Mechanism of Action of Ca2+ Sensitizers—Update 2001

Ca²⁺ sensitizers act on the central mechanism (Ca²⁺ binding affinity of troponin C) and/or downstream mechanisms (thin filament regulation of actin and direct action on crossbridge cycling) of cardiac E–C coupling. Ca²⁺ sensitizers have mechanistic and energetic advantages over the agents that act through the upstream mechanism (intracellular Ca²⁺ mobilization). Ca²⁺ sensitizers and the agents that act through cyclic AMP-mediated signaling process have been postulated to belong to different classes, however, recent experimental findings revealed that certain Ca²⁺ sensitizers, such as levosimendan, OR 1896 and UD-CG 212 Cl, require cyclic AMP-mediated signaling for induction of the Ca²⁺ sensitizing effect. No clinically available agents act primarily via Ca²⁺ sensitization, but the positive inotropic effect of pimobendan and levosimendan is partly due to an increase in myofilament Ca²⁺ sensitivity. These agents are the hybrid of Ca²⁺ sensitizer and PDE III inhibitor. The extent of contribution of Ca²⁺ sensitizing effect of these agents to the clinical effectiveness to improve the hemodynamics in patients with heart failure is uncertain. Nevertheless pieces of evidence have been accumulating that these agents with Ca²⁺ sensitizing effect are clinically more effective than the agents that act purely via the upstream mechanism.     

Hemodilution does not alter the aortic-to-femoral arterial pressure difference in dogs

Introduction.Distal arterial pressure normally differs from aorticpressure. This difference is modified by changes of vascular resistance.Hemodilution, due to decreased viscosity, decreases vascular resistance.Therefore, the difference between aortic and distal arterial pressures couldbe altered as well. We investigated whether acute hemodilution affected thisdifference in dogs. Methods.Eleven mongrel dogs weighing 16.6 ±4.4 kg were anesthetized with pentobarbital and sufentanyl and mechanicallyventilated. Arterial presssure was recorded using Millar catheter-tippedpressure transducers in the proximal aorta and in the distal femoral artery.An electromagnetic flowmeter probe was placed around the aorta. Effectivedownstream pressure was estimated by extrapolation of exponential arterialpressure decay during 3-second occlusion of the proximal aorta. Hemodilutionwas effected by removal of 30 ml/kg of blood and replacement with 60 ml/kg ofwarmed saline. In addition, the effects of 1 µg/kg phenylephrine and 4µg/kg of sodium nitroprusside were measured before and afterhemodilution. Results.Hemodilution decreased hematocrit from 39± 11.2% to 25.6 ± 4.95%. Systolic and mean pressures wereunchanged but aortic diastolic pressure decreased significantly, from 86± 17 to 79 ± 15 mmHg (p < 0.005). Peak systolicpressure was 13.5 ± 7.2 mmHg higher in the femoral artery than in theaorta before, and 16 ± 8.7 mmHg after, hemodilution (p >0.05). Nitroprusside decreased the femoral to aortic peak systolic pressuredifference from 14.3 ± 6.3 to 7.7 ± 15.3 mmHg, p = 0.05before hemodilution and from 14.3 ± 8.8 to 2.5 ± 11 mmHg,p < 0.005 afterwards. Hemodilution significantly decreased theeffective downstream pressure, from 44 ± 9 to 36 ± 6.8 mmHg inthe aorta (p< 0.05), and from 51 ± 2 to 37 ± 3.1mmHg in the distal femoral artery (p< 0.05). Conclusion.Acute hemodilution did not alter the aortic-to-distal arterial pressuredifference in dogs.     

