Periostin: its role in asthma and its potential as a diagnostic or therapeutic target

Accumulating evidence shows that periostin, a matricellular protein, is involved in many fundamental biological processes such as cell proliferation, cell invasion, and angiogenesis. Changes in periostin expression are commonly detected in various cancers and pre-cancerous conditions, and periostin may be involved in regulating a diverse set of cancer cell activities that contribute to tumorigenesis, cancer progression, and metastasis. Periostin has also been shown to be involved in many aspects of allergic inflammation, such as eosinophil recruitment, airway remodeling, development of a Th2 phenotype, and increased expression of inflammatory mediators. In an in vivo model, bronchoalveolar lavage (BAL) fluid obtained from ovalbumin-challenged mice was found to contain significantly higher levels of periostin compared to BAL samples from control mice. To date, the molecular mechanisms involving periostin in relation to asthma in humans have not been fully elucidated. This review will focus on what is known about periostin and its role in the pathophysiological mechanisms that mediate asthma in order to evaluate the potential for periostin to serve as a biomarker and therapeutic target for the detection and treatment of asthma, respectively.     

S100P: a novel therapeutic target for cancer

S100P expression is described in many different cancers, and its expression is associated with drug resistance, metastasis, and poor clinical outcome. S100P is member of the S100 family of small calcium-binding proteins that have been reported to have either intracellular or extracellular functions, or both. Extracellular S100P can bind with the receptor for advanced glycation end products (RAGE) and activate cellular signaling. Through RAGE, S100P has been shown to mediate tumor growth, drug resistance, and metastasis. S100P is specifically expressed in cancer cells in the adult. Therefore, S100P is a useful marker for differentiating cancer cells from normal cells, and can aid in the diagnosis of cancer by cytological examination. The expression of S100P in cancer cells has been related to hypomethylation of the gene. Multiple studies have confirmed the beneficial effects of blocking S100P/RAGE in cancer cells, and different blockers are being developed including small molecules and antagonist peptides. This review summarizes the role and significance of S100P in different cancers.     

Skp2: A novel potential therapeutic target for prostate cancer

Prostate cancer is the most frequently diagnosed tumor in men and the second most common cause of cancer-related death for males in the United States. It has been shown that multiple signaling pathways are involved in the pathogenesis of prostate cancer, such as androgen receptor (AR), Akt, Wnt, Hedgehog (Hh) and Notch. Recently, burgeoning amounts of evidence have implicated that the F-box protein Skp2 (S-phase kinase associated protein 2), a well-characterized oncoprotein, also plays a critical role in the development and progression of prostate cancer. Therefore, this review discusses the recent literature regarding the function and regulation of Skp2 in the pathogenesis of prostate cancer. Furthermore, we highlight that Skp2 may represent an attractive therapeutic target, thus warrants further development of agents to target Skp2, which could have significant therapeutic impact on prostate cancer.     

Delta-5-desaturase: A novel therapeutic target for cancer management

Delta-5 desaturase (D5D) is a rate-limiting enzyme that introduces double-bonds to the delta-5 position of the n-3 and n-6 polyunsaturated fatty acid chain. Since fatty acid metabolism is a vital factor in cancer development, several recent studies have revealed that D5D activity and expression could be an independent prognostic factor in cancers. However, the mechanistic basis of D5D in cancer progression is still controversial. The classical concept believes that D5D could aggravate cancer progression via mediating arachidonic acid (AA)/prostaglandin E₂ production from dihomo-γ-linolenic acid (DGLA), resulting in activation of EP receptors, inflammatory pathways, and immunosuppression. On the contrary, D5D may prevent cancer progression through activating ferroptosis, which is iron-dependent cell death. Suppression of D5D by RNA interference and small-molecule inhibitor has been identified as a promising anti-cancer strategy. Inhibition of D5D could shift DGLA peroxidation pattern from generating AA to a distinct anti-cancer free radical byproduct, 8-hydroxyoctanoic acid, resulting in activation of apoptosis pathway and simultaneously suppression of cancer cell survival, proliferation, migration, and invasion. Hence, understanding the molecular mechanisms of D5D on cancer may therefore facilitate the development of novel therapeutical applications. Given that D5D may serve as a promising target in cancer, in this review, we provide an updated summary of current knowledge on the role of D5D in cancer development and potentially useful therapeutic strategies.     

