Bardoxolone methyl: a potential therapeutic for the prevention of anti-psychotic drug-induced obesity?

Abstract of a presentation

Global population structure and evolution of Bordetella pertussis and their relationship with vaccination.

Bordetella pertussis causes pertussis, a respiratory disease that is most severe for infants. Vaccination was introduced in the 1950s, and in recent years, a resurgence of disease was observed worldwide, with significant mortality in infants. Possible causes for this include the switch from whole-cell vaccines (WCVs) to less effective acellular vaccines (ACVs), waning immunity, and pathogen adaptation. Pathogen adaptation is suggested by antigenic divergence between vaccine strains and circulating strains and by the emergence of strains with increased pertussis toxin production. We applied comparative genomics to a worldwide collection of 343 B. pertussis strains isolated between 1920 and 2010. The global phylogeny showed two deep branches; the largest of these contained 98% of all strains, and its expansion correlated temporally with the first descriptions of pertussis outbreaks in Europe in the 16th century. We found little evidence of recent geographical clustering of the strains within this lineage, suggesting rapid strain flow between countries. We observed that changes in genes encoding proteins implicated in protective immunity that are included in ACVs occurred after the introduction of WCVs but before the switch to ACVs. Furthermore, our analyses consistently suggested that virulence-associated genes and genes coding for surface-exposed proteins were involved in adaptation. However, many of the putative adaptive loci identified have a physiological role, and further studies of these loci may reveal less obvious ways in which B. pertussis and the host interact. This work provides insight into ways in which pathogens may adapt to vaccination and suggests ways to improve pertussis vaccines. IMPORTANCE Whooping cough is mainly caused by Bordetella pertussis, and current vaccines are targeted against this organism. Recently, there have been increasing outbreaks of whooping cough, even where vaccine coverage is high. Analysis of the genomes of 343 B. pertussis isolates from around the world over the last 100 years suggests that the organism has emerged within the last 500 years, consistent with historical records. We show that global transmission of new strains is very rapid and that the worldwide population of B. pertussis is evolving in response to vaccine introduction, potentially enabling vaccine escape

A multi-shift phase angle control strategy for bidirectional wireless power transmission system

Using the charging and discharging capability of battery-based loads and a two-way wireless energy transmission system, grid-load balancing can be achieved in both directions. The system can be applied to many locations by deploying power flow in real time. In the scenario of vehicle network interconnection, it realizes peak-shaving and valley-filling to optimize grid dispatching capability; in the scenario of modular satellite interconnection, it realizes load balancing and effectively improves energy utilization. Therefore, a suitable control strategy is needed to precisely change the output power flow and the output power magnitude. A method to coordinate multiple phase shifting angles in the system hierarchy to achieve power flow regulation is proposed for a bidirectional wireless power transmission system with a dual full-bridge topology. In this paper, we first model the bidirectional transmission system and analyze the relationship between each phase shift angle and active and reactive power. The traditional control strategy is optimized by reducing the number of control loop variables and using the system power factor angle instead of the difficult-to-control external phase shift angle, while ensuring the voltage gain for optimal system efficiency. Finally, only two control loops are used to control the direction and magnitude of the output power respectively, and the effectiveness and correctness of the control strategy are verified by using the corresponding simulation experiments to achieve smooth switching of the bidirectional electric power transmission power flow

Bardoxolone methyl prevents high-fat diet-induced alterations in prefrontal cortex signalling molecules involved in recognition memory

