Symmetrical peripheral gangrene: potential mechanisms and therapeutic approaches in severe COVID-19.

Symmetrical peripheral gangrene is a rare condition that is characterized by ischemic damage and tissue death (gangrene) in the extremities. Recent reports have shed light on SPG in patients with severe COVID-19. This condition presents with symmetrical cyanosis of the extremities and common COVID-19 symptoms and what the most frightening is within a few days, cutaneous necrosis occurred and patients died. Skin biopsy results have shown the presence of microthrombi in small vessels. The formation of SPG in COVID-19 patients results from immunothrombosis, endothelial dysfunction, and procoagulant platelets, leading to a hypercoagulation state and microvascular thrombosis. Thrombotic microangiopathy, shock, disseminated intravascular coagulation, and anticoagulant depletion promote the development of SPG in COVID-19. At the early stage, SPG patients with COVID-19 exhibit similar clinical manifestations. TMA causes early damage to microvasculature in SPG, and the shock state further exacerbates the ischemic injury due to local hypo-perfusion. The disturbed procoagulant-anticoagulant balance caused by DIC and anticoagulant depletion, combined with the pre-ischemic state brought on by TMA and shock, leads to the rapid formation of extensive microthrombi in the late stage of COVID-19 associated SPG. This review will delve into the clinical features, possible mechanisms, and potential therapeutic managements for COVID-19 associated SPG.

Complement factor H inhibits endothelial cell migration through suppression of STAT3 signaling.

Complement factor H (CFH), a major soluble inhibitor of complement, is a plasma protein that directly interacts with the endothelium of blood vessels. Mutations in the CFH gene lead to diseases associated with excessive angiogenesis; however, the underlying mechanisms are unknown. The present study aimed to determine the effects of CFH on endothelial cells and to explore the underlying mechanisms. The adenoviral plasmid expressing CFH was transduced into HepG2 cells, and the culture medium supernatant was collected and co-cultured with human umbilical vein endothelial cells (HUVECs). Cell proliferation was measured by CCK8 and MTT assays, and cell migration was measured by wound healing and Transwell assays. Reverse transcription-quantitative PCR was performed to detect gene transcription. Western blotting was used to determine protein levels. The results revealed that CFH can inhibit migration, but not viability, of HUVECs. In addition, CFH did not significantly alter MAPK or TGF-ß signaling, whereas it decreased STAT3 phosphorylation in HUVECs. Furthermore, CFH failed to reduce migration of HUVECs, with inhibition of STAT3 signaling by STATTIC or activation of STAT3 signaling by overexpression of STAT3 (Y705D) compromising CFH-inhibited HUVEC migration. CFH also decreased the expression levels of vascular endothelial growth factor receptor 2, a downstream effector of STAT3 mediating endothelial cell migration. In conclusion, the present study suggested that CFH may be a potential therapeutic target for angiogenesis-related diseases.

Curdlan sulfate/O-linked quaternized chitosan nanoparticles acting as potential adjuvants promote multiple arms of immune responses.

Nasal immunization to prevent and treat diseases caused by infection through the respiratory tract cannot be actualized because of the lack of effective adjuvants. We have proven that compared with antigens loaded on CS or O-HTCC alone in nasal vaccination, antigens loaded on the nanoparticles of curdlan sulfate/O-(2-hydroxyl) propyl-3-trimethyl ammonium chitosan chloride (CS/O-HTCC) can induce stronger systemic and mucosal immune responses. In this study, we evaluated the immunostimulatory activity and mechanisms of CS/O-HTCC nanoparticles. The results showed that CS/O-HTCC nanoparticles can improve the activation of antigen-presenting cells, upregulate the production of inflammatory factors and cytokines, induce cross-presentation, and simultaneously activate type I interferon-related genes. CS/O-HTCC nanoparticles also activated the PI3K/AKT and MAPK pathways and significantly promoted IL-2 transcription to induce the proliferation of lymphocytes. The results revealed that CS/O-HTCC nanoparticles as a type of multifunctional adjuvant can improve multiple arms of immune responses.

Tunicamycin potentiates paclitaxel-induced apoptosis through inhibition of PI3K/AKT and MAPK pathways in breast cancer.

PURPOSE: Paclitaxel has been reported to upregulate both AKT and MAPK signaling pathways and thereby compromises its antitumor efficacy. However, tunicamycin has the ability to downregulate AKT and MAPK pathways. The aim of the study is to investigate the antitumor activity of the combination treatment of paclitaxel with tunicamycin and the mechanisms involving the changes of antitumor efficacy. METHODS: Sulforhodamine B (SRB) assay was used to examine the cell viability upon treatment of breast cancer cells with paclitaxel, tunicamycin and the combination of both. Cell cycle distributions and apoptosis were detected by flow cytometry. Western blotting and immunofluorescence staining were used to analyze the effect of drugs on tubulin polymerization. The antitumor growth of combined treatment was measured in nude mice bearing MDA-MB-231 xenograft. Western blotting was performed to explore the alteration of AKT and MAPK pathways in vitro and in vivo. RESULTS: SRB assay and nude mice experiment showed that tunicamycin synergistically enhanced paclitaxel-induced inhibition of cell proliferation and tumor growth. Tunicamycin had no clear effect on paclitaxel-induced cell cycle arrest, demonstrating that cell cycle distribution was not involved in the enhanced antitumor activity. Both annexin V-FITC/propidium iodide assay and TUNEL assay indicated that the combination of tunicamycin with paclitaxel resulted in significant increased cell apoptosis as compared with individual treatment in vitro and in vivo. Tunicamycin decreased paclitaxel-induced microtubulin polymerization, suggesting that enhanced antitumor effect of paclitaxel was not dependent of microtubulin polymerization. Western blotting analysis confirmed that tunicamycin decreased paclitaxel-induced upregulation of survival signal pathways such as AKT and MAPK. CONCLUSION: These results revealed that tunicamycin synergistically enhanced the antitumor effects of paclitaxel through potentiating apoptosis via inhibiting paclitaxel-induced elevation of AKT and MAPK pathways. This study raised the possibility that the combination of paclitaxel with tunicamycin may be a promising approach for improving the clinical activity of paclitaxel.

Tunicamycin enhances the antitumor activity of trastuzumab on breast cancer in vitro and in vivo.

Trastuzumab, a humanized monoclonal antibody targeting HER2, has demonstrated clinical benefits for women with HER2-positive breast cancer; however, trastuzumab resistance remains the biggest clinical challenge. In this study, results showed that tunicamycin, an inhibitor of N-glycosylation, synergistically enhanced the antitumor activity of trastuzumab against HER2-overexpressing breast cancer cells through induction of cell cycle arrest and apoptosis. Combined treatment of tunicamycin with trastuzumab dramatically decreased the expression of EGFR family and its down signaling pathway in SKBR3 and MCF-7/HER2 cells. Tunicamycin dose-dependently inhibited tumor growth in both of SKBR3 xenografts and MCF-7/HER2 xenografts. Optimal tunicamycin without inducing ER stress in liver tissue significantly increased the antitumor effect of trastuzumab in MCF-7/HER2 xenografts. Combinations of trastuzumab with N-glycosylation inhibitors tunicamycin may be a promising approach for improving clinical efficacy of trastuzumab.