Integrated Multiomics Analysis Sheds Light on the Mechanisms of Color and Fragrance Biosynthesis in Wintersweet Flowers.

Wintersweet () is known for its flowering in winter and its rich floral aroma; the whole flower is yellow and the inner petals are red. In this study, we chose the wintersweet genotypes HLT040 and HLT015 as the research materials, and studied the co-regulatory mechanism of color and fragrance of wintersweet through metabolomics and transcriptomics. This study found that there were more flavonoids in HLT015, and anthocyanins (cyanidin-3-O-rutinoside and cyanidin-3-O-glucoside) were only present in HLT015, but HLT040 contained more monoterpenes and FVBPs (phenylpropanoid volatile compounds) than HLT015.

Gas1-Mediated Suppression of Hepatoblastoma Tumorigenesis.

Hepatoblastoma (HB), the most common pediatric liver cancer, is associated with dysregulated Wnt/β-catenin, Hippo, and/or nuclear factor erythroid 2 ligand 2/nuclear respiratory factor 2 (NFE2L2/NRF2) pathways. In mice, pairwise combinations of oncogenically active forms of the terminal transcription factors of these pathways, namely, β-catenin (B), Yes-associated protein (YAP; Y), and Nrf2 (N), generated HBs, with the triple combination (B + Y + N) being particularly potent. Each tumor group alters the expression of thousands of B-, Y-, and N-driven unique and common target genes.

Design, synthesis and biological evaluation of novel pyrazolinone derivatives as multifunctional ligands for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the depletion of cholinergic neurons and the accumulation of amyloid β (Aβ) plaques. The complexity and multifaceted nature of AD necessitate further exploration of multi-target drugs for its treatment. In this study, a series of novel pyrazolinone-based compounds were designed, synthesized, and evaluated as acetylcholinesterase (AChE) inhibitors and antioxidants.

Demographics, comorbidities, and comedications in newly diagnosed patients with Alzheimer's disease and related dementias: Findings from United States Medicare claims data.

Background: Medicare claims data enables broad characterization of United States (US) patients with Alzheimer's disease and related dementias (ADRD). Resulting insights can be used as a reference to describe this population and as a benchmark for generalizability of patients with ADRD enrolled in clinical trials.

Objective: To characterize demographics, comorbidities, comedications, and healthcare resource utilization in US patients with newly diagnosed ADRD, focusing on differences across Medicare fee-for-service (FFS) and Medicare Advantage enrollees.

MYC Binding Near Transcriptional End Sites Regulates Basal Gene Expression, Read-Through Transcription and Intragenic Contacts.

The MYC oncoprotein regulates numerous genes involved in cellular processes such as cell cycle and mitochondrial and ribosomal structure and function. This requires heterodimerization with its partner, MAX, and binding to specific promoter and enhancer elements. Here, we show that MYC and MAX also bind near transcriptional end sites (TESs) of over one-sixth of all annotated genes.

Body-Wide Inactivation of the Myc-Like Mlx Transcription Factor Network Accelerates Aging and Increases the Lifetime Cancer Incidence.

The "Mlx" and "Myc" transcription factor networks cross-communicate and share many common gene targets. Myc's activity depends upon its heterodimerization with Max, whereas the Mlx Network requires that the Max-like factor Mlx associate with the Myc-like factors MondoA or ChREBP. The current work demonstrates that body-wide Mlx inactivation, like that of Myc, accelerates numerous aging-related phenotypes pertaining to body habitus and metabolism.

The Myc-Like Mlx Network Impacts Aging and Metabolism.

The "Mlx" and "Myc" Networks share many common gene targets. Just as Myc's activity depends upon its heterodimerization with Max, the Mlx Network requires that the Max-like factor Mlx associate with the Myc-like factors MondoA or ChREBP. We show here that body-wide inactivation, like that of accelerates numerous aging-related phenotypes pertaining to body habitus and metabolism.

Genome-Wide Identification and Expression Analysis of the bHLH Transcription Factor Family in Wintersweet ().

