CXCR4 Negatively Regulates Keratinocyte Proliferation in IL-23-Mediated Psoriasiform Dermatitis

CXCR4 is expressed by basal keratinocytes (KCs), but little is known about its function in inflamed skin. We crossed K14-Cre and CXCR4flox/flox (f/f) transgenic mice, resulting in mice with specific loss of the CXCR4 gene in K14-expressing cells (K14-CXCR4KO), including basal KCs. K14-CXCR4KO pups had no obvious skin defects. We compared K14-CXCR4KO and CXCR4f/f control mice in an IL-23-mediated psoriasiform dermatitis model and measured skin edema, and histologic and immunohistological changes. IL-23-treated K14-CXCR4KO mice showed a 1.3-fold increase in mean ear swelling, a 2-fold increase in epidermal thickness, and greater parakeratosis. IL-23-treated wild-type (WT) mice showed weak CXCR4 expression in areas of severe epidermal hyperplasia, but strong CXCR4 expression in nonhyperplastic regions, suggesting that CXCR4 may regulate KC proliferation. To test this hypothesis, we overexpressed CXCR4 in HaCaT KC cells and treated them with IL-22 and/or CXCL12 (chemokine (C-X-C motif) ligand 12). CXCL12 blocked IL-22-mediated HaCaT cell proliferation in vitro and synergized with IL-22 in upregulating SOCS3 (suppressor of cytokine signaling 3), a key regulator of STAT3 (signal transducer and activator of transcription 3). SOCS3 was required for CXCR4-mediated growth inhibition. In human psoriatic skin, both CXCR4 and SOCS3 were upregulated in the junctional region at the border of psoriatic plaques. Thus, CXCR4 has an unexpected role in inhibiting KC proliferation and mitigating the effects of proliferative T helper type 17 cytokines

徳島県の訪問看護提供状況

This survey aimed to clarify the current status of providing nursing services and the characteristics of visiting nursing stations (VNSs), which were classified by the size of VNS in Tokushima Prefecture. A questionnaire survey was conducted from January to March 2015 among all 71 VNSs in the prefecture. The questionnaire included questions regarding the implementation framework of home nursing, actual situations of service provision, conditions of patients, and issues and challenges of home care in Tokushima Prefecture. Of 71 VNSs, 34 responded to the questionnaire（response rate, 47.9％）. The proportion of VNSs that provided complicated medical procedures was low ; e.g., 27.6％ of VNSs provided self-peritoneal dialysis at home, 48.3％ provided services for narcotic pain control, and 58.6％ provided total parenteral nutrition. Home visits for patients with mental illnesses were provided significantly more by large size VNSs Home visits were frequently provided for households located far from VNSs, thus raising concerns regarding the workload of nurses and the convenient use of VNSs by clients. For patients to comfortably live in local areas that are familiar to them, it was considered that correcting the uneven geographical distribution of VNSs might be important

Proteasome Inhibitor Bortezomib Ameliorates Intestinal Injury in Mice

Background: Bortezomib is a proteasome inhibitor that has shown impressive efficacy in the treatment of multiple myeloma. In mice, the addition of dextran sulfate sodium (DSS) to drinking water leads to acute colitis that can serve as an experimental animal model for human ulcerative colitis. Methodology/Principal Findings: Bortezomib treatment was shown to potently inhibit murine DSS-induced colitis. The attenuation of DSS-induced colitis was associated with decreased inflammatory cell infiltration in the colon. Specifically, bortezomib-treated mice showed significantly decreased numbers of CD4 + and CD8 + T cells in the colon and mesenteric lymph nodes. Bortezomib treatment significantly diminished interferon (IFN)-c expression in the colon and mesenteric lymph nodes. Furthermore, cytoplasmic IFN-c production by CD4 + and CD8 + T cells in mesenteric lymph nodes was substantially decreased by bortezomib treatment. Notably, bortezomib enhanced T cell apoptosis by inhibiting nuclear factor-kB activation during DSS-induced colitis. Conclusions/Significance: Bortezomib treatment is likely to induce T cell death, thereby suppressing DSS-induced colitis by reducing IFN-c production

