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CXCL12/SDF-1α Activates NF-κB and Promotes Oral Cancer Invasion through the Carma3/Bcl10/Malt1 Complex

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International Journal of Oral Science 2009年第3期1卷 105-118页

作者： Aasia O. Rehman Cun-yu Wang Laboratory of Molecular Signaling Division of Oral Biology and Medicine UCLA School of Dentistry Los Angeles USA

Aim To determine how SDF-1α/CXCR4 activates nuclear factor-kappa B （NF-κB） and promotes oral squamous cell carcinoma （OSCC） invasion.Methodology A lentivirus-based knockdown approach was utilized to deplete gene expression. NF-κB activation was evaluated by Western blot analysis and electrophoretic mobility shift （EMSA）. Results We show that the activation of NF-κB by CXCR4 occurs through the Carma3/Bcl10/Maltl （CBM） complex in OSCC. We found that loss of components of the CBM complex in HNSCC can inhibit SDF-1α induced phosphorylation and degradation of IκBα, while TNFα induced IKK activation remains unchanged. Further, we identified a role for novel and atypical, but not classical, PKCs in activating IKK through CXCR4. Importantly, inhibition of the CBM complex leads to a significant decrease in SDF-1α mediated invasion of OSCC. Conclusion The CBM complex plays a critical role in CXCR4-induced NF-κB activation in OSCC. Targeting molecular components of the NF-κB signaling pathway may provide an important therapeutic opportunity in controlling the progression and metastasis of OSCC mediated by SDF-1α.

关键词： CXCR4 NF-κB head and neck cancer invasion signal transduction

Cross-talk between calcium and reactive oxygen species signaling

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Acta Pharmacologica Sinica 2006年第7期27卷 821-826页

作者： Yuan YAN Chao-liang WEI Wan-rui ZHANG He-ping CHENG Jie LIU~1 laboratory of Calcium signaling,Institute of molecular Medicine,Peking University,Beijing 100871,China laboratory of Calcium signaling Institute of Molecular Medicine Peking University Beijing 100871 China

Calcium(Ca2+)and reactive oxygen species(ROS)constitute the most importantintracellular signaling molecules participating in the regulation and integration ofdiverse cellular functions.Here we briefly review cross-talk between the two promi-nent signaling systems that finely tune the homeostasis and integrate functional-ity of Ca2+and ROS in different types of cells.Ca2+modulates ROS homeostasisby regulating ROS generation and annihilation mechanisms in both the mitochon-dria and the cytosol.Reciprocal redox regulation of Ca2+homeostasis occurs indifferent physiological and pathological processes,by modulating componentsof the Ca2+signaling toolkit and altering characteristics of local and global Ca2+signals.Functionally,interactions between Ca2+and ROS signaling systems canbe both stimulatory and inhibitory,depending on the type of target proteins,theROS species,the dose,duration of exposure,and the cell contexts.Such extensiveand complex cross-talk might enhance signaling coordination and integration,whereas abnormalities in either system might propagate into the other system andundermine the stability of both systems.

关键词： calcium reactive oxygen species signal transduction receptor cross talk

Local icariin application enhanced periodontal tissue regeneration and relieved local inflammation in a minipig model of periodontitis

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International Journal of Oral Science 2018年第3期10卷 168-173页

作者： Xiuli Zhang Nannan Han Guoqing Li Haoqing Yang Yangyang Cao Zhipeng Fan Fengqiu Zhang Department of Periodontology Capital Medical University School of Stomatology Laboratory of Molecular Signaling and Stem Cells Therapy Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction Capital Medical University School of Stomatology molecular laboratory for Gene Therapy and Tooth Regeneration Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction Capital Medical University School of Stomatology

