Intestinal microbiota dysbiosis is an established characteristic of ulcerative colitis (UC). Regulating the gut microbiota is an attractive alternative UC treatment strategy, considering the ...potential adverse effects of synthetic drugs used to treat UC. Kaempferol (Kae) is an anti-inflammatory and antioxidant flavonoid derived from a variety of medicinal plants. In this study, we determined the efficacy and mechanism of action of Kae as an anti-UC agent in dextran sulfate sodium (DSS)-induced colitis mice. DSS challenge in a mouse model of UC led to weight loss, diarrhea accompanied by mucous and blood, histological abnormalities, and shortening of the colon, all of which were significantly alleviated by pretreatment with Kae. In addition, intestinal permeability was shown to improve using fluorescein isothiocyanate (FITC)–dextran administration. DSS-induced destruction of the intestinal barrier was also significantly prevented by Kae administration
via
increases in the levels of ZO-1, occludin, and claudin-1. Furthermore, Kae pretreatment decreased the levels of
IL-1β, IL-6
, and
TNF-α
and downregulated transcription of an array of inflammatory signaling molecules, while it increased
IL-10
mRNA expression. Notably, Kae reshaped the intestinal microbiome by elevating the
Firmicutes
to
Bacteroidetes
ratio; increasing the linear discriminant analysis scores of beneficial bacteria, such as
Prevotellaceae
and
Ruminococcaceae
; and reducing the richness of
Proteobacteria
in DSS-challenged mice. There was also an evident shift in the profile of fecal metabolites in the Kae treatment group. Serum LPS levels and downstream TLR4-NF-κB signaling were downregulated by Kae supplementation. Moreover, fecal microbiota transplantation from Kae-treated mice to the DSS-induced mice confirmed the effects of Kae on modulating the gut microbiota to alleviate UC. Therefore, Kae may exert protective effects against colitis mice through regulating the gut microbiota and TLR4-related signaling pathways. This study demonstrates the anti-UC effects of Kae and its potential therapeutic mechanisms, and offers novel insights into the prevention of inflammatory diseases using natural products.
It is well documented that the rate of aging can be slowed, but it remains unclear to which extent aging-associated conditions can be reversed. How the interface of immunity and metabolism impinges ...upon the diabetes pandemic is largely unknown. Here, we show that NLRP3, a pattern recognition receptor, is modified by acetylation in macrophages and is deacetylated by SIRT2, an NAD+-dependent deacetylase and a metabolic sensor. We have developed a cell-based system that models aging-associated inflammation, a defined co-culture system that simulates the effects of inflammatory milieu on insulin resistance in metabolic tissues during aging, and aging mouse models; and demonstrate that SIRT2 and NLRP3 deacetylation prevent, and can be targeted to reverse, aging-associated inflammation and insulin resistance. These results establish the dysregulation of the acetylation switch of the NLRP3 inflammasome as an origin of aging-associated chronic inflammation and highlight the reversibility of aging-associated chronic inflammation and insulin resistance.
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•NLRP3 is modified by acetylation and deacetylated by SIRT2•NLRP3 acetylation facilitates the activation of the NLRP3 inflammasome•SIRT2 prevents and reverses aging-associated inflammation and insulin resistance•NLRP3 deacetylation regulates aging-associated inflammation and insulin resistance
He et al. show that SIRT2 deacetylates NLRP3 and inactivates the NLRP3 inflammasome. This interplay prevents, and can be targeted to reverse, aging-associated inflammation and insulin resistance. This study uncovers a mechanism underlying inflammaging and highlights the reversibility of aging-associated conditions.
Altered metabolism is one of the hallmarks of cancer cells. The best-known metabolic abnormality in cancer cells is the Warburg effect, which demonstrates an increased glycolysis even in the presence ...of oxygen. However, tumor-related metabolic abnormalities are not limited to altered balance between glucose fermentation and oxida- tive phosphorylation. Key tumor genes such as p53 and c-myc are found to be master regulators of metabolism. Metabolic enzymes such as succinate dehydrogenase, fumarate hydratase, pyruvate kinase, and isocitrate dehydrogenase mutations or expressing level alterations are all linked to tumorigenesis. In this review, we intro- duce some of the cancer-associated metabolic disorders and current understanding of their molecular tumorigenic mechanisms.
