Fibroblast growth factor 18 stimulates the proliferation of hepatic stellate cells, thereby inducing liver fibrosis.

Liver fibrosis results from chronic liver injury triggered by factors such as viral infection, excess alcohol intake, and lipid accumulation. However, the mechanisms underlying liver fibrosis are not fully understood. Here, we demonstrate that the expression of fibroblast growth factor 18 (Fgf18) is elevated in mouse livers following the induction of chronic liver fibrosis models. Deletion of Fgf18 in hepatocytes attenuates liver fibrosis; conversely, overexpression of Fgf18 promotes liver fibrosis. Single-cell RNA sequencing reveals that overexpression of Fgf18 in hepatocytes results in an increase in the number of Lrat+ hepatic stellate cells (HSCs), thereby inducing fibrosis. Mechanistically, FGF18 stimulates the proliferation of HSCs by inducing the expression of Ccnd1. Moreover, the expression of FGF18 is correlated with the expression of profibrotic genes, such as COL1A1 and ACTA2, in human liver biopsy samples. Thus, FGF18 promotes liver fibrosis and could serve as a therapeutic target to treat liver fibrosis.

High-Sulfated Hyaluronic Acid Ameliorates Radiation-Induced Intestinal Damage Without Blood Anticoagulation.

Purpose: Many growth factors, such as fibroblast growth factors (FGFs), are useful for the treatment or prevention of radiation damage after radiation therapy. Although heparin can be supplemented to increase the therapeutic effects of FGFs, it possesses strong anticoagulant effects, which limit its potential for clinical use. Therefore, chemically sulfated hyaluronic acid (HA) was developed as a safe alternative to heparin. This study examined the involvement of sulfated HA in radioprotective and anticoagulant effects. Methods and Materials: FGF1 was administered intraperitoneally to BALB/c mice with sulfated HA 24 hours before or after total body irradiation with γ-rays. Several radioprotective effects were examined in the jejunum. The blood coagulation time in the presence of sulfated HA was measured using murine whole blood. Results: FGF1 with high-sulfated HA (HA-HS) exhibited almost the same level of in vitro mitogenic activity as heparin, whereas FGF1 with HA or low-sulfated HA exhibited almost no mitogenic activity. Furthermore, HA-HS had high binding capability with FGF1. FGF1 with HA-HS significantly promoted crypt survival to the same level as heparin after total body irradiation and reduced radiation-induced apoptosis in crypt cells. Moreover, pretreatment of HA-HS without FGF1 also increased crypt survival and reduced apoptosis. Crypt survival with FGF1 in the presence of HA depended on the extent of sulfation of HA. Moreover, the blood anticoagulant effects of sulfated HA were weaker than those of heparin. As sulfated HA did not promote the reactivity of antithrombin III to thrombin, it did not increase anticoagulative effects to the same extent as heparin. Conclusions: This study suggested that HA-HS promotes the radioprotective effects of FGF1 without anticoagulant effects. HA-HS has great potential for practical use to promote tissue regeneration after radiation damage.

Histamine H1 receptor antagonists selectively kill cisplatin-resistant human cancer cells.

Cancer therapy is often hampered by the disease's development of resistance to anticancer drugs. We previously showed that the autonomously upregulated product of fibroblast growth factor 13 gene (FGF13; also known as FGF homologous factor 2 (FHF2)) is responsible for the cisplatin resistance of HeLa cisR cells and that it is likely responsible for the poor prognosis of cervical cancer patients treated with cisplatin. Here we show that cloperastine and two other histamine H1 receptor antagonists selectively kill HeLa cisR cells at concentrations that little affect parental HeLa S cells. The sensitivity of HeLa cisR cells to cloperastine was abolished by knocking down FGF13 expression. Cisplatin-resistant A549 cisR cells were similarly susceptible to cloperastine. H2, H3, and H4 receptor antagonists showed less or no cytotoxicity toward HeLa cisR or A549 cisR cells. These results indicate that histamine H1 receptor antagonists selectively kill cisplatin-resistant human cancer cells and suggest that this effect is exerted through a molecular mechanism involving autocrine histamine activity and high-level expression of FGF13. We think this represents a potential opportunity to utilize H1 receptor antagonists in combination with anticancer agents to treat cancers in which emergent drug-resistance is preventing effective treatment.

Tissue-specific analysis of Fgf18 gene function in palate development.

