Effects of Heparan Sulfate Trisaccharide Containing Oleanolic Acid in Attenuating Hyperphosphorylated Tau-Induced Cell Dysfunction Associated with Alzheimer's Disease.

Alzheimer's disease (AD) is the most common form of dementia, marked by progressive brain degeneration and cognitive decline. A major pathological feature of AD is the accumulation of hyperphosphorylated tau (p-tau) in the form of neurofibrillary tangles (NFTs), which leads to neuronal death and neurodegeneration. P-tau also induces endoplasmic reticulum (ER) stress and activates the unfolded protein response, causing inflammation and apoptosis.

ER-tethered stress sensor CREBH regulates mitochondrial unfolded protein response to maintain energy homeostasis.

The Mitochondrial Unfolded Protein Response (UPR), a mitochondria-originated stress response to altered mitochondrial proteostasis, plays important roles in various pathophysiological processes. In this study, we revealed that the endoplasmic reticulum (ER)-tethered stress sensor CREBH regulates UPR to maintain mitochondrial homeostasis and function in the liver. CREBH is enriched in and required for hepatic Mitochondria-Associated Membrane (MAM) expansion induced by energy demands.

Effects of Aerobic vs. Resistance Exercise on Vascular Function and Vascular Endothelial Growth Factor in Older Women.

This study aimed to investigate the effects of different types of exercise (aerobic vs. resistance) on vascular function and vascular endothelial growth factor in older women. Forty-three older women, aged 65-75 years old, voluntarily participated in this study.

The links of fine airborne particulate matter exposure to occurrence of cardiovascular and metabolic diseases in Michigan, USA.

Air pollutants, particularly airborne particulate matter with aerodynamic diameter < 2.5μm (PM2.5), have been linked to the increase in mortality and morbidity associated with cardiovascular and metabolic diseases.

Boosting UPR transcriptional activator XBP1 accelerates acute wound healing.

Patients' suffering from large or deep wounds caused by traumatic and/or thermal injuries have significantly lower chances of recapitulating lost skin function through natural healing. We tested whether enhanced unfolded protein response (UPR) by expression of a UPR transcriptional activator, X-box-binding protein 1 (XBP1) can significantly promote wound repair through stimulating growth factor production and promoting angiogenesis. In mouse models of a second-degree thermal wound, a full-thickness traumatic wound, and a full-thickness diabetic wound, the topical gene transfer of the activated form of XBP1 (spliced XBP1, XBP1s) can significantly enhance re-epithelialization and increase angiogenesis, leading to rapid, nearly complete wound closure with intact regenerated epidermis and dermis.

Homocysteine-induced endoplasmic reticulum stress activates FGF21 and is associated with browning and atrophy of white adipose tissue in knockout mice.

Betaine-homocysteine methyltransferase (BHMT) catalyzes the transfer of methyl groups from betaine to homocysteine (Hcy), producing methionine and dimethylglycine. In this work, we characterize wild type (-WT) and knockout (-KO) mice that were fully backcrossed to a C57Bl6/J background. Consistent with our previous findings, KO mice had decreased body weight, fat mass, and adipose tissue weight compared to WT.

A hepatokine derived from the ER protein CREBH promotes triglyceride metabolism by stimulating lipoprotein lipase activity.

The endoplasmic reticulum (ER)-tethered, liver-enriched stress sensor CREBH is processed in response to increased energy demands or hepatic stress to release an amino-terminal fragment that functions as a transcription factor for hepatic genes encoding lipid and glucose metabolic factors. Here, we discovered that the carboxyl-terminal fragment of CREBH (CREBH-C) derived from membrane-bound, full-length CREBH was secreted as a hepatokine in response to fasting or hepatic stress. Phosphorylation of CREBH-C mediated by the kinase CaMKII was required for efficient secretion of CREBH-C through exocytosis.

The mitochondrial NAD kinase functions as a major metabolic regulator upon increased energy demand.

Objective: The mitochondrial nicotinamide adenine dinucleotide (NAD) kinase (MNADK) mediates de novo mitochondrial NADP biosynthesis by catalyzing the phosphorylation of NAD to yield NADP. In this study, we investigated the function and mechanistic basis by which MNADK regulates metabolic homeostasis.

