Shark Cartilage-Derived Anti-Angiogenic Peptide Inhibits Corneal Neovascularization.

Corneal neovascularization is a significant cause of vision loss, often resulting in corneal clouding and chronic inflammation. Shark cartilage is widely recognized as a significant natural source of anti-angiogenic compounds. Our previous studies have shown that a polypeptide from white-spotted catshark (Chiloscyllium plagiosum Bonnet) has the potential to inhibit the angiogenesis of breast tumors. This study applied this peptide (SAIF) to a corneal alkali injury model to assess its effect on corneal neovascularization. Results revealed that SAIF inhibits endothelial cell proliferation, migration, and tube formation. SAIF inhibited VEGF-induced angiogenesis in the matrigel plug. Using the corneal alkali injury model, SAIF significantly inhibited corneal vascular neovascularization in mice. We found that SAIF not only significantly inhibited the upregulation of pro-angiogenic factors such as VEGF, bFGF, and PDGF expression induced by alkali injury, but also promoted the expression of anti-angiogenesis factor PEDF. Moreover, we also analyzed the MMPs and TIMPs involved in extracellular matrix (ECM) remodeling, angiogenesis, and lymphangiogenesis. We found that SAIF treatment inhibited the expression of pro-angiogenic factors like MMP1, MMP2, MMP3, MMP9, MMP13, and MMP14, and promoted the expression of anti-angiogenesis factors such as MMP7, TIMP1, TIMP2, and TIMP3. In conclusion, SAIF acts as an anti-angiogenic factor to inhibit the proliferation, migration, and tube formation of endothelial cells, inhibit pro-angiogenic factors, promote anti-angiogenic factors, and regulate the expression of MMPs, ultimately inhibiting corneal neovascularization.

Promotion of ICD via Nanotechnology.

Immunotherapy represents the most promising treatment strategy for cancer, but suffers from compromised therapeutic efficiency due to low immune activity of tumor cells and an immunosuppressive microenvironment, which significantly hampers the clinical translations of this treatment strategy. To promote immunotherapy with desired therapeutic efficiency, immunogenic cell death (ICD), a particular type of death capable of reshaping body's antitumor immune activity, has drawn considerable attention due to the potential to stimulate a potent immune response. Still, the potential of ICD effect remains unsatisfactory because of the intricate tumor microenvironment and multiple drawbacks of the used inducing agents. ICD has been thoroughly reviewed so far with a general classification of ICD as a kind of immunotherapy strategy and repeated discussion of the related mechanism. However, there are no published reviews, to the authors' knowledge, providing a systematic summarization on the enhancement of ICD via nanotechnology. For this purpose, this review first discusses the four stages of ICD according to the development mechanisms, followed by a comprehensive description on the use of nanotechnology to enhance ICD in the corresponding four stages. The challenges of ICD inducers and possible solutions are finally summarized for future ICD-based enhanced immunotherapy.

Recombinant Expression of Human IL-33 Protein and Its Effect on Skin Wound Healing in Diabetic Mice.

Chronic refractory wounds are one of the complications of diabetes mellitus that require effective therapy. The dermal-wound-healing property of IL-33 in diabetics is little understood. Therefore, this study aimed to express recombinant humanized mature IL-33 (rhmatIL-33) in Escherichia coli BL21 (DE3) and demonstrate its efficacy on dermal wounds in streptozotocin (STZ)-induced diabetic and nondiabetic mice by the dorsal incisional skin wound model. Results revealed that the rhmatIL-33 accelerated the scratch-healing of keratinocytes and fibroblasts at the cellular level. The wounds of diabetic mice (DM) showed more severe ulceration and inflammation than wild-type mice (WT), and the exogenous administration of rhmatIL-33 increased wound healing in both diabetic and wild-type mice. Compared with the up-regulation of endogenous IL-33 mRNA after injury in WT mice, the IL-33 mRNA decreased after injury in DM mice. Exogenous IL-33 administration increased the endogenous IL-33 mRNA in the DM group but decreased the IL-33 mRNA expression level of the WT group, indicating that IL-33 plays a balancing role in wound healing. IL-33 administration also elevated ILC2 cells in the wounds of diabetic and non-diabetic mice and improve the transcript levels of YM1, a marker of M2 macrophages. In conclusion, Hyperglycemia in diabetic mice inhibited the expression of IL-33 in the dermal wound. Exogenous addition of recombinant IL-33 promoted wound healing in diabetic mice by effectively increasing the level of IL-33 in wound tissue, increasing ILC2 cells, and accelerating the transformation of macrophage M1 to M2 phenotype.

An integrated transcriptomic and metabolomic analysis for changes in rose plant induced by rose powdery mildew and exogenous salicylic acid.

We explored the transcriptomic and metabolomic changes in Rosa chinensis after the infection with Podosphaera pannosa and after the treatment with exogenous salicylic acid (SA), separately. The rose responses to the mildew-infection were clearly similar to the responses to the SA-treatment. Based on the combined omics analysis, after the induction by both P. pannosa and SA, R. chinensis responded consistently by MAPK cascades, plant-pathogen interaction pathway activation, and resistance (R) genes expression, and further, triterpenoid biosynthesis, glutathione metabolism, and linoleic acid metabolism were significantly enriched when compared with the control. The levels of the triterpenoids with the largest fold change values were significantly up-regulated such as dehydro (11,12) ursolic acid lactone and maslinic acid, suggesting that these pathways and metabolites were involved in the resistance to P. pannosa. The contents of salicylic acid beta-D-glucoside, methyl salicylate, and methyl jasmonate increased significantly resulting from both P. pannosa-infection and exogenous SA-treatment.

