Immunogenic clearance combined with PD-1 blockade elicits antitumor effect by promoting the recruitment and expansion of the effector memory-like CD8T cell.

Immune checkpoint inhibition shows promise for cancer treatment, but only a minority of patients respond. Combination strategies have been explored to overcome this resistance. Combining immunogenic clearance using immunogenic cell death inducers with a rho kinase inhibitor enhances phagocytosis of immunogenically dying cancer cells by antigen-presenting cells, stimulating tumor-specific immune responses by activating CD8T cells via dendritic cell-mediated priming.

Gulp1 regulates chondrocyte growth arrest and differentiation via the TGF-β/SMAD2/3 pathway.

Chondrocyte differentiation is crucial for cartilage formation. However, the complex processes and mechanisms coordinating chondrocyte proliferation and differentiation remain incompletely understood. Here, we report a novel function of the adaptor protein Gulp1 in chondrocyte differentiation.

GULP1 deficiency reduces adipogenesis and glucose uptake via downregulation of PPAR signaling and disturbing of insulin/ERK signaling in 3T3-L1 cells.

Obesity and metabolic disorders caused by alterations in lipid metabolism are major health issues in developed, affluent societies. Adipose tissue is the only organ that stores lipids and prevents lipotoxicity in other organs. Mature adipocytes can affect themselves and distant metabolism-related tissues by producing various adipokines, including adiponectin and leptin.

Gulp1 deficiency augments bone mass in male mice by affecting osteoclasts due to elevated 17β-estradiol levels.

The engulfment adaptor phosphotyrosine-binding domain containing 1 (GULP1) is an adaptor protein involved in the engulfment of apoptotic cells via phagocytosis. Gulp1 was first found to promote the phagocytosis of apoptotic cells by macrophages, and its role in various tissues, including neurons and ovaries, has been well studied. However, the expression and function of GULP1 in bone tissue are poorly understood.

Recombinant Unique Cartilage Matrix-associated Protein Potentiates Osteogenic Differentiation and Mineralization of MC3T3-E1 Cells.

Objective: The relative balance of osteoblasts in bone formation and osteoclasts in bone resorption is crucial for maintaining bone health. With age, this balance between osteoblasts and osteoclasts is broken, resulting in bone loss. Anabolic drugs are continuously being developed to counteract this low bone mass.

Statin-mediated inhibition of RAS prenylation activates ER stress to enhance the immunogenicity of KRAS mutant cancer.

Background: Statins preferentially promote tumor-specific apoptosis by depleting isoprenoid such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate. However, statins have not yet been approved for clinical cancer treatment due, in part, to poor understanding of molecular determinants on statin sensitivity. Here, we investigated the potential of statins to elicit enhanced immunogenicity of -mutant () tumors.

CFL2 is an essential mediator for myogenic differentiation in C2C12 myoblasts.

CFL2, a skeletal muscle-specific member of the actin depolymerizing factor/cofilin protein family, is known to be involved in the regulation of actin filament dynamics. Although the impact of CFL2 has been studied in human myopathy, its functional contribution to myogenic differentiation, in terms of its effects on cell proliferation, cell cycle, and myogenic factor modulation, remains largely unknown. Here, we report that CFL2 is required for the myogenic differentiation of C2C12 myoblasts by regulating proliferation and myogenic transcription factors expressions.

Identifying Stabilin-1 and Stabilin-2 Double Knockouts in Reproduction and Placentation: A Descriptive Study.

The placenta undergoes reconstruction at different times during fetal development to supply oxygen and nutrients required throughout pregnancy. To accommodate the rapid growth of the fetus, small spiral arteries undergo remodeling in the placenta. This remodeling includes apoptosis of endothelial cells that line spiral arteries, which are replaced by trophoblasts of fetal origin.

Stabilin Receptors: Role as Phosphatidylserine Receptors.

Phosphatidylserine is a membrane phospholipid that is localized to the inner leaflet of the plasma membrane. Phosphatidylserine externalization to the outer leaflet of the plasma membrane is an important signal for various physiological processes, including apoptosis, platelet activation, cell fusion, lymphocyte activation, and regenerative axonal fusion. Stabilin-1 and stabilin-2 are membrane receptors that recognize phosphatidylserine on the cell surface.

