2016 Vol. 30, No. 4
2016, 30(4): 251-252. doi: 10.7555/JBR.30.20160002
2016, 30(4): 253-263. doi: 10.7555/JBR.30.20150038
In addition to their well-established role in allergy mast cells have been described as contributing to functional regulation of both innate and adaptive immune responses in host defense. Mast cells are of hematopoietic origin but typically complete their differentiation in tissues where they express immune regulatory functions by releasing diverse mediators and cytokines. Mast cells are abundant at mucosal tissues which are portals of entry for common infectious agents in addition to allergens. Here, we review the current understanding of the participation of mast cells in defense against infection. We also discuss possibilities of exploiting mast cell activation to provide adequate adjuvant activity that is needed in high-quality vaccination against infectious diseases.
Small interfering RNAs (siRNA) have enormous potential as therapeutics to target and treat various bone disor-ders such as osteoporosis and cancer bone metastases. However, effective and specifc delivery of siRNA therapeu-tics to bone and bone-specifc cells in vivo is very challenging. To realize the full therapeutic potential of siRNA intreating bone disorders, a safe and effcient, tissue- and cell-specifc delivery system must be developed. This review focuses on recent advances in bone site-specifc delivery of siRNA at the tissue or cellular level. Bone-targeted nanoparticulate siRNA carriers and various bone-targeted moieties such as bisphosphonates, oligopeptides (Asp)8and (AspSerSer)6, and aptamers are highlighted. Incorporation of these bone-seeking targeting moieties into siRNA carriers allows for recognition of different sub-tissue functional domains of bone and also specifc cell types residing in bone tissue. It also provides a means for bone-formation surface-, bone-resorption surface-, or osteoblast- specifc targeting and transportation of siRNA therapeutics. The discussion mainly focuses on systemic and local bone-specifc delivery of siRNA in osteoporosis and bone metastasis preclinical models.
Extracellular lysophosphatidate (LPA) is a potent bioactive lipid that signals through six G-protein-coupled receptors. This signaling is required for embryogenesis, tissue repair and remodeling processes. LPA is produced from circulating lysophosphatidylcholine by autotaxin (ATX), and is degraded outside cells by a family of three enzymes called the lipid phosphate phosphatases (LPPs). In many pathological conditions, particularly in cancers, LPA concentrations are increased due to high ATX expression and low LPP activity. In cancers, LPA signaling drives tumor growth, angiogenesis, metastasis, resistance to chemotherapy and decreased effcacy of radiotherapy. Hence, targeting the ATX-LPA-LPP axis is an attractive strategy for introducing novel adjuvant therapeutic options. In this review, we will summarize current progress in targeting the ATX-LPA-LPP axis with inhibitors of autotaxin activity, LPA receptor antagonists, LPA monoclonal antibodies, and increasing low LPP expression. Some of these agents are already in clinical trials and have applications beyond cancer, including chronic infammatory diseases.
Ankle brachial index (ABI) and brachial-ankle pulse wave velocity (baPWV) are widely used noninvasive modalities to evaluate atherosclerosis. Recently, evidence has increased supporting the use of ABI and baPWV as markers of cerebrovascular disease. This study sought to examine the relationship between ABI and baPWV with ischemic stroke. This study also aimed to determine which pathogenic mechanism, large artery disease (LAD) or small vessel disease (SVD), is related to ABI or baPWV. Retrospectively, 121 patients with ischemic stroke and 38 subjects with no obvious ischemic stroke history were recruited. First, ABI and baPWV were compared between the groups. Then, within the stroke group, the relevance of ABI and baPWV with regard to SVD and LAD, which were classified by brain magnetic resonance image (MRI) and magnetic resonance angiography (MRA) or computed tomography angiography (CTA) findings, was assessed. The baPWV was higher in the stroke group than non-stroke group (1,944.18土416.6 cm/s vs. 1,749.76土669.6 cm/s， P< 0.01). Regarding LAD, we found that mean ABI value was lower in the group with extacranial large artety stenosis (P < 0.01), and there was an inverse linear correlation between ABI and the grade of extracranial large artery stenosis (P<0.01). For SVD, there was a significant correlation between SVD and baPWV (2,057.6土456.57 cm/s in the SVD (+) group vs. 1,491 土271.62 cm/s in the SVD (-) group; P<0.01). However, the grade of abnormalities detected in SVD did not correlate linearly with baPWV. These findings show that baPWV is a reliable surrogate marker of ischemic stroke. Furthermore, baPWV and ABI can be used to indicate the presence of small vessel disease and large arterial disease, respectively.