Bromodomain and extraterminal domain (BET) protein inhibitors are emerging as promising anticancer therapies. The gene encoding the E3 ubiquitin ligase substrate-binding adaptor speckle-type POZ ...protein (SPOP) is the most frequently mutated in primary prostate cancer. Here we demonstrate that wild-type SPOP binds to and induces ubiquitination and proteasomal degradation of BET proteins (BRD2, BRD3 and BRD4) by recognizing a degron motif common among them. In contrast, prostate cancer-associated SPOP mutants show impaired binding to BET proteins, resulting in decreased proteasomal degradation and accumulation of these proteins in prostate cancer cell lines and patient specimens and causing resistance to BET inhibitors. Transcriptome and BRD4 cistrome analyses reveal enhanced expression of the GTPase RAC1 and cholesterol-biosynthesis-associated genes together with activation of AKT-mTORC1 signaling as a consequence of BRD4 stabilization. Our data show that resistance to BET inhibitors in SPOP-mutant prostate cancer can be overcome by combination with AKT inhibitors and further support the evaluation of SPOP mutations as biomarkers to guide BET-inhibitor-oriented therapy in patients with prostate cancer.
LPS-activated macrophages undergo a metabolic shift from dependence on mitochondria-produced ATP to reliance on aerobic glycolysis, where PKM2 is a critical determinant. Here, we show that PKM2 is a ...physiological substrate of SIRT5 and that SIRT5-regulated hypersuccinylation inhibits the pyruvate kinase activity of PKM2 by promoting its tetramer-to-dimer transition. Moreover, a succinylation-mimetic PKM2 K311E mutation promotes nuclear accumulation and increases protein kinase activity. Furthermore, we show that SIRT5-dependent succinylation promotes PKM2 entry into nucleus, where a complex of PKM2-HIF1α is formed at the promoter of IL-1β gene in LPS-stimulated macrophages. Activation of PKM2 using TEPP-46 attenuates Sirt5-deficiency-mediated IL-1β upregulation in LPS-stimulated macrophages. Finally, we find that Sirt5-deficient mice are more susceptible to DSS-induced colitis, which is associated with Sirt5 deficiency prompted PKM2 hypersuccinylation and boosted IL-1β production. In conclusion, our findings reveal a mechanism by which SIRT5 suppresses the pro-inflammatory response in macrophages at least in part by regulating PKM2 succinylation, activity, and function.
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•SIRT5 desuccinylates and activates PKM2•Lys311 is a key succinylated site in the regulation of PKM2 activity•Sirt5 blocks IL-1β production in LPS-activated macrophages by regulating PKM2•SIRT5 plays an important role in inhibiting inflammation
Activated immune cells reprogram their metabolism in infection or injury response. Wang et al. reveal that SIRT5 desuccinylates and activates PKM2 to block macrophage IL-1β production and to prevent DSS-induced colitis in mice, highlighting the role of SIRT5 and PKM2 in the process of macrophage metabolic reprogramming, sirtuin biology, and inflammation.
Male infertility is a major concern affecting human reproductive health. Asthenoteratospermia can cause male infertility through reduced motility and abnormal morphology of spermatozoa. Several ...genes, including DNAH1 and some CFAP family members, are involved in multiple morphological abnormalities of the sperm flagella (MMAF). However, these known genes only account for approximately 60% of human MMAF cases. Here, we conducted further genetic analyses by using whole-exome sequencing in a cohort of 65 Han Chinese men with MMAF. Intriguingly, bi-allelic mutations of TTC21A (tetratricopeptide repeat domain 21A) were identified in three (5%) unrelated, MMAF-affected men, including two with homozygous stop-gain mutations and one with compound heterozygous mutations of TTC21A. Notably, these men consistently presented with MMAF and additional abnormalities of sperm head-tail conjunction. Furthermore, a homozygous TTC21A splicing mutation was identified in two Tunisian cases from an independent MMAF cohort. TTC21A is preferentially expressed in the testis and encodes an intraflagellar transport (IFT)-associated protein that possesses several tetratricopeptide repeat domains that perform functions crucial for ciliary function. To further investigate the potential roles of TTC21A in spermatogenesis, we generated Ttc21a mutant mice by using CRISPR-Cas9 technology and revealed sperm structural defects of the flagella and the connecting piece. Our consistent observations across human populations and in the mouse model strongly support the notion that bi-allelic mutations in TTC21A can induce asthenoteratospermia with defects of the sperm flagella and head-tail conjunction.
