Investigation of the mechanism of nephrotoxicity of nux-vomica by PTGS2/CYP2C9-mediated arachidonic acid pathway and Jian Pi Tong Luo compound's protective effect.

The clinical effectiveness of nux-vomica in treating rheumatism and arthralgia is noteworthy; however, its nephrotoxicity has sparked global concerns. Hence, there is value in conducting studies on detoxification methods based on traditional Chinese medicine compatibility theory. Blood biochemistry, enzyme-linked immunosorbent assay, and pathological sections were used to evaluate both the nephrotoxicity of nux-vomica and the efficacy of the Jian Pi Tong Luo (JPTL) compound in mitigating this toxicity. Kidney metabolomics, using ultra-high-performance liquid chromatography-quadrupole-time-of-flight-MS (UPLC-Q-TOF-MS), was applied to elucidate the alterations in small-molecule metabolites in vivo. In addition, network pharmacology analysis was used to verify the mechanism and pathways underlying the nephrotoxicity associated with nux-vomica. Finally, essential targets were validated through molecular docking and western blotting. The findings indicated significant nephrotoxicity associated with nux-vomica, while the JPTL compound demonstrated the ability to alleviate this toxicity. The mechanism potentially involves nux-vomica activating the "PTGS2/CYP2C9-phosphatidylcholine-arachidonic acid metabolic pathway." This study establishes a scientific foundation for the clinical use of nux-vomica and lays groundwork for further research and safety assessment of toxic Chinese herbal medicines.

Effects of Cannabidiol on Parkinson's Disease in a Transgenic Mouse Model by Gut-Brain Metabolic Analysis.

Parkinson's disease (PD) is a common neurodegenerative disease characterized by a disorder of the dopaminergic system in the midbrain, causing classical PD motor symptoms. The therapeutic effect of cannabidiol (CBD) on PD has been a research frontier in recent years. However, the pathogenesis of PD and the therapeutic mechanism of cannabinoid remain unclear. To further study the causes of PD and the effect of CBD on PD, we exposed the PD transgenic mouse model to CBD and then estimated the motorial and postural coordination through a modified swim test. Afterwards, the mechanism was investigated via the histopathology of substantia nigra and the gut-brain metabolic analysis in the approach of UHPLC-TOF-MS. The results showed that CBD significantly improved motor deficits of PD model and protected the substantia nigra area. The metabolic function of fatty acid biosynthesis, arginine biosynthesis/metabolism, butanoate (ketone body) metabolism, ß-alanine metabolism, and pantothenate/CoA biosynthesis was highlighted in the pathological and therapeutic process along the gut-brain axis. In conclusion, CBD could attenuate PD via the neuroprotective effect on the midbrain. The attenuation of the central nervous system in turn improved motor performance of PD, which might be partially induced by the metabolic interaction between the gut-brain. In view of gut-brain metabolomics, the mechanism of PD pathogenesis and the effect of CBD on PD are highly related to the biosynthesis and metabolism of energy and essential substance.

Rutin Ameliorates Cadmium-Induced Necroptosis in the Chicken Liver via Inhibiting Oxidative Stress and MAPK/NF-κB Pathway.

