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Cholesterol, as an important component in mammalian cells, is efficient for viral entry, replication, and assembly. Oxysterols especially hydroxylated cholesterols are recognized as novel regulators of the innate immune response. The antiviral ability of 25HC (25-Hydroxycholesterol) is uncovered due to its role as a metabolic product of the interferon-stimulated gene CH25H (cholesterol-25-hydroxylase). With the advancement of research, the biological functions of 25HC and its structural functions have been interpreted gradually. Furthermore, the underlying mechanisms of antiviral effect of 25HC are not only limited to interferon regulation. Taken up by the special biosynthetic ways and structure, 25HC contributes to modulate not only the cholesterol metabolism but also autophagy and inflammation by regulating signaling pathways. The outcome of modulation by 25HC seems to be largely dependent on the cell types, viruses and context of cell microenvironments. In this paper, we review the recent proceedings on the regulatory effect of 25HC on interferon-independent signaling pathways related to its antiviral capacity and its putative underlying mechanisms.

Escherichia coli is one of the most important pathogens that cause clinical mastitis in dairy cattle worldwide and lead to severe economic losses. Antibiotics are often used to treat this inflammatory disease; however, antimicrobial resistance and environmental pollution cannot be ignored. Probiotic is the best alternative; however, its mechanisms of action to prevent mastitis remain unclear. Moreover, the role of probiotics in regulating mitophagy, a selective autophagy that maintains mitochondrial quality, needs to be explored. E. coli infection induced NOD-like receptor family member pyrin domain-containing protein 3 (NLRP3) inflammasome assembly, Caspase-1 activation, and apoptosis in MAC-T cells. Infection also resulted in mitochondrial damage and subsequent increase in reactive oxygen species (ROS) production. Moreover, inhibition of ROS release by scavenger N-acetyl-L-cysteine (NAC) abrogated the importance of ROS in NLRP3 assembly and apoptosis in MAC-T cells. Pretreatment with Lactobacillus rhamnosus GR-1 (LGR-1), a probiotic, alleviated E. coli -induced NLRP3 inflammasome activation and apoptosis via ROS inhibition. Besides, E. coli infection inhibited mitophagy while LGR-1 pretreatment augmented PINK1/Parkin–mediated mitophagy activation, which further blocked ROS generation. To explore the effect of LGR-1 in vivo , a mouse mastitis model was established. The results showed that LGR-1 pretreatment had preventive and protective effects on E. coli induced mastitis, and could reduce cytokines levels such as IL-1β and TNF-α. In accordance with the results in vitro , E. coli can inhibit mitophagy and activate NLRP3 inflammasome and apoptosis, while LGR-1 can weaken the effect of E. coli . Taken together, our data indicated that LGR-1 pretreatment induced PINK1/Parkin-mediated mitophagy that eliminated damaged mitochondria and reduced ROS production and NLRP3 inflammasome activation, which subsequently decreased E. coli -induced apoptosis. To conclude, our study suggests that therapeutic strategies aiming at the upregulation of mitophagy under E. coli -induced mastitis may preserve mitochondrial function and provide theoretical support for the application of probiotics in bovine mastitis.

Antimicrobial peptides (AMPs) are instrumental in maintaining intestinal homeostasis and have emerged as potential therapeutic candidates for ameliorating intestinal bacterial infections. However, the intrinsic instability associated with the in vivo delivery of AMPs constitutes a substantial impediment to their therapeutic efficacy in treating infections. In this study, we genetically modified Bacillus subtilis ( B. subtilis ) WB600 to express Zophobas atratus defensin (ZD), an antimicrobial peptide with broad-spectrum activity isolated from Zophobas atratus , for oral administration. This engineered strain effectively protects against Salmonella Infantis ( S. Infantis) infection in mice. Pretreatment with WB600/ZD prevented NF-κB pathway activation induced by S. Infantis infection and increased expression of antioxidant and tight junction proteins, thus alleviating the severity of intestinal inflammation in both the jejunum and ileum ( P  < 0.01). Moreover, WB600/ZD pretreatment facilitated the growth of beneficial bacteria such as Lachnospiraceae , Butyricicoccus , Eubacterium_xylanophilum , and Clostridia_UCG-014 while decreasing the abundance of pathogenic bacteria such as Escherichia-Shigella and Salmonella ( P  < 0.05). In conclusion, this study underscores the protective effects of WB600/ZD on S. Infantis-induced intestinal inflammation, suggesting that oral delivery of B. subtilis WB600/ZD may be a promising prophylactic strategy for combating bacterial infections in the intestine.

