High glucose microenvironment and human mesenchymal stem cell behavior

High glucose(HG)culture conditions in vitro and persistent exposure to hyperglycemia in diabetes patients are detrimental to stem cells,analogous to any other cell type in our body.It interferes with diverse signaling pathways,i.e.mammalian target of rapamycin(mTOR)-phosphoinositide 3-kinase(PI3K)-Akt signaling,to impact physiological cellular functions,leading to low cell survival and higher cell apoptosis rates.While elucidating the underlying mechanism responsible for the apoptosis of adipose tissue-derived mesenchymal stem cells(MSCs),a recent study has shown that HG culture conditions dysregulate mTORPI3K-Akt signaling in addition to mitochondrial malfunctioning due to defective mitochondrial membrane potential(MtMP)that lowers ATP production.This organelle-level dysfunction energy-starves the cells and increases oxidative stress and ultrastructural abnormalities.Disruption of the mitochondrial electron transport chain produces an altered mitochondrial NAD+/NADH redox state as evidenced by a low NAD+/NADH ratio that primarily contributes to the reduced cell survival in HG.Some previous studies have also reported altered mitochondrial membrane polarity(causing hyperpolarization)and reduced mitochondrial cell mass,leading to perturbed mitochondrial homeostasis.The hostile microenvironment created by HG exposure creates structural and functional changes in the mitochondria,altering their bioenergetics and reducing their capacity to produce ATP.These are significant data,as MSCs are extensively studied for tissue regeneration and restoring their normal functioning in cell-based therapy.Therefore,MSCs from hyperglycemic donors should be cautiously used in clinical settings for cell-based therapy due to concerns of their poor sur-vival rates and increased rates of post engraftment proliferation.As hypergly-cemia alters the bioenergetics of donor MSCs,rectifying the loss of MtMP may be an excellent target for future research to restore the normal functioning of MSCs in hyperglycemic patients.

Metabolic shift in liver: Correlation between perfusion temperature and hypoxia inducible factor-1α

AIM: To study at what temperature the oxygen carried by the perfusate meets liver requirements in a model of organ perfusion. METHODS: in this study, we correlated hypoxia induciblefactor(Hi F)-1α expression to the perfusion temperature and the hepatic oxygen uptake in a model of isolated perfused rat liver. Livers from Wistar rats were perfused for 6 h with an oxygenated medium at 10, 20, 30 and 37 ℃. Oxygen uptake was measured by an oxygen probe; lactate dehydrogenase activity, lactate release and glycogen were measured spectrophotometrically; bile flow was gravitationally determined; p H of the perfusate was also evaluated; Hi F-1α m RNA and protein expression were analyzed by real time-polymerase chain reaction and ELi SA, respectively. RESULTS: Livers perfused at 10 and 20 ℃ showed no difference in lactate dehydrogenase release after 6 h of perfusion(0.96 ± 0.23 vs 0.93 ± 0.09 m U/min per g) and had lower hepatic damage as compared to 30 and 37 ℃(5.63 ± 0.76 vs 527.69 ± 45.27 m U/min per g, respectively, P s < 0.01). After 6 h, tissue ATP was significantly higher in livers perfused at 10 and 20 ℃than in livers perfused at 30 and 37 ℃(0.89 ± 0.06 and 1.16 ± 0.05 vs 0.57 ± 0.09 and 0.33 ± 0.08 nmol/mg, respectively, P s < 0.01). No sign of hypoxia was observed at 10 and 20 ℃, as highlighted by low lactate release respect to livers perfused at 30 and 37 ℃(121.4 ± 12.6 and 146.3 ± 7.3 vs 281.8 ± 45.3 and 1094.5 ± 71.7 nmol/m L, respectively, P s < 0.02), and low relative Hi F-1α m RNA(0.40 ± 0.08 and 0.20 ± 0.03 vs 0.60 ± 0.20 and 1.47 ± 0.30, respectively, P s < 0.05) and protein(3.72 ± 0.16 and 3.65 ± 0.06 vs 4.43 ± 0.41 and 6.44 ± 0.82, respectively, P s < 0.05) expression.CONCLUSION: Livers perfused at 10 and 20 ℃ show no sign of liver injury or anaerobiosis, in contrast to livers perfused at 30 and 37 ℃.

