PDGF/PDGFR: A Possible Molecular Target in Scleroderma Fibrosis

Systemic sclerosis (SSc) is a clinically heterogeneous disorder of the connective tissue characterized by vascular alterations, immune/inflammatory manifestations, and organ fibrosis. SSc pathogenesis is complex and still poorly understood. Therefore, effective therapies are lacking and remain nonspecific and limited to disease symptoms. In the last few years, many molecular and cellular mediators of SSc fibrosis have been described, providing new potential options for targeted therapies. In this review: (i) we focused on the PDGF/PDGFR pathway as key signaling molecules in the development of tissue fibrosis; (ii) we highlighted the possible role of stimulatory anti-PDGFRα autoantibodies in the pathogenesis of SSc; (iii) we reported the most promising PDGF/PDGFR targeting therapies.     

Role of growth factors and their receptors in gastric ulcer healing

The repair of gastric ulcers requires the reconstitution of epithelial structures and the underlying connective tissue, including vessels and muscle layers. Several growth factors have been implicated in this process, since they are able to regulate important cell functions, such as cell proliferation, migration, differentiation, secretion, and degradation of extracellular matrix, all of which are essential during tissue healing. Epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), hepatocyte growth factor (HGF), and trefoil factors (TFFs) are mainly involved in the reconstitution of the epithelial structures. Platelet derived growth factor (PDGF), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and transforming growth factor-beta (TGF-beta) play a major role in the reconstitution of connective tissue, including vessels and smooth muscle cells, and provide the extracellular matrix substrate for cell migration and differentiation. The expression of these growth factors and their receptors is increased during ulcer healing and, in some cases, intracellular signaling related to receptor binding and transduction has been demonstrated. EGF, TGF-alpha and TFFs are normally present either in the gastric juice or in the mucosa, and may exert their effects immediately after damage, before newly synthesized EGF and TFFs are released from the ulcer margin. The inhibition of their effects by neutralizing antibodies may result in delayed ulcer healing, while the administration of recombinant or natural analogues may improve ulcer repair. In this review, we will summarize the basic molecular characteristics of some of these growth factors, and will discuss available evidence supporting their role in the ulcer repair process.     

Toward the biomimetic implant surface: Biopolymers on titanium-based implants for bone regeneration

Replacing malfunctioning tissues with titanium-based implants has become a widespread practice spurred by population aging. Advances in biomaterials, technology and implantation protocols have led to increasing expectations on the applicability and durability of implants. The field has recently moved from a bioinert to a bioactive paradigm due to surface modifications that trigger specific responses on the surrounding tissues. Biopolymeric surface coatings have taken up a central role in these developments. The use of these and other biomimetic strategies on implants provides greater control over material–cell interactions and it is aimed at improving long-term clinical results by replicating some of the structures and mechanisms of living tissues. This review summarizes the state of the art of biomimetic implants and discusses the main directions and challenges of this field toward a more predictable and successful implant osseointegration.     

Chitin and chitosan in selected biomedical applications

Chitin (CT), the well-known natural biopolymer and chitosan (CS) (bio-based or “artificial polymer”) are non-toxic, biodegradable and biocompatible in nature. The advantages of these biomaterials are such that, they can be easily processed into different forms such as membranes, sponges, gels, scaffolds, microparticles, nanoparticles and nanofibers for a variety of biomedical applications such as drug delivery, gene therapy, tissue engineering and wound healing. Present review focuses on the diverse applications of CT and CS membranes and scaffolds for drug delivery, tissue engineering and targeted regenerative medicine. The chitinous scaffolds of marine sponges’ origin are discussed here for the first time. These CT based scaffolds obtained from Porifera possess remarkable and unique properties such as hydration, interconnected channels and diverse structural architecture. This review will provide a brief overview of CT and CS membranes and scaffolds toward different kinds of delivery applications such as anticancer drug delivery, osteogenic drug delivery, and growth factor delivery, because of their inimitable release behavior, degradation profile, mucoadhesive nature, etc. The review also provides an overview of the key features of CT and CS membranes and scaffolds such as their biodegradability, cytocompatibility and mechanical properties toward applications in tissue engineering and wound healing.     

Design,Synthesis, and Characterization of a Photoactivatable Caged Prodrug of Imatinib

Imatinib is the first protein kinase inhibitor approved for clinical use and is a seminal drug for the concept of targeted therapy. Herein we report on the design, synthesis, photokinetic properties, and in vitro enzymatic evaluation of a photoactivatable caged prodrug of imatinib. This approach allows spatial and temporal control over the activation of imatinib triggered by ultraviolet light. The successful application of the photoactivation concept to this significant kinase inhibitor provides further evidence for the caging technique as a feasible approach in the kinase field. The presented photoactivatable imatinib prodrug will be highly useful as a pharmacological tool to study the impact of imatinib toward biological systems in greater detail.     

