Stanford Advisors

  • Yang Sun, Postdoctoral Faculty Sponsor

All Publications

  • PANoptosis signaling enables broad immune response in psoriasis: From pathogenesis to new therapeutic strategies. Computational and structural biotechnology journal Hu, X. M., Zheng, S., Zhang, Q., Wan, X., Li, J., Mao, R., Yang, R., Xiong, K. 2024; 23: 64-76


    Accumulating evidence suggests that regulated cell death, such as pyroptosis, apoptosis, and necroptosis, is deeply involved in the pathogenesis of psoriasis. As a newly recognized form of systematic cell death, PANoptosis is involved in a variety of inflammatory disorders through amplifying inflammatory and immune cascades, but its role in psoriasis remains elusive.To reveal the role of PANoptosis in psoriasis for a potential therapeutic strategy.Multitranscriptomic analysis and experimental validation were used to identify PANoptosis signaling in psoriasis. RNA-seq and scRNA-seq analyses were performed to establish a PANoptosis-mediated immune response in psoriasis, which revealed hub genes through WGCNA and predicted disulfiram as a potential drug. The effect and mechanism of disulfiram were verified in imiquimod (IMQ)-induced psoriasis.Here, we found a highlighted PANoptosis signature in psoriasis patients through multitranscriptomic analysis and experimental validation. Based on this, two distinct PANoptosis patterns (non/high) were identified, which were the options for clinical classification. The high-PANoptosis-related group had a higher response rate to immune cell infiltration (such as M1 macrophages and keratinocytes). Subsequently, WGCNA showed the hub genes (e.g., S100A12, CYCS, NOD2, STAT1, HSPA4, AIM2, MAPK7), which were significantly associated with clinical phenotype, PANoptosis signature, and identified immune response in psoriasis. Finally, we explored disulfiram (DSF) as a candidate drug for psoriasis through network pharmacology, which ameliorated IMQ-mediated psoriatic symptoms through antipyroptosis-mediated inflammation and enhanced apoptotic progression. By analyzing the specific ligand-receptor interaction pairs within and between cell lineages, we speculated that DSF might exert its effects by targeting keratinocytes directly or targeting M1 macrophages to downregulate the proliferation of keratinocytes.PANoptosis with its mediated immune cell infiltration provides a roadmap for research on the pathogenesis and therapeutic strategies of psoriasis.

    View details for DOI 10.1016/j.csbj.2023.11.049

    View details for PubMedID 38125299

    View details for PubMedCentralID PMC10730955

  • Editorial: Novel strategies to target cell death signaling in cancer and neurodegenerative diseases: new findings and mechanistic studies. Frontiers in cell and developmental biology Zhang, Q., Xiong, K. 2024; 12: 1383301

    View details for DOI 10.3389/fcell.2024.1383301

    View details for PubMedID 38469180

    View details for PubMedCentralID PMC10925791

  • Copper Metabolism and Cuproptosis: Molecular Mechanisms and Therapeutic Perspectives in Neurodegenerative Diseases. Current medical science Ban, X., Wan, H., Wan, X., Tan, Y., Hu, X., Ban, H., Chen, X., Huang, K., Zhang, Q., Xiong, K. 2024


    Copper is an essential trace element, and plays a vital role in numerous physiological processes within the human body. During normal metabolism, the human body maintains copper homeostasis. Copper deficiency or excess can adversely affect cellular function. Therefore, copper homeostasis is stringently regulated. Recent studies suggest that copper can trigger a specific form of cell death, namely, cuproptosis, which is triggered by excessive levels of intracellular copper. Cuproptosis induces the aggregation of mitochondrial lipoylated proteins, and the loss of iron-sulfur cluster proteins. In neurodegenerative diseases, the pathogenesis and progression of neurological disorders are linked to copper homeostasis. This review summarizes the advances in copper homeostasis and cuproptosis in the nervous system and neurodegenerative diseases. This offers research perspectives that provide new insights into the targeted treatment of neurodegenerative diseases based on cuproptosis.

    View details for DOI 10.1007/s11596-024-2832-z

    View details for PubMedID 38336987

  • VDAC1, as a downstream molecule of MLKL, participates in OGD/R-induced necroptosis by inducing mitochondrial damage. Heliyon Wan, H., Yang, Y. D., Zhang, Q., Chen, Y. H., Hu, X. M., Huang, Y. X., Shang, L., Xiong, K. 2024; 10 (1): e23426


    Ischemia-reperfusion (I/R) injury constitutes a significant risk factor for a range of diseases, including ischemic stroke, myocardial infarction, and trauma. Following the restoration of blood flow post-tissue ischemia, oxidative stress can lead to various forms of cell death, including necrosis, apoptosis, autophagy, and necroptosis. Recent evidence has highlighted the crucial role of mitochondrial dysfunction in I/R injury. Nevertheless, there remains much to be explored regarding the molecular signaling network governing cell death under conditions of oxidative stress. Voltage-dependent anion channel 1 (VDAC1), a major component in the outer mitochondrial membrane, is closely involved in the regulation of cell death. In a cellular model of oxygen-glucose deprivation and reoxygenation (OGD/R), which effectively simulates I/R injury in vitro, our study reveals that OGD/R induces VDAC1 oligomerization, consequently exacerbating cell death. Furthermore, we have revealed the translocation of mixed lineage kinase domain-like protein (MLKL) to the mitochondria, where it interacts with VDAC1 following OGD/R injury, leading to an increased mitochondrial membrane permeability. Notably, the inhibition of MLKL by necrosulfonamide hinders the binding of MLKL to VDAC1, primarily by affecting the membrane translocation of MLKL, and reduces OGD/R-induced VDAC1 oligomerization. Collectively, our findings provide preliminary evidence of the functional association between MLKL and VDAC1 in the regulation of necroptosis.

