Dysfunctional stem and progenitor cells impair fracture healing with age

Successful fracture healing requires the simultaneous regeneration of both the bone and vasculature;mesenchymal stem cells (MSCs) are directed to replace the bone tissue, while endothelial progenitor cells (EPCs) form the new vasculature that supplies blood to the fracture site. In the elderly, the healing process is slowed, partly due to decreased regenerative function of these stem and progenitor cells. MSCs from older individuals are impaired with regard to cell number, proliferative capacity, ability to migrate, and osteochondrogenic differentiation potential. The proliferation, migration and function of EPCs are also compromised with advanced age. Although the reasons for cellular dysfunction with age are complex and multidimensional, reduced expression of growth factors, accumulation of oxidative damage from reactive oxygen species, and altered signaling of the Sirtuin-1 pathway are contributing factors to aging at the cellular level of both MSCs and EPCs. Because of these geriatric-specific issues, effective treatment for fracture repair may require new therapeutic techniques to restore cellular function. Some suggested directions for potential treatments include cellular therapies, pharmacological agents, treatments targeting age-related molecular mechanisms, and physical therapeutics. Advanced age is the primary risk factor for a fracture, due to the low bone mass and inferior bone quality associated with aging;a better understanding of the dysfunctional behavior of the aging cell will provide a foundation for new treatments to decrease healing time and reduce the development of complications during the extended recovery from fracture healing in the elderly.

Deficiency of anti-inflammatory cytokine IL-4 leads to neural hyperexcitability and aggravates cerebral ischemia-reperfusion injury

Systematic administration of anti-inflammatory cytokine interleukin 4(IL-4)has been shown to improve recovery after cerebral ischemic stroke.However,whether IL-4 affects neuronal excitability and how IL-4 improves ischemic injury remain largely unknown.Here we report the neuroprotective role of endogenous IL-4 in focal cerebral ischemia-repertusion(I/R)injury.In multi-electrode array(MEA)recordings,IL-4 reduces spontaneous firings and network activities of mouse primary cortical neurons.IL-4 mRNA and protein expressions are upregulated after I/R injury.Genetic deletion of 11-4 gene aggravates I/R injury in vivo and exacerbates oxygen-glucose deprivation(OGD)injury in cortical neurons.Conversely,supplemental IL-4 protects 11-4-/-cortical neurons against OGD injury.Mechanistically,cortical pyramidal and stellate neurons common for ischemic penumbra after I/R injury exhibit intrinsic hyperexcitability and enhanced excitatory synaptic transmissions in Il-4-/-mice.Furthermore,upregulation of Nav1.1 channel,and downregulations of KCa3.1 channel and a6 subunit of GABAA receptors are detected in the cortical tissues and primary cortical neurons from Il-4-/-mice.Taken together,our findings demonstrate that IL-4 deficiency results in neural hyperexcitability and aggravates I/R injury,thus activation of IL-4 signaling may protect the brain against the development of permanent damage and help recover from ischemic injury after stroke.

Isolation of a (+)-δ-cadinene synthase gene CAD1-A and analysis of its expression pattern in seedlings of Gossypium arboreum L.

The cotton sesquiterpene cyclase, (+)-δ-cadinene synthase.is encoded by a gene family, which can be divided into two subfamilies: CAD1-A and CAD1-C. The gene CAD1-A was isolated from G. arboreum. In situ hybridization performed on seven-day-old cotton seedlings localized transcripts of both the CAD1-A and CAD1-C mainly in lateral root primordium and apical ground meristem, vascular tissues of emerging lateral roots, and also in procambium and some subepidermal cells of the hypocotyl. The CAD1-A promoter showed a similar tissue-specificity in transgenic tobacco plants. Histochemistry showed occurrence of sesquiterpene aldehydes in outer cells of the lateral root tips, as well as in pigment glands. The CAD1 gene expression in G. arboreum seedlings and the spatial pattern of sesquiterpene biosynthesis constitute a chemical defense machinery in cotton seedlings.

The paradoxical functions of EGFR during breast cancer progression

The epidermal growth factor receptor(EGFR)is one of the most well-studied signaling pathways in cancer progression.As a result,numerous therapeutics including small-molecule inhibitors and monoclonal antibodies have been developed to target this critical oncogenic driver.Several of these EGFR inhibitors(EGFRi)have been evaluated in metastatic breast cancer,as high-level EGFR expression in primary tumors correlates with the highly aggressive basal-like phenotype and predicts for poor patient prognosis.Surprisingly,these trials have been unanimously unsuccessful at improving patient outcomes.Numerous factors,such as lack of proper patient selection may have contributed to the failure of these trials.However,recent findings suggest that there are fundamental changes in EGFR signaling that take place during primary tumor invasion,dissemination and ultimate metastasis of breast cancer cells.Herein,we review the outcomes of EGFR-targeted clinical trials in breast cancer and explore our current understanding of EGFR signaling within primary mammary tumors and how these events are altered in the metastatic setting.Overall,we put forth the hypothesis that fundamental changes in EGFR signaling between primary and metastatic tumors,a process we term the‘EGFR paradox,’contribute to the clinically observed inherent resistance to EGFRi.Furthermore,this hypothesis introduces the possibility of utilizing EGFR agonism as a potential therapeutic approach for the treatment of metastatic breast cancer.

亚洲棉(+)-δ-杜松烯合成酶基因CAD1-A的分离及其在幼苗中的表达特征分析

棉花倍半萜环化酶，即（＋）－δ－杜松烯合成酶（ＣＡＤ），由一个基因家族编码．该 基因家族可分为两个亚族：ＣＡＤ１－Ａ和ＣＡＤ１－Ｃ．分离了亚洲棉ＣＡＤ１－Ａ基因．对亚洲棉 ７天龄幼苗的ｍＲＮＡ原位杂交表明，ＣＡＤ１－Ａ和ＣＡＤ１－Ｃ的转录子主要分布在侧根原 基、顶端分生组织和新生侧根的维管组织中，在幼苗下胚轴的原形成层和部分表皮、下 表皮细胞中也有分布．ＣＡＤ１－Ａ启动子在转基因烟草中表现出相似的活性．组织化学实 验发现，倍半萜醛类分布于侧根根尖的外层细胞以及地上部分的色素腺体中．ＣＡＤ１基 因在亚洲棉幼苗中的表达特征，以及倍半萜醛类的分布特征，组成了棉花幼苗的化学 防御体系。