Mechanisms of action of etanercept in psoriasis

Psoriasis is a chronic inflammatory disease of the skin affecting up to 2.5% of the world's population. The scaly, erythematous plaques characteristic of this papulosquamous disorder are likely triggered and maintained by cytokines and chemokines manufactured by cells of the immune system. Overproduction of inflammatory mediators, such as tumor necrosis factor-alpha (TNF-alpha) and IFN-gamma, results in a self-sustaining inflammatory cascade, causing abnormal keratinocyte proliferation and differentiation. Therapeutic drug design targeting TNF has led to the emergence of successful biologic agents, such as etanercept, in recent years. Despite extensive clinical trials documenting efficacious clinical response to therapy, there is a paucity of data investigating the molecular mechanisms by which etanercept modulates the improvement of psoriasis. This brief review summarizes recent work investigating the in vivo actions of etanercept, including its effects on various cell types, inflammatory pathways, gene activation, nuclear factor kappa B expression, and apoptosis. The anti-inflammatory properties of etanercept reveal mechanisms by which a TNF blockade may result in the improvement of psoriasis.     

Herman Beerman lecture. Mechanisms of steroid hormone action.

The molecular biology of steroid hormone action is reviewed. Topics discussed include the chick oviduct system as a model for exploring the effects of steroid hormones, the nature of steroid hormone receptors, the nuclear uptake of receptor-hormone complexes, nuclear retention of the receptor-hormone complex, the initiation of RNA synthesis by steroid hormones, the synthesis, modification, and export of messenger RNA, and translation of mRNA. It has been possible to induce ovalbumin mRNA synthesis in vitro by combining purified steroid hormone-receptor complexes with RNA polymerase, interphase chromosomes, and necessary substrates. A similar effect is observed in vivo with progesterone treatment. It is suggested that steroid hormone receptors act directly on the cell's genetic apparatus to promote gene expression.     

宿主氧化损伤及致病真菌抗氧化损伤机制的究进展

病原体入侵机体后,诱导机体进入一种氧化应激状态,吞噬细胞释放大量活性氧介质,当活性氧介质的产生和清除存在不平衡时,会造成细胞氧化损伤.而病原体本身在遇到氧化应激时也表达一些抗氧化物质,来启动抗氧化机制,以降低氧化损伤对其杀伤和破坏.阐述宿主释放的活性氧介质如过氧化氢、超氧阴离子、羟自由基等对致病真菌的氧化损伤,以及致病真菌表达抗氧化物质如过氧化氢酶、超氧化物歧化酶等抗氧化损伤的机制.     

Minoxidil: mechanisms of action on hair growth

We have known for over 30 years that minoxidil stimulates hair growth, yet our understanding of its mechanism of action on the hair follicle is very limited. In animal studies, topical minoxidil shortens telogen, causing premature entry of resting hair follicles into anagen, and it probably has a similar action in humans. Minoxidil may also cause prolongation of anagen and increases hair follicle size. Orally administered minoxidil lowers blood pressure by relaxing vascular smooth muscle through the action of its sulphated metabolite, minoxidil sulphate, as an opener of sarcolemmal KATP channels. There is some evidence that the stimulatory effect of minoxidil on hair growth is also due to the opening of potassium channels by minoxidil sulphate, but this idea has been difficult to prove and to date there has been no clear demonstration that KATP channels are expressed in the hair follicle. A number of in vitro effects of minoxidil have been described in monocultures of various skin and hair follicle cell types including stimulation of cell proliferation, inhibition of collagen synthesis, and stimulation of vascular endothelial growth factor and prostaglandin synthesis. Some or all of these effects may be relevant to hair growth, but the application of results obtained in cell culture studies to the complex biology of the hair follicle is uncertain. In this article we review the current state of knowledge on the mode of action of minoxidil on hair growth and indicate lines of future research.     

蜗牛酶对3种致病性真菌细胞壁作用的研究

用蜗牛酶对犬小孢子菌、石膏样小孢子菌和白念珠菌进行了消化.结果50%以上菌丝细胞壁粗糙,失去折光性、变形或断裂.大分生孢子出现更多的颗粒,隔膜消失,某些细胞壁硬裂.白念珠菌仅10~%多的孢子发生改变.真菌在消化后作了4种染色.乳酸酚棉蓝比正常蓝色更深;0.5%台盼蓝液显示着色;革兰氏染色呈阴性反应;雪夫氏过碘酸糖原染色变为淡红色.     

