Mechanisms of Antitumor Invasion and Metastasis of the Marine Fungal Derivative Epi-Aszonalenin A in HT1080 Cells.

Epi-aszonalenin A (EAA) is an alkaloid that is isolated and purified from the secondary metabolites of coral symbiotic fungi and has been shown to have good atherosclerotic intervention activity and anti-angiogenic activity in our previous studies. In the present study, antiangiogenic activity was used as a basis of an intensive study of its mechanism of action against tumor metastasis and invasion. Invasive metastatic pairs are a hallmark of malignancy, and the dissemination of tumor cells is the most dangerous process in the development of tumors. The results of cell wound healing and the Transwell chamber assay showed that EAA interfered well with PMA-induced migration and invasion of HT1080 cells. Western blot and the ELISA assay showed that EAA decreased MMPs and vascular endothelial growth factor (VEGF) activity and inhibited the expression of N-cadherin and hypoxia-inducible factor-1α (HIF-1α) by regulating the phosphorylation of downstream mitogen-activated protein kinase (MAPK), PI3K/AKT, and NF-κB pathways. Simultaneous molecular docking results revealed that the mimic coupling between the EAA and MMP-2/-9 molecules formed a stable interaction. The results of this study provide a research basis for the inhibition of tumor metastasis by EAA, and together with previous studies, confirm the potential pharmacology and drug potential for this class of compound for application in angiogenesis-related diseases and further improve the availability of coral symbiotic fungi.

Novel insight from the first lung transplant of a COVID-19 patient.

BACKGROUND: To reveal detailed histopathological changes, virus distributions, immunologic properties and multi-omic features caused by SARS-CoV-2 in the explanted lungs from the world's first successful lung transplantation of a COVID-19 patient. MATERIALS AND METHODS: A total of 36 samples were collected from the lungs. Histopathological features and virus distribution were observed by optical microscope and transmission electron microscope (TEM). Immune cells were detected by flow cytometry and immunohistochemistry. Transcriptome and proteome approaches were used to investigate main biological processes involved in COVID-19-associated pulmonary fibrosis. RESULTS: The histopathological changes of the lung tissues were characterized by extensive pulmonary interstitial fibrosis and haemorrhage. Viral particles were observed in the cytoplasm of macrophages. CD3+ CD4- T cells, neutrophils, NK cells, γ/δ T cells and monocytes, but not B cells, were abundant in the lungs. Higher levels of proinflammatory cytokines iNOS, IL-1ß and IL-6 were in the area of mild fibrosis. Multi-omics analyses revealed a total of 126 out of 20,356 significant different transcription and 114 out of 8,493 protein expression in lung samples with mild and severe fibrosis, most of which were related to fibrosis and inflammation. CONCLUSIONS: Our results provide novel insight that the significant neutrophil/ CD3+ CD4- T cell/ macrophage activation leads to cytokine storm and severe fibrosis in the lungs of COVID-19 patient and may contribute to a better understanding of COVID-19 pathogenesis.

Heptapeptide Isolated from Isochrysis zhanjiangensis Exhibited Anti-Photoaging Potential via MAPK/AP-1/MMP Pathway and Anti-Apoptosis in UVB-Irradiated HaCaT Cells.

Marine microalgae can be used as sustainable protein sources in many fields with positive effects on human and animal health. DAPTMGY is a heptapeptide isolated from Isochrysis zhanjiangensis which is a microalga. In this study, we evaluated its anti-photoaging properties and mechanism of action in human immortalized keratinocytes cells (HaCaT). The results showed that DAPTMGY scavenged reactive oxygen species (ROS) and increase the level of endogenous antioxidants. In addition, through the exploration of its mechanism, it was determined that DAPIMGY exerted anti-photoaging effects. Specifically, the heptapeptide inhibits UVB-induced apoptosis through down-regulation of p53, caspase-8, caspase-3 and Bax and up-regulation of Bcl-2. Thus, DAPTMGY, isolated from I. zhanjiangensis, exhibits protective effects against UVB-induced damage.

Comparative in silico and in vitro study of the stability and biological activity of an octapeptide from microalgae Isochrysis zhanjiangensis and its truncated short peptide.