Titin as a potential novel therapeutic target in colorectal cancer

Colorectal cancer (CRC) is identified as a primary cause of death around the world. The current chemotherapies are not cost-effective. Therefore, finding novel potential therapeutic target is urgent. Titin (TTN) is a muscle protein that is critical in hypertrophic cardiomyopathy. However, its role in CRC is not well understood. The study focused on exploring the possible role of TTN in CRC carcinogenesis. TTN mRNA and protein expression levels presented an obvious downregulation in CRC tissue samples, relative to normal control (p < 0.05). TTN expression significantly correlated with the clinical stage (normal vs. Stage 1, p < 0.05; normal vs. Stage 4, p < 0.05), node metastasis (normal vs. N1, p < 0.05; N1 vs. N2, p < 0.05), histological type (normal vs. adenocarcinoma, p < 0.05), race (Caucasian vs. Asian, p < 0.05; African-American vs. Asian, p < 0.05) and TP53 mutation (normal vs. TP53 mutation, p < 0.05), considering The Cancer Genome Atlas database. However, for patients who had higher TTN expression, the overall survival was remarkably shorter than patients who had low TTN expression. Furthermore, TTN was lowly expressed in four CRC cell lines. TTN overexpression facilitated CRC cells in terms of the proliferation, metastasis and invasion. Based on gene set enrichment analysis, the ERB pathway might be responsible for TTN-related CRC. Besides, TTN was involved in the response to azacitidine. Overall, TTN might serve as a potential novel therapeutic target for treating and overcoming chemotherapy resistance in CRC.     

PAD4:一种治疗类风湿性关节炎的新靶酶

肽酰基精氨酸脱亚氨酶4(PAD4)催化肽酰精氨酸残基转变为肽酰瓜氨酸残基,其活性失调与类风湿性关节炎(RA)的发生与发展有关.目前PAD4被认为是开发新RA治疗药物的一种新靶酶.认识PAD4的结构与可能的作用机制,对于开发新RA治疗药物是重要的.     

ACE2: A novel therapeutic target for cardiovascular diseases

Hypertension afflicts over 65 million Americans and poses an increased risk for cardiovascular morbidity such as stroke, myocardial infarction and end-stage renal disease resulting in significant mortality. Overactivity of the renin-angiotensin system (RAS) has been identified as an important determinant that is implicated in the etiology of these diseases and therefore represents a major target for therapy. In spite of the successes of drugs inhibiting various elements of the RAS, the incidence of hypertension and cardiovascular diseases remain steadily on the rise. This has lead many investigators to seek novel and innovative approaches, taking advantage of new pathways and technologies, for the control and possibly the cure of hypertension and related pathologies. The main objective of this review is to forward the concept that gene therapy and the genetic targeting of the RAS is the future avenue for the successful control and treatment of hypertension and cardiovascular diseases. We will present argument that genetic targeting of angiotensin-converting enzyme 2 (ACE2), a newly discovered member of the RAS, is ideally poised for this purpose. This will be accomplished by discussion of the following: (i) summary of our current understanding of the RAS with a focus on the systemic versus tissue counterparts as they relate to hypertension and other cardiovascular pathologies; (ii) the newly discovered ACE2 enzyme with its physiological and pathophysiological implications; (iii) summary of the current antihypertensive pharmacotherapy and its limitations; (iv) the discovery and design of ACE inhibitors; (v) the emerging concepts for ACE2 drug design; (vi) the current status of genetic targeting of the RAS; (vii) the potential of ACE2 as a therapeutic target for hypertension and cardiovascular disease treatment; and (viii) future perspectives for the treatment of cardiovascular diseases.     

Aldose reductase: A novel therapeutic target for inflammatory pathologies

Aldose reductase (AR), that catalyzes the rate limiting step of the polyol pathway of glucose metabolism, besides reducing glucose to sorbitol, reduces a number of lipid peroxidation – derived aldehydes and their glutathione conjugates. Recent studies suggest that apart from its involvement in diabetic complications, AR's catalytic activity plays a key role in a number of inflammatory diseases such as atherosclerosis, sepsis, asthma, uveitis, and colon cancer. Furthermore, AR is overexpressed in human cancers such as liver, colon, breast, cervical and ovarian. Since AR inhibitors have already undergone up to phase-iii clinical trials for diabetic complications, they could be safe anti-inflammatory drugs. Therefore the future use of AR inhibitors in down-regulating major inflammatory pathologies such as cancer and cardiovascular diseases could relieve some of the major health concerns of worldwide.     

Oligodendrocyte NMDA receptors: a novel therapeutic target

Excessive glutamate signaling can lead to excitotoxicity, a phenomenon whereby over-activation of glutamate receptors initiates neuronal death. In recent years, it has been shown that glutamate can be toxic to white-matter oligodendrocytes. Up to recently, the prevailing view was that oligodendrocyte excitotoxicity is mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate glutamate receptor types. Three recent studies have shown that oligodendrocytes also express N-methyl-D-aspartate (NMDA) receptors, which are activated under pathological conditions. Thus, NMDA receptors seem to be a promising target for the development of new drugs to treat white-matter damage in acute and chronic diseases.     

