E93 is indispensable for reproduction in ametabolous and hemimetabolous insects.

Ecdysone-induced protein 93 (E93), known as the 'adult-specifier' transcription factor in insects, triggers metamorphosis in both hemimetabolous and holometabolous insects. Although E93 is conserved in ametabolous insects, its spatiotemporal expression and physiological function remain poorly understood. In this study, we first discover that, in the ametabolous firebrat Thermobia domestica, the previtellogenic ovary exhibits cyclically high E93 expression, and E93 mRNA is broadly distributed in previtellogenic ovarioles. E93 homozygous mutant females of T. domestica exhibit severe fecundity deficiency due to impaired previtellogenic development of the ovarian follicles, likely because E93 induces the expression of genes involved in ECM (extracellular matrix)-receptor interactions during previtellogenesis. Moreover, we reveal that in the hemimetabolous cockroach Blattella germanica, E93 similarly promotes previtellogenic ovarian development. In addition, E93 is also essential for vitellogenesis that is necessary to guarantee ovarian maturation and promotes the vitellogenesis-previtellogenesis switch in the fat body of adult female cockroaches. Our findings deepen the understanding of the roles of E93 in controlling reproduction in insects, and of E93 expression and functional evolution, which are proposed to have made crucial contributions to the origin of insect metamorphosis.

Revisiting the four Hexapoda classes: Protura as the sister group to all other hexapods.

Insects represent the most diverse animal group, yet previous phylogenetic analyses based on morphological and molecular data have failed to agree on the evolutionary relationships of early insects and their six-legged relatives (together constituting the clade Hexapoda). In particular, the phylogenetic positions of the three early-diverging hexapod lineages-the coneheads (Protura), springtails (Collembola), and two-pronged bristletails (Diplura)-have been debated for over a century, with alternative topologies implying drastically different scenarios of the evolution of the insect body plan and hexapod terrestrialization. We addressed this issue by sampling all hexapod orders and experimenting with a broad range of across-site compositional heterogeneous models designed to tackle ancient divergences. Our analyses support Protura as the earliest-diverging hexapod lineage ("Protura-sister") and Collembola as a sister group to Diplura, a clade corresponding to the original composition of Entognatha, and characterized by the shared possession of internal muscles in the antennal flagellum. The previously recognized 'Elliplura' hypothesis is recovered only under the site-homogeneous substitution models with partial supermatrices. Our cross-validation analysis shows that the site-heterogeneous CAT-GTR model, which recovers "Protura-sister," fits significantly better than homogeneous models. Furthermore, the morphologically unusual Protura are also supported as the earliest-diverging hexapod lineage by other lines of evidence, such as mitogenomes, comparative embryology, and sperm morphology, which produced results similar to those in this study. Our backbone phylogeny of hexapods will facilitate the exploration of the underpinnings of hexapod terrestrialization and megadiversity.

MSC-derived exosomes attenuates pulmonary hypertension via inhibiting pulmonary vascular remodeling.

BACKGROUND: Pulmonary hypertension (PH) is a serious cardiopulmonary disease with significant morbidity and mortality. Vascular obstruction leads to a continuous increase in pulmonary vascular resistance, vascular remodeling, and right ventricular hypertrophy and failure, which are the main pathological features of PH. Currently, the treatments for PH are very limited, so new methods are urgently needed. Msenchymal stem cells-derived exosomes have been shown to have significant therapeutic effects in PH, however, the the mechanism still very blurry. Here, we investigated the possible mechanism by which umbilical cord mesenchymal stem cell-derived exosomes (hUC-MSC-EXO) inhibited monocrotaline (MCT)-induced pulmonary vascular remodeling in a rat model of PH by regulating the NF-κB/BMP signaling pathway. Our data revealed that hUC-MSC-EXO could significantly attenuate MCT-induced PH and right ventricular hypertrophy. Moreover, the protein expression level of BMPR2, BMP-4, BMP-9 and ID1 was significantly increased, but NF-κB p65, p-NF-κB-p65 and BMP antagonists Gremlin-1 was increased in vitro and vivo. Collectively, this study revealed that the mechanism of hUC-MSC-EXO attenuates pulmonary hypertension may be related to inhibition of NF-κB signaling to further activation of BMP signaling. The present study provided a promising therapeutic strategy for PH vascular remodeling.

