310 nm UV-LEDs attenuate imiquimod-induced psoriasis-like skin lesions in C57BL/6 mice and inhibit IL-22-induced STAT3 expression in HaCaT cells.

Ultraviolet light-emitting diodes (UV-LEDs) are a novel light source for phototherapy. This study aimed to evaluate the therapeutic effects of UV-LEDs on psoriasis. Importantly, 310 nm UV-LEDs have not been studied in psoriasis in vitro and in vivo. Effects due to 310 nm UV-LED and 311 nm narrowband ultraviolet B (NBUVB) irradiation were compared for suppressing IL-22-induced activation of STAT3 expression using cell viability assay, western blotting, and immunocytochemistry. C57BL/6 mice were topically treated with imiquimod (IMQ) for 6 consecutive days and degenerative changes were observed. Test groups were irradiated with a 310 nm UV-LED and 311 nm NBUVB. Phenotypic observations, histopathological examinations, and ELISA were conducted with skin and blood samples. STAT3-dependent IL-22 signalling and effects in keratinocytes are negatively regulated by the 310 nm UV-LED, which significantly ameliorated IMQ-induced psoriasis-like dermatitis development and reduced Th17 cytokine levels (IL-17A, IL-22) in serum and dorsal skin. Histopathological findings showed decreases in epidermal thickness and inflammatory T-cell infiltration in the UV-LED-irradiated groups. Quantitative PCR confirmed a UV radiation energy-dependent decrease in IL-17A and IL-22 mRNA levels. The results demonstrated that UV-LEDs had anti-inflammatory and immunoregulatory effects. So, UV-LED phototherapy inhibits psoriasis development by suppressing STAT3 protein and inflammatory cytokines and could be useful in treating psoriasis.

The Effects of Fabric Containing Chamaecyparis obtusa Essential Oil on Atopic Dermatitis-Like Lesions: A Functional Clothing Possibility.

BACKGROUND: Essential oil derived from Chamaecyparis obtusa (EOCO) has been used as an alternative treatment for allergy-related diseases due to its immune-modulating characteristics. Clothing has the longest and most intense contact with human skin, and functional fabrics with intrinsic properties have been increasingly implemented in medical applications. Specially designed fabrics may support atopic dermatitis (AD) treatment. In this study, the effects of fabric containing EOCO on AD were investigated using an NC/Nga mouse model. METHODS: The fabric was applied for 6 h per day for 14 days. The therapeutic effects were evaluated according to measurements of skin lesion severity (modified SCORAD score), transepidermal water loss (TEWL), serum IgE and inflammatory cytokine levels, lesion thickness measured after hematoxylin and eosin staining, and immunohistochemical and Western blot analysis for skin epidermal differentiation protein. RESULTS: The EOCO group exhibited significantly reduced modified SCORAD score, TEWL, and serum IgE levels. Among the inflammatory cytokines analyzed, only the mean values of regulated on activation, normal T cell expressed and secreted were observed to be decreased compared with other control groups. The histological analysis of the skin also revealed that the EOCO group expressed reduced epidermal hyperplasia and recovered filaggrin, involucrin, and loricrin expression. CONCLUSIONS: It was confirmed that fabric containing EOCO has anti-atopic and anti-inflammatory properties. The study data show that fabric containing EOCO can be implemented as an alternative functional clothing for people suffering from AD.

Prospective, preclinical comparison of the performance between radiofrequency microneedling and microneedling alone in reversing photoaged skin.

