J147 treatment protects against traumatic brain injury by inhibiting neuronal endoplasmic reticulum stress potentially via the AMPK/SREBP-1 pathway.

Endoplasmic reticulum (ER) stress is recognized as a crucial contributor to the progression of traumatic brain injury (TBI) and represents a potential target for therapeutic intervention. This study aimed to assess the potential of J147, a novel neurotrophic compound, in alleviating ER stress by modulating related signaling pathways, thereby promoting functional recovery in TBI. To this end, adult mice underwent controlled cortical impact (CCI) injury to induce TBI, followed by oral administration of J147 one-hour post-injury, with daily dosing for 3 to 7 days. Multiple behavioral assessments were conducted over 35 days, revealing a significant, dose-dependent improvement in neurofunctional recovery with J147 treatment. The neuropathological analysis demonstrated reduced acute neurodegeneration (observed at three days through FJC staining), enhanced long-term neuron survival (H&E and Nissl staining), and improved neuroplasticity (Golgi staining) at 35 days post-TBI. At the molecular level, TBIinduced AMP-activated protein kinase (AMPK) dephosphorylation, sterol regulatory element binding protein-1 (SREBP-1) activation, and upregulation of ER stress marker proteins, including phosphorylated eukaryotic initiation factor-2α (p-eIF2a), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP) in perilesional cortex neurons at three days post-injury. Notably, the J147 treatment significantly attenuated AMPK dephosphorylation, SERBP-1 activation, and expression of the ER stress markers. In summary, this study reveals the therapeutic promise of J147 in mitigating secondary brain damage associated with TBI and improving long-term functional recovery by modulating ER stress pathways.

Design, biological activity and signaling pathway of bovine consensus omega interferon expressed in Pichia pastoris.

The bovine IFN-ω (BoIFN-ω) multigene family is located on chromosome 8, which has 14 potential functional genes and 10 pseudogenes. After aligning 14 BoIFN-ω subtypes and assigning the most frequently occurring amino acids in each position, one artificial consensus BoIFN-ω (CoBoIFN-ω) gene was designed, optimized and synthesized. Then, CoBoIFN-ω was expressed in Pichia pastoris, which was demonstrated to have 3.94-fold and 14.3-fold higher antiviral activity against VSV on MDBK cells than that of BoIFN-ω24 and BoIFN-ω3, respectively. Besides this, CoBoIFN-ω was confirmed to have antiviral activity against VSV on BL, BT, PK-15 cells, and against BEV, BHV-1, BPIV3 on MDBK cells. Additionally, CoBoIFN-ω could bind with bovine type I IFN receptors, and then activate the promoters of NF-κB, ISRE and BoIFN-ß, and induce the transcription of ISGs and expression of Mx1 and NF-κB p65, which suggested CoBoIFN-ω exerts antiviral activity via activation of the JAK-STAT signaling pathway. Overall, this research on CoBoIFN-ω not only extends and improves consensus IFN research, but also reveals that CoBoIFN-ω has the potential to be used in the therapy of bovine viral diseases.

Evolutional conservation of molecular structure and antiviral function of a type I interferon, IFN-kappa, in poultry.

IFN-kappa (IFN-κ) is a type I IFN expressed by keratinocytes, monocytes and dendritic cells with important roles during the innate immune response period. This research was conducted to elaborate the evolution and characteristics of IFN-κ in poultry. Chicken IFN-κ is located on the sex-determining Z chromosome, which is greatly different from mammals. Poultry IFN-κ cluster together in a species-specific manner through positive selection pressure and share only 19-33% homology with mammalian IFN-κ and poultry other type I IFN. Both chicken and duck IFN-κ was constitutively expressed in spleen, skin, lung, and peripheral blood mononuclear cells (PBMC), as well as being significantly induced after treatment with virus in PBMC. Biologically, poultry IFN-κ has antiviral activity against VSV in chicken embryonic fibroblasts and duck embryonic fibroblasts (CEF and DEF) cells, and induces the expression of IFN stimulated genes (ISGs). After treatment with JAK1 inhibitor, the ISGs expression can be down-regulated. Overall, our research on poultry IFN-κ not only enriches the knowledge about IFN-κ but also facilitates further research on the role of type I IFNs in antiviral defense responses in poultry.