Methods: Generalized gene set analysis by aggregating human patient genomic databases, metabolic studies with genetically engineered animal models, mitochondrial bioenergetic analysis, as well as gain- and loss- of-function studies were performed to address the functions and mechanistic basis by which MNADK regulates energy metabolism and redox state associated with metabolic disease.

The mitochondrial NAD transporter SLC25A51 is a fasting-induced gene affecting SIRT3 functions.

Introduction: Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism and energy production. NAD-dependent deacetylase sirtuin 3 (SIRT3) regulates the acetylation levels of mitochondrial proteins that are involved in mitochondrial homeostasis. Fasting up-regulates hepatic SIRT3 activity, which requires mitochondrial NAD.

Analysis of Insulin Resistance in Nonalcoholic Steatohepatitis.

Insulin resistance is a major phenotype observed in nonalcoholic steatohepatitis (NASH), the advanced stage of nonalcoholic fatty liver disease (NAFLD). Insulin resistance in NASH is characterized by reductions in whole body, hepatic, and adipose tissue insulin sensitivity. The mechanisms underlying hepatic insulin resistance is primarily associated with hepatic glucose production (HGP) rate.

Type 2 diabetes sex-specific effects associated with E167K coding variant in .

The rs58542926C >T (E167K) variant of the transmembrane 6 superfamily member 2 gene () is associated with increased risks for nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). Nevertheless, the role of the rs58542926 variant in glucose metabolism is poorly understood. We performed a sex-stratified analysis of the association between the rs58542926C >T variant and T2D in multiple cohorts.

Regulation of hepatic circadian metabolism by the E3 ubiquitin ligase HRD1-controlled CREBH/PPARα transcriptional program.

Objective: The endoplasmic reticulum (ER)-resident E3 ligase HRD1 and its co-activator Sel1L are major components of ER-associated degradation (ERAD) machinery. Here, we investigated the molecular mechanism and functional significance underlying the circadian regulation of HRD1/Sel1L-mediated protein degradation program in hepatic energy metabolism.

Methods: Genetically engineered animal models as well as gain- and loss-of-function studies were employed to address the circadian regulatory mechanism and functional significance.

Regulation of hepatic autophagy by stress-sensing transcription factor CREBH.

Autophagy, a lysosomal degradative pathway in response to nutrient limitation, plays an important regulatory role in lipid homeostasis upon energy demands. Here, we demonstrated that the endoplasmic reticulum-tethered, stress-sensing transcription factor cAMP-responsive element-binding protein, hepatic-specific (CREBH) functions as a major transcriptional regulator of hepatic autophagy and lysosomal biogenesis in response to nutritional or circadian signals. CREBH deficiency led to decreased hepatic autophagic activities and increased hepatic lipid accumulation upon starvation.

IRE1α prevents hepatic steatosis by processing and promoting the degradation of select microRNAs.

Obesity or a high-fat diet represses the endoribonuclease activity of inositol-requiring enzyme 1α (IRE1α), a transducer of the unfolded protein response (UPR) in cells under endoplasmic reticulum (ER) stress. An impaired UPR is associated with hepatic steatosis and nonalcoholic fatty liver disease (NAFLD), which is caused by lipid accumulation in the liver. We found that IRE1α was critical to maintaining lipid homeostasis in the liver by repressing the biogenesis of microRNAs (miRNAs) that regulate lipid mobilization.

Interaction between stress responses and circadian metabolism in metabolic disease.

Circadian rhythms play crucial roles in orchestrating diverse physiological processes that are critical for health and disease. Dysregulated circadian rhythms are closely associated with various human metabolic diseases, including type 2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease. Modern lifestyles are frequently associated with an irregular circadian rhythm, which poses a significant risk to public health.

Inhalation Exposure to PM Counteracts Hepatic Steatosis in Mice Fed High-fat Diet by Stimulating Hepatic Autophagy.