    View details for DOI 10.1016/j.heliyon.2023.e23426

    View details for PubMedID 38173512

    View details for PubMedCentralID PMC10761567

  • Mesenchymal Stem Cell Transplantation in Type 1 Diabetes Treatment: Current Advances and Future Opportunity. Current stem cell research & therapy Liu, J., Wan, X. X., Zheng, S. Y., He, H. H., Khan, M. A., Feng, Y. X., Xiao, J. G., Chen, Y., Hu, X. M., Zhang, Q., Xiong, K. 2023


    Type 1 Diabetes (T1D) is characterized by hyperglycemia, and caused by a lack of insulin secretion. At present there is no cure for T1D and patients are dependent on exogenous insulin for lifelong, which seriously affects their lives. Mesenchymal stem cells (MSCs) can be differentiated to β cell-like cells to rescue the secretion of insulin and reconstruct immunotolerance to preserve the function of islet β cells. Due to the higher proportion of children and adolescents in T1D patients, the efficacy and safety issue of the application of MSC's transplant in T1D was primarily demonstrated and identified by human clinical trials in this review. Then we clarified the mechanism of MSCs to relieve the symptom of T1D and found out that UC-MSCs have no obvious advantage over the other types of MSCs, the autologous MSCs from BM or menstrual blood with less expanded ex vivo could be the better choice for clinical application to treat with T1D through documentary analysis. Finally, we summarized the advances of MSCs with different interventions such as genetic engineering in the treatment of T1D, and demonstrated the advantages and shortage of MSCs intervened by different treatments in the transplantation, which may enhance the clinical efficacy and overcome the shortcomings in the application of MSCs to T1D in future.

    View details for DOI 10.2174/011574888X268740231002054459

    View details for PubMedID 37817652

  • Integration of Theory and Practice in Medical Morphology Curriculum in Postgraduate Training: A Flipped Classroom and Case-based Learning Exercise. Current medical science Hu, X. M., Li, Z. X., Deng, J., Han, Y., Lu, S., Zhang, Q., Luo, Z. Q., Xiong, K. 2023; 43 (4): 741-748


    The integration of training in theory and practice across the medical education spectrum is being encouraged to increase student understanding and skills in the sciences. This study aimed to determine the deciding factors that drive students' perceived advantages in class to improve precision education and the teaching model.A mixed strategy of an existing flipped classroom (FC) and a case-based learning (CBL) model was conducted in a medical morphology curriculum for 575 postgraduate students. The subjective learning evaluation of the individuals (learning time, engagement, study interest and concentration, and professional integration) was collected and analyzed after FC-CBL model learning.The results from the general evaluation showed promising results of the medical morphology in the FC-CBL model. Students felt more engaged by instructors in person and benefited in terms of time-saving, flexible arrangements, and professional improvement. Our study contributed to the FC-CBL model in Research Design in postgraduate training in 4 categories: 1) advancing a guideline of precision teaching according to individual characteristics; 2) revealing whether a learning background is needed for a Research Design course to guide setting up a preliminary course; 3) understanding the perceived advantages and their interfaces; and 4) barriers and/or improvement to implement the FC-CBL model in the Research Design class, such as a richer description of e-learning and hands-on practice.Undertaking a FC-CBL combined model could be a useful addition to pedagogy for medical morphology learning in postgraduate training.

    View details for DOI 10.1007/s11596-023-2759-9

    View details for PubMedID 37455278

    View details for PubMedCentralID 9830514

  • Regulated Cell Death of Retinal Ganglion Cells in Glaucoma: Molecular Insights and Therapeutic Potentials CELLULAR AND MOLECULAR NEUROBIOLOGY Zhao, W., Fan, C., Hu, X., Ban, X., Wan, H., He, Y., Zhang, Q., Xiong, K. 2023; 43 (7): 3161-3178


    Glaucoma is a group of diseases characterized by the degeneration of retinal ganglion cells (RGCs) and progressive, irreversible vision loss. High intraocular pressure (IOP) heightens the likelihood of glaucoma and correlates with RGC loss. While the current glaucoma therapy prioritizes lower the IOP; however, RGC, and visual loss may persist even when the IOP is well-controlled. As such, discovering and creating IOP-independent neuroprotective strategies for safeguard RGCs is crucial for glaucoma management. Investigating and clarifying the mechanism behind RGC death to counteract its effects is a promising direction for glaucoma control. Empirical studies of glaucoma reveal the role of multiple regulated cell death (RCD) pathways in RGC death. This review delineates the RCD of RGCs following IOP elevation and optic nerve damage and discusses the substantial benefits of mitigating RCD in RGCs in preserving visual function.

    View details for DOI 10.1007/s10571-023-01373-1

    View details for Web of Science ID 001015502900001

    View details for PubMedID 37338781

  • Pyroptosis-related gene signature elicits immune response in rosacea. Experimental dermatology Hu, X. M., Zheng, S. Y., Mao, R., Zhang, Q., Wan, X. X., Zhang, Y. Y., Li, J., Yang, R. H., Xiong, K. 2023


    Rosacea is a complex chronic inflammatory skin disorder with high morbidity. Pyroptosis is known as a regulated inflammatory cell death. While its association with immune response to various inflammatory disorders is well established, little is known about its functional relevance of rosacea. So, we aimed to explore and enrich the pathogenesis involved in pyroptosis-related rosacea aggravations. In this study, we evaluated the pyroptosis-related patterns of rosacea by consensus clustering analysis of 45 ferroptosis-related genes (FRGs), with multiple immune cell infiltration analysis to identify the pyroptosis-mediated immune response in rosacea using GSE65914 dataset. The co-co-work between PRGs and WGCNA-revealed hub genes has established using PPI network. FRG signature was highlighted in rosacea using multi-transcriptomic and experiment analysis. Based on this, three distinct pyroptosis-related rosacea patterns (non/moderate/high) were identified, and the notably enriched pathways have revealed through GO, KEGG and GSEA analysis, especially immune-related pathways. Also, the XCell/MCPcount/ssGSEA/Cibersort underlined the immune-related signalling (NK cells, Monocyte, Neutrophil, Th2 cells, Macrophage), whose hub genes were identified through WGCNA (NOD2, MYD88, STAT1, HSPA4, CXCL8). Finally, we established a pyroptosis-immune co-work during the rosacea aggravations. FRGs may affect the progression of rosacea by regulating the immune cell infiltrations. In all, pyroptosis with its mediated immune cell infiltration is a critical factor during the development of rosacea.

