Adiponectin Regulates Bone Marrow Mesenchymal Stem Cell Niche Through a Unique Signal Transduction Pathway: An Approach for Treating Bone Disease in Diabetes : Adiponectin Regulates BMSC Niche

Yu, Liming,Tu, Qisheng,Han, Qianqian,Zhang, Lan,Sui, Lei,Zheng, Leilei,Meng, Shu,Tang, Yin,Xuan, Dongying,Zhang, Jin,Murray, Dana,Shen, Qingping,Cheng, Jessica,Kim, Sung-Hoon,Dong, Lily Q.,Valverde, P Wiley (John WileySons) 2015 Stem Cells Vol.33 No.1

<P>Adiponectin (APN) is an adipocyte-secreted adipokine that exerts well-characterized antidiabetic properties. Patients with type 2 diabetes (T2D) are characterized by reduced APN levels in circulation and impaired stem cell and progenitor cell mobilization from the bone marrow for tissue repair and remodeling. In this study, we found that APN regulates the mobilization and recruitment of bone marrow-derived mesenchymal stem cells (BMSCs) to participate in tissue repair and regeneration. APN facilitated BMSCs migrating from the bone marrow into the circulation to regenerate bone by regulating stromal cell-derived factor (SDF)-1 in a mouse bone defect model. More importantly, we found that systemic APN infusion ameliorated diabetic mobilopathy of BMSCs, lowered glucose concentration, and promoted bone regeneration in diet-induced obesity mice. In vitro studies allowed us to identify Smad1/5/8 as a novel signaling mediator of APN receptor (AdipoR)-1 in BMSCs and osteoblasts. APN stimulation of MC3T3-E1 osteoblastic cells led to Smad1/5/8 phosphorylation and nuclear localization and increased SDF1 mRNA expression. Although APN-mediated phosphorylation of Smad1/5/8 occurred independently from adaptor protein, phosphotyrosine interaction, pleckstrin homology domain, and leucine zipper containing 1, it correlated with the disassembly of protein kinase casein kinase 2 and AdipoR1 in immunoprecipitation experiments. Taken together, this study identified APN as a regulator of BMSCs migration in response to bone injury. Therefore, our findings suggest APN signaling could be a potential therapeutic target to improve bone regeneration and homeostasis, especially in obese and T2D patients.</P>

Optimal Area and Intrinsic Coherent Resonance of Neurons due to Ion Channel Noise under an external Stimulus

Zhengzhen Zhang,Shaowen Zeng,Wenyan Tang,Jinlin Hu,Rongfeng Wang,Liming Zhou,Shangyou Zeng 한국물리학회 2012 THE JOURNAL OF THE KOREAN PHYSICAL SOCIETY Vol.61 No.1

In this paper, we study the intrinsic coherence resonance of neurons due to ion channel noise under an external stimulus. We find that the external stimulus cannot only increase the spiking coherence of neurons but also increase the optimal area of neuronal membrane for maximal spiking coherence. The optimal membrane area is approximately 3 μm² without the external stimulus. However, when the external stimulus is 6 μA/cm², the optimal membrane area is approximately 400 μm². Because 400 μm² is the area of a common neuronal soma, our finding has a realistic meaning. Under the external stimulus, common neurons have an optimized conformation to guarantee maximal spiking coherence and the best sub-threshold signal encoding.

Identification of a novel prognostic signature composed of 3 cuproptosis-related transcription factors in colon adenocarcinoma

Zhou Lei,Zhang Yuwan,Xu Yixin,Jiang Tao,Tang Liming 한국유전학회 2023 Genes & Genomics Vol.45 No.8

Background Since the mechanism of cuproptosis was recently revealed, many molecules related to this pathway have been widely concerned and exploited to have prognostic potential. However, it is still unknown whether the transcription factors related to cuproptosis could be competent as tumor biomarkers of colon adenocarcinoma (COAD). Objective To analyze the prognostic potential of cuproptosis-related transcription factors in COAD, and validate the representative molecule. Methods Transcriptome data and patients’ clinical parameters were obtained from the TCGA and GEO database. 19 cuproptosis genes were identified through literature consulting. Cuproptosis-related transcription factors were screened by COX regression analyses. Multivariate Cox regression was applied to construct the signature. Prognostic effects were evaluated by Kaplan Meier survival analyses and ROC analyses. KEGG, GO, and ssGSEA analyses were performed for function prediction. 48 COAD tissues were collected for immunohistochemistry stain to observe the expression level and prognostic value of E2F3. qRT-PCR was performed to detect mRNA expression levels, while cell viability assay was applied to detect the response of COAD cells to elesclomol treatment. Results A novel signature based on 3 prognostic transcription factors related to cuproptosis was successfully established and verified. Patients in the low-risk group tended to have better overall survival and lower immune phenotype scores than those in the high-risk group. Meanwhile, we also constructed a nomogram based on this signature and predict 10 candidate compounds targeting this signature. As an essential member of this signature, E2F3 was confirmed to be overexpressed in COAD tissues and was associated with poor prognosis of COAD patients. Importantly, CuCl2 and cuproptosis inducer elesclomol treatment could increase the expression of E2F3 in COAD cell while the overexpression of E2F3 significantly enhanced the resistance of COAD cells to elesclomol treatment. Conclusion Our research has identified a new prognostic biomarker and provides some innovative insights into the diagnosis and therapy of patients with COAD.

