Fructose overconsumption impairs hepatic manganese homeostasis and ammonia disposal.

Arginase, a manganese (Mn)-dependent enzyme, is indispensable for urea generation and ammonia disposal in the liver. The potential role of fructose in Mn and ammonia metabolism is undefined. Here we demonstrate that fructose overconsumption impairs hepatic Mn homeostasis and ammonia disposal in male mice. Fructose overexposure reduces liver Mn content as well as its activity of arginase and Mn-SOD, and impairs the clearance of blood ammonia under liver dysfunction. Mechanistically, fructose activates the Mn exporter Slc30a10 gene transcription in the liver in a ChREBP-dependent manner. Hepatic overexpression of Slc30a10 can mimic the effect of fructose on liver Mn content and ammonia disposal. Hepatocyte-specific deletion of Slc30a10 or ChREBP increases liver Mn contents and arginase activity, and abolishes their responsiveness to fructose. Collectively, our data establish a role of fructose in hepatic Mn and ammonia metabolism through ChREBP/Slc30a10 pathway, and postulate fructose dietary restriction for the prevention and treatment of hyperammonemia.

A novel smart somatosensory wearable assistive device for older adults' home rehabilitation during the COVID-19 pandemic.

Background: Due to the Coronavirus disease 19 (COVID-19) related social distancing measures and health service suspension, physical activity has declined, leading to increased falling risk and disability, and consequently, compromising the older adult health. How to improve the quality of older adult life has become a crucial social issue. Objective: In traditional rehabilitation, manual and repetitive muscle training cannot identify the patient's rehabilitation effect, and increasing the willingness to use it is not easy. Therefore, based on the usability perspective, this study aims to develop a novel smart somatosensory wearable assistive device (called SSWAD) combined with wireless surface electromyography (sEMG) and exergame software and hardware technology. The older adult can do knee extension, ankle dorsiflexion, and ankle plantar flexion rehabilitation exercises at home. Meanwhile, sEMG values can be digitally recorded to assist physicians (or professionals) in judgment, treatment, or diagnosis. Methods: To explore whether the novel SSWAD could improve the older adult willingness to use and motivation for home rehabilitation, 25 frail older adult (12 males and 13 females with an average age of 69.3) perform the rehabilitation program with the SSWAD, followed by completing the system usability scale (SUS) questionnaire and the semi-structured interview for the quantitative and qualitative analyses. In addition, we further investigate whether the factor of gender or prior rehabilitation experience would affect the home rehabilitation willingness or not. Results: According to the overall SUS score, the novel SSWAD has good overall usability performance (77.70), meaning that the SSWAD makes older adult feel interested and improves their willingness for continuous rehabilitation at home. In addition, the individual item scores of SUS are shown that female older adult with prior rehabilitation experience perform better in "Learnability" (t = 2.35, p = 0.03) and "Confidence" (t = -3.24, p = 0.01). On the contrary, male older adult without rehabilitation experience are more willing to adopt new technologies (t = -2.73, p = 0.02), and perform better in "Learnability" (t = 2.18, p = 0.04) and "Confidence" (t = -3.75, p < 0.001) with the SSWAD. In addition, the result of the semi-structured interview shows that the operation of the SSWAD is highly flexible, thus reducing older adult burden during the rehabilitation exercise and using them long-term. Conclusion: This novel SSWAD receives consistently positive feedback regardless of the gender or prior rehabilitation experience of elders. The SSWAD could be used as a novel way of home rehabilitation for elders, especially during the COVID-19 pandemic. Older adult can do rehabilitation exercises at home, and physicians could make proper judgments or adjust suitable treatments online according to the sEMG data, which older adult can know their rehabilitation progress at the same time. Most importantly, older adult do not have to go to the hospital every time for rehabilitation, which significantly reduces time and the risk of infection.

The zinc finger and BTB domain containing protein ZBTB20 regulates plasma triglyceride metabolism by repressing lipoprotein lipase gene transcription in hepatocytes.

