scholarly journals Transdermal Delivery of Adipocyte Phospholipase A2 siRNA using Microneedles to Treat Thyroid Associated Ophthalmopathy-Related Proptosis

2021 ◽  
Vol 30 ◽  
pp. 096368972110106
Author(s):  
Guiqin Liu ◽  
Yan Deng ◽  
Yi Song ◽  
Yi Sui ◽  
Juan Cen ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Phospholipase A2 ◽  
Transdermal Delivery ◽  
Sirna Delivery ◽  
Microneedle Array ◽  
Adipose Tissues ◽  
Thyroid Associated Ophthalmopathy ◽  
Organ Specific ◽  
Adipocyte Cell ◽  
Human And Mouse

Thyroid associated ophthalmopathy (TAO) is an organ-specific autoimmune disease occurring in patients with thyroid disease. Patients with TAO-related proptosis is largely due to excessive orbital adipose tissue Adipocyte phospholipase A2 (AdPLA) is one of the most important regulatory factors in adipocyte lipolysis, which may be associated with TAO-related proptosis. Thus, silencing AdPLA by RNA interference may be beneficial for the treatment of TAO. In this study, we sought to evaluate the efficiency of two types of microneedles to deliver siRNAs for silencing AdPLA. Our results showed that AdPLA mRNA was up-regulated in the orbit adipose tissues from TAO patients. Silence of AdPLA by siRNA can reduce lipid accumulation in both human and mouse adipocyte cell lines. Moreover, silence effects of silicon microneedle array patch-based and injectable microneedle device-based siRNA administration were examined at the belly site of the mice, and injectable microneedle device showed higher knockdown efficiency than silicon microneedle array patch. This study sets the stage not only for future treatment of TAO-related proptosis using AdPLA siRNA, but also provides the foundation for targeted siRNA delivery by using microneedles.

Assessment of Persistent, Bioaccumulative and Toxic Organic Environmental Pollutants in Liver and Adipose Tissue of Alzheimer’s Disease Patients and Age-matched Controls

2019 ◽  
Vol 16 (11) ◽  
pp. 1039-1049 ◽  
Author(s):  
Bhagyashree Manivannan ◽  
Manivannan Yegambaram ◽  
Samuel Supowit ◽  
Thomas G. Beach ◽  
Rolf U. Halden
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Adipose Tissue ◽  
Environmental Pollutants ◽  
Small Sample ◽  
Adipose Tissues ◽  
Chromatography Tandem Mass Spectrometry ◽  
Organ Specific ◽  
Lifetime Exposure ◽  
High Concentrations

Background: Lifetime exposure to environmental (neuro) toxicants may contribute to the pathogenesis of Alzheimer’s Disease (AD). Since many contaminants do not cross the blood-brain barrier, brain tissue alone cannot serve to assess the spectrum of environmental exposures. Methods: We used liquid and gas chromatography tandem mass spectrometry to monitor, in postmortem liver and adipose tissues of AD patients and age-matched controls, the occurrence and concentrations of 11 environmental contaminants. Results: Seven toxicants were detected at 100% frequency: p,p'-DDE, dieldrin, triclosan, methylparaben, bisphenol A, fipronil and tetrabromobisphenol A (TBBPA). Intra-individual, tissuedependent differences were detected for triclosan, methylparaben, fipronil and TBBPA. High concentrations of p,p’-DDE and dieldrin were observed in adipose tissue when compared to liver values for both AD cases and controls. Conclusion: This study provides vital data on organ-specific human body burdens to select analytes and demonstrate the feasibility of analyzing small sample quantities for toxicants suspected to constitute AD risk factors.

scholarly journals Redox Regulation of Lipid Mobilization in Adipose Tissues

Antioxidants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1090
Author(s):  
Ursula Abou-Rjeileh ◽  
G. Andres Contreras
Keyword(s):  
Adipose Tissue ◽  
Energy Metabolism ◽  
Redox Regulation ◽  
Cellular Metabolism ◽  
Antioxidant Response ◽  
Redox Signaling ◽  
Nitrogen Species ◽  
Adipose Tissues ◽  
Lipid Mobilization ◽  
Cellular Processes

Lipid mobilization in adipose tissues, which includes lipogenesis and lipolysis, is a paramount process in regulating systemic energy metabolism. Reactive oxygen and nitrogen species (ROS and RNS) are byproducts of cellular metabolism that exert signaling functions in several cellular processes, including lipolysis and lipogenesis. During lipolysis, the adipose tissue generates ROS and RNS and thus requires a robust antioxidant response to maintain tight regulation of redox signaling. This review will discuss the production of ROS and RNS within the adipose tissue, their role in regulating lipolysis and lipogenesis, and the implications of antioxidants on lipid mobilization.