Air pollution is associated with the increased risk of metabolic syndrome. In this study, we performed inhalation exposure of mice fed normal chow or a high-fat diet to airborne fine particulate matters (PM), and then investigated the complex effects and mechanisms of inhalation exposure to PM on hepatic steatosis, a precursor or manifestation of metabolic syndrome. Our studies demonstrated that inhalation exposure of mice fed normal chow to concentrated ambient PM repressed hepatic transcriptional regulators involved in fatty acid oxidation and lipolysis, and thus promoted hepatic steatosis.

Deficiency of the Mitochondrial NAD Kinase Causes Stress-Induced Hepatic Steatosis in Mice.

Background & Aims: The mitochondrial nicotinamide adenine dinucleotide (NAD) kinase (NADK2, also called MNADK) catalyzes phosphorylation of NAD to yield NADP. Little is known about the functions of mitochondrial NADP and MNADK in liver physiology and pathology. We investigated the effects of reduced mitochondrial NADP by deleting MNADK in mice.

Feasibility of Rehabilitation Training With a Newly Developed, Portable, Gait Assistive Robot for Balance Function in Hemiplegic Patients.

Objective: To investigate the clinical feasibility of a newly developed, portable, gait assistive robot (WA-H, 'walking assist for hemiplegia') for improving the balance function of patients with stroke-induced hemiplegia.

Methods: Thirteen patients underwent 12 weeks of gait training on the treadmill while wearing WA-H for 30 minutes per day, 4 days a week. Patients' balance function was evaluated by the Berg Balance Scale (BBS), Fugl-Meyer Assessment Scale (FMAS), Timed Up and Go Test (TUGT), and Short Physical Performance Battery (SPPB) before and after 6 and 12 weeks of training.

CREBH Maintains Circadian Glucose Homeostasis by Regulating Hepatic Glycogenolysis and Gluconeogenesis.

Cyclic AMP-responsive element binding protein, hepatocyte specific (CREBH), is a liver-enriched, endoplasmic reticulum-tethered transcription factor known to regulate the hepatic acute-phase response and lipid homeostasis. In this study, we demonstrate that CREBH functions as a circadian transcriptional regulator that plays major roles in maintaining glucose homeostasis. The proteolytic cleavage and posttranslational acetylation modification of CREBH are regulated by the circadian clock.

High-intensity interval training and athletic performance in Taekwondo athletes.

Background: The purpose of this study was to determine the effects of high-intensity interval training (HIIT) on athletic performance in Taekwondo athletes.

Methods: Thirty-three male and female collegiate Taekwondo athletes were randomly divided into a HIIT group (N.=16) or a high-intensity continuous running (HICR) group (N.

CREBH Couples Circadian Clock With Hepatic Lipid Metabolism.

The circadian clock orchestrates diverse physiological processes critical for health and disease. CREB, hepatocyte specific (CREBH) is a liver-enriched, endoplasmic reticulum (ER)-tethered transcription factor known to regulate the hepatic acute phase response and energy homeostasis under stress conditions. We demonstrate that CREBH is regulated by the circadian clock and functions as a circadian regulator of hepatic lipid metabolism.

Comparison of nutritional intake, body composition, bone mineral density, and isokinetic strength in collegiate female dancers.

This study compared nutritional intake, body composition, bone mineral density, and isokinetic strength by dance type in collegiate female dancers. The study subjects included Korean dancers (n=12), ballet dancers (n=13), contemporary dancers (n=8), and controls (n=12). Nutritional intake was estimated using the Computer Aided Nutritional Analysis Program.

Lysine Acetylation of CREBH Regulates Fasting-Induced Hepatic Lipid Metabolism.

Cyclic AMP-responsive element-binding protein 3-like 3, hepatocyte specific (CREBH), is a hepatic transcription factor that functions as a key regulator of energy homeostasis. Here, we defined a regulatory CREBH posttranslational modification process, namely, lysine-specific acetylation, and its functional involvement in fasting-induced hepatic lipid metabolism. Fasting induces CREBH acetylation in mouse livers in a time-dependent manner, and this event is critical for CREBH transcriptional activity in regulating hepatic lipid homeostasis.