Effect of Oridonin on Experimental Animal Model of Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) is a serious disease that occurs in premature and low-birth-weight infants. In recent years, the incidence of BPD has not decreased, and there is no effective treatment for it. Oridonin (Ori) is a traditional Chinese medicine with a wide range of biological activities, especially pharmacological and anti-inflammatory. It is well known that inflammation plays a key role in BPD. However, the therapeutic effect of Ori on BPD has not been studied. Therefore, in the present study, we will observe the anti-inflammatory activity of Ori in an experimental animal model of BPD. Here, we showed that Ori could significantly decrease hyperoxia-induced alveolar injury, inhibit neutrophil recruitment, myeloperoxidase concentrations, and release inflammatory factors in BPD neonatal rats. Taken together, the experimental results suggested that Ori can significantly improve BPD in neonatal rats by inhibiting inflammatory response.

The functional evolution of collembolan Ubx on the regulation of abdominal appendage formation.

Folsomia candida is a tiny soil-living arthropod belonging to the Collembola, which is an outgroup to Insecta. It resembles insects as having a pair of antennae and three pairs of thorax legs, while it also possesses three abdominal appendages: a ventral tube located in the first abdominal segment (A1), a retinaculum in A3, and a furca in A4. Collembolan Ubx and AbdA specify abdominal appendages, but they are unable to repress appendage marker gene Dll. The genetic basis of collembolan appendage formation and the mechanisms by which Ubx and AbdA regulate Dll transcription and appendage development remains unknown. In this study, we analysed the developmental transcriptomes of F. candida and identified candidate appendage formation genes, including Ubx (FcUbx). The expression data revealed the dominance of Dll over Ubx during the embryonic 3.5 and 4.5 days, suggesting that Ubx is deficient in suppressing Dll at early appendage formation stages. Furthermore, via electrophoretic mobility shift assays and dual luciferase assays, we found that the binding and repression capacity of FcUbx on Drosophila Dll resembles those of the longest isoform of Drosophila Ubx (DmUbx_Ib), while the regulatory mechanism of the C-terminus of FcUbx on Dll repression is similar to that of the crustacean Artemia franciscana Ubx (AfUbx), demonstrating that the function of collembolan Ubx is intermediate between that of Insecta and Crustacea. In summary, our study provides novel insights into collembolan appendage formation and sheds light on the functional evolution of Ubx. Additionally, we propose a model that collembolan Ubx regulates abdominal segments in a context-specific manner.

Convergent Adaptation of Ootheca Formation as a Reproductive Strategy in Polyneoptera.

Insects have evolved numerous adaptations and colonized diverse terrestrial environments. Several polyneopterans, including dictyopterans (cockroaches and mantids) and locusts, have developed oothecae, but little is known about the molecular mechanism, physiological function, and evolutionary significance of ootheca formation. Here, we demonstrate that the cockroach asymmetric colleterial glands produce vitellogenins, proline-rich protein, and glycine-rich protein as major ootheca structural proteins (OSPs) that undergo sclerotization and melanization for ootheca formation through the cooperative protocatechuic acid pathway and dopachrome and dopaminechrome subpathway. Functionally, OSP sclerotization and melanization prevent eggs from losing water at warm and dry conditions, and thus effectively maintain embryo viability. Dictyopterans and locusts convergently evolved vitellogenins, apolipoprotein D, and laminins as OSPs, whereas within Dictyoptera, cockroaches and mantids independently developed glycine-rich protein and fibroins as OSPs. Highlighting the ecological-evolutionary importance, convergent ootheca formation represents a successful reproductive strategy in Polyneoptera that promoted the radiation and establishment of cockroaches, mantids, and locusts.

300 Million years of coral treaders (Insecta: Heteroptera: Hermatobatidae) back to the ocean in the phylogenetic context of Arthropoda.