BACKGROUND: Previous studies showed that mice lacking Fgf18 function had cleft palate defects and that the FGF18 locus was associated with cleft lip and palate in humans, but what specific roles Fgf18 plays during palatogenesis are unclear. RESULTS: We show that Fgf18 exhibits regionally restricted expression in developing palatal shelves, mandible, and tongue, during palatal outgrowth and fusion in mouse embryos. Tissue-specific inactivation of Fgf18 throughout neural crest-derived craniofacial mesenchyme caused shortened mandible and reduction in ossification of the frontal, nasal, and anterior cranial base skeletal elements in Fgf18c/c ;Wnt1-Cre mutant mice. About 64% of Fgf18c/c ;Wnt1-Cre mice exhibited cleft palate. Whereas palatal shelf elevation was impaired in many Fgf18c/c ;Wnt1-Cre embryos, no significant difference in palatal cell proliferation was detected between Fgf18c/c ;Wnt1-Cre embryos and their control littermates. Embryonic maxillary explants from Fgf18c/c ;Wnt1-Cre embryos showed successful palatal shelf elevation and fusion in organ culture similar to the maxillary explants from control embryos. Furthermore, tissue-specific inactivation of Fgf18 in the early palatal mesenchyme did not cause cleft palate. CONCLUSION: These results demonstrate a critical role for Fgf18 expression in the neural crest-derived mesenchyme for the development of the mandible and multiple craniofacial bones but Fgf18 expression in the palatal mesenchyme is dispensable for palatogenesis.

Vegetable Freshness Perception in Dementia with Lewy Bodies and Alzheimer's Disease.

INTRODUCTION: Although various visual function deficits have been reported in patients with Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), vegetable freshness perception has not been thoroughly examined. OBJECTIVE: To investigate vegetable freshness perception in patients with AD and DLB and to clarify the relationship between vegetable freshness perception and various visuoperceptual functions. METHODS: We enrolled 37 patients with probable DLB, 58 patients with probable AD, and 32 age-matched healthy controls. We assessed vegetable freshness perception and visuoperceptual functions, including vegetable brightness perception, contrast sensitivity, color perception, and stereopsis. Patients with DLB showed disproportionate deficits in vegetable freshness perception and vegetable luminance perception compared to patients with AD and controls. Analyses of the groups with higher and lower vegetable freshness perceptions revealed significant differences in contrast sensitivity and visual texture recognition. RESULTS: In the vegetable freshness test, we found significant differences among the 3 groups (F = 30.029, p < 0.0001); the extent of impairment in patients with DLB was greater than that in patients with AD. In patients with DLB, the vegetable freshness judgments were significantly correlated with texture judgment scores and contrast sensitivity. CONCLUSION: Our findings revealed significantly impaired vegetable freshness perception in patients with DLB. Vegetable freshness perception may be related to visual texture recognition in patients with DLB.

Visual texture agnosia influences object identification in dementia with Lewy bodies and Alzheimer's disease.

BACKGROUND: Numerous studies have shown visuoperceptual/visuospatial deficits in dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). Visual texture recognition is also impaired in patients with DLB and AD. Although patients with DLB often exhibit visual misidentifications of objects, there are few studies on the relationships between visual texture recognition and viewpoints for object recognition. OBJECTIVES: The aim of this study was to clarify how viewpoints, textures, and visual cognitive functions affect object recognition and result in visual misidentifications in patients with DLB or AD. METHODS: A total of 37 patients with probable DLB and 58 with probable AD and 32 age-matched healthy controls underwent neuropsychological and visuoperceptual assessments, and performed object identification tasks under four conditions (non-canonical view + blurry texture, non-canonical view + clear texture, canonical view + blurry texture, canonical view + clear texture). The relationship between object identification and other visuoperceptual functions was analyzed. RESULTS: Patients with DLB and AD exhibited significantly impaired object recognition under non-canonical viewing with blurry texture conditions, with the DLB patients exhibiting a significantly worse performance than the AD patients. Patients with DLB and AD exhibited visual misidentifications during object identification tasks under non-canonical viewing. In patients with DLB, the number of visual misidentifications was significantly correlated with the scores of visual texture recognition. CONCLUSIONS: The present study showed that significantly impaired object recognition in patients with DLB under the influences by both viewpoint and visual texture and in those with AD under the influence by viewpoint. Visual misidentification in object recognition could be associated with impaired visual texture recognition in DLB.

