Background: Although Alzheimer's disease (AD) is a central nervous system disease and type 2 diabetes mellitus (T2DM) is a metabolic disorder, an increasing number of genetic epidemiological studies show clear link between AD and T2DM. The current approach to uncovering the shared pathways between AD and T2DM involves association analysis; however, such analyses lack power to discover the mechanisms of the diseases. Methods:We develop novel statistical methods to shift the current paradigm of genetic analysis from association analysis to deep causal inference for uncovering the shared mechanisms between AD and T2DM, and develop pipelines to infer multilevel omics causal networks which lead to shifting the current paradigm of genetic analysis from genetic analysis alone to integrated causal genomic, epigenomic, transcriptional and phenotypic data analysis. To discover common causal paths from genetic variants to AD and T2DM, we also develop algorithms that can automatically search the causal paths from genetic variants to diseases and Results: The proposed methods and algorithms are applied to ROSMAP dataset with 432 individuals who simultaneously had genotype, RNA-seq, DNA methylation and some phenotypes. We construct multi-omics causal networks and identify 13 shared causal genes, 16 shared causal pathways between AD and T2DM, and 754 gene expression and 101 gene methylation nodes that were connected to both AD and T2DM in multi-omics causal networks. Conclusions:The results of application of the proposed pipelines for identifying causal paths to real data analysis of AD and T2DM provided strong evidence to support the link between AD and T2DM and unraveled causal mechanism to explain this link.

RNA-sequencing, a powerful tool, yields a comprehensive view of whole transcriptome. Intracerebral hemorrhage (ICH) is a devastating form of stroke. To date, RNA-sequencing analysis of ICH has not been reported. Peripheral blood mononuclear cells (PBMCs) were used as a source of mRNA for gene expression profile analysis in stroke. In this study, we performed transcriptome analyses for PBMCs from four ICH patients and four healthy volunteers on Illumina platform. We identified 4040 significantly differentially expressed genes (DEGs). Functional annotation of DEGs with DAVID Bioinformatics Resources indicated that genes associated with cell apoptosis, autophagy, cell-cell adhesion, inflammatory response, protein binding, positive regulation of gene expression, and signal transduction were most significantly enriched by DEGs. Gene set enrichment analysis identified 40 significant Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, including chemokine signaling, cytokine-cytokine receptor interaction, oxidative phosphorylation, and glutathione metabolism processes. These data point to a complex mechanism for ICH pathogenesis. Overall, the present study demonstrated an altered gene expression profile of PBMCs in response to acute ICH. Our study provided important information for understanding the molecular mechanisms of ICH pathogenesis at system-wide levels.

Pachymic acid (PA), a lanostane-type triterpenoid and the major component of Poria cocos alcoholic extracts, has various pharmacological effects, including anti-inflammatory, anti-oxidative and anti-apoptotic. However, few studies have investigated the effects of PA on lipopolysaccharide (LPS)-induced H9c2 cell apoptosis and inflammation, or identified the possible mechanisms underlying these effects. In the present study, H9c2 cardiomyocytes were stimulated by LPS and treated with or without PA. The increased mRNA expression levels of tumor necrosis factor-α, interleukin (IL)-1 and IL-6 induced by LPS were attenuated following treatment with PA. PA also attenuated LPS-induced apoptosis, as determined by a terminal deoxynucleotidyl transferase dUTP nick end labeling assay, and regulated the LPS-induced protein expression levels of caspase 3, 8 and 9. Furthermore, the phosphorylations of extracellular-regulated kinase (Erk)1/2 and p38 in the LPS-treated H9c2 cells were inhibited by PA. These results suggested that treatment with PA prevented the LPS-induced inflammatory and apoptotic response in cardiomyocytes, which may be mediated by inhibition of the Erk1/2 and p38 pathways.

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Supramolecular chemotherapy is a strategy that is currently used to improve the therapeutic efficacy of traditional chemotherapy while mitigating side effects. Heptaplatin, a platinum chemotherapeutic antitumor drug in colorectal tumors, is traditionally used in the clinic. However, its side effects and low efficiency in killing tumors remain unresolved. Herein, a facile supramolecular chemotherapy platform on account of the host–guest chemistry between cucurbit[7]­uril and the commercially available heptaplatin was studied. At pH 7.4, heptaplatin showed a strong binding to the cucurbit[7]­uril nanocarrier by 1H NMR, whose K a was (1.38 ± 0.06) × 106 M–1 by isothermal titration calorimetry (ITC). At pH 6.0 in a tumor microenvironment, overexpressed spermine can exchange competitively heptaplatin from heptaplatin-CB[7]. This supramolecular complex achieved higher antitumor activity on colorectal tumor cells and lower cytotoxicity than the drug alone on colorectal normal cells. Furthermore, the antitumor mechanisms of supramolecular complex were investigated by apoptosis, cell cycle, and spermine synthase. It was found that heptaplatin-CB[7] consumed more colorectal tumorous intracellular spermine by the spermine synthase assay (413.85 ± 0.004 pg/mL); hepataplatin-CB[7] caused early apoptosis (87.73%) of colorectal tumor cells; heptaplatin-CB[7] induced an inhibitory response in the G1 phase of the tumor cell cycle. These findings demonstrated that heptaplatin-CB[7] had higher antitumor activity toward human colorectal tumor cells but lower cytotoxicity toward human colorectal normal cells. It is expected to promote the supramolecular chemotherapy and translational development of the nanocomplex into the clinical field.