The Effects of Metformin on Obesity-Induced Diabetic Retinas

Diabetic retinopathy is a major secondary complication of type 2 diabetes. To regulate blood glucose levels in type 2 diabetic patients, metformin is popularly prescribed as an oral drug in mono- and combination therapies. Metformin was used as a responsive and preventative drug on high-fat diet (HFD) induced obese mice that emulate type 2 diabetes. Body weight was monitored weekly and systemic glucose levels including resting blood glucose levels, the glucose tolerance test, and the insulin resistance test were measured monthly. The electroretinogram (ERG) was used to measure the retinal light responses, immunohistochemistry to quantify changes in retinal protein expression, western blot to assess inflammatory markers, and fluorescein angiography to measure neovascularization. HFD-fed mice became hyperglycemic after 2 months of feeding regimen. Metformin treatment following hyperglycemia slowed body weight gain and restored systemic glucose levels to control levels. Retinal function measured by ERG showed decreased amplitudes and delayed implicit times in oscillatory potentials after 1 month of HFD and decreased amplitudes and delayed implicit times in a-wave, b-wave, and oscillatory potentials starting 2 months of HFD. Metformin treatment after 2 months of HFD was not able to restore ERG responses in HFD-fed mice. Furthermore, metformin treatment was not able to recover HFD-induced neovascularization. However, metformin treatment for the last 4 months in mice fed a HFD for 6 months was able to reduce inflammatory marker expression and the immunofluorescent proteins affected by HFD-feeding. HFD-fed mice treated with metformin from the beginning of feeding regimen as a preventative strategy not only showed slower weight gain but also do not become hyperglycemic. However, this preventative strategy did not prevent the HFD-induced retinal dysfunction measured by ERG even after 3 months of treatment. Furthermore, some HFD-induced changes in retinal protein expression began after 1 month of HFD-treatment, but metformin treatment concurrent with HFD was not able to prevent HFD-induced changes

Identifying neural mechanisms and behavioral effects of anxiety on attentional capture

Attention research has long investigated the mechanisms by which sensory information is selectively filtered for neural representation. Models for visual selective attention initially formed a theoretical dichotomy in which goal-oriented or salience-driven mechanisms were argued as the predominant modes for attentional selection. However, this theoretical dichotomy was challenged when new experimental findings could not be reduced to goal-oriented or salience-driven mechanisms. These results were grouped into a new component of attentional control by an experience-driven mechanism and expanded models of selective attention into a theoretical trichotomy under the third label selection history. In the context of attention research, threat has been investigated primarily by measuring rapid orienting towards threatening stimuli. Individuals with elevated state anxiety measured via self-report demonstrate increased attentional orienting towards threatening stimuli and enhanced attentional capture by physically salient stimuli. However, such findings are limited to attentional mechanisms toward the threatening nature of a stimulus and do not extend to more systemic changes in attentional control when the observer is in a threatened state. It is yet unknown whether elevated state anxiety globally modulates attentional capture through a core mechanism or whether such changes in observer state uniquely modulate different modes of attentional control. Furthermore, the mechanism by which threatening stimuli are afforded greater attentional priority in individuals with elevated state anxiety is still unclear. In this dissertation, I investigate how attentional priority can be modulated by changing the state of an individual by experimentally inducing anxiety through the Threat of Shock (ToS) paradigm. I first present a series of behavior experiments that investigate how unpredictable threat modulates the three predominant mechanisms of attentional selection: attentional capture by reward history (selection history), color (salience-driven), and strategic goals. Then, I present a neuroimaging experiment that investigates how the neural mechanisms of processing threat interacts with mechanisms of attentional selection by previously-reward associated stimuli. I conclude by expanding on the core findings of this dissertation and its implications concerning how changes in observer state modulates attentional control and how the identified mechanisms can be expanded to inform our understanding of attentional biases toward threatening stimuli

Indocyanine Green Loaded Reduced Graphene Oxide for In Vivo Photoacoustic/Fluorescence Dual-Modality Tumor Imaging