Angiogenesis-Related Pathways in the Pathogenesis of Ovarian Cancer

Ovarian Cancer represents the most fatal type of gynecological malignancies. A number of processes are involved in the pathogenesis of ovarian cancer, especially within the tumor microenvironment. Angiogenesis represents a hallmark phenomenon in cancer, and it is responsible for tumor spread and metastasis in ovarian cancer, among other tumor types, as it leads to new blood vessel formation. In recent years angiogenesis has been given considerable attention in order to identify targets for developing effective anti-tumor therapies. Growth factors have been identified to play key roles in driving angiogenesis and, thus, the formation of new blood vessels that assist in “feeding” cancer. Such molecules include the vascular endothelial growth factor (VEGF), the platelet derived growth factor (PDGF), the fibroblast growth factor (FGF), and the angiopoietin/Tie2 receptor complex. These proteins are key players in complex molecular pathways within the tumor cell and they have been in the spotlight of the development of anti-angiogenic molecules that may act as stand-alone therapeutics, or in concert with standard treatment regimes such as chemotherapy. The pathways involved in angiogenesis and molecules that have been developed in order to combat angiogenesis are described in this paper.     

激光血管成形术对血管壁血小板源生长因子基因表达的影响

应用核酸探针杂交技术检测激光血管成形术后局部血管组织血小板源生长因于（PDGF）基因表达情况，结果表明激光血管成形术能诱导血管壁PDGF基因表达，提示PDGF可能参与了激光血管成形术后成形段血管的增生反应和再狭窄形成。     

血小板源性生长因子-D和表皮生长因子受体Ⅲ型突变体在膀胱移行细胞癌中的表达及其临床意义

目的探讨血小板源性生长因子-D(Platelet-derived growth factor D,PDGF-D)和表皮生长因子受体Ⅲ型突变体(Epidermal growth factor receptor typeⅢmutant,EGFRvⅢ)在膀胱移行细胞癌(Bladder transitional cell carcinoma,BTCC)中的表达及其临床意义。方法分别采用RT-PCR法和免疫组织化学SP法检测PDGF-D和EGFRvⅢ在80例BTCC组织和10份癌旁正常组织中的转录及表达情况,并分析二者与患者临床病理特征之间的相关性。结果 BTCC组织中PDGF-D和EGFRvⅢ在mRNA和蛋白水平上的表达均显著高于癌旁正常组织(P<0.05);PDGF-D和EGFRvⅢ的表达与BTCC不同病理分级和TNM分期有关(P<0.05),与患者年龄、性别、肿瘤单发和多发、初发和复发无关(P>0.05);PDGF-D与EGFRvⅢ的表达呈正相关(r=0.994,P<0.01)。结论 PDGF-D和EGFRvⅢ在BTCC组织中的表达与病理分级及TNM分期明显相关,可作为判断BTCC恶性程度、浸润与进展的重要生物学指标。     

Eviprostat Activates cAMP Signaling Pathway and Suppresses Bladder Smooth Muscle Cell Proliferation

Eviprostat is a popular phytotherapeutic agent for the treatment of lower urinary tract symptoms (LUTS). At present, the signaling mechanisms underlying its therapeutic effects are still poorly understood. Given that cAMP has been reported to suppress cell hyperplasia and hypertrophy in various pathological situations, we asked whether the effect of Eviprostat could be ascribed to the activation of the cAMP signaling pathway. In the study, exposure of cAMP response element (CRE)-secreted alkaline phosphatase (SEAP) (CRE-SEAP)-reporter cells to Eviprostat elevated SEAP secretion, which was associated with an increased phosphorylation of vasodilator-stimulated phosphoprotein (VASP) and cAMP-response element-binding protein (CREB), as well as enhanced expression of CRE-regulated protein connexin43, indicating an activation of the cAMP signaling pathway. Consistent with these observations, Eviprostat-induced expression of Cx43 was abolished in the presence of adenylyl cyclase inhibitor SQ22536 or PKA inhibitor H89, whereas it was mimicked by adenylyl cyclase activator, forskolin. Further analysis demonstrated that Eviprostat significantly potentiated the effect of phosphodiesterase 3 (PDE3) inhibitor, but not that of PDE4 inhibitor, on CRE activation. Moreover, Eviprostat suppressed PDGF-induced activation of ERK and Akt and inhibited cell proliferation and hillock formation in both mesangial cells and bladder smooth muscle cells. Collectively, activation of the cAMP signaling pathway could be an important mechanism by which Eviprostat exerts its therapeutic effects for LUTS.