Advances in the research of cytokine storm mechanism induced by Corona Virus Disease 2019 and the corresponding immunotherapies / 中华烧伤杂志

Corona Virus Disease 2019 (COVID-19) has seriously affected the treatment of patients and social stability. In the later stage of disease, some COVID-19 patients may develop into acute respiratory distress syndrome or even multiple organ failure. However, one of the most important mechanism underlying the deterioration of disease is cytokine storm. At present, some therapies such as interleukin-6 antibody blocker, stem cell therapy, and transfusion of convalescent plasma have been applied to counteract the cytokine storm and have made some progress. This article reviews the influences of cytokine storm syndrome on the COVID-19 and the corresponding immunotherapies to resist cytokine storm.

CXCL-13 Regulates Resistance to 5-Fluorouracil in Colorectal Cancer / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#5-Fluorouracil (5-Fu) is used as a conventional chemotherapy drug in chemotherapy forpatients with advanced colorectal cancer, but many patients still suffer from treatment failuredue to 5-Fu resistance. Emerging observations revealed the important role of chemokine(C-X-C motif) ligand 13 (CXCL-13) in tumor microenvironment and its relationship with prognosisin patients with colorectal cancer. This study is designed to reveal the important roleof CXCL-13 in causing colorectal cancer resistance to 5-Fu. @*Materials and Methods@#CXCL-13 levels of patient's serum or cell culture supernatants were measured separatelyby enzyme-linked immunosorbent assay. In cell assays, cell viability is detected by Cell CountingKit-8. Therefore, the recombinant human CXCL-13 was used to simulate its high expressionin cells while its antibody and siRNA were used to reduce CXCL-13 expression in cells. @*Results@#In this study, we demonstrated that CXCL-13 is associated with 5-Fu resistance by culturemedium exchange experiments and cytokine arrays of colorectal cancer resistant and nonresistantcells. Clinical studies showed that CXCL-13 is highly expressed in the serum of5-Fu–resistant patients. High levels of serum CXCL-13 also predict a worse clinical outcome.The addition of recombinant CXCL-13 cytokine resulted in 5-Fu resistance, while its antibodyovercame 5-Fu resistance, and knockdown of CXCL-13 expression by siRNA also reduced5-Fu resistance, which can be saved by added recombination CXCL-13. @*Conclusion@#These results not only identify a CXCL-13 mediated 5-Fu resistance mechanism but alsoprovide a novel target for 5-Fu–resistant colorectal cancer in prevention and treatmentstrategies.

Chemical screen identifies a geroprotective role of quercetin in premature aging

Aging increases the risk of various diseases. The main goal of aging research is to find therapies that attenuate aging and alleviate aging-related diseases. In this study, we screened a natural product library for geroprotective compounds using Werner syndrome (WS) human mesenchymal stem cells (hMSCs), a premature aging model that we recently established. Ten candidate compounds were identified and quercetin was investigated in detail due to its leading effects. Mechanistic studies revealed that quercetin alleviated senescence via the enhancement of cell proliferation and restoration of heterochromatin architecture in WS hMSCs. RNA-sequencing analysis revealed the transcriptional commonalities and differences in the geroprotective effects by quercetin and Vitamin C. Besides WS hMSCs, quercetin also attenuated cellular senescence in Hutchinson-Gilford progeria syndrome (HGPS) and physiological-aging hMSCs. Taken together, our study identifies quercetin as a geroprotective agent against accelerated and natural aging in hMSCs, providing a potential therapeutic intervention for treating age-associated disorders.

CRISPR/Cas9-mediated gene knockout reveals a guardian role of NF-κB/RelA in maintaining the homeostasis of human vascular cells

Vascular cell functionality is critical to blood vessel homeostasis. Constitutive NF-κB activation in vascular cells results in chronic vascular inflammation, leading to various cardiovascular diseases. However, how NF-κB regulates human blood vessel homeostasis remains largely elusive. Here, using CRISPR/Cas9-mediated gene editing, we generated RelA knockout human embryonic stem cells (hESCs) and differentiated them into various vascular cell derivatives to study how NF-κB modulates human vascular cells under basal and inflammatory conditions. Multi-dimensional phenotypic assessments and transcriptomic analyses revealed that RelA deficiency affected vascular cells via modulating inflammation, survival, vasculogenesis, cell differentiation and extracellular matrix organization in a cell type-specific manner under basal condition, and that RelA protected vascular cells against apoptosis and modulated vascular inflammatory response upon tumor necrosis factor α (TNFα) stimulation. Lastly, further evaluation of gene expression patterns in IκBα knockout vascular cells demonstrated that IκBα acted largely independent of RelA signaling. Taken together, our data reveal a protective role of NF-κB/RelA in modulating human blood vessel homeostasis and map the human vascular transcriptomic landscapes for the discovery of novel therapeutic targets.

Gadd45a deletion aggravates hematopoietic stem cell dysfunction in ATM-deficient mice

Ataxia telangiectasia mutated (ATM) kinase plays an essential role in the maintenance of genomic stability. ATM-deficient (ATM(-/-)) mice exhibit hematopoietic stem cell (HSC) dysfunction and a high incidence of lymphoma. Gadd45a controls cell cycle arrest, apoptosis and DNA repair, and is involved in the ATM-p53 mediated DNA damage response. However, the role of Gadd45a in regulating the functionality of ATM(-/-) HSCs is unknown. Here we report that Gadd45a deletion did not rescue the defects of T-cells and B-cells development in ATM(-/-) mice. Instead, ATM and Gadd45a double knockout (ATM(-/-) Gadd45a(-/-)) HSCs exhibited an aggravated defect in long-term self-renewal capacity compared to ATM(-/-) HSCs in HSC transplantation experiments. Further experiments revealed that the aggravated defect of ATM(-/-) Gadd45a(-/-) HSCs was due to a reduction of cell proliferation, associated with an accumulation of DNA damage and subsequent activation of DNA damage response including an up-regulation of p53-p21 signaling pathway. Additionally, ATM(-/-) Gadd45a(-/-) mice showed an increased incidence of hematopoietic malignancies, as well as an increased rate of metastasis than ATM(-/-) mice. In conclusion, Gadd45a deletion aggravated the DNA damage accumulation, which subsequently resulted in a further impaired self-renewal capacity and an increased malignant transformation in ATM(-/-) HSCs.