Periodontitis is an inflammatory autoimmune disease. Treatment should alleviate inflammation, regulate the immune reaction and promote periodontal tissue regeneration. Icariin is the main active ingredient of Epimedii Folium, and it is a promising compound for the enhancement of mesenchymal stem cell function, promotion of bone formation, inhibition of bone resorption, alleviation of inflammation and regulation of immunity. The study investigated the effect of icariin on periodontal tissue regeneration in a minipig model of periodontitis. The minipig model of periodontitis was established. Icariin was injected locally. The periodontal clinical assessment index, a computed tomography(CT) scan, histopathology and enzyme-linked immune sorbent assay(ELISA)were used to evaluate the effects of icariin. Quantitative analysis results 12 weeks post-injection demonstrated that probing depth,gingival recession, attachment loss and alveolar bone regeneration values were(3.72 ± 1.18) mm vs.(6.56 ± 1.47) mm,(1.67 ± 0.59)mm vs.(2.38 ± 0.61) mm,(5.56 ± 1.29) mm vs.(8.61 ± 1.72) mm, and(25.65 ± 5.13) mm3 vs.(9.48 ± 1.78) mm3 in the icariin group and0.9% NaCl group, respectively. The clinical assessment, CT scan, and histopathology results demonstrated significant enhancement of periodontal tissue regeneration in the icariin group compared to the 0.9% NaCl group. The ELISA results suggested that the concentration of interleukin-1 beta(IL-1β) in the icariin group was downregulated compared to the 0.9% NaCl group, which indicates that local injection of icariin relieved local inflammation in a minipig model of periodontitis. Local injection of icariin promoted periodontal tissue regeneration and exerted anti-inflammatory and immunomodulatory function. These results support the application of icariin for the clinical treatment of periodontitis.

关键词： Local icariin application enhanced periodontal tissue regeneration and relieved local inflammation in a minipig model of periodontitis ELISA

Receptor-like kinase OsCR4 controls leaf morphogenesis and embryogenesis by fixing the distribution of auxin in rice

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Journal of Genetics and Genomics 2020年第9期47卷 577-589页

作者： Jiao Wang Lin-Lin Yan Zhi-Liang Yue Hao-Yue Li Xiu-Jie Ji Cui-Xia Pu Ying Sun College of Life Science Hebei Normal UniversityHebei Key Laboratory of Molecular and Cellular BiologyKey Laboratory of Molecular and Cellular Biology of Ministry of EducationHebei Collaboration Innovation Center for Cell SignalingShijiazhuang050024China Institute of Cash Crops Hebei Academy of Agriculture&Forestry SciencesShijiazhuang050051China

Cell differentiation is a key event in organ development;it involves auxin gradient formation, cell signaling, and transcriptional regulation. Yet, how these processes are orchestrated during leaf morphogenesis is poorly understood. Here, we demonstrate an essential role for the receptor-like kinase Os CR4 in leaf development. oscr4 loss-of-function mutants displayed short shoots and roots, with tiny,crinkly, or even dead leaves. The delayed outgrowth of the first three leaves and seminal root in oscr4 was due to defects in plumule and radicle formation during embryogenesis. The deformed epidermal,mesophyll, and vascular tissues observed in oscr4 leaves arose at the postembryo stage;the corresponding expression pattern of pro Os CR4:GUS in embryos and young leaves suggests that Os CR4 functions in these tissues. Signals from the auxin reporter DR5 rev:VENUS were found to be altered in oscr4 embryos and disorganized in oscr4 leaves, in which indole-3-acetic acid accumulation was further revealed by immunofluorescence. Os WOX3 A, which is auxin responsive and related to leaf development,was activated extensively and ectopically in oscr4 leaves, partially accounting for the observed lack of cell differentiation. Our data suggest that Os CR4 plays a fundamental role in leaf morphogenesis and embryogenesis by fixing the distribution of auxin.

