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Radotinib (Supect™) was developed to treat chronic myeloid leukemia (CML) as a BCR-ABL1 tyrosine kinase inhibitor (TKI). Other TKIs, including imatinib and nilotinib, were also developed for treatment of CML, and recent studies were increasing about the therapeutic effects of other TKIs on solid tumors. However, the effect of radotinib on solid tumors has not yet been investigated. In this study, radotinib killed CML cell line K562 directly; however, radotinib did not enhance NK cell cytotoxicity against K562 cells. Because K562 is known as a Fas-negative cell line, we investigated whether radotinib could regulate cell cytotoxicity against various Fas-expressing solid cancer cell lines. Radotinib dramatically increased NK cell cytotoxicity against various Fas-expressing solid cancer cells, including lung, breast, and melanoma cells. Additionally, the efficiency of radotinib-enhanced cytotoxicity was lower in Fas siRNA-transfected cells than in negative controls, suggesting that Fas signaling might be involved in the radotinib-enhanced NK cell cytotoxicity. This study provides the first evidence that radotinib could be used as an effective and strong therapeutic to treat solid tumors via upregulation of NK cell cytotoxicity, suggesting that radotinib has indirect killing mechanisms via upregulation of antitumor innate immune responses as well as direct killing activities for CML cells. [ABSTRACT FROM AUTHOR]

Efficient oral administration of protein-based therapeutics faces significant challenges due to degradation from the highly acidic conditions present in the stomach and proteases present in the digestive tract. Herein, investigations into spike-covered sunflower sporopollenin exine capsules (SECs) for oral protein delivery using bovine serum albumin (BSA) as a model drug are reported and provide significant insights into the optimization of SEC extraction, SEC loading, and controlled release. The phosphoric-acid-based SEC extraction process is optimized. Compound loading is shown to be driven by the evacuation of air bubbles from SEC cavities through the porous SEC shell wall, and vacuum loading is shown to be the optimal loading method. Three initial BSA-loading proportions are evaluated, leading to a practical loading efficiency of 22.3 ± 1.5 wt% and the determination that the theoretical maximum loading is 46.4 ± 2.5 wt%. Finally, an oral delivery formulation for targeted intestinal delivery is developed by tableting BSA-loaded SECs and enteric coating. BSA release is inhibited for 2 h in simulated gastric conditions followed by 100% release within 8 h in simulated intestinal conditions. Collectively, these results indicate that sunflower SECs provide a versatile platform for the oral delivery of therapeutics. [ABSTRACT FROM AUTHOR]

Myeloid‐derived suppressor cells (MDSCs) contribute to tumor‐mediated immune escape by suppressing antitumor immune responses. Interleukin‐33 (IL‐33) is capable of regulating various immune cell populations; however, the effects of IL‐33 on the differentiation of MDSCs have not been well characterized. In this study, we evaluated the effects of IL‐33 on MDSCs and found that IL‐33 significantly reduced the differentiation of lineage‐negative bone marrow progenitor cells into granulocytic MDSCs (G‐MDSCs). IL‐33‐treated MDSCs exhibited diminished immunosuppressive capacity; reduced inhibition on T‐cell proliferation and interferon‐γ production, and diminished production of reactive oxygen species. However, IL‐33 treatment did not affect the frequency of monocytic MDSCs (M‐MDSCs) or their production of nitric oxide and expression of arginase‐1. Additionally, compared with control MDSCs, IL‐33‐treated MDSCs had reduced capacity to induce the differentiation or expansion of Treg cells. Moreover, in vivo IL‐33 administration significantly decreased MDSCs and G‐MDSCs accumulation in the spleen and tumor microenvironment. Also, despite increasing CD4+ and CD8+ T‐cell infiltration, IL‐33 administration markedly decreased Treg‐cell population in tumor microenvironment. Taken together, our findings indicate that IL‐33 reduces the frequency and immunosuppressive activity of G‐MDSCs and ultimately the extent of tumor growth. [ABSTRACT FROM AUTHOR]

The erythroid differentiation regulator 1 (Erdr1), which is a novel and highly conserved factor, was recently reported to be negatively regulated by IL-18 and to play a crucial role as an antimetastatic factor. IL-18 is a proinflammatory cytokine that functions as an angiogenic mediator in inflammation. Rosacea is a chronic inflammatory skin disorder that is characterized by abnormal inflammation and vascular hyperactivity of the facial skin. To determine whether Erdr1 contributes to the regulation of the chronic inflammatory process in the development of rosacea, an immunohistochemical analysis was performed in healthy donors and patients with rosacea. In this study, we showed that Erdr1 was downregulated, whereas IL-18 was upregulated, in patients with rosacea, which led us to question the role of Erdr1 in this disorder. Moreover, a rosacea-like BALB/c mouse model was used to determine the role of Erdr1 in rosacea in vivo. LL-37 injection induced typical rosacea features, including erythema, telangiectasia and inflammation. Treatment with recombinant Erdr1 (r Erdr1) resulted in a significant reduction of erythema, inflammatory cell infiltration (including CD4+ and CD8+ T cells), and microvessel density with vascular endothelial growth factor ( VEGF). Taken together, our findings suggest that r Erdr1 may be involved in attenuating the inflammation and angiogenesis associated with the pathogenesis of rosacea. Thus, these results provide new insight into the mechanism involved in this condition and indicate that r Erdr1 could be a potential target for therapeutic intervention of rosacea. [ABSTRACT FROM AUTHOR]

