New opportunities: harnessing induced pluripotency for discovery in diabetes and metabolism.
Ontology highlight
ABSTRACT:
SUBMITTER: Teo AK
PROVIDER: S-EPMC3858409 | biostudies-literature | 2013 Dec
REPOSITORIES: biostudies-literature
Publications
New opportunities: harnessing induced pluripotency for discovery in diabetes and metabolism.
Teo Adrian Kee Keong AK Wagers Amy J AJ Kulkarni Rohit N RN
Cell metabolism 20130912 6
The landmark discovery of induced pluripotent stem cells (iPSCs) by Shinya Yamanaka has transformed regenerative biology. Previously, insights into the pathogenesis of chronic human diseases have been hindered by the inaccessibility of patient samples. However, scientists are now able to convert patient fibroblasts into iPSCs and differentiate them into disease-relevant cell types. This ability opens new avenues for investigating disease pathogenesis and designing novel treatments. In this revie ...[more]
Similar Datasets
Project description:Four-membered heterocycles such as oxetanes and azetidines represent attractive and emergent design options in medicinal chemistry due to their small and polar nature and potential to significantly impact the physiochemical properties of drug molecules. The challenging preparation of these derivatives, especially in a divergent manner, has severely limited their combination with other medicinally and biologically important groups. Consequently, there is a substantial demand for mild and effective synthetic strategies to access new oxetane and azetidine derivatives and molecular scaffolds. Here, we report the development and use of oxetane sulfonyl fluorides (OSFs) and azetidine sulfonyl fluorides (ASFs), which behave as precursors to carbocations in an unusual defluorosulfonylation reaction pathway (deFS). The small-ring sulfonyl fluorides are activated under mild thermal conditions (60 °C), and the generated reactive intermediates couple with a broad range of nucleophiles. Oxetane and azetidine heterocyclic, -sulfoximine, and -phosphonate derivatives are prepared, several of which do not have comparable carbonyl analogs, providing new chemical motifs and design elements for drug discovery. Alternatively, a SuFEx pathway under anionic conditions accesses oxetane-sulfur(VI) derivatives. We demonstrate the synthetic utility of novel OSF and ASF reagents through the synthesis of 11 drug analogs, showcasing their potential for subsequent diversification and facile inclusion into medicinal chemistry programs. Moreover, we propose the application of the OSF and ASF reagents as linker motifs and demonstrate the incorporation of pendant groups suitable for common conjugation reactions. Productive deFS reactions with E3 ligase recruiters such as pomalidomide and related derivatives provide new degrader motifs and potential PROTAC linkers.
| S-EPMC11673132 | biostudies-literature
Project description:The design of new ligands with high affinity and specificity against the targets of interest has been a central focus in drug discovery. As one of the most commonly used methods in drug discovery, the cyclization represents a feasible strategy to identify new lead compounds by increasing structural novelty, scaffold diversity and complexity. Such strategy could also be potentially used for the follow-on drug discovery without patent infringement. In recent years, the cyclization strategy has witnessed great success in the discovery of new lead compounds against different targets for treating various diseases. Herein, we first briefly summarize the use of the cyclization strategy in the discovery of new small-molecule lead compounds, including the proteolysis targeting chimeras (PROTAC) molecules. Particularly, we focus on four main strategies including fused ring cyclization, chain cyclization, spirocyclization and macrocyclization and highlight the use of the cyclization strategy in lead generation. Finally, the challenges including the synthetic intractability, relatively poor pharmacokinetics (PK) profiles and the absence of the structural information for rational structure-based cyclization are also briefly discussed. We hope this review, not exhaustive, could provide a timely overview on the cyclization strategy for the discovery of new lead compounds.
| S-EPMC9764076 | biostudies-literature
Project description:Chemistry-alone approach has recently been applied for incepting pluripotency in somatic cells, representing a breakthrough in biology. However, chemical reprogramming is hampered by low efficiency, and the underlying molecular mechanisms remain unclear. Particularly, chemical compounds do not have specific DNA-recognition domains or transcription regulatory domains, and then how do small molecules work as a driving force for reinstating pluripotency in somatic cells? Furthermore, how to efficiently clear materials and structures of an old cell to prepare the rebuilding of a new one? Here, we show that small molecule CD3254 activates endogenous existing transcription factor RXRα to significantly promote mouse chemical reprogramming. Mechanistically, CD3254-RXRα axis can directly activate all the 11 RNA exosome component genes (Exosc1-10 and Dis3) at transcriptional level. Unexpectedly, rather than degrading mRNAs as its substrates, RNA exosome mainly modulates the degradation of transposable element (TE)-associated RNAs, particularly MMVL30, which is identified as a new barrier for cell-fate determination. In turn, MMVL30-mediated inflammation (IFN-γ and TNF-α pathways) is reduced, contributing to the promotion of successful reprogramming. Collectively, our study provides conceptual advances for translating environmental cues into pluripotency inception, particularly, identifies that CD3254-RXRα-RNA exosome axis can promote chemical reprogramming, and suggests modulation of TE-mediated inflammation via CD3254-inducible RNA exosome as important opportunities for controlling cell fates and regenerative medicine.