BACKGROUND: There is a tremendous demand for dermal rejuvenation with minimal invasiveness and patient downtime. AIMS: In this study, we evaluated the performance of nonfractional monopolar radiofrequency for the improvement of photoaged skin texture and wrinkles. METHODS: In total, 32 6-week-old female hairless mice were randomized into four groups of eight mice each: (a) healthy control, (b) UVB-exposed, (c) UVB + microneedling, and (d) UVB + microneedle RF. After applying each treatment modality, skin surface was globally investigated and histologically evaluated senile skin change. Immunohistochemistry was tested with the primary antibody to collagen type I and III. RESULTS: After UVB exposure, the Ra value was significantly increased, leading to clinical development of wrinkles with xerotic scales. Depth and number of wrinkles showed gradual improvement in RF-treated mice. The mean Ra value of the RF-treated group decreased significantly. The RF-treated group showed decreased epidermal thickness, suppression of dermal inflammatory cell infiltration, and increased density of collagen fibers and amount of elastic fibers. CONCLUSIONS: Microneedle RF treatment alleviates photoaged skin texture and wrinkles in this mouse model. To the best of our knowledge, our results provide the first evidence that a nonfractional monopolar microneedle radiofrequency device may contribute to the treatment of UV-damaged skin.

Boehmite enhances hair follicle growth via stimulation of dermal papilla cells by upregulating ß-catenin signalling.

Hair growth, a complex process, has long been the subject of intense research. Recent developments in material technology have revealed boehmite as a new therapeutic modality for use in wound healing and scar reduction, indicating its beneficial effects. Nonetheless, the biological bases of the beneficial effects of boehmite remain unknown. We investigated the hair growth properties of boehmite in vitro and in vivo and observed dose-dependent proliferation of human dermal papilla cells (hDPCs) in vitro and hair regrowth in a mouse model. To investigate the effects of boehmite on the promotion of cell transition to the anagen phase, we evaluated hDPC viability, alkaline phosphatase (ALP) activity, protein expression and vascular endothelial growth factor (VEGF) secretion in vitro and assessed the anagen-promoting effects of boehmite via gross observation and histological analysis in a mouse model. Boehmite increased hDPC viability, ALP activity, AKT/GSK3ß/ß-catenin pathway activity, anagen-related gene expression and VEGF secretion; moreover, it accelerated hair regrowth in a catagen-anagen transition model via upregulation of ß-catenin signalling and follicular cell proliferation. Collectively, our results indicate that boehmite accelerates hair growth, partly via its effects on critical events in the active phase of the hair follicle cycle, including the promotion of the proliferation of hDPCs and their immediate progeny to the follicle base.

Biostimulatory effects of polydioxanone, poly-d, l lactic acid, and polycaprolactone fillers in mouse model.

BACKGROUND: Numerous fillers are increasingly used for augmentation of volume loss and relaxation of facial wrinkles. Collagen stimulators are the latest next-generation dermal fillers that can induce neocollagenesis. To investigate biophysical characteristics, safety, and efficacy of newly developed polydioxanone (PDO) filler in comparison with poly-l lactic acid (PLLA) and polycaprolactone (PCL) fillers. METHODS: In vitro assay, morphology of particles, and rheological property of fillers were measured. A total of 24 female hairless mice (SKH1-Hrhr ) were randomly divided into three groups and injected with PDO, PLLA, or PCL fillers. Durability of fillers was assessed at 0, 3 days, and 1, 4, 8, 12 weeks after injection using folliscope and PRIMOS. To determine biocompatibility and neocollagenesis, histologic evaluation was performed at 1, 4, 8, and 12 weeks after injection. Efficacy was also evaluated based on skin surface roughness changes using PRIMOS in a hairless mouse photoaging model. RESULTS: In the particle morphology test, PDO microspheres had an irregular surface and were spherical and uniformly sized. PDO filler demonstrated similar neocollagenesis and inflammatory response to other collagen stimulators. PDO filler showed better biodegradability than PLLA and PCL fillers. In the hairless mouse photoaging model, there was a statistically significant decrease in skin surface roughness after PDO filler injection. CONCLUSIONS: Our data suggest that newly developed collagen stimulating PDO filler might be a safe and effective option for correction of volume loss and rejuvenation of photoaging skin.

Effects of Intradermal Radiofrequency Treatment and Intense Pulsed Light Therapy in an Acne-induced Rabbit Ear Model.

