Jungho Cha

Synergistic effects of mycophenolate mofetil and losartan in a model of chronic cyclosporine nephropathy.

Background. Combined treatments of mycophenolate mofetil (MMF) and losartan (LSRT) have synergistic effects on various renal diseases through their hemodynamic and anti-inflammatory effects. This study investigated whether MMF treatment is effective in inhibiting inflammatory processes in chronic cyclosporine A (CsA) nephrotoxicity, and whether combined treatment using MMF and LSRT affords superior protection compared with the respective monotherapies. Methods. Rats on a low-salt diet were given vehicle (VH group, olive oil, 1 mg/kg per day), CsA (15 mg/kg per day), CsA and LSRT (CsA+LSRT group, 100 mg/L per day), CsA and MMF (CsA+MMF group; 40 mg/kg per day), or CsA, LSRT and MMF (CsA+LSRT MMF group). Control groups received each drug without CsA treatment. Renal function, histologic parameters (arteriolopathy, tubulointerstitial fibrosis, and inflammatory cell infiltration), and mediators of CsA-induced nephrotoxicity (angiotensin-II, osteopontin, and transforming growth factor [TGF]-&bgr;1) were studied. Results. The CsA-treated rats showed decreased renal function and increased histologic parameters compared with the VH-treated rats. The CsA+MMF treatment significantly improved renal function and histopathologic parameters compared with the CsA group, and combined treatment with MMF and LSRT further improved those parameters compared with the CsA+LSRT and CsA+MMF groups. At a molecular level, increased expression of angiotensin II protein, osteopontin, and TGF-&bgr;1 mRNAs in the CsA group were significantly decreased with MMF, and further decrease was observed with the combined treatment using MMF and LSRT. Conclusions. MMF treatment decreases CsA-induced nephrotoxicity, and combined treatment with LSRT has a synergistic effect in preventing chronic CsA nephrotoxicity.

Combined Effects of Losartan and Pravastatin on Interstitial Inflammation and Fibrosis in Chronic Cyclosporine-induced Nephropathy

Background. Statins and angiotensin II type I receptor blockers have synergistic effects on vascular smooth–muscle-cell proliferation and the progression of renal diseases. We evaluated whether combined treatment with losartan (LSRT) and pravastatin (PRVT) affords superior protection compared with their respective monotherapies in treating chronic cyclosporine (CsA)-induced nephropathy in rats. Methods. Rats maintained on a low salt diet were given vehicle, CsA (15 mg/kg), CsA and LSRT (10 mg/kg), CsA and PRVT (5 mg/kg), or a combination of CsA, LSRT, and PRVT for 28 days. Basic parameters (renal function, systolic blood pressure, serum high-sensitivity C-reactive protein [hs-CRP], and lipid profiles), histopathology (arteriolopathy, tubulointerstitial fibrosis, and inflammatory cell infiltration), and inflammatory and fibrotic factors (intrarenal CRP, angiotensin II, osteopontin, and transforming growth factor [TGF]-&bgr;1) were studied. Results. LSRT or PRVT treatment significantly attenuated the histopathologic changes induced by CsA, and combined treatment with LSRT and PRVT further decreased these parameters compared with giving each drug alone. Increased levels of angiotensin II, intrarenal CRP, osteopontin, and TGF-&bgr;1 in CsA-treated rat kidney were reduced by treatment with either LSRT or PRVT and were further decreased by the combination of the two drugs. There were no significant differences in systolic blood pressure or serum lipid parameters between groups. Conclusions. Combined treatment with LSRT and PRVT provided synergistic effects in attenuating inflammatory and fibrotic processes in a rat model of chronic CsA-induced nephropathy, and this effect was independent of their hypolipidemic and hypotensive actions.

Dopaminergic modulation of resting-state functional connectivity in de novo patients with Parkinson's disease

Parkinsons disease (PD) is characterized by degenerative changes of nigral dopamine neurons, resulting in the dopaminergic denervation of the striatum. Resting state networks studies have demonstrated that dopamine modulates distinct network connectivity patterns in both a linear and a nonlinear fashion, but quantitative analyses of dopamine‐dependent functional connectivity secondary to PD pathology were less informative. In the present study, we performed a correlation analysis between striatal dopamine levels assessed quantitatively by FP‐CIT positron emission tomography imaging and resting‐state functional connectivity in 23 drug naïve de novo patients with PD to elucidate dopamine‐dependent functional networks. The major finding is that the patterns of dopamine‐dependent positive functional connectivity varied depending on the location of striatal seeds. Dopamine‐dependent functional connectivity with the caudate predominantly overlay pericentral cortical areas, whereas dopamine‐dependent structures functionally connected with the posterior putamen predominantly involved cerebellar areas. The dorsolateral frontal area overlapped as a dopamine‐dependent cortical region that was positively connected with the anterior and posterior putamen. On the other hand, cortical areas where functional connectivity from the posterior cingulate was negatively correlated with dopaminergic status in the posterior putamen were localized in the left anterior prefrontal area and the parietal area. Additionally, functional connectivity between the anterior putamen and mesiofrontal areas was negatively coupled with striatal dopamine levels. The present study demonstrated that dopamine‐dependent functional network connectivity secondary to PD pathology mainly exhibits a consistent pattern, albeit with some variation. These patterns may reflect the diverse effects of dopaminergic medication on parkinsonian‐related motor and cognitive performance. Hum Brain Mapp 35:5431–5441, 2014.

