Safety and effectiveness of dulaglutide in Chinese adults with type 2 diabetes mellitus in a real-world setting: A prospective, observational post-marketing study.

AIM: To our knowledge, this is the first real-world study to investigate the safety and effectiveness of a glucagon-like peptide-1 receptor agonist in Chinese patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: This prospective, observational, post-marketing study conducted at 46 hospitals in China included adults with T2DM prescribed dulaglutide in routine clinical practice. The primary endpoint was the incidence of treatment-emergent adverse events (TEAEs) and serious AEs in patients who received ≥1 dose of dulaglutide, for up to 24 weeks. Exploratory endpoints included changes in patient-reported glycated haemoglobin (HbA1c) and body weight. Post hoc analyses and multivariate regression were also performed. RESULTS: From 20 January 2020 to 24 November 2021, 3291 patients received dulaglutide and entered the safety analysis. TEAEs were reported in 1333 (40.5%) patients; the most commonly reported were nausea (n = 193, 5.9%), diarrhoea (n = 183, 5.6%) and decreased appetite (n = 179, 5.4%). serious AEs were reported in 160 (4.9%) patients. TEAEs led to treatment discontinuation in 212 (6.4%) patients. The mean absolute change in HbA1c from baseline to week 24 was -1.65% (p < .001). Greater reductions in HbA1c at week 24 were observed in patients with T2DM duration ≤5 years (p = .002), baseline HbA1c ≥8.5% (p < .001), and without atherosclerotic cardiovascular disease (p = .002). The mean absolute change in body weight from baseline at week 24 was -2.62 kg (p < .001). CONCLUSION: Dulaglutide showed a safety profile consistent with previous reports and significantly reduced HbA1c in a real-world setting. These findings support the clinical use of dulaglutide and inform the individualized treatment of patients with T2DM in China.

Pathway-Specific Mediation Effect Between Structure, Function, and Motor Impairment After Subcortical Stroke.

BACKGROUND AND OBJECTIVE: To investigate the pathway-specific correspondence between structural and functional changes resulting from focal subcortical stroke and their causal influence on clinical symptom. METHODS: In this retrospective, cross-sectional study, we mainly focused on patients with unilateral subcortical chronic stroke with moderate-severe motor impairment assessed by Fugl-Meyer Assessment (upper extremity) and healthy controls. All participants underwent both resting-state fMRI and diffusion tensor imaging. To parse the pathway-specific structure-function covariation, we performed association analyses between the fine-grained corticospinal tracts (CSTs) originating from 6 subareas of the sensorimotor cortex and functional connectivity (FC) of the corresponding subarea, along with the refined corpus callosum (CC) sections and interhemispheric FC. A mediation analysis with FC as the mediator was used to further assess the pathway-specific effects of structural damage on motor impairment. RESULTS: Thirty-five patients (mean age 52.7 ± 10.2 years, 27 men) and 43 healthy controls (mean age 56.2 ± 9.3 years, 21 men) were enrolled. Among the 6 CSTs, we identified 9 structurally and functionally covaried pathways, originating from the ipsilesional primary motor area (M1), dorsal premotor area (PMd), and primary somatosensory cortex (p < 0.05, corrected). FC for the bilateral M1, PMd, and ventral premotor cortex covaried with secondary degeneration of the corresponding CC sections (p < 0.05, corrected). Moreover, these covarying structures and functions were significantly correlated with the Fugl-Meyer Assessment (upper extremity) scores (p < 0.05, uncorrected). In particular, FC between the ipsilesional PMd and contralesional cerebellum (ß = -0.141, p < 0.05, CI = [-0.319 to -0.015]) and interhemispheric FC of the PMd (ß = 0.169, p < 0.05, CI = [0.015-0.391]) showed significant mediation effects in the prediction of motor impairment with structural damage of the CST and CC. DISCUSSIONS: This study reveals causal influence of structural and functional pathways on motor impairment after subcortical stroke and provides a promising way to investigate pathway-specific structure-function coupling. Clinically, our findings may offer a circuit-based evidence for the PMd as a critical neuromodulation target in more impaired patients with stroke and also suggest the cerebellum as a potential target.

