Ascophyllum nodosum polysaccharide regulates gut microbiota metabolites to protect against colonic inflammation in mice.

Ascophyllum nodosum polysaccharide (ANP) can protect against colonic inflammation but the underlying mechanism is still unclear. This study has determined the metabolites of gut microbiota regulated by ANP to reveal the mechanism of the anti-inflammation effect of ANP. Using an in vitro colonic fermentation model, the results indicate that gut microbiota could utilize a proportion of ANP to increase the concentrations of short-chain fatty acids (SCFAs) and decrease ammonia content. Metabolomics revealed that 46 differential metabolites, such as betaine, L-carnitine, and aminoimidazole carboxamide ribonucleotide (AICAR), could be altered by ANP. Metabolic pathway analysis showed that ANP mainly up-regulated the phenylalanine, tyrosine, and tryptophan biosynthesis and aminoacyl-tRNA biosynthesis, which were negatively correlated with inflammation progression. Interestingly, these metabolites associated with inflammation were also up-regulated by ANP in colitis mice, including betaine, L-carnitine, AICAR, N-acetyl-glutamine, tryptophan, and valine, which were mainly associated with amino acid metabolism and aminoacyl-tRNA biosynthesis. Furthermore, the metabolites modulated by ANP were associated with the relative abundances of Akkermansia, Bacteroides, Blautia, Coprobacillus, Enterobacter, and Klebsiella. Additionally, based on VIP values, betaine is a key metabolite after the ANP supplement in vitro and in vivo. As indicated by these findings, ANP can up-regulate the production of SCFAs, betaine, L-carnitine, and AICAR and aminoacyl-tRNA biosynthesis to protect against colonic inflammation and maintain intestinal health.

Responses of the gut microbiota and metabolite profiles to sulfated polysaccharides from sea cucumber in humanized microbiota mice.

Sea cucumber Stichopus japonicus has been consumed as functional food traditionally in Asia, and its sulfated polysaccharide (SCSPsj) demonstrates health-promoting effects in rodents which are related to the regulation of the gut microbiota. However, little is known about the response of the human gut microbiota to SCSPsj. Therefore, the present study aimed to study the response of the donor microbiota to SCSPsj in vivo through a humanized microbiota mice model, which was constructed by antibiotic treatment combined with fecal microbiota transplant. The results revealed that the SCSPsj supplement could positively interact with the specific donor microbiota. It could significantly regulate the gut microbiota community, especially the abundance of Lactobacillus. In addition, SCSPsj could modulate the metabolites in serum and cecal contents of mice, including short-chain fatty acids (SCFAs) and lactic acid, and the changes of some bioactive metabolites were associated with the gut microbiota enriched by SCSPsj. Furthermore, in vitro experiments demonstrated that the Lactobacillus strains isolated could not be proliferated directly by SCSPsj, but SCSPsj significantly promoted biofilm formation and mucus binding of Lactobacillus spp., which contributed to the enrichment of Lactobacillus in vivo. The present study could provide insight into the application of SCSPsj as microbiota-directed food.

Gadolinium-Loaded Solid Lipid Nanoparticles for Colorectal Tumor in MR Colonography.

The current study aims to investigate the possibility of using solid lipid nanoparticles (SLNs)-enhanced magnetic resonance (MR) colonography to diagnose colorectal cancer. Gd-FITC-SLNs were synthesized by loading gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) and fluorescein isothiocyanate (FITC) simultaneously. Twenty mice received azoxymethane/dextran sulfate sodium (AOM/DSS) to induce adenocarcinoma of the colon and were divided into 4 groups, and 5 in per group. MR colonography were performed at different time periods before and after enema or intravenous injection of Gd-FITC-SLNs or Gd-DTPA. The results demonstrated SNR (signal-to-noise ratio) significantly increased from 1.56- to 1.76-fold within the colorectal tumors after the enema of Gd-FITC-SLNs (p < 0.001). No differences in SNR were observed after the enema of Gd-DTPA (p > 0.05). Besides, SNR increased from 1.54- to 1.72-fold within the colorectal tumors after the intravenous injection of Gd-FITC-SLNs (p < 0.001) while SNR increased from 1.39to 1.57-fold within the colorectal tumors after the injection of Gd-DTPA (p < 0.001). In addition, SNR within colorectal tumors significantly increased ranging from 20th to 140th min, and lasted for about 120 min (p < 0.05) after the enema of Gd-FITC-SLNs and SNR within colorectal tumors also significantly increased ranging from 0th hour to 8th hour, lasted for about 8 hour (p < 0.05) after the injection of Gd-FITC-SLNs. However, after the injection of Gd-DTPA, SNR within colorectal tumors significantly increased only ranging from 0th min to 20th min after administration (p < 0.01). Furthermore, hematoxylin and eosin (H&E) staining revealed that all mice developed adenocarcinoma of the colon. In summary, it is feasible by using Gd-FITC-SLNs in MR colonography to diagnose colorectal cancer. Enema of Gd-FITC-SLNs can provide marked enhancement of colorectal tumors quickly, and safer while intravenous injection of Gd-FITC-SLNs can provide a long-lasting enhancement of colorectal tumors in MR colonography. These findings present a potential clinical application of Gd-FITC-SLNs on MR colonography.