    View details for DOI 10.1111/exd.14812

    View details for PubMedID 37086043

  • Inhibition of mitochondrial VDAC1 oligomerization alleviates apoptosis and necroptosis of retinal neurons following OGD/R injury. Annals of anatomy = Anatomischer Anzeiger : official organ of the Anatomische Gesellschaft Wan, H., Yan, Y. D., Hu, X. M., Shang, L., Chen, Y. H., Huang, Y. X., Zhang, Q., Yan, W. T., Xiong, K. 2023; 247: 152049


    Ischemia-reperfusion (I/R) injury is a common pathological mechanism in many retinal diseases, which can lead to cell death via mitochondrial dysfunction. Voltage-dependent anion channel 1 (VDAC1), which is mainly located in the outer mitochondrial membrane, is the gatekeeper of mitochondria. The permeability of mitochondrial membrane can be regulated by controlling the oligomerization of VDAC1. However, the functional mechanism of VDAC1 in retinal I/R injury was unclear. Our results demonstrate that oxygen-glucose deprivation and re-oxygenation (OGD/R) injury leads to apoptosis, necroptosis, and mitochondrial dysfunction of R28 cells. The OGD/R injury increases the levels of VDAC1 oligomerization. Inhibition of VDAC1 oligomerization by VBIT-12 rescued mitochondrial dysfunction by OGD/R and also reduced apoptosis/necroptosis of R28 cells. In vivo, the use of VBIT-12 significantly reduced aHIOP-induced neuronal death (apoptosis/necroptosis) in the rat retina. Our findings indicate that VDAC1 oligomers may open and enlarge mitochondrial membrane pores during OGD/R injury, leading to the release of death-related factors in mitochondria, resulting in apoptosis and necroptosis. This study provides a potential therapeutic strategy against ocular diseases caused by I/R injury.

    View details for DOI 10.1016/j.aanat.2023.152049

    View details for PubMedID 36690044

  • DTX3L induced NLRP3 ubiquitination inhibit R28 cell pyroptosis in OGD/R injury. Biochimica et biophysica acta. Molecular cell research Zhou, Z., Shang, L., Zhang, Q., Hu, X., Huang, J. F., Xiong, K. 2023; 1870 (3): 119433


    Ischemia/reperfusion (I/R) injury is one of the most common etiologies in many diseases. Retinal I/R leads to cytokine storm, resulting in tissue damage and cell death. Pyroptosis, a novel type of regulated cell death, occurs after cellular I/R injury. In this study, we established an oxygen glucose deprivation (OGD/R) cellular model (R28) to simulate retinal I/R injury. We conducted an LDH assay, and EthD-III and PI staining procedures to confirm pyroptosis. Mass spectrometry and bioinformatics analysis were used to identify the possible proteins interacting with NLRP3. Co-IP and various molecular biology techniques were used to investigate the possible modes regulating NLRP3 by DTX3L. EthD-III, PI staining and LDH assays demonstrated pyroptosis induced by OGD/R injury, mediated via NLRP3 pathway. Mass spectrometry and bioinformatics analysis screened out three candidate proteins interacting with NLRP3, and further Co-IP experiment indicated that DTX-3L may interact with NLRP3 to regulate its protein levels after injury. Co-IP experiments and various molecular biology methods demonstrated that DTX3L ubiquitinates NLRP3 resulting in pyroptosis after R28 OGD/R injury. Further, NLRP3 LRR and DTX3L RING domains interact with each other. Our study demonstrated that DTX3L may ubiquitinate NLRP3 to regulate OGD/R-induced pyroptosis globally in R28 cells.

    View details for DOI 10.1016/j.bbamcr.2023.119433

    View details for PubMedID 36706922

  • PANoptosis-like cell death in ischemia/reperfusion injury of retinal neurons. Neural regeneration research Yan, W. T., Zhao, W. J., Hu, X. M., Ban, X. X., Ning, W. Y., Wan, H., Zhang, Q., Xiong, K. 2023; 18 (2): 357-363


    PANoptosis is a newly identified type of regulated cell death that consists of pyroptosis, apoptosis, and necroptosis, which simultaneously occur during the pathophysiological process of infectious and inflammatory diseases. Although our previous literature mining study suggested that PANoptosis might occur in neuronal ischemia/reperfusion injury, little experimental research has been reported on the existence of PANoptosis. In this study, we used in vivo and in vitro retinal neuronal models of ischemia/reperfusion injury to investigate whether PANoptosis-like cell death (simultaneous occurrence of pyroptosis, apoptosis, and necroptosis) exists in retinal neuronal ischemia/reperfusion injury. Our results showed that ischemia/reperfusion injury induced changes in morphological features and protein levels that indicate PANoptosis-like cell death in retinal neurons both in vitro and in vivo. Ischemia/reperfusion injury also significantly upregulated caspase-1, caspase-8, and NLRP3 expression, which are important components of the PANoptosome. These results indicate the existence of PANoptosis-like cell death in ischemia/reperfusion injury of retinal neurons and provide preliminary experimental evidence for future study of this new type of regulated cell death.

    View details for DOI 10.4103/1673-5374.346545

    View details for PubMedID 35900430

    View details for PubMedCentralID PMC9396479

  • Targeting Necroptosis: A Novel Therapeutic Option for Retinal Degenerative Diseases. International journal of biological sciences Zhang, Q., Hu, X. M., Zhao, W. J., Ban, X. X., Li, Y., Huang, Y. X., Wan, H., He, Y., Liao, L. S., Shang, L., Jiang, B., Qing, G. P., Xiong, K. 2023; 19 (2): 658-674


    The discovery of the necroptosis, a form of regulated necrosis that is mediated by receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed-lineage kinase domain-like pseudokinase (MLKL), represents a major breakthrough that has dramatically altered the conception of necrosis - traditionally thought of as uncontrolled cell death - in various human diseases. Retinal cell death is a leading cause of blindness and has been identified in most retinal diseases, e.g., age-related macular degeneration, glaucoma, retinal detachment, retinitis pigmentosa, etc. Increasing evidence demonstrates that retinal degenerative diseases also share a common mechanism in necroptosis. Exacerbated necroptotic cell death hinders the treatment for retinal degenerative diseases. In this review, we highlight recent advances in identifying retinal necroptosis, summarize the underlying mechanisms of necroptosis in retinal degenerative diseases, and discuss potential anti-necroptosis strategies, such as selective inhibitors and chemical agents, for treating retinal degenerative diseases.