Motor function and fALFF modulation in convalescent-period ischemic stroke patients after scalp acupuncture therapy: a multi-centre randomized controlled trial.

BACKGROUND: Scalp acupuncture has been found to be effective at improving motor function after ischemic stroke, but few studies examining its central mechanisms of action have been carried out. The aim of this study was to investigate the clinical effects of scalp acupuncture on motor dysfunction and changes in spontaneous brain activity in patients with ischemic stroke. METHODS: This was an evaluator- and analyst-blinded, multi-center randomized controlled trial. A total of 108 convalescent-stage ischemic stroke patients with motor dysfunction were allocated to receive either scalp acupuncture combined with rehabilitation treatment (SR group) or rehabilitation treatment alone (RE group). Patients in both groups received treatment 5 times per week for 8 weeks. The primary outcome measure was the Fugl-Meyer assessment (FMA). Secondary outcome measures included the modified Barthel index (mBI), modified Rankin scale (mRS) and values of fractional amplitude of low frequency fluctuation (fALFF) acquired using a resting-state functional magnetic resonance imaging (rs-fMRI) technique. RESULTS: Both groups showed significant improvements in motor function, daily life ability and degree of disability, as measured by FMA, mRS and mBI (p < 0.05), and the SR group showed a significantly greater improvement (p < 0.05). Compared with the RE group, the areas where the fALFF values increased in the SR group were located in the cerebellum, praecuneus, precentral gyrus, superior frontal gyrus and parietal lobe. The improvement in FMA scores had the strongest correlation with the baseline fALFF values of the ipsilateral precentral gyrus. CONCLUSION: Scalp acupuncture improved motor function in convalescent-period ischemic stroke patients, and effects were correlated with regulation of motor-relevant brain regions. The fALFF value of the ipsilateral precentral and postcentral gyri could be potential clinical indices for prognostication of motor dysfunction. TRIAL REGISTRATION NUMBER: NCT03120650 (http://www.clinicaltrials.gov).

Multi-modal fMRI and TMS follow-up study of motor cortical stroke caused by hyaluronic acid filler: A case report.

Background: Blindness and stroke resulting from hyaluronic acid (HA) fillers are not frequently reported complications. Reports on stroke recovery after HA injection are limited. In the current study, the recovery process, task-based functional magnetic resonance imaging (fMRI), diffusion tensor imaging (DTI), and neurophysiological changes of a patient with monocular blindness and ipsilateral motor cortical stroke after forehead injection of HA are explored. Case-report: The study comprised a 34-year-old female patient who presented with left eye blindness and a stroke after receiving an HA injection a month before admission. The lesion was mainly limited to the left precentral gyrus, and the patient had pure arm monoparesis. For 3 weeks, the patient received conventional rehabilitation treatments and ten sessions of repetitive transcranial magnetic stimulation (rTMS) intervention. Clinical assessments, neurophysiological evaluation, task-based fMRI, and DTI examinations were conducted to assess her motor improvement and the possible neuro mechanism. Clinical rehabilitation impact: The patient's right upper limb motor function was almost completely restored after receiving rehabilitation therapy. However, the vision in her left eye did not show significant improvement. The neurophysiological evaluation showed partial recovery of the ipsilesional motor evoked potentials (MEPs). DTI results showed that the ipsilesional corticospinal tract (CST) was intact. Task-based fMRI results indicated that the activation pattern of the affected hand movement was gradually restored to normal. Conclusion: A case of good motor recovery after stroke due to HA injection with a lesion mainly restricted to the precentral gyrus but without CST damage is presented in the current study. Further studies should be conducted to explore the efficacy and the mechanisms of rehabilitation and neuromodulation approaches to motor cortical stroke.

Modulation of Brain Activity and Functional Connectivity by Acupuncture Combined With Donepezil on Mild-to-Moderate Alzheimer's Disease: A Neuroimaging Pilot Study.