Oxidative protein folding: Selective pressure for prolamin evolution in rice

During seed development, endosperm cells of highly productive cereals, including rice, synthesize disulfide-rich proteins in large amounts and deposit them into storage organelles. Disulfide bond formation involves electron transfer and generates H2O2 as a by-product. To ensure proper development and maturation of seeds, the endosperm cells must supply large amounts of oxidizing equivalents to dithiols in nascent proteins in a controlled manner. This review compares multiple oxidative protein folding systems in yeast, cultured human cells, and rice endosperm. We discuss possible roles of ERO1, other sulfhydryl oxidases, and the protein disulfide isomerase family in the formation of disulfide bonds in storage proteins and the development of protein bodies. Rice prolamins, encoded by a multigene family, are divided into Cys-rich and Cys-depleted subgroups. We discuss the potential importance of disulfide bond formation in the evolution of the prolamin family in japonica rice

Topical insulin-like growth factor 1 treatment using gelatin hydrogels for glucocorticoid-resistant sudden sensorineural hearing loss: a prospective clinical trial

<p>Abstract</p> <p>Background</p> <p>Sudden sensorineural hearing loss (SSHL) is a common condition in which patients lose the hearing in one ear within 3 days. Systemic glucocorticoid treatments have been used as standard therapy for SSHL; however, about 20% of patients do not respond. We tested the safety and efficacy of topical insulin-like growth factor 1 (IGF1) application using gelatin hydrogels as a treatment for SSHL.</p> <p>Methods</p> <p>Patients with SSHL that showed no recovery to systemic glucocorticoid administration were recruited. We applied gelatin hydrogels, impregnated with recombinant human IGF1, into the middle ear. The primary outcome measure was the proportion of patients showing hearing improvement 12 weeks after the test treatment. The secondary outcome measures were the proportion of patients showing improvement at 24 weeks and the incidence of adverse events. The null hypothesis was that 33% of patients would show hearing improvement, as was reported for a historical control after hyperbaric oxygen therapy.</p> <p>Results</p> <p>In total, 25 patients received the test treatment at a median of 23 days (range 15-32) after the onset of SSHL, between 2007 and 2009. At 12 weeks after the test treatment, 48% (95% CI 28% to 69%; <it>P </it>= 0.086) of patients showed hearing improvement, and the proportion increased to 56% (95% CI 35% to 76%; <it>P </it>= 0.015) at 24 weeks. No serious adverse events were observed.</p> <p>Conclusions</p> <p>Topical IGF1 application using gelatin hydrogels is well tolerated and may be efficacious for hearing recovery in patients with SSHL that is resistant to systemic glucocorticoids.</p

A Possible Contribution of Altered Cathepsin B Expression to the Development of Skin Sclerosis and Vasculopathy in Systemic Sclerosis