    View details for DOI 10.7150/ijbs.77994

    View details for PubMedID 36632450

    View details for PubMedCentralID PMC9830514

  • ZBP1-Mediated Necroptosis: Mechanisms and Therapeutic Implications. Molecules (Basel, Switzerland) Chen, X. Y., Dai, Y. H., Wan, X. X., Hu, X. M., Zhao, W. J., Ban, X. X., Wan, H., Huang, K., Zhang, Q., Xiong, K. 2022; 28 (1)


    Cell death is a fundamental pathophysiological process in human disease. The discovery of necroptosis, a form of regulated necrosis that is induced by the activation of death receptors and formation of necrosome, represents a major breakthrough in the field of cell death in the past decade. Z-DNA-binding protein (ZBP1) is an interferon (IFN)-inducing protein, initially reported as a double-stranded DNA (dsDNA) sensor, which induces an innate inflammatory response. Recently, ZBP1 was identified as an important sensor of necroptosis during virus infection. It connects viral nucleic acid and receptor-interacting protein kinase 3 (RIPK3) via two domains and induces the formation of a necrosome. Recent studies have also reported that ZBP1 induces necroptosis in non-viral infections and mediates necrotic signal transduction by a unique mechanism. This review highlights the discovery of ZBP1 and its novel findings in necroptosis and provides an insight into its critical role in the crosstalk between different types of cell death, which may represent a new therapeutic option.

    View details for DOI 10.3390/molecules28010052

    View details for PubMedID 36615244

    View details for PubMedCentralID PMC9822119

  • Current research and clinical trends in rosacea pathogenesis. Heliyon Hu, X. M., Li, Z. X., Zhang, D. Y., Yang, Y. C., Zheng, S. Y., Zhang, Q., Wan, X. X., Li, J., Yang, R. H., Xiong, K. 2022; 8 (10): e10874


    Rosacea is a common and complex chronic inflammatory skin disorder, the pathophysiology and etiology of which remain unclear. Recently, significant new insights into rosacea pathogenesis have enriched and reshaped our understanding of the disorder. A systematic analysis based on current studies will facilitate further research on rosacea pathogenesis.To establish an international core outcome and knowledge system of rosacea pathogenesis and develop a challenge, trend and hot spot analysis set for research and clinical studies on rosacea using bibliometric analysis and data mining.A search of the WoS, and PubMed, MEDLINE, Embase and Cochrane collaboration databases was conducted to perform visual bibliometric and data analysis.A total of 2,654 studies were used for the visualization and 302 of the 6,769 outcomes for data analysis. It reveals an increased trend line in the field of rosacea, in which its fast-growing pathogenesis attracted attention closely related to risk, comorbidity and therapeutic strategies. The rosacea pathogenesis has undergone the great development on immunology, microorganisms, genes, skin barriers and neurogenetics. The major of studies have focused on immune and microorganisms. And keyword visualization and data analyses demonstrated the cross-talk between cells or each aspect of pathogenesis, such as gene-gene or gene-environment interactions, and neurological mechanisms associated with the rosacea phenotype warrant further research.Inherent limitations of bibliometrics; and reliance on research and retrospective studies.The understanding of rosacea's pathogenesis has been significantly enhanced with the improved technology and multidisciplinary integration, but high-quality, strong evidence in favor of genomic and neurogenic requires further research combined with a better understanding of risks and comorbidities to guide clinical practice.

    View details for DOI 10.1016/j.heliyon.2022.e10874

    View details for PubMedID 36276718

    View details for PubMedCentralID PMC9578998

  • Do pyroptosis, apoptosis, and necroptosis (PANoptosis) exist in cerebral ischemia? Evidence from cell and rodent studies. Neural regeneration research Yan, W. T., Yang, Y. D., Hu, X. M., Ning, W. Y., Liao, L. S., Lu, S., Zhao, W. J., Zhang, Q., Xiong, K. 2022; 17 (8): 1761-1768


    Some scholars have recently developed the concept of PANoptosis in the study of infectious diseases where pyroptosis, apoptosis and necroptosis act in consort in a multimeric protein complex, PANoptosome. This allows all the components of PANoptosis to be regulated simultaneously. PANoptosis provides a new way to study the regulation of cell death, in that different types of cell death may be regulated at the same time. To test whether PANoptosis exists in diseases other than infectious diseases, we chose cerebral ischemia/reperfusion injury as the research model, collected articles researching cerebral ischemia/reperfusion from three major databases, obtained the original research data from these articles by bibliometrics, data mining and other methods, then integrated and analyzed these data. We selected papers that investigated at least two of the components of PANoptosis to check its occurrence in ischemia/reperfusion. In the cell model simulating ischemic brain injury, pyroptosis, apoptosis and necroptosis occur together and this phenomenon exists widely in different passage cell lines or primary neurons. Pyroptosis, apoptosis and necroptosis also occurred in rat and mouse models of ischemia/reperfusion injury. This confirms that PANoptosis is observed in ischemic brain injury and indicates that PANoptosis can be a target in the regulation of various central nervous system diseases.

    View details for DOI 10.4103/1673-5374.331539

    View details for PubMedID 35017436

    View details for PubMedCentralID PMC8820688

  • Insight into Crosstalk Between Mitophagy and Apoptosis/Necroptosis: Mechanisms and Clinical Applications in Ischemic Stroke. Current medical science Yang, Y. D., Li, Z. X., Hu, X. M., Wan, H., Zhang, Q., Xiao, R., Xiong, K. 2022; 42 (2): 237-248


    Ischemic stroke is a serious cerebrovascular disease with high morbidity and mortality. As a result of ischemia-reperfusion, a cascade of pathophysiological responses is triggered by the imbalance in metabolic supply and demand, resulting in cell loss. These cellular injuries follow various molecular mechanisms solely or in combination with this disorder. Mitochondria play a driving role in the pathophysiological processes of ischemic stroke. Once ischemic stroke occurs, damaged cells would respond to such stress through mitophagy. Mitophagy is known as a conservatively selective autophagy, contributing to the removal of excessive protein aggregates and damaged intracellular components, as well as aging mitochondria. Moderate mitophagy may exert neuroprotection against stroke. Several pathways associated with the mitochondrial network collectively contribute to recovering the homeostasis of the neurovascular unit. However, excessive mitophagy would also promote ischemia-reperfusion injury. Therefore, mitophagy is a double-edged sword, which suggests that maximizing the benefits of mitophagy is one of the direction of future efforts. This review emphasized the role of mitophagy in ischemic stroke, and highlighted the crosstalk between mitophagy and apoptosis/necroptosis.

