PI3K/AKT mediated De novo fatty acid synthesis regulates RIG-1/MDA-5-dependent type I IFN responses in BVDV-infected CD8+T cells.

Bovine viral diarrhea virus (BVDV) has caused massive economic losses in the cattle business worldwide. Fatty acid synthase (FASN), a key enzyme of the fatty acid synthesis (FAS) pathway, has been shown to support virus replication. To investigate the role of fatty acids (FAs) in BVDV infection, we infected CD8+T lymphocytes obtained from healthy cattle with BVDV in vitro. During early cytopathic (CP) and noncytopathic (NCP) BVDV infection in CD8+ T cells, there is an increase in de novo lipid biosynthesis, resulting in elevated levels of free fatty acids (FFAs) and triglycerides (TG). BVDV infection promotes de novo lipid biosynthesis in a dose-dependent manner. Treatment with the FASN inhibitor C75 significantly reduces the phosphorylation of PI3K and AKT in BVDV-infected CD8+ T cells, while inhibition of PI3K with LY294002 decreases FASN expression. Both CP and NCP BVDV strains promote de novo fatty acid synthesis by activating the PI3K/AKT pathway. Further investigation shows that pharmacological inhibitors targeting FASN and PI3K concurrently reduce FFAs, TG levels, and ATP production, effectively inhibiting BVDV replication. Conversely, the in vitro supplementation of oleic acid (OA) to replace fatty acids successfully restored BVDV replication, underscoring the impact of abnormal de novo fatty acid metabolism on BVDV replication. Intriguingly, during BVDV infection of CD8+T cells, the use of FASN inhibitors prompted the production of IFN-α and IFN-ß, as well as the expression of interferon-stimulated genes (ISGs). Moreover, FASN inhibitors induce TBK-1 phosphorylation through the activation of RIG-1 and MDA-5, subsequently activating IRF-3 and ultimately enhancing the IFN-1 response. In conclusion, our study demonstrates that BVDV infection activates the PI3K/AKT pathway to boost de novo fatty acid synthesis, and inhibition of FASN suppresses BVDV replication by activating the RIG-1/MDA-5-dependent IFN response.

Vegetarian diets and the risk of gastrointestinal cancers: a meta-analysis of observational studies.

The systematic review aimed to assess the association between vegetarian diet and the risk of gastrointestinal tumorigenesis. PubMed, Embase, Cochrane Library, and Web of Science were searched from inception to August 2022 for observational studies on vegetarian diets and the risk of gastrointestinal tumorigenesis. The primary outcome was morbidity due to gastrointestinal cancer. The Newcastle-Ottawa Scale was used to assess the quality of included studies. Pooled effects were analyzed using a random-effects model. The study protocol was registered in PROSPERO (no. CRD42022310187). Eight original studies (seven cohorts and one case-control), involving 686 691 participants, were included. Meta-analysis showed a negative correlation between vegetarian diets and gastrointestinal tumorigenesis risk [relative risk (RR) equals 0.77, 95% confidence interval (CI) is (0.65-0.90)], compared with non-vegetarian diets. Subgroup analysis indicated that vegetarian diets were negatively correlated with the risks of gastric cancer [RR = 0.41, 95% CI (0.28-0.61)] and colorectal cancer [RR = 0.85, 95% CI (0.76-0.95)], but not with that of upper gastrointestinal cancer (excluding stomach) [RR = 0.93, 95% CI (0.61-1.42)]. Vegetarian diets were negatively correlated with the risk of gastrointestinal tumorigenesis in men [RR = 0.57, 95% CI (0.36-0.91)], but were uncorrelated in women [RR = 0.89, 95% CI (0.71-1.11)]. Vegetarian diets were negatively correlated with the risk of gastrointestinal tumorigenesis in North American [RR = 0.76, 95% CI (0.61-0.95)] and Asian populations [RR = 0.43, 95% CI (0.26-0.72)] and were uncorrelated in the European population [RR = 0.83, 95% CI (0.68-1.01)]. Adhering to vegetarian diets reduces the risk of gastrointestinal tumorigenesis. More data from well-conducted cohort and other studies are needed.

Cascaded terahertz hollow-core Bragg waveguide: numerical design and experimental demonstration.

A THz hollow-core Bragg waveguide with discontinuous support bridges in both radial and axial directions is proposed. The influence of the support bridges on the transmission loss of the waveguide is demonstrated numerically. The proposed waveguide shows confinement loss two orders of magnitude lower than that of the Bragg waveguide with conventional support bridges. A waveguide sample is fabricated by 3D printing technology, and the experimental results show that the transmission loss is in agreement with that of the simulation results. It is also demonstrated that the transmission loss of the fabricated waveguide is mainly determined by the large absorption loss of the waveguide material used in the experiment.

