The Warburg effect, which originally described increased production of lactate in cancer, is associated with diverse cellular processes such as angiogenesis, hypoxia, polarization of macrophages and ...activation of T cells. This phenomenon is intimately linked to several diseases including neoplasia, sepsis and autoimmune diseases
. Lactate, which is converted from pyruvate in tumour cells, is widely known as an energy source and metabolic by-product. However, its non-metabolic functions in physiology and disease remain unknown. Here we show that lactate-derived lactylation of histone lysine residues serves as an epigenetic modification that directly stimulates gene transcription from chromatin. We identify 28 lactylation sites on core histones in human and mouse cells. Hypoxia and bacterial challenges induce the production of lactate by glycolysis, and this acts as a precursor that stimulates histone lactylation. Using M1 macrophages that have been exposed to bacteria as a model system, we show that histone lactylation has different temporal dynamics from acetylation. In the late phase of M1 macrophage polarization, increased histone lactylation induces homeostatic genes that are involved in wound healing, including Arg1. Collectively, our results suggest that an endogenous 'lactate clock' in bacterially challenged M1 macrophages turns on gene expression to promote homeostasis. Histone lactylation thus represents an opportunity to improve our understanding of the functions of lactate and its role in diverse pathophysiological conditions, including infection and cancer.
Protein arginine methyltransferase 1 (PRMT1) catalyzing the formation of asymmetric dimethylarginines has been implicated in cancer development, metastasis, and prognosis. In this study, we ...investigated the effects of low PRMT1 levels on a non-MYCN amplified neuroblastoma SK-N-SH cell line. Stable PRMT1-knockdown (PRMT1-KD) cells showed reduced growth rates and cell cycle arrest at G
/M. They also exhibited senescent phenotypes and increased p53 expression. p21 and PAI-1, which are two p53 downstream targets critical for senescence, were significantly induced in SK-N-SH cells subjected to either PRMT1-KD or inhibitor treatment. The induction was suppressed by a p53 inhibitor and marginal in a p53-null SK-N-AS cell line, suggesting dependence on p53. In general, the DNA damage and ROS levels of the PRMT1-KD SK-N-SH cells were slightly increased. Their migration activity also increased with the induction of PAI-1. Thus, PRMT1 downregulation released the repression of cellular senescence and migration activity in SK-N-SH cells. These results might partially explain the poor prognostic outcome of low PRMT1 in a non-MYCN-amplified cohort and indicate the multifaceted complexity of PRMT1 as a biological regulator of neuroblastoma.
We report the design and synthesis of two novel indigo donor-acceptor (D-A) polymers,
PIDG-T-C20
and
PIDG-BT-C20
, comprising an indigo moiety that has intramolecular hydrogen-bonds as the acceptor ...building block and thiophene (T) and bithiophene (BT) as the donor building block, respectively.
PIDG-T-C20
and
PIDG-BT-C20
exhibited characteristic p-type semiconductor performance, achieving hole mobilities of up to 0.016 and 0.028 cm
2
V
−1
s
−1
, respectively, which are highest values reported for indigo-based polymers. The better performing
PIDG-BT-C20
was used for the fabrication of water-gated organic field-effect transistors (WGOFETs), which showed excellent stability at ambient conditions. The
PIDG-BT-C20
-based WGOFETs exhibited rapid response when fluoride ions were introduced to the water gate dielectric, achieving a limit of detection (LOD) of 0.40 mM. On the other hand, the devices showed much lower sensitivities towards other halide ions with the order of relative response: F
−
> Cl
−
> Br
−
> I
−
. The high sensitivity and selectivity of
PIDG-BT-C20
to fluoride over other halides is considered to be realized through the strong interaction of the hydrogen atoms of the N-H groups in the indigo unit with fluoride ions, which alters the intramolecular hydrogen-bonding arrangement, the electronic structures, and thus the charge transport properties of the polymer.
A p-type indigo polymer semiconductor is developed for water-gated organic field-effect transistors (WGOFET) for sensing fluoride ions.