High fat (HF) diets are known to induce changes in synaptic plasticity in the forebrain leading to learning and memory impairments. Previous studies of oleanolic acid derivatives have found that these compounds can cross the blood-brain barrier to prevent neuronal cell death. We examined the hypothesis that the oleanolic acid derivative, bardoxolone methyl (BM) would prevent diet-induced cognitive deficits in mice fed a HF diet. C57BL/6J male mice were fed a lab chow (LC) (5% of energy as fat), a HF (40% of energy as fat), or a HF diet supplemented with 10 mg/kg/day BM orally for 21 weeks. Recognition memory was assessed by performing a novel object recognition test on the treated mice. Downstream brain-derived neurotrophic factor (BDNF) signalling molecules were examined in the prefrontal cortex (PFC) and hippocampus of mice via Western blotting and N-methyl-d-aspartate (NMDA) receptor binding. BM treatment prevented HF diet-induced impairment in recognition memory (p \u3c 0.001). In HF diet fed mice, BM administration attenuated alterations in the NMDA receptor binding density in the PFC (p \u3c 0.05), however, no changes were seen in the hippocampus (p \u3e 0.05). In the PFC and hippocampus of the HF diet fed mice, BM administration improved downstream BDNF signalling as indicated by increased protein levels of BDNF, phosphorylated tropomyosin related kinase B (pTrkB) and phosphorylated protein kinase B (pAkt), and increased phosphorylated AMP-activated protein kinase (pAMPK) (p \u3c 0.05). BM administration also prevented the HF diet-induced increase in the protein levels of inflammatory molecules, phosphorylated c-Jun N-terminal kinase (pJNK) in the PFC, and protein tyrosine phosphatase 1B (PTP1B) in both the PFC and hippocampus. In summary, these findings suggest that BM prevents HF diet-induced impairments in recognition memory by improving downstream BDNF signal transduction, increasing pAMPK, and reducing inflammation in the PFC and hippocampus

Mobilization of Au and Ag during Supergene Processes in the Linglong Gold Deposit: Evidence from SEM and LA–ICP–MS Analyses of Sulfides

Precious metals can be mobilized during supergene processes, which are important for the formation of high-grade or high-purity ores. The world-class Linglong gold deposit has high-grade ores that have undergone supergene processes in the near-surface zone. Under which conditions the supergene modification occurred and how Au and Ag behaved during the supergene processes have been poorly studied in this deposit. Here, we performed scanning electron microscope (SEM) and laser ablation–inductively coupled plasma–mass spectrometry (LA–ICP–MS) analyses on samples from the supergene enrichment zone of the Linglong gold deposit. The results show that secondary minerals were formed sequentially from magnetite-goethite-limonite to marcasite-acanthite, and finally to siderite after the primary minerals of pyrite-pyrrhotite-chalcopyrite. These mineral assemblages and variations indicate that the supergene modification by groundwater occurred under oxidative and weakly acidic conditions in the near-surface zone and evolved to reductive and near neutral conditions in the supergene enrichment zone. The newly formed marcasite has much higher Au (0.003–23.5 ppm, mean of 1.33 ppm) and Ag (81.7–6021 ppm, mean of 1111 ppm) concentrations than those of the primary pyrite (Au of 0.004–0.029 ppm and Ag of 0.22–4.14 ppm), which together with the formation of independent Ag–S mineral (acanthite), indicates that Au and Ag were significantly mobilized and fractionated during the supergene processes. These processes improved the Au and Ag grades in the supergene enrichment zone and thus facilitate their extraction

Bardoxolone methyl prevents insulin resistance and the development of hepatic steatosis in mice fed a high-fat diet