Acne vulgaris is a common condition that can have psychologically deleterious effects. Since current treatments carry the risks of antibiotic resistance or teratogenicity, novel treatment modalities are under investigation. Our study investigated the efficacy of intradermal radiofrequency treatment (RF) and intense pulsed light (IPL) in the treatment of acne vulgaris in a rabbit ear model. We evaluated the effectiveness of IPL, RF, and a combination treatment on cultured Cuticobacterium acnes strains in an induced rabbit ear model, according to clinical outcomes as well as histological and immunological approaches. We found that RF treatment markedly decreases papule volume, while IPL appears to have an immunomodulatory effect. In combination, the two have an additive effect in treatment. These findings suggest that combination of RF and IPL may be an effective therapeutic option for the treatment of acne vulgaris.

Therapeutic potential of topically administered γ-AlOOH on 2,4-dinitrochlorobenzene-induced atopic dermatitis-like lesions in Balb/c mice.

Boehmite (γ-AlOOH) has a wide range of applications in a variety of industrial and biological fields. However, little is known about its potential roles in skin diseases. The current study investigated its effect on atopic dermatitis (AD). Following characterization, cytotoxicity, pro-inflammatory response and oxidative stress associated with boehmite were assessed, using TNF-α-induced keratinocytes and mast cells. In addition, therapeutic effects of boehmite, topically administered to Balb/c mice induced by 2,4-dinitrochlorobenzene (DNCB), were evaluated. Expression of cytokines (TLSP, IL-25 and IL-33) and the generation of ROS from keratinocytes induced by TNF-α were significantly inhibited by boehmite without affecting cell viability. MAPKs (ERK, JNK and p38) required for cytokine expression were suppressed by boehmite treatment. Up-regulation of cytokines (TSLP, IL-4, IL-5, IL-13, RANTES) in human mast cells treated with phorbol 12-myristate 13-acetate and calcium ionophore was also suppressed by boehmite. Boehmite improved the AD severity score, epidermal hyperplasia and transepidermal water loss in DNCB-induced AD-like lesions. Moreover, Th2-mediated cytokine expression, mast cell hyperplasia and destruction of the skin barrier were improved by boehmite treatment. Overall, we demonstrated that boehmite may potentially protect against AD.

Effects on skin of Stichopus japonicus viscera extracts detected with saponin including Holothurin A: Down-regulation of melanin synthesis and up-regulation of neocollagenesis mediated by ERK signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Stichopus japonicus (sea cucumber), edible traditional food in Asia, and its extracts are renowned for their wound healing, pain relieving, and cosmetic effects in traditional medicine. Holothurins, toxins isolated from sea cucumber, are thought to be active components for their beneficial effects. However, researchers have yet to outline specific mechanisms thereof. AIM OF THE STUDY: The present study was designed to evaluate the anti-melanogenic and anti-wrinkle properties of S. japonicus viscera extracts (VF) on the skin via in vitro and ex vivo experiments and to assess the anti-aging effects of S. japonicus viscera extracts in relation to known wound healing and cosmetic processes. MATERIALS AND METHODS: The viscera of live S. japonicus specimens were freeze dried and ground into a powder. Aqueous extracts were subsequently prepared from the concentrated powder using a water extraction method. To investigate the inhibitory effects of VF on melanogenesis, mushroom tyrosinase activity assay and melanin assay were performed on Melan-A cells. To further delineate the anti-melanogenic properties of VF, western blot analysis for tyrosinase, TRP-1, TRP-2, MITF, and ERK was conducted. Changes in collagen synthesis in human dermal fibroblast (HDF) were evaluated via CCK-8 assay and immunocytochemistry to determine the anti-wrinkle effects of VF. Finally, anti-aging properties were examined in a human skin equivalent ex vivo model. RESULTS: In Melan-A cells, VF treatment reduced melanin contents in a concentration-dependent manner. The anti-melanogenic effects of VF appeared to be due to enzymatic inhibition of tyrosinase. In CCK-8 assay, VF also significantly increased the viability of HDFs in a concentration-dependent manner. Immunoblot analysis revealed phosphorylation of ERK in HDFs treated with VF. In a human skin equivalent ex vivo model (Neoderm®-ED), VF treatment at a concentration of 50 µg/ml enhanced collagen type IV and Ki-67 expression and downregulated MMP-9 expression. CONCLUSION: This study demonstrated that aqueous extracts from S. japonicus viscera are effective whitening and anti-aging agents that stimulate ERK signaling to inhibit melanin synthesis and promote collagen synthesis.