Endometritis is a common reproductive disorder in dairy cows, with antibiotics being the primary treatment option. However, the overuse of antibiotics has contributed to the growing problem of antimicrobial resistance. Antimicrobial peptides (AMPs) have been widely studied for their ability to kill bacteria and modulate immune responses. Previous research has focused on modifying natural AMPs extracted from Zophabas atratus haemolymph; however, these peptides have displayed limited effectiveness against bacteria. To overcome this limitation, researchers engineered a modified AMP, Z-FV7, by incorporating the sequence of the human-derived AMP LL-37. The resulting peptide demonstrated a favourable safety profile, with a minimum inhibitory concentration (MIC) reduced to 32 μg/mL and improved antibacterial activity against pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa . Z-FV7 was tested in a bovine uterine epithelial cell model infected with Escherichia coli and in a murine model of endometritis. The findings showed that Z-FV7 alleviated clinical symptoms, inhibited the activation of the NF-κB signalling pathway induced by drug-resistant E. coli , reduced the expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), and promoted the expression of tight junction proteins (Claudin-1 and ZO-1). These results indicated that Z-FV7 can help reduce uterine inflammation and provide therapeutic outcomes similar to those of antibiotics during E. coli infection. Overall, Z-FV7 holds promise as a potential alternative to antibiotics for treating endometriosis in the future.

Bovine viral diarrhea virus (BVDV) causes a severe threat to the cattle industry due to ineffective control measures. Gypenoside is the primary component of Gynostemma pentaphyllum, which has potential medicinal value and has been widely applied as a food additive and herbal supplement. However, little is known about the antiviral effects of gypenoside. The present study aimed to explore the antiviral activities of gypenoside against BVDV infection. The inhibitory activity of gypenoside against BVDV was assessed by using virus titration and performing Western blotting, quantitative reverse transcription PCR (RT-qPCR), and immunofluorescence assays in MDBK cells. We found that gypenoside exhibited high anti-BVDV activity by interfering with the viral attachment to and internalization in cells. The study showed that BVDV infection inhibits apoptosis of infected cells from escaping the innate defense of host cells. Our data further demonstrated that gypenoside inhibited BVDV infection by electively activating the apoptosis of BVDV-infected cells for execution, as evidenced by the regulation of the expression of the apoptosis-related protein, promotion of caspase-3 activation, and display of positive TUNEL staining; no toxicity was observed in non-infected cells. Collectively, the data identified that gypenoside exerts an anti-BVDV-infection role by inhibiting viral attachment and internalization and selectively purging virally infected cells. Therefore, our study will contribute to the development of a novel prophylactic and therapeutic strategy against BVDV infection.

Salmonella Typhimurium (S. Typhimurium) is an aggressive zoonotic pathogen that causes enteritis and diarrhea. Antibiotic therapy is still the primary method at present. However, the increasing emergence of multi-drug resistant bacteria weakens the therapeutic efficacy of antibiotics. Probiotics have been widely studied as an alternative antibiotic therapy. In this study, we established an IPEC-J2 cell model of S. Typhimurium infection, aiming to determine the protective effect of Lactobacillus johnsonii L531 (L. johnsonii L531) on S. Typhimurium infection. As our data showed, S. Typhimurium infection resulted in a robust inflammatory response demonstrated by promoted protein levels of the inflammatory-related pathway (TLR4, MyD88, p-IκBα, and p-p65), increased cytokine levels of IL-6, IL-1β, IL-18, and TNF-α, and activated the NLRP3 inflammasome via promoting its assembly. However, L. johnsonii L531 pre-incubation inhibited the activation of the above inflammatory signaling pathways and reduced the expression levels of pro-inflammatory cytokines. In addition, L. johnsonii L531 alleviated the damage of S. Typhimurium to tight junctions ZO-1, Occludin, and Claudin-1. In summary, our findings suggested that L. johnsonii L531 alleviated S. Typhimurium-induced tight junction injury by inhibiting the TLR4/NF-κB/NLRP3 inflammasome signaling pathway.

With the in-depth advancement of underground transportation in China, the connecting aisle is used as a link between different underground spaces to provide sufficient security and connection. The basic structural units of underground and aboveground spaces play an extremely important role. The use of the mechanical connecting aisle construction of over mucky strata is difficult, and it is easy to have an impact on the main tunnel. To ensure the safety of connecting aisle construction, studies should be performed on the construction technology, equipment, scheme, and related risk analysis of mechanical connecting aisle construction. In this study the work breakdown structure-risk breakdown structure combined with the expert investigation method is used to comprehensively identify the construction process, construct the risk index system of mechanical connecting aisle construction, determine the initial risk value, and comprehensively use the fuzzy-analytic hierarchical process to establish a fuzzy complementary judgment matrix, obtain the risk-weighted correction value, and quantitatively evaluate the risk source level of the mechanical connecting aisle construction. Based on the assessment method, the risk assessment of the mechanical connecting aisle construction project in Daqing section of Qingdao Metro Line 8 was performed, 113 potential risk sources were identified, and the comprehensive assessment obtained 7 major risk sources such as “improperly designed construction organization,” “instability of excavation surface,” and “easy leakage of lower river crossing” that were greater than the total risk average of 2.053. Corresponding risk response measures were proposed, which provided a reference for the risk assessment of similar projects in the construction of similar projects on mechanical connecting aisle construction in the Bohai mudstone stratum with high water pressure.