Epigenetically Modified Bone Marrow Stromal Cells in Silk Scaffolds Promote Craniofacial Bone Repair and Wound Healing

Han, Qianqian,Yang, Pishan,Wu, Yuwei,Meng, Shu,Sui, Lei,Zhang, Lan,Yu, Liming,Tang, Yin,Jiang, Hua,Xuan, Dongying,Kaplan, David L.,Kim, Sung Hoon,Tu, Qisheng,Chen, Jake Mary Ann Liebert 2015 Tissue engineering. Part A Vol.21 No.15

<P>Epigenetic regulation of gene expression is a central mechanism that governs cell stemness, determination, commitment, and differentiation. It has been recently found that PHF8, a major H4K20/H3K9 demethylase, plays a critical role in craniofacial and bone development. In this study, we hypothesize that PHF8 promotes osteoblastogenesis by epigenetically regulating the expression of a nuclear matrix protein, special AT-rich sequence-binding protein 2 (SATB2) that plays pivotal roles in skeletal patterning and osteoblast differentiation. Our results showed that expression levels of PHF8 and SATB2 in preosteoblasts and bone marrow stromal cells (BMSCs) increased simultaneously during osteogenic induction. Overexpressing PHF8 in these cells upregulated the expression of SATB2, Runx2, osterix, and bone matrix proteins. Conversely, knockdown of PHF8 reduced the expression of these genes. Furthermore, ChIP assays confirmed that PHF8 specifically bound to the transcription start site (TSS) of the SATB2 promoter, and the expression of H3K9me1 at the TSS region of SATB2 decreased in PHF8 overexpressed group. Implantation of the BMSCs overexpressing PHF8 with silk protein scaffolds promoted bone regeneration in critical-sized defects in mouse calvaria. Taken together, our results demonstrated that PHF8 epigenetically modulates SATB2 activity, triggering BMSCs osteogenic differentiation and facilitating bone formation and regeneration in biodegradable silk scaffolds.</P>

Fe-curcumin Nanozyme-Mediated Immunosuppression and Anti-inflammation in Experimental Autoimmune Uveitis

Zhengxuan Jiang,Kun Liang,Xiang Gao,Fan Cao,Guangqi An,Siyu Gui,Weiwei Tang,Liping Du,Liming Tao,Xianwen Wang 한국생체재료학회 2023 생체재료학회지 Vol.27 No.00

Background EAU is an inflammatory disease usually characterized by autoinflammation and autoimmunity and is aggravated by excessive generation of ROS. Conventional hormone therapy often has more adverse effects. It is urgent to find a therapeutic drug with higher efficiency and fewer adverse effects. Methods We developed an Fe-curcumin nanozyme in which natural antioxidants coordinate with Fe3+ to form nanoparticles with excellent solubility for directing anti-inflammatory and ROS scavenging effects to treat EAU. Several experiments were used to detect the characteristics of nanozymes. EAU model rats were used to detect the abilities of decreasing autoinflammation and autoimmunity. PBMCs were used to detect the ability to inhibit cell proliferation. Results Free radical scavenging experiments showed that nanozymes decreased the level of free radicals at low concentrations. In vitro and in vivo experiments revealed that the group treated with Fe-curcumin nanozymes had lower inflammatory reactions and ROS levels than the control group, as reflected by the downregulated levels of several critical inflammatory cytokines, such as IFN-γ, IL-17, and TNF-α; decreased H2O2 release; inhibited proliferation of Th1 and Th17 cells; and alleviated pathological changes in the eye. Importantly, the Fe-curcumin nanozyme was detected in the retina using Prussian blue staining. Additionally, Fe-curcumin nanozyme is noncytotoxic when directing these biological activities. Conclusion This study has demonstrated the feasibility of using the Fe-curcumin nanozyme as a nanodrug to inhibit inflammatory reactions and scavenge ROS in the treatment of EAU, indicating that it may serve as a promising therapeutic agent in clinical treatment.