The secondary damage in traumatic brain injury (TBI) can lead to lifelong disabilities, bringing enormous economic and psychological burden to patients and their families. Mitochondria, as the core mediator of the secondary injury cascade reaction in TBI, is an important target to prevent the spread of cell death and dysfunction. Thus, therapeutics that can accumulate at the damaged sites and subsequently rescue the functions of mitochondria would largely improve the outcome of TBI. Cyclosporine A (CsA), which can maintain the integrity of mitochondrial function, is among the most promising neuroprotective therapeutics for TBI treatment. However, the clinical application of CsA in TBI is largely hindered because of its poor access to the targets. Here, to realize targeted intracellular CsA delivery, we designed a lipoprotein biomimetic nanocarrier by incorporating CsA in the core and decorating a matrix metalloproteinase-9 activatable cell-penetrating peptide onto the surface of the lipoprotein-mimic nanocarrier. This CsA-loaded tailored reconstituted lipoprotein efficiently accumulated at the damaged brain sites, entered the target cells, bound to the membrane of mitochondria, more efficiently reduced neuronal damage, alleviated neuroinflammation, and rescued memory deficits at the dose 1/16 of free CsA in a controlled cortical impact injury mice model. The findings provide strong evidence that the secondary damages in TBI can be well controlled through targeted CsA delivery and highlight the potential of a lipoprotein biomimetic nanocarrier as a flexible nanoplatform for the management of TBI.

Background: Colitis-associated cancer (CAC) is a complication of inflammatory bowel disease (IBD) with a poor prognosis because it is often diagnosed in advanced stages with local progression or metastasis. Compared with the more common polyp-induced sporadic colorectal cancer (sCRC), CAC has different molecular mechanisms. Toll-like receptor 2 (TLR2) expression is not limited to cells related to inflammation and immune function. High levels of TLR2 expression in tumor tissues of colorectal cancer (CRC) patients have been reported. This report is to investigate the effects of knockout and knockdown of the TLR2 gene on the proliferation of CAC and sCRC. Methods: Twelve C57BL/6 J wild-type mice (WT) and 12 TLR2 knockout mice (TLR2-/-) were used to rapidly establish a colitis-associated cancer (CAC) model via the 1,2-dimethylhydrazine-dextran sodium sulfate (DMH-DSS) method and were divided into the normal WT control group (NC), TLR2 knockout control group (KC), normal wild-type tumor modeling group (NT), and TLR2 knockout tumor modeling group (KT), with 6 mice in each group. The general performance of the mice during modeling, the gross changes of the colon and the rectum, and the pathological score of HE staining were used to observe tumor growth. The expression of TLR2 was detected by immunohistochemistry, and tumor proliferation was detected by Ki67 labeling. Lentivirus carrying TLR2-RNAi was used to stably infect colorectal cancer cells (HCT116 and HT29) to knock down TLR2 gene expression. The experimental groups included the uninfected control group, negative control group, and gene knockdown group. After infection, the expression of TLR2 protein was detected by Western blot, and cell proliferation and the cell cycle were detected by the CCK-8 method and fluorescence-activated cell sorting. Western blot was used to detect the expression levels of p-NF-κβ, cyclin D1 and cyclin D3 protein in each group of cells. Results: TLR2 knockout in the CAC model resulted in greater changes in body weight and more severe diarrhea and colorectal hemorrhage. However, knocking out the TLR2 gene reduced the shortening of colorectal length, the number of tumors, and the total tumor volume and inhibited the growth of CAC. Knocking out the TLR2 gene also reduced the pathological score and tumor severity. TLR2 was localized in the cell membrane of the colorectal epithelium of the NC group and of the colorectal tumors of the NT group and was highly expressed in the NT group, while antigen Ki67 was localized in the nucleus of the colorectal tumor cells of the NT group and the KT group, and its expression was reduced in the KT group. In an in vitro sporadic colorectal cancer cell experiment, TLR2 protein in the TLR2 knockdown group was significantly downregulated, and TLR2 knockdown significantly inhibited the