Among hundreds of insect families, Hermatobatidae (commonly known as coral treaders) is one of the most unique. They are small, wingless predaceous bugs in the suborder Heteroptera. Adults are almost black in colour, measuring about 5 mm in body length and 3 mm in width. Thirteen species are known from tropical coral reefs or rocky shores, but their origin and evolutionary adaptation to their unusual marine habitat were unexplored. We report here the genome and metagenome of Hermatobates lingyangjiaoensis, hitherto known only from its type locality in the South China Sea. We further reconstructed the evolutionary history and origin of these marine bugs in the broader context of Arthropoda. The dated phylogeny indicates that Hexapoda diverged from their marine sister groups approximately 498 Ma and that Hermatobatidae originated 192 Ma, indicating that they returned to an oceanic life some 300 Myr after their ancestors became terrestrial. Their origin is consistent with the recovery of tropical reef ecosystems after the end-Triassic mass extinction, which might have provided new and open niches for them to occupy and thrive. Our analyses also revealed that both the genome changes and the symbiotic bacteria might have contributed to adaptations necessary for life in the sea.

Development of novel palbociclib-based CDK4/6 inhibitors exploring the back pocket behind the gatekeeper.

CDK4/6 inhibitors plus endocrine therapy is a standard therapy for HR+/HER2- breast cancer. Herein, using structure-based drug design strategy, a novel series of palbociclib derivatives were designed and synthesized as CDK4/6 inhibitors, among which compound 17m exhibited more potent CDK4/6 inhibitory activity and in vitro antiproliferative activity against the phosphorylated Rb-positive cell line MDA-MB-453 than the approved drug palbociclib. Moreover, compound 17m possessed remarkable CDK4/6 selectivity over other CDK family members including CDK1, CDK2, CDK3, CDK5, CDK7 and CDK9. The potent and selective CDK4/6 inhibitory activity endowed compound 17m with robust G1 cell cycle arrest ability in MDA-MB-453 cells. The intracellular inhibition of CDK4/6 by 17m was confirmed by western blot analysis of the levels of phosphorylated Rb in MDA-MB-453 cells. With respect to the metabolic stability, compound 17m possessed longer half-life (t1/2) in mouse liver microsome than palbociclib.

Serum protein profile analysis via label-free quantitation proteomics in patients with early-onset preeclampsia.

BACKGROUND: Preeclampsia (PE) is a serious pregnancy complication, resulting in potentially life-threatening conditions for both mother and foetus. It is worth noting that early-onset PE has become a great challenge for clinicians due to its complex manifestation, rapid progression and serious complications. This study aims to investigate differential serum proteome profiles in patients with early-onset PE. METHODS: Each serum sample was separated using a nanoliter flow rate Easy-nLC chromatography system. Then the samples were analysed by mass spectrometry. Bioinformatics analyses were conducted to analyse the functional categories or signal transduction pathways for differentially abundant proteins. Key proteins identified by mass spectrometry were verified by ELISA. RESULTS: We found 30 and 34 proteins were upregulated and downregulated in early-onset PE patients (n = 3) vs controls (n = 3), respectively. Functional enrichment analysis revealed differentially expressed proteins related to the immune response and regulation of peptidase activity. ELISA confirmed that there were lower CSH1 levels and higher LPA concentrations in the serum samples of early-onset PE patients (n = 22) than in healthy controls (n = 19) (p < 0.05 for CSH1 and p < 0.001 for LPA). CONCLUSIONS: This study revealed the critical features of serum proteins in early-onset PE patients. LPA and CSH1 may serve as biomarkers for early-onset PE diagnosis and therapy.

Early-onset preeclampsia (PE) is still lacking definitive diagnostic or therapeutic strategies. Thus, we tried to identify effective and specific biomarkers for early-onset PE. In this study, we explored the serum protein profiles through the approach of label-free quantitation proteomics between early-onset PE patients and healthy controls. We identified 64 differentially expressed proteins in early-onset PE patients' serum samples. These differentially expressed proteins are associated with the immune response and regulation of peptidase activity. In addition, our findings suggest that LPA and CSH1 may serve as candidate biomarkers for early-onset PE diagnosis and therapy. These results may help physicians to diagnose early-onset PE clinically. What's more, our findings provide new insights into the onset and progression of early-onset PE disease.

Genetic susceptibility analysis of FGF5 polymorphism to preeclampsia in Chinese Han population.