Corrigendum to "Apoptosis Induced by Tanshinone IIA and Cryptotanshinone Is Mediated by Distinct JAK/STAT3/5 and SHP1/2 Signaling in Chronic Myeloid Leukemia K562 Cells".

[This corrects the article DOI: 10.1155/2013/805639.].

Inhibitory effects of Stichopus japonicus extract on melanogenesis of mouse cells via ERK phosphorylation.

Stichopus japonicus has been used as a folk medicine and as an ingredient in traditional food in East Asian countries. In recent years, the bioactive compounds found in S. japonicus have been reported to possess efficacy in wound healing and may be of potential use in the cosmeceutical, pharmaceutical and biomedical industries. Although the components and their functions require further investigation, S. japonicus extracts exhibit anti­inflammatory properties, and may be used for cancer prevention and treatment. Although several reports have examined different aspects of S. japo-nicus, the effects of S. japonicus extract on melanogenesis in the skin has not been reported to date. Therefore the present study aimed to investigate the effects of S. japonicus extract on melanogenesis. Treatment with a mixture of S. japonicus extracts (MSCE) reduced melanin synthesis and tyrosinase (TYR) activity in mouse melanocyte cells lines, B16F10 and Melan­A. In addition, MSCE treatment reduced the protein expression levels of TYR, tyrosinase­related protein­1 and tyrosinase­related protein­2. The reduced protein levels may be the result of decreased microphthalmia­associated transcription factor (MITF) expression, which is an important regulator of melanogenesis. The reduced expression level of MITF was associated with delayed phosphorylation of extracellular signal­regulated kinase (ERK) induced by MSCE treatment. A specific MEK inhibitor, PD98059, significantly blocked MSCE­mediated inhibition of melanin synthesis. In conclusion, these results indicate that MSCE may be useful as a potential skin­whitening compound in the skin medical industry.

Effect of isosecotanapartholide isolated from Artemisia princeps Pampanini on IL­33 production and STAT­1 activation in HaCaT keratinocytes.

The present study aimed to investigate the anti­inflammatory effect and mechanism of action of isosecotanapartholide (ISTP), isolated from Artemisia princeps Pampanini extract (APE). The effects of ISTP and APE on the proliferation of human keratinocytes following stimulation by tumor necrosis factor­α/interferon­Î³ were assessed. ISTP and APE downregulated the expression levels of signal transducer and activator of transcription­1 (STAT­1), and reduced interleukin­33 (IL­33) production. ISTP and APE inhibited the mRNA expression levels of thymus and activation­regulated chemokine (TARC/CCL17) in a dose­dependent manner. Western blot analysis demonstrated that ISTP and APE dose­dependently inhibited protein expression levels of intercellular adhesion molecule­1 and phosphorylation of STAT­1. The results of the present study indicate that ISTP may inhibit TARC/CCL17 production in human epidermal keratinocytes via the STAT­1 signaling pathway and may be associated with the inhibition of IL­33 production. The current study indicated that ISTP is an active component in APE and may be a potential therapeutic agent for the treatment of inflammatory skin disorders.

Inhibitory effect of 660-nm LED on melanin synthesis in in vitro and in vivo.