| S-EPMC10214147 | biostudies-literature
Project description:Although cancers have altered glucose metabolism, termed the Warburg effect, which describes the increased uptake and conversion of glucose to lactate by cancer cells under adequate oxygen tension, changes in the metabolism of glutamine and fatty acid have also been documented. The MYC oncogene, which contributes to the genesis of many human cancers, encodes a transcription factor c-Myc, which links altered cellular metabolism to tumorigenesis. c-Myc regulates genes involved in the biogenesis of ribosomes and mitochondria, and regulation of glucose and glutamine metabolism. With E2F1, c-Myc induces genes involved in nucleotide metabolism and DNA replication, and microRNAs that homeostatically attenuate E2F1 expression. With the hypoxia inducible transcription factor HIF-1, ectopic c-Myc cooperatively induces a transcriptional program for hypoxic adaptation. Myc regulates gene expression either directly, such as glycolytic genes including lactate dehydrogenase A (LDHA), or indirectly, such as repression of microRNAs miR-23a/b to increase glutaminase (GLS) protein expression and glutamine metabolism. Ectopic MYC expression in cancers, therefore, could concurrently drive aerobic glycolysis and/or oxidative phosphorylation to provide sufficient energy and anabolic substrates for cell growth and proliferation in the context of the tumor microenvironment. Collectively, these studies indicate that Myc-mediated altered cancer cell energy metabolism could be translated for the development of new anticancer therapies.
| S-EPMC2783410 | biostudies-literature
Project description:IntroductionAge-related macular degeneration (AMD) is the leading cause of irreversible blindness among people age 60 years or older in developed countries. Current standard-of-care anti-vascular endothelial growth factor (VEGF) therapy, which inhibits angiogenesis and vascular permeability, has been shown to stabilize choroidal neovascularization and increase visual acuity in neovascular AMD. However, therapeutic limitations of anti-VEGF therapy include limited durability with consequent need for frequent intravitreal injections, and a ceiling of efficacy. Current strategies under investigation include targeting VEGF-C and VEGF-D, integrins, tyrosine kinase receptors, and the Tie2/angiopoietin-2 pathway. A literature search was conducted through November 30, 2021 on PubMed, Medline, Google Scholar, and associated digital platforms with the following keywords: wet macular degeneration, age-related macular degeneration, therapy, VEGF-A, VEGF-C, VEGF-D, integrins, Tie2/Ang2, and tyrosine kinase inhibitors.Areas coveredThe authors provide a comprehensive review of AMD disease pathways and mechanisms involved in wet AMD as well as novel targets for future therapies.Expert opinionWith novel targets and advancements in drug delivery, there is potential to address treatment burden and to improve outcomes for patients afflicted with neovascular AMD.
| S-EPMC8915198 | biostudies-literature
Project description:Efficient drug discovery is based on a concerted effort in optimizing bioactivity and compound properties such as lipophilicity, and is guided by efficiency metrics that reflect both aspects. While conformation-activity relationships and ligand conformational control are known strategies to improve bioactivity, the use of conformer-specific lipophilicities (logp) is much less explored. Here we show how conformer-specific logp values can be obtained from knowledge of the macroscopic logP value, and of the equilibrium constants between the individual species in water and in octanol. This is illustrated with fluorinated amide rotamers, with integration of rotamer 19 F NMR signals as a facile, direct method to obtain logp values. The difference between logp and logP optimization is highlighted, giving rise to a novel avenue for lipophilicity control in drug discovery.
| S-EPMC9304282 | biostudies-literature
Project description:Cancer cells rewire their metabolism to promote cell proliferation, invasion, and metastasis. Alterations in the lactate pathway have been characterized in diverse cancers, correlate with outcomes, and lead to many downstream effects, including decreasing oxidative stress, promoting an immunosuppressive tumor microenvironment, lipid synthesis, and building chemo- or radio-resistance. Radiotherapy is a key modality of treatment for many cancers and approximately 50% of patients with cancer will receive radiation for cure or palliation; thus, overcoming radio-resistance is important for improving outcomes. Growing research suggests that important molecular controls of the lactate pathway may serve as novel therapeutic targets and in particular, radiosensitizers. In this mini-review, we will provide an overview of lactate metabolism in cancer, discuss three important contributors to lactate metabolism (lactate dehydrogenase, monocarboxylate transporters, and mitochondrial pyruvate carrier), and present data that inhibition of these three pathways can lead to radiosensitization. Future research is needed to further understand critical regulators of lactate metabolism and explore clinical safety and efficacy of inhibitors of lactate dehydrogenase, monocarboxylate transporters, and mitochondrial pyruvate carrier alone and in combination with radiation.