In this study, the structural characteristics and active sites of the octapeptide (IIAVEAGC), the pentapeptide (IIAVE) and tripeptide (AGC) were studied in silica and in vitro. The quantum mechanics results show that the pentapeptide has better structural features. In addition, the docking of three peptides with Keap1 was compared through molecular docking, indicating that the potential molecular mechanism may show antioxidant activity by occupying the Nrf2 binding site on Keap1. The above results are consistent with the cell (SH-SY5Y cell) experiment. In the cell experiment, the three peptides can reduce the damage of hydrogen peroxide to cells under a non-toxic effect. Among them, pentapeptide has better activity than the other two peptides, and can inhibit the production of reactive oxygen species and reduce the potential damage to the mitochondrial membrane. Interestingly, these three peptides can promote the nuclear expression of Nrf2 and inhibit the PI3K, MAPK, and NF-κB signaling pathways' corresponding influence, but their influence degree is different. This study can provide a theoretical basis for the structure-activity relationship of the active peptide, and also broaden the field of vision for the application of the polypeptide from the microalgal Isochrysis zhanjiangensis in food.

A Phlorotanin, 6,6'-bieckol from Ecklonia cava, Against Photoaging by Inhibiting MMP-1, -3 and -9 Expression on UVB-induced HaCaT Keratinocytes.

Skin is the outmost layer of human and sustains most of the external UVB irradiation, which possibly causes the skin photoaging. As a natural antioxidant, marine natural products have been paid more and more attention to their positive effects on photoaging. 6,6'-bieckol is a phlorotanin isolated from Ecklonia cava, while its antiphotoaging bioactivity and mechanism have not been clear yet. This study proves that 6,6'-bieckol enhances cells viability and decreases the level of ROS in UVB-induced human immortalized keratinocytes (HaCaT) cells. It also resulted in significant downregulation of matrix metalloproteinases (MMPs), p-c-Fos, phosphorylated JNK, p38, IκB and p65. In addition, molecular docking also showed that 6,6'-bieckol could bind to MMP-1, MMP-3 and MMP-9. Finally, it was proved that 6,6'-bieckol acts on MMPs through the MAPK/AP-1 and NF-κB pathways to reduce UVB-induced oxidative stress damage in HaCaT cells. Therefore, 6,6'-bieckol is a functional food and skin care ingredient with great potential in preventing photoaging.

Mechanism analysis of octapeptide from microalgae, Isochrysis zhanjiangensis for suppressing vascular injury and angiogenesis in human umbilical vein endothelial cell.

Incorporating microalgae active peptides into functional foods is one of the hottest topics in algae research. Ile-Ile-Ala-Val-Glu-Ala-Gly-Cys (IEC) is a novel octapeptide isolated from the microalgae, Isochrysis Zhanjiangensis that inhibits the vascular injury, angiogenesis and has a protective effect on cardiovascular diseases. In this study, IEC can suppress ROS production and inhibit pro-inflammatory factors through the Nrf2/SOD/HO-1 and NF-κB signaling pathways. Additionally, IEC inhibits angiogenesis by reducing the expression of MMP2 and MMP9 via the PI3K/AKT, NF-κB, and MAPK pathways. Molecular docking also demonstrated that IEC possesses an excellent docking effect with SOD, Bcl-2 and VEGFR-2. In conclusion, this study not only provides a new idea for the prevention of cardiovascular diseases, but also proves the possibility of octapeptide (IEC) in functional food and drugs, and further improves the use value of microalgae (Isochrysis Zhanjiangensis).

A Sulfated Polysaccharide from Red Algae (Gelidium crinale) to Suppress Cells Metastasis and MMP-9 Expression of HT1080 Cells.

Sulfated polysaccharides from red algae have a variety of biological activities, especially antitumor activities. Matrix metalloproteinase-9 (MMP-9) is a proteolytic metalloenzyme that degrades the central part of the extracellular matrix (ECM) and promotes tumor metastasis. In this research, we have investigated the influence and mechanism of GNP (sulfated polysaccharide from Gelidium crinale) on tumor metastasis and MMP-9 expression of human fibrosarcoma (HT1080) cells. The results inflected that the concentration of GNP below 100 µg/mL has no toxicity to HT1080 cells, but showed excellent activity in inhibiting cells migration and invasion. In addition, GNP effectively inhibits the mRNA of MMP-9 and reduces its expression and activity by regulating nuclear factor-kappa B (NF-κB), mitogen-activated protein kinases (MAPK) and mTOR/PI3K/Akt signaling pathways. GNP has great potential as MMP-9 inhibitor and could be developed as a functional food or drug to prevent tumor metastasis.