Localization and role of metabotropic glutamate receptors subtype 5 in the gastrointestinal tract

Metabotropic glutamate receptor subtype 5 (mGluR5) is a Group I mGlu subfamily of receptors coupled to the inositol trisphosphate/diacylglycerol pathway. Like other mGluR subtypes, mGluR5s contain a phylogenetically conserved, extracellular orthosteric binding site and a more variable allosteric binding site, located on the heptahelical transmembrane domain. The mGluR5 receptor has proved to be a key pharmacological target in conditions affecting the central nervous system (CNS) but its presence outside the CNS underscores its potential role in pathologies affecting peripheral organs such as the gastrointestinal (GI) tract and accessory digestive organs such as the tongue, liver and pancreas. Following identification of mGluR5s in the mouth, various studies have subsequently demonstrated its involvement in mechanical allodynia, inflammation, pain and oral cancer. mGluR5 expression has also been identified in gastroesophageal vagal pathways. Indeed, experimental and human studies have demonstrated that mGluR5 blockade reduces transient lower sphincter relaxation and reflux episodes. In the intestine, mGluR5s have been shown to be involved in the control of intestinal inflammation, visceral pain and the epithelial barrier function. In the liver, mGluR5s have a permissive role in the onset of ischemic injury in rat and mice hepatocytes. Conversely, livers from mice treated with selective negative allosteric modulators and mGluR5 knockout mice are protected against ischemic injury. Similar results have been observed in experimental models of free-radical injury and in vivo mouse models of acetaminophen intoxication. Finally, mGluR5s in the pancreas are associated with insulin secretion control. The picture is, however, far from complete as the review attempts to establish in particular as regards identifying specific targets and innovative therapeutic approaches for the treatment of GI disorders.

Minimally manipulated autologous adherent bone marrow cells (ABMCs):a promising cell therapy of spinal cord injury

Spinal cord injury（SCI）is a devastating ailment that results in drastic life style alterations for the patients and their family members（Mc Donald and Sadowsky,2002）.Damage post injury causes necrosis,edema,hemorrhage and vasospasm.Post injury,secondary damage is caused by ischemia,

用荧光剂Fura-2连续测定大鼠泪腺细胞胞浆内Ca^(2+)浓度的变化

普遍认为，激素及神经递质对细胞作用的机理涉及到胞内CA^(2+)浓度的改变。

Cytochrome P450 endoplasmic reticulumassociated degradation(ERAD): therapeutic and pathophysiological implications

The hepatic endoplasmic reticulum(ER)-anchored cytochromes P450(P450s)are mixedfunction oxidases engaged in the biotransformation of physiologically relevant endobiotics as well as of myriad xenobiotics of therapeutic and environmental relevance.P450 ER-content and hence function is regulated by their coordinated hemoprotein syntheses and proteolytic turnover.Such P450 proteolytic turnover occurs through a process known as ER-associated degradation(ERAD)that involves ubiquitindependent proteasomal degradation(UPD)and/or autophagic-lysosomal degradation(ALD).Herein,on the basis of available literature reports and our own recent findings of in vitro as well as in vivo experimental studies,we discuss the therapeutic and pathophysiological implications of altered P450 ERAD and its plausible clinical relevance.We specifically(i)describe the P450 ERAD-machinery and how it may be repurposed for the generation of antigenic P450 peptides involved in P450 autoantibodypathogenesis in drug-induced acute hypersensitivity reactions and liver injury,or viral hepatitis;(ⅱ)discuss the relevance of accelerated or disrupted P450-ERAD to the pharmacological and/or toxicological effects of clinically relevant P450 drug substrates;and(ⅲ)detail the pathophysiological consequences of disrupted P450 ERAD,contributing to non-alcoholic fatty liver disease(NAFLD)/non-alcoholic steatohepatitis(NASH)under certain synergistic cellular conditions.

Prostate cancer and chemoprevention by natural dietary phytochemicals

Prostate cancer is the second leading cancer among men in the United States. Several studies have correlated the development of prostate cancer with diet and life-style. Therefore, a balanced diet and improved life style might inhibit prostate cancer progression. Cancer chemoprevention has emerged as an important factor in controlling cancer development through natural or synthetic compounds. Oxidative stress is among the factors contributing to prostate cancer development. The transcription factor nuclear factor(erythroid-derived 2)-like 2(Nrf2) controls detoxifying antioxidant enzymes expression by binding to the antioxidant response element(ARE) in the promoter of these genes to activate their expression. Many natural products can fight oxidative stress and protects cells from DNA damage by activating the Nrf2/ARE pathway. High consumption of fruits and vegetables can reduce disease incidence and invasive tumors. In this review, the roles of important fruit and vegetable phytochemicals in regulating prostate cancer progression and tumor growth are discussed.

iBioChina and iBiology: spreading scientific knowledge together

It is becoming increasingly important for the public to un- derstand how new scientific information and technology impact their lives and how scientists obtain new knowledge. Without this understanding, how do people know if global warming is real or if it is safe to eat genetically modified crops？ Dr. Chen ZhangLiang, the Vice President of China Association of Science and Technology （CAST）, conveyed this message in his talk at the Chinese Society for Cell Bi- ology （CSCB） Biennial Conference held in Shenzhen in April, 2015.