BACKGROUND AND AIMS: Lipoprotein lipase (LPL) is responsible for the lipolytic processing of triglyceride-rich lipoproteins, the deficiency of which causes severe hypertriglyceridemia. Liver LPL expression is high in suckling rodents but relatively low at adulthood. However, the regulatory mechanism and functional significance of liver LPL expression are incompletely understood. We have established the zinc finger protein ZBTB20 as a critical factor for hepatic lipogenesis. Here, we evaluated the role of ZBTB20 in regulating liver Lpl gene transcription and plasma triglyceride metabolism. APPROACH AND RESULTS: Hepatocyte-specific inactivation of ZBTB20 in mice led to a remarkable increase in LPL expression at the mRNA and protein levels in adult liver, in which LPL protein was mainly localized onto sinusoidal epithelial cells and Kupffer cells. As a result, the LPL activity in postheparin plasma was substantially increased, and postprandial plasma triglyceride clearance was significantly enhanced, whereas plasma triglyceride levels were decreased. The dysregulated liver LPL expression and low plasma triglyceride levels in ZBTB20-deficient mice were normalized by inactivating hepatic LPL expression. ZBTB20 deficiency protected the mice against high-fat diet-induced hyperlipidemia without causing excessive triglyceride accumulation in the liver. Chromatin immunoprecipitation and gel-shift assay studies revealed that ZBTB20 binds to the LPL promoter in the liver. A luciferase reporter assay revealed that ZBTB20 inhibits the transcriptional activity of LPL promoter. The regulation of LPL expression by ZBTB20 is liver-specific under physiological conditions. CONCLUSIONS: Liver ZBTB20 serves as a key regulator of LPL expression and plasma triglyceride metabolism and could be a therapeutic target for hypertriglyceridemia.

Liver ChREBP Protects Against Fructose-Induced Glycogenic Hepatotoxicity by Regulating L-Type Pyruvate Kinase.

Excessive fructose consumption is closely linked to the pathogenesis of metabolic disease. Carbohydrate response element-binding protein (ChREBP) is a transcription factor essential for fructose tolerance in mice. However, the functional significance of liver ChREBP in fructose metabolism remains unclear. Here, we show that liver ChREBP protects mice against fructose-induced hepatotoxicity by regulating liver glycogen metabolism and ATP homeostasis. Liver-specific ablation of ChREBP did not compromise fructose tolerance, but rather caused severe transaminitis and hepatomegaly with massive glycogen overload in mice fed a high-fructose diet, while no obvious inflammation, cell death, or fibrosis was detected in the liver. In addition, liver ATP contents were significantly decreased by ChREBP deficiency in the fed state, which was rendered more pronounced by fructose feeding. Mechanistically, liver contents of glucose-6-phosphate (G6P), an allosteric activator of glycogen synthase, were markedly increased in the absence of liver ChREBP, while fasting-induced glycogen breakdown was not compromised. Furthermore, hepatic overexpression of LPK, a ChREBP target gene in glycolysis, could effectively rescue glycogen overload and ATP reduction, as well as mitigate fructose-induced hepatotoxicity in ChREBP-deficient mice. Taken together, our findings establish a critical role of liver ChREBP in coping with hepatic fructose stress and protecting from hepatotoxicity by regulating LPK.

NAD replenishment with nicotinamide mononucleotide protects blood-brain barrier integrity and attenuates delayed tissue plasminogen activator-induced haemorrhagic transformation after cerebral ischaemia.

