Indoxyl sulphate-TNFα axis mediates uremic encephalopathy in rodent acute kidney injury.

Acute kidney injury (AKI) is often accompanied by uremic encephalopathy resulting from accumulation of uremic toxins in brain possibly due to impaired blood-brain barrier (BBB) function. Anionic uremic toxins are substrates or inhibitors of organic anionic transporters (OATs). In this study we investigated the CNS behaviors and expression/function of BBB OAT3 in AKI rats and mice, which received intraperitoneal injection of cisplatin 8 and 20 mg/kg, respectively. We showed that cisplatin treatment significantly inhibited the expressions of OAT3, synaptophysin and microtubule-associated protein 2 (MAP2), impaired locomotor and exploration activities, and increased accumulation of uremic toxins in the brain of AKI rats and mice. In vitro studies showed that uremic toxins neither alter OAT3 expression in human cerebral microvascular endothelial cells, nor synaptophysin and MAP2 expressions in human neuroblastoma (SH-SY5Y) cells. In contrast, tumour necrosis factor alpha (TNFα) and the conditioned medium (CM) from RAW264.7 cells treated with indoxyl sulfate (IS) significantly impaired OAT3 expression. TNFα and CM from IS-treated BV-2 cells also inhibited synaptophysin and MAP2 expressions in SH-SY5Y cells. The alterations caused by TNFα and CMs in vitro, and by AKI and TNFα in vivo were abolished by infliximab, a monoclonal antibody designed to intercept and neutralize TNFα, suggesting that AKI impaired the expressions of OAT3, synaptophysin and MAP2 in the brain via IS-induced TNFα release from macrophages or microglia (termed as IS-TNFα axis). Treatment of mice with TNFα (0.5 mg·kg-1·d-1, i.p. for 3 days) significantly increased p-p65 expression and reduced the expressions of Nrf2 and HO-1. Inhibiting NF-κB pathway, silencing p65, or activating Nrf2 and HO-1 obviously attenuated TNFα-induced downregulation of OAT3, synaptophysin and MAP2 expressions. Significantly increased p-p65 and decreased Nrf2 and HO-1 protein levels were also detected in brain of AKI mice and rats. We conclude that AKI inhibits the expressions of OAT3, synaptophysin and MAP2 due to IS-induced TNFα release from macrophages or microglia. TNFα impairs the expressions of OAT3, synaptophysin and MAP2 partly via activating NF-κB pathway and inhibiting Nrf2-HO-1 pathway.

Efficacy and neural mechanism of acupuncture treatment in older adults with subjective cognitive decline: study protocol for a randomised controlled clinical trial.

INTRODUCTION: Subjective cognitive decline (SCD) refers to individuals' perceived decline in memory and/or other cognitive abilities relative to their previous level of performance, while objective neuropsychological deficits are not observed. SCD may represent a preclinical phase of Alzheimer's disease. At this very early stage of decline, intervention could slow the rate of incipient decline to prolong and preserve cognitive and functional abilities. However, there is no effective treatment recommended for individuals with SCD. Acupuncture, as a non-pharmacological intervention, has been widely employed for patients with cognitive disorders. METHODS AND ANALYSIS: The proposed study is a randomised, assessor-blinded and placebo-controlled study that investigates the efficacy and mechanism of acupuncture in SCD. Sixty patients with SCD will be randomly allocated either into an acupuncture group or a sham acupuncture group. They will receive 24 sessions of real acupuncture treatment or identical treatment sessions using a placebo needle. Global cognitive changes based on a multidomain neuropsychological test battery will be evaluated to detect the clinical efficacy of acupuncture treatment at baseline and end of treatment. MRI scans will be used to explore acupuncture-related neuroplasticity changes. Correlation analyses will be performed to investigate the relationships between the changes in brain function and symptom improvement. ETHICS AND DISSEMINATION: The trial was approved by the research ethics committee. The results of the study will be published in a peer-reviewed academic journal and will also be disseminated electronically through conference presentations. TRIAL REGISTRATION NUMBER: NCT03444896.

Abnormal Global Brain Functional Connectivity in Primary Insomnia Patients: A Resting-State Functional MRI Study.