Background: Functional brain imaging changes have been proven as potential pathophysiological targets in early-stage AD. Current longitudinal neuroimaging studies of AD treated by acupuncture, which is one of the growingly acknowledged non-pharmacological interventions, have neither adopted comprehensive acupuncture protocols, nor explored the changes after a complete treatment duration. Thus, the mechanisms of acupuncture effects remain not fully investigated. Objective: This study aimed to investigate the changes in spontaneous brain activity and functional connectivity and provide evidence for central mechanism of a 12-week acupuncture program on mild-to-moderate AD. Methods: A total of forty-four patients with mild-to-moderate AD and twenty-two age- and education-level-matched healthy subjects were enrolled in this study. The forty-four patients with AD received a 12-week intervention of either acupuncture combined with Donepezil (the treatment group) or Donepezil alone (the control group). The two groups received two functional magnetic resonance imaging (fMRI) scans before and after treatment. The healthy subject group underwent no intervention, and only one fMRI scan was performed after enrollment. The fractional amplitude of low-frequency fluctuation (fALFF) and functional connectivity (FC) were applied to analyze the imaging data. The correlations between the imaging indicators and the changed score of Alzheimer's Disease Assessment Scale-Cognitive Section (ADAS-cog) were also explored. Results: After the 12-week intervention, compared to those in the control group, patients with AD in the treatment group scored significantly lower on ADAS-cog value. Moreover, compared to healthy subjects, the areas where the fALFF value decreased in patients with AD were mainly located in the right inferior temporal gyrus, middle/inferior frontal gyrus, middle occipital gyrus, left precuneus, and bilateral superior temporal gyrus. Compared with the control group, the right precuneus demonstrated the greatest changed value of fALFF after the intervention in the treatment group. The difference in ADAS-cog after interventions was positively correlated with the difference in fALFF value in the left temporal lobe. Right precuneus-based FC analysis showed that the altered FC by the treatment group compared to the control group was mainly located in the bilateral middle temporal gyrus. Conclusion: The study revealed the key role of precuneus in the effect of the combination of acupuncture and Donepezil on mild-to-moderate AD for cognitive function, as well as its connection with middle temporal gyrus, which provided a potential treating target for AD. Trial Registration Number: NCT03810794 (http://www.clinicaltrials.gov).

Study Design and Baseline Characteristics of Patients with T2DM in the Post-marketing Safety Study of Dulaglutide in China (TRUST-CHN).

BACKGROUND: TRUST-CHN is a prospective, post-marketing safety study in patients with type 2 diabetes mellitus (T2DM) in China to evaluate the safety and effectiveness of dulaglutide in real-world clinical practice. We report here the study design and baseline characteristics of enrolled patients. METHODS: The study design was described, and baseline data were analyzed, including demographic characteristics, T2DM duration, comorbidities, dulaglutide treatment patterns, and concomitant medications. RESULTS: For the present analysis of this ongoing study, data were collected from January 2020 to November 2021. A total of 3313 patients were enrolled, of whom 3294 patients were included in the safety analysis. In total, 1047 patients had a prior history of dulaglutide use before being enrolled in the study. The mean (standard deviation [SD]) age of study subjects was 50.1 (13.2) years, 85.1% were aged < 65 years; 67.9% were male, and 35.9% had an education of university level or higher. Mean (SD) duration of T2DM was 6.4 (6.7) years. Baseline mean (SD) glycated hemoglobin was 8.8% (2.2%), and mean (SD) body mass index was 28.1 (4.1) kg/m2. A total of 2867 (87%) patients had at least one comorbidity, the most frequently reported of which were overweight/obesity (87.1%), hyperlipidemia (50.5%), hypertension (47.9%), diabetic neuropathy (18.9%), and coronary artery disease (15.7%). Almost all (99.7%) patients were treated with 1.5 mg dulaglutide; at baseline, 24.8% were treated with this medication as monotherapy and 75.2% in combination therapy with other medications, including metformin (42.3%), sodium glucose co-transporter2 inhibitor (26.7%), insulin (18.3%), α-glucosidase inhibitor (13.1%), sulfonylurea (5.3%), dipeptidyl peptidase 4 inhibitor (4.4%), glucagon-like peptide 1 receptor agonist (2.7%), and thiazolidinedione (2.4%). CONCLUSION: The present analysis revealed real-world baseline characteristics of patients with T2DM in China who use dulaglutide enrolled in TRUST-CHN. These data will enable further exploration of the characteristics of patients with T2DM in China and provide an insight on the current use of dulaglutide in clinical practice.