Biology by the numbers on the Hawaiian Islands

One could imagine it might be hard to focus on science at a beautiful location such as the famous Waikiki Beach on Oahu Island, Hawaii. Amazingly, however, that＇s just what more than 330 participants did at the First Annual Winter Q-Bio Meeting at the Hilton Hawaiian Village resort February 18 21, 2013.

Targeting matrix metalloproteinases in cancer:Bringing new life to old ideas

Since the identification of matrix metalloproteinases(MMPs),a family of zincdependent endopeptidases,as being a driving factor for cancer progression and patient prognosis,MMPs have been studied extensively.Although early programs targeting MMPs were largely unsuccessful in clinical trials,they remain a viable and highly desirable therapeutic target based on preclinical studies and their role in disease progression.As information regarding the structure and function of these proteinases is compiled and biotechnology evolves,tools to develop better inhibitors are within our grasp.Improved methods for high throughput screening and in silico drug design programs have identified compounds which are highly potent,have high binding affinities,and exhibit favorable pharmacokinetic profiles.More recently,advances in drug delivery methods or compounds which bind outside the active site have brought new light to the field.In this review,we highlight the role of MMPs in cancer,clinical trials for MMP inhibitors,and novel approaches to targeting MMPs in cancer.

Chromophore-assisted laser inactivation in neural development

Chromophore-assisted laser inactivation（CALI） is a technique that uses photochemically-generated reactive oxygen species to acutely inactivate target proteins in living cells.Neural development includes highly dynamic cellular processes such as asymmetric cell division,migration,axon and dendrite outgrowth and synaptogenesis.Although many key molecules of neural development have been identified since the past decades,their spatiotemporal contributions to these cellular events are not well understood.CALI provides an appealing tool for elucidating the precise functions of these molecules during neural development.In this review,we summarize the principles of CALI,a recent microscopic setup to perform CALI experiments,and the application of CALI to the study of growth-cone motility and neuroblast asymmetric division.

Overcoming the challenges of cancer drug resistance through bacterial-mediated therapy

Despite tremendous efforts to fight cancer,it remains a major public health problem and a leading cause of death worldwide.With increased knowledge of cancer pathways and improved technological platforms,precision therapeutics that specifically target aberrant cancer pathways have improved patient outcomes.Nevertheless,a primary cause of unsuccessful cancer therapy remains cancer drug resistance.In this review,we summarize the broad classes of resistance to cancer therapy,particularly pharmacokinetics,the tumor microenvironment,and drug resistance mechanisms.Furthermore,we describe how bacterial-mediated cancer therapy,a bygone mode of treatment,has been revitalized by synthetic biology and is uniquely suited to address the primary resistance mechanisms that confound traditional therapies.Through genetic engineering,we discuss how bacteria can be potent anticancer agents given their tumor targeting potential,anti-tumor activity,safety,and coordinated delivery of anti-cancer drugs.

Nat Methods:利用CRISPR-Cas9组合筛选发现癌症弱点

导致癌症的基因突变也会削弱癌细胞，从而使得人们有机会开发选择性地杀死它们同时不影响正常细胞的药物。这一概念被称作”合成致死性（synthetic lethality）”，这是因为这些药物仅对发生突变的（或者说合成的）细胞是致命性的。在一项新的研究中。来自美国加州大学圣地亚哥分校、加州大学旧金山分校、斯坦福大学和癌细胞图谱项目（Cancer Cell Map Initiative）的研究人员开发出一种新的方法来寻找合成致死性的基因组合。

iBioChina和iBiology:携手将科学的光辉传递给全世界

在这个科技日新月异的时代,对于公众而言,了解新的科技如何改变生活以及科学家如何获得这些新知识变得日益重要.如果缺乏这样的了解,人们就无从判断全球变暖是否正在切实地发生,也无法确定转基因食品是否安全.2015年4月,中国科学技术协会副主席陈章良博士出席了于深圳举行的中国细胞生物学会全国学术大会,并在其中的i Bio China（生物医学大讲堂）推介专场做了报告.

Identification of Styryl Sulfonyl Fluoride as a Near-Perfect Michael Acceptor for Diversified Protein Bioconjugations

Cysteine(Cys)-specific bioconjugation has widespread applications in the synthesis of protein conjugates,particularly for the functionalization of antibodies.Here,we report the discovery of transstyryl sulfonyl fluoride(SSF)as a near-perfect Michael acceptor for Cys-specific protein bioconjugation.Compared to maleimides,which are predominantly used,SSF exhibited better chemoselectivity,selfstability,and conjugate stability while maintaining comparable reactivity.Using SSF-derived probes,proteins can be readily modified on the Cys residue(s)to install functionalities,for example,fluorescent dyes,toxins,and oligonucleotides,without influencing the activity.Further applications of SSF-derived serum-stable antibody-drug conjugates and PD-L1 nanobody-oligo conjugates demonstrate the great translational value of SSF-based bioconjugation in drug development and single-cell sequencing.