BACKGROUND: Skin hyperpigmentary disorders including postinflammatory hyperpigmentation, melasma, solar lentigines, and conditions like freckles are common. The light-emitting diodes (LEDs) are the latest category of nonthermal and noninvasive phototherapy to be considered in skin pigmentation disorder treatment. PURPOSE: The purpose of this study was to investigate the effects of 660-nm LED on inhibition of melanogenesis. We investigated whether a 660-nm LED affected melanin synthesis in in vitro and in vivo models, and we explored the mechanisms involved. METHODS: The inhibitory effect of 660-nm LED on melanin synthesis was evaluated in B16F10 cells and HRM-2 melanin-possessing hairless mice were used to evaluate the antimelanogenic effects of 660-nm LED. RESULTS: Interestingly, 660-nm LED inhibited alpha-melanocyte-stimulating hormone-induced tyrosinase activity in B16F10 cells. We also found that 660-nm LED decreased MITF and tyrosinase expression and induced the activation of ERK. These findings suggest that the depigmenting effects of 660-nm LED result from downregulation of MITF and tyrosinase expression due to increased ERK activity. The 660-nm LED reduced UVB-induced melanogenesis in the skin of HRM-2 via downregulation of tyrosinase and MITF. CONCLUSION: These findings suggest 660-nm LED is a potentially depigmentation strategy.

Gain-switched 311-nm Ti:Sapphire laser might be a potential treatment modality for atopic dermatitis.

Phototherapy with 311-nm narrowband-UVB (NBUVB) is an effective adjuvant treatment modality for atopic dermatitis (AD). In this study, we evaluated the therapeutic effect of the newly developed gain-switched 311-nm Ti:Sapphire laser device using a NC/Nga mouse AD model. A total number of 50 mice were used in this study. Atopic dermatitis (AD) was induced in mice by exposure to Dermatophagoides farina. These, NC/Nga mice were then treated with conventional 311-nm NBUVB or the newly developed gain-switched 311-nm Ti:Sapphire laser. The clinical features, dermatitis severity scores, and scratching behavior were assessed. In addition, serologic analyses including inflammatory cytokines and histological analyses were performed. Gain-switched 311-nm Ti:Sapphire laser improved the AD-like skin lesions, severity, and symptoms of AD in the NC/Nga mouse model. This new laser also modulated the immune response found in the AD model, including hyper-IgE, upregulated Th2 cytokines, and the Th2-mediated allergic inflammatory reaction. Gain-switched 311-nm Ti:Sapphire laser shows therapeutic promise via an immune-modulation mechanism in an AD mouse model. These data suggest that gain-switched 311-nm Ti:Sapphire laser may be useful as a targeted phototherapy modality for AD.

Ultraviolet light-emitting-diode irradiation inhibits TNF-α and IFN-γ-induced expression of ICAM-1 and STAT1 phosphorylation in human keratinocytes.

BACKGROUND AND OBJECTIVES: Ultraviolet light-emitting diodes (UV-LEDs) are a novel light source for phototherapy. This research investigated the in vitro safety and efficacy of UV-LEDs as a phototherapeutic device for atopic dermatitis (AD). STUDY DESIGN/MATERIALS AND METHODS: Human keratinocytes and fibroblasts were irradiated by UV-LEDs with a center wavelength of 310 and 340 nm. We examined the effects of UV-LED irradiation on the suppression of TNF-α/IFN-γ-induced activation of STAT1 and ICAM-1 and on NF-κB expression; we used the following methods: cell viability assay, reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, Western blotting, and immunocytochemistry. RESULTS: We observed anti-inflammatory responses through the suppression of TNF-α/IFN-γ-induced expression of TARC and MCP-1/CCL2, IL-1beta, IL-6, and sICAM-1 via blockage of ICAM-1 activation and subsequent activation of STAT1 and NF-κB. The results suggested that UV-LED irradiation inhibited ICAM expression by suppressing TNF-α/IFN-γ-induced NF-κB activation in vitro. CONCLUSION: We concluded that novel UV-LED (310 and 340 nm) modalities were effective for the treatment of AD and may be promising for the treatment of inflammatory skin diseases.

Therapeutic effects of full spectrum light on the development of atopic dermatitis-like lesions in NC/Nga mice.