Cadmium (Cd) is a recognized toxic metal and exerts serious hepatotoxicity in animals and humans. Rutin (RUT) is a dietary bioflavonoid with strong antioxidant and anti-inflammatory potential. However, little is known about the alleviating effect of RUT against Cd-induced liver necroptosis. The aim of this study was to ascertain the ameliorative mechanism of RUT on necroptosis triggered by Cd in chicken liver. One hundred twenty-eight 100-day-old Isa hens were randomly divided into four groups: the control group, RUT group, Cd + RUT cotreated group, and Cd group. Cd exposure prominently elevated Cd accumulation and the activities of liver function indicators (ALT and AST). Furthermore, the histopathological results, the overexpression of genes (RIPK1, RIPK3, and MLKL) related to the necroptosis pathway, and low Caspase 8 levels in Cd-exposed chicken liver indicated that Cd intoxication induced necroptosis in chicken liver. Meanwhile, Cd administration drastically increased the levels of oxidizing stress biomarkers (ROS production, MDA content, iNOS activity, and NO generation), and obviously reduced the activities of antioxidant enzymes (SOD, GPx, and CAT) and total antioxidant capacity (T-AOC) in chicken liver. Cd treatment promoted the expression of the main members of the MAPK and NF-κB pathways (JNK, ERK, P38, NF-κB, and TNF-α) and activated heat shock proteins (HSP27, HSP40, HSP60, HSP70, and HSP90). However, RUT application remarkably alleviated these Cd-induced variations and necroptosis injury. Overall, our study demonstrated that RUT might prevent Cd-induced necroptosis in the chicken liver by inhibiting oxidative stress and MAPK/NF-κB pathway.

1,8-cineole alleviates bisphenol A-induced apoptosis and necroptosis in bursa of Fabricius in chicken through regulating oxidative stress and PI3K/AKT pathway.

Bisphenol A (BPA), an important chemical raw material, is now a ubiquitous environmental contaminant. As an endocrine disruptor similar to estrogen, BPA increases the risk of various metabolic and chronic diseases. BPA has immunotoxicity to humans and animals. 1,8-cineole (CIN) is a plant-derived monoterpene with antioxidant and antiapoptosis actions. However, there are no reports about whether CIN could antagonize the BPA-induced apoptosis and necroptosis in bursa of Fabricius (BF) of chicken. This study was to elucidate the ameliorative mechanism of CIN on the apoptosis and necroptosis in BF induced by BPA. 120 broilers (1-day-old) were randomly divided into four groups: control group, CIN group, CIN and BPA co-treatment group, and BPA group. TUNEL analysis results, histopathological variations, and the overexpression of proapoptosis biomakers (Caspase 3, Bax, Cyt-c, and p53) and necroptosis pathway-related factors (RIPK1, RIPK3, MLKL, and FADD) indicated that BPA exposure induced the apoptosis and necroptosis in chicken BF. Moreover, BPA treatment elevated the levels of oxidative stress indexes (MDA, iNOS, and NO) and weaken antioxidases activity (SOD, GPx, and CAT) and total antioxidant capacity in chicken BF. BPA administration also lessened the expression of PI3K and AKT and promoted HSPs (HSP27, HSP40, HSP60, and HSP70) activation. whereas CIN supplementation prominently mitigated BPA-caused these changes and the apoptosis and necroptosis damages. In brief, this study illuminated that CIN could protect the chicken BF against BPA-induced apoptosis and necroptosis through restraining oxidative stress and activating PI3K/AKT pathway.

A Lactococcus lactis-vectored oral vaccine induces protective immunity of mice against enterotoxigenic Escherichia coli lethal challenge.

Enterotoxigenic Escherichia coli (ETEC) is a global primary pathogenic bacterium causing diarrhoea in human and a wide variety of neonatal animals. Lactococcus lactis as non-pathogenic and food-grade lactic acid bacteria has already been explored as a vector for mucosal vaccine. Here, the current study was undertaken to evaluate the live recombinant L. lactis (rL. lactis) vaccine expressing the trivalent enterotoxin protein STa-LTB-STb and the F5 fimbrial antigen (SLS-F5) with OmpH of Yersinia enterocolitica in protection against ETEC. Western blot confirmed the expression of fusion protein SLS-F5-OmpH in nisin-controlled expression (NICE) system. Mice orally immunized with rL. lactis-SLS-F5-OmpH were observed to produce high levels of mucosal SIgA and serum IgG antibodies, while also inducing increases in the production of CD4+ and CD8+ T cells, lymphocyte proliferation, and secretion of cytokines. Moreover, orally immunized mice produced complete protection after ETEC challenge. The above results suggested that rL. lactis-SLS-F5-OmpH has the potential as a candidate for oral vaccine against ETEC.