Background Bacillus cereus is an important pathogen that causes human food poisoning, specifically diarrhea and vomiting. B. cereus can also induce mastitis in dairy cows and has a strong survival ability in milk, as it cannot be inactivated by high-temperature short-time pasteurization. Therefore, B. cereus can enter the market through pasteurized milk and other dairy products, imposing enormous hidden dangers on food safety and human health. Results In this study, B. cereus 2101 (BC) was isolated from milk samples of cows with mastitis. BC grew rapidly with strong hemolysis, making it difficult to prevent mastitis and ensure food security. MAC-T cells were treated with BC and/or Lactobacillus rhamnosus GR-1 (LGR-1). Pretreatment with LGR-1 protected the integrity of tight junctions and the expression of zonula occludens-1 (ZO-1) and occludin destroyed by BC. Furthermore, LGR-1 pretreatment reduced the expression of NOD-like receptor family member pyrin domain-containing protein 3 (NLRP3), caspase recruitment and activation domain (ASC), Caspase-1 p20, gasdermin D (GSDMD) p30, inflammatory factors (interleukin (IL)-1β and IL-18), and cell death induced by BC. Moreover, LGR-1 pretreatment reduced NLRP3 inflammasome activity and increased expressions of ZO-1 and occludin induced by lipopolysaccharides (LPS) + ATP stimulation. MAC-T cells were transfected with NLRP3 siRNA or MCC950 and/or treated with BC and/or LGR-1. NLRP3-siRNA transfection and MCC950 attenuated BC-induced NLRP3 inflammasome activity. Expression of inflammatory cytokines and cell death suggested that the inflammatory pathway might play an important role in the induction of the NLRP3 inflammasome by BC and the protection of LGR-1. Conclusions These results suggest that LGR-1 might be a probiotic alternative to antibiotics and could be administered to prevent mastitis in dairy cows, thus ensuring food security.

Probiotics as an effective and safe strategy for controlling Salmonella infection are much sought after, while autophagy is a central issue in eliminating intracellular pathogens of intestinal epithelial cells. In this study, an animal model of colitis has been developed by infecting weaned pigs orally with a strain of Salmonella Infantis in order to illuminate the potential efficacy of a mixture of Lactobacillus and Bacillus (CBB-MIX) in the resistance to Salmonella infection by regulating butyrate-mediated autophagy. We found that CBB-MIX alleviated S . Infantis-induced colitis and tissue damage. Autophagy markers ATG5, Beclin-1, and the LC3-II/I ratio were significantly enhanced by S . Infantis infection, while treatment with CBB-MIX suppressed S . Infantis-induced autophagy. Additionally, S . Infantis-induced colonic microbial dysbiosis was restored by this treatment, which also preserved the abundance of the butyrate-producing bacteria and the butyrate concentration in the colon. A Caco-2 cell model of S . Infantis infection showed that butyrate had the same effect as the CBB-MIX in restraining S . Infantis-induced autophagy activation. Further, the intracellular S . Infantis load assay indicated that butyrate restricted the replication of cytosolic S . Infantis rather than that in Salmonella -containing vacuoles. Suppression of autophagy by knockdown of ATG5 also attenuated S . Infantis-induced cell injury. Moreover, hyper-replication of cytosolic S . Infantis in Caco-2 cells was significantly decreased when autophagy was inhibited. Our data demonstrated that Salmonella may benefit from autophagy for cytosolic replication and butyrate-mediated autophagy inhibition reduced the intracellular Salmonella load in pigs treated with a probiotic mixture of Lactobacillus and Bacillus.

The mechanical construction method for a subway contact channel has the advantages of a short construction period and high safety, and is more and more being applied in coastal soft-soil areas. In order to explore the suitability of this method in inland areas, a full-scale model test platform is used to simulate the shield-cutting construction process of the subway contact channel. The convergence deformation of the segments and the strain of the reinforcement and concrete are tested, so as to analyze the internal force and deformation law of the tunnel structure during cutting construction. The influence of the steel ring on the deformation of the subway contact channel is also studied. It is found that the segment convergence at the top is less than that at the waist position, and the convergence deformation of the waist is less than 30 mm; the internal force of the segment redistributes and the axial force mainly decreases during the cutting process; the stress state may change from compression to tension. The segment structure of the main tunnel, the supporting structure in the tunnel, and the stiffness of the steel-ring-lined composite pipe segment have little influence on the cutting force of the contact channel. The research results provide the corresponding technical indexes for the construction of a contact channel by the mechanical method, as well as a reference for the design and optimization of a steel-ring-lined composite pipe segment.