Background Erythroid differentiation regulator 1 is decreased in malignant melanoma. However, the expression of erythroid differentiation regulator 1 has not been reported in normal epidermis, vessel, nerve, dermal adnexae, and various skin tumors. Methods To investigate the expression of erythroid differentiation regulator 1 in normal skin and various skin tumors, immunohistochemical analysis of normal skin, epidermal tumors, sebaceous tumors, and eccrine tumors was performed. The image analysis was quantitatively performed using HistoQuant™ software. Results Erythroid differentiation regulator 1 was strongly expressed in the nuclei of normal epidermis, sebaceous gland, eccrine gland, vessel, and nerve. Expression of erythroid differentiation regulator 1 was weak in seborrheic keratosis, sebaceous hyperplasia, and eccrine spiradenoma. Erythroid differentiation regulator 1 was rarely observed in malignant skin tumors, including squamous cell carcinoma, basal cell carcinoma, malignant melanoma, sebaceous carcinoma, and eccrine porocarcinoma. Conclusions The expression of erythroid differentiation regulator 1 was negatively correlated with the malignant potential in various skin tumors. The results support the role of erythroid differentiation regulator 1 in cutaneous carcinogenesis and indicate its potential as a novel marker of skin tumors. [ABSTRACT FROM AUTHOR]

The active metabolite of vitamin D3, 1α,25(OH)2D3, displays anticancer effects by regulating cell cycle and apoptosis in many cancer cells. However, it has not been determined whether 1α,25(OH)2D3 increases the susceptibility of cancer cells to NK cells. Here, we investigated the anticancer effect of 1α,25(OH)2D3 in human melanoma cell lines by investigating enhancement of NK susceptibility and elucidating the mediator of NK cytotoxicity. 1α,25(OH)2D3-resistant melanoma cells (G-361 and SK-MEL-5) treated with 1α,25(OH)2D3 showed higher susceptibility to NK cells with up-regulation of Fas expression. Furthermore, G-361 cells treated with 1α,25(OH)2D3 showed significantly increased caspase activity. In addition to Fas up-regulation, expression of heat shock protein 60 (Hsp60) was elevated by 1α,25(OH)2D3. Increased expression of Hsp60 by 1α,25(OH)2D3 was related to not only up-regulation of Fas expression but also to NK susceptibility of G-361 cells. Taken together, our data suggest that 1α,25(OH)2D3 acts as an anticancer agent by increasing expression of Fas on the surface of melanoma cells through Hsp60 induction and strengthens caspase sensitivity to Fas-mediated apoptotic pathway by NK cells. 1α,25(OH)2D3 treatment may therefore have a preventive role in melanoma occurrence or potentiate the anticancer effects of NK-cell immune therapy. [ABSTRACT FROM AUTHOR]

Summary Aminoacyl tRNA synthetase-interacting protein 1 (AIMP1) is a novel pleiotropic cytokine that was identified initially from Meth A-induced fibrosarcoma. It is expressed in the salivary glands, small intestine and large intestine, and is associated with the innate immune system. Previously, we demonstrated that AIMP1 might function as a regulator of innate immune responses by inducing the maturation and activation of bone-marrow-derived dendritic cells (BM-DCs). Toll-like receptors (TLRs) are major pathogen-recognition receptors that are constitutively expressed on DCs. In this study, we attempted to determine whether AIMP1 is capable of regulating the expression of TLRs, and also capable of affecting the TLR-mediated activation of DCs. Expression of TLR1, -2, -3 and -7 was highly induced by AIMP1 treatment in BM-DCs, whereas the expression of other TLRs was either down-regulated or remained unchanged. In particular, the expression of the TLR2 protein was up-regulated by AIMP1 in a time-dependent and dose-dependent manner, and was suppressed upon the addition of BAY11-7082, an inhibitor of nuclear factor-κB. AIMP1 was also shown to increase nuclear factor-κB binding activity. Importantly, AIMP1 enhanced the production of interleukin-6 and interleukin-12, and the expression of co-stimulatory molecules on BM-DCs when combined with lipoteichoic acid or Pam3Cys, two well-known TLR2 agonists. Collectively, these results demonstrate that the AIMP1 protein enhances TLR2-mediated immune responses via the up-regulation of TLR2 expression. [ABSTRACT FROM AUTHOR]

The article presents a study that studies role of down-regulation on erythroid differentiation regulator 1 (Erdr1) in psoriasis pathogene. Topics discussed include Psoriasis as a common chronic skin disease that followed by chronic inflammation, investigation of whether erythroid differentiation regulator 1 (Erdr1)is negatively regulated by Interleukin-18 (IL-18) in human keratinocyte and an inverse correlation found between Erdr1 and IL-18 expression.