New Insights into the Role and Therapeutic Potential of Heat Shock Protein 70 in Bovine Viral Diarrhea Virus Infection.

Bovine viral diarrhea virus (BVDV), a positive-strand RNA virus of the genus Pestivirus in the Flaviviridae family, is the causative agent of bovine viral diarrhea-mucosal disease (BVD-MD). BVDV's unique virion structure, genome, and replication mechanism in the Flaviviridae family render it a useful alternative model for evaluating the effectiveness of antiviral drugs used against the hepatitis C virus (HCV). As one of the most abundant and typical heat shock proteins, HSP70 plays an important role in viral infection caused by the family Flaviviridae and is considered a logical target of viral regulation in the context of immune escape. However, the mechanism of HSP70 in BVDV infection and the latest insights have not been reported in sufficient detail. In this review, we focus on the role and mechanisms of HSP70 in BVDV-infected animals/cells to further explore the possibility of targeting this protein for antiviral therapy during viral infection.

Anti-BVDV Activity of Traditional Chinese Medicine Monomers Targeting NS5B (RNA-Dependent RNA Polymerase) In Vitro and In Vivo.

Natural products have emerged as "rising stars" for treating viral diseases and useful chemical scaffolds for developing effective therapeutic agents. The nonstructural protein NS5B (RNA-dependent RNA polymerase) of NADL strain BVDV was used as the action target based on a molecular docking technique to screen herbal monomers for anti-BVDV viral activity. The in vivo and in vitro anti-BVDV virus activity studies screened the Chinese herbal monomers with significant anti-BVDV virus effects, and their antiviral mechanisms were initially explored. The molecular docking screening showed that daidzein, curcumin, artemisinine, and apigenin could interact with BVDV-NADL-NS5B with the best binding energy fraction. In vitro and in vivo tests demonstrated that none of the four herbal monomers significantly affected MDBK cell activity. Daidzein and apigenin affected BVDV virus replication mainly in the attachment and internalization phases, artemisinine mainly in the replication phase, and curcumin was active in the attachment, internalization, replication, and release phases. In vivo tests demonstrated that daidzein was the most effective in preventing and protecting BALB/C mice from BVDV infection, and artemisinine was the most effective in treating BVDV infection. This study lays the foundation for developing targeted Chinese pharmaceutical formulations against the BVDV virus.

Quercetin Inhibits Hsp70 Blocking of Bovine Viral Diarrhea Virus Infection and Replication in the Early Stage of Virus Infection.

Bovine viral diarrhea virus (BVDV), a positive-strand RNA virus of the genus Pestivirus in the Flaviviridae family, is the causative agent of viral diarrheal disease in bovine. BVDV has been used as a surrogate model for the hepatitis C virus (HCV) to evaluate the efficacy of antiviral drugs. The plant flavonol quercetin causes multiple health-promoting effects in humans and animals. It can be made into a variety of additives, and it exerts a variety of immunomodulatory effects with the potential to be used as an antiviral agent. However, quercetin's antiviral effect and mechanism of action on BVDV are still unclear. Therefore, this study was designed to evaluate quercetin's effect on BVDV virus replication in vitro and in vivo and elucidate its mechanism of action. A CCK-8 kit was used to analyze the toxicity of the quercetin to the MDBK cells. Western blot, qRT-PCR, TCID50, and histological analysis were used to determine the mechanism of quercetin's anti-BVDV activity. An oxidative stress kit was used to evaluate the effects of quercetin on ROS, antioxidant enzymes, and MDA indexes. The effect of quercetin on IL-2 and IFN-γ in the serum of mice was determined by using an ELISA kit. The results showed that quercetin inhibits Hsp70, blocks BVDV infection in the early stage of virus infection and inhibits BVDV replication by inhibiting oxidative stress or ERK phosphorylation. In addition, quercetin alleviated the decrease in IFN-γ and IL-2 in the serum of BVDV-infected mice. Quercetin ameliorated BVDV-induced histopathological changes. In summary, this study demonstrated for the first time the role of Hsp70 in BVDV infection and the potential application of quercetin in treating BVDV infection.

PD-1 Blockade Restores the Proliferation of Peripheral Blood Lymphocyte and Inhibits Lymphocyte Apoptosis in a BALB/c Mouse Model of CP BVDV Acute Infection.