Rapid dissemination of antibiotic resistance genes among bacterial isolates is an increasing problem in China.Integron，a conserved DNA sequence, which is caMed on episomal genetic stoctoes， plays a very important role in development of antibiotic resistance. This systematic analysis was based on MEDLINE and EMBASE databases. We summarized the distribution and proportion of different types of gene cassette arrays of integrons (including class 1,2,3 and atypical class 1 integron) from clinical bacteria isolates in China. Fifty-six literatures were included in this study. Most of the strains were Gram-negative bacteria (94.1%, 7,364/7,822) while only 5.9% strains were Grampositive bacteria. Class 1 integrons were detected in 54.2% (3956/7295) Gram-negative strains. aadA2 was the most popular gene cassette array detected from 60 Gram-positive bacteria while dfrA17-aadA5 were detected in 426 Gramnegative bacteria. This study identified 12 novel gene cassette arrays which have not been previously found in any species. All the novel gene cassette arrays were detected from Gram-negative bacteria. A regional characteristic of distribution of integrons was presented in this study. The results highlight a need for continuous surveillance of integrons and provide a guide for fixture research on integron-mediated bacteria resistance.
The current study was designed to examine the protective efficacy of DNA vaccines based on gp63 and Hsp70 against murine visceral leishmaniasis. Inbred BALB/c mice were immunized subcutaneously twice at an interval of three weeks with pcDNA3.1(+) encoding T cell epitopes of gp63 and Hsp70 individually and in combination.Animals were challenged intracardially with 107 promastigotes of Leishmania donovani 10 days post immunization and sacrificed 1, 2 and 3 months post challenge. The immunized animals revealed a significant reduction (P < 0.05)in splenic and hepatic parasite burden as compared to the infected controls. Maximum reduction in parasite load (P < 0.05) was observed in animals treated with a combination of pcDNA/gp63 and pcDNA/Hsp70. These animals also showed heightened DTH response, increased IgG2a, elevated Th1 cytokines (IFN-γ and IL-2) and reduced IgG1 and IL-10 levels. Thus, mice immunized with the cocktail vaccine exhibited significantly greater protection in comparison to those immunized with individual antigens.
Melatonin plays a critical role in regulating photoperiodic signals and has recently been shown to decrease immunosenescence with age. In this study, we examined whether melatonin activates T lymphocytes as major adaptive immune cells in in vitro and in vivo models. Splenocytes, CD4+, and naive CD4 T lymphocytes were isolated from the spleen of BALB/c mice and the cell population patterns and mRNA profiles associated with T cell activation (CD28 and p21) and the melatonin receptor (MT1A and MT1B) were assessed. The T cell activationrelated proteins Ki67 and Bcl2 were also evaluated to confirm the relationship between gene and protein levels. Our data clearly revealed that CD28, p21, MT1A, and MT1B mRNA were highly expressed in the presence of melatonin.Co-culture of CD4+ T lymphocyte and peritoneal macrophage 7 days after melatonin administration to young and aged mice significantly increased APRIL mRNA, suggesting induction or maintenance of T lymphocyte response We also found that the intracellular amount of Ki67 and Bcl2 proteins were significantly upregulated in aged CD4+ Tlymphoc^es, suggesting enhancing T cell proliferation and ling-term maintenance of memory T cells. Taken together, we conclude that melatonin supplementation may enhance immunity in aged individuals by upregulating immunosenescence indices in association with T lymphocytes and may be an attractive pharmacological candidate for aged and immunocompromised individuals.