Distinctive Resting State Network Disruptions Among Alzheimer’s Disease, Subcortical Vascular Dementia, and Mixed Dementia Patients

BACKGROUND Recent advances in resting-state functional MRI have revealed altered functional networks in Alzheimers disease (AD), especially those of the default mode network (DMN) and central executive network (CEN). However, few studies have evaluated whether small vessel disease (SVD) or combined amyloid and SVD burdens affect the DMN or CEN. OBJECTIVE The aim of this study was to evaluate whether SVD or combined amyloid and SVD burdens affect the DMN or CEN. METHODS In this cross-sectional study, we investigated the resting-state functional connectivity within DMN and CEN in 37 Pittsburgh compound-B (PiB)(+) AD, 37 PiB(-) subcortical vascular dementia (SVaD), 13 mixed dementia patients, and 65 normal controls. RESULTS When the resting-state DMN of PiB(+) AD and PiB(-) SVaD patients were compared, the PiB(+) AD patients displayed lower functional connectivity in the inferior parietal lobule while the PiB(-) SVaD patients displayed lower functional connectivity in the medial frontal and superior frontal gyri. Compared to the PiB(-) SVaD or PiB(+) AD, the mixed dementia patients displayed lower functional connectivity within the DMN in the posterior cingulate gyrus. When the resting-state CEN connectivity of PiB(+) AD and PiB(-) SVaD patients were compared, the PiB(-) SVaD patients displayed lower functional connectivity in the anterior insular region. Compared to the PiB(-) SVaD or PiB(+) AD, the mixed dementia patients displayed lower functional connectivity within the CEN in the inferior frontal gyrus. CONCLUSIONS Our findings suggest that in PiB(+) AD and PiB(-) SVaD, there is divergent disruptions in resting-state DMN and CEN. Furthermore, patients with combined amyloid and SVD burdens exhibited more disrupted resting-state DMN and CEN than patients with only amyloid or SVD burden.

Brain mechanisms of pain relief by transcutaneous electrical nerve stimulation: A functional magnetic resonance imaging study

Although the exact mechanism of TENS pain relief is unknown, it is believed that TENS impulses interrupt nociceptive signals at the dorsal horn of the spinal cord.

Change of Brain Functional Connectivity in Patients With Spinal Cord Injury: Graph Theory Based Approach.

Objective To investigate the global functional reorganization of the brain following spinal cord injury with graph theory based approach by creating whole brain functional connectivity networks from resting state-functional magnetic resonance imaging (rs-fMRI), characterizing the reorganization of these networks using graph theoretical metrics and to compare these metrics between patients with spinal cord injury (SCI) and age-matched controls. Methods Twenty patients with incomplete cervical SCI (14 males, 6 females; age, 55±14.1 years) and 20 healthy subjects (10 males, 10 females; age, 52.9±13.6 years) participated in this study. To analyze the characteristics of the whole brain network constructed with functional connectivity using rs-fMRI, graph theoretical measures were calculated including clustering coefficient, characteristic path length, global efficiency and small-worldness. Results Clustering coefficient, global efficiency and small-worldness did not show any difference between controls and SCIs in all density ranges. The normalized characteristic path length to random network was higher in SCI patients than in controls and reached statistical significance at 12%-13% of density (p<0.05, uncorrected). Conclusion The graph theoretical approach in brain functional connectivity might be helpful to reveal the information processing after SCI. These findings imply that patients with SCI can build on preserved competent brain control. Further analyses, such as topological rearrangement and hub region identification, will be needed for better understanding of neuroplasticity in patients with SCI.

Assessment of Functional Characteristics of Amnestic Mild Cognitive Impairment and Alzheimer’s Disease Using Various Methods of Resting-State FMRI Analysis

Resting-state functional magnetic resonance imaging (RS FMRI) has been widely used to analyze functional alterations in amnestic mild cognitive impairment (aMCI) and Alzheimers disease (AD) patients. Although many clinical studies of aMCI and AD patients using RS FMRI have been undertaken, conducting a meta-analysis has not been easy because of seed selection bias by the investigators. The purpose of our study was to investigate the functional differences in aMCI and AD patients compared with healthy subjects in a meta-analysis. Thus, a multimethod approach using regional homogeneity, amplitude of low-frequency fluctuation (ALFF), fractional ALFF (fALFF), and global brain connectivity was used to investigate differences between three groups based on previously published data. According to the choice of RS FMRI approach used, the patterns of functional alteration were slightly different. Nevertheless, patients with aMCI and AD displayed consistently decreased functional characteristics with all approaches. All approaches showed that the functional characteristics in the left parahippocampal gyrus were decreased in AD patients compared with healthy subjects. Although some regions were slightly different according to the different RS FMRI approaches, patients with aMCI and AD showed a consistent pattern of decreased functional characteristics with all approaches.

