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。     

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。     

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.     

Tau as a potential novel therapeutic target in ischemic stroke

Stroke is associated with high mortality and major disability burdens worldwide, but there are few effective and widely available therapies. Tau plays an important role in promoting microtubule assembly and stabilizing microtubule networks with phosphorylation regulating these functions. Based on the “ischemia‐reperfusion theory” of Alzheimer's disease, some previous studies have focused on the relationship of tau and Alzheimer lesions in experimental brain ischemia. Thus, we hypothesize that the alterations in phosphorylation of tau are critical to microtubule dynamics and metabolism, and contribute to the pathophysiologic mechanisms during brain ischemia and/or reperfusion processes. We infer that regulation of phosphorylation of tau may be considered as a potential new therapeutic target in ischemic stroke. J. Cell. Biochem. 109: 26–29, 2010. © 2009 Wiley‐Liss, Inc.     

Molecular therapeutic target for type-2 diabetes

Many lines of evidences indicate that increased flux of glucose through the pathway, in which glutamine:fructose-6-phosphate amidotransferase (GFPT or GFAT) is a key catalyst while uridine-5'-diphosphate-N-acetylglucosamine (UDP-GlcNAc) functions as an energy sensor, can lead to the insulin resistance that is characteristic of Type-2 diabetes. In view of this, GFAT and its interaction mechanism with UDP-GlcNAc may become a novel therapeutic target for the treatment of type 2 diabetes. To stimulate the structure-based drug design, the three-dimensional structures of human GFAT1 monomer and dimer have been developed. It has been found by docking UDP-GlcNAc to the dimer (the smallest unit for catalyzing the substrate) that UDP-GlcNAc is bound to the interface of the dimer by 12 hydrogen bonds. On the basis of the docking results, a binding pocket of human GFAT1 dimer for UDP-GlcNAc is defined. All of these findings can serve as a reference or footing in developing new therapeutic strategy for the treatment of type-2 diabetes.     

Targeting AQP4 localization as a novel therapeutic target in CNS edema

CNS edema is a pathological phenomenon after trauma, infection, tumor growth, or obstruction of blood supply, and it also can be fatal or lead to long-term disability, psychiatric disorders, substance abuse, or self-harm [1,2]. One exciting possibility would be to control excessive water accumulation in cells. However, all trials that inhibit water channel protein failed in clinic. A recent study by Kitchen et al. [3] reported that targeting the astrocytes’ surface localization of water channel protein aquaporin-4 (AQP4) significantly relieves CNS edema. Astrocytes are the most abundant cell type of the brain and generally have a greater capacity than neurons to survive stresses [4]. Astrocyte cell function is critically affected by the lack of oxygen supply (hypoxia) to the brain, which is usually associated with CNS edema [5]. Their work holds new promise for our ability to use water-transfer strategies to treat CNS edema. Cytotoxic and vasogenic edema are primary interrelated etiological factors for the progress of CNS edema [6]. Vasogenic edema also depends on the extent of cytotoxic edema and the nature/severity of the underlying cause of the cytotoxic edema. So, understanding the pathogenesis of cytotoxic edema is important for the treatment of CNS edema. Aquaporins (AQPs) are historically known to be passive transporters of water. Lines of evidence in the last decade have highlighted the diverse function of AQPs beyond water homeostasis, including regulation of renal water balance, brain-fluid homeostasis, triglyceride cycling, and skin hydration [7]. Moreover, a subgroup of AQP water channels, termed ‘aquaglyceroporins’, also facilitates transmembrane diffusion of small, polar solutes not only water but also solutes [8,9]. AQP4 is the major subtype of AQPs expressed in astrocytes throughout the nervous system and facilitates astroglial cell migration via increasing plasma membrane water permeability, which in turn upregulates the transmembrane water fluxes during astroglial cell movement and is thus considered as an interesting therapeutic target in various neurological disorders. Astrocyte swellingmay also cause cytotoxic component disruptions of the blood–brain barrier, suggesting that astrocytes seem so sensitive to cytotoxic edema. AQP4 is a recognized contributor for the formation of cytotoxic brain edema, which is mainly a phenomenon of intracellular swelling of astrocytes. Knockdown of ‘AQP4’ or removal of the perivascular AQP4 pool by α-syntrophin or α-syntrophin deletion has been convincingly proven to counteract osmotically induced acute brain edema following ischemia and other brain injuries [10–12]. A previous study revealed that the NH2-cytosolic terminus of AQP4 interacts with metabotropic glutamate receptor 5 and assembles with the catalytic subunit of Na,K-ATPase to form a complex that has the potential function for the regulation of water permeability and potassium homeostasis in the astrocytes [13] (Fig. 1). In addition, AQP4 may trigger astrocytic Ca2+ responses, which is partly dependent on autocrine purinergic signaling (P2 purinergic receptor) activation in response to hypoosmotic stress [14] (Fig. 1). Additionally, subcellular relocalization of AQP4 in primary astrocytes is induced by calmodulin (CaM), calcium, and PKA in response to hypotonicity [15]. Further study proved that hypoxia-driven astrocyte swelling induces the increased abundance of AQP4 and initiates AQP4 cell-surface relocalization in a CaM- and PKA-dependent manner [3] (Fig. 1).     