Full spectrum light (FSL) includes UVA, visible light and infrared light. Many studies have investigated the application of FSL in severe cases of atopic dermatitis (AD) in humans; however, FSL has not yet been studied in an animal model. The purpose of this study was to evaluate the therapeutic effects of FSL on AD-like skin lesions using NC/Nga mice, with the aim of mitigating itching and attenuating the expression of adhesion molecules. We examined the effects of FSL on mite allergen-treated NC/Nga mice by assessing skin symptom severity, ear thickness, serum IgE levels, and the cytokine expression. We examined the histology of lesions using hematoxylin-eosin, toluidine blue and immunohistochemical staining. Our findings suggest that FSL phototherapy exerts positive therapeutic effects on Dermatophagoides farinae (Df)-induced AD-like skin lesions in NC/Nga mice by reducing IgE levels, thus promoting recovery of the skin barrier. The mechanisms by which FSL phototherapy exerts its effects may also involve the inhibition of scratching behavior, reduction of IL-6 levels and reductions in adhesion molecule expression. The present study indicates that FSL phototherapy inhibits the development of AD in NC/Nga mice by suppressing cytokine, chemokine and adhesion molecule expression, and thus, could potentially be useful in treating AD.

Apoptosis Induced by Tanshinone IIA and Cryptotanshinone Is Mediated by Distinct JAK/STAT3/5 and SHP1/2 Signaling in Chronic Myeloid Leukemia K562 Cells.

Though tanshinone IIA and cryptotanshinone possess a variety of biological effects such as anti-inflammatory, antioxidative, antimetabolic, and anticancer effects, the precise molecular targets or pathways responsible for anticancer activities of tanshinone IIA and cryptotanshinone in chronic myeloid leukemia (CML) still remain unclear. In the present study, we investigated the effect of tanshinone IIA and cryptotanshinone on the Janus activated kinase (JAK)/signal transducer and activator of transcription (STAT) signaling during apoptotic process. We found that both tanshinone IIA and cryptotanshinone induced apoptosis by activation of caspase-9/3 and Sub-G1 accumulation in K562 cells. However, they have the distinct JAK/STAT pathway, in which tanshinone IIA inhibits JAK2/STAT5 signaling, whereas cryptotanshinone targets the JAK2/STAT3. In addition, tanshinone IIA enhanced the expression of both SHP-1 and -2, while cryptotanshinone regulated the expression of only SHP-1. Both tanshinone IIA and cryptotanshinone attenuated the expression of bcl-xL, survivin, and cyclin D1. Furthermore, tanshinone IIA augmented synergy with imatinib, a CML chemotherapeutic drug, better than cryptotanshinone in K562 cells. Overall, our findings suggest that the anticancer activity of tanshinone IIA and cryptotanshinone is mediated by the distinct the JAK/STAT3/5 and SHP1/2 signaling, and tanshinone IIA has the potential for combination therapy with imatinib in K562 CML cells.

Herbal cocktail ka-mi-kae-kyuk-tang stimulates mouse bone marrow stem cell hematopoiesis and janus-activated kinase 2/signal transducer and activator of transcription 5 pathway.

Ka-mi-kae-kyuk-tang (KMKKT) is an Oriental herbal medicinal cocktail. Our collaborative team has shown that it has potent anti-angiogenic, anti-cancer and anti-metastatic activities in vivo without observable side effects. We have documented evidence for KMKKT to alleviate drug-induced hematotoxicity in vivo. In the present study, we investigated the mechanistic and signaling events through which KMKKT enhances hematopoiesis, using hematopoietic stem cells (HSCs) isolated from the bone marrow of 8-12 week-old C57BL/6 mice. Our results show that KMKKT significantly increased the expression of the hematopoietic cytokines interleukin (IL)-3, stem cell factor (SCF), granulocyte-macrophage-colony stimulating factor (GM-CSF), thrombopoietin (TPO) and erythropoietin (EPO) at the level of mRNA and secretion in HSCs. KMKKT also increased the expression of c-Kit, a cytokine receptor expressed in HSCs. In addition, KMKKT enhanced phosphorylation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5), and increased the binding activity of STAT5 to gamma interferon activated sites (GAS) that mediate JAK2 downstream signaling. Furthermore, we found that KMKKT significantly enhanced the growth rate of colony-forming unit granulocyte erythrocyte monocyte macrophages (CFU-GEMM) and burst forming unit erythroid (BFU-E) of mouse HSCs (mHSCs) stimulated by IL-3/EPO. Overall, our results demonstrated that KMKKT alleviated drug-induced side effects through enhanced hematopoiesis, at least in part through cytokine-mediated JAK2/STAT5 signaling.