白细胞介素22诱导HaCaT细胞表达肝素结合表皮生长因子样生长因子的作用机制探讨

目的 探讨白细胞介素22（IL-22）诱导HaCaT细胞表达肝素结合表皮生长因子样生长因子（HB-EGF）的相关作用机制。 方法 用不同浓度的IL-22（12.5、25、50、100 μg/L）干预处理HaCaT细胞,对照组选择等量磷酸盐缓冲液（PBS）处理。24 h后,提取HaCaT细胞总蛋白进行蛋白免疫印迹,检测丝裂原活化蛋白激酶-细胞外信号调节激酶1/2（MAPK-ERK1/2）通路中磷酸化ERK1/2（P-ERK1/2）的表达和转录激活因子途径（JAK/STAT）中磷酸化JAK2（P-JAK2）和磷酸化STAT3（P-STAT3）的表达。将HaCaT细胞分4组,分别用PBS、IL-22、MAPK-ERK1/2抑制剂PD98059、JAK2/STAT3通路抑制剂AG490与IL-22共同干预HaCaT细胞,24 h后,提取细胞总蛋白和总mRNA,分别用蛋白免疫印迹法和实时定量逆转录（RT）-PCR法检测不同处理组HB-EGF蛋白和mRNA水平的改变。采用SPSS16.0软件进行单因素方差分析检验组间差异,Bonferroni检验进行多重比较。结果 不同浓度的IL-22干预处理后,HaCaT细胞中P-ERK1/2、P-JAK2和P-STAT3蛋白表达均高于对照组（P < 0.05）。HB-EGF蛋白水平（HB-EGF/内参照的灰度比值）在PD98059组和AG490组分别为0.183 ± 0.020和0.199 ± 0.011,与IL-22组（0.924 ± 0.032）相比,差异具有统计学意义（F值分别为37.700、36.400,均P < 0.05）。HB-EGF mRNA水平在PD98059组和AG490组分别为1.034 ± 0.072和0.989 ± 0.038,与IL-22组（1.844 ± 0.135）相比,差异具有统计学意义（F值分别为11.271、13.429,均P < 0.05）。 结论 IL-22可以引起HaCaT细胞中MAPK-ERK1/2和JAK2/STAT3这两条信号通路激活。IL-22诱导HaCaT细胞产生HB-EGF蛋白的作用机制可能与MAPK-ERK1/2和JAK2/STAT3这两条信号通路有关。     

Basic fibroblast growth factor stimulation of epidermal wound healing in pigs

Basic fibroblast growth factor (bFGF) has recently been shown to be a mitogen for keratinocytes. This observation has now been extended in a porcine model of epidermal wound healing. A single application of recombinant human bFGF given at the time of injury to healthy animals accelerated the rate of epithelialization by 20%; multiple applications gave no greater effect than the single application. Histologic analysis of biopsies of these partial-thickness wounds taken during bFGF-mediated healing supported the assessment of an enhanced rate of epithelialization and an earlier onset of dermal healing. Because no histologic abnormalities were observed, bFGF induced an acceleration of what appears to be the normal healing process.     

Photobiomodulation with non-thermal lasers: Mechanisms of action and therapeutic uses in dermatology and aesthetic medicine

Background: Non-thermal laser therapy in dermatology, is a growing field in medical technology by which therapeutic effects are achieved by exposing tissues to specific wavelengths of light. Objectives: The purpose of this review was to gain a better understanding of the science behind non-thermal laser and the evidence supporting its use in dermatology. Methods: A group of dermatologists and surgeons recently convened to review the evidence supporting the use of non-thermal laser for body sculpting, improving the appearance of cellulite, and treating onychomycosis. Results: The use of non-thermal laser for body sculpting is supported by three randomized, double-blind, sham-controlled studies (N = 161), one prospective open-label study (N = 54), and two retrospective studies (N = 775). Non-thermal laser application for improving the appearance of cellulite is supported by one randomized, double-blind, sham-controlled study (N = 38). The use of non-thermal laser for the treatment of onychomycosis is supported by an analysis of three non-randomized, open-label studies demonstrating clinical improvement of nails (N = 292). Conclusions: Non-thermal laser is steadily moving into mainstream medical practice, such as dermatology. Although present studies have demonstrated the safety and efficacy of non-thermal laser for body sculpting, cellulite reduction and onychomycosis treatment, studies demonstrating the efficacy of non-thermal laser as a stand-alone procedure are still inadequate.     

Mechanisms of action of topical 5-fluorouracil: review and implications for the treatment of dermatological disorders

Topical 5-fluorouracil has proved to be a useful therapy since its discovery nearly 50 years ago for the treatment of a range of cancers (e.g. skin, colorectal, breast) and dermatological conditions (e.g. cancerous and precancerous conditions such as actinic keratosis, benign tumors, nail psoriasis, mycosis fungoides, and porokeratoses). As a result of the enduring utility in these conditions, the mechanism of action of 5-fluorouracil has been studied extensively in vivo and in vitro. This review provides an overview of the history and general mechanism of action of 5-fluorouracil and discusses the dermatological implications of the drug, including systemic absorption, selectivity for abnormal skin, targeted delivery, and skin-specific molecular effects. Considerations of 5-fluorouracil treatment in specific dermatological settings are also discussed, as well as recent findings of a role for 5-fluorouracil in the treatment of photoaging.     

Intracellular calcium as a second messenger following growth stimulation of human keratinocytes

Summary The mitogenic effect of the neuropeptide substance P and bombesin was investigated in normal human keratinocytes in serum-free culture, both with and without the presence of epidermal growth factor (EGF). Although both neuropeptides induced a small Increase in cell numbers in the presence of EGF. the response was much greater in its absence, and cell numbers Increased to 200% of controls at 5 days. Changes in intracellular free calcium are frequently seen following mitogenic stimulation of cells, and this phenomenon was studied in individual keratinocytes. Epidermal growth factor (10 ng/ml) induced calcium transients in 57% (n = 21) of cells. The mean Intracellular free calcium was 97 ± 11 nM (mean ± SEM) in quiescent cells, and the calcium transients reached approximately 250 nM for 3–4 min. In the presence of EGF. calcium transients were never observed with the addition of either substance P or bombesin. For EGF-deprived cultures. 20% of keratinocytes (n = 10) showed a large calcium transient following the addition of 500 nM bombesin, and ft 63% (n = 12) of cells gave calcium transients following the addition of 700 nM of substance P. Studies in calcium-free medium, and following depletion of intracellular calcium stores with thapsigargin. showed that all of the calcium transients were dependent on the presence of intracellular stores, but also partially mediated by an influx of extracellular calcium. These studies demonstrate the mitogenic effect of substance P and bombesin on human keratinocytes in the absence of EGF. The ability of the neuropeptides to increase keratinocyte growth In culture suggests a possible role in wound healing.