Lysine acetylation regulates many eukaryotic cellular processes, but its function in prokaryotes is largely unknown. We demonstrated that central metabolism enzymes in Salmonella were acetylated ...extensively and differentially in response to different carbon sources, concomitantly with changes in cell growth and metabolic flux. The relative activities of key enzymes controlling the direction of glycolysis versus gluconeogenesis and the branching between citrate cycle and glyoxylate bypass were all regulated by acetylation. This modulation is mainly controlled by a pair of lysine acetyltransferase and deacetylase, whose expressions are coordinated with growth status. Reversible acetylation of metabolic enzymes ensure that cells respond environmental changes via promptly sensing cellular energy status and flexibly altering reaction rates or directions. It represents a metabolic regulatory mechanism conserved from bacteria to mammals.
Cancer-associated fibroblasts (CAFs) provide critical metabolites for tumor growth and undergo metabolic reprogramming to support glycolysis. However, the molecular mechanisms responsible for this ...change remain unclear. Here, we report that TGF-β1- or PDGF-induced CAFs switch from oxidative phosphorylation to aerobic glycolysis. We identify downregulation of isocitrate dehydrogenase 3α (IDH3α) as a marker for this switch. Furthermore, miR-424 downregulates IDH3α during CAF formation. Downregulation of IDH3α decreases the effective level of α-ketoglutarate (α-KG) by reducing the ratio of α-KG to fumarate and succinate, resulting in PHD2 inhibition and HIF-1α protein stabilization. The accumulation of HIF-1α, in turn, promotes glycolysis by increasing the uptake of glucose, upregulating expression of glycolytic enzymes under normoxic conditions, and inhibiting oxidative phosphorylation by upregulating NDUFA4L2. CAFs from tumor samples exhibit low levels of IDH3α, and overexpression of IDH3α prevents transformation of fibroblasts into CAFs. Our studies reveal IDH3α to be a critical metabolic switch in CAFs.
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•IDH3α is uniformly decreased in CAFs•Downregulation of IDH3α promotes metabolic switch to glycolysis in CAFs•Decreased IDH3α reduces the ratio of α-KG to fumarate and succinate•Reduced α-KG leads to the stabilization of HIF-1α under normoxic conditions
Zhang et al. provide conclusive evidence that CAFs are prone to glycolysis and that this metabolic change is responsible for the tumor-promoting effect of CAFs. In addition, their study identifies a detailed molecular mechanism underlying glycolytic reprogramming in CAFs.
The effect of preparation conditions (molar ratio of S/Mo, hydrothermal temperature and time) on the morphologies of MoS2 was investigated. The as-synthesized materials were characterized by X-ray ...diffraction (XRD), field emission scanning microscopy (FESEM), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), Raman spectra and Brunauer–Emmett–Teller’s (BET) surface area measurement. Results showed that the three kinds of morphologies of MoS2 were obtained. Morphologies varied gradually from the coral-like aggregated particles to flower-like spheres to wrapped nano-sheet structure with increasing hydrothermal temperature and time. It is meaningful for specific morphology demand in different fields. Moreover, the prepared materials were used as tentative adsorbents for the removal of bisphenol A (BPA) as a representative of endocrine disruptors. The results showed that the prepared MoS2 materials with wrapped nano-sheet structure had good adsorption capacity (39.03 mg/g) and fast adsorption rate (0.0053 g/(mg/min). The adsorption process was thermodynamically exothermic and spontaneous. The study indicated that electrostatic interaction is strong and π-π interaction between BPA and the MoS2 materials play an important role for BPA adsorption.
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