Effects of high frequency rTMS of contralesional dorsal premotor cortex in severe subcortical chronic stroke: protocol of a randomized controlled trial with multimodal neuroimaging assessments.

BACKGROUND: Previous studies have revealed that low frequency repeated transcranial magnetic stimulation (rTMS) on the contralesional primary motor cortex (cM1) is less effective in severe stroke patients with poor neural structural reserve than in patients with highly reserved descending motor pathway. This may be attributed to the fact that secondary motor cortex, especially contralesional dorsal premotor cortex (cPMd), might play an important compensatory role in the motor function recovery of severely affected upper extremity. The main purpose of this study is to compare the effectiveness of low frequency rTMS on cM1 and high frequency rTMS on cPMd in subcortical chronic stroke patients with severe hemiplegia. By longitudinal analysis of multimodal neuroimaging data, we hope to elucidate the possible mechanism of brain reorganization following different treatment regimens of rTMS therapy, and to determine the cut-off of stimulation strategy selection based on the degree of neural structural reserve. METHODS/DESIGN: The study will be a single-blinded randomized controlled trial involving a total of 60 subcortical chronic stroke patients with severe upper limb motor impairments. All patients will receive 3 weeks of conventional rehabilitation treatment, while they will be divided into three groups and receive different rTMS treatments: cM1 low frequency rTMS (n = 20), cPMd high frequency rTMS (n = 20), and sham stimulation group (n = 20). Clinical functional assessment, multimodal functional MRI (fMRI) scanning, and electrophysiological measurement will be performed before intervention, 3 weeks after intervention, and 4 weeks after the treatment, respectively. DISCUSSION: This will be the first study to compare the effects of low-frequency rTMS of cM1 and high-frequency rTMS of cPMd. The outcome of this study will provide a theoretical basis for clarifying the bimodal balance-recovery model of stroke, and provide a strategy for individualized rTMS treatment for stroke in future studies and clinical practice. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1900027399. Registered on 12 Nov 2019, http://www.chictr.org.cn/showproj.aspx?proj=43686 .

Improved magnetic resonance myelin water imaging using multi-channel denoising convolutional neural networks (MCDnCNN).

Background: Myelin water imaging (MWI) is powerful and important for studying and diagnosing neurological and psychiatric diseases. In particular, myelin water fraction (MWF) is derived from MWI data for quantifying myelination. However, MWF estimation is typically sensitive to noise. Improving the accuracy of MWF estimation based on WMI data acquired using a magnetic resonance (MR) multiple gradient recalled echo (mGRE) imaging sequence is desired. Methods: The proposed method employs a recently introduced the multi-channel denoising convolutional neural networks (MCDnCNN). Five different MCDnCNN models, denoted as Delevel1, Delevel2, Delevel3, Delevel4 and DelevelMix corresponding to five noise levels (Level1, Level2, Level3, Level4 and LevelMix), were trained using the data of the first echo of the mGRE brain images acquired from 15 healthy human subjects. Using simulated noisy data that employed a hollow cylinder model, we first evaluated the improvement in estimating MWF based on data denoised by the five different MCDnCNNs, by comparing the MWF maps calculated from the denoised data with ground truth. Next, we again evaluated the improvement using real-world in vivo datasets of 11 human participants acquired using the mGRE sequence. The datasets were first denoised by five different MCDnCNNs (Delevel1, 2, 3, 4 and DelevelMix), and subsequently their MWF maps were calculated and compared with the MWF maps directly calculated from the raw mGRE images without being denoised. Results: Experiments using the simulation data denoised by the appropriate MCDnCNN models showed that the standard deviation (SD) of the absolute error (AE) of the derived MWF results was significantly reduced (maximal reduction =15.5%, Level3 simulated noisy data, orientation angle =0, all the five MCDnCNN models). In the test using in vivo data, estimating MWF based on data particularly denoised by the appropriate MCDnCNN models was found to be the best, compared to otherwise not using the appropriate models. The results demonstrated that the appropriate MCDnCNN models may permit high-quality MWF mapping, i.e., substantial reduction of random variation in estimating MWF-maps while preserving accuracy and structural details. Conclusions: Appropriate MCDnCNN models as proposed may improve both the accuracy and precision in estimating MWF maps, thereby making it a more clinically feasible alternative.