ArhGAP12 plays dual roles in Stabilin-2 mediated efferocytosis: Regulates Rac1 basal activity and spatiotemporally turns off the Rac1 to orchestrate phagosome maturation.

The rapid and precise clearance of apoptotic cells (efferocytosis) involves a series of phagocytic processes through which apoptotic cells are recognized, engulfed, and degraded within phagocytes. The Rho-family GTPases critically rearrange the cytoskeleton for these phagocytic processes, but we know little about the mechanisms by which regulatory proteins control the spatiotemporal activities of the Rho-family GTPases. Here, we identify ArhGAP12 as a functional GTPase-activating protein (GAP) of Rac1 during Stabilin-2 mediated efferocytosis.

Ablation of Stabilin-1 Enhances Bone-Resorbing Activity in Osteoclasts In Vitro.

Stabilin-1 is a transmembrane receptor that regulates molecule recycling and cell homeostasis by controlling the intracellular trafficking and participates in cell-cell adhesion and transmigration. Stabilin-1 expression is observed in various organs, including bones; however, its function and regulatory mechanisms in the bone remain unclear. In this study, we evaluated the physiological function of stabilin-1 in bone cells and tissue using a stabilin-1 knockout (Stab1 KO) mouse model.

Nkx-2.5 Regulates MDR1 Expression via Its Upstream Promoter in Breast Cancer Cells.

Background: Increased expression of MDR1 gene is one of the major mechanisms responsible for multidrug resistance in cancer cells. Two alternative promoters, upstream and downstream, are responsible for transcription of MDR1 gene in the human. However, the molecular mechanism regarding the transactivation of MDR1 upstream promoter (USP) has not been determined.

Harnessing immune checkpoints in myeloid lineage cells for cancer immunotherapy.

Myeloid lineage immune cells, such as macrophages and dendritic cells, play important roles in the induction of antitumor immunity during the initial stage of the cancer-immunity cycle, eliciting antitumor adaptive immunity by phagocytosing cancer cells and processing cancer-specific antigens, and then presenting these antigens to T cells. During this process, cancer cell phagocytosis can be prevented by inhibitory signals, and the signaling cascades that elicit immune responses against cancer antigens can be inhibited by immunosuppressive myeloid cells in the tumor microenvironment. A number of therapeutic strategies for enhancing cancer cell phagocytosis and promoting antitumor immunity by targeting myeloid lineage cells have recently been developed.

Unique cartilage matrix-associated protein regulates fibrillin-2 expression and directly interacts with fibrillin-2 protein independent of calcium binding.

Unique cartilage matrix-associated protein (UCMA) is a secretory γ-carboxyglutamate (Gla) containing protein that is mainly expressed in the cartilage. Ucma, a downstream gene of both Runx2 and Osterix, has recently been described to promote osteoblast differentiation and matrix mineralization. However, till date, no studies have focused on the role of downstream target genes of Ucma in osteogenesis.

C1q and TNF related protein 1 regulates expression of inflammatory genes in vascular smooth muscle cells.

Background: C1q and TNF related protein 1 (C1QTNF1) is known to be associated with coronary artery diseases. However, the molecular function of C1QTNF1 on the vascular smooth muscles remains to be investigated.

Objective: This study was therefore undertaken to investigate the effect of C1QTNF1 on gene expression of human smooth muscle cells and to reveal potential molecular mechanisms mediated by C1QTNF1.

Macrophagic Stabilin-1 Restored Disruption of Vascular Integrity Caused by Sepsis.

Sepsis develops because of overwhelming inflammatory responses to bacterial infection, and disrupts vascular integrity. Stabilin-1 (STAB-1) is a phagocytic receptor, which mediates efferocytosis in a phosphatidylserine (PS)-dependent manner. STAB-1 is expected to play important roles in efferocytosis during sepsis.

Combined Rho-kinase inhibition and immunogenic cell death triggers and propagates immunity against cancer.