[Modulation effect of Acanthopanax senticosus polysaccharides through inflammatory cytokines in protecting immunological liver-injured mice].

The aim of this paper was to discuss the protective effect and mechanism of Acanthopanax senticosus polysaccharides( ASPs) on immunological liver injury caused by conanavalin A( Con A). BALB/c mice were randomly divided into seven groups: control group,model group( Con A),low-,medium-,and high-dose( 36. 25,72. 5,145 mg·kg~(-1)) ASPs groups,bifendate( 200 mg·kg~(-1),positive drug) group and pyrrolidinedithiocarbamate( PDTC,NF-κB inhibitor,200 mg·kg~(-1)) group. ASPs groups and bifendate group were given with corresponding drugs by ig administration once daily for 7 d. Control group,model group and PDTC group were given with normal saline by ig administration once daily for 7 d. After the last ig administration,PDTC was given in DTC group by iv administration( 200 mg·kg~(-1)); 0. 5 h after that,Con A( 20 mg·kg~(-1)) was injected via the tail vein to induce immunological liver injury in all the mice except normal control group. The mice were killed 8 h later and their liver tissues were collected for histopathological examination. The contents of nitric oxide( NO),superoxide dismutase( SOD),malondialdehyde( MDA),reduced glutathione( GSHPX),interleukin( IL-1ß) and tumor necrosis factor( TNF-α) in liver tissues were detected by kit assay. Western blot method was used to detect TNF-α,intercellular cell adhesion molecule-1( ICAM-1),inducible nitric oxide synthase( i NOS) and nuclear factor( NF-κB) protein expression in liver tissues. As compared with model group,ASPs not only could reduce the activity of MDA,NO,IL-1ß and TNF-α,but also increase the content of GSH-PX and SOD; at the same time,the protein expression levels of TNF-α,ICAM-1,i NOS and NF-κB were reduced in liver tissues; in addition,inflammatory cell infiltration was alleviated,hepatocyte cytoplasm was loose and swollen,and nuclear condensation and staining were improved. ASPs has a protective effect on immunological liver injury,and the mechanism may be associated with regulating secretion of inflammatory cytokines and the expression of adhesion factor through NF-κB signaling pathway.

Deletion of the vacJ gene affects the biology and virulence in Haemophilus parasuis serovar 5.

Haemophilus parasuis is an important pathogen causing severe infections in pigs. However, the specific bacterial factors that participate in pathogenic process are poorly understood. VacJ protein is a recently discovered outer membrane lipoprotein that relates to virulence in several pathogens. To characterize the function of the vacJ gene in H. parasuis virulent strain HS49, a vacJ gene-deletion mutant ΔvacJ and its complemented strain were constructed. Our findings supported that VacJ is essential for maintenance of cellular integrity and stress tolerance of H. parasuis, by the demonstrations that the ΔvacJ mutant showed morphological change, increased NPN fluorescence and, and decreased resistance to SDS-EDTA, osmotic and oxidation pressure. The increased susceptibility to several antibiotics in the ΔvacJ mutant further suggested that the stability of the outer membrane was impaired as a result of the mutation in the vacJ gene. Compared to the wild-type strain, the ΔvacJ mutant strain caused a decreased survival ratio from the serum and complement killing, and exhibited a significant decrease ability to adhere to and invade PK-15 cell. In addition, the ΔvacJ mutant showed reduced biofilm formation compared to the wild-type strain. Furthermore, the ΔvacJ was attenuated in a murine (Balb/C) model of infection and its LD50 value was approximately fifteen-fold higher than that of the wild-type or complementation strain. The data obtained in this study indicate that vacJ plays an essential role in maintaining outer membrane integrity, stress tolerance, biofilm formation, serum resistance, and adherence to and invasion of host cells related to H. parasuis and further suggest a putative role of VacJ lipoprotein in virulence regulation.