Background: Resting-state functional magnetic resonance imaging (fMRI) studies have uncovered the disruptions of functional brain networks in primary insomnia (PI) patients. However, the etiology and pathogenesis underlying this disorder remains ambiguous, and the insomnia related symptoms are influenced by a complex network organization in the brain. The purpose of this study was to explore the abnormal intrinsic functional hubs in PI patients using a voxel-wise degree centrality (DC) analysis and seed-based functional connectivity (FC) approach. Methods: A total of 26 PI patients and 28 healthy controls were enrolled, and they underwent resting-state fMRI. Degree centrality was measured across the whole brain, and group differences in DC were compared. The peak points, which significantly altered DC between the two groups, were defined as the seed regions and were further used to calculate FC of the whole brain. Later, correlation analyses were performed between the changes in brain function and clinical features. Results: Primary insomnia patients showed DC values lower than healthy controls in the left inferior frontal gyrus (IFG) and middle temporal gyrus (MTG) and showed a higher DC value in the right precuneus. The seed-based analyses demonstrated decreased FC between the left MTG and the left posterior cingulate cortex (PCC), and decreased FC was observed between the right precuneus and the right lateral occipital cortex. Reduced DC in the left IFG and decreased FC in the left PCC were positively correlated with the Pittsburgh sleep quality index and the insomnia severity index. Conclusions: This study revealed that PI patients exhibited abnormal intrinsic functional hubs in the left IFG, MTG, and the right precuneus, as well as abnormal seed-based FC in these hubs. These results contribute to better understanding of how brain function influences the symptoms of PI.

Abnormal Functional Connectivity of Anterior Cingulate Cortex in Patients With Primary Insomnia: A Resting-State Functional Magnetic Resonance Imaging Study.

Background: Recently, there have been many reports about abnormalities regarding structural and functional brain connectivity of the patients with primary insomnia. However, the alterations in functional interaction between the left and right cerebral hemispheres have not been well understood. The resting-state fMRI approach, which reveals spontaneous neural fluctuations in blood-oxygen-level-dependent signals, offers a method to quantify functional interactions between the hemispheres directly. Methods: We compared interhemispheric functional connectivity (FC) between 26 patients with primary insomnia (48.85 ± 12.02 years) and 28 healthy controls (49.07 ± 11.81 years) using a voxel-mirrored homotopic connectivity (VMHC) method. The patients with primary insomnia and healthy controls were matched for age, gender, and education. Brain regions, which had significant differences in VMHC maps between the primary insomnia and healthy control groups, were defined as seed region of interests. A seed-based approach was further used to reveal significant differences of FC between the seeds and the whole contralateral hemisphere. Results: The patients with primary insomnia showed higher VMHC than healthy controls in the anterior cingulate cortex (ACC) bilaterally. The seed-based analyses demonstrated increased FC between the left ACC and right thalamus (and the right ACC and left orbitofrontal cortex) in patients with primary insomnia, revealing abnormal connectivity between the two cerebral hemispheres. The VMHC values in the ACC were positively correlated with the time to fall asleep and Self-Rating Depression Scale scores (SDS). Conclusions: The results demonstrate that there is abnormal interhemispheric resting-state FC in the brain regions of patients with primary insomnia, especially in the ACC. Our finding demonstrates valid evidence that the ACC is an area of interest in the neurobiology of primary insomnia.

Different mechanisms of contralateral- or ipsilateral-acupuncture to modulate the brain activity in patients with unilateral chronic shoulder pain: a pilot fMRI study.