Melanoma is a malignant skin cancer that displays a high rate of tumor cell migration and metastasis. This study examined how corticotropin-releasing hormone (CRH) affects the migration of melanoma cells in order to further understand the relationship between stress and tumor cell migration. The migration assay data showed that CRH treatment increased the level of B16F10 cell migration in a dose- and time-dependent manner. To determine whether the extracellular signal-regulated protein kinase 1/2 (ERK1/2) signaling pathway is involved in the upregulation of melanoma migration, cells were pretreated with an inhibitor of ERK1/2 (PD098059). The pretreatment of PD098059 blocked the increase in cell migration. Furthermore, CRH induced the phosphorylation of ERK1/2. The maximum activation of ERK1/2 by CRH was observed at 15 min. Taken together, these results suggest that CRH is an important mediator that regulates the migration of melanoma cells in the skin during stress through the ERK1/2 signaling pathway. [ABSTRACT FROM AUTHOR]

Lipo-PGE1 [EGLANDIN®; a lipid microsphere-incorporated prostaglandin E1 (PGE1)] stimulates angiogenesis and promotes the healing of skin ulcers. Because the effects of Lipo-PGE1 on cutaneous wound healing are not completely understood, we investigated the ability of Lipo-PGE1 to affect in vivo wound healing and regulate the migration of human dermal fibroblasts (HDFs). In a murine wound model, Lipo-PGE1 reduced the wound size compared with control mice. Lipo-PGE1 significantly increased HDF migration in a dose- and time-dependent manner. Lipo-PGE1 markedly increased the expression of CXC chemokine receptor 4 (CXCR4), which controls the migration of HDFs, at the mRNA and protein levels. Small interfering RNA (siRNA)-mediated knockdown of CXCR4 inhibited Lipo-PGE1-enhanced HDF migration. Moreover, Lipo-PGE1 directly induced the phosphorylation of c-Jun N-terminal kinase (JNK), and the JNK-specific inhibitor Sp6000125 blocked Lipo-PGE1-enhanced migration and CXCR4 expression of HDFs. Our results demonstrate that Lipo-PGE1 accelerates wound healing in vivo and increases the CXCR4-mediated migration of HDFs through the JNK pathway. [ABSTRACT FROM AUTHOR]

In the past few years, there have been many efforts underway to develop effective wound healing treatments for traumatic injuries. In particular, wound‐healing peptides (WHPs) and peptide‐grafted dressings hold great promise for novel therapeutic strategies for wound management. This study reports a topical formulation of a new synthetic WHP (REGRT, REG) embedded in a hyaluronic acid (HA)‐based hydrogel dressing for the enhancement of acute excisional wound repair. The copper‐free click chemistry is utilized to form biocompatible HA hydrogels by cross‐linking dibenzocyclooctyl‐functionalized HA with 4‐arm poly(ethylene glycol) (PEG) azide. The HA hydrogels are grafted with the REG peptide, a functional derivative of erythroid differentiation regulator1, displaying potent cell motility‐stimulating ability, thus sustainably releasing physiologically active peptides for a prolonged period. Combined with the traditional wound healing benefits of HA, the HA hydrogel embedded REG (REG‐HAgel) accelerates re‐epithelialization in skin wound healing, particularly by promoting migration of fibroblasts, keratinocytes, and endothelial cells. REG‐HAgels improve not only rate, but quality of wound healing with higher collagen deposition and more microvascular formation while being nontoxic. The peptide‐grafted HA hydrogel system can be considered as a promising new wound dressing formulation strategy for the treatment of different types of wounds with combinations of various natural and synthetic WHPs. A novel synthetic wound healing peptide (REGRT)‐grafted biocompatible hyaluronic acid hydrogel (HAgel) is introduced as a potential wound care strategy for the enhancement of acute excisional wound repair. As an advanced wound dressing platform, the bioactive REGRT and the HAgels cross‐linked via copper‐free click chemistry can have a synergistic effect in wound management. [ABSTRACT FROM AUTHOR]

In article number 1700270, Sa‐Ik Bang, Nam‐Joon Cho, and co‐workers describe how to optimize loading and controlled release of plant‐based hollow microcapsules for oral drug delivery. Extracted sporopollenin exine capsules from sun flowers are successfully loaded with protein and formulated into enterically coated tablets. [ABSTRACT FROM AUTHOR]