There is an increasing interest in development of novel anticancer agents that target oncogenes. We have recently discovered that nuclear factor of activated T cells 1 (NFAT1) is a novel regulator of the Mouse Double Minute 2 (MDM2) oncogene and the NFAT1-MDM2 pathway has been implicated in human cancer development and progression, justifying that targeting the NFAT1-MDM2 pathway could be a novel strategy for discovery and development of novel cancer therapeutics. The present study was designed to examine the anticancer activity and underlying mechanisms of action of lineariifolianoid A (LinA), a novel natural product inhibitor of the NFAT1-MDM2 pathway. The cytotoxicity of LinA was first tested in various human cancer cell lines in comparison with normal cell lines. The results showed that the breast cancer cells were highly sensitive to LinA treatment. We next demonstrated the effects of LinA on cell proliferation, colony formation, cell cycle progression, and apoptosis in breast cancer MCF7 and MDA-MB-231 cells, in dose-dependent and p53-independent manners. LinA also inhibited the migration and invasion of these cancer cells. Our mechanistic studies further indicated that its anticancer activities were attributed to its inhibitory effects on the NFAT1-MDM2 pathway and modulatory effects on the expression of key proteins involved in cell cycle progression, apoptosis, and DNA damage. In summary, LinA is a novel NFAT1-MDM2 inhibitor and may be developed as a preventive and therapeutic agent against human cancer.
The fermentation of natural plants has a favorable effect on the functional and biological activities of living systems. These include anti-oxidative, anti-inflammatory, and anti-platelet aggregation activities. This is attributed to the chemical conversion of the parent plants to functional constituents, which show more potent biological activity. In our study, rice bran along with oriental medicinal plants (Angelicae gigantis, Cnidium officinale, Artemisia princeps, and Camellia sinensis) was fermented by Lactobacillus rhamnosus and Pichia deserticola (FRBE). We evaluated the effects of oral administration of FRBE on atopic dermatitis in l -chloro-2,4-dinitrobenzene (DNCB)-treated NC/Nga mice. FRBE significantly ameliorated the macroscopic and microscopic appearance of skin lesions in DNCB-induced atopic dermatitis and reduced levels of serum immunoglobulin E and the differential white blood cell count. In addition, it reduced skin thickness compared to that of atopic dermatitis-affected skin. FRBE treatment also reduced mast cell incorporation in skin lesions of atopic dermatitis. The total cell number in dorsal skin tissue and the axillary lymph node increased following DNCB application， and this was normalized by FRBE treatment. Moreover, it decreased the levels of CD8+ helper T cells and Gr-1+/CD1 lb+ B cells in peripheral blood mononuclear cells and skin lesions in DNCB-induced atopic dermatitis. Using real-time polymerase chain reaction analysis, we demonstrated that FRBE significantly inhibited mRNA expression of cytokines (e.g.? interleukin-5 and interleukin-13) and cyclooxygenase-2 in AD skin lesions. These results suggest that FRBE could be a valuable herbal remedy for the treatment of atopic dermatitis.
We report a rare case of internal carotid artery agenesis with stenosed intercavernous anastomosis. A 59-yearold male patient presented with a new infarction in the left basal ganglia. Magnetic resonance angiography and cerebral angiography showed that the right internal carotid artery disappeared from the origin to the foramen lacerum segment, and there was an anastomotic artery with severe stenosis passed through the floor of the sella and in front of the cavernous sinus. The right A1 segment of the anterior cerebral artery was absent and A2 segment was supplied by the normal contralateral internal carotid artery via the anterior communicating artery