Fibroblast growth factor 5 (FGF5), which is a well-established causative factor for blood pressure, has been identified as a susceptibility gene for preeclampsia (PE) in European and Central Asian women. Here, we examined whether polymorphism rs16998073 in FGF5 confer a significant risk to PE in Chinese Han population by case-control association analysis. FGF5 rs16998073 was genotyped by Sanger sequencing in women with preeclampsia (n = 187) and healthy controls (n = 229) of Han Chinese. We found the frequency of rs16998073T allele was significantly higher in PE patients than that in controls. Next, we utilized dual-luciferase reporter assays and electrophoretic mobility shift assay (EMSA) reactions to investigate whether rs16998073 different alleles could affect the transcriptional activity of FGF5. The dual luciferase reporter assay showed that T allele increased the transcriptional efficiency by 1.5-fold compared with the G allele. Similarly, EMSA revealed that the T allele had a strong transcription factor binding strength compared with the G allele. We then examined the mRNA and protein expression levels of FGF5 in placental tissues by real-time PCR and Western blot assays. We found FGF5 were significantly upregulated in placental tissues from PE patients or PE mouse model than their corresponding controls. In addition, in vitro cell experiments confirmed that FGF5 could promote cell apoptosis of HTR8/SVneo and inhibit cell invasion. Taken together, our data provide evidence implicating rs16998073 of FGF5 as a functional genetic risk variant for PE disease and FGF5 might participate in development of PE disease.

Design, synthesis and biological evaluation of dual HDAC and VEGFR inhibitors as multitargeted anticancer agents.

Herein, a novel series of dual histone deacetylase (HDAC) and vascular endothelial growth factor receptor (VEGFR) inhibitors were designed, synthesized and biologically evaluated based on previously reported pazopanib-based HDAC and VEGFR dual inhibitors. Most target compounds showed significant HDAC1, HDAC6 and VEGFR2 inhibition, which contributed to their potent antiproliferative activities against multiple cancer cell lines and significant antiangiogenic potencies in both human umbilical vein endothelial cell (HUVEC) tube formation assays and rat thoracic aorta ring assays. Further HDAC selectivity evaluations indicated that hydroxamic acids 5 and 9e possessed HDAC isoform selectivity profiles similar to that of the approved HDAC inhibitor suberoylanilide hydroxamic acid(SAHA), while hydrazide12 presented an HDAC isoform selectivity profilesimilar to that of the clinical HDAC inhibitor MS-275. The VEGFR inhibition profiles of 5, 9e and 12 were similar to that of the approved VEGFR inhibitor pazopanib. The intracellular target engagements of Compounds 5 and 12 were confirmed by western blot analysis. The metabolic stabilities of 5, 9e and 12 in mouse liver microsomes were inferior to that of pazopanib. These dual HDAC and VEGFR inhibitors provide lead compounds for further structural optimization to obtainpolypharmacological anticancer agents.

A review of BMP and Wnt signaling pathway in the pathogenesis of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a chronic disease characterized by a progressive elevation in mean pulmonary arterial pressure. This occurs due to abnormal remodeling of small peripheral lung vasculature resulting in progressive occlusion of the artery lumen that eventually causes right heart failure and death. Current therapeutic options for PAH are limited and focused mainly on reversal of pulmonary vasoconstriction and proliferation of vascular cells. Although these treatments can relieve disease symptoms, PAH remains a progressive lethal disease.Bone morphogenetic proteins (BMPs) and their receptors were required for PAH-induced right ventricular hypertrophy. Emerging data suggest that restoration of BMP type II receptor (BMPR2) signaling in PAH is a promising alternative that could prevent and reverse pulmonary vascular remodeling. BMPR2 mutations have been identified in >70% of familial and roughly 15% of sporadic PAH cases. Wingless (Wnt) are a family of secreted glycoproteins with varying expression patterns and a range of functions, Wnt signaling pathway is divided into canonical signaling pathway and non-canonical signaling pathway. A recent study reports that interaction between BMP and Wnt closely associated with lung development, those cascade coordination regulation stem cell fate which determine lung branching morphogenes. The promoting effect of BMPR2 on proliferation, survival, and motility of endothelial cells was through recruiting Wnts signaling pathway, the interaction between BMP and Wnt closely associated with lung development.Therefore, in this review, we outline the latest advances of BMP and Wnt signaling pathway in the pathogenesis of PAH and disease progression.

Absent atherosclerotic risk factors are associated with carotid stiffening quantified with ultrafast ultrasound imaging.

