Exploring the potential therapeutic effect of Eucommia ulmoides–Dipsaci Radix herbal pair on osteoporosis based on network pharmacology and molecular docking technology

This study elaborated the multi-component, multi-target, and multi-pathway interaction mechanism of Eucommia ulmoides-Dipsaci Radix herbal pair in the treatment of osteoporosis.

Vorinostat exhibits anticancer effects in triple-negative breast cancer cells by preventing nitric oxide-driven histone deacetylation

Triple-negative breast cancers (TNBC) that produce nitric oxide (NO) are more aggressive, and the expression of the inducible form of nitric oxide synthase (NOS2) is a negative prognostic indicator. In these studies, we set out to investigate potential therapeutic strategies to counter the tumor-permissive properties of NO. We found that exposure to NO increased proliferation of TNBC cells and that treatment with the histone deacetylase inhibitor Vorinostat (SAHA) prevented this proliferation. When histone acetylation was measured in response to NO and/or SAHA, NO significantly decreased acetylation on histone 3 lysine 9 (H3K9ac) and SAHA increased H3K9ac. If NO and SAHA were sequentially administered to cells (in either order), an increase in acetylation was observed in all cases. Mechanistic studies suggest that the “deacetylase” activity of NO does not involve S-nitrosothiols or soluble guanylyl cyclase activation. The observed decrease in histone acetylation by NO required the interaction of NO with cellular iron pools and may be an overriding effect of NO-mediated increases in histone methylation at the same lysine residues. Our data revealed a novel pathway interaction of Vorinostat and provides new insight in therapeutic strategy for aggressive TNBCs.

Autophagy and Exosomes Relationship in Cancer: Friends or Foes?

Autophagy is an intracellular degradation process involved in the removal of proteins and damaged organelles by the formation of a double-membrane vesicle named autophagosome and degraded through fusion with lysosomes. An intricate relationship between autophagy and the endosomal and exosomal pathways can occur at different stages with important implications for normal physiology and human diseases. Recent researches have revealed that extracellular vesicles (EVs), such as exosomes, could have a cytoprotective role by inducing intracellular autophagy; on the other hand, autophagy plays a crucial role in the biogenesis and degradation of exosomes. Although the importance of these processes in cancer is well established, their interplay in tumor is only beginning to be documented. In some tumor contexts (1) autophagy and exosome-mediated release are coordinately activated, sharing the molecular machinery and regulatory mechanisms; (2) cancer cell-released exosomes impact on autophagy in recipient cells through mechanisms yet to be determined; (3) exosome-autophagy relationship could affect drug resistance and tumor microenvironment (TME). In this review, we survey emerging discoveries relevant to the exosomes and autophagy crosstalk in the context of cancer initiation, progression and recurrence. Consequently, we discuss clinical implications by targeting autophagy-exosomal pathway interaction and how this could lay a basis for the purpose of novel cancer therapeutics.

The nature of fast and slow pathway interaction during premature pacing: evaluation with high density mapping

Background Dual AV Nodal (AVN) inputs are associated with the fast pathway (FPW) superiorly, while the SPW activates inferiorly. In the present study, we evaluate the impact of PES on dual antegrade conduction. Objective To Define Antegrade Conduction Properties of the AV Node during PES Methods High density mapping (Orion, Rhythmia) was performed and analyzed in SR and S2 PES in 12 pts. The FPW activates the AVN and travels inferiorly, there is a point where the activation pivots toward the SPW and travels superiorly along the TV. The distance from the pivot point was measured to the HIS location in sinus rhythm and for each coupling interval. Both the distance and prematurity of the S2 coupling was normalized to the BCL during sinus rhythm. The coupling interval was then plotted vs the HIS-Collision distance. A regression analysis was used to compare data sets with significance defined a <0.05. Results Data was obtained in all 12 patients. In all patients, as pre-maturity of S2 increased, the pivot point moved superiorly until there was block in the FPW and activation to the AV node was entirely from the SPW. There is a functional line of block (LOB) between the FPW and SPW. Comparing normalized data decrement vs change in pivot point: R=0.8 p<0.0001 Conclusion During PES, the F/SPW interaction changes: increasing prematurity causes pivot point to move superiorly until the FPW blocks and AVN activates via the SPW. Decremental antegrade conduction occurs within FPW and is associated with the superior pivot shift toward the AVN suggesting a functional LOB. This relationship is linear. Funding Acknowledgement Type of funding source: None

Cell Signaling Pathway Reporters in Adult Hematopoietic Stem Cells

Hematopoietic stem cells (HSCs) develop at several anatomical locations and are thought to undergo different niche regulatory cues originating from highly conserved cell signaling pathways, such as Wnt, Notch, TGF-β family, and Hedgehog signaling. Most insight into these pathways has been obtained by reporter models and loss- or gain of function experiments, yet results differ in many cases according to the approach. In this review, we discuss existing murine reporter models regarding these pathways, considering the genetic constructs and reporter proteins in the context of HSC studies; yet these models are relevant for all other stem cell systems. Lastly, we describe a multi-reporter model to properly study and understand the cross-pathway interaction and how reporter models are highly valuable tools to understand complex signaling dynamics in stem cells.