The Resting State Central Auditory Network: a Potential Marker of HIV-Related Central Nervous System Alterations.

OBJECTIVE: HIV positive (HIV+) individuals with otherwise normal hearing ability show central auditory processing deficits as evidenced by worse performance in speech-in-noise perception compared with HIV negative (HIV-) controls. HIV infection and treatment are also associated with lower neurocognitive screening test scores, suggesting underlying central nervous system damage. To determine how central auditory processing deficits in HIV+ individuals relate to brain alterations in the cortex involved with auditory processing, we compared auditory network (AN) functional connectivity between HIV+ adults with or without speech-in-noise perception difficulties and age-matched HIV- controls using resting-state fMRI. DESIGN: Based on the speech recognition threshold of the hearing-in-noise test, twenty-seven HIV+ individuals were divided into a group with speech-in-noise perception abnormalities (HIV+SPabnl, 38.2 ± 6.8 years; 11 males and 2 females) and one without (HIV+SPnl 34.4 ± 8.8 years; 14 males). An HIV- group with normal speech-in-noise perception (HIV-, 31.3 ± 5.2 years; 9 males and 3 females) was also enrolled. All of these younger and middle-aged adults had normal peripheral hearing determined by audiometry. Participants were studied using resting-state fMRI. Independent component analysis was applied to identify the AN. Group differences in the AN were identified using statistical parametric mapping. RESULTS: Both HIV+ groups had increased functional connectivity (FC) in parts of the AN including the superior temporal gyrus, middle temporal gyrus, supramarginal gyrus, and Rolandic operculum compared to the HIV- group. Compared with the HIV+SPnl group, the HIV+SPabnl group showed greater FC in parts of the AN including the middle frontal and inferior frontal gyri. CONCLUSIONS: The classical auditory areas in the temporal lobe are affected by HIV regardless of speech perception ability. Increased temporal FC in HIV+ individuals might reflect functional compensation to achieve normal primary auditory perception. Furthermore, increased frontal FC in the HIV+SPabnl group compared with the HIV+SPnl group suggest that speech-in-noise perception difficulties in HIV-infected adults also affect areas involved in higher-level cognition, providing imaging evidence consistent with the hypothesis that HIV-related neurocognitive deficits can include central auditory processing deficits.

Dissociable plasticity of visual-motor system in functional specialization and flexibility in expert table tennis players.

Specialization and flexibility are two basic attributes of functional brain organization, enabling efficient cognition and behavior. However, it is largely unknown what plastic changes in specialization and flexibility in visual-motor areas occur in support of extraordinary motor skills in expert athletes and how the selective adaptability of the visual-motor system affects general perceptual or cognitive domains. Here, we used a dynamic network framework to investigate intrinsic functional specialization and flexibility of visual-motor system in expert table tennis players (TTP). Our results showed that sensorimotor areas increased intrinsic functional flexibility, whereas visual areas increased intrinsic functional specialization in expert TTP compared to nonathletes. Moreover, the flexibility of the left putamen was positively correlated with skill level, and that of the left lingual gyrus was positively correlated with behavioral accuracy of a sport-unrelated attention task. This study has uncovered dissociable plasticity of the visual-motor system and their predictions of individual differences in skill level and general attention processing. Furthermore, our time-resolved analytic approach is applicable across other professional athletes for understanding their brain plasticity and superior behavior.