scholarly journals Microneedle Arrays Combined with Nanomedicine Approaches for Transdermal Delivery of Therapeutics

2021 ◽  
Vol 10 (2) ◽  
pp. 181
Author(s):  
Vahid Alimardani ◽  
Samira Sadat Abolmaali ◽  
Gholamhossein Yousefi ◽  
Zahra Rahiminezhad ◽  
Mehdi Abedi ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Transdermal Delivery ◽  
Transdermal Drug Delivery ◽  
Skin Barrier ◽  
Skin Penetration ◽  
Therapeutic Agents ◽  
Inorganic Nanoparticles ◽  
Microneedle Array ◽  
Wide Range ◽  
Microneedle Arrays

Organic and inorganic nanoparticles (NPs) have shown promising outcomes in transdermal drug delivery. NPs can not only enhance the skin penetration of small/biomacromolecule therapeutic agents but can also impart control over drug release or target impaired tissue. Thanks to their unique optical, photothermal, and superparamagnetic features, NPs have been also utilized for the treatment of skin disorders, imaging, and biosensing applications. Despite the widespread transdermal applications of NPs, their delivery across the stratum corneum, which is the main skin barrier, has remained challenging. Microneedle array (MN) technology has recently revealed promising outcomes in the delivery of various formulations, especially NPs to deliver both hydrophilic and hydrophobic therapeutic agents. The present work reviews the advancements in the application of MNs and NPs for an effective transdermal delivery of a wide range of therapeutics in cancer chemotherapy and immunotherapy, photothermal and photodynamic therapy, peptide/protein vaccination, and the gene therapy of various diseases. In addition, this paper provides an overall insight on MNs’ challenges and summarizes the recent achievements in clinical trials with future outlooks on the transdermal delivery of a wide range of nanomedicines.

scholarly journals Differential organ-specific inflammatory response to progranulin in high-fat diet-fed mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Maki Murakoshi ◽  
Tomohito Gohda ◽  
Eri Adachi ◽  
Saki Ichikawa ◽  
Shinji Hagiwara ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
High Fat Diet ◽  
Kidney Injury ◽  
Proximal Tubules ◽  
Tubular Damage ◽  
Standard Diet ◽  
Mrna Levels ◽  
High Fat ◽  
Organ Specific

AbstractProgranulin (PGRN) has been reported to bind tumor necrosis factor (TNF) receptor and to inhibit TNFα signaling. We evaluated the effect of augmentation of TNFα signaling by PGRN deficiency on the progression of kidney injury. Eight-week-old PGRN knockout (KO) and wild-type (WT) mice were fed a standard diet or high-fat diet (HFD) for 12 weeks. Albuminuria, markers of tubular damage, and renal mRNA levels of inflammatory cytokines were higher in HFD-fed KO (KO-HFD) mice than in HFD-fed WT (WT-HFD) mice. Body weight, vacuolization in proximal tubules, and systemic and adipose tissue inflammatory markers were lower in the KO-HFD mice than in the WT-HFD mice. The renal megalin expression was lower in the KO mice than in the WT mice regardless of the diet type. The megalin expression was also reduced in mouse proximal tubule epithelial cells stimulated with TNFα and in those with PGRN knockdown by small interfering RNA in vitro. PGRN deficiency was associated with both exacerbated renal inflammation and decreased systemic inflammation, including that in the adipose tissue of mice with HFD-induced obesity. Improved tubular vacuolization in the KO-HFD mice might partially be explained by the decreased expression of megalin in proximal tubules.

scholarly journals Reduced Expression of Urokinase Plasminogen Activator in Brown Adipose Tissue of Obese Mouse Models

2021 ◽  
Vol 22 (7) ◽  
pp. 3407
Author(s):  
Chung-Ze Wu ◽  
Li-Chien Chang ◽  
Chao-Wen Cheng ◽  
Te-Chao Fang ◽  
Yuh-Feng Lin ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Glomerular Filtration Rate ◽  
Brown Adipose Tissue ◽  
Glomerular Filtration ◽  
Plasminogen Activator ◽  
Mouse Models ◽  
Filtration Rate ◽  
Obese Mouse ◽  
Adipose Tissues ◽  
Brown Adipose

