Effects of Natural Products on Nonalcoholic Fatty Liver Disease through Nrf2 Epigenetic Regulation

Non-alcoholic fatty liver disease has become one of the common illnesses among urban dwellers worldwide. Many consider natural products as better options for medicine and diet supplements. In recent years, researchers found that natural products can prevent human diseases by reactivating silencing genes through epigenetic regulation. They also discovered nuclear factor erythroid-2-related factor-2 (Nrf2) as is an important factor in the response of anti-oxidation has a close relation to lipogenesis. Studies showed with the higher expression of DNA methyl-transferases, the higher methylation of Nrf2 promoter occurred. With the high methylation rate of the Nrf2 promoter, the expression of Nrf2 reduced thus enhanced lipid accumulation, which may cause NAFLD. Furthermore, with lower expression of Nrf2, the downstream antioxidant genes’ expression decreased, which may cause oxidative stress to human body cells. Understanding the pathway of Nrf2 and NAFLD can shed a light on discovering new development of drugs. This paper reviews several natural products and their mechanisms of alleviating NAFLD and hopes to bring in new perspectives on the treatment and the development of new drugs on NAFLD

Mapping and Modulating the Stomach-Brain Neuroaxis

The stomach and the brain interact closely with each other. Their interactions are central to digestive functions and the “gut feeling”. The neural pathways that mediate the stomach-brain interactions include the vagus nerve and the thoracic nerve. Through these nerves, the stomach can relay neural signals to a number of brain regions that span a central gastric network. This gastric network allows the brain to monitor and regulate gastric physiology and allows the stomach to influence emotion and cognition. Impairment of this gastric network may lead to both gastric and neurological disorders, e.g., anxiety, gastroparesis, functional dyspepsia, and obesity. However, the structural constituents and functional roles of the central gastric network remain unclear. In my dissertation research, I leveraged complementary techniques to characterize the central gastric network in rats across a wide range of scales and different gastric states. I used functional magnetic resonance imaging (fMRI) to map blood-oxygen-level-dependent (BOLD) activity synchronized with gastric electrical activity and to map brain activations induced by electrical stimulation applied to the vagus nerve or its afferent terminals on the stomach. I also used neurophysiology to characterize gastric neurons in the brainstem in response to gastric electrical stimulation. My results suggest that gastric neurons in the brainstem are selective to the orientation of gastric electrical stimulation. This electrical stimulation can also evoke neural activity beyond the brainstem and drive fast blood oxygenation level dependent (BOLD) activity in the central gastric network, primarily covering the cingulate cortex, somatosensory cortex, motor cortex, and insular cortex. Stimulating the vagus nerve – the primary neural pathway between the stomach and the brain, can evoke BOLD responses across widespread brain regions partially overlapped with the brain network evoked by gastric electrical stimulation. BOLD activity within the gastric network is also coupled to intrinsic gastric activity. Specifically, gastric slow waves are synchronized with the BOLD activity in the central gastric network. The synchronization manifests itself as the phase-coupling between BOLD activity and gastric slow waves as well as the correlation between BOLD activity and power fluctuations of gastric slow waves. This synchronization is primarily supported by the vagus nerve and varies across the postprandial and fasting states. My dissertation research contributes to the foundation of mapping and characterizing the central and peripheral mechanisms of gastric interoception and sheds new light on where and how to stimulate the peripheral nerves to modulate stomach-brain interactions.PHDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/170007/1/jccao_1.pd

Method Validation of Functional Magnetic Resonance Imaging and Electrophysiological Recording to Investigate Mechanisms of Vagus Nerve

Vagus nerve stimulation (VNS) is used clinically to treat epilepsy and depression, but its mechanism of action is unknown. Useful techniques to study this are functional magnetic resonance imaging (fMRI) and the local field potential (LFP). fMRI relies on oxygen use in the brain to show areas where neurons are active. The LFP is an electrical signal created by neuron action potentials and other current moving across cell membranes. The most information can be gained when the two methods are used simultaneously, however, this is difficult to do. This study seeks to validate the technique of fMRI-LFP as applied to study the mechanism of VNS. The rat is used as an animal model. Previously collected data is analyzed to determine effects of stimulation on respiration, since this will affect oxygen levels in the blood. Recording electrodes of different materials are tested to find the artifact size created in an MRI environment. Iridium electrodes were found to have the smallest artifact and therefore the best performance. It is unclear whether the stimulation used affects respiration, so a simultaneous fMRI-LFP experiment is needed to interpret fMR images. More work needs to be done before fMRI-LFP recordings can be taken during VNS

Acute effects of vagus nerve stimulation parameters on gastric motility assessed with magnetic resonance imaging

