MGF

Abstract

African swine fever (ASF) is a highly contagious viral disease caused by the African swine fever virus (ASFV), which primarily affects pigs. ASFV encodes a variety of proteins that contribute to immune evasion, with the mechanisms of immune escape being diverse, complex, and not yet fully understood. In this study, the MGF 505-3R protein of ASFV was identified as a potential inhibitor of the host's inflammatory response. We demonstrate that MGF 505-3R suppresses the host antiviral response by promoting the ubiquitin-mediated degradation of MyD88, with the amino acid region 89-277 being essential for this function. Notably, this region directly mediates the interaction with MyD88 and induces its ubiquitination. Furthermore, MGF 505-3R and its derived peptide significantly inhibit the production of type I (IFN-α/β) and type III (IFN-λ) interferons, in addition to impairing NF-κB activation by blocking p65 phosphorylation and nuclear translocation. The MGF 505-3R peptide effectively attenuates the host inflammatory storm, decreasing the expression of cytokines such as TNF-α and IL-1β, and alleviating DSS-induced colitis in male C57BL/6 mice. These findings highlight the dual role of MGF 505-3R in suppressing both inflammatory and interferon pathways, underscoring its potential as a therapeutic candidate for inflammatory diseases and a target for antiviral strategies.

Abstract

Amyloid aggregation is a pathological hallmark of several neurodegenerative disorders, including Alzheimer's disease. Polyphenolic compounds are emerging as promising candidates for therapeutic intervention due to their capacity to interfere with multiple stages of amyloidogenesis. In this study, we investigated, in vitro, the antiamyloidogenic potential of mangiferin (MGF), a xanthonoid polyphenol with established pharmacological activity but previously unexplored in the context of amyloid modulation. Using a combination of biophysical, spectroscopic, and microscopic techniques, we assessed the effects of MGF on the aggregation behavior of two distinct amyloidogenic peptides: Aβ1-42 and Cterm_mutA. Thioflavin T (ThT) assays revealed that MGF significantly inhibited aggregation in a concentration-dependent manner, with maximal inhibition at a 1:5 peptide:MGF ratio. Nanoparticle tracking analysis (NTA) and microscopy studies demonstrated peptide-specific differences in the mechanism of action of MGF: MGF promoted the formation of larger, nonfibrillar oligomers in Aβ1-42, while it reduced oligomer size in Cterm_mutA. This effect was most likely attributable to the disruption of π-π interactions. Importantly, MGF exhibited no cytotoxicity in SH-SY5Y cells and significantly attenuated the amyloid-induced toxicity of both peptides. These findings highlight MGF as a promising, multitargeted modulator of amyloid aggregation with potential applications in neuroprotection and the development of novel antiamyloid therapies.

Abstract

Magnesium alloy stents (MASs) provide significant therapeutic benefits for the treatment of cardiovascular disease. Unlike conventional permanent stents, MASs gradually degrade after fulfilling their mechanical support function, thereby reducing the risk of long-term complications. However, the clinical application of MAS is hindered by two primary challenges: excessively rapid degradation in physiological environments and inadequate biocompatibility resulting from the alloy's corrosion behavior. Herein, we developed a multifunctional composite coating on Mg-Zn-Y-Nd (ZE21B) alloy that incorporated a MgF2 layer, amphiphilic methoxy-terminated poly-(ethylene glycol)-b-poly-(lactide-co-glycolide) (mPEG-PLGA) polymer, and bioactive CAG peptides to enhance its corrosion resistance, hemocompatibility, and pro-endothelialization potential. The ZE21B with mPEG-PLGA/CAG coating showed a slower degradation rate. In addition, the modified ZE21B alloy exhibited the appropriate lower levels of hemolysis rate, fibrinogen adsorption, and denaturation. Furthermore, the mPEG-PLGA/CAG composite coating promoted the adhesion and proliferation of endothelial cells (ECs), inhibited the same behaviors of smooth muscle cells (SMCs), and enhanced the competitive growth of ECs over SMCs. These findings suggested that the mPEG-PLGA/CAG coating effectively enhanced the corrosion resistance and pro-endothelialization capacity of the ZE21B magnesium alloy, addressing urgent clinical demands for biodegradable vascular stents that balance degradation rate with biological safety, and offering a promising strategy for its advancement. By improving both corrosion resistance and endothelialization, this work contributed to the development of next-generation stents with the potential to reduce long-term complications and healthcare burdens.