Regulatory expression of bone morphogenetic protein 6 by 2,2'-dipyridyl.

BACKGROUND: Expression of hepcidin, a hormone produced by hepatocytes which negatively regulates the circulating iron levels, is known to be positively regulated by BMP6, a member of transforming growth factor (TGF)-ß family. Previous studies have shown that iron status is sensed by sinusoidal endothelial cells of hepatic lamina, leading to the modulation of BMP6 expression. METHODS: ISOS-1, HUVEC, F-2, and SK-HEP1 endothelial cells were treated with either iron or 2,2'-dipyridyl (2DP), a cell-permeable iron-chelator, and expression level of Bmp6 was examined. To identify factors affecting Bmp6 transcription, stimulus screening for regulator of transcription (SSRT) was developed. RESULTS: Treatment with iron slightly increased the expression levels of Bmp6, while 2DP unexpectedly increased Bmp6 expression in a dose-dependent manner. 2DP-induced Bmp6 expression was resistant to co-treatment with iron. 2DP-induced Bmp6 expression was also detected in HUVEC, F-2 cells, and SK-HEP1 cells. Luciferase-based reporter assays indicated that forced expression of JunB increased the transcription of Bmp6. 2DP induced phosphorylation of JunB; co-treatment with SP600125 blocked the 2DP-induced Bmp6 expression partially. JunB-induced Bmp6 transcription was not affected by mutations of putative JunB-responsive elements. Some endoplasmic reticulum stress inducers increased the expression of Bmp6. SSRT revealed pathways regulating Bmp6 transcription positively and negatively. Hepa1-6 liver cells and C2C12 myogenic cells were prone to 2DP induced Bmp6 expression. CONCLUSIONS: The present study reveals non­iron-regulated Bmp6 expression in endothelial cells. GENERAL SIGNIFICANCE: Regulatory expression of Bmp6 may be important as a key step for fine tuning of BMP activity.

An epidermis-permeable dipeptide is a potential cosmetic ingredient with partial agonist/antagonist activity toward fibroblast growth factor receptors.

BACKGROUND: Fibroblast growth factors (FGFs) are promising agents with which to treat problems of skin and hair. But their inability to penetrate into the skin due to their large size and hydrophilic nature prevents their topical application as effective cosmetic ingredients. AIMS: To identify small peptide(s) with FGF-like activity and epidermis permeability. METHODS: Several peptides deduced from our earlier studies were tested for their ability to promote keratinocyte growth and to activate FGF receptors (FGFRs). Permeability was assessed using HPLC after derivatization. RESULTS: A dipeptide, prolyl-isoleucine (Pro-Ile), not only stimulated growth of human keratinocytes, it also moderately activated FGFR3c and FGFR4, and activated FGFR1c to a lesser extent. This receptor specificity of Pro-Ile is similar to that of FGF18. The activity of Pro-Ile toward FGFR/BaF3 cells was enhanced by heparin and was inhibited by an FGFR inhibitor, PD173074. Pro-Ile enhanced the activity of 5 ng/mL FGF18, but suppressed the activity of 50 ng/mL FGF18 toward FGFR3c and FGFR4. Pro-Ile was found to permeate through validated model human epidermis. CONCLUSIONS: These results indicate that the dipeptide Pro-Ile acts as a partial agonist/antagonist for FGFR signaling, that it has receptor specificity similar to FGF18, and that it is able to penetrate into the model epidermis. Because FGFs expressed in the cutaneous system are physiological regulators, these results suggest the potential utility of this peptide as a topically applicable cosmetic ingredient for the regulation of skin physiology, hair growth, and wound healing.

Age-related changes in the vasculature of the dermis of the upper lip vermilion.

Lip redness is unique to humans and creates an important facial impression, but this redness decreases with age. Here, using histological and immunohistological staining of human upper lip vermilion from donors of different ages, we investigated blood vessels in the upper lip dermis and age-dependent histological changes. We found that both total vessel area in the dermis and vessel number in the upper dermis decreased with aging. Moreover, vessel number in the upper dermis correlated positively with development of rete ridges, which flattened with age, despite no significant change in the thickness of the stratified squamous epithelium. These findings suggest that age-related reductions in lip redness result from a decrease of blood vessels, which in turn leads to a flattening of the epithelium caused by the loss of rete ridges. This is the first study to histologically demonstrate age-related reductions in blood vessels in the lip. Our results provide an opportunity for enhancing blood flow/vascularization to improve the aesthetic appearance of the lips in the elderly.