Common therapeutic target for both cancer and obesity

Obesity and cancer are two interrelated conditions of high epidemiological need, with studies showing that obesity is responsible for nearly 25% of the relative contribution to cancer incidence. Given the connection between these conditions, a drug that can operate on both obesity and cancer is highly desirable. Such a drug is accomplishablethrough the development of potent anti-angiogenesis agents due to the shared underlying role of angiogenesis in the development of both diseases. Prior research has demonstrated a key role of type-2 methionine aminopeptidase(Met AP2) for angiogenesis, which has led to the development of numerous of novel inhibitors. Several irreversible Met AP2 inhibitors have entered clinical trials without great success. Though this lack of success could be attributed to off-target adverse effects, the underlying causes remain unclear. More promising reversible inhibitors have been recently developed with excellent pre-clinical results. However, due to insufficient knowledge of the biological functions of N-terminal protein processing, it is hard to predict whether these novel inhibitors would successfully pass clinical trials and thereby benefit cancer and obesity patients. Significantly more efforts are needed to advance our understanding of the regulation of methionine aminopeptidases and the processes by which they govern the function of proteins.     

溶酶体损伤与细胞死亡:疾病治疗新靶点

溶酶体(lysosome)是真核细胞中重要的细胞器,其结构的完整性及功能平衡与细胞生存及功能密切相关.溶酶体损伤(lysosome damage)可触发细胞不同的死亡方式,参与多种疾病的发生发展过程,如感染、炎症性疾病和肿瘤等.溶酶体损伤应答(endo-lysosomal damage response,EL-DR)是...     

p28GANK is a novel marker for prognosis and therapeutic target in gastric cancer

P28/PSMD10, a regulatory complex of the human 26S proteasome, plays a critical role in tumor genesis. This study was designed to clarify the clinical significance of p28GANK in gastric cancer. In order to demonstrate the importance of p28GANK expression for the prognosis of gastric cancer, p28GANK expression in 124 paired cases of gastric cancer and noncancerous regions and immortal gastric epithelial cell GES-1 and 5 human gastric cancer cell lines was analyzed by RT-PCR in real-time. MTT was used to observe the effect of P28GANK on cell growth. p28GANK expression was higher in gastric cancer tissues than in corresponding normal tissues (p = 0.0033), and patients comprising the group with p28GANK high expression had a poorer overall survival rate than those from the low expression group (p = 0.0037). Further, the results of multivariate analysis demonstrated that the high p28GANK expression was an independent prognostic factor of gastric cancer process. p28GANK expression was also up-regulated in five gastric cancer cell lines. As it has been shown by in vitro proliferation assay, p28GANK expression correlated with tumor growth. On the base results of present study one can suggests the p28GANK being useful as a predictive marker for patient prognosis and a novel therapeutic target for gastric cancer.     

胰高血糖素样肽1受体--治疗糖尿病新药的研究热点

胰高血糖素样肽l(glucagon—like peptide—l,GLP-1)与胰岛素分泌和糖代谢调节密切相关。GLP-1与其受体(GLP-1receptor,GLP-1R)结合后,主要通过cAMP和P13K两条信号途径,促进胰岛素的分泌,刺激胰岛β细胞的增殖和分化。对GLP-1R结构和信号传导机制的研究,有助于了解其在糖尿病病理进程中的作用,为开发新型糖尿病治疗药物指明方向。     

G蛋白偶联受体119——治疗糖尿病的新靶点

G蛋白偶联受体119(GPR119)与激动剂结合后,通过cAMP信号转导途径,促进葡萄糖依赖性胰岛素和肠肽激素的分泌,是新一代的治疗2型糖尿病药物靶点。本文对GPR119的组织学分布、生理学作用、内源性配体以及小分子激动剂作一简要的介绍。     

Novel oncogene HCCR: its diagnostic and therapeutic implications for cancer

Identification of robust diagnostic and therapeutic target molecules for human malignancy is still an important issue. If we identify novel proteins which play a stem-line role for cellular transformation or aggravation of malignancy, it could give us a clue to diagnose a tumor in an earlier stage and to develop more reliable therapeutic tools. For this purpose, we have screened abnormally expressed genes in various human cancers by differential display RT-PCR. One of the overexpressed genes was a human cervical cancer oncogene (HCCR). HCCR was not only identified in cervical cancer tissues, but also found to be overexpressed in various human malignancies such as leukemia/lymphoma, breast, kidney, stomach, colon, liver and ovarian cancer. This molecule appeared to be a negative regulator of p53. In this paper, we discuss the biological functions of HCCR molecules and its implications for early diagnosis and future development of therapeutic devices of cancer.