    View details for DOI 10.1007/s11596-022-2579-3

    View details for PubMedID 35391618

  • Stem Cell Transplantation in the Treatment of Type 1 Diabetes Mellitus: From Insulin Replacement to Beta-Cell Replacement. Frontiers in endocrinology Wan, X. X., Zhang, D. Y., Khan, M. A., Zheng, S. Y., Hu, X. M., Zhang, Q., Yang, R. H., Xiong, K. 2022; 13: 859638


    Type 1 diabetes mellitus (T1DM) is an autoimmune disease that attacks pancreatic β-cells, leading to the destruction of insulitis-related islet β-cells. Islet β-cell transplantation has been proven as a curative measure in T1DM. However, a logarithmic increase in the global population with diabetes, limited donor supply, and the need for lifelong immunosuppression restrict the widespread use of β-cell transplantation. Numerous therapeutic approaches have been taken to search for substitutes of β-cells, among which stem cell transplantation is one of the most promising alternatives. Stem cells have demonstrated the potential efficacy to treat T1DM by reconstitution of immunotolerance and preservation of islet β-cell function in recent research. cGMP-grade stem cell products have been used in human clinical trials, showing that stem cell transplantation has beneficial effects on T1DM, with no obvious adverse reactions. To better achieve remission of T1DM by stem cell transplantation, in this work, we explain the progression of stem cell transplantation such as mesenchymal stem cells (MSCs), human embryonic stem cells (hESCs), and bone marrow hematopoietic stem cells (BM-HSCs) to restore the immunotolerance and preserve the islet β-cell function of T1DM in recent years. This review article provides evidence of the clinical applications of stem cell therapy in the treatment of T1DM.

    View details for DOI 10.3389/fendo.2022.859638

    View details for PubMedID 35370989

    View details for PubMedCentralID PMC8972968

  • Targeting Programmed Cell Death to Improve Stem Cell Therapy: Implications for Treating Diabetes and Diabetes-Related Diseases. Frontiers in cell and developmental biology Zhang, Q., Wan, X. X., Hu, X. M., Zhao, W. J., Ban, X. X., Huang, Y. X., Yan, W. T., Xiong, K. 2021; 9: 809656


    Stem cell therapies have shown promising therapeutic effects in restoring damaged tissue and promoting functional repair in a wide range of human diseases. Generations of insulin-producing cells and pancreatic progenitors from stem cells are potential therapeutic methods for treating diabetes and diabetes-related diseases. However, accumulated evidence has demonstrated that multiple types of programmed cell death (PCD) existed in stem cells post-transplantation and compromise their therapeutic efficiency, including apoptosis, autophagy, necroptosis, pyroptosis, and ferroptosis. Understanding the molecular mechanisms in PCD during stem cell transplantation and targeting cell death signaling pathways are vital to successful stem cell therapies. In this review, we highlight the research advances in PCD mechanisms that guide the development of multiple strategies to prevent the loss of stem cells and discuss promising implications for improving stem cell therapy in diabetes and diabetes-related diseases.

    View details for DOI 10.3389/fcell.2021.809656

    View details for PubMedID 34977045

    View details for PubMedCentralID PMC8717932

  • The Retrotransposition of L1 is Involved in the Reconsolidation of Contextual Fear Memory in Mice. CNS & neurological disorders drug targets Zhang, W. J., Huang, Y. Q., Fu, A., Chen, K. Z., Li, S. J., Zhang, Q., Zou, G. J., Liu, Y., Su, J. Z., Zhou, S. F., Liu, J. W., Li, F., Bi, F. F., Li, C. Q. 2021; 20 (3): 273-284


    The long interspersed element-1 (L1) participates in memory formation, and DNA methylation patterns of L1 may suggest resilience or vulnerability factors for Post-Traumatic Stress Disorder (PTSD), of which the principal manifestation is a pathological exacerbation of fear memory. However, the unique roles of L1 in the reconsolidation of fear memory remain poorly understood.The study aimed to investigate the role of L1 in the reconsolidation of context-dependent fear memory.Mice underwent fear conditioning and fear recall in the observation chambers. Fear memory was assessed by calculating the percentage of time spent freezing in 5 min. The medial prefrontal cortex (mPFC) and hippocampus were removed for further analysis. Open Reading Frame 1 (ORF1) mRNA and ORF2 mRNA of L1 were analyzed by real-time quantitative polymerase chain reaction. After reactivation of fear memory, lamivudine was administered and its effects on fear memory reconsolidation were observed.ORF1 and ORF2 mRNA expressions in the mPFC and hippocampus after recent (24 h) and remote (14 days) fear memory recall exhibited augmentation via different temporal and spatial patterns. Reconsolidation of fear memory was markedly inhibited in mice treated with lamivudine, which could block L1. DNA methyltransferase mRNA expression declined following lamivudine treatment in remote fear memory recall.The retrotransposition of L1 participated in the reconsolidation of fear memory after reactivation of fear memory, and with lamivudine treatment, spontaneous recovery decreased with time after recent and remote fear memory recall, providing clues for understanding the roles of L1 in fear memory.

    View details for DOI 10.2174/1871527319666200812225509

    View details for PubMedID 32787766

  • Regulatory Role of Chinese Herbal Medicine in Regulated Neuronal Death. CNS & neurological disorders drug targets Wu, X., Hu, X., Zhang, Q., Liu, F., Xiong, K. 2021; 20 (3): 228-248


    Ischemic neuronal injury results from a complex series of pathophysiological events, including oxidative, excitotoxicity, inflammation and nitrative stress. Consequently, many of these events can induce cell death, including necrosis (unregulated cell death) and apoptosis (a type of regulated cell death). These are long-established paradigms to which newly discovered regulated cell death processes have been added, such as necroptosis (a regulated form of necrosis) and autophagydependent cell death. Moreover, many researchers have targeted products associated with Chinese herbal medicine at regulated pathways for the treatment of ischemic neuronal injury. In East Asia, these drugs have been known for centuries to protect and improve the nervous system. Herbal extracts, especially those used in Chinese herbal medicine, have emerged as new pharmaceuticals for the treatment of ischemic neuronal injury. Here, we review the evidence from preclinical studies investigating the neuroprotective properties and therapeutic application of Chinese herbal medicines (Chinese herbal monomer, extract, and medicinal compounds) and highlight the potential mechanisms underlying their therapeutic effects via targeting differently regulated cell death pathways. Notably, many herbs have been shown to target multiple mechanisms of regulated cell death and, in combination, may exert synergistic effects on signaling pathways, thereby attenuating multiple aspects of ischemic pathology. In this review, we summarize a generally regulated pathway of cell death as a target for novel natural herbal regimens against ischemic neuronal injury.