[Health-related Quality of Life in Patients with Mild-to-moderate Alzheimer's Disease: A Study Using the Five-level Version of European Quality of Life-5 Dimensions (EQ-5D-5L)].

OBJECTIVE: To investigate the relation between health-related quality of life (QOL) rated by proxy and various characteristics of patients with mild-to-moderate Alzheimer's disease (AD) using European Quality of Life-5 Dimensions (EQ-5D). PATIENTS: We recruited 128 AD patients with a Clinical Dementia Rating (CDR) of 0.5 (very mild) to 2 (moderate) who were cognitively assessed using the Mini-Mental State examination, Alzheimer's Disease Assessment Scale, and Frontal Assessment Battery, and whose family caregivers underwent an interview with CDR, Neuropsychiatric Inventory (NPI) and the five-level version of the EQ-5D for the proxy rating. METHODS: We obtained Pearson's correlation coefficients between the EQ-5D utility score and each demographic, clinical, and cognitive measure. All measures with moderate or large effect sizes (0.3 or more of absolute value of the correlation coefficient) were included in a multiple correlation analysis. RESULTS: The CDR sum of boxes (CDR-SOB), NPI total score, and educational attainment showed moderate effect sizes in the single correlation analyses. The effect sizes of the cognitive measures were small. The multiple correlation analysis showed that the CDR-SOB and NPI total score independently contributed to the EQ-5D utility score. CONCLUSION: Two independent factors, that is, overall severities of functional impairment and behavioral and psychological symptoms of dementia seemed to contribute to QOL in AD patients. (Received August 20, 2018; Accepted September 12, 2018; Published January 1, 2019).

The FGF1/CPP-C chimera protein protects against intestinal adverse effects of C-ion radiotherapy without exacerbating pancreatic carcinoma.

BACKGROUND AND PURPOSE: Carbon ion (C-ion) beams are concentrated to irradiate pancreatic carcinoma in the upper abdomen; however, this radiotherapy potentially causes adverse reactions in the gastrointestinal tract. FGF1 is a candidate radioprotector for radiation-induced intestinal damage, but may promote the malignancy of pancreatic cancer. An FGF1/CPP-C chimeric protein was created to enhance the intracellular signaling mode of FGF1 instead of FGFR signaling. The present study investigated the effects of FGF1/CPP-C on the intestinal adverse reactions of C-ion radiotherapy as well as its influence on the malignancy of pancreatic cancer. MATERIALS AND METHODS: FGF1/CPP-C was administered intraperitoneally to BALB/c mice without heparin 12 h before total body irradiation (TBI) with low-LET C-ion (17 keV/µm) at 6-8 Gy. Several radioprotective effects were examined in the jejunum. The invasion and migration of the human pancreatic carcinoma cell lines MIAPaCa-2 and PANC-1 were assessed using Boyden chambers after cultures with FGF1/CPP-C. RESULTS: The FGF1/CPP-C treatment promoted crypt survival after C-ion irradiation at 7-8 Gy significantly more than the FGF1 treatment. FGF1/CPP-C also inhibited C-ion radiotherapy-induced apoptosis and reduced γH2AX foci in crypt cells more than FGF1. However, FGF1/CPP-C inhibited the downstream signaling pathways of FGFRs and suppressed the activation of cell-cycle regulatory molecules in the intestine until 4 h after TBI. Furthermore, IEC6 cells were arrested in G2M after cultures with FGF1/CPP-C or FGF1, suggesting that DNA repair after irradiation is promoted by FGF1/CPP-C-induced G2M arrest. In contrast, FGF1/CPP-C appeared to be internalized into MIAPaCa-2 and PANC-1 cells more efficiently than FGF1. Therefore, FGF1/CPP-C reduced the in vitro proliferation, invasion, and migration of MIAPaCa-2 and PANC-1 cells significantly more than FGF1 through the cellular internalization of FGF1. CONCLUSION: These results suggest that the intracellular signaling mode of FGF1/CPP-C attenuates the intestinal adverse effects of C-ion radiotherapy without enhancing the malignancy of pancreatic carcinoma.

[Everyday Memory Deficits in Alzheimer's Disease].