Molecular characterization, biological function, tumor microenvironment association and clinical significance of m6A regulators in lung adenocarcinoma

N6-methyladenosine (m6A) modification can regulate a variety of biological processes. However, the implications of m6A modification in lung adenocarcinoma (LUAD) remain largely unknown. Here, we systematically evaluated the m6A modification features in more than 2400 LUAD samples by analyzing the multi-omics features of 23 m6A regulators. We depicted the genetic variation features of m6A regulators, and found mutations of FTO and YTHDF3 were linked to worse overall survival. Many m6A regulators were aberrantly expressed in tumors, among which FTO, IGF2BP3, YTHDF1 and RBM15 showed consistent alteration features across 11 independent cohorts. Besides, the regulator-pathway interaction network demonstrated that m6A modification was associated with various biological pathways, including immune-related pathways. The correlation between m6A regulators and tumor microenvironment was also assessed. We found that LRPPRC was negatively correlated with most tumor-infiltrating immune cells. On the other hand, we established a scoring tool named m6Sig, which was positively correlated with PD-L1 expression and could reflect both the tumor microenvironment characterization and prognosis of LUAD patients. Comparison of CNV between high and low m6Sig groups revealed differences on chromosome 7. Application of m6Sig on an anti-PD-L1 immunotherapy cohort confirmed that the high m6Sig group demonstrated therapeutic advantages and clinical benefits. Our study indicated that m6A modification is involved in many aspects of LUAD and contributes to tumor microenvironment formation. A better understanding of m6A modification will provide more insights into the molecular mechanisms of LUAD and facilitate developing more effective personalized treatment strategies. A web application was built along with this study (http://www.bioinfo-zs.com/luadexpress/).

Locomotor deficits in ALS mice are paralleled by loss of V1-interneuron-connections onto fast motor neurons

ALS is characterized by progressive inability to execute movements. Motor neurons innervating fast-twitch muscle fibers exhibit preferential degeneration. The reason for differential vulnerability of fast motor neurons, and its consequence on motor output is not known. Here, we show that fast motor neurons receive more inhibitory synaptic inputs than slow motor neurons, and loss of inhibitory synapses onto fast motor neurons precedes disease progression in the SOD1G93A mouse model of ALS. Loss of inhibitory synapses on fast motor neurons is accounted for by a loss of synapses from inhibitory V1 spinal interneurons. Deficits in V1-motor neuron connectivity appear prior to motor neuron death and are paralleled by development of specific SOD1G93A locomotor deficits. These distinct SOD1G93A locomotor deficits are phenocopied by silencing of inhibitory V1 spinal interneurons in wild-type mice. Silencing inhibitory V1 spinal interneurons does not exacerbate SOD1G93A locomotor deficits, suggesting phenotypic pathway interaction. Our study identifies a potential cell non-autonomous source of motor neuronal vulnerability in ALS, and links ALS-induced changes in locomotor phenotypes to inhibitory V1 interneurons.

A systems pharmacology approach to determine the mechanisms of action of pleiotropic natural products in breast cancer from transcriptome data

Plant-derived compounds as natural products have attracted a lot of attention in the treatment of complex diseases, especially cancers, primarily due to their poly-pharmacologic mechanisms of action. However, methodological limitations have impeded gaining complete knowledge of their molecular targets. While most of the current understanding of these compounds is based on reductive methods, it is increasingly becoming clear that holistic techniques, leveraging current improvements in omic data collection and bioinformatics methods, are better suited for elucidating their systemic effects. Here, to provide an explanation to the mechanisms of action of plant-derived natural products in breast cancer, we applied a data integration approach to comprehensively study oncogenic signaling pathways targeted by withaferin A, actein, compound kushen injection and indole-3-carbinol. Specifically, we mapped the transcriptome-level response of cancer cell lines to these molecules on a human protein-protein interaction network and constructed the underlying active subnetworks. We used these subnetworks to define the perturbed signaling pathways and validated their relevance in carcinogenesis. The similarity of each identified oncogenic signaling pathway in terms of overlapping genes was subsequently used to construct pathway-pathway interaction networks, which were used to reduce pathway redundancy and to identify pathway crosstalk. Filtered pathways were then mapped on three major carcinogenesis processes. The results showed that the pleiotropic effects of plant-derived drugs at the gene expression level can be used to predict targeted pathways. Thus, from such pathways, it is possible to infer a systemic mechanism of action of such natural products.

Cooperative driver pathway discovery via fusion of multi-relational data of genes, miRNAs and pathways

Discovering driver pathways is an essential step to uncover the molecular mechanism underlying cancer and to explore precise treatments for cancer patients. However, due to the difficulties of mapping genes to pathways and the limited knowledge about pathway interactions, most previous work focus on identifying individual pathways. In practice, two (or even more) pathways interplay and often cooperatively trigger cancer. In this study, we proposed a new approach called CDPathway to discover cooperative driver pathways. First, CDPathway introduces a driver impact quantification function to quantify the driver weight of each gene. CDPathway assumes that genes with larger weights contribute more to the occurrence of the target disease and identifies them as candidate driver genes. Next, it constructs a heterogeneous network composed of genes, miRNAs and pathways nodes based on the known intra(inter)-relations between them and assigns the quantified driver weights to gene–pathway and gene–miRNA relational edges. To transfer driver impacts of genes to pathway interaction pairs, CDPathway collaboratively factorizes the weighted adjacency matrices of the heterogeneous network to explore the latent relations between genes, miRNAs and pathways. After this, it reconstructs the pathway interaction network and identifies the pathway pairs with maximal interactive and driver weights as cooperative driver pathways. Experimental results on the breast, uterine corpus endometrial carcinoma and ovarian cancer data from The Cancer Genome Atlas show that CDPathway can effectively identify candidate driver genes [area under the receiver operating characteristic curve (AUROC) of $\geq $0.9] and reconstruct the pathway interaction network (AUROC of>0.9), and it uncovers much more known (potential) driver genes than other competitive methods. In addition, CDPathway identifies 150% more driver pathways and 60% more potential cooperative driver pathways than the competing methods. The code of CDPathway is available at http://mlda.swu.edu.cn/codes.php?name=CDPathway.