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Abstract Intracerebral hemorrhage (ICH) is reported as a common and often fatal type of stroke accompanied with high morbidity and mortality, and it frequently results in long-lasting neurological dysfunctions. However, the pathogenesis that contributes to ICH has not been fully understood. Rnf112, also known as Znf179, is a member of the RING finger protein family. The expression of Rnf112 is abundant in the brain and is modulated during brain progression and development. The study aimed to explore the role of Rnf112 in brain injury after ICH, as well as the underlying molecular mechanisms. The results indicated that ICH led to a significant decrease in Rnf112, which was confirmed in oxyhemoglobin (oxyHb)-incubated astrocytes and microglial cells. Moreover, the Rnf112 knockout (Rnf112−/−) mice and wild type (WT) mice induced by ICH were further employed. Compared to the WT/ICH group, Rnf112−/− mice exhibited accelerated brain injury, as evidenced by the increased brain water contents and neurological deficit scores (NDS). In comparison to WT/ICH group, a remarkable up-regulation in the release of pro-inflammatory cytokines, including tumor necrotic factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β, was observed in perihematoma tissues of Rnf112−/− mice on day 3 post-ICH. The process was along with promoted glial fibrillary acidic protein (GFAP) and Iba1 expression and reduced NeuN levels. Furthermore, ICH-induced increases in toll-like receptor (TLR)-4 and myeloid differentiation primary response protein (MyD88) expression were exacerbated by the loss of Rnf112. The phosphorylated expression of IKKα, inhibitor of NF-κB (IκBα) and nuclear factor-kappa B (NF-κB) induced by ICH in perihematoma tissues of mice was markedly enhanced in Rnf112−/− mice. Rnf112 repression-induced inflammatory response was verified in lipopolysaccharide (LPS)-incubated glial cells. In contrast, over-expressing Rnf112 markedly attenuated ICH-induced brain injury by restraining inflammation via inactivating TLR-4/NF-κB pathway. In summary, our findings suggested that Rnf112 expression was highly involved in the progression of ICH, and targeting Rnf112 signaling might be a promising therapeutic strategy against ICH development. Highlights • Rnf112−/− mice exhibits accelerated brain injury and neuroinflammation. • Rnf112−/− promotes inflammation by enhancing TLR-4/NF-κB pathway. • Over-expressing Rnf112 attenuates brain injury after intracerebral hemorrhage. [ABSTRACT FROM AUTHOR]

Structural disruption of gut microbiota and associated inflammation are considered important etiological factors in high fat diet (HFD)-induced metabolic syndrome (MS). Three candidate probiotic strains, Lactobacillus paracasei CNCM I-4270 (LC), L. rhamnosus I-3690 (LR) and Bifidobacterium animalis subsp. lactis I-2494 (BA), were individually administered to HFD-fed mice (108 cells day−1) for 12 weeks. Each strain attenuated weight gain and macrophage infiltration into epididymal adipose tissue and markedly improved glucose-insulin homeostasis and hepatic steatosis. Weighted UniFrac principal coordinate analysis based on 454 pyrosequencing of fecal bacterial 16S rRNA genes showed that the probiotic strains shifted the overall structure of the HFD-disrupted gut microbiota toward that of lean mice fed a normal (chow) diet. Redundancy analysis revealed that abundances of 83 operational taxonomic units (OTUs) were altered by probiotics. Forty-nine altered OTUs were significantly correlated with one or more host MS parameters and were designated 'functionally relevant phylotypes'. Thirteen of the 15 functionally relevant OTUs that were negatively correlated with MS phenotypes were promoted, and 26 of the 34 functionally relevant OTUs that were positively correlated with MS were reduced by at least one of the probiotics, but each strain changed a distinct set of functionally relevant OTUs. LC and LR increased cecal acetate but did not affect circulating lipopolysaccharide-binding protein; in contrast, BA did not increase acetate but significantly decreased adipose and hepatic tumor necrosis factor-α gene expression. These results suggest that Lactobacillus and Bifidobacterium differentially attenuate obesity comorbidities in part through strain-specific impacts on MS-associated phylotypes of gut microbiota in mice. [ABSTRACT FROM AUTHOR]

Disruption of the gut microbiota by high-fat diet (HFD) has been implicated in the development of obesity. It remains to be elucidated whether the HFD-induced shifts occur at the phylum level or whether they can be attributed to specific phylotypes; additionally, it is unclear to what extent the changes are reversible under normal chow (NC) feeding. One group (diet-induced obesity, DIO) of adult C57BL/6J mice was fed a HFD for 12 weeks until significant obesity and insulin resistance were observed, and then these mice were switched to NC feeding for 10 weeks. Upon switching to NC feeding, the metabolic deteriorations observed during HFD consumption were significantly alleviated. The second group (control, CHO) remained healthy under continuous NC feeding. UniFrac analysis of bar-coded pyrosequencing data showed continued structural segregation of DIO from CHO on HFD. At 4 weeks after switching back to NC, the gut microbiota in the DIO group had already moved back to the CHO space, and continued to progress along the same age trajectory and completely converged with CHO after 10 weeks. Redundancy analysis identified 77 key phylotypes responding to the dietary perturbations. HFD-induced shifts of these phylotypes all reverted to CHO levels over time. Some of these phylotypes exhibited robust age-related changes despite the dramatic abundance variations in response to dietary alternations. These findings suggest that HFD-induced structural changes of the gut microbiota can be attributed to reversible elevation or diminution of specific phylotypes, indicating the significant structural resilience of the gut microbiota of adult mice to dietary perturbations. [ABSTRACT FROM AUTHOR]