Everyday memory refers to the operational memory required in daily life. Some patients with dementia shows a dissociation between impairment in everyday memory and deterioration in the score of common test for recent memory. We examined the Alzheimer's disease and other dementia patients whose score of the Everyday Memory Test for Memory Clinic is preserved when compared to their performance in a word recall task. We found that these patients showed significantly better scores on the construction task and orientation task than did the other patients. We conclude that better visuocognitive function and orientation is associated with the preserved everyday memory in these patients.

Visual texture agnosia in dementia with Lewy bodies and Alzheimer's disease.

BACKGROUND: Neuroimaging and some clinical studies have reported that the ventral visual pathway is relevant for visual texture recognition. Although a variety of visual deficits have been reported in patients with Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), visual material identification and texture recognition have not been thoroughly examined. OBJECTIVES: To investigate visual texture recognition in patients with AD and DLB and to clarify the relationship between visual texture recognition and various visuoperceptual functions. METHODS: Twenty-five patients with probable DLB, 53 patients with probable AD, and 32 age-matched healthy controls were included. We assessed visual texture recognition of real materials/images and visuoperceptual functions including contrast sensitivity, color perception, stereopsis, shape detection, and position in space. RESULTS: DLB patients showed disproportionate deficits in visuoperceptual functions and visual texture recognition compared with AD patients and controls, but these dysfunctions were not correlated with each other. AD patients had significantly impaired visual texture recognition but with intact visuoperceptual functions, except contrast sensitivity. Using an optimal cut-off score according to the receiver operating characteristic (ROC) curve analysis, the results from the visual texture recognition of images could differentiate DLB patients from controls with a sensitivity of 92% and a specificity of 97%. CONCLUSIONS: We demonstrated significantly impaired visual texture recognition in patients with DLB and AD, with patients with DLB performing significantly worse than patients with AD. Additionally, visual texture recognition and visuoperceptual functions are independently disturbed in DLB.

Regulatory responses of hepatocytes, macrophages and vascular endothelial cells to magnesium deficiency.

The liver is the organ that responds to nutritional disturbances including magnesium deficiency. The present study evaluated cellular responses to magnesium deficiency using model cells of the liver, namely, HepG2 cells as hepatocytes, RAW264.7 cells as Kupffer cells and human umbilical vein endothelial cells (HUVECs) as vascular endothelial cells; we examined effects of culture with magnesium deficient medium on cell responses in individual types of cells as well as interactive responses among cells. Metabolomic analyses indicated that magnesium deficiency differentially affected the cellular content of metabolites among HepG2 cells, RAW264.7 cells and HUVECs. The cellular content of the metabolites in HepG2 cells and HUVECs was also affected by the conditioned medium from RAW264.7 cells cultured with the magnesium-deficient media. The changes in HUVECs partly resembled those of the livers of magnesium-deficient rats previously described. RNA-seq analyses indicated that magnesium deficiency modulated the expression levels of molecules related to the ubiquitin-proteasome pathway and oxidative stress/antioxidant response in HepG2 cells and RAW264.7 cells, respectively. Furthermore, when HUVECs were co-cultured with RAW264.7 cells, lipopolysaccharide-induced expression of interleukin (IL)-1ß and IL-6 was enhanced by magnesium deficiency, depending on the presence of RAW264.7 cells. The present study reveals that magnesium deficiency affects cellular metabolism in HepG2 liver cells, RAW264.7 macrophages and HUVECs, and that the modulation of cellular responses to extracellular magnesium deficiency in HUVECs depends on the presence of RAW264.7 cells. The complex responses in individual cells and through cell interactions partly explain the regulatory reaction to magnesium deficiency in the liver.

An iminium ion metabolite hampers the production of the pharmacologically active metabolite of a multikinase inhibitor KW-2449 in primates: irreversible inhibition of aldehyde oxidase and covalent binding with endogenous proteins.