JAK2/STAT5 signaling pathway mediates Bojungbangdocktang enhanced hematopoiesis.

Bojungbangdocktang (BJBDT) is a medicinal herbal cocktail that has been used for cancer prevention and treatment in traditional Korean medicine. In the current study, BJBDT was demonstrated to regulate hematopoiesis. BJBDT significantly increased the expression of hematopoietic cytokines interleukin (IL)-3, stem cell factor (SCF), granulocyte-macrophage-colony stimulating factor (GM-CSF), thrombopoietin (TPO) and erythropoietin (EPO) at the level of mRNA and secretion in hematopoietic stem cells (HSCs). Additionally, BJBDT enhanced the phosphorylation of Janus activated kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5) and STAT binding to gamma interferon activated sites (GAS) in HSCs. Furthermore, BJBDT significantly enhanced the growth rate of granulocyte erythrocyte monocyte macrophage colony-forming units (CFU-GEMM) and erythroid burst forming units (BFU-E) in vitro. Moreover, BJBDT increased the level of EPO at mRNA in kidney and plasma, and the numbers of erythroid-specific antigen Ter-119(+) erythroid cells in mice with aplastic anemia induced by 20% benzene. Consistently, histochemical staining revealed BJBDT increased the bone marrow and stromal cells as well as decreased macrophages and adipocytes in bone marrow tissues of mice with aplastic anemia. Taken together, the results suggest that BJBDT can enhance hematopoiesis via hematopoietic cytokine-mediated JAK2/STAT5 pathway as a potent hematopoietic candidate. Copyright © 2010 John Wiley & Sons, Ltd.

Tanshinone IIA induces mitochondria dependent apoptosis in prostate cancer cells in association with an inhibition of phosphoinositide 3-kinase/AKT pathway.

Tanshinone IIA (Tan IIA; 14,16-epoxy-20-nor-5(10),6,8,13,15-abietapentaene-11,12-dione), a phytochemical derived from the roots of Salvia miltiorrhiza BUNGE, has been reported to posses anti-angiogenic, anti-oxidant, anti-inflammatory and apoptotic activities. However, the cancer growth inhibitory/cytocidal effects and molecular mechanisms in prostate cancer cells have not been well studied. In the present study, we demonstrate that Tan IIA significantly decreased the viable cell number of LNCaP (phosphate and tensin homolog (PTEN) mutant, high AKT, wild type p53) prostate cancer cells more sensitively than against the PC-3 (PTEN null, high AKT, p53 null) prostate cancer cells. Tan IIA significantly increased TdT-mediated dUTP nick-end labeling (TUNEL) positive index and sub-G1 DNA contents of treated cells, consistent with apoptosis. Tan IIA treatment led to cleavage activation of pro-caspases-9 and 3, but not pro-caspase-8, and cleavage of poly (ADP ribose) polymerase (PARP), a caspase-3 substrate. Additionally, Tan IIA treatment induced cytochrome c release from the mitochondria into the cytosol and reduced mitochondrial membrane potential and suppressed the expression of mitochondria protective Bcl-2 family protein Mcl-1(L). Tan IIA reduced the expression of phosphoinositide 3-kinase (PI3K) p85 subunit, and the phosphorylation of AKT and mammalian target of rapamycin (mTOR) in a concentration-dependent manner. Moreover, the combination of Tan IIA and LY294002, a specific PI3K inhibitor, enhanced PARP cleavage of LNCaP and PC-3, but not in MDA-MB-231 breast cancer cells which do not contain detectable active AKT. The findings suggest that Tan IIA-induced apoptosis involves mitochondria intrinsic caspase activation cascade and an inhibition of the PI3K/AKT survival pathway.