EPAC inhibitor suppresses angiogenesis and tumor growth of triple-negative breast cancer.

AIMS: Exchange protein directly activated by cAMP 1 (EPAC1), a major isoform of guanine nucleotide exchange factors, is highly expressed in vascular endothelia cells and regulates angiogenesis in the retina. High intratumor microvascular densities (MVD) resulting from angiogenesis is responsible for breast cancer development. Downregulation of EPAC1 in tumor cell reduces triple-negative breast cancer (TNBC)-induced angiogenesis. However, whether Epac1 expressed in vascular endothelial cells contributes to angiogenesis and tumor development of TNBC remains elusive. MAIN METHODS: We employed NY0123, a previously identified potent EPAC inhibitor, to explore the anti-angiogenic biological role of EPAC1 in vitro and in vivo through vascular endothelial cells, rat aortic ring, Matrigel plug, and chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) assays, as well as the in vivo xenograft tumor models of TNBC in both chick embryo and mice. KEY FINDINGS: Inhibiting EPAC1 in vascular endothelial cells by NY0123 significantly suppresses angiogenesis and tumor growth of TNBC. In addition, NY0123 possesses a better inhibitory efficacy than ESI-09, a reported specific EPAC inhibitor tool compound. Importantly, inhibiting EPAC1 in vascular endothelia cells regulates the typical angiogenic signaling network, which is associated with not only vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor-2 (VEGFR2) signaling, but also PI3K/AKT, MEK/ERK and Notch pathway. CONCLUSIONS: Our findings support that EPAC1 may serve as an effective anti-angiogenic therapeutic target of TNBC, and EPAC inhibitor NY0123 has the therapeutic potential to be developed for the treatment of TNBC.

Injectable cell-laden hybrid bioactive scaffold containing bioactive glass microspheres.

The rising incidence of bone disorders has resulted in the need for minimally invasive therapies to meet this demand. Injectable bioactive filler, alone or with cells, could be applied in a minimally invasive manner to fulfill irregular cavities in non-load bearing sites, which do not require high mechanical properties. Thermosensitive chitosan hydrogels that transition from a liquid to a mechanically stable solid at body temperature provide interesting features as in-situ injectable cytocompatible biomaterials, but they are not osteoconductive. Osteoconductivity can be applied in combination with bioactive ceramics e.g., 45S5-Bioglass® (BG). However, BG addition in chitosan hydrogels results in pH elevation, due to rapid ions release, which adversely affects gel formation, mechanical properties, and cytocompatibility. To address this, we created hybrid hydrogels, where BG is concentrated in chitosan-based microbeads, incorporated in in-situ gelling chitosan hydrogels. We then compared the hybrid hydrogels' properties to chitosan hydrogels with homogenously distributed BG. By varying the stirred emulsification process, BG percentage, and CH formulation, we could tune the microbeads' properties. Incorporation of BG microbeads drastically improved the hydrogel's compressive modulus in comparison to homogeneously distributed BG. It also strongly increased the survival and metabolic activities of encapsulated cells. Calcium/phosphate increase on BG microbeads suggests hydroxyapatite formation. The small diameter of microbeads allows minimally invasive injection through small needles. The feasibility of freezing and thawing microbeads provides the possibility of long-term storage for potential clinical applications. These data indicate that this hybrid hydrogel forms a promising injectable cell-laden bioactive biomaterial for the treatment of unloaded bone defects.

SEL1L-HRD1 endoplasmic reticulum-associated degradation controls STING-mediated innate immunity by limiting the size of the activable STING pool.

Stimulator of interferon genes (STING) orchestrates the production of proinflammatory cytokines in response to cytosolic double-stranded DNA; however, the pathophysiological significance and molecular mechanism underlying the folding and maturation of nascent STING protein at the endoplasmic reticulum (ER) remain unknown. Here we report that the SEL1L-HRD1 protein complex-the most conserved branch of ER-associated degradation (ERAD)-is a negative regulator of the STING innate immunity by ubiquitinating and targeting nascent STING protein for proteasomal degradation in the basal state. SEL1L or HRD1 deficiency in macrophages specifically amplifies STING signalling and immunity against viral infection and tumour growth. Mechanistically, nascent STING protein is a bona fide substrate of SEL1L-HRD1 in the basal state, uncoupled from ER stress or its sensor inositol-requiring enzyme 1α. Hence, our study not only establishes a key role of SEL1L-HRD1 ERAD in innate immunity by limiting the size of the activable STING pool, but identifies a regulatory mechanism and therapeutic approach to targeting STING.

Andrographolide Suppresses the Growth and Metastasis of Luminal-Like Breast Cancer by Inhibiting the NF-κB/miR-21-5p/PDCD4 Signaling Pathway.

Tumor growth and metastasis are responsible for breast cancer-related mortality. Andrographolide (Andro) is a traditional anti-inflammatory drug used in the clinic that inhibits NF-κB activation. Recently, Andro has been found in the treatment of various cancers. Andro inhibits breast cell proliferation and invasion and induces apoptosis via activating various signaling pathways. Therefore, the underlying mechanisms with regard to the antitumor effects of Andro still need to be further confirmed. Herein, a MMTV-PyMT spontaneous luminal-like breast cancer lung metastatic transgenic tumor model was employed to estimate the antitumor effects of Andro on breast cancer in vivo. Andro significantly inhibited tumor growth and metastasis in MMTV-PyMT mice and suppressed the cell proliferation, migration, and invasion of MCF-7 breast cancer cells in vitro. Meanwhile, Andro significantly inhibited the expression of NF-κB, and the downregulated NF-κB reduced miR-21-5p expression. In addition, miR-21-5p dramatically inhibited the target gene expression of programmed cell death protein 4 (PDCD4). In the current study, we demonstrated the potential anticancer effects of Andro on luminal-like breast cancer and indicated that Andro inhibits the expression of miR-21-5p and further promotes PDCD4 via NF-κB suppression. Therefore, Andro could be an antitumor agent for the treatment of luminal-like breast cancer in the clinic.

Anthropomorphic and biomechanical mockup for abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is an asymptomatic condition due to the dilation of abdominal aorta along with progressive wall degeneration, where rupture of AAA is life-threatening. Failures of AAA endovascular repair (EVAR) reflect our inadequate knowledge about the complex interaction between the aortic wall and medical devices. In this regard, we are presenting a hydrogel-based anthropomorphic mockup (AMM) to better understand the biomechanical constraints during EVAR. By adjusting the cryogenic treatments, we tailored the hydrogel to mimic the mechanical behavior of human AAA wall, thrombus and abdominal fat. A specific molding sequence and a pressurizing system were designed to reproduce the geometrical and diseased characteristics of AAA. A mechanically, anatomically and pathologically realistic AMM for AAA was developed for the first time, EVAR experiments were then performed with and without the surrounding fat. Substantial displacements of the aortic centerlines and vessel expansion were observed in the case without surrounding fat, revealing an essential framework created by the surrounding fat to account for the interactions with medical devices. In conclusion, the importance to consider surrounding tissue for the global deformation of AAA during EVAR was highlighted. Furthermore, potential use of this AMM for medical training was also suggested.