Activation of T cell immune response is critical for the therapeutic efficacy of cancer immunotherapy. Current immunotherapies have shown remarkable clinical success against several cancers; however, significant responses remain restricted to a minority of patients. Here, we show a therapeutic strategy that combines enhancing the phagocytic activity of antigen-presenting cells with immunogenic cell death to trigger efficient antitumour immunity.

Nanocage-Therapeutics Prevailing Phagocytosis and Immunogenic Cell Death Awakens Immunity against Cancer.

A growing appreciation of the relationship between the immune system and the tumorigenesis has led to the development of strategies aimed at "re-editing" the immune system to kill tumors. Here, a novel tactic is reported for overcoming the activation-energy threshold of the immunosuppressive tumor microenvironment and mediating the delivery and presentation of tumor neoantigens to the host's immune system. This nature-derived nanocage not only efficiently presents ligands that enhance cancer cell phagocytosis, but also delivers drugs that induce immunogenic cancer cell death.

Xk-related protein 8 regulates myoblast differentiation and survival.

Xk-related protein 8 (Xkr8) is a scramblase and responsible for phosphatidylserine (PS) exposure on the cell surface in a caspase-dependent manner. Although PS exposure is found to be important for myotube formation during myoblast differentiation, the role of Xkr8 during myogenesis has not been elucidated. Here we show that Xkr8 contributes to myoblast differentiation.

Engulfment signals and the phagocytic machinery for apoptotic cell clearance.

The clearance of apoptotic cells is an essential process for tissue homeostasis. To this end, cells undergoing apoptosis must display engulfment signals, such as 'find-me' and 'eat-me' signals. Engulfment signals are recognized by multiple types of phagocytic machinery in phagocytes, leading to prompt clearance of apoptotic cells.

Coordinated balance of Rac1 and RhoA plays key roles in determining phagocytic appetite.

The removal of unwanted or damaged cells by phagocytes is achieved via a finely regulated cleaning process called efferocytosis. To characterize the mechanisms through which phagocytes control the intake of apoptotic cells, we investigated how the phagocyte's appetite for engulfed cells may be coordinated by RhoA and Rac1 in the phagocytic cup. We used FRET biosensors to visualize the spatiotemporal dynamics of Rho-family GTPases, and found that RhoA, which is known to be downregulated during phagocytosis, was transiently upregulated at the phagocytic cup immediately prior to ingestion.

Homotypic Interaction of Stabilin-2 Plays a Critical Role in Lymph Node Metastasis of Tongue Cancer.

Background/aim: Lymph node (LN) metastasis of solid types of tumors has important clinical significance and it is therefore critical to identify molecular biomarkers that would enable the selection of patients with LN metastases.

Patients And Methods: We evaluated the expression of stabilin-2 in primary oral tongue tumors and metastatic LNs using immunohistochemical staining. The correlation between risk factors and nodal metastasis was assessed and disease-free survival was analyzed.

Induction of fibrillin-2 and periostin expression in Osterix-knockdown MC3T3-E1 cells.

Osteoporosis is the most common age-related bone disease that is characterized by an imbalance between osteoblasts for bone formation and osteoclasts for bone resorption. Anti-catabolic drugs have been developed to inhibit osteoclast activity and to prevent bone loss in osteoporosis. However, because it is difficult to increase bone mass in osteoporotic bone, it would be beneficial to simultaneously enhance osteoblast function and thus form bone.

Novel function of stabilin-2 in myoblast fusion: the recognition of extracellular phosphatidylserine as a "fuse-me" signal.

Myoblast fusion is important for skeletal muscle formation. Even though the knowledge of myoblast fusion mechanism has accumulated over the years, the initial signal of fusion is yet to be elucidated. Our study reveals the novel function of a phosphatidylserine (PS) receptor, stabilin-2 (Stab2), in the modulation of myoblast fusion, through the recognition of PS exposed on myoblasts.

Stabilin-2 modulates the efficiency of myoblast fusion during myogenic differentiation and muscle regeneration.

Myoblast fusion is essential for the formation of skeletal muscle myofibres. Studies have shown that phosphatidylserine is necessary for myoblast fusion, but the underlying mechanism is not known. Here we show that the phosphatidylserine receptor stabilin-2 acts as a membrane protein for myoblast fusion during myogenic differentiation and muscle regeneration.