OBJECTIVES: To evaluate carotid stiffening in participants without conventional cardiovascular risk factors (CVRFs) by using ultrafast pulse wave velocity (ufPWV). METHODS: The present study enrolled 517 participants without conventional CVRFs (CVRF-Free total population). Subjects in this population were defined as current non-smokers with untreated blood pressure < 140/90 mmHg, fasting blood glucose (FBG) < 7.0 mmol/L, total cholesterol (TC) < 6.2 mmol/L, low-density lipoprotein cholesterol < 4.1 mmol/L, and high-density lipoprotein cholesterol ≥ 1.0 mmol/L. Participants in the subgroup with optimal CVRFs (CVRF-Optimal subgroup; n = 188) were defined as having blood pressure < 120/80 mmHg, TC < 5.2 mmol/L, and FBG < 5.6 mmol/L. Clinical interviews, physical examinations, serum draw, carotid intima-media thickness (cIMT), and ufPWV were evaluated. Adjusted odds ratios (ORs) with 95% confidence intervals and ordinal logistic regression models were used. RESULTS: Carotid stiffening was present in 46.2-54.5% of CVRF-Free subjects. Age, male sex, and body mass index (BMI) were independently associated with carotid stiffening in both the CVRF-Free total population and CVRF-Optimal subgroup (OR for age = 1.10-1.11, OR for male sex = 2.65-7.19, OR for BMI = 1.34-1.62; p < 0.05). Carotid stiffening was associated with TC only in the CVRF-Free total population (OR for TC = 1.84; p = 0.034). CONCLUSIONS: Many CVRF-Free individuals have carotid stiffening. ufPWV for atherosclerotic stiffening aids the assessment of early atherogenesis and may further clarify the true status of healthy adults without CVRFs. KEY POINTS: • CVRF-Optimal individuals have a lower carotid stiffness than CVRF-Free populations. • ufPWV is a quantitative predictor for the early assessment of AS. • Absent major CVRFs cannot be considered low risk for carotid stiffening and atherosclerosis.

The protective effects of MSC-EXO against pulmonary hypertension through regulating Wnt5a/BMP signalling pathway.

The aim of the study was to explore the mechanism of mesenchymal stem cell-derived exosomes (MSC-EXO) to protect against experimentally induced pulmonary hypertension (PH). Monocrotaline (MCT)-induced rat model of PH was successfully established by a single intraperitoneal injection of 50 mg/kg MCT, 3 weeks later the animals were treated with MSC-EXO via tail vein injection. Post-operation, our results showed that MSC-EXO could significantly reduce right ventricular systolic pressure (RVSP) and the right ventricular hypertrophy index, attenuate pulmonary vascular remodelling and lung fibrosis in vivo. In vitro experiment, the hypoxia models of pulmonary artery endothelial cell (PAEC) and pulmonary vascular smooth muscle cell (PASMC) were used. We found that the expression levels of Wnt5a, Wnt11, BMPR2, BMP4 and BMP9 were increased, but ß-catenin, cyclin D1 and TGF-ß1 were decreased in MSC-EXO group as compared with MCT or hypoxia group in vivo or vitro. However, these increased could be blocked when cells were transfected with Wnt5a siRNA in vitro. Taken together, these results suggested that the mechanism of MSC-EXO to prevent PH vascular remodelling may be via regulation of Wnt5a/BMP signalling pathway.

Mesenchymal stromal cell-derived exosomes improve pulmonary hypertension through inhibition of pulmonary vascular remodeling.

BACKGROUND: Pulmonary hypertension (PH) is a life-threatening disease characterized by pulmonary vascular remodeling, right ventricular hypertrophy and failure. So far no effective treatment exists for this disease; hence, novel approaches are urgently needed. The aim of the present research was to observe the treatment effect of mesenchymal stromal cell derived exosomes and reveal the mechanism. METHODS: Monocrotaline (MCT)-induced PH in rats and hypoxia-induced cell damage model were established, respectively. Exosomes derived from the supernatant of human umbilical cord mesenchymal stem cells (MSC-exo) were injected into MCT-PH model rat or added into the cells cultured medium. Immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot methods were used in vivo and vitro. RESULTS: The results showed that MSC-exo could significantly attenuate right ventricular (RV) hypertrophy and pulmonary vascular remodelling in MCT-PH rats. In the cell culture experiments, we found that MSC-exo could significantly inhibit hypoxia-induced pulmonary arterial endothelial cell (PAEC) apoptosis and pulmonary arterial smooth muscle cells (PASMC) proliferation. Furthermore, the pulmonary arterioles endothelial-to-mesenchymal transition (EndMT) was obviously suppressed. Moreover, the present study suggest that MSC-exo can significantly upregulate the expression of Wnt5a in MCT-PH rats and hypoxic pulmonary vascular cells. Furthermore, with Wnt5a gene silencing, the therapeutic effect of MSC-exo against hypoxia injury was restrained. CONCLUSIONS: Synthetically, our data provide a strong evidence for the therapeutic of MSC-exo on PH, more importantly, we confirmed that the mechanism was associated with up-regulation of the expression of Wnt5a. These results offer a theoretical basis for clinical prevention and treatment of PH.