The development of lateral flow immunoassay strip tests based on surface enhanced Raman spectroscopy coupled with gold nanoparticles for the rapid detection of soybean allergen ß-conglycinin.

ß-Conglycinin is an important storage protein in soybean, which can potentially cause food allergies in human. In this study, a sensitive mouse monoclonal antibody (3D11 mAb) with a high affinity was prepared, and sandwich lateral flow immunochromatographic detection strips were developed for the rapid detections of the soybean allergen ß-conglycinin. The 3D11 mAb was combined with a rabbit polyclonal antibody in order to establish strips. The titer of 3D11 mAb was 1:2.56 × 105. The affinity constant of the 3D11 mAb was 9.6 × 109. The lowest detection limit with the naked eye of the double antibody sandwich strips was 1 µg/mL. In addition, chemical molecules p-aminothiophenol with colloidal gold were used as Raman enhancement signals in order to achieve quantitative detections of the ß-conglycinin. It was determined in this study that the practical working range of the ß-conglycinin concentrations was between 160 ng/mL and 100 µg/mL with the developed assay.

Altered intra- and inter-network functional coupling of resting-state networks associated with motor dysfunction in stroke.

Motor functions are supported through functional integration across the extended motor system network. Individuals following stroke often show deficits on motor performance requiring coordination of multiple brain networks; however, the assessment of connectivity patterns after stroke was still unclear. This study aimed to investigate the changes in intra- and inter-network functional connectivity (FC) of multiple networks following stroke and further correlate FC with motor performance. Thirty-three left subcortical chronic stroke patients and 34 healthy controls underwent resting-state functional magnetic resonance imaging. Eleven resting-state networks were identified via independent component analysis (ICA). Compared with healthy controls, the stroke group showed abnormal FC within the motor network (MN), visual network (VN), dorsal attention network (DAN), and executive control network (ECN). Additionally, the FC values of the ipsilesional inferior parietal lobule (IPL) within the ECN were negatively correlated with the Fugl-Meyer Assessment (FMA) scores (hand + wrist). With respect to inter-network interactions, the ipsilesional frontoparietal network (FPN) decreased FC with the MN and DAN; the contralesional FPN decreased FC with the ECN, but it increased FC with the default mode network (DMN); and the posterior DMN decreased FC with the VN. In sum, this study demonstrated the coexistence of intra- and inter-network alterations associated with motor-visual attention and high-order cognitive control function in chronic stroke, which might provide insights into brain network plasticity following stroke.

[Changes in monochromatic higher-order aberrations in different pupil sizes with accommodation in young emmetropes].

OBJECTIVE: To study the effect of accommodation on monochromatic higher-order aberrations in different pupil sizes in the young emmetropes. METHODS: Intervention trial design was used in the study. The monochromatic aberrations were measured in 12 eyes from 12 undulated young emmetropes in 4.0 mm, 3.0 mm, and 2.0 mm pupil sizes with a ray tracing wavefront aberrometer under accommodative stimuli from 0 to 4.00 D. RESULTS: RMS values of total high-order aberrations (HOAs), total coma, total higher-order astigmatism, total spherical, and total trefoil aberrations significantly decreased as pupil size decreased in the relax state. In 4.0 mm, 3.0 mm, and 2.0 mm pupil sizes, the average root mean square (RMS) value of total coma was the highest item of HOAs in the relaxed state. With accommodation up to 3.00 D, the RMS of HOAs remained constant but changed significantly at 4.00 D stimulation (P <0.05) in all these three pupil sizes. The 4th spherical aberration decreased and changed from positive to negative with increasing accommodation over 4.0 mm size, whereas it remained positive under all accommodative levels over the 3.0 mm and 2.0 mm zones, and no trend was found. The 3rd order trefoil 0 changed from negative to positive with increasing accommodation, with 4.0 mm, 3.0 mm, and 2.0 mm pupil sizes. CONCLUSIONS: In 4.0 mm, 3.0 mm, and 2.0 mm pupil sizes, under accommodative stimuli from 0.00 to 4.00 D, dramatical trends amongst the HOAs, spherical, coma, and trefoil aberrations were demonstrated. Most of the higher-order aberrations induced by accommodation deserves further investigation. Simple elimination of the higher-order aberrations will be replaced by the optimization of aberrations.