High-fat (HF) diet-induced obesity is a major risk factor for the development of insulin resistance and hepatic steatosis. We examined the hypothesis that bardoxolone methyl (BM) would prevent the development of insulin resistance and hepatic steatosis in mice fed a HF diet. C57BL/6J male mice were fed a lab chow (LC), HF (40% fat), or HF diet supplemented with 10 mg/kg/day BM orally for 21 weeks. Glucose metabolism was assessed using a glucose tolerance test (GTT) and insulin sensitivity test (IST). Signalling molecules involved in insulin resistance, inflammation, and lipid metabolism were examined in liver tissue via western blotting and RT-PCR. BM prevented HF diet-induced insulin resistance and alterations in the protein levels of protein tyrosine phosphatase 1B (PTP1B), forkhead box protein O1 (FOXO1) and BDNF, and expression of the insulin receptor (IR), IRS-1 and glucose-6-phosphatase (G6Pase) genes. Furthermore, BM prevented fat accumulation in the liver and decreases in the β-oxidation gene, peroxisomal acyl-coenzyme A oxidase 1 (ACOX) in mice fed a HF diet. In the livers of HF fed mice, BM administration prevented HF diet-induced macrophage infiltration, inflammation as indicated by reduced IL-6 and signal transducer and activator of transcription 3 (STAT3) protein levels and TNFα mRNA expression, and increased nuclear factor-like 2 (Nrf2) mRNA expression and nuclear protein levels. These findings suggest that BM prevents HF diet induced insulin resistance and the development of hepatic steatosis in mice fed a chronic HF diet through modulation of molecules involved in insulin signalling, lipid metabolism and inflammation in the liver

Per-cell histone acetylation is associated with terminal differentiation in human T cells

Abstract Background Epigenetic remodeling at effector gene loci has been reported to be critical in regulating T cell differentiation and function. However, efforts to investigate underlying epigenetic mechanisms that control T cell behaviors have been largely hindered by very limited experimental tools, especially in humans. Results In this study, we employed a flow cytometric assay to analyze histone acetylation at single-cell level in human T cells. The data showed that histone acetylation was increased during T cell activation. Among T cell subsets, terminally differentiated effector memory T (TEMRA) cells robustly producing effector cytokines were hyper-acetylated. Conversely, these TEMRA cells had lower expression levels of TCF-1, a key transcription factor for maintaining stem cell features. Pharmaceutical inhibition of histone acetylation using a small molecule C646 restrained the production of effector molecules, but retained stem cell-like properties in T cells after expansion. Conclusions Per-cell histone acetylation is associated with terminal differentiation and poor stemness in human T cells. These observations suggest a new approach to enhance the stem cell-like properties of T cells and improve the efficacy of immunotherapy

Bardoxolone methyl prevents fat deposition and inflammation in the visceral fat of mice fed a high-fat diet

Key features of diet-induced obesity are visceral fat deposition, macrophage infiltration and inflammation that can lead to metabolic disorders. This study examined the effects of bardoxolone methyl (BARD) in preventing obesity and inflammation in the visceral fat of mice fed high-fat diet. Male C57BL/6J mice were fed a high-fat diet (HFD), a low-fat diet (LFD, i.e., lab chow diet) or a high-fat diet supplemented with BARD (HFD/BARD) for 21 weeks. BARD at a dosage of 10 mg/kg body weight was administered orally in drinking water. Histology, immunohistochemistry and Western blot were used for the analysis of epididymal adipose tissue. Morphological results demonstrated that HFD fed mice treated with BARD had smaller adipocytes and fewer macrophages present in epididymal adipose tissue than the HFD group. Furthermore, BARD administration reduced the inflammatory profile in this tissue by increasing the expression of nuclear factor of kappa-light-polypeptide gene enhancer in B-cells inhibitor, alpha (IκB-α) protein and decreasing the protein expression of tumour necrosis factor alpha (TNF-α). BARD also prevented oxidative stress reflected by a reduction in stress activated proteins, including signal transducer and activator of transcription 3 (STAT3), protein kinase B (Akt), extracellular-signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). BARD administration activated the sympathetic nervous system in epididymal adipose tissue assessed by the increased synthesis of tyrosine hydroxylase (TH) and uncoupling protein 2 (UCP2). The expression of inflammatory and sympathetic nervous system proteins in BARD mice fed a HFD was equivalent to that of the LFD control mice, indicating the anti-inflammatory and anti-obesity properties of this drug. In conclusion, the oral administration of BARD in HFD mice prevented fat deposition, inflammation and oxidative stress, and improved sympathetic activity in visceral fat. This study suggests a potential therapeutic role of BARD in preventing the development of obesity