Cathepsin B (CTSB) is a proteolytic enzyme potentially modulating angiogenic processes and extracellular matrix remodeling. While matrix metalloproteinases are shown to be implicated in tissue fibrosis and vasculopathy associated with systemic sclerosis (SSc), the role of cathepsins in this disease has not been well studied. The aim of this study is to evaluate the roles of CTSB in SSc. Serum pro-CTSB levels were determined by enzyme-linked immunosorbent assay in 55 SSc patients and 19 normal controls. Since the deficiency of transcription factor Fli1 in endothelial cells is potentially associated with the development of SSc vasculopathy, cutaneous CTSB expression was evaluated by immunostaining in Fli1+/− and wild type mice as well as in SSc and control subjects. The effects of Fli1 gene silencing and transforming growth factor-β (TGF-β) on CTSB expression were determined by real-time PCR in human dermal microvascular endothelial cells (HDMECs) and dermal fibroblasts, respectively. Serum pro-CTSB levels were significantly higher in limited cutaneous SSc (lcSSc) and late-stage diffuse cutaneous SSc (dcSSc) patients than in healthy controls. In dcSSc, patients with increased serum pro-CTSB levels showed a significantly higher frequency of digital ulcers than those with normal levels. CTSB expression in dermal blood vessels was increased in Fli1+/− mice compared with wild type mice and in SSc patients compared with healthy controls. Consistently, Fli1 gene silencing increased CTSB expression in HDMECs. In cultured dermal fibroblasts from early dcSSc, CTSB expression was decreased compared with normal fibroblasts and significantly reversed by TGF-β1 antisense oligonucleotide. In conclusion, up-regulation of endothelial CTSB due to Fli1 deficiency may contribute to the development of SSc vasculopathy, especially digital ulcers, while reduced expression of CTSB in lesional dermal fibroblasts is likely to be associated with skin sclerosis in early dcSSc

固体-液体相転移におけるポリ(3-オクタデシルチオフェン)のキャリア輸送現象と電子状態

We have studied on carrier transport phenomena, especially the evaluation of the mobility and the nature of photocarrier, of regiorandom poly(3-octadecylthiophene), PAT 18 at solid-liquid phase transition by using a time-of-flight technique. With increasing temperature, the hole mobility gradually decreases and decreases sharply at solid-liquid phase transition. On the other hand, the negative carrier mobility can be evaluated in the range from 10^ to 10^ cm^2/Vs, which is comparably the hole mobility at solid state, above solid-liquid phase transition. Then the observed small hydrostatic pressure dependence of conductivity seems to support the interpretation of electronic transport even in liquid phase. Accordingly, the negative carrier is electron. These unique phenomena have been interpreted as modulation of electronic energy state based on conformational change of the PAT18 main chain

Crosstalk: keratinocytes and immune cells in psoriasis

In the past, psoriasis was considered a skin disease caused only by keratinocyte disorders. However, the efficacy of immunosuppressive drugs and biologics used to treat psoriasis proves that psoriasis is an immune-mediated disease. Indeed, a variety of immune cells are involved in the pathogenesis of psoriasis, including dendritic cells, Th17 cells, and resident memory T cells. Furthermore, keratinocytes play a role in the development of psoriasis as immune cells by secreting antibacterial peptides, chemokines, tumor necrosis factor-α, interleukin (IL)-36, and IL-23. These immune cells and skin cells interact and drive the aberrant differentiation and proliferation of keratinocytes. This crosstalk between keratinocytes and immune cells critical in the pathogenesis of psoriasis forms an inflammatory loop, resulting in the persistence or exacerbation of psoriasis plaques

Optimal Use of Jak Inhibitors and Biologics for Atopic Dermatitis on the Basis of the Current Evidence

Recently, Jak inhibitors such as baricitinib, upadacitinib, and abrocitinib were approved for the treatment of atopic dermatitis (AD) in addition to biologics, including dupilumab, tralokinumab, and nemolizumab. The increase in treatment options can be a benefit to patients with AD. Meanwhile, it could make it difficult for physicians to choose the best treatment among those treatment options. Biologics and Jak inhibitors differ in efficacy, safety, route of administration, and whether or not there is a concern about immunogenicity in addition to the evidence on comorbidities. Among the three Jak inhibitors, the degree of inhibition of signal transducer and activator of transcription differs in each Jak inhibitor. Therefore, the efficacy and safety profiles of the three Jak inhibitors are different. Physicians who treat patients with AD with Jak inhibitors and biologics need to understand the current evidence and choose the best treatment for individual patients. In this review, we discuss how integrating knowledge of the mechanisms of action of Jak inhibitors and biologics, the potential significant adverse events of these drugs, and the age and comorbidities of the patient can help achieve optimal clinical benefit for patients with moderate-to-severe AD refractory to topical agents