    View details for DOI 10.2174/1871527319666200730165011

    View details for PubMedID 32744977

  • Research trends, hot spots and prospects for necroptosis in the field of neuroscience. Neural regeneration research Yan, W. T., Lu, S., Yang, Y. D., Ning, W. Y., Cai, Y., Hu, X. M., Zhang, Q., Xiong, K. 2021; 16 (8): 1628-1637


    There are two types of cell death-apoptosis and necrosis. Apoptosis is cell death regulated by cell signaling pathways, while necrosis has until recently been considered a passive mechanism of cell death caused by environmental pressures. However, recent studies show that necrosis can also be regulated by specific cell signaling pathways. This mode of death, termed necroptosis, has been found to be related to the occurrence and development of many diseases. We used bibliometrics to analyze the global output of literature on necroptosis in the field of neuroscience published in the period 2007-2019 to identify research hotspots and prospects. We included 145 necroptosis-related publications and 2239 references published in the Web of Science during 2007-2019. Visualization analysis revealed that the number of publications related to necroptosis has increased year by year, reaching a peak in 2019. China is the country with the largest number of publications. Key word and literature analyses demonstrated that mitochondrial function change, stroke, ischemia/reperfusion and neuroinflammation are likely the research hotspots and future directions of necroptosis research in the nervous system. The relationship between immune response-related factors, damage-associated molecular patterns, pathogen-associated molecular patterns and necroptosis may become a potential research hotspot in the future. Taken together, our findings suggest that although the inherent limitations of bibliometrics may affect the accuracy of the literature-based prediction of research hotspots, the results obtained from the included publications can provide a reference for the study of necroptosis in the field of neuroscience.

    View details for DOI 10.4103/1673-5374.303032

    View details for PubMedID 33433494

    View details for PubMedCentralID PMC8323674

  • The Role of HSP90α in Methamphetamine/Hyperthermia-Induced Necroptosis in Rat Striatal Neurons. Frontiers in pharmacology Liao, L. S., Lu, S., Yan, W. T., Wang, S. C., Guo, L. M., Yang, Y. D., Huang, K., Hu, X. M., Zhang, Q., Yan, J., Xiong, K. 2021; 12: 716394


    Methamphetamine (METH) is one of the most widely abused synthetic drugs in the world. The users generally present hyperthermia (HT) and psychiatric symptoms. However, the mechanisms involved in METH/HT-induced neurotoxicity remain elusive. Here, we investigated the role of heat shock protein 90 alpha (HSP90α) in METH/HT (39.5°C)-induced necroptosis in rat striatal neurons and an in vivo rat model. METH treatment increased core body temperature and up-regulated LDH activity and the molecular expression of canonical necroptotic factors in the striatum of rats. METH and HT can induce necroptosis in primary cultures of striatal neurons. The expression of HSP90α increased following METH/HT injuries. The specific inhibitor of HSP90α, geldanamycin (GA), and HSP90α shRNA attenuated the METH/HT-induced upregulation of receptor-interacting protein 3 (RIP3), phosphorylated RIP3, mixed lineage kinase domain-like protein (MLKL), and phosphorylated MLKL. The inhibition of HSP90α protected the primary cultures of striatal neurons from METH/HT-induced necroptosis. In conclusion, HSP90α plays an important role in METH/HT-induced neuronal necroptosis and the HSP90α-RIP3 pathway is a promising therapeutic target for METH/HT-induced neurotoxicity in the striatum.

    View details for DOI 10.3389/fphar.2021.716394

    View details for PubMedID 34349659

    View details for PubMedCentralID PMC8326403

  • Extracellular vesicles derived from mesenchymal stem cells: A platform that can be engineered. Histology and histopathology Qin, B., Zhang, Q., Chen, D., Yu, H. Y., Luo, A. X., Suo, L. P., Cai, Y., Cai, D. Y., Luo, J., Huang, J. F., Xiong, K. 2021; 36 (6): 615-632


    Mesenchymal stem cells play an important role in tissue damage and repair. This role is mainly due to a paracrine mechanism, and extracellular vesicles (EVs) are an important part of the paracrine function. EVs play a vital role in many aspects of cell homeostasis, physiology, and pathology, and EVs can be used as clinical biomarkers, vaccines, or drug delivery vehicles. A large number of studies have shown that EVs derived from mesenchymal stem cells (MSC-EVs) play an important role in the treatment of various diseases. However, the problems of low production, low retention rate, and poor targeting of MSC-EVs are obstacles to current clinical applications. The engineering transformation of MSC-EVs can make up for those shortcomings, thereby improving treatment efficiency. This review summarizes the latest research progress of MSC-EV direct and indirect engineering transformation from the aspects of improving MSC-EV retention rate, yield, targeting, and MSC-EV visualization research, and proposes some feasible MSC-EV engineering methods of transformation.

    View details for DOI 10.14670/HH-18-297

    View details for PubMedID 33398872

    View details for PubMedCentralID PMC6531310

  • Programmed cell death in stem cell-based therapy: Mechanisms and clinical applications. World journal of stem cells Hu, X. M., Zhang, Q., Zhou, R. X., Wu, Y. L., Li, Z. X., Zhang, D. Y., Yang, Y. C., Yang, R. H., Hu, Y. J., Xiong, K. 2021; 13 (5): 386-415


    Stem cell-based therapy raises hopes for a better approach to promoting tissue repair and functional recovery. However, transplanted stem cells show a high death percentage, creating challenges to successful transplantation and prognosis. Thus, it is necessary to investigate the mechanisms underlying stem cell death, such as apoptotic cascade activation, excessive autophagy, inflammatory response, reactive oxygen species, excitotoxicity, and ischemia/hypoxia. Targeting the molecular pathways involved may be an efficient strategy to enhance stem cell viability and maximize transplantation success. Notably, a more complex network of cell death receives more attention than one crucial pathway in determining stem cell fate, highlighting the challenges in exploring mechanisms and therapeutic targets. In this review, we focus on programmed cell death in transplanted stem cells. We also discuss some promising strategies and challenges in promoting survival for further study.