HIV-1 Tat protein alter the tight junction integrity and function of retinal pigment epithelium: an in vitro study.

BACKGROUND: How HIV-1 enter into the eyes remains obscure. We postulated that HIV-1 Tat protein can alter the expression of specific tight-junction proteins and disturb the blood retinal barrier, and contributes to HIV trafficking into the eyes. This study is to determine the effects of HIV-1 Tat proteins on the barrier function and tight-junction protein expression of retinal pigment epithelial cell (RPE). METHODS: A human RPE cell line (D407) cultured on microporous filter-supports was used. After treating with HIV-1 Tat protein, transepithelial electrical resistance (TER) of confluent RPE cells was measured by epithelial voltmeter. The permeability of the RPE cells to sodium fluorescein was measured. The expressions of the occludin and claudins were determined by real-time polymerase chain reaction, immunofluorescence, and Western blot analysis. Activation of ERK1/2 was detected by Western blot analysis with specific antiphospho protein antibodies. NF-kappaB DNA binding activity was determined by transcription factor assay. Specific pharmacologic inhibitors directed against the MAPKs were used to analyze the signaling involved in barrier destruction of RPE cells exposed to HIV-1 Tat. RESULTS: Treating cultured human retinal pigment epithelial cells with 100 nM Tat for 24 hours increased the permeability and decreased the TER of the epithelial monolayer. HIV-1 Tat also disrupted and downregulated the tight-junction proteins claudin-1, claudin-3, and claudin-4 in these cells, whereas claudin-2 was upregulated, and the expression of occludin was unaffected. HIV-1 Tat protein also induced activation of ERK1/2 and NF-kappaB. HIV-1 Tat protein induced barrier destruction, changes in expression of TJs, and activation of ERK1/2 and NF-kappaB were abrogated by inhibitor of ERK1/2 and NF-kappaB. CONCLUSION: HIV-1 Tat protein causes increases in the paracellular permeability of RPE cells in vitro concomitant with changes in expression of certain transmembrane proteins associated with the tight junction. The effects of HIV-1 Tat on barrier function of the RPE may be mediated by ERK MAPK and NF-kappaB activation, which may represent potential targets for novel therapeutic approaches for the retinopathy induced by HIV infection.

Inducible nitric oxide synthase is involved in the oxidation stress induced by HIV-1 gp120 in human retina pigment epithelial cells.

BACKGROUND: The human immunodeficiency virus-1 (HIV-1) envelope glycoprotein gp120 has been implicated in the development of AIDS-associated retinopathy. The present study tested the hypothesis that gp120 may induce oxidative stress including up regulation of inducible nitric oxide synthase (iNOS) and production of malondialdehyde (MDA) and nitric oxide (NO) to mediate retinopathy in retinal pigment epithelial (RPE) cells. METHODS: Human RPE cell line D407 was cultured and treated with gp120. HIV-1 gp120 protein induced lipid peroxidation product MDA. NO production and iNOS expression were examined in vitro by spectrophomtometry, real-time PCR, Western blotting, and confocal microscope. RESULTS: Addition of gp120 was able to induce RPE cells to produce NO and MDA in time- and dose-dependent manners (P < 0.05). Similarly, gp120 was also capable of up-regulating iNOS mRNA and protein in D407 cells in time- and dose-dependent manners. CONCLUSIONS: Gp120 induces oxidative stress in D407 cell by stimulating MDA and NO production, which is mediated by up-regulating iNOS expression. Gp120 may mediate oxidation stress in AIDS-associated retinopathy.