N-myc下游调控基因1在呼吸系统疾病中的研究进展

 N-myc下游调控基因1（N-myc downstream regulated gene-1,NDRG1）是NDRG家族的第一个成员,与低氧和应激相关。NDRG1广泛分布在全身多种组织器官中,具有特有的分子结构和化学修饰。在肺中NDRG1主要表达在呼吸道组织内,其表达水平和化学修饰与多种呼吸系统疾病的发生发展有密切关系,包括感染性疾病、慢性气道炎性疾病、低氧相关疾病（如肺损伤、急性呼吸窘迫综合征）等,同时在肿瘤低氧微环境、肿瘤进展及耐药等方面也发挥重要作用。本文就NDRG1在呼吸系统疾病中的相关研究进展作一综述。     

Structure,expression pattern and biological activity of molecular complex TREM-2/DAP12

DNAX-activating protein of 12 kDa (DAP12) is a member of type I transmembrane adapter proteins containing immunoreceptor tyrosine-based activation motifs (ITAMs). In humans DAP12 gene is located on chromosome 19q13.1. DAP12 forms a molecular complex with triggering receptor expressed on myeloid cells two (TREM-2). TREM-2 ligation leads to the activation of Src family kinases, phosphorylation of tyrosine residues in the ITAM of DAP12, recruitment of the Syk and ZAP70 tyrosine kinases and initiation of an intracellular signaling cascade. Depending on the cell type, DAP12/TREM-2 activation plays an important role in activation and differentiation of osteoclasts, phagocytosis of bacteria, brain and bone homeostasis and inhibition of the toll-like receptor (TLR) signaling in macrophages and dendritic cells. A proper understanding of the function of this complex receptor has been restrained because of the elusive nature of TREM-2 ligands.     

p38 MAPK inhibitors: a patent review (2012 – 2013)

Introduction: The p38 MAPK is a ubiquitous target in the research-based pharmaceutical industry. It plays a decisive role in the regulation of the production of proinflammatory cytokines. Since novel biological therapies have revolutionized the treatment of chronic inflammatory diseases, an intensive global search is underway for small molecules for the same application.

Areas covered: Herein, the patents and the corresponding publications of international companies, which focus on the development and identification of a new generation of small-molecule p38 inhibitors, are summarized.

Expert opinion: The most promising approach is the development of linear binders, which induce a glycine flip at Gly110 of the kinase hinge region by a carbonyl oxygen atom of the respective ligand. The major focus of the patent works was the application of molecules in new indications. Previous applications were in the treatment of rheumatoid arthritis; currently, there are several new applications, including pulmonary diseases, cancer and Alzheimer's disease. Targeting p38 upstream kinases and downstream effectors has also proved to be a very promising step in the development of more effective inhibitors. A further trend is drug combination, applied to a wide range of indications, such as chronic obstructive pulmonary disease and cancer.     

Downstream intracellular effectors of epidermal growth factor receptor as targets for anticancer therapy

In recent years, the knowledge about mutations in components of the intracellular signal transduction pathway has greatly improved. Pivotal target molecules, such as Ras, PI3K, mammalian target of rapamycin (mTOR) and PKC, form an important biochemical network, which, when mutated, drives cell growth in an unlimited manner. Cancer cells have been shown to be able to harness different growth factor signalling pathways. Protein kinase inhibitors, targeted to the above pathways, have demonstrated activity against several solid tumours and are generally better tolerated than standard cytotoxic agents. The future challenge will be to find the most clever way to use combinations of these novel compounds.     

A novel NDRG1 mutation in a non‐Romani patient with CMT4D/HMSN‐Lom

Charcot‐Marie‐Tooth disease type 4D (CMT4D), also known as hereditary motor and sensory neuropathy Lom type (HMSNL), is an autosomal recessive, early onset, severe demyelinating neuropathy with hearing loss, caused by N‐Myc downstream‐regulated gene 1 (NDRG1) mutations. CMT4D is rare with only three known mutations, one of which (p.Arg148Ter) is found in patients of Romani ancestry and accounts for the vast majority of cases. We report a 38‐year‐old Italian female with motor development delay, progressive neuropathy, and sensorineural deafness. Magnetic resonance imaging showed slight atrophy of cerebellum, medulla oblongata, and upper cervical spinal cord. She had a novel homozygous NDRG1 frameshift mutation (c.739delC; p.His247ThrfsTer74). The identification of this NDRG1 mutation confirms that CMT4D is not a private Romani disease and should be considered in the differential diagnosis of recessive demyelinating CMT.