MR imaging tracking of inflammation-activatable engineered neutrophils for targeted therapy of surgically treated glioma.

Cell-based drug delivery systems have shown promising capability for tumor-targeted therapy owing to the intrinsic tumor-homing and drug-carrying property of some living cells. However, imaging tracking of their migration and bio-effects is urgently needed for clinical application, especially for glioma. Here, we report the inflammation-activatable engineered neutrophils by internalizing doxorubicin-loaded magnetic mesoporous silica nanoparticles (ND-MMSNs) which can provide the potential for magnetic resonance (MR) imaging tracking of the drug-loaded cells to actively target inflamed brain tumor after surgical resection of primary tumor. The phagocytized D-MMSNs possess high drug loading efficiency and do not affect the host neutrophils' viability, thus remarkably improving intratumoral drug concentration and delaying relapse of surgically treated glioma. Our study offers a new strategy in targeted cancer theranostics through combining the merits of living cells and nanoparticle carriers.

Pomegranate extract decreases oxidative stress and alleviates mitochondrial impairment by activating AMPK-Nrf2 in hypothalamic paraventricular nucleus of spontaneously hypertensive rats.

High blood pressure, or "hypertension," is associated with high levels of oxidative stress in the paraventricular nucleus of the hypothalamus. While pomegranate extract is a known antioxidant that is thought to have antihypertensive effects, the mechanism whereby pomegranate extract lowers blood pressure and the tissue that mediates its antihypertensive effects are currently unknown. We have used a spontaneously hypertensive rat model to investigate the antihypertensive properties of pomegranate extract. We found that chronic treatment of hypertensive rats with pomegranate extract significantly reduced blood pressure and cardiac hypertrophy. Furthermore, pomegranate extract reduced oxidative stress, increased the antioxidant defense system, and decreased inflammation in the paraventricular nucleus of hypertensive rats. We determined that pomegranate extract reduced mitochondrial superoxide anion levels and increased mitochondrial function in the paraventricular nucleus of hypertensive rats by promoting mitochondrial biogenesis and improving mitochondrial dynamics and clearance. We went on to identify the AMPK-nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) pathway as a mechanism whereby pomegranate extract reduces oxidative stress in the paraventricular nucleus to relieve hypertension. Our findings demonstrate that pomegranate extract alleviates hypertension by reducing oxidative stress and improving mitochondrial function in the paraventricular nucleus, and reveal multiple novel targets for therapeutic treatment of hypertension.

Coral calcium hydride prevents hepatic steatosis in high fat diet-induced obese rats: A potent mitochondrial nutrient and phase II enzyme inducer.

Diet-induced nonalcoholic fatty liver disease (NAFLD) is characterized by profound lipid accumulation and associated with an inflammatory response, oxidative stress and hepatic mitochondrial dysfunction. We previously demonstrated that some mitochondrial nutrients effectively ameliorated high fat diet (HFD)-induced hepatic steatosis and metabolic disorders. Molecular hydrogen in hydrogen-rich liquid or inhaling gas, which has been confirmed in scavenging reactive oxygen species and preventing mitochondrial decay, improved metabolic syndrome in patients and animal models. Coral calcium hydride (CCH) is a new solid molecular hydrogen carrier made of coral calcium. However, whether and how CCH impacts HFD-induced hepatic steatosis remains uninvestigated. In the present study, we applied CCH to a HFD-induced NAFLD rat model for 13 weeks. We found that CCH durably generated hydrogen in vivo and in vitro. CCH treatment significantly reduced body weight gain, improved glucose and lipid metabolism and attenuated hepatic steatosis in HFD-induced obese rats with no influence on food and water intake. Moreover, CCH effectively improved HFD-induced hepatic mitochondrial dysfunction, reduced oxidative stress, and activated phase II enzymes. Our results suggest that CCH is an efficient hydrogen-rich agent, which could prevent HFD-induced NAFLD via activating phase II enzymes and improving mitochondrial function.

Mitochondrial dysfunction in obesity-associated nonalcoholic fatty liver disease: the protective effects of pomegranate with its active component punicalagin.