BACKGROUND AND PURPOSE: Tissue plasminogen activator (tPA) is the only approved pharmacological therapy for acute brain ischaemia; however, a major limitation of tPA is the haemorrhagic transformation that follows tPA treatment. Here, we determined whether nicotinamide mononucleotide (NMN), a key intermediate of nicotinamide adenine dinucleotide biosynthesis, affects tPA-induced haemorrhagic transformation. EXPERIMENTAL APPROACH: Middle cerebral artery occlusion (MCAO) was achieved in CD1 mice by introducing a filament to the left MCA for 5 h. When the filament was removed for reperfusion, tPA was infused via the tail vein. A single dose of NMN was injected i.p. (300 mg·kg-1 ). Mice were killed at 24 h post ischaemia, and their brains were evaluated for brain infarction, oedema, haemoglobin content, apoptosis, neuroinflammation, blood-brain barrier (BBB) permeability, the expression of tight junction proteins (TJPs) and the activity/expression of MMPs. KEY RESULTS: In the mice infused with tPA at 5 h post ischaemia, there were significant increases in mortality, brain infarction, brain oedema, brain haemoglobin level, neural apoptosis, Iba-1 staining (microglia activation) and myeloperoxidase staining (neutrophil infiltration). All these tPA-induced alterations were significantly prevented by NMN administration. Mechanistically, the delayed tPA treatment increased BBB permeability by down-regulating TJPs, including claudin-1, occludin and zonula occludens-1, and enhancing the activities and protein expression of MMP9 and MMP2. Similarly, NMN administration partly blocked these tPA-induced molecular changes. CONCLUSIONS AND IMPLICATIONS: Our results demonstrate that NMN ameliorates tPA-induced haemorrhagic transformation in brain ischaemia by maintaining the integrity of the BBB.

Nicotinamide mononucleotide attenuates brain injury after intracerebral hemorrhage by activating Nrf2/HO-1 signaling pathway.

Replenishment of NAD+ has been shown to protect against brain disorders such as amyotrophic lateral sclerosis and ischemic stroke. However, whether this intervention has therapeutic effects in intracerebral hemorrhage (ICH) is unknown. In this study, we sought to determine the potential therapeutic value of replenishment of NAD+ in ICH. In a collagenase-induced ICH (cICH) mouse model, nicotinamide mononucleotide (NMN), a key intermediate of nicotinamide adenine dinucleotide (NAD+) biosynthesis, was administrated at 30 minutes post cICH from tail vein to replenish NAD+. NMN treatment did not decrease hematoma volume and hemoglobin content. However, NMN treatment significantly reduced brain edema, brain cell death, oxidative stress, neuroinflammation, intercellular adhesion molecule-1 expression, microglia activation and neutrophil infiltration in brain hemorrhagic area. Mechanistically, NMN enhanced the expression of two cytoprotective proteins: heme oxygenase 1 (HO-1) and nuclear factor-like 2 (Nrf2). Moreover, NMN increased the nuclear translocation of Nrf2 for its activation. Finally, a prolonged NMN treatment for 7 days markedly promoted the recovery of body weight and neurological function. These results demonstrate that NMN treats brain injury in ICH by suppressing neuroinflammation/oxidative stress. The activation of Nrf2/HO-1 signaling pathway may contribute to the neuroprotection of NMN in ICH.

Is the linear modeling technique good enough for optimal form design? A comparison of quantitative analysis models.

How to design highly reputable and hot-selling products is an essential issue in product design. Whether consumers choose a product depends largely on their perception of the product image. A consumer-oriented design approach presented in this paper helps product designers incorporate consumers' perceptions of product forms in the design process. The consumer-oriented design approach uses quantification theory type I, grey prediction (the linear modeling technique), and neural networks (the nonlinear modeling technique) to determine the optimal form combination of product design for matching a given product image. An experimental study based on the concept of Kansei Engineering is conducted to collect numerical data for examining the relationship between consumers' perception of product image and product form elements of personal digital assistants (PDAs). The result of performance comparison shows that the QTTI model is good enough to help product designers determine the optimal form combination of product design. Although the PDA form design is used as a case study, the approach is applicable to other consumer products with various design elements and product images. The approach provides an effective mechanism for facilitating the consumer-oriented product design process.