Baicalin attenuates myocardial ischemia-reperfusion injury through Akt/NF-κB pathway.

BACKGROUND: Baicalin can attenuate myocardial ischemia-reperfusion (I/R) on damage. However, the mechanisms are still not fully understood. The study aimed to investigate the antiapoptosis and anti-inflammatory effects of baicalin on myocardial I/R-induced injury. METHODS: We established male rats I/R model, and baicalin was intragastric administration after ischemia onset. All experimental animals were randomly divided into five groups: group I, sham; group II, I/R; group III, 50 mg/kg; group IV, 100 mg/kg; and group V, 200 mg/kg baicalin. Postoperation, left ventricular (LV) function was recorded by transthoracic echocardiography. Myocardial infarct size, number of vessels and apoptosis were detected by histology and immunohistochemistry. Furthermore, the messenger RNA (mRNA) and protein levels of tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), IL-6, IL-8, IL-10, Bcl2, Bax, caspase-3, phosphatidylinositol 3-kinase (PI3K), Akt, p-Akt, and nuclear factor-κB (NF-κB) p65 in myocardial tissues were measured by quantitative real-time polymerase chain reaction and Western blot analysis assays. RESULT: When compared with I/R groups, baicalin could significantly improve LV hemodynamic parameters. Myocardial infarct size and apoptosis were significantly decreased, but the vessel density was increased. The mRNA levels of TNF-α, IL-1ß, IL-6, and IL-8 were downregulated, but the levels of IL-10, proapoptotic genes caspase-3, and the ratio of Bax/Bcl2 were upregulated. Moreover, the protein expression of PI3K, p-Akt, and Akt were upregulated but NF-κB p65 was downregulated in the groups III, IV, and V than in group II. CONCLUSION: Our current study suggested that baicalin attenuated myocardial I/R-induced damage, inhibited myocardial apoptosis, and inflammation by activating PI3K/Akt but suppressing NF-κB signaling.

Carotid stiffness and atherosclerotic risk: non-invasive quantification with ultrafast ultrasound pulse wave velocity.

OBJECTIVES: To evaluate the value of ultrafast pulse wave velocity (ufPWV) for the quantitative assessment of carotid stiffness and its associated with atherosclerosis (AS) risk. METHODS: The present study included 233 patients with hyperlipoidaemia (AS risk group) and 114 healthy adults as the control group. The carotid (n = 694) intima-media thickness (cIMT), pulse wave velocity-beginning of systole (PWV-BS) and pulse wave velocity-end of systole (PWV-ES) were measured on sample images. Differences, distributive characteristics and correlation evaluation were assessed in patients (ages 18-29, 30-39, 40-49, 50-59, 60-69 and ≥70) and carotids (control group vs AS risk group). RESULTS: The cIMT, PWV-BS and PWV-ES increased with age; PWV-ES and cIMT showed an early significant increase in the 30-39 years group, whereas PWV-BS displayed a significant increase at 40-49 years compared with the 18- to 29-years group. Besides, PWV-ES correlated well with age compared with PWV-BS and cIMT. For carotid level, cIMT, PWV-BS and PWV-ES measurements were higher in the AS risk group compared with control. To compare the value of ufPWV and cIMT in early AS assessment, we subdivided groups into cIMT subgroups using a cut-off thickness of 0.050 cm. PWV-ES measurements were higher in the AS risk group compared with the control in the 0.040-0.050 cm (not thickened) and 0.051-0.060 cm (thickened) cIMT subgroups. CONCLUSIONS: Carotid ufPWV measurement at PWV-ES is a novel modality for the early diagnosis and quantitative assessment of arterial stiffness associated with atherosclerotic risk. KEY POINTS: • ufPWV technique is real-time and well repeatable for assessing carotid stiffness • ufPWV measurements increase and correlate well with age • PWV-ES is a quantitative predictor for the early assessment of AS.