    View details for DOI 10.4252/wjsc.v13.i5.386

    View details for PubMedID 34136072

    View details for PubMedCentralID PMC8176847

  • c-FLIP regulates pyroptosis in retinal neurons following oxygen-glucose deprivation/recovery via a GSDMD-mediated pathway. Annals of anatomy = Anatomischer Anzeiger : official organ of the Anatomische Gesellschaft Huang, Y., Wang, S., Huang, F., Zhang, Q., Qin, B., Liao, L., Wang, M., Wan, H., Yan, W., Chen, D., Liu, F., Jiang, B., Ji, D., Xia, X., Huang, J., Xiong, K. 2021; 235: 151672


    Cellular FLICE-inhibitory protein (c-FLIP), an anti-apoptotic regulator, shows remarkable similarities to caspase-8, which plays a key role in the cleavage of gasdermin D (GSDMD). It has been reported that the oxygen-glucose deprivation/recovery (OGD/R) model and lipopolysaccharide (LPS)/adenosine triphosphate (ATP) treatment could induce inflammation and pyroptosis. However, the regulatory role of c-FLIP in the pyroptotic death of retinal neurons is unclear. In this study, we hypothesized that c-FLIP might regulate retinal neuronal pyroptosis by GSDMD cleavage. To investigate this hypothesis, we induced retinal neuronal damage in vitro (OGD/R and LPS/ATP) and in vivo (acute high intraocular pressure [aHIOP]). Our results demonstrated that the three injuries triggered the up-regulation of pyroptosis-related proteins, and c-FLIP could cleave GSDMD to generate a functional N-terminal (NT) domain of GSDMD, causing retinal neuronal pyroptosis. In addition, c-FLIP knockdown in vivo ameliorated the already established visual impairment mediated by acute IOP elevation. Taken together, these findings revealed that decreased c-FLIP expression protected against pyroptotic death of retinal neurons possibly by inhibiting GSDMD-NT generation. Therefore, c-FLIP might provide new insights into the pathogenesis of pyroptosis-related diseases and help to elucidate new therapeutic targets and potential treatment strategies.

    View details for DOI 10.1016/j.aanat.2020.151672

    View details for PubMedID 33434657

  • Guidelines for Regulated Cell Death Assays: A Systematic Summary, A Categorical Comparison, A Prospective. Frontiers in cell and developmental biology Hu, X. M., Li, Z. X., Lin, R. H., Shan, J. Q., Yu, Q. W., Wang, R. X., Liao, L. S., Yan, W. T., Wang, Z., Shang, L., Huang, Y., Zhang, Q., Xiong, K. 2021; 9: 634690


    Over the past few years, the field of regulated cell death continues to expand and novel mechanisms that orchestrate multiple regulated cell death pathways are being unveiled. Meanwhile, researchers are focused on targeting these regulated pathways which are closely associated with various diseases for diagnosis, treatment, and prognosis. However, the complexity of the mechanisms and the difficulties of distinguishing among various regulated types of cell death make it harder to carry out the work and delay its progression. Here, we provide a systematic guideline for the fundamental detection and distinction of the major regulated cell death pathways following morphological, biochemical, and functional perspectives. Moreover, a comprehensive evaluation of different assay methods is critically reviewed, helping researchers to make a reliable selection from among the cell death assays. Also, we highlight the recent events that have demonstrated some novel regulated cell death processes, including newly reported biomarkers (e.g., non-coding RNA, exosomes, and proteins) and detection techniques.

    View details for DOI 10.3389/fcell.2021.634690

    View details for PubMedID 33748119

    View details for PubMedCentralID PMC7970050

  • How does temperature play a role in the storage of extracellular vesicles? Journal of cellular physiology Qin, B., Zhang, Q., Hu, X. M., Mi, T. Y., Yu, H. Y., Liu, S. S., Zhang, B., Tang, M., Huang, J. F., Xiong, K. 2020; 235 (11): 7663-7680


    Extracellular vesicles (EVs) contain specific proteins, lipids, and nucleic acids that can be passed to other cells as signal molecules to alter their function. However, there are many problems and challenges in the conversion and clinical application of EVs. Storage and protection of EVs is one of the issues that need further research. To adapt to potential clinical applications, this type of problem must be solved. This review summarizes the storage practices of EVs in recent years, and explains the impact of temperature on the quality and stability of EVs during storage based on current research, and explains the potential mechanisms involved in this effect as much as possible.

    View details for DOI 10.1002/jcp.29700

    View details for PubMedID 32324279

  • Who is willing to donate their bodies in China? Perceptions, attitudes and influencing factors among citizens of Changsha. Annals of anatomy = Anatomischer Anzeiger : official organ of the Anatomische Gesellschaft Zhang, Q., Deng, J., Yan, C., Yan, X. X., Li, F., Pan, A. H. 2020; 229: 151483


    Body donation has far-reaching significance for modern medical research and education. However, body donation in China lags far behind the demand. To assess the perception and attitude toward body donation, a survey of 2535 community residents was conducted in Changsha. The result showed that 89.5% of the respondents have heard about body donation through different sources, such as public media, medical college, and hospital. However, 61.8% of the respondents have limited knowledge of these body donation programs. The majority of respondents believed that body donation would contribute to researches in neuroanatomy, tumor biology, and ophthalmology, as well as anatomical education for medical students, and surgical training for clinicians/surgeons. Regarding the public's willingness to donate, 27.5% of respondents expressed a clear willingness. Further analysis revealed that people aged above 60 are less willing to donate. Compared with people having Confucianism funeral belief, those without the belief were 9.8 times more willing to donate. Furthermore, it was shown that respondents who had a good understanding of body donation were more willing to donate their bodies. Moreover, people thought body donation was beneficial to medical research and education were almost 10 times more willing to donate compared to those who thought it had no benefit. To promote body donation in China, greater efforts need to be made in promoting body donor programs and so increasing the public's perception toward body donation. Moreover, re-assessing and re-interpreting Confucianism beliefs regarding body donation also needs to be considered for future promotion of body donation in China and other East Asian countries.