Abstract

Coronary stents are widely used in the interventional treatment of cardiovascular disease. Biodegradable magnesium alloy stents are ideal candidates to replace traditional non-biodegradable stents due to their excellent mechanical properties and biodegradation. However, too fast degradation and poor biocompatibility limit the further clinical application of magnesium alloy stents. Herein, a composite coating consisting of an MgF2 layer, PDA layer, ChS, and CAG peptide was constructed on the Mg-Zn-Y-Nd (ZE21B) alloy to enhance its corrosion resistance, hemocompatibility, and cytocompatibility. The MgF2 and PDA layers in the composite coating could collectively enhance the corrosion resistance of ZE21B alloy, and the ChS and CAG peptides in the composite coating could improve the anticoagulant and pro-endothelialization capacity of ZE21B alloy. The corrosion current density of the modified ZE21B alloy was much lower than that of bare ZE21B alloy, proving the better corrosion resistance. Moreover, the excellent hemocompatibility of modified ZE21B alloy was verified by the lower levels of hemolysis rate, fibrinogen adsorption and denaturation, and platelet adhesion and activation. Furthermore, the composite coating could selectively promote the adhesion, proliferation, migration, and competitive growth of endothelial cells rather than smooth muscle cells on the ZE21B alloy owing to the synergistic biological effects of ChS and CAG peptides. The ChS/CAG modified samples also exhibited excellent biosafety and histocompatibility in vivo implantation experiments. The composite coating significantly improved the corrosion resistance and biocompatibility of ZE21B alloy, and provided a simple and effective strategy for developing degradable vascular stents.

Abstract

Gymnopodium floribundum Rolfe, known locally as "Dzidzilche" or "Ts'its'ilche," is a native species from Mexico and Central America. In Mayan communities, this plant is used to relieve inflammation and diverse respiratory diseases such as colds, catarrh, bronchitis, and asthma. Usually, a decoction of leaves or flowers is prepared and administered orally.

Abstract

Multigene family (MGF) 360 genes, which are African swine fever virus (ASFV) virulence genes, primarily target key host immune molecules to suppress host interferon (IFN) production and interferon-stimulated gene (ISG) transcription, impairing host innate immune responses for efficient viral replication. However, the interactions between MGF 360 virulence genes and host molecules, as well as the mechanisms through which MGF 360 genes regulate host immune responses and IFN signaling, require further elucidation. In this study, we discovered that ASFV MGF_360-4L interacts with MDA5 and recruits the mitochondrial selective autophagy receptor SQSTM1 to degrade MDA5, thus impairing IFN signaling and compromising host innate immune responses. Furthermore, MGF_360-4L inhibits the interaction between MDA5 and MAVS, blocking ISG15-mediated ISGylation of MDA5. MGF_360-4L deficiency significantly attenuated virus-induced mitochondrial autophagy in vitro. Additionally, OAS1 ubiquitinates MGF_360-4L at residues K290, K295, and K327. Finally, a recombinant ASFV lacking the MGF_360-4L gene (ASFV-∆MGF_360-4L) was generated using ASFV-CN/SC/2019 as the backbone, which demonstrated that the replication kinetics of ASFV-∆MGF_360-4L in PAM cells were like those of the highly virulent parental ASFV-WT in vitro. Domestic pigs infected with ASFV-∆MGF_360-4L exhibited milder symptoms than those infected with parental ASFV-WT, and ASFV-∆MGF_360-4L-infected pigs presented with enhanced host innate antiviral immune response, confirming that the deletion of the MGF_360-4L gene from the ASFV genome highly attenuated virulence in pigs and provided effective protection against parental ASFV challenge. In conclusion, we identified a novel ASFV virulence gene, MGF_360-4L, further elucidating ASFV infection mechanisms and providing a new candidate for vaccine development.IMPORTANCEAfrican swine fever virus (ASFV) infection causes acute death in pigs, and there is currently no effective vaccine available for prevention. Multigene family (MGF) virulence genes have been shown to be crucial for ASFV's ability to evade host innate immune responses. However, the functions of most MGF genes remain unknown, which poses significant challenges for the development of ASFV vaccines and antiviral drugs. In this study, we identified a virulence gene of ASFV, MGF_360-4L, that targets and recruits the selective autophagy receptor p62 to mediate the degradation of the dsRNA sensor MDA5, thereby blocking interferon signaling. Additionally, it inhibits the ISG15-mediated ISGylation activation of MDA5. ASFV lacking MGF_360-4L showed reduced virulence and provided protection in pigs. Our data identify a novel virulence gene and provide new insights for ASFV vaccine development.