关键词： Receptor-like kinase OsCR4 OsWOX3A Auxin distribution Leaf Embryo Rice

Impacting dementia and cognitive loss with innovative strategies: mechanistic target of rapamycin, clock genes, circular non-coding ribonucleic acids, and Rho/Rock

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Neural Regeneration Research 2019年第5期14卷 773-774页

作者： Kenneth Maiese Cellular and molecular signaling

A significant global impact from dementia:According to the World Health Organization(Dua et al.,2017),the current numbers for the prevalence and treatment costs for dementia worldwide are staggering.Almost 50 million individuals suffer from dementia.Dementia is now considered to be the 7^th leading cause of death.Currently,at least five percent of the world’s elderly population,equal to approximately 47 million individuals,have dementia.Moreover,at least sixty percent reside in low and middle income countries.Almost seventy-five percent of these new cases are to occur in these countries.The number of new cases each year throughout the globe is increasing at approximately 10 million per year.By the year 2030,82 million people are expected to have dementia and by the year 2050,152 million are expected to have the disease.

关键词： Impacting dementia cognitive loss innovative strategies

Environmentally responsive dual-targeting nanotheranostics for overcoming cancer multidrug resistance

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Science Bulletin 2019年第10期64卷 705-714页

作者： Caixia Yang Xin Pang Weihai Chen Xiaoyong Wang Gan Lin Chengchao Chu Xianzheng Zhang Xianming Deng Xiaoyuan Chen Gang Liu State Key laboratory of molecular Vaccinology and molecular Diagnostics and Center for molecular Imaging and Translational Medicine School of Public Health Xiamen University Xiamen 361102 China Key laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry Wuhan University Wuhan 430072 China State Key laboratory of Cellular Stress Biology Innovation Center for Cell Signaling Network School of Life Sciences Xiamen University Xiamen 361102 China laboratory of molecular Imaging and Nanomedicine National Institute of Biomedical Imaging and Bioengineering (NIBIB) National Institutes of Health (NIH) Bethesda MD 20892 USA

The development of multiple drug resistance(MDR) to chemotherapy and subsequent treatment failures are major obstacles in cancer therapy. An attractive option for combating MDR is inhibiting the expression of P-glycoprotein(P-gp) in tumor cells. Here, we report a novel chemosensitizing agent, XMD8-92,which can down-regulate P-gp. To enhance the specificity of MDR chemotherapy, a promising nanotheranostic micelle system based on poly(ethylene glycol)-blocked-poly(L-leucine)(PEG-b-Leu) was developed to simultaneously carry the anticancer drug doxorubicin, chemosensitizing agent XMD8-92, and superparamagnetic iron oxide nanoparticles(SPIOs). Featured with MDR environmentally responsive dual-targeting capability, controllable drug delivery, and efficient magnetic resonance(MR) imaging characteristics, the prepared nanotheranostics(DXS@NPs) showed outstanding in vitro cytotoxicity on MDR cells(SCG 7901/VCR) with only 53% of cells surviving compared to 90% of DOX-treated cells.Furthermore, efficient tumor inhibition and highly reduced systemic toxicity were exhibited by MDR tumor-bearing mice treated with DXS@NPs. Overall, the environmentally responsive dual-targeting nanotheranostics represent a promising approach for overcoming cancer MDR.

关键词： Cancer chemosensitization Multidrug resistance P-glycoprotein pH-responsive Magnetic resonance imaging

Generation and characterization of nanobodies targeting GPCR

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Biophysics Reports 2024年第1期10卷 22-30页

作者： Shenglan Zhang Zhiran Fan Jianfeng Liu Bioland laboratory (Guangzhou Regenerative Medicine and Health Guangdong laboratory) Cellular signaling laboratory International Research Center for Sensory Biology and Technology of MOST Key Laboratory of Molecular Biophysics of MOE College of Life Science and Technology Huazhong University of Science and Technology