Overlapping Distribution of Osteopontin and Calcium in the Ischemic Core of Rat Brain after Transient Focal Ischemia

Osteopontin (OPN), an adhesive glycoprotein, has recently been proposed to act as an opsonin that facilitates phagocytosis of neuronal debris by macrophages in the ischemic brain. The present study was designed to elucidate the process whereby OPN binds to neuronal cell debris in a rat model of ischemic stroke. Significant co-localization of the OPN protein and calcium deposits in the ischemic core were observed by combining alizarin red staining and OPN immunohistochemistry. In addition, electron microscopy (EM) using the osmium/potassium dichromate method revealed that electron-dense precipitates, typical of calcium deposits, were localized mainly along the periphery of putative degenerating neurites. This topical pattern of calcium precipitates resembled the distribution of OPN as detected by immunogold-silver EM. Combining immunogold-silver EM and electron probe microanalysis further demonstrated that the OPN protein was localized at the periphery of cell debris or degenerating neurites, corresponding with locally higher concentrations of calcium and phosphorus, and that the relative magnitude of OPN accumulation was comparable to that of calcium and phosphorus. These data suggest that calcium precipitation provides a matrix for the binding of the OPN protein within the debris or degenerating neurites induced by ischemic injury. Therefore, OPN binding to calcium deposits may be involved in phagocytosis of such debris, and may participate in the regulation of ectopic calcification in the ischemic brain.

Proteomic analysis of alpha-1-antitrypsin in immunoglobulin A nephropathy

Immunoglobulin A nephropathy (IgAN) is recognized as the most common form of primary glomerulonephritis worldwide. It is characterized by mesangial cell proliferation with mesangial IgA deposition in the glomeruli, and is usually associated with secondary tubulointerstitial injury. Although significant progress has been made in the clarification of the pathogenesis of IgAN, the exact pathogenetic mechanism remains unclear. To find out the candidate proteins that play an important role in IgAN, renal cortex tissues and urine from IgAN patients were studied. The 2‐DE was performed on renal tissues of IgAN and normal controls. A series of spots identified as alpha‐1‐antitrypsin (AAT) by mass spectrometry, were found to be significantly increased in patients with IgAN. Up‐regulation of AAT variants was validated in renal cortex tissues of IgAN using Western blot and 2‐DE immunoblot. Lower isoforms (˜48 kDa) and fragments (˜33 kDa), suspected as cleavage forms by proteinase attack, were especially increased in IgAN compared to normal controls. In addition, AAT proteins modified by tyrosine nitration (approximately 57 and 48 kDa), which reflects excessive oxidative stress, were increased in IgAN tissue. Additionally in the urine of IgAN, increase of AAT variants and fragments was detected by 2‐DE immunoblot as well as Western blot. Immunohistochemical staining of IgAN kidney tissue revealed that the increase of AAT appeared to be derived from hypertrophic proximal tubules. The AAT staining in the glomerulus was not clear in IgAN. In addition, immunodepletion‐zymography showed a positive correlation between AAT and 80–110‐kDa proteinases in IgAN tissue. Further studies regarding the functional roles of AAT and the proteinases will allow better understanding of the pathogenesis of IgAN.

Nigrostriatal dopamine-independent resting-state functional networks in Parkinson's disease

As an indicator of synchronous neural activity, resting-state functional networks are influenced by neuropathological and neurochemical changes in degenerative diseases. To further advance understanding about neurochemical and neuropathological basis for resting-state functional maps, we performed a comparative analysis of resting-state functional connectivity in patients with Parkinsons disease (PD) and drug induced parkinsonism (DIP). Resting-state neuroimaging data were analyzed with a seed-based approach to investigate striatocortical functional connectivity and cortical functional connectivity within the default mode network, executive control network, and the dorsal attention network. The striatal subregions were divided into the more or less affected sides in terms of dopamine transporter uptake. Compared with DIP, PD exhibited an increased cerebellar connectivity from the more affected side of the caudate and the less affected sides of the anterior and the posterior putamen. Additionally, PD showed increased functional connectivity in the anterior prefrontal areas from the more affected side of the anterior putamen and from the less affected side of the posterior putamen. However, PD exhibited decreased cortical functional connectivity from the posterior cingulate cortex in the left temporal area. Finally, DIP patients showed decreased cortical functional connectivity from the dorsolateral prefrontal cortex in frontal and parietal areas compared with PD patients. In summary, the present study demonstrates that PD patients exhibited a unique resting state functional connectivity that may be associated with PD-related pathological changes beyond the dopaminergic system, whereas DIP patients showed altered functional connectivity within executive control network.