BACKGROUND: Chronic shoulder pain (CSP) is a common disease causing pain and functional limitation, which is highly prevalent and has substantial negative effects on the quality of life. Acupuncture has gained popularity and has been accepted gradually by many countries because it can successfully treat patients with chronic pain, but the specific brain mechanisms under acupuncture treatment for CSP remain unclear. Therefore, in this study, we aimed to 1) compare the clinical effects between acupuncture at the contralateral and ipsilateral Tiaokou (ST 38) point in patients with unilateral shoulder pain and 2) explore how contralateral- and ipsilateral-acupuncture modulates the regional homogeneity (ReHo) of patients with CSP. PATIENTS AND METHODS: This was a pilot functional magnetic resonance imaging (fMRI) trial. Twenty-four patients with CSP were recruited and randomized to the contralateral acupuncture group (contra-group) and the ipsilateral acupuncture group (ipsi-group). All patients completed resting-state functional magnetic resonance imaging (fMRI) scans before and after acupuncture treatment. Shoulder pain intensity (visual analog scale [VAS]) and shoulder joint function (Constant-Murley score [CMS]) were used to evaluate clinical efficiency of treatment. ReHo was used to assess resting-state brain activity. RESULTS: We found clinical improvement in decreasing pain intensity and increasing shoulder function in both groups, and the mean objective shoulder functional improvement in contra-group was better than that in ipsi-group (p = 0.010). Interestingly, the brain mechanism of contra-acupuncture at ST 38 was distinguishable from ipsi-acupuncture regarding ReHo values. CONCLUSION: Anterior cingulate cortex (ACC) may play a direct role in the regulation of brain by the contralateral acupuncture at ST 38 in patients with shoulder pain. On the contrary, the pathway of brainstem-thalamus-cortex may be likely to work in mechanism of acupuncture at ipsilateral ST 38. SIGNIFICANCE: Our results indicate that the clinical effects and brain mechanisms are different between the stimulation given at contralateral and ipsilateral acupoints in patients with CSP and imply that the selection of either contralateral or ipsilateral acupuncture therapy to treat some chronic pain conditions is necessary.

Changes in the Vision-related Resting-state Network in Pituitary Adenoma Patients After Vision Improvement.

BACKGROUND: The aim of this research was to investigate the changes in the vision-related resting-state network (V-RSN) in pituitary adenoma (PA) patients after vision improvement, which was induced by operative treatment. METHODS: Ten PA patients with an improved visual acuity or/and visual field after transsphenoidal pituitary tumor resection were recruited and underwent a complete neuro-ophthalmologic evaluation, as well as an magnetic resonance imaging (MRI) protocol, including structural and resting-state functional MRI sequences before and after the operation. The regional homogeneity (ReHo) of the V-RSN was evaluated. Two sample t-test was performed to identify the significant differences in the V-RSN in the PA patients before and after transsphenoidal pituitary tumor resection. RESULTS: Compared with the preoperation counterparts, the PA patients with improved vision after the operation exhibited reduced ReHo in the bilateral thalamus, globus pallidus, caudate nucleus, putamen nucleus, supplementary motor area, and left hippocampal formation, and increased ReHo in the bilateral cuneus gyrus, calcarine gyrus, right lingual gyrus, and fusiform gyrus. CONCLUSIONS: PA patients with improved vision exhibit increased neural activity within the visual cortex, but decreased neural activity in subareas of the multisensory and multimodal systems beyond the vision cortex.

High-temperature inhibition of biosynthesis and transportation of anthocyanins results in the poor red coloration in red-fleshed Actinidia chinensis.

In plants, the role of anthocyanins trafficking in response to high temperature has been rarely studied, and therefore poorly understood. Red-fleshed kiwifruit has stimulated the world kiwifruit industry owing to its appealing color. However, fruit in warmer climates have been found to have poor flesh coloration, and the factors responsible for this response remain elusive. Partial correlation and regression analysis confirmed that accumulative temperatures above 25 °C (T25) was one of the dominant factors inhibiting anthocyanin accumulation in red-fleshed Actinidia chinensis, 'Hongyang'. Expression of structural genes, AcMRP and AcMYB1 in inner pericarp sampled from the two high altitudes (low temperature area), was notably higher than the low altitude (high temperature area) during fruit coloration. AcMYB1 and structural genes coordinate expression supported the MYB-bHLH (basic helix-loop-helix)-WD40 regulatory complex mediated downregulation of anthocyanin biosynthesis induced by high temperatures in kiwifruit. Moreover, cytological observations using the light and transmission electronic microscopy showed that there were a series of anthocyanic vacuolar inclusion (AVI)-like structures involved in their vacuolization process and dissolution of the pigmented bodies inside cells of fruit inner pericarp. Anthocyanin transport was inhibited by high temperature via retardation of vacuolization or reduction in AIV-like structure formation. Our findings strongly suggested that complex multimechanisms influenced the effects of high temperature on red-fleshed kiwifruit coloration.