| 1. |
- Ma, Haixia, et al.
(author)
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The transcription factor Foxp1 regulates aerobic glycolysis in adipocytes and myocytes
- 2023
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In: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 299:6
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Journal article (peer-reviewed)abstract
- In recent years, lactate has been recognized as an important circulating energy substrate rather than only a dead-end metabolic waste product generated during glucose oxidation at low levels of oxygen. The term "aerobic glycolysis" has been coined to denote increased glucose uptake and lactate pro-duction despite normal oxygen levels and functional mito-chondria. Hence, in "aerobic glycolysis," lactate production is a metabolic choice, whereas in "anaerobic glycolysis," it is a metabolic necessity based on inadequate levels of oxygen. Interestingly, lactate can be taken up by cells and oxidized to pyruvate and thus constitutes a source of pyruvate that is in-dependent of insulin. Here, we show that the transcription factor Foxp1 regulates glucose uptake and lactate production in adipocytes and myocytes. Overexpression of Foxp1 leads to increased glucose uptake and lactate production. In addition, protein levels of several enzymes in the glycolytic pathway are upregulated, such as hexokinase 2, phosphofructokinase, aldolase, and lactate dehydrogenase. Using chromatin immu-noprecipitation and real-time quantitative PCR assays, we demonstrate that Foxp1 directly interacts with promoter consensus cis-elements that regulate expression of several of these target genes. Conversely, knockdown of Foxp1 suppresses these enzyme levels and lowers glucose uptake and lactate production. Moreover, mice with a targeted deletion of Foxp1 in muscle display systemic glucose intolerance with decreased muscle glucose uptake. In primary human adipocytes with induced expression of Foxp1, we find increased glycolysis and glycolytic capacity. Our results indicate Foxp1 may play an important role as a regulator of aerobic glycolysis in adipose tissue and muscle.
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| 2. |
- Sukonina, Valentina, et al.
(author)
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FOXK1 and FOXK2 regulate aerobic glycolysis.
- 2019
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 566, s. 279-283
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Journal article (peer-reviewed)abstract
- Adaptation to the environment and extraction of energy are essential for survival. Some species have found niches and specialized in using a particular source of energy, whereas others-including humans and several other mammals-have developed a high degree of flexibility1. A lot is known about the general metabolic fates of different substrates but we still lack a detailed mechanistic understanding of how cells adapt in their use of basic nutrients2. Here we show that the closely related fasting/starvation-induced forkhead transcription factors FOXK1 and FOXK2 induce aerobic glycolysis by upregulating the enzymatic machinery required for this (for example, hexokinase-2, phosphofructokinase, pyruvate kinase, and lactate dehydrogenase), while at the same time suppressing further oxidation of pyruvate in the mitochondria by increasing the activity of pyruvate dehydrogenase kinases 1 and 4. Together with suppression of the catalytic subunit of pyruvate dehydrogenase phosphatase 1 this leads to increased phosphorylation of the E1α regulatory subunit of the pyruvate dehydrogenase complex, which in turn inhibits further oxidation of pyruvate in the mitochondria-instead, pyruvate is reduced to lactate. Suppression of FOXK1 and FOXK2 induce the opposite phenotype. Both in vitro and in vivo experiments, including studies of primary human cells, show how FOXK1 and/or FOXK2 are likely to act as important regulators that reprogram cellular metabolism to induce aerobic glycolysis.
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| 3. |
- Yin, Yue, et al.
(author)
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In Situ Transforming RNA Nanovaccines from Polyethylenimine Functionalized Graphene Oxide Hydrogel for Durable Cancer Immunotherapy
- 2021
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In: Nano Letters. - : American Chemical Society (ACS). - 1530-6984 .- 1530-6992. ; 21:5, s. 2224-2231
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Journal article (peer-reviewed)abstract
- Messenger RNA (mRNA) vaccine is a promising candidate in cancer immunotherapy as it can encode tumor-associated antigens with an excellent safety profile. Unfortunately, the inherent instability of RNA and translational efficiency are major limitations of RNA vaccine. Here, we report an injectable hydrogel formed with graphene oxide (GO) and polyethylenimine (PEI), which can generate mRNA (ovalbumin, a model antigen) and adjuvants (R848)-laden nanovaccines for at least 30 days after subcutaneous injection. The released nanovaccines can protect the mRNA from degradation and confer targeted delivering capacity to lymph nodes. The data show that this transformable hydrogel can significantly increase the number of antigen-specific CD8+ T cells and subsequently inhibit the tumor growth with only one treatment. Meanwhile, this hydrogel can generate an antigen specific antibody in the serum which in turn prevents the occurrence of metastasis. Collectively, these results demonstrate the potential of the PEI-functionalized GO transformable hydrogel for effective cancer immunotherapy.
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| 4. |
- Yin, Yue, et al.
(author)
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Separable Microneedle Patch to Protect and Deliver DNA Nanovaccines Against COVID-19
- 2021
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In: ACS Nano. - : American Chemical Society (ACS). - 1936-0851 .- 1936-086X. ; 15:9, s. 14347-14359
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Journal article (peer-reviewed)abstract
- The successful control of coronavirus disease 2019 (COVID-19) pandemic is not only relying on the development of vaccines, but also depending on the storage, transportation, and administration of vaccines. Ideally, nucleic acid vaccine should be directly delivered to proper immune cells or tissue (such as lymph nodes). However, current developed vaccines are normally treated through intramuscular injection, where immune cells do not normally reside. Meanwhile, current nucleic acid vaccines must be stored in a frozen state that may hinder their application in developing countries. Here, we report a separable microneedle (SMN) patch to deliver polymer encapsulated spike (or nucleocapsid) protein encoding DNA vaccines and immune adjuvant for efficient immunization. Compared with intramuscular injection, SMN patch can deliver nanovaccines into intradermal for inducing potent and durable adaptive immunity. IFN-gamma(+)CD4/8(+) and IL-2(+)CD4/8(+) T cells or virus specific IgG are significantly increased after vaccination. Moreover, in vivo results show the SMN patches can be stored at room temperature for at least 30 days without decreases in immune responses. These features of nanovaccines-laden SMN patch are important for developing advanced COVID-19 vaccines with global accessibility.
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