Kaempferol ameliorate the prognosis of Aspergillus fumigatus keratitis by reducing fungal load and inhibiting the Dectin-1 and p38 MAPK pathway.

Fungal keratitis is one of leading reasons for blindness in the world, which causes corneal blindness mainly due to excessive inflammatory responses. Kaempferol (KAE) is a natural flavonoid which has potent anti-inflammatory effects. However, whether KAE plays protective roles in fungal keratitis and the potentially protective mechanisms are unrevealed. Here we first investigated the anti-inflammatory and antifungal effects of KAE on Aspergillus fumigatus (A. fumigatus) keratitis in C57BL/6 mice. We found that treatment of KAE ameliorated the severity of keratitis, inhibited macrophages and neutrophils recruitment, depressed corneal fungal load, and declined the expression of TLR4 and Dectin-1 in A. fumigatus infected mice corneas. And in activated hyphae or Curdlan stimulated macrophages, pretreatment of KAE also significantly decreased the mRNA and protein expression of IL-1ß, TNF-α, MIP-2 and the phosphorylated-p38 (p-p38)/p38 MAPK ratio. In summary, KAE ameliorated the prognosis of fungal keratitis in C57BL/6 mice by reducing corneal fungal load, depressing the inflammatory cells recruitment, and downregulating the expression of inflammatory factors, and those effects depended on the inhibition of Dectin-1 and p38 MAPK pathway.

The efficacy and safety of platinum-based chemotherapy for ovarian cancer in pregnancy: A protocol for systematic review and meta-analysis.

BACKGROUND: Ovarian cancer during pregnancy is a rare event. Little is known about the treatment of this condition due to lack of high level evidence. Therefore, we performed a protocol for systematic review and meta-analysis to evaluate the efficacy and safety of platinum-based chemotherapy for the treatment of ovarian cancer during pregnancy. METHODS: This systematic review has been registered in PROSPERO (CRD42022370709), which will be conducted in accordance with preferred reporting items for systematic review and meta-analysis protocols 2015 statement. We will search 7 electronic databases to identify relevant studies from inception to October, 2022, which includes PubMed, MEDLINE, Embase, Cochrane Clinical Trials Database, Web of Science, China National Knowledge Infrastructure, and Chinese Biomedical Literature Database. The Cochrane Handbook for systematic reviews of interventions will be performed to assess a broad category of biases in the included studies. The Grading of Recommendations Assessment, Development and Evaluation system will be used to judge the overall quality of evidence supporting outcomes in this work. Data are analyzed with the Review Manager Version 5.3 software. RESULTS: The results of this meta-analysis would be submitted to peer-reviewed journals for publication. CONCLUSION: This paper will provide high-quality synthesis to assess the efficacy and safety of platinum-based chemotherapy for ovarian cancer in pregnancy.

Eugenol protects against Aspergillus fumigatus keratitis by inhibiting inflammatory response and reducing fungal load.

Fungal keratitis is a corneal infection, which severely impairs vision. The fungal pathogen provokes host immune response, but the excessive inflammatory response causes significant collateral damage to the cornea. Eugenol, the main component of clove oil, has been found to have a broad range of pharmacological activities including anti-microbial, antioxidation and anti-inflammation. However, the role of eugenol in Aspergillus fumigatus (A. fumigatus) keratitis is unknown. In this study, we demonstrated that eugenol reduced mice keratitis severity, inflammatory cells infiltration, pro-inflammatory cytokine expression, and the fungal load. Eugenol also decreased the expressions of pro-inflammatory cytokines in human corneal epithelial cells (HCECs). We confirmed that the anti-inflammatory effects of eugenol were related to activating nuclear factor erythroid 2-related factor 2/Heme Oxygenase-1 (Nrf2/HO-1) signaling pathway. Moreover, we demonstrated that eugenol could inhibit the A. fumigatus growth and adhesion to host cells, as well as damage the fungal biofilm. The antifungal mechanism seemed to be disrupting the integrity of the fungal membrane and reducing the biosynthesis of ergosterol. Taken together, our research suggested that eugenol exerted protective effects on mouse A. fumigatus keratitis, due to its anti-inflammatory and antifungal activity.