Wintersweet ( (L.) Link, Calycanthaceae) is an esteemed ornamental flowering shrub known for its distinct blooming period in winter, vibrant color petals, and captivating floral fragrance. Basic helix-loop-helix (bHLH) transcription factors (TFs) play pivotal roles as key regulators in secondary metabolites biosynthesis, growth, and development in plants.

Lessons in aging from Myc knockout mouse models.

Despite being among the most intensively studied oncogenes, its role in normal development has not been determined as mice do not survival beyond mid-gestation. ± mice live longer than their wild-type counterparts and are slower to accumulate many age-related phenotypes. However, haplo-insufficiency likely conceals other important phenotypes as many high-affinity Myc targets genes continue to be regulated normally.

Premature aging and reduced cancer incidence associated with near-complete body-wide Myc inactivation.

MYC proto-oncogene dysregulation alters metabolism, translation, and other functions in ways that support tumor induction and maintenance. Although Myc mice are healthier and longer-lived than control mice, the long-term ramifications of more complete Myc loss remain unknown. We now describe the chronic consequences of body-wide Myc inactivation initiated postnatally.

Disruption of Multiple Overlapping Functions Following Stepwise Inactivation of the Extended Myc Network.

Myc, a member of the "Myc Network" of bHLH-ZIP transcription factors, supervises proliferation, metabolism, and translation. It also engages in crosstalk with the related "Mlx Network" to co-regulate overlapping genes and functions. We investigated the consequences of stepwise conditional inactivation of Myc and Mlx in primary and SV40 T-antigen-immortalized murine embryonic fibroblasts (MEFs).

Coordinated Cross-Talk Between the Myc and Mlx Networks in Liver Regeneration and Neoplasia.

Background & Aims: The c-Myc (Myc) Basic helix-loop-helix leucine zipper (bHLH-ZIP) transcription factor is deregulated in most cancers. In association with Max, Myc controls target genes that supervise metabolism, ribosome biogenesis, translation, and proliferation. This Myc network crosstalks with the Mlx network, which consists of the Myc-like proteins MondoA and ChREBP, and Max-like Mlx.

Normal and Neoplastic Growth Suppression by the Extended Myc Network.

Among the first discovered and most prominent cellular oncogenes is which encodes a bHLH-ZIP transcription factor (Myc) that both activates and suppresses numerous genes involved in proliferation, energy production, metabolism and translation. Myc belongs to a small group of bHLH-ZIP transcriptional regulators (the Myc Network) that includes its obligate heterodimerization partner Max and six "Mxd proteins" (Mxd1-4, Mnt and Mga), each of which heterodimerizes with Max and largely opposes Myc's functions. More recently, a second group of bHLH-ZIP proteins (the Mlx Network) has emerged that bears many parallels with the Myc Network.

Trends in Characteristics of Adults Enrolled in Traditional Fee-for-Service Medicare and Medicare Advantage, 2011-2019.

Background: While overall Medicare Part C (Medicare Advantage) enrollment has grown more rapidly than fee-for-service Medicare enrollment, changes in the growth and characteristics of different enrollee populations have not been examined.

Objectives: For 2011-2019, to compare changes in the growth and characteristics of younger (age younger than 65) and older (age 65 and older) Medicare beneficiaries enrolled in Medicare Part A only, Medicare Parts A & B, and Medicare Part C.

Research Design: This was a retrospective, observational study.

The Metabolic Fates of Pyruvate in Normal and Neoplastic Cells.

Pyruvate occupies a central metabolic node by virtue of its position at the crossroads of glycolysis and the tricarboxylic acid (TCA) cycle and its production and fate being governed by numerous cell-intrinsic and extrinsic factors. The former includes the cell's type, redox state, ATP content, metabolic requirements and the activities of other metabolic pathways. The latter include the extracellular oxygen concentration, pH and nutrient levels, which are in turn governed by the vascular supply.

Patient-Derived Mutant Forms of NFE2L2/NRF2 Drive Aggressive Murine Hepatoblastomas.