Multimodality imaging based on multifunctional nanocomposites holds great promise to fundamentally augment the capability of biomedical imaging. Specifically, photoacoustic and fluorescence dual-modality imaging is gaining much interest because of their non-invasiveness and the complementary nature of the two modalities in terms of imaging resolution, depth, sensitivity, and speed. Herein, using a green and facile method, we synthesize indocyanine green (ICG) loaded, polyethylene glycol (PEG) ylated, reduced nano-graphene oxide nanocomposite (rNGO-PEG/ICG) as a new type of fluorescence and photoacoustic dual-modality imaging contrast. The nanocomposite is shown to have minimal toxicity and excellent photoacoustic/fluorescence signals both in vitro and in vivo. Compared with free ICG, the nanocomposite is demonstrated to possess greater stability, longer blood circulation time, and superior passive tumor targeting capability. In vivo study shows that the circulation time of rNGO-PEG/ICG in the mouse body can sustain up to 6 h upon intravenous injection; while after 1 day, no obvious accumulation of rNGO-PEG/ICG is found in any major organs except the tumor regions. The demonstrated high fluorescence/photoacoustic dual contrasts, together with its low toxicity and excellent circulation life time, suggest that the synthesized rNGO-PEG/ICG can be a promising candidate for further translational studies on both the early diagnosis and image-guided therapy/surgery of cancer.11248Ysciescopu

Deletion of miR-150 Exacerbates Retinal Vascular Overgrowth in High-Fat-Diet Induced Diabetic Mice

Diabetic retinopathy (DR) is the leading cause of blindness among American adults above 40 years old. The vascular complication in DR is a major cause of visual impairment, making finding therapeutic targets to block pathological angiogenesis a primary goal for developing DR treatments. MicroRNAs (miRs) have been proposed as diagnostic biomarkers and potential therapeutic targets for various ocular diseases including DR. In diabetic animals, the expression levels of several miRs, including miR-150, are altered. The expression of miR-150 is significantly suppressed in pathological neovascularization in mice with hyperoxia-induced retinopathy. The purpose of this study was to investigate the functional role of miR-150 in the development of retinal microvasculature complications in high-fat-diet (HFD) induced type 2 diabetic mice. Wild type (WT) and miR-150 null mutant (miR-150-/-) male mice were given a HFD (59% fat calories) or normal chow diet. Chronic HFD caused a decrease of serum miR-150 in WT mice. Mice on HFD for 7 months (both WT and miR-150-/-) had significant decreases in retinal light responses measured by electroretinograms (ERGs). The retinal neovascularization in miR-150-/--HFD mice was significantly higher compared to their age matched WT-HFD mice, which indicates that miR-150 null mutation exacerbates chronic HFD-induced neovascularization in the retina. Overexpression of miR-150 in cultured endothelial cells caused a significant reduction of vascular endothelial growth factor receptor 2 (VEGFR2) protein levels. Hence, deletion of miR-150 significantly increased the retinal pathological angiogenesis in HFD induced type 2 diabetic mice, which was in part through VEGFR2

Recent Advances in Ultrasound and Photoacoustic Analysis for Thyroid Cancer Diagnosis

Abstract Thyroid cancer is one of the most commonly diagnosed cancers worldwide, with a continuously increasing incidence rate in recent decades. Although ultrasonography, which is the current screening method in clinical workflows, has successfully triaged cancerous nodules for biopsy, overdiagnosis has also grown due to the relatively low specificity of the method. Studies are conducted to overcome this overdiagnosis issue by complementing ultrasonography with additional image‐based analysis techniques. This review presents an overview of the current advances in clinical trials using advanced ultrasound (US) and photoacoustic (PA) imaging techniques for thyroid nodules in humans. A summary of initial trials by Doppler US and US elastography to improve the classification accuracy of thyroid nodules is presented. Furthermore, recent PA techniques with multispectral analyses utilizing clinically available machines are explored. By amending the existing ultrasonography, the advanced US and PA techniques can enhance the triaging accuracy by analyzing both structural and functional information of thyroid nodules in vivo

Multiplane Spectroscopic Whole Body Photoacoustic Imaging of Small Animals In Vivo