AIMS: Punicalagin (PU) is one of the major ellagitannins found in the pomegranate (Punica granatum), which is a popular fruit with several health benefits. So far, no studies have evaluated the effects of PU on nonalcoholic fatty liver disease (NAFLD). Our work aims at studying the effect of PU-enriched pomegranate extract (PE) on high fat diet (HFD)-induced NAFLD. RESULTS: PE administration at a dosage of 150 mg/kg/day significantly inhibited HFD-induced hyperlipidemia and hepatic lipid deposition. As major contributors to NAFLD, increased expression of pro-inflammatory cytokines such as tumor necrosis factor-alpha, interleukins 1, 4, and 6 as well as augmented oxidative stress in hepatocytes followed by nuclear factor (erythroid-derived-2)-like 2 (Nrf2) activation were normalized through PE supplementation. In addition, PE treatment reduced uncoupling protein 2 (UCP2) expression, restored ATP content, suppressed mitochondrial protein oxidation, and improved mitochondrial complex activity in the liver. In contrast, mitochondrial content was not affected despite increased peroxisomal proliferator-activated receptor-gamma coactivator-1α (PGC-1α) and elevated expression of genes related to mitochondrial beta-oxidation after PE treatment. Finally, PU was identified as the predominant active component of PE with regard to the lowering of triglyceride and cholesterol content in HepG2 cells, and both PU- and PE-protected cells from palmitate induced mitochondrial dysfunction and insulin resistance. INNOVATION: Our work presents the beneficial effects of PE on obesity-associated NAFLD and multiple risk factors. PU was proposed to be the major active component. CONCLUSIONS: By promoting mitochondrial function, eliminating oxidative stress and inflammation, PU may be a useful nutrient for the treatment of NAFLD.

A small-molecule p53 activator induces apoptosis through inhibiting MDMX expression in breast cancer cells.

The tumor suppressor p53 is often inactivated in breast cancer cells because the overexpression of its repressors (e.g., MDM2 and MDMX). Restoration of p53 activity by small molecules through counteracting p53 repressors can lead to in vivo tumor regression and is therefore considered a promising strategy for treatments of cancer. Recent efforts in high-throughput drug screening and rational drug design have identified several structurally diverse small-molecule p53 activators, including a pseudourea derivative XI-011 (NSC146109). This small molecule strongly activates p53 while selectively inhibiting growth of transformed cells without inducing genotoxicity, indicating its potential as a drug lead for p53-targeted therapy. However, the mechanism(s) by which XI-011 activates p53 and the effects of XI-011 on growth of breast cancer cells are currently unknown. Here, we report that XI-011 promoted breast cancer cells to undergo apoptosis through activating p53 and inducing expression of proapoptotic genes. Importantly, we found that activation of p53 by this small molecule was achieved through a novel mechanism, that is, inhibition of MDMX expression. XI-011 repressed the MDMX promoter, resulting in down-regulation of MDMX messenger RNA level in MCF-7 cells. In line with these results, XI-011 decreased the viability of breast cancer cells expressing low levels of MDMX in a less-efficient manner. Interestingly, XI-011 acted additively with the MDM2 antagonist Nutlin-3a to inhibit growth of breast cancer cells. We conclude that XI-011 belongs to a novel class of small-molecule p53 activators that target MDMX and could be of value in treating breast cancer.

A novel high-throughput screening system identifies a small molecule repressive for matrix metalloproteinase-9 expression.

Aberrant gene expression is one of the driving forces for cancer progression and is considered an ideal target for chemical intervention. Although emerging bioluminescence reporter systems allow high-throughput searches for small molecules regulatory for gene expression, frequent silencing of reporter genes by epigenetic mechanisms hinders wide application of this drug discovery strategy. Here we report a novel system that directs the integration of a promoter-reporter construct to an open chromosomal location by Flp-mediated homologous recombination, thereby overcoming reporter-gene silencing. Using this system, we have screened more than 8000 compounds in the DIVERSet chemical library for repressors of a matrix metalloproteinase-9 (MMP-9) promoter and identified 5-methyl-2-(4-methylphenyl)-1H-benzimidazole (MPBD) inhibitory for MMP-9 gene expression. Consistent with this effect, MPBD inhibits MMP-9-dependent invasion of UMSCC-1 oral cancer cells, preosteoclast migration, and receptor activator of nuclear factor-kappaB ligand-induced osteoclast activity over concentration ranges that repressed MMP-9 expression. Mechanistic studies indicated that MPBD antagonizes AP-1 function by inhibiting its transactivation activity. We conclude that the Flp-mediated homologous recombination system to direct reporter integration into open chromatin regions represents a novel strategy allowing for the development of high-throughput systems screening for lead compounds targeting aberrant gene expression in cancer.