BackgroundVagus nerve stimulation (VNS) is an emerging bioelectronic therapy for regulating food intake and controlling gastric motility. However, the effects of different VNS parameters and polarity on postprandial gastric motility remain incompletely characterized.MethodsIn anesthetized rats (N = 3), we applied monophasic electrical stimuli to the left cervical vagus and recorded compound nerve action potential (CNAP) as a measure of nerve response. We evaluated to what extent afferent or efferent pathway could be selectively activated by monophasic VNS. In a different group of rats (N = 13), we fed each rat a gadolinium- labeled meal and scanned the rat stomach with oral contrast- enhanced magnetic resonance imaging (MRI) while the rat was anesthetized. We evaluated the antral and pyloric motility as a function of pulse amplitude (0.13, 0.25, 0.5, 1 mA), width (0.13, 0.25, 0.5 ms), frequency (5, 10 Hz), and polarity of VNS.Key ResultsMonophasic VNS activated efferent and afferent pathways with about 67% and 82% selectivity, respectively. Primarily afferent VNS increased antral motility across a wide range of parameters. Primarily efferent VNS induced a significant decrease in antral motility as the stimulus intensity increased (R = - .93, P < .05 for 5 Hz, R = - .85, P < .05 for 10 Hz). The VNS with either polarity tended to promote pyloric motility to a greater extent given increasing stimulus intensity.Conclusions and InferencesMonophasic VNS biased toward the afferent pathway is potentially more effective for facilitating occlusive contractions than that biased toward the efferent pathway.We investigated a possible differential effect of primarily afferent versus efferent cervical VNS on gastric motility under a range of VNS parameters. Gastric MRI data revealed that primarily afferent VNS induced stronger antral contractions relative to primarily efferent VNS. These results could serve as an index for optimizing VNS parameters for promoting gastric motility. Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155957/1/nmo13853_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155957/2/nmo13853.pd

Magnetic field induced discontinuous spin reorientation in ErFeO3 single crystal

The spin reorientation of ErFeO3 that spontaneously occurs at low temperature has been previously determined to be a process involving the continuous rotation of Fe3þ spins. In this work, the dynamic process of spin reorientation in ErFeO3 single crystal has been investigated by AC susceptibility measurements at various frequencies and static magnetic fields. Interestingly, two completely discontinuous steps are induced by a relatively large static magnetic field due to the variation in the magnetic anisotropy during this process. It provides deeper insights into the intriguing magnetic exchange interactions which dominate the sophisticated magnetic phase transitions in the orthoferrite systems

In vivo tracing of the ascending vagal projections to the brain with manganese enhanced magnetic resonance imaging

IntroductionThe vagus nerve, the primary neural pathway mediating brain-body interactions, plays an essential role in transmitting bodily signals to the brain. Despite its significance, our understanding of the detailed organization and functionality of vagal afferent projections remains incomplete.MethodsIn this study, we utilized manganese-enhanced magnetic resonance imaging (MEMRI) as a non-invasive and in vivo method for tracing vagal nerve projections to the brainstem and assessing their functional dependence on cervical vagus nerve stimulation (VNS). Manganese chloride solution was injected into the nodose ganglion of rats, and T1-weighted MRI scans were performed at both 12 and 24 h after the injection.ResultsOur findings reveal that vagal afferent neurons can uptake and transport manganese ions, serving as a surrogate for calcium ions, to the nucleus tractus solitarius (NTS) in the brainstem. In the absence of VNS, we observed significant contrast enhancements of around 19–24% in the NTS ipsilateral to the injection side. Application of VNS for 4 h further promoted nerve activity, leading to greater contrast enhancements of 40–43% in the NTS.DiscussionThese results demonstrate the potential of MEMRI for high-resolution, activity-dependent tracing of vagal afferents, providing a valuable tool for the structural and functional assessment of the vagus nerve and its influence on brain activity

Magnetic field induced discontinuous spin reorientation in ErFeO 3

The spin reorientation of ErFeO3 that spontaneously occurs at low temperature has been previously determined to be a process involving the continuous rotation of Fe3þ spins. In this work, the dynamic process of spin reorientation in ErFeO3 single crystal has been investigated by AC susceptibility measurements at various frequencies and static magnetic fields. Interestingly, two completely discontinuous steps are induced by a relatively large static magnetic field due to the variation in the magnetic anisotropy during this process. It provides deeper insights into the intriguing magnetic exchange interactions which dominate the sophisticated magnetic phase transitions in the orthoferrite systems

The influence of methotrexate-related transporter and metabolizing enzyme gene polymorphisms on peri-engraftment syndrome and graft-versus-host disease after haplo-hematopoietic stem cell transplantation in pediatric patients with malignant hematological diseases

