends to decrease among ADs patients living in communities. Treatment priority should be given for ADs patients with disability and those in middle age. Treatments for the comorbidity of other mental disorders or physical diseases should be considered when treating anxiety.

Promotion Effect of the X-Zeolite Host on Encapsulated Platinum Clusters for Selective Hydrogenation of Phenylacetylene to Styrene.

The microenvironment surrounding the metal clusters on a carrier produces a tremendous influence on its catalytic performance. In this work, the promotion effect of the zeolitic inner host on catalytic performance of encapsulated platinum nanoclusters is reported. In the reaction of phenylacetylene semihydrogenation to styrene, Pt@X-zeolite, where platinum nanoclusters are encapsulated into the inner microporosity of the X-zeolite, exhibits an ∼3.37 times increased turnover frequency and a much better selectivity of 87.6% in comparison to the referenced Pt/X-zeolite of 79.3% selectivity to styrene at the same reaction conditions, in which the platinum nanoclusters are located at the exterior of the zeolite. Meanwhile, the Pt@X-zeolite displays a higher stability after 10 cycles of the reaction. Through the detailed characteristics, the excellent performance of Pt@X-zeolite is mainly due to the promotion of the zeolitic framework on the encapsulated Pt clusters, resulting in "electron-deficient" Pt clusters, leading to a stronger interaction with the π* molecular orbitals of phenylacetylene and thus enhancing the activation and conversion of phenylacetylene. The zeolite cavity wrapped with encapsulated Pt clusters regulates the adsorption trend of phenylacetylene through the acetylene group on it, promotes the desorption of styrene, and strengthens its selectivity. Meanwhile, Pt@X-zeolite has an excellent stability through the zeolite framework, which protects the Pt species from being lost. This investigation reveals the importance of the zeolitic microenvironment on the catalytic performance of encapsulated metal species and deepens the cognition for this type of catalyst.

Emerging roles of growth differentiation factor-15 in brain disorders (Review).

Brain disorders, such as Alzheimer's and Parkinson's disease and cerebral stroke, are an important contributor to mortality and disability worldwide, where their pathogenesis is currently a topic of intense research. The mechanisms underlying the development of brain disorders are complex and vary widely, including aberrant protein aggregation, ischemic cell necrosis and neuronal dysfunction. Previous studies have found that the expression and function of growth differentiation factor-15 (GDF15) is closely associated with the incidence of brain disorders. GDF15 is a member of the TGFß superfamily, which is a dimer-structured stress-response protein. The expression of GDF15 is regulated by a number of proteins upstream, including p53, early growth response-1, non-coding RNAs and hormones. In particular, GDF15 has been reported to serve an important role in regulating angiogenesis, apoptosis, lipid metabolism and inflammation. For example, GDF15 can promote angiogenesis by promoting the proliferation of human umbilical vein endothelial cells, apoptosis of prostate cancer cells and fat metabolism in fasted mice, and GDF15 can decrease the inflammatory response of lipopolysaccharide-treated mice. The present article reviews the structure and biosynthesis of GDF15, in addition to the possible roles of GDF15 in Alzheimer's disease, cerebral stroke and Parkinson's disease. The purpose of the present review is to summarize the mechanism underlying the role of GDF15 in various brain disorders, which hopes to provide evidence and guide the prevention and treatment of these debilitating conditions.

A natural acylphloroglucinol triggered antiproliferative possessions in HEL cells by impeding STAT3 signaling and attenuating angiogenesis in transgenic zebrafish model.

Leukemia is responsible for a reason of death, globally. Even though there are several treatment regimens available in the clinics against this disease, a perfect chemotherapeutic agent for the same is still under investigation. Natural plant-derived secondary metabolites are used in clinics to treat leukemia for better benefits with reduced side-effects. Likely, several bioactive compounds from Callistemon sp. were reported for their bioactive benefits. Furthermore, acylphloroglucinol derivatives from Callistemon salignus, showed both antimicrobial and cytotoxic activities in various adherent human cancer cell lines. Thus, in the present study, a natural acylphloroglucinol (2,6-dihydroxy-4-methoxyisobutyrophenone, L72) was tested for its antiproliferative efficacy in HEL cells. The MTT and the cell cycle analysis study revealed that L72 treatment can offer antiproliferative effects, both time and dose-dependent manner, causing G2/M cell cycle arrest. The western blot analysis revealed that L72 treatment triggered intrinsic apoptotic machinery and activated p21. Likewise, L72 could downregulate the gene expressions of XIAP, FLT3, IDH2, and SOD2, which was demonstrated by qPCR analysis, thus promoting its antiproliferative action. The L72 could impede STAT3 expression, which was evidenced by insilico autodock analysis and western blot analysis using STAT3 inhibitor, Pimozide. The treatment of transgenic (Flk-1+/egfr+) zebrafish embryos resulted in the STAT3 gene inhibition, proving its anti-angiogenic effect, as well. Thus, the study revealed that L72 could act as an antiproliferative agent, by triggering caspase-dependent intrinsic apoptosis, reducing cell proliferation by attenuating STAT3, and activating an anti-angiogenic pathway via Flk-1inhibition.

Dimethylglyoxime Clathrate as Ligand Derived Nitrogen-Doped Carbon-Supported Nano-Metal Particles as Catalysts for Oxygen Reduction Reaction.