The aim of this study was to investigate the effects of a natural component, theissenolactone C (LC53), on the ocular inflammation of experimental endotoxin-induced uveitis (EIU) and its related ...mechanisms in microglia. Evaluation of the severity of anterior uveitis indicated that LC53 treatment significantly decreased iridal hyperemia and restored the clinical scores. Additionally, the deficient retina functions of electroretinography were improved by LC53. LC53 significantly reduced levels of tumor necrosis factor (TNF)-α, monocyte chemoattractant protein-1, protein leakage and activation of matrix metalloproteinases in the anterior section during EIU. Moreover, LC53 treatment decreased the oxidative stress as well as neuroinflammatory reactivities of GFAP and Iba-1 in the posterior section. Furthermore, LC53 decreased the phosphorylation of p65, expression of HSP90, Bax, and cleaved-caspase-3 in EIU. According to the microglia studies, LC53 significantly abrogated the productions of TNF-α, PGE
, NO and ROS, as well as inducible NO synthase and cyclooxygenase-2 expression in LPS-stimulated microglial BV2 cells. The microglial activation of IKKβ, p65 phosphorylation and nuclear phosphorylated p65 translocation were strongly attenuated by LC53. On the other hand, LC53 exhibited the inhibitory effects on JNK and ERK MAPKs activation. Our findings indicated that LC53 exerted the ocular-protective effect through its inhibition on neuroinflammation, glial activation, and apoptosis in EIU, suggesting a therapeutic potential with down-regulation of the NF-κB signaling for uveitis and retinal inflammatory diseases.
Aberrant expression of protein arginine methyltransferases (PRMTs) has been implicated in a number of cancers, making PRMTs potential therapeutic targets. But it remains not well understood how PRMTs ...impact specific oncogenic pathways. We previously identified PRMTs as important regulators of cell growth in neuroblastoma, a deadly childhood tumor of the sympathetic nervous system. Here, we demonstrate a critical role for PRMT1 in neuroblastoma cell survival. PRMT1 depletion decreased the ability of murine neuroblastoma sphere cells to grow and form spheres, and suppressed proliferation and induced apoptosis of human neuroblastoma cells. Mechanistic studies reveal the prosurvival factor, activating transcription factor 5 (ATF5) as a downstream effector of PRMT1-mediated survival signaling. Furthermore, a diamidine class of PRMT1 inhibitors exhibited anti-neuroblastoma efficacy both in vitro and in vivo. Importantly, overexpression of ATF5 rescued cell apoptosis triggered by PRMT1 inhibition genetically or pharmacologically. Taken together, our findings shed new insights into PRMT1 signaling pathway, and provide evidence for PRMT1 as an actionable therapeutic target in neuroblastoma.
Elevated intraocular pressure (IOP) is a major risk factor for glaucoma that has been found to induce matrix metalloproteinase-9 (MMP-9) activation and result in eventual retinal dysfunction. ...Proinflammatory cytokines such as monocyte chemoattractant protein-1 (MCP-1) and interleukin-1β (IL-1β) were also found to be involved in disease progression by mediating MMP-9 production. We previously reported that fungal derivative theissenolactone C (LC53) could exert ocular protective effects by suppressing neuroinflammation in experimental uveitis.
The aim of this study was to investigate the retinoprotective effects of natural compound LC53 on the high IOP-induced ischemia/reperfusion (I/R)-injury model of glaucoma and its cellular mechanisms.
A high IOP-induced I/R-injury model was manipulated by normal saline injection into the anterior chamber of the rat eye. MCP-1-stimulated monocytes and IL-1β-activated primary astrocytes were used to investigate the cellular mechanisms of LC53. Retinal function was evaluated with the scotopic threshold response (STR) and combined rod–cone response by electroretinography (ERG). As a positive control, rats were treated with memantine. MMP-9 gelatinolysis, mRNA expression and protein expression were analyzed by gelatin zymography, RT-PCR, and Western Blot, respectively. The phosphorylation levels of MAPKs and NF-κB p65 were tested by Western Blot. Additionally, the levels of inflammatory MCP-1 and IL-1β were determined by ELISA.
The present study revealed that LC53 preserved the retina functional deficiency assessed by scotopic threshold response (STR) and combined rod–cone response of ERG after high IOP-induced I/R injury. These retinal protective effects of LC53 were positively correlated with inhibitory activities in I/R injury-elicited ocular MMP-9 activation and expression. The increased level of MCP-1 was not affected, and the enhanced IL-1β production was partially reduced by LC53 in the retina after I/R injury. According to cellular studies, LC53 significantly and concentration-dependently abrogated MMP-9 activation and expression in MCP-1-stimulated THP-1 monocytes. We found the inhibitory activities of LC53 were through the ERK- and NF-κB-dependent pathways. In addition, LC53 dramatically suppressed IL-1β-induced MMP-9 activation and expression in primary astrocytes. The phosphorylation of 65-kD protein (p65) of NF-κB was substantially blocked by LC53 in IL-1β-stimulated primary astrocytes.