BackgroundMethotrexate (MTX), utilized as a graft-versus-host disease (GvHD) prophylactic agent in allogeneic hematopoietic stem cell transplantation (allo-HSCT), has been proven to effectively decrease the occurrence of the peri-engraftment syndrome (Peri-ES) and acute GvHD (aGvHD). Changes in the pharmacodynamics of MTX are closely associated with gene polymorphisms in genes encoding drug-metabolizing enzymes and transporters. Nevertheless, the current studies mainly concentrate on leukemia or autoimmune diseases, and limited studies on allo-HSCT were reported.MethodsHere, we retrospectively assessed the relationship between MTX-related transporter and metabolizing enzyme gene polymorphisms, clinical characteristics, and outcomes in 57 pediatric patients who received haploid HSCT (haplo-HSCT) with malignant tumors at a single center.ResultsWe discovered all gene polymorphisms were in the Hardy–Weinberg equilibrium in our cohort. We discovered a significant correlation between platelet recovery time and ABCB1 (1236C&gt;T) (p = 0.042). Compared with patients with SLCO1B1 (1865+4846T&gt;C) TT, patients with SLCO1B1 (1865+4846T&gt;C) TC/CC had an increased incidence of Peri-ES (p = 0.030). Based on the multivariate Cox analysis, we discovered that SLCO1B1 (1865+4846T&gt;C) TT genotype was an independent protective factor for Peri-ES morbidity (hazard ratio (HR) = 0.464, p = 0.031), and the dose of mononuclear cells reinfused was significantly correlated with II–IV aGvHD (HR = 2.604, p = 0.039).ConclusionIn summary, our findings prove that the host’s genotypes might modify the risk of developing Peri-ES, contribute to a better understanding of the inter-individual difference in efficacy, and facilitate the development of individualized approaches to GvHD prophylaxis

Association Between the Severity of Obstructive Sleep Apnea and the Risk Stratification of Acute Pulmonary Embolism

Obstructive sleep apnea (OSA) has been associated with the initiation and progression of cardiovascular disease. This study aimed to explore the relationship between the severity of OSA and the risk stratification of acute pulmonary embolism (PE). In this single-center cohort study, patients diagnosed with PE were evaluated for OSA via polygraphy monitoring. The simplified PE severity index (sPESI) and the number of patients requiring systemic thrombolysis were used to determine the severity of the disease. Echocardiography was performed on all participants. All patients were divided into 2 groups (OSA group and non-OSA group), and the patients in OSA group were then divided into 3 groups based on the severity of OSA. Patients with severe OSA had a significantly higher number of patients with sPESI ≥ 1 ( P  = .005). A higher proportion of patients with severe OSA require systemic thrombolysis ( P  = .010). Patients with apnea–hypopnea index (AHI) > 30/h had a much higher fibrinogen ( P  = .004) and D-dimer ( P  = .040) level than those in the non-OSA group. The levels of creatinine were significantly higher in patients with OSA ( P  = .040). Echocardiography showed a significant difference in left ventricular ejection fraction (LVEF) between patients in non-OSA and severe OSA groups ( P  = .035). And brain natriuretic peptide (BNP) also exhibited a progressive worsening related to the deepest desaturation and oxygen desaturation index. OSA, especially with AHI > 30/h, is correlated with the severity and prognosis of acute PE. This might be attributed to the prothrombotic effect, renal impairment, and cardiac dysfunction in patients with severe OSA

Vagal nerve stimulation triggers widespread responses and alters large-scale functional connectivity in the rat brain.

Vagus nerve stimulation (VNS) is a therapy for epilepsy and depression. However, its efficacy varies and its mechanism remains unclear. Prior studies have used functional magnetic resonance imaging (fMRI) to map brain activations with VNS in human brains, but have reported inconsistent findings. The source of inconsistency is likely attributable to the complex temporal characteristics of VNS-evoked fMRI responses that cannot be fully explained by simplified response models in the conventional model-based analysis for activation mapping. To address this issue, we acquired 7-Tesla blood oxygenation level dependent fMRI data from anesthetized Sprague-Dawley rats receiving electrical stimulation at the left cervical vagus nerve. Using spatially independent component analysis, we identified 20 functional brain networks and detected the network-wise activations with VNS in a data-driven manner. Our results showed that VNS activated 15 out of 20 brain networks, and the activated regions covered >76% of the brain volume. The time course of the evoked response was complex and distinct across regions and networks. In addition, VNS altered the strengths and patterns of correlations among brain networks relative to those in the resting state. The most notable changes in network-network interactions were related to the limbic system. Together, such profound and widespread effects of VNS may underlie its unique potential for a wide range of therapeutics to relieve central or peripheral conditions