HTR7 promotes laryngeal cancer growth through PI3K/AKT pathway activation.

BACKGROUND: Laryngeal cancer is a common malignancy of the head and neck, it's important to find novel targets for its therapy. The 5-hydroxytryptamine receptor 7 (HTR7) belongs to the G protein-coupled receptors (GPCRs) family which are easily druggable in diseases; however, its role in laryngeal cancer remains unknown. METHODS: Colony formation assay, Soft agar growth assay, BrdU incorporation assay and MTT assay were used to analyze the effect of HTR7 on laryngeal cancer cell proliferation. Xenograft tumors in nude mice was used to analyze the effect of HTR7 on laryngeal cancer growth. Luciferase reporter assay was used to analyze the effect of HTR7 on phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT) pathway activity. RESULTS: We found that HTR7 was significantly upregulated in laryngeal cancer tissues and cells, and patients with high HTR7 expression had shorter survival time than those with low HTR7 expression. Univariate and multivariate Cox regression models showed that HTR7 was an independent predictive factor for the prognosis of patients with laryngeal cancer. Cell proliferation assays and an animal model showed that HTR7 overexpression promoted laryngeal cancer proliferation and growth, while HTR7 knockdown inhibited laryngeal cancer proliferation and growth. Further analysis showed HTR7 activated the PI3K/AKT pathway, characterized by increased phosphorylation of AKT, luciferase reporter activity of forkhead box O (FOXO) factors, and target expression. Inhibition of the PI3K/AKT pathway in HTR7-overexpressing cells suppressed proliferation and growth, suggesting that HTR7 promotes laryngeal cancer proliferation and growth by activating the PI3K/AKT pathway. CONCLUSIONS: HTR7 is not only a target for laryngeal cancer therapy but also a prognostic factor for the prognosis of patients with laryngeal cancer.

PLOD2 contributes to drug resistance in laryngeal cancer by promoting cancer stem cell-like characteristics.

BACKGROUND: Advanced stage laryngeal squamous cell carcinoma (LSCC) presents a poor prognosis; thus, there is a great need to identify novel prognostic molecular markers. Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) is thought to be a novel prognostic factor in several cancers, but its role in LSCC remains unknown. Cancer stem cells (CSCs) are responsible for most instances of tumor recurrence and the development of drug resistance and have been proven to be present in head and neck cancers. Our preliminary study indicated that PLOD2 was elevated in LSCC tissues; therefore, we hypothesized that PLOD2 is related to the prognosis of LSCC patients and aimed to explore the role and underlying mechanism of PLOD2 in LSCC. METHODS: We validated the prognostic role of PLOD2 in 114 LSCC patients by immunohistochemistry. Stable PLOD2-overexpressing Hep-2 and FaDu cells were established and assessed by molecular biology and biochemistry methods both in vitro and in vivo. RESULTS: We confirmed that PLOD2 overexpression was correlated with poor prognosis in LSCC patients. PLOD2 overexpression strengthened the CSC-like properties of Hep-2 and FaDu cells, activated the Wnt signaling pathway and conferred drug resistance in LSCC in vitro and in vivo. CONCLUSIONS: We found that PLOD2 could serve as a prognostic marker in patients with LSCC and confer drug resistance in LSCC by increasing CSC-like traits; in addition, a Wnt-responsive CSC pathway was identified.

Therapeutic efficacy of combined BRAF and MEK inhibition in metastatic melanoma: a comprehensive network meta-analysis of randomized controlled trials.

BACKGROUND: Several recent randomized clinical trials have preliminarily demonstrated that initial targeted therapy with combined BRAF and MEK inhibition is more effective in metastatic melanoma (MM) than single agent. To guide therapeutic decisions, we did a comprehensive network meta-analysis to identify evidence to robustly support whether combined BRAF and MEK inhibition is the best initial targeted therapeutic strategy for patients with MM. METHODS: The databases of PubMed and trial registries were researched for randomized clinical trials of targeted therapy. Data of outcome were extracted on progression-free survival (PFS), objective response rate (ORR), and overall survival (OS). Network meta-analysis using a Bayesian statistical model was performed to evaluate relative hazard ratio (HR) for PFS and OS, odds ratio (OR) for ORR. RESULTS: Finally, 16 eligible trials comprising 5976 participants were included in this meta-analysis. PFS were significantly prolonged in patients who received combined BRAF-MEK inhibition compared with those who received BRAF inhibition (HR: 0.58, 95%CI: 0.51-0.67, P < 0.0001) or MEK inhibition alone (HR: 0.29, 95%CI: 0.22-0.37, P < 0.0001). Combined BRAF-MEK inhibition also improved the OS over BRAF inhibition (HR: 0.67, 95%CI: 0.56-0.81, P < 0.0001) or MEK inhibition alone (HR: 0.48, 95%CI: 0.36-0.65, P < 0.0001). The ORR was superior in combined BRAF and MEK inhibition comparing with BRAF inhibition (OR: 2.00, 95%CI: 1.66-2.44, P < 0.0001) or MEK inhibition alone (OR: 20.66, 95%CI: 12.22-35.47, P < 0.0001). CONCLUSIONS: This study indicates that concurrent inhibition of BRAF and MEK improved the most effective therapeutic modality as compared as single BRAF or MEK inhibition for patients with MM.