    View details for DOI 10.1016/j.aanat.2020.151483

    View details for PubMedID 32061836

  • Evaluating phone camera and cloud service-based 3D imaging and printing of human bones for anatomical education. BMJ open Li, Q. Y., Zhang, Q., Yan, C., He, Y., Phillip, M., Li, F., Pan, A. H. 2020; 10 (2): e034900


    To evaluate the feasibility of a phone camera and cloud service-based workflow to image bone specimens and print their three-dimensional (3D) models for anatomical education.The images of four typical human bone specimens, photographed by a phone camera, were aligned and converted into digital images for incorporation into a digital model through the Get3D website and submitted to an online 3D printing platform to obtain the 3D printed models. The fidelity of the 3D digital, printed models relative to the original specimens, was evaluated through anatomical annotations and 3D scanning.The Morphologic Science Experimental Center, Central South University, China.Specimens of four typical bones-the femur, rib, cervical vertebra and skull-were used to evaluate the feasibility of the workflow.The gross fidelity of anatomical features within the digital models and 3D printed models was evaluated first using anatomical annotations in reference to Netter's Atlas of Human Anatomy. The measurements of the deviation were quantised and visualised for analysis in Geomagic Control 2015.All the specimens were reconstructed in 3D and printed using this workflow. The overall morphology of the digital and 3D printed models displayed a large extent of similarity to the corresponding specimens from a gross anatomical perspective. A high degree of similarity was also noticed in the quantitative analysis, with distance deviations ≤2 mm present among 99% of the random sampling points that were tested.The photogrammetric digitisation workflow adapted in the present study demonstrates fairly high precision with relatively low cost and fewer equipment requirements. This workflow is expected to be used in morphological/anatomical science education, particularly in institutions and schools with limited funds or in certain field research projects involving the fast acquisition of 3D digital data on human/animal bone specimens or on other remains.

    View details for DOI 10.1136/bmjopen-2019-034900

    View details for PubMedID 32041863

    View details for PubMedCentralID PMC7044880

  • Regional and Cellular Mapping of Sortilin Immunoreactivity in Adult Human Brain. Frontiers in neuroanatomy Xu, S. Y., Zhang, Q. L., Zhang, Q., Wan, L., Jiang, J., Tu, T., Manavis, J., Pan, A., Cai, Y., Yan, X. X. 2019; 13: 31


    Sortilin is a member of the vacuolar protein sorting 10 protein (VPS10P) domain receptor family, which carries out signal transduction and protein transport in cells. Sortilin serves as the third, G-protein uncoupled, receptor of neurotensin that can modulate various brain functions. More recent data indicate an involvement of sortilin in mood disorders, dementia and Alzheimer-type neuropathology. However, data regarding the normal pattern of regional and cellular expression of sortilin in the human brain are not available to date. Using postmortem adult human brains free of neuropathology, the current study determined sortilin immunoreactivity (IR) across the entire brain. Sortilin IR was broadly present in the cerebrum and subcortical structures, localizing to neurons in the somatodendritic compartment, but not to glial cells. In the cerebrum, sortilin IR exhibited differential regional and laminar patterns, with pyramidal, multipolar and polymorphic neurons in cortical layers II-VI, hippocampal formation and amygdaloid complex more distinctly labeled relative to GABAergic interneurons. In the striatum and thalamus, numerous small-to-medium sized neurons showed light IR, with a small group of large sized neurons heavily labeled. In the midbrain and brainstem, sortilin IR was distinct in neurons at the relay centers of descending and ascending neuroanatomical pathways. Dopaminergic neurons in the substantia nigra, cholinergic neurons in the basal nuclei of Meynert and noradrenergic neurons in the locus coeruleus co-expressed strong sortilin IR in double immunofluorescence. In comparison, sortilin IR was weak in the olfactory bulb and cerebellar cortex, with the mitral and Purkinje cells barely visualized. A quantitative analysis was carried out in the lateral, basolateral, and basomedial nuclei of the amygdaloid complex, as well as cortical layers II-VI, which established a positive correlation between the somal size and the intensity of sortilin IR among labeled neurons. Together, the present study demonstrates a predominantly neuronal expression of sortilin in the human brain with substantial regional and cell-type variability. The enriched expression of sortilin in pyramidal, dopaminergic, noradrenergic and cholinergic neurons suggests that this protein may be particularly required for signal transduction, protein trafficking and metabolic homeostasis in populations of relatively large-sized projective neurons.

    View details for DOI 10.3389/fnana.2019.00031

    View details for PubMedID 30914927

    View details for PubMedCentralID PMC6422922

  • A shortage of cadavers: The predicament of regional anatomy education in mainland China. Anatomical sciences education Chen, D., Zhang, Q., Deng, J., Cai, Y., Huang, J., Li, F., Xiong, K. 2018; 11 (4): 397-402


    Both in mainland China and around the world, regional anatomy stands as one of the most important basic science courses in medical school curricula. As such, dissection of human cadavers and use of prosected specimens remains the most essential teaching method in anatomy education. However, medical educators have raised increasing concerns about an ongoing shortage of cadavers for medical use in mainland China, a problem which may seriously limit the future development of human anatomy education. Based on a survey on cadaver usage in anatomy education in mainland China, this study found that the cadaver resources of most given medical schools in mainland China are associated with their geographic location, academic ranking, and local support for body donation policies. Effective measures to alleviate this shortage of cadavers may include future efforts to promote national-level body donation legislation, broader acceptance of body donation among Chinese citizens, and an efficient and humane protocol for body donation. Anat Sci Educ 11: 397-402. © 2018 American Association of Anatomists.

    View details for DOI 10.1002/ase.1788

    View details for PubMedID 29648678

  • Rice and cold stress: methods for its evaluation and summary of cold tolerance-related quantitative trait loci. Rice (New York, N.Y.) Zhang, Q., Chen, Q., Wang, S., Hong, Y., Wang, Z. 2014; 7 (1): 24


    Cold stress adversely affects rice (Oryza sativa L.) growth and productivity, and has so far determined its geographical distribution. Dissecting cold stress-mediated physiological changes and understanding their genetic causes will facilitate the breeding of rice for cold tolerance. Here, we review recent progress in research on cold stress-mediated physiological traits and metabolites, and indicate their roles in the cold-response network and cold-tolerance evaluation. We also discuss criteria for evaluating cold tolerance and evaluate the scope and shortcomings of each application. Moreover, we summarize research on quantitative trait loci (QTL) related to cold stress at the germination, seedling, and reproductive stages that should provide useful information to accelerate progress in breeding cold-tolerant rice.

    View details for DOI 10.1186/s12284-014-0024-3

    View details for PubMedID 25279026

    View details for PubMedCentralID PMC4182278