MicroRNAs as a therapeutic target for cardiovascular diseases

MicroRNAs (miRNAs) are tiny, endogenous, conserved, non-coding RNAs that negatively modulate gene expression by either promoting the degradation of mRNA or down-regulating the protein production by translational repression. They maintain optimal dose of cellular proteins and thus play a crucial role in the regulation of biological functions. Recent discovery of miRNAs in the heart and their differential expressions in pathological conditions provide glimpses of undiscovered regulatory mechanisms underlying cardiovascular diseases. Nearly 50 miRNAs are overexpressed in mouse heart. The implication of several miRNAs in cardiovascular diseases has been well documented such as miRNA-1 in arrhythmia, miRNA-29 in cardiac fibrosis, miRNA-126 in angiogenesis and miRNA-133 in cardiac hypertrophy. Aberrant expression of Dicer (an enzyme required for maturation of all miRNAs) during heart failure indicates its direct involvement in the regulation of cardiac diseases. MiRNAs and Dicer provide a particular layer of network of precise gene regulation in heart and vascular tissues in a spatiotemporal manner suggesting their implications as a powerful intervention tool for therapy. The combined strategy of manipulating miRNAs in stem cells for their target directed differentiation and optimizing the mode of delivery of miRNAs to the desired cells would determine the future potential of miRNAs to treat a disease. This review embodies the recent progress made in microRNomics of cardiovascular diseases and the future of miRNAs as a potential therapeutic target - the putative challenges and the approaches to deal with it.     

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.     

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.     

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.     

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.     

Dihydrofolate reductase as a therapeutic target

The folate antagonists are an important class of therapeutic compounds, as evidenced by their use as antiinfective, antineoplastic, and antiinflammatory drugs. Thus far, all of the clinically useful drugs of this class have been inhibitors of dihydrofolate reductase (DHFR), a key enzyme in the synthesis of thymidylate, and therefore, of DNA. The basis of the antiinfective selectivity of these compounds is clear; the antifolates trimethoprim and pyrimethamine are potent inhibitors of bacterial and protozoal DHFRs, respectively, but are only weak inhibitors of mammalian DHFRs. These species-selective agents apparently exploit the differences in the active site regions of the parasite and host enzymes. Methotrexate is the DHFR inhibitor used most often in a clinical setting as an anticancer drug and as an antiinflammatory and immunosuppressive agent. Considerable progress has been made recently in understanding the biochemical basis for the selectivity of this drug and the biochemical mechanism (or mechanisms) responsible for the development of resistance to treatment with the drug. This understanding has led to a new generation of DHFR inhibitors that are now in clinical trials.     

CD38 as a therapeutic target

The CD38 molecule is well represented on cell surfaces in many cases of a variety of lymphoid tumors, notably multiple myeloma, AIDS-associated lymphomas, and post-transplant lymphoproliferations. As such, this molecule is a promising target for antibody therapy. After early disappointments, improved anti-CD38 antibodies of strong cytolytic potential have been described by 3 groups. First, a human IgG monoclonal anti-CD38 antibody raised in mice transgenic for human Ig has been found to induce potent complement and cellular cytotoxicities against both myeloma cell lines and fresh harvests from myeloma marrow and leukemic blood. This antibody also exhibits the singular property of inhibiting the CD38 cyclase activity. Second, a series of CD38-specific human antibodies, with high affinities and high ADCC activities against cell lines and primary cultures of myeloma, has been selected from a unique phage-display library. Finally, to enhance specificity for myeloma cells, bispecific domain antibodies targeting both CD38 and CD138 have been developed. As they lack any Fc module, these constructs rely on cytotoxicity for delivering a toxin to tumor cells. The list of candidate CD38-bearing neoplasms as targets for these antibody constructs can now be expanded to include acute promyelocytic leukemia, and possibly other myeloid leukemias, in which surface CD38 can be induced by retinoid treatment. One caveat here is that evidence has been produced to suggest that CD38 promotes pulmonary manifestations of the hazardous retinoic acid syndrome.