Ulcerative colitis (UC), which is a type of inflammatory bowel disease, is a chronic intestinal disorder of multifactorial etiology. Numerous studies have indicated an association between UC and intestinal bacteria. However, a limited number of studies regarding the expression of interleukin-17 (IL-17) and interleukin-23 (IL-23) in association with intestinal bacteria have been performed. The aim of the current study was to investigate the gut microbiota alterations in patients with UC, at a number of taxonomic levels, and their relationship with intestinal inflammation by analyzing the protein expression of IL-17 and IL-23. Specimens were collected from 10 healthy controls and 16 patients with UC. A histological examination was performed in colonic tissues, IL-17 and IL-23 protein expression was detected by immunohistochemistry, fecal samples were sequenced using 16S rDNA sequencing and bioinformatics analysis was performed. The UC group exhibited an increased histological score (P<0.01) and upregulated IL-17 and IL-23 expression (P<0.01). At the order level, the bacterial diversity of the UC group was decreased. β-diversity analyses, including principal component analysis, principal coordinate analysis and non-metric multidimensional scaling, demonstrated that the two groups of samples were separated into two taxonomic categories, as distinct variations were observed in the analysis of group differences (P=0.001). Regarding the differences in species composition between the groups, Enterococcus was indicated to be the species with the greatest difference in abundance compared with the healthy control group (P<0.01), followed by Lactobacillus (P<0.05), Escherichia-Shigella (P<0.05), Bifidobacterium and Bacteroides. In addition, the average optical density of IL-17 was positively correlated with the histological score (ρ= 0.669; P= 0.035), Enterococcus (r= 0.843; P<0.001), Lactobacillus (r= 0.737; P= 0.001), Bifidobacterium (r= 0.773; P<0.001) and Escherichia-Shigella (r=0.663; P=0.005), and the average optical density of IL-23 was positively correlated with the histological score (ρ= 0.733; P= 0.016), Enterococcus (r= 0.771; P<0.001), Lactobacillus (r= 0.566; P= 0.022), Bifidobacterium (r= 0.517; P= 0.041) and Escherichia-Shigella (r= 0.613; P= 0.012). The results of the present study indicated that the intestinal microbiota of patients with UC differed from that of healthy controls at multiple taxonomic levels. The alterations of the intestinal microflora were closely associated with the degree of inflammation. The IL-23/IL-17 axis, as a key factor in the development of UC, maybe associated with the alterations of intestinal microflora. The interaction between intestinal microflora and the IL-23/IL-17 axis may serve an important role in the pathogenesis of UC.

Background: To assess the changes to left ventricular (LV) function of patients with coronary slow flow (CSF) in response to stress induced by low dose dobutamine. Methods: Based on coronary angiography (CAG) results, total of 186 patients undergoing CAG for chest pain and suspected coronary heart disease were assigned to the CSF group (n = 142) and control group (n = 44). Patients in the CSF group underwent two-dimensional speckle-tracking echocardiography (STE) during the dobutamine stress test to evaluate LV systolic and diastolic functions. Results: At rest, there were no statistically significant differences in LV peak systolic longitudinal strain (LS), LV peak systolic longitudinal strain rate (LSRs), LV peak early diastolic longitudinal strain rate (LSRed), LV circumferential strain (CS), or LV circumferential strain rate (CSRed) between the CSF and control groups. In the CSF group, LS and LSRs first increased as the infusion rate was increased to 10 µg/kg/min (all, p < 0.05), before decreasing at infusion rates of 15 and 20 g/kg/min (all, p < 0.05). CS and CSRed increased in the CSF group at infusion rates of 5, 10, and 15 µg/kg/min, (all, p < 0.05), but decreased significantly at 20 g/kg/min (all, p < 0.05). Conclusions: At rest, LV systolic and diastolic functions were comparable between the CSF and control groups. However, when blood flow to the heart muscles was insufficient, LSRed decreased first, followed by LS. In terms of sensitivity to myocardial ischemia, LS is a better strain parameter than CS.

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