G protein-coupled receptors(GPCRs) are a large family of cell membrane proteins that are important targets for drug discovery. Nanobodies, also known as VHH(variable domains of heavy chain-only antibodies, HcAbs) antibodies, are small antibody fragments derived from camelids that have gained significant attention as potential therapeutics for targeting GPCRs due to their advantages over conventional antibodies. However, there are challenges in developing nanobodies targeting GPCRs, among which epitope accessibility is the most significant because the cell membrane partially shields the GPCR surface. We developed a universal protocol for making nanobodies targeting GPCRs using the cell membrane extract of GPCR-overexpressing HEK293 cells as the llama/alpaca immunization antigen. We constructed an immune VHH library and identified nanobodies by phage display bio-panning. The monoclonal nanobodies were recombinantly expressed in Escherichia coli(E. coli) and purified to characterize their binding potency.

关键词： Nanobody Single domain antibody Heavy chain-only antibody GPCR G protein-coupled receptor

A need for stratification of metastasis samples according to secondary site in gene expression studies

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BIOCELL 2022年第7期46卷 1747-1750页

作者： IVANA SAMARŽIJA laboratory for Epigenomics Division of Molecular MedicineRuđer BoškovićInstituteZagreb10000Croatia laboratory for Cell Biology and signaling Division of Molecular BiologyRuđer BoškovićInstituteZagreb10000Croatia

Comparisons of gene expression profiles between primary tumors and metastasis have revealed genes that are implicated in metastasis formation.However,gene expression studies conducted on metastasis samples from the same primary site usually do not discriminate between different secondary sites.Although the change in the expression of number of genes is expected to be common to metastasis from the same primary but different secondary sites,herein the data that point to substantial differences are presented.Furthermore,the reciprocal communication between metastatic and host cells that is influencing these differences is outlined to emphasize the need for stratification of metastasis samples in gene expression studies.

关键词： Bone metastasis Brain metastasis Liver metastasis Lung metastases Gene expression

Novel applications of trophic factors,Wnt and WISP for neuronal repair and regeneration in metabolic disease

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Neural Regeneration Research 2015年第4期10卷 518-528页

作者： Kenneth Maiese Cellular and molecular signaling

Diabetes mellitus affects almost 350 million individuals throughout the globe resulting in sig-niifcant morbidity and mortality. Of further concern is the growing population of individuals that remain undiagnosed but are susceptible to the detrimental outcomes of this disorder. Dia-betes mellitus leads to multiple complications in the central and peripheral nervous systems that include cognitive impairment, retinal disease, neuropsychiatric disease, cerebral ischemia, and peripheral nerve degeneration. Although multiple strategies are being considered, novel target-ing of trophic factors, Wnt signaling, Wnt1 inducible signaling pathway protein 1, and stem cell tissue regeneration are considered to be exciting prospects to overcome the cellular mechanisms that lead to neuronal injury in diabetes mellitus involving oxidative stress, apoptosis, and au-tophagy. Pathways that involve insulin-like growth factor-1, ifbroblast growth factor, epidermal growth factor, and erythropoietin can govern glucose homeostasis and are intimately tied to Wnt signaling that involves Wnt1 and Wnt1 inducible signaling pathway protein 1 （CCN4） to foster control over stem cell proliferation, wound repair, cognitive decline,β-cell proliferation, vascular regeneration, and programmed cell death. Ultimately, cellular metabolism through Wnt signal-ing is driven by primary metabolic pathways of the mechanistic target of rapamycin and AMP activated protein kinase. These pathways offer precise biological control of cellular metabolism, but are exquisitely sensitive to the different components of Wnt signaling. As a result, unexpected clinical outcomes can ensue and therefore demand careful translation of the mechanisms that govern neural repair and regeneration in diabetes mellitus.

关键词： Alzheimer’s disease AMPK apoptosis autophagy central nervous system CCN4 EGF diabetes mellitus erythropoietin EPO FGF IGF-1 mTOR neuron neuropathy oxidative stress psychiatric stem cells WISP1 Wnt