| S-EPMC8343095 | biostudies-literature
Project description:Effective conservation of threatened biota relies on accurate assessments and scientific guidance. As an unfortunate example, Chinese giant salamanders ( Andrias, CGS) remain critically endangered in nature. Misguided conservation efforts, e.g., commercial propagation and releasing of millions of likely non-indigenous or interspecific hybrids, have further compromised conservation initiatives. Limited information on wild populations of CGS poses a significant conservation challenge. Following 18-month long field monitoring, we now report the discovery of a wild population of CGS in a closed nature reserve in Jiangxi Province, China. Genomic assessments reveal its genetic distinctiveness and do not detect genetic admixture with other species. Based on morphological and molecular evidences, we describe this CGS as a new species Andrias jiangxiensis sp. nov. This is the only known species of CGS today with a genetically pure, reproducing, in situ population. This discovery emphasizes the important role that closed nature reserves play in protecting species, and the necessity of integrating long-term field monitoring and genetic assessments. It sets a new pathway for discovering and conserving endangered species, especially for those biotas that are similarly being extirpated by anthropogenic translocations and overexploitation.
| S-EPMC9113980 | biostudies-literature
Project description:Multiple myeloma (MM) is an incurable malignancy of plasma cells that grow within a permissive bone marrow microenvironment (BMM). The bone marrow milieu supports the malignant transformation both by promoting uncontrolled proliferation and resistance to cell death in MM cells, and by hampering the immune response against the tumor clone. Hence, it is expected that restoring host anti-MM immunity may provide therapeutic benefit for MM patients. Already several immunotherapeutic approaches have shown promising results in the clinical setting. In this review, we outline recent findings demonstrating the potential advantages of targeting the immunosuppressive bone marrow niche to restore effective anti-MM immunity. We discuss different approaches aiming to boost the effector function of T cells and/or exploit innate or adaptive immunity, and highlight novel therapeutic opportunities to increase the immunogenicity of the MM clone. We also discuss the main challenges that hamper the efficacy of immune-based approaches, including intrinsic resistance of MM cells to activated immune-effectors, as well as the protective role of the immune-suppressive and inflammatory bone marrow milieu. Targeting mechanisms to convert the immunologically "cold" to "hot" MM BMM may induce durable immune responses, which in turn may result in long-lasting clinical benefit, even in patient subgroups with high-risk features and poor survival.
| S-EPMC7873734 | biostudies-literature
Project description:Pluripotent stem cells (PSCs) are characterized by their unique capacity for both unlimited self-renewal and their potential to differentiate to all cell lineages contained within the three primary germ layers. While once considered a distinct cellular state, it is becoming clear that pluripotency is in fact a continuum of cellular states, all capable of self-renewal and differentiation, yet with distinct metabolic, mitochondrial and epigenetic features dependent on gestational stage. In this review we focus on two of the most clearly defined states: "naïve" and "primed" PSCs. Like other rapidly dividing cells, PSCs have a high demand for anabolic precursors necessary to replicate their genome, cytoplasm and organelles, while concurrently consuming energy in the form of ATP. This requirement for both anabolic and catabolic processes sufficient to supply a highly adapted cell cycle in the context of reduced oxygen availability, distinguishes PSCs from their differentiated progeny. During early embryogenesis PSCs adapt their substrate preference to match the bioenergetic requirements of each specific developmental stage. This is reflected in different mitochondrial morphologies, membrane potentials, electron transport chain (ETC) compositions, and utilization of glycolysis. Additionally, metabolites produced in PSCs can directly influence epigenetic and transcriptional programs, which in turn can affect self-renewal characteristics. Thus, our understanding of the role of metabolism in PSC fate has expanded from anabolism and catabolism to include governance of the pluripotent epigenetic landscape. Understanding the roles of metabolism and the factors influencing metabolic pathways in naïve and primed pluripotent states provide a platform for understanding the drivers of cell fate during development. This review highlights the roles of the major metabolic pathways in the acquisition and maintenance of the different states of pluripotency.
| S-EPMC7059177 | biostudies-literature