Potential anti-skin aging effect of a peptide AYAPE isolated from Isochrysis zhanjiangensis on UVB-induced HaCaT cells and H2O2-induced BJ cells.

AYAPE (Ala-Tyr-Ala-Pro-Glu) is a pentapeptide isolated from Isochrysis zhanjiangensis, previous studies have proved that this pentapeptide has antioxidant and inflammatory activities. In this study, we determined the anti-skin aging bioactivity of AYAPE with UVB-induced human immortalized keratinocytes (HaCaT) and H2O2-induced human skin fibroblasts (BJ cells) as models. The results showed that AYAPE against UVB-induced photoaging on HaCaT cells via alleviating DNA damage, reducing intracellular reactive oxygen (ROS) levels, down regulating phosphorylation of proteins in MAPK/AP-1 signaling pathways. In addition, AYAPE attenuated senescence related effectors expression in H2O2-induced BJ cells. Furthermore, p53 showed an important role in regulation effect of AYAPE in both two cells, and AYAPE showed a directly combination with p53 by molecular docking. These results demonstrated that AYAPE is potential to against skin aging by decreasing matrix metalloproteinase-1 (MMP-1) production, inhibiting inflammation and apoptosis, and attenuating fibroblast senescence.

Efficacy and safety of raltitrexed plus S-1 versus regorafenib in patients with refractory metastatic colorectal cancer: a real-world propensity score matching study.

Background: Raltitrexed plus S-1 (RS) and regorafenib both showed considerable efficacy for metastatic colorectal cancer (mCRC) patients. This study aims to compare the effectiveness and safety of two different regimens in patients with refractory mCRC. Methods: This retrospective cohort study included mCRC patients who were treated with RS or regorafenib from February 2017 to June 2021. A propensity score matching (PSM) analysis was conducted to balance the baseline characteristics of all patients. Progression-free survival (PFS), overall survival (OS), tumor response, and safety of two regimens were evaluated. Results: A total of 187 patients were included in our study, with 107 patients in the RS group and 80 patients in the regorafenib group. After PSM, 78 pairs were recognized. Patients treated with RS had a semblable PFS compared to those treated with regorafenib before PSM (4.8 months vs 5.5 months, p = 0.400) and after PSM (4.7 months vs 5.4 months, p = 0.430). Patients in the RS group were associated with a longer OS than those in the regorafenib group (13.4 months vs 10.1 months, p = 0.010). A similar trend of OS was also obtained in the matched cohort (13.3 months vs 10.0 months, p = 0.024). Both objective response rate (12.8% vs 5.1%, p = 0.093) and disease control rate (53.8% vs 46.2%, p = 0.337) in the RS cohort were higher than those in the regorafenib group, without significant differences. Adverse events (AEs) of each group were well tolerated. Conclusion: Patients treated with RS demonstrated a longer OS than those treated with regorafenib and had manageable AEs, which could be recognized as a primary choice for refractory mCRC. Plain Language Summary: Efficacy and Safety of Raltitrexed plus S-1 Versus Regorafenib in Patients with Refractory Metastatic Colorectal Cancer: A Real-world Propensity Score Matching StudyBoth raltitrexed plus S-1 (RS) and regorafenib showed considerable efficacy for metastatic colorectal cancer (mCRC) patients. No study has compared the two regimens yet. Therefore, we compare the efficacy and safety between RS and regorafenib to provide an optimal treatment option. We retrospectively included patients with mCRC who failed at least two standard treatments. All enrolled patients received RS or regorafenib treatments. We conducted a propensity score matching to eliminate differences in the enrolled patients. After the analysis, we found no significant differences in progression-free survival in patients between the two groups. However, patients treated with RS had a longer OS than those treated with regorafenib, whether before matching (13.4 months vs 10.1 months, p = 0.010) or after matching (13.3 months vs 10.0 months, p = 0.024). In addition, the adverse effects caused by cancer-related therapy were tolerable for the patient. Certainly, this is a non-randomized retrospective study with a small sample size, so we conducted a propensity score matching to minimize potential bias. Importantly, this is the first research comparing the two treatments, and we believe that the results of this article could present a primary choice for clinical doctors dealing with patients with standard treatments that failed mCRC.