We have successfully developed a multiscale acoustic-resolution photoacoustic tomography system in a single imaging platform. By switching between ultrasound transducers (center frequencies 5 and 40 MHz) and optical condensers, we have photoacoustically imaged microvasculatures of small animals in vivo at different scales. Further, we have extended the field of view of our imaging system to entire bodies of small animals. At different imaging planes, we have noninvasively imaged the major blood vessels (e.g., descending aorta, intercostal vessels, cephalic vessels, brachial vessels, femoral vessels, popliteal vessels, lateral marginal vessels, cranial mesenteric vessels, mammalian vessels, carotid artery, jugular vein, subclavian vessels, iliac vessels, and caudal vessels) as well as intact internal organs (e.g., spleen, liver, kidney, intestine, cecum, and spinal cord) of the animals in vivo. The spectroscopic whole-body photoacoustic imaging clearly reveals the spectral responses of the internal structures. Similar to other existing preclinical whole-body imaging systems, this whole-body photoacoustic tomography can be a useful tool for small-animal research.1137sciescopu

Photothermal strain imaging for diagnosis of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) refers to the accumulation of excess fat in the liver without excessive alcohol consumption. Failure to detect NAFLD in advance can lead to fatal and irreversible liver diseases such as liver fibrosis, cirrhosis, and liver cancer, and thus the clinical need for rapid diagnosis of NAFLD is being raised. However, conventional NAFLD diagnostic methods, including biopsy and imaging, have inherent limitations due to technical or cost issues. For example, liver biopsy is invasive, MRI imaging is very expensive, CT is harmful for routine clinical use, and ultrasound is not very specific in diagnosing NAFLD. Here, we present photothermal strain imaging (pTSI), which uses the difference in thermal strain between fat and water during temperature change, as a new method for NAFLD diagnosis. The pTSI is a non-invasive, convenient, and cost-effective method of using a laser that matches the optical characteristics of the target. We developed a liver pTSI system to find fat accumulated in the liver using a clinical ultrasound imaging system and a lipid-sensitive continuous-wave laser. To demonstrate the feasibility of the pTSI system, in vitro experiments were performed using fat and chicken breast. The results showed that fat in the chicken breast was clearly distinguished. Finally, we performed in vivo experiments using NAFLD and normal rat. Through the difference in the strains that occurs when the laser heats the target, the progression of NAFLD could be determined.1

Functional photoacoustic imaging: from nano- and micro- to macro-scale

Abstract Functional photoacoustic imaging is a promising biological imaging technique that offers such unique benefits as scalable resolution and imaging depth, as well as the ability to provide functional information. At nanoscale, photoacoustic imaging has provided super-resolution images of the surface light absorption characteristics of materials and of single organelles in cells. At the microscopic and macroscopic scales. photoacoustic imaging techniques have precisely measured and quantified various physiological parameters, such as oxygen saturation, vessel morphology, blood flow, and the metabolic rate of oxygen, in both human and animal subjects. This comprehensive review provides an overview of functional photoacoustic imaging across multiple scales, from nano to macro, and highlights recent advances in technology developments and applications. Finally, the review surveys the future prospects of functional photoacoustic imaging in the biomedical field

Non-Invasive Photothermal Strain Imaging of Non-Alcoholic Fatty Liver Disease in Live Animals

The prevalence of non-alcoholic fatty liver diseases (NAFLD) has increased steadily over the past decade. Thus, diagnosing NAFLD at the earliest stage, which is a reversible condition, has become increasingly important. Here, photothermal strain imaging (pTSI) is presented as a novel non-invasive tool for NAFLD diagnosis. The pTSI uses ultrasound to detect the difference in thermal strain between fat and water during a light-induced temperature rise, which is directly related to the pathological evidence of NAFLD. To demonstrate its feasibility, fat accumulation in in vivo rat livers is monitored non-invasively using pTSI, based on clinical ultrasound B-mode images. A total of 21 male Wistar rats of 3 weeks of age were prepared. Of these, 18 rats received methionine-choline deficient diet for 1 to 6 weeks (n = 3 per week) to induce NAFLD, whereas 3 rats received normal diet as controls (n = 3). Livers were heated by a lipid-sensitive continuous-wave laser, and strain was measured. Quantitative results from the pTSI were compared with histological analysis results using Oil-Red-O (ORO). The receiver operating characteristic curve of in vivo pTSI results for detecting moderate steatosis (ORO-stained area >= 33%) was constructed based on strain change rate measured in the liver region. The sensitivity and specificity of pTSI were 90% and 82%, respectively, and the area-under-the-curve was measured as 0.85 +/- 0.03 (95% confidence interval). The pTSI results tested in the rodent NAFLD model showed great potential for pTSI to be used as a new diagnostic tool for NAFLD in the future.11Nsciescopu