Acute infection of bovine viral diarrhea virus (BVDV) is associated with immune dysfunction and can cause peripheral blood lymphopenia and lymphocyte apoptosis. Our previous study has confirmed that programmed death-1 (PD-1) blockade inhibits peripheral blood lymphocytes (PBL) apoptosis and restores proliferation and anti-viral immune functions of lymphocytes after BVDV infection in vitro. However, the situation in vivo remains to be further studied and confirmed. Therefore, in this study, we established a BALB/c mouse model of acute BVDV infection with cytopathic (CP) BVDV (strain NADL) and non-cytopathic (NCP) BVDV (strain NY-1). Then, we examined the mRNA and protein levels of PD-1 and programmed death-ligand 1 (PD-L1) in peripheral blood mononuclear cells (PBMC) from BVDV-infected mice and analyzed the effects of PD-1 blockade on the proportions of CD3+, CD4+, and CD8+ T cell subsets, the apoptosis and proliferation of PBL, and the production of IL-2 and IFN-γ. We found that leukopenia, lymphocytopenia, and thrombocytopenia were developed in both CP and NCP BVDV-infected mice at day 7 of post-infection. The mRNA and protein expression of PD-1 and PD-L1 were significantly upregulated in CP and NCP BVDV-infected mice. Moreover, PD-1/PD-L1 upregulation was accompanied by leukopenia and lymphopenia. Additionally, PD-1 blockade inhibited PBL apoptosis and virus replication, restored the proportions of CD3+, CD4+, and CD8+ T cell subsets, and increased IFN-γ production and p-ERK expression in BVDV-infected mice. However, blocking PD-1 did not significantly affect PBL proliferation and IL-2 production in NCP BVDV-infected mice. Our findings further confirmed the immunomodulatory role of PD-1 in peripheral blood lymphocytopenia in vivo and provided a scientific basis for exploring the molecular mechanism of immune dysfunction caused by acute BVDV infection.

Facile synthesis of air-stable heterobimetallic osmium-silver hydride complexes.

The synthesis and characterization of air-stable heterobimetallic Os-Ag hydrides are described. All of the new heterobimetallic Os-Ag hydrides are neutral, and the in situ generated and presynthesized cis-[Os](H)-CC-R units in these frameworks act as organometallic bidentate chelating ligands coordinating with the AgPPh3 cation, which makes these complexes more stable. Our results provide a new synthetic route for the construction of stable heterobimetallic complexes.

Comparison of the bacteriostatic effects of quaternary ammonium compounds and their combinations on a dairy farm environment and the microbial contamination of dairy products.

Disinfection is key for controlling microbial contamination and ensuring the safe production of milk and dairy products. In this study, we developed a new disinfection method using quaternary ammonium surfactant N-dodecyl-2-(pyridin-1-yl) acetamide chloride as the main component to form a bactericidal complex with either chlorhexidine acetate or glutaraldehyde, and we evaluated the bactericidal effects, safety, and clinical application value of the compound disinfectants. An in vivo acute oral toxicity assay in mice showed an LD50 > 5000 mg/kg body weight without abnormality in pathological tissue sections. Comparison with commercially available products also showed that they have outstanding bactericidal effects. Clinical trials proved that the compound disinfectants have excellent bactericidal effects on the air and ground of the dairy farm and on the skin of cattle, especially in a dairy farm environment. Our findings confirm that the new compound disinfectants have excellent bactericidal performance and are safe to use as disinfectants to prevent mastitis and contamination of the cattle farm environment.

La désinfection est essentielle pour maitriser la contamination microbienne et garantir une production sécuritaire de lait et de produits laitiers. Dans cette étude, nous avons développé une nouvelle méthode de désinfection utilisant l'ammonium quaternaire tensioactif d'acétamide de chlorure de N-dodécyl-2-(pyridin-1-yl) comme composant principal pour former un complexe bactéricide avec l'acétate de chlorhexidine ou le glutaraldéhyde, et nous avons évalué les effets bactéricides, la sécurité et la valeur d'application clinique des désinfectants composés. Un test de toxicité orale aiguë in vivo chez la souris a montré une DL50 > 5000 mg/kg de poids corporel sans anomalie pathologique dans les sections de tissus. La comparaison avec les produits disponibles dans le commerce a également montré qu'ils ont des effets bactéricides remarquables. Des essais cliniques ont démontré que les désinfectants composés ont d'excellents effets bactéricides sur l'air et le sol de la ferme laitière et sur la peau des bovins, en particulier dans un environnement de ferme laitière. Nos résultats confirment que les nouveaux désinfectants composés ont d'excellentes performances bactéricides et sont sécuritaires à utiliser comme désinfectants pour prévenir la mammite et la contamination de l'environnement de l'élevage bovin.(Traduit par Docteur Serge Messier).