We previously reported that KW-2449, (E)-1-{4-[2-(1H-Indazol-3-yl)vinyl]benzoyl}piperazine, a novel multikinase inhibitor developed for the treatment of leukemia patients, was oxidized to an iminium ion intermediate by monoamine oxidase B (MAO-B) and then converted to its oxo-piperazine form (M1) by aldehyde oxidase (AO). However, it was found that the significant decrease in the pharmacologically active metabolite M1 following repeated administration of KW-2449 in primates might hamper the effectiveness of the drug. The mechanism underlying this phenomenon was investigated and it was found that the AO activity was inhibited in a time-dependent manner in vitro under the co-incubation of KW-2449 and MAO-B, while neither KW-2449 nor M1 strongly inhibited MAO-B or AO activity. These results clearly suggest that MAO-B catalysed iminium ion metabolite inhibited AO, prompting us to investigate whether or not the iminium ion metabolite covalently binds to endogenous proteins, as has been reported with other reactive metabolites as a cause for idiosyncratic toxicity. The association of the radioactivity derived from 14 C-KW-2449 with endogenous proteins both in vivo and in vitro was confirmed and it was verified that this covalent binding was inhibited by the addition of sodium cyanide, an iminium ion-trapping reagent, and pargyline, a MAO-B inhibitor. These findings strongly suggest that the iminium ion metabolite of KW-2449 is highly reactive in inhibiting AO irreversibly and binding to endogenous macromolecules covalently.

Evaluation of fibroblast growth factor activity exerted by placental extract used as a cosmetic ingredient.

BACKGROUND: The biological activities claimed for placental extract (PE) in its medical and cosmetic applications are largely assumed to be the combined effects of its various signaling molecules and nutritional constituents. But there are considerable uncertainties about this assumption. AIMS: To determine the specific biological activity of PE at a molecular level. METHODS: Fibroblast growth factor (FGF) activity was assessed based on the ability to induce proliferation of FGF receptor (FGFR)-overexpressing BaF3 cells. RESULTS: Porcine PE (PPE), an ingredient in numerous cosmetics, activated proliferation of BaF3 cells overexpressing FGFR subtypes 1c, 2c, 2b, 3c, or 4, that is, all the major FGFR subtypes. The effect was suppressed largely or partially when the cells were treated with a FGFR inhibitor PD173074, and the FGFR-negative BaF3 parent cells exhibited minimal growth promotion as compared to the FGFR-expressing BaF3 cells. The high (>10 kDa) and low (<3 kDa) molecular weight fractions of PPE were effective activators of FGFR signaling. PPE was found to contain sulfated glycosaminoglycans, including heparin/heparan sulfate and chondroitin sulfate, which serve as both structural stabilizers of FGFs and indispensable cofactors for FGF-FGFR signaling. CONCLUSIONS: These results indicate that PPE is capable of evoking FGF signaling in cells via FGFRs. Given that recombinant FGFs have proven useful for medical/cosmetic purposes, our results suggest that the medical/cosmetic utility of PPE is provided at least partly through the activation of FGF signaling in epidermal, dermal, and subdermal tissues.

Strong radioprotective FGF1 signaling down-regulates proliferative and metastatic capabilities of the angiosarcoma cell line, ISOS-1, through the dual inhibition of EGFR and VEGFR pathways.

BACKGROUND AND PURPOSE: Angiosarcoma is associated with a poor prognosis and is treated with radiotherapy. Although FGF1 is a potential radioprotector, the influence of FGF1 on the malignancy of angiosarcoma remains unknown. MATERIALS AND METHODS: Highly stable FGF1 mutants, which exhibit stronger mitogenic activity than wild-type FGF1, were examined as strong radioprotectors and signaling agonists to clarify the effects of FGF1 on the murine angiosarcoma cell line ISOS-1. RESULTS: FGF1 mutants reduced colony formation by and the in vitro invasion and migration of ISOS-1 cells, in addition to an increase in radiosensitivity to X-rays. In contrast, an FGFR inhibitor blocked the inhibitory effects of FGF1 mutants on colony formation, invasion, and migration. siRNA targeting the Fgfr1 gene showed that strong FGFR1 signaling reduced colony formation by ISOS-1 cells. However, the FGF1 mutant reduced the activation of VEGFRs and EGFRs in ISOS-1 cells more strongly than wild-type FGF1. Moreover, the inhibition of VEGFRs and EGFRs synergistically reduced colony formation by and invasion and migration of ISOS-1 cells. CONCLUSION: These results suggest that strong FGF1 signaling exerts not only radioprotective effects, but also inhibitory effects on proliferative and metastatic capacities of angiosarcoma through the dual inhibition of EGFR and VEGFR pathways.

FGF18 signaling in the hair cycle resting phase determines radioresistance of hair follicles by arresting hair cycling.