In recent decades, the obesity epidemic has resulted in morbidity and mortality rates increasing globally. In this study, using obese mouse models, we investigated the relationship among urokinase plasminogen activator (uPA), metabolic disorders, glomerular filtration rate, and adipose tissues. Two groups, each comprised of C57BL/6J and BALB/c male mice, were fed a chow diet (CD) and a high fat diet (HFD), respectively. Within the two HFD groups, half of each group were euthanized at 8 weeks (W8) or 16 weeks (W16). Blood, urine and adipose tissues were collected and harvested for evaluation of the effects of obesity. In both mouse models, triglyceride with insulin resistance and body weight increased with duration when fed a HFD in comparison to those in the groups on a CD. In both C57BL/6J and BALB/c HFD mice, levels of serum uPA initially increased significantly in the W8 group, and then the increment decreased in the W16 group. The glomerular filtration rate declined in both HFD groups. The expression of uPA significantly decreased in brown adipose tissue (BAT), but not in white adipose tissue, when compared with that in the CD group. The results suggest a decline in the expression of uPA in BAT in obese m models as the serum uPA increases. There is possibly an association with BAT fibrosis and dysfunction, which may need further study.

Tryptophan metabolism activation by indoleamine 2,3-dioxygenase in adipose tissue of obese women: an attempt to maintain immune homeostasis and vascular tone

2012 ◽  
Vol 303 (2) ◽  
pp. R135-R143 ◽  
Author(s):  
Isabelle Wolowczuk ◽  
Benjamin Hennart ◽  
Audrey Leloire ◽  
Alban Bessede ◽  
Marion Soichot ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
T Cell ◽  
White Adipose Tissue ◽  
Vascular Tone ◽  
T Cell Subsets ◽  
Low Grade ◽  
Adipose Tissues ◽  
Indoleamine 2,3 Dioxygenase ◽  
Arterial Blood ◽  
Ido1 Expression

Human obesity is characterized by chronic low-grade inflammation in white adipose tissue and is often associated with hypertension. The potential induction of indoleamine 2,3-dioxygenase-1 (IDO1), the rate-limiting enzyme in tryptophan/kynurenine degradation pathway, by proinflammatory cytokines, could be associated with these disorders but has remained unexplored in obesity. Using immunohistochemistry, we detected IDO1 expression in white adipose tissue of obese patients, and we focused on its contribution in the regulation of vascular tone and on its immunoregulatory effects. Concentrations of tryptophan and kynurenine were measured in sera of 36 obese and 15 lean women. The expression of IDO1 in corresponding omental and subcutaneous adipose tissues and liver was evaluated. Proinflammatory markers and T-cell subsets were analyzed in adipose tissue via the expression of CD14, IL-18, CD68, TNFα, CD3ε, FOXP3 [a regulatory T-cell (Treg) marker] and RORC (a Th17 marker). In obese subjects, the ratio of kynurenine to tryptophan, which reflects IDO1 activation, is higher than in lean subjects. Furthermore, IDO1 expression in both adipose tissues and liver is increased and is inversely correlated with arterial blood pressure. Inflammation is associated with a T-cell infiltration in obese adipose tissue, with predominance of Th17 in the omental compartment and of Treg in the subcutaneous depot. The Th17/Treg balance is decreased in subcutaneous fat and correlates with IDO1 activation. In contrast, in the omental compartment, despite IDO1 activation, the Th17/Treg balance control is impaired. Taken together, our results suggest that IDO1 activation represents a local compensatory mechanism to limit obesity-induced inflammation and hypertension.

scholarly journals Smartphone-powered iontophoresis-microneedle array patch for controlled transdermal delivery

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Jingbo Yang ◽  
Yanjun Li ◽  
Rui Ye ◽  
Ying Zheng ◽  
Xiangling Li ◽  
...  
Keyword(s):  
Transdermal Delivery ◽  
Insulin Delivery ◽  
Diabetic Rat ◽  
Microneedle Array ◽  
Control Drug ◽  
Control Of Diabetes ◽  
One Step ◽  
Glycemic Regulation

AbstractThe incidence rate of diabetes has been increasing every year in nearly all nations and regions. The traditional control of diabetes using transdermal insulin delivery by metal needles is generally associated with pain and potential infections. While microneedle arrays (MAs) have emerged as painless delivery techniques, the integration of MA systems with electronic devices to precisely control drug delivery has rarely been realized. In this study, we developed an iontophoresis-microneedle array patch (IMAP) powered by a portable smartphone for the active and controllable transdermal delivery of insulin. The IMAP in situ integrates iontophoresis and charged nanovesicles into one patch, achieving a one-step drug administration strategy of “penetration, diffusion and iontophoresis”. The MA of the IMAP is first pressed on the skin to create microholes and then is retracted, followed by the iontophoresis delivery of insulin-loaded nanovesicles through these microholes in an electrically controlled manner. This method has synergistically and remarkably enhanced controlled insulin delivery. The amount of insulin can be effectively regulated by the IMAP by applying different current intensities. This in vivo study has demonstrated that the IMAP effectively delivers insulin and produces robust hypoglycemic effects in a type-1 diabetic rat model, with more advanced controllability and efficiency than delivery by a pristine microneedle or iontophoresis. The IMAP system shows high potential for diabetes therapy and the capacity to provide active as well as long-term glycemic regulation without medical staff care.