Mechanism of antifungal activity and therapeutic action of ß-ionone on Aspergillus fumigatus keratitis via suppressing LOX1 and JNK/p38 MAPK activation.

PURPOSE: To investigate the anti-inflammatory and antifungal role of ß-ionone (BI) in fungal keratitis (FK). METHODS: In vitro antifungal activity of BI against Aspergillus fumigatus (A. fumigatus) was evaluated by using minimum inhibitory concentration (MIC), crystal violet staining, biofilm biomass measurement, propidium iodide uptake test, and adherence assay. And RT-PCR was carried out to measure the levels of RodA, RodB, Rho, FKs, CshA-D, RlmA, Cyp51A-B and Cdr1B. Network pharmacology analysis was applied to predict the relationship between BI and FK. Cell Count Kit-8 (CCK8) assay was utilized to detect the cytotoxicity of BI to RAW264.7 and immortalized human corneal epithelial cells (HCECs). The underlying mechanism of BI at regulating the level of inflammatory factors in FK was assessed by RT-PCR, ELISA and Western blot in vitro and in vivo. The therapeutic effect of BI has investigated in A. fumigatus keratitis by employing the clinical score, pathological examination, plate count, immunofluorescence and myeloperoxidase (MPO) assay. We also used the slit-lamp microscopy, clinical scores, and HE staining to assess the effect of natamycin compared with BI treatment in vivo. RESULTS: BI suppressed the growth of A. fumigatus and had a significant effect on A. fumigatus biofilms and membrane permeability. RT-PCR demonstrated that exposure of A. fumigatus to BI inhibited the expression of genes that function in hydrophobin (RodA, RodB), cell wall integrity (Rho, FKs, CshA-D, RlmA), azole susceptibility (Cyp51A-B, Cdr1B). Network pharmacology showed that the effects of BI in FK implicate with C-type lectin receptor signaling pathway. In vivo, after A. fumigatus infection, BI treatment markedly reduced the severity of FK by decreasing clinical score, neutrophil recruitment, and fungal load. And BI treatment also obviously reduced the expression of inflammatory cytokines, Lectin-like oxidized LDL receptor (LOX-1), phosphorylation of p38MAPK and p-JNK versus the DMSO-treated group. BI and natamycin both significantly increased corneal transparency and decreased inflammatory cell recruitment in the FK in the mice model. CONCLUSION: These results indicated that BI had fungicidal activities against A. fumigatus. It also ameliorated FK in mice by reducing inflammation, which was regulated by LOX-1, p-p38MAPK and p-JNK.

Calcium Phosphate-Reinforced Metal-Organic Frameworks Regulate Adenosine-Mediated Immunosuppression.

Long-term accumulation of adenosine (Ado) in tumor tissues helps to establish the immunosuppressive tumor microenvironment and to promote tumor development. Regulation of Ado metabolism is particularly pivotal for blocking Ado-mediated immunosuppression. The activity of adenosine kinase (ADK) for catalyzing the phosphorylation of Ado plays an essential role in regulating Ado metabolism. Specifically, accumulated Ado in the tumor microenvironment occupies the active site of ADK, inhibiting the phosphorylation of Ado. Phosphate can protect ADK from inactivation and restore the activity of ADK. Herein, calcium phosphate-reinforced iron-based metal-organic frameworks (CaP@Fe-MOFs) are designed to reduce Ado accumulation and to inhibit Ado-mediated immunosuppressive response in the tumor microenvironment. CaP@Fe-MOFs are found to regulate the Ado metabolism by promoting ADK-mediated phosphorylation and relieving the hypoxic tumor microenvironment. Moreover, CaP@Fe-MOFs can enhance the antitumor immune response via Ado regulation, including the increase of T lymphocytes and dendritic cells and the decrease of regulatory T lymphocytes. Finally, CaP@Fe-MOFs are used for cancer treatment in mice, alleviating the Ado-mediated immunosuppressive response and achieving tumor suppression. This study may offer a general strategy for blocking the Ado-mediated immunosuppression in the tumor microenvironment and further for enhancing the immunotherapy efficacy in vivo.