Timing of erythropoietin modified mesenchymal stromal cell transplantation for the treatment of experimental bronchopulmonary dysplasia.

The aim of this study is to optimize the timing of erythropoietin gene modified mesenchymal stem cells (EPO-MSCs) transplantation for bronchopulmonary dysplasia (BPD). Three weeks post-operation, the results indicated that the damage of airway structure and apoptosis were significantly decreased, the proliferation was increased in three EPO-MSCs transplantation groups as compared with BPD mice. Moreover, the inflammation cytokines were improvement in early EPO-MSCs injection mice than in BPD mice, but there was no significant difference between late injection and BPD groups. Furthermore, the protein expression ratio of p-p38/p38MAPK was down-regulation in early mice but not in late transplantation mice. Our findings suggest that EPO-MSCs maybe attenuate BPD injury in early than in late administration by inhibiting inflammation response through down-regulation of the p38MAPK signalling pathway.

Platelet releasate promotes breast cancer growth and angiogenesis via VEGF-integrin cooperative signalling.

BACKGROUND: Selective platelet release of pro- or anti-angiogenic factors distinctly regulated angiogenesis. We hypothesised that selective release of platelet angiogenic factors could differently regulate tumour growth. METHODS: Breast cancer cell proliferation, cancer cell-induced endothelial tube formation in vitro, and tumour growth in vivo were studied in the presence of protease-activated receptor 1-stimulated platelet releasate (PAR1-PR; rich in pro-angiogenic factors) or PAR4-PR (rich in anti-angiogenic factors). RESULTS: The PAR1-PR and PAR4-PR supplementation (10%) similarly enhanced cell proliferation of MCF-7 and MDA-MB-231 breast cancer cells. The cancer cells triggered capillary-like tube formation of endothelial cells that was further enhanced by pro-angiogenic factor-rich PAR1-PR. The VEGF, but not SDF-1α, receptor blockade abolished PAR1-PR/PAR4-PR-enhanced cancer cell proliferation. Integrin blockade by RGDS had identical effects as VEGF inhibition. The Src and ERK inhibition diminished, whereas PI3K and PKC blockade abolished platelet releasate-enhanced cancer cell proliferation. Using a model of subcutaneous implantation of MDA-MB-231 cells in nude mice, PAR1-PR enhanced tumour growth more markedly than PAR4-PR, and seemed to achieve the exaggeration by promoting more profound tumour angiogenesis. CONCLUSIONS: Platelet releasate increases breast cancer cell proliferation through VEGF-integrin cooperative signalling. Pro-angiogenic factor-rich platelet releasate enhances cancer cell-induced angiogenesis more markedly, and thus exaggerates tumour growth in vivo.

Proteomic profiling identified multiple short-lived members of the central proteome as the direct targets of the addicted oncogenes in cancer cells.

"Oncogene addiction" is an unexplained phenomenon in the area of cancer targeted therapy. In this study, we have tested a hypothesis that rapid apoptotic response of cancer cells following acute inhibition of the addicted oncogenes is because of loss of multiple short-lived proteins whose activity normally maintain cell survival by blocking caspase activation directly or indirectly. It was shown that rapid apoptotic response or acute apoptosis could be induced in both A431 and MiaPaCa-2 cells, and quick down-regulation of 17 proteins, which were all members of the central proteome of human cells, was found to be associated with the onset of acute apoptosis. Knockdown of PSMD11 could partially promote the occurrence of acute apoptosis in both MiaPaCa-2 and PANC-1 pancreatic cancer cells. These findings indicate that maintaining the stability of central proteome may be a primary mechanism for addicted oncogenes to maintain the survival of cancer cells through various signaling pathways, and quick loss of some of the short-lived members of the central proteome may be the direct reason for the rapid apoptotic response or acute apoptosis following acute inhibition of the addicted oncogenes in cancer cells. These findings we have presented can help us better understand the phenomenon of oncogene-addiction and may have important implications for the targeted therapy of cancer.