A Tale of Three Systems: Toward a Neuroimmunoendocrine Model of Obesity

2021 ◽  
Vol 37 (1) ◽  
pp. 549-573
Author(s):  
Conan J.O. O'Brien ◽  
Emma R. Haberman ◽  
Ana I. Domingos
Keyword(s):  
Adipose Tissue ◽  
Energy Homeostasis ◽  
Current Knowledge ◽  
Neural Circuitry ◽  
Leptin Resistance ◽  
Direct Role ◽  
Adipose Tissues ◽  
Adipose Tissue Macrophages ◽  
Prevalence Of Obesity ◽  
Established Role

The prevalence of obesity is on the rise. What was once considered a simple disease of energy imbalance is now recognized as a complex condition perpetuated by neuro- and immunopathologies. In this review, we summarize the current knowledge of the neuroimmunoendocrine mechanisms underlying obesity. We examine the pleiotropic effects of leptin action in addition to its established role in the modulation of appetite, and we discuss the neural circuitry mediating leptin action and how this is altered with obesity, both centrally (leptin resistance) and in adipose tissues (sympathetic neuropathy). Finally, we dissect the numerous causal and consequential roles of adipose tissue macrophages in obesity and highlight recent key studies demonstrating their direct role in organismal energy homeostasis.

Abstract 3672: Loss of Perivascular Adipocyte Paracrine Function Leads to Increased Vascular Tone and Glucose Intolerance in Hypertension

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Kaivan Khavandi ◽  
Adam Greenstein ◽  
Sarah Withers ◽  
Kazuhiko Sonoyama ◽  
Sarah Lewis ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Metabolic Syndrome ◽  
Adipose Tissue ◽  
Vascular Tone ◽  
Tnf Alpha ◽  
Perivascular Adipose Tissue ◽  
The Metabolic Syndrome ◽  
Adipocyte Cell ◽  
Therapeutic Opportunity

In order to investigate the contribution of perivascular adipose tissue (PVAT) to arterial function, a total of 55 small arteries harvested from 35 skin biopsies of patients with Metabolic Syndrome and matched controls were mounted as ring preparations in a wire myograph. Contractility to cumulative doses of Norepinephrine in the presence or absence of PVAT showed an anticontractile effect in arteries from healthy volunteers (p=0.009), which was lost in patients with Metabolic Syndrome. Bioassay studies confirmed that PVAT releases a hydrophilic anticontractile factor in health, which is absent in obesity. Using a soluble fragment of the human Type 1 receptor, we identified that the anticontractile factor was adiponectin, which is the sole mediator of vasodilation, acting by increasing endothelial bioavailability of nitric oxide. Significant endothelial dysfunction was observed in patients with Metabolic Syndrome (p<0.001). Quantitative image analysis of adipose tissue revealed significantly increased adipocyte cell size in patients with Metabolic Syndrome, compared with healthy controls (p<0.006). There was immunohistochemical evidence of inflammation with upregulation of TNF-alpha receptor 1 in these patients (p<0.001). Application of exogenous TNF-alpha abolished the anticontractile effect of PVAT by reducing adiponectin bioavailability. Oxidative stress also induced by cytokines TNF-alpha and IL-6 but not IL-1, reduced adiponectin production from PVAT and increased basal tone. When the obese microenvironment was replicated in vitro by inflicting hypoxia on PVAT, adiponectin activity was lost but then rescued by incubation with cytokine antagonists. Further application of the adiponectin receptor fragment abolished PVAT relaxation. We conclude that in healthy arteries, PVAT releases adiponectin which reduces vascular tone. In obesity, this is lost by a cascade of adipocyte hypertrophy, hypoxia, inflammation and oxidative stress. The resulting vasoconstriction contributes to hypertension, hypertriglyceridaemia and insulin resistance. Direct targeting of adiponectin release from PVAT therefore provides a novel therapeutic opportunity in the Metabolic Syndrome.

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