PURPOSE: Telogen (resting phase) hair follicles (HFs) are more radioresistant than their anagen (growth phase) counterparts. Fibroblast growth factor (FGF) 18 is strongly expressed in telogen HFs to maintain the telogen phase, whereas several other FGFs exert radioprotective effects; however, the role of FGF18 in the radioresistance of HFs remains unknown. This study focused on clarifying the role of FGF18 in the radioresistance of telogen HFs and its potential as a radioprotector. METHODS AND MATERIALS: BALB/c mice with telogen or plucking-induced anagen HFs were exposed to total body irradiation with γ-rays at 4 to 12 Gy after intraperitoneal treatment with FGF18 or an FGF receptor inhibitor. A time course analysis was performed histologically and hair growth was observed 14 or 15 days after depilation. Skin specimens were analyzed by DNA microarrays and Western blotting. RESULTS: Telogen irradiation at 6 Gy resulted in transient cell growth arrest, leading to successful hair growth, whereas anagen irradiation failed to promote hair growth. Telogen irradiation did not induce apoptosis in HFs or reduce HF stem cells, whereas anagen irradiation induced apoptosis and reduced stem cell numbers. The Inhibition of FGF receptor signaling during the telogen phase promoted HF cell proliferation; however, hair failed to grow after irradiation. In contrast, recombinant FGF18 induced transient cell growth arrest after anagen irradiation with enhanced DNA repair, leading to the inhibition of apoptosis, maintenance of HF stem cells, and successful hair growth. Moreover, FGF18 reduced the expression levels of genes promoting G2/M transition as well as the protein expression levels of cyclin B1 and cdc2 in skin, and induced G2/M arrest in the keratinocyte cell line HaCaT. CONCLUSIONS: These results suggest that FGF18 signaling mediates radioresistance in telogen HFs by arresting the cell cycle, and that FGF18 has potential as a radioprotector for radiation-induced alopecia.

Impaired wound healing in bleomycin-induced murine scleroderma: a new model of wound retardation.

Bleomycin-induced scleroderma in mice is an established model for human scleroderma. Making use of this, we have established a new model for wound retardation. After inducing dermal sclerosis by local bleomycin treatment in nude mice, a full-thickness wound was made by punch excision on the bleomycin application site. Mice pretreated with bleomycin showed a significant delay in wound closure, as compared with mice pretreated with phosphate-buffered saline. Proliferation of keratinocytes was significantly inhibited and the number of Ki-67-positive keratinocytes was significantly lower in the bleomycin-pretreated skin. Also, the number of CD31-positive blood vessels was markedly reduced in the bleomycin-treated skin. The topical daily application of basic fibroblast growth factor (bFGF) significantly promoted wound closure, while increasing blood vessel formation and reducing transforming growth factor-ß and alpha-smooth muscle actin mRNA levels. Furthermore, only two applications of PG-FGF1, a fusion protein of FGF1 with heparan sulfate proteoglycan, overcame the delay in wound closure. Wound delay in this model mainly occurred as a result of decreased vessel formation and keratinocyte migration following bleomycin treatment. It is expected that this model will provide novel insights into the pathogenesis of wound healing and the exploration of possible candidate drugs for refractory or chronic wounds in the clinical setting.

Relationship between Dementia Severity and Behavioral and Psychological Symptoms of Dementia in Dementia with Lewy Bodies and Alzheimer's Disease Patients.

BACKGROUND/AIMS: Behavioral and psychological symptoms of dementia (BPSD) are common in the clinical manifestation of dementia. Although most patients with dementia exhibit some BPSD during the course of the illness, the association of BPSD with the stage of dementia remains unclear. It was the aim of this study to evaluate the impact of severity of dementia on the expression of BPSD in patients with dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). METHODS: Ninety-seven patients with DLB and 393 patients with AD were recruited from 8 dementia clinics across Japan. BPSD were assessed by the Neuropsychiatric Inventory (NPI). A relationship between BPSD and dementia stage classified by the Clinical Dementia Rating (CDR) in each type of dementia was assessed. RESULTS: No significant difference was seen in NPI total score across CDR staging in the DLB group. On the other hand, the NPI total score significantly increased with dementia stage in the AD group. CONCLUSION: The relationship of dementia stage with the expression of BPSD was different according to the type of dementia. BPSD and dementia stage were correlated in AD subjects, in whom psychiatric symptoms increase as the disease progresses, but not in DLB subjects.