Nitrogen-doped carbon-supported metal nano-particles show great promise as high-performance catalysts for novel energies, organic synthesis, environmental protection, and other fields. The synergistic effect between nitrogen-doped carbon and metal nano-particles enhances the catalytic properties. Thus, how to effectively combine nitrogen-doped carbon with metal nano-particles is a crucial factor for the synthesis of novel catalysts. In this paper, we report on a facile method to prepare nitrogen-doped carbon-supported metal nano-particles by using dimethylgly-oxime as ligand. The nano-particles of Pd, Ni, Cu, and Fe were successfully prepared by the pyrolysis of the corresponding clathrate of ions and dimethylglyoxime. The ligand of dimethylglyoxime is adopted as the source for the nitrogen-doped carbon. The nano-structure of the prepared Pd, Ni, Cu, and Fe particles are confirmed by X-ray diffraction, scanning electron microscopy, and trans-mission electron microscopy tests. The catalytic performances of the obtained metal nano-particles for oxygen reduction reaction (ORR) are investigated by cyclic voltammetry, Tafel, linear sweeping voltammetry, rotating disc electrode, rotating ring disc electrode, and other technologies. Results show that the nitrogen-doped carbon-supported metal nano-particles can be highly efficient catalysts for ORR. The results of the paper exhibit a facile methodology to prepare nitrogen-doped carbon-supported metal nano-particles.

Endocan: A Key Player of Cardiovascular Disease.

Endothelial dysfunction is considered to be an early change in atherosclerosis. Endocan, also known as endothelial cell specific molecule-1, is a soluble proteoglycan mainly secreted by endothelial cells. Inflammatory factors such as IL-1ß and TNF-α can up regulate the expression of endocan and then affect the expression of cell adhesion molecules, such as ICAM-1 and VCAM-1, which play an important role in promoting leukocyte migration and inflammatory response. Elevated plasma levels of endocan may reflect endothelial activation and dysfunction, and is considered to be a potential immuno-inflammatory marker that may be related to cardiovascular disease. In the case of hypertension, diabetes, angina pectoris and acute myocardial infarction, the increase or decrease of serum endocan levels is of great significance. Here, we reviewed the current research on endocan, and emphasis its possible clinical value as a prognostic marker of cardiovascular disease. Endocan may be a useful biomarker for the prognosis of cardiovascular disease, but more research is needed on its mechanism of action.

Substrate stiffness differentially impacts autophagy of endothelial cells and smooth muscle cells.

Stiffening of blood vessels is one of the most important characteristics in the process of many cardiovascular pathologies such as atherosclerosis, angiosteosis, and vascular aging. Increased stiffness of the vascular extracellular matrix drives artery pathology and alters phenotypes of vascular cell. Understanding how substrate stiffness impacts vascular cell behaviors is of great importance to the biomaterial design in tissue engineering, regenerative medicine, and medical devices. Here we report that changing substrate stiffness has a significant impact on the autophagy of vascular endothelial cells (VECs) and smooth muscle cells (VSMCs). Interestingly, our findings demonstrate that, with the increase of substrate stiffness, the autophagy level of VECs and VSMCs showed differential changes: endothelial autophagy levels reduced, leading to the reductions in a range of gene expression associated with endothelial function; while, autophagy levels of VSMCs increased, showing a transition from contractile to the synthetic phenotype. We further demonstrate that, by inhibiting cell autophagy, the expressions of endothelial functional gene were further reduced and the expression of VSMC calponin increased, suggesting an important role of autophagy in response of the cells to the challenge of microenvironment stiffness changing. Although the underlying mechanism requires further study, this work highlights the relationship of substrate stiffness, autophagy, and vascular cell behaviors, and enlightening the design principles of surface stiffness of biomaterials in cardiovascular practical applications.

ZG02 Improved Hepatic Glucose Metabolism and Insulin Sensitivity via Activation of AMPK/Sirt1 Signaling Pathways in a High-fat Diet/Streptozotocin-induced Type 2 Diabetes Model.

PURPOSE: The aim of the present study was to investigate the hypoglycemic activity and potential mechanism of tetrahydrocarbazole derivatives ZG02 in high-fat diet/streptozotocin-induced type 2 diabetes model. METHODS: C57BL/6 mice (n=30) were randomly assigned to three groups: control group (n=10) was fed with normal diet, the diabetes group (n=10) was fed with high-fat diet for eight weeks followed by intraperitoneal injection of streptozotocin (25 mg/kg) and the ZG02 group (n=10) injected intraperitoneally with ZG02 (30 mg/kg/day) for two weeks after successful modeling. The changes of weight, fasting blood glucose, oral glucose tolerance and fasting blood insulin levels in each group were evaluated. In addition, we also assessed the expression level of total AMPK, phosphorylation AMPK, SIRT1, PGC-1 and the activity of G6PC in liver. RESULTS: The results demonstrated that ZG02 could significantly antagonize the high-fat diet/streptozotocin-induced fasting hyperglycemia, restore fasting blood insulin levels and also improve activity of G6PC in liver. The results from Western blot indicated that ZG02 significantly restored the expression level of phosphorylation AMPK, Sirt1 and PGC-1. CONCLUSION: ZG02 improve hepatic glucose metabolism and insulin sensitivity via activation AMPK/Sirt1 signaling pathways in type 2 diabetes mice model.