LC53 exerted a retinal protective effect through NF-κB inhibition and was highly potent against MMP-9 activities after high IOP-induced I/R injury, suggesting that LC53 would be a promising drug lead for glaucoma or related medical conditions attributed to retinal ischemia.
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Retinitis pigmentosa (RP) is an inherited photoreceptor-degenerative disease, and neuronal degeneration in RP is exacerbated by glial activation. Cassia seed (Jue-ming-zi) is a traditional herbal ...medicine commonly used to treat ocular diseases in Asia. In this report, we investigated the retina-protective effect of chrysophanol, an active component of Cassia seed, in an N-methyl-N-nitrosourea (MNU)-induced mouse model of RP. We determined that chrysophanol inhibited the functional and morphological features of MNU-induced retinal degeneration using scotopic electroretinography (ERG), optical coherence tomography (OCT), and immunohistochemistry analysis of R/G opsin and rhodopsin. Furthermore, TUNEL assays revealed that chrysophanol attenuated MNU-induced photoreceptor cell apoptosis and inhibited the expression of the apoptosis-associated proteins PARP, Bax, and caspase-3. In addition, chrysophanol ameliorated reactive gliosis, as demonstrated by a decrease in GFAP immunolabeling, and suppressed the activation of matrix metalloproteinase (MMP)-9-mediated gelatinolysis. In vitro studies indicated that chrysophanol inhibited lipopolysaccharide (LPS)-induced iNOS and COX-2 expression in the BV2 mouse microglia cell line and inhibited MMP-9 activation in primary microglia. Our results demonstrate that chrysophanol provided neuroprotective effects and inhibited glial activation, suggesting that chrysophanol might have therapeutic value for the treatment of human RP and other retinopathies.
Background: Uveitis, an ocular inflammatory emergency, is one of the most common causes of severe visual loss. A fungal ingredient, theissenolactone C (LC53), has been shown to suppress ...lipopolysaccharide (LPS)-induced inflammation in monocytes. In this study, we investigated the ocular protective effects of LC53 on experimental endotoxin-induced uveitis (EIU) and related mechanisms involved.Methods: EIU was induced in Sprague-Dawley (SD) rat by subcutaneous injection of LPS (1 mg/kg) into a single footpad. For the LC53 treatment group, the rat was intraperitoneally injected with LC53 (20 mg/kg) before LPS injection. Ophthalmic scoring and scotopic electroretinographic (ERG) analyses were evaluated for anterior inflammatory reactivity and retinal function, respectively. The eye tissue and aqueous humor were harvested and evaluated by immunofluorescence, Western blot, zymography, Oxyblot, and enzyme-linked immunosorbent assay (ELISA). In addition, Western blot, ELISA, and reactive oxygen species (ROS) assay were carried out in LPS-stimulated BV-2 microglial cells to clarify the effects and mechanisms of LC53.Results: The administration of LC53 suppressed the EIU-induced hyperemia in the iris and restored the clinical scoring. Additionally, the retina functional deficiency of EIU was protected by LC53. LC53 significantly reduced tumor necrosis factor (TNF)-a, monocyte chemoattractant protein-1 (MCP-1), activation of matrix metalloproteinase (MMP)-2 and MMP-9, the protein leakage, and oxidative stress in EIU. The neuroinflammatory reactivity of GFAP and accumulation of monocytes/macrophages were also down-regulated by LC53 during EIU. In EIU eye, LC53 decreased the phosphorylation of p65, expression of HSP90, Bax, and cleaved-caspase-3. Moreover, LC53 induced Bcl-2 expression after EIU induction. According to the microglia studies, LC53 significantly inhibited the release of TNF-a, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression, as well as ROS production in LPS-stimulated microglial BV2 cells. The microglial activation of IKKb and p65 phosphorylation was concentration-dependently attenuated by LC53.Conclusion: Our findings indicated that LC53 exerted the ocular-protective effect through its inhibition on neuroinflammation, glial activation, and apoptosis in EIU, suggesting a therapeutic potential with down-regulation of the NF-kB signaling for uveitis and retinal inflammatory diseases.
There has been much progress in our understanding of molecular mechanisms in the pathogenesis of inherited metabolic disorders. In addition, powerful new molecular techniques have made possible ...phenotypic alterations by delivery of foreign genes to target cells. As a result, concepts and methods that would have been considered purely science fiction 10 years ago can now be found in human clinical trials engaged in the treatment of these disorders. In this review, we have attempted to provide an introduction and survey of the topic of gene therapy, with specific examples of laboratory and clinical achievements to date, and highlights on potentials for applications in digestive diseases.
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