Ketogenic diet-produced ß-hydroxybutyric acid accumulates brain GABA and increases GABA/glutamate ratio to inhibit epilepsy.

Ketogenic diet (KD) alleviates refractory epilepsy and reduces seizures in children. However, the metabolic/cell biologic mechanisms by which the KD exerts its antiepileptic efficacy remain elusive. Herein, we report that KD-produced ß-hydroxybutyric acid (BHB) augments brain gamma-aminobutyric acid (GABA) and the GABA/glutamate ratio to inhibit epilepsy. The KD ameliorated pentetrazol-induced epilepsy in mice. Mechanistically, KD-produced BHB, but not other ketone bodies, inhibited HDAC1/HDAC2, increased H3K27 acetylation, and transcriptionally upregulated SIRT4 and glutamate decarboxylase 1 (GAD1). BHB-induced SIRT4 de-carbamylated and inactivated glutamate dehydrogenase to preserve glutamate for GABA synthesis, and GAD1 upregulation increased mouse brain GABA/glutamate ratio to inhibit neuron excitation. BHB administration in mice inhibited epilepsy induced by pentetrazol. BHB-mediated relief of epilepsy required high GABA level and GABA/glutamate ratio. These results identified BHB as the major antiepileptic metabolite of the KD and suggested that BHB may serve as an alternative and less toxic antiepileptic agent than KD.

Proteome profiling of early gestational plasma reveals novel biomarkers of congenital heart disease.

Prenatal diagnosis of congenital heart disease (CHD) relies primarily on fetal echocardiography conducted at mid-gestational age-the sensitivity of which varies among centers and practitioners. An objective method for early diagnosis is needed. Here, we conducted a case-control study recruiting 103 pregnant women with healthy offspring and 104 cases with CHD offspring, including VSD (42/104), ASD (20/104), and other CHD phenotypes. Plasma was collected during the first trimester and proteomic analysis was performed. Principal component analysis revealed considerable differences between the controls and the CHDs. Among the significantly altered proteins, 25 upregulated proteins in CHDs were enriched in amino acid metabolism, extracellular matrix receptor, and actin skeleton regulation, whereas 49 downregulated proteins were enriched in carbohydrate metabolism, cardiac muscle contraction, and cardiomyopathy. The machine learning model reached an area under the curve of 0.964 and was highly accurate in recognizing CHDs. This study provides a highly valuable proteomics resource to better recognize the cause of CHD and has developed a reliable objective method for the early recognition of CHD, facilitating early intervention and better prognosis.

Amino acids downregulate SIRT4 to detoxify ammonia through the urea cycle.

Ammonia production via glutamate dehydrogenase is inhibited by SIRT4, a sirtuin that displays both amidase and non-amidase activities. The processes underlying the regulation of ammonia removal by amino acids remain unclear. Here, we report that SIRT4 acts as a decarbamylase that responds to amino acid sufficiency and regulates ammonia removal. Amino acids promote lysine 307 carbamylation (OTCCP-K307) of ornithine transcarbamylase (OTC), which activates OTC and the urea cycle. Proteomic and interactome screening identified OTC as a substrate of SIRT4. SIRT4 decarbamylates OTCCP-K307 and inactivates OTC in an NAD+-dependent manner. SIRT4 expression was transcriptionally upregulated by the amino acid insufficiency-activated GCN2-eIF2α-ATF4 axis. SIRT4 knockout in cultured cells caused higher OTCCP-K307 levels, activated OTC, elevated urea cycle intermediates and urea production via amino acid catabolism. Sirt4 ablation decreased male mouse blood ammonia levels and ameliorated CCl4-induced hepatic encephalopathy phenotypes. We reveal that SIRT4 safeguards cellular ammonia toxicity during amino acid catabolism.

Tin bisulfide nanoplates anchored onto flower-like bismuth tungstate nanosheets for enhancement in the photocatalytic degradation of organic pollutant.

The development of efficient heterojunctions through a simple and facile method is an effective way to enhance the photocatalytic performance of bismuth-based oxide semiconductors for industrial applications. Here, the novel flower-like type II SnS2/Bi2WO6 heterostructure consisting of bismuth tungstate (Bi2WO6) nanosheets and tin bisulfide (SnS2) nanoplates was successfully designed and synthesized. The crystal structure, composition, morphology, and photoelectric properties of the heterostructure were systematically characterized. In addition, the photocatalytic activity of SnS2/Bi2WO6 was analyzed and compared with Bi2WO6 or SnS2 alone or physical mixture of SnS2 and Bi2WO6. 2%SnS2/Bi2WO6 presents a 3.1 times greater degradation rate constant (0.0065 min-1) than that of Bi2WO6 (0.0021 min-1) under low visible light irradiation (5.3 mW·cm-2, a 44 W LED), while SnS2 alone exhibits no photocatalytic effect toward glyphosate. Furthermore, 2%SnS2/Bi2WO6 maintains 93% of its original photocatalytic activity even after four cycles. The possible photocatalytic degradation pathway of glyphosate and photocatalytic mechanism are also proposed. The excellent photocatalytic performance of SnS2/Bi2WO6 is attributed to the decoration of SnS2 nanoplates on the surface of Bi2WO6, appropriate (113)/(020) ratio, increased visible-light absorption, and effective separation of photoinduced carriers. This paper reports a new methodology that can act as a reference basis to design and develop visible-light responsive photocatalysts with outstanding photocatalytic performance for carbon dioxide reduction, water splitting, and pollutant degradation.