Background & Aims: Hepatoblastoma (HB), the most common pediatric liver cancer, often bears β-catenin mutations and deregulates the Hippo tumor suppressor pathway. Murine HBs can be generated by co-expressing β-catenin mutants and the constitutively active Hippo effector YAP. Some HBs and other cancers also express mutants of NFE2L2/NRF2 (NFE2L2), a transcription factor that tempers oxidative and electrophilic stress.

Acquired deficiency of peroxisomal dicarboxylic acid catabolism is a metabolic vulnerability in hepatoblastoma.

Metabolic reprogramming provides transformed cells with proliferative and/or survival advantages. Capitalizing on this therapeutically, however, has been only moderately successful because of the relatively small magnitude of these differences and because cancers may further adapt their metabolism to evade metabolic pathway inhibition. Mice lacking the peroxisomal bifunctional enzyme enoyl-CoA hydratase/3-hydroxyacyl CoA dehydrogenase (Ehhadh) and supplemented with the 12-carbon fatty acid lauric acid (C12) accumulate the toxic metabolite dodecanedioic acid (DDDA), which causes acute hepatocyte necrosis and liver failure.

β-Catenin mutations as determinants of hepatoblastoma phenotypes in mice.

Hepatoblastoma (HB) is the most common pediatric liver cancer. Although long-term survival of HB is generally favorable, it depends on clinical stage, tumor histology, and a variety of biochemical and molecular features. HB appears almost exclusively before the age of 3 years, is represented by seven histological subtypes, and is usually associated with highly heterogeneous somatic mutations in the catenin β1 () gene, which encodes β-catenin, a Wnt ligand-responsive transcriptional co-factor.

Expression patterns of small numbers of transcripts from functionally-related pathways predict survival in multiple cancers.

Background: Genetic profiling of cancers for variations in copy number, structure or expression of certain genes has improved diagnosis, risk-stratification and therapeutic decision-making. However the tumor-restricted nature of these changes limits their application to certain cancer types or sub-types. Tests with broader prognostic capabilities are lacking.

Inhibition of hepatocellular carcinoma by metabolic normalization.

In two different mouse liver cancer models, we recently showed that a switch from oxidative phosphorylation (Oxphos) to glycolysis (the Warburg effect) is invariably accompanied by a marked decline in fatty acid oxidation (FAO) and a reciprocal increase in the activity of pyruvate dehydrogenase (PDH), which links glycolysis to the TCA cycle. We now show that short-term implementation of either medium-chain (MC) or long-chain (LC) high fat diets (HFDs) nearly doubled the survival of mice with c-Myc oncoprotein-driven hepatocellular carcinoma (HCC). Mechanistically, HFDs forced tumors to become more reliant on fatty acids as an energy source, thus normalizing both FAO and PDH activities.

Metabolic and oncogenic adaptations to pyruvate dehydrogenase inactivation in fibroblasts.

Eukaryotic cell metabolism consists of processes that generate available energy, such as glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation (Oxphos), and those that consume it, including macromolecular synthesis, the maintenance of ionic gradients, and cellular detoxification. By converting pyruvate to acetyl-CoA (AcCoA), the pyruvate dehydrogenase (PDH) complex (PDC) links glycolysis and the TCA cycle. Surprisingly, disrupting the connection between glycolysis and the TCA cycle by inactivation of PDC has only minor effects on cell replication.

Erratum: Disruption of Myc-Max Heterodimerization with Improved Cell-Penetrating Analogs of the Small Molecule 10074-G5.

[This corrects the article DOI: 10.18632/oncotarget.1108.

Myc and ChREBP transcription factors cooperatively regulate normal and neoplastic hepatocyte proliferation in mice.

Analogous to the c-Myc (Myc)/Max family of bHLH-ZIP transcription factors, there exists a parallel regulatory network of structurally and functionally related proteins with Myc-like functions. Two related Myc-like paralogs, termed MondoA and MondoB/carbohydrate response element-binding protein (ChREBP), up-regulate gene expression in heterodimeric association with the bHLH-ZIP Max-like factor Mlx. Myc is necessary to support liver cancer growth, but not for normal hepatocyte proliferation.