Journal of biomolecular research & therapeutics最新文献

Diabetes mellitus in early pregnancy is the most severe maternal disease that is counted for 10% of newborn infants with structural defects. With the rapid increases in the number of diabetic women in childbearing age, the birth defect rate is projected to elevate dramatically. Thus, prevention of embryonic malformations becomes an urgent task. Animal studies have revealed an involvement of oxidative stress in diabetic embryopathy and treatment with antioxidants can reduce embryonic abnormalities. However, the failure of clinical trials using free radical-scavenging antioxidants to alleviate oxidative stress-related diseases prompts researchers to reevaluate the strategy in birth defect prevention. Hyperglycemia also disturbs other intracellular homeostasis, generating aberrant conditions. Perturbed folding of newly synthesized proteins causes accumulation of unfolded and misfolded proteins in the lumen of the endoplasmic reticulum (ER). The ER under the stress activates signaling cascades, known as unfolded protein response, to suppress cell mitosis and/or trigger apoptosis. ER stress can be ameliorated by chemical chaperones, which promote protein folding. Hyperglycemia also stimulates the expression of nitric oxide (NO) synthase 2 (NOS2) to produce high levels of NO and reactive nitrogen species and augment protein nitrosylation and nitration, resulting in nitrosative stress. Inhibition of NOS2 using inhibitors has been demonstrated to reduce embryonic malformations in diabetic animals. Therefore, targeting ER and nitrosative stress conditions using specific agents to prevent birth defects in diabetic pregnancies warrant further investigations. Simultaneously targeting multiple stress conditions using combined agents is a potentially effective and feasible approach.

Congenital birth defects, manifested in newborn infants, are formed during early embryogenesis. Targeted and individualized interventions to prevent birth defects require early detection of risk and signs of developmental abnormalities. Current diagnosis of structural anomalies largely relies on ultrasonography, which can only detect abnormities after their formation in fetuses. Biomolecules, mainly proteins, in maternal blood have been used as indicators of fetal anomalies; however, they lack adequate sensitivity for detecting embryonic malformations. Recently, cell-free microRNAs (miRNAs) have been found in blood and evaluated as biomarkers for diseases. Expression of certain miRNAs in maternal plasma has been shown to be correlated with birth defects in infants. Although their reliability and sensitivity remain to be validated, miRNAs, which can be amplified and sequenced, are potentially sensitive and specific biomarkers for early embryonic dysmorphogenesis.

Current advances in nanotechnology have paved the way for the early detection, prevention and treatment of various diseases such as vascular disorders and cancer. These advances have provided novel approaches or modalities of incorporating or adsorbing therapeutic, biosensor and targeting agents into/on nanoparticles. With significant progress, nanomedicine for vascular therapy has shown significant advantages over traditional medicine because of its ability to selectively target the disease site and reduce adverse side effects. Targeted delivery of nanoparticles to vascular endothelial cells or the vascular wall provides an effective and more efficient way for early detection and/or treatment of vascular diseases such as atherosclerosis, thrombosis and Cerebrovascular Amyloid Angiopathy (CAA). Clinical applications of biocompatible and biodegradable polymers in areas such as vascular graft, implantable drug delivery, stent devices and tissue engineering scaffolds have advanced the candidature of polymers as potential nano-carriers for vascular-targeted delivery of diagnostic agents and drugs. This review focuses on the basic aspects of the vasculature and its associated diseases and relates them to polymeric nanoparticle-based strategies for targeting therapeutic agents to diseased vascular site.

Calpain is a conserved family of calcium-dependent, cytosolic, neutral cysteine proteases. The best characterized members of the family are the ubiquitously expressed calpain 1 and calpain 2. They perform controlled proteolysis of their target proteins. The regulation of these enzymes includes autolysis, calcium, phosphorylation as a posttranslational modification, and binding of calpastatin, phospholipids or activator proteins, respectively. Calpain are implicated in many physiological and pathological processes. They have significant role in the cell proliferation, differentiation and migration in a variety of mammalian cell types, contributing to the development of angiogenesis, vascular remodeling, and cancer. Therefore the knowledge of the precise mechanism of calpain signaling could provide therapeutic approaches in these processes.

Herein we describe the evaluation of GW0742 analogs in respect to their ability to modulate transcription mediated by the vitamin D receptor (VDR) and the peroxisome proliferator activated receptor (PPAR) δ. The GW0742 analog bearing a carboxylic ester functionality in place of the carboxylic acid was partially activating both nuclear receptors at low concentration and inhibited transcription at higher compound concentrations. The GW0742 alcohol derivative was more active than the ester in respect to VDR but less active in regard to PPARδ. Importantly, the alcohol derivative was significantly more toxic than the corresponding acid and ester.