Formulation buoyancy of nanoencapsulated gliclazide using primary, conjugated and deconjugated bile acids

Aim: Recent studies suggest potential applications of endogenously produced human bile acids as formulation-excipient and drug tissue permeation enhancers in Type 1 diabetes. We aimed to examine the stability, tissue permeation and ex vivo muscle-cell effects of microencapsulated gliclazide (G) incorporated with a primary (chenodeoxycholic acid [CDCA]), a secondary (ursodeoxycholic acid [UDCA]) or a tertiary (taurocholic acid [TCA]) bile acid. Materials & methods: Four formulations made of sodium alginate, CDCA, UDCA and TCA were examined for buoyancy, tissue-enhancing effects ( in vivo) and local ( ex vivo) viability effects. Results & conclusion: CDCA, UDCA and TCA improved buoyancy and cell viability but not tissue-specific uptake. G-TCA-sodium alginate microcapsules exerted hypoglycemic effects, suggesting significant improvement of G gut-uptake by TCA, possibly via improving buoyancy.

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Chemical Permeation Enhancers for Transdermal Delivery of Thiocolchicoside: Assessment of Ex-vivo Skin Flux and In-vivo Pharmacokinetics

International Journal of Pharmaceutical Sciences and Nanotechnology ◽

10.37285/ijpsn.2017.10.5.3 ◽

2017 ◽

Vol 10 (5) ◽

pp. 3827-3835

Author(s):

Y Madhusudan Rao ◽

Gayatri P ◽

Ajitha M ◽

P. Pavan Kumar ◽

Kiran kumar

Keyword(s):

Passive Control ◽

Ex Vivo ◽

Skin Permeation ◽

In Vivo Studies ◽

Permeation Enhancers ◽

Casting Technique ◽

Chemical Permeation Enhancers ◽

Chemical Permeation ◽

In Vivo Pharmacokinetics

Present investigation comprises the study of ex-vivo skin flux and in-vivo pharmacokinetics of Thiocolchicoside (THC) from transdermal films. The films were fabricated by solvent casting technique employing combination of hydrophilic and hydrophobic polymers. A flux of 18.08 µg/cm2h and 13.37µg/cm2h was achieved for optimized formulations containing 1, 8-cineole and oleic acid respectively as permeation enhancers. The observed flux values were higher when compared to passive control (8.66 µg/cm2h). Highest skin permeation was observed when 1,8-cineole was used as chemical permeation enhancer and it considerably (2-2.5 fold) improved the THC transport across the rat skin. In vivo studies were performed in rabbits and samples were analysed by LC-MS-MS. The mean area under the curve (AUC) values of transdermal film showed about 2.35 times statistically significant (p<0.05) improvement in bioavailability when compared with the oral administration of THC solution. The developed transdermal therapeutic systems using chemical permeation enhancers were suitable for drugs like THC in effective management of muscular pain.

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In Vivo Insulin Peptide Autoantigen Delivery by Mannosylated Sodium Alginate Nanoparticles Delayed but Could Not Prevent the Onset of Type 1 Diabetes in Nonobese Diabetic Mice

Molecular Pharmaceutics ◽

10.1021/acs.molpharmaceut.1c00054 ◽

2021 ◽

Vol 18 (4) ◽

pp. 1806-1818

Author(s):

Yue Qu ◽

Hang Shi ◽

Mohan Liu ◽

Mingming Zhang ◽

Hai Wang ◽

...

Keyword(s):

Type 1 Diabetes ◽

Sodium Alginate ◽

Diabetic Mice ◽

Nonobese Diabetic ◽

Nonobese Diabetic Mice

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Early Spatial and Temporal Events of Human T-Lymphotropic Virus Type 1 Spread following Blood-Borne Transmission in a Rabbit Model of Infection

Journal of Virology ◽

10.1128/jvi.01537-09 ◽

2010 ◽

Vol 84 (10) ◽

pp. 5124-5130 ◽

Cited By ~ 2

Author(s):

Rashade A. H. Haynes ◽

Bevin Zimmerman ◽

Laurie Millward ◽

Evan Ware ◽

Christopher Premanandan ◽

...

Keyword(s):

Virus Type ◽

Ex Vivo ◽

Rabbit Model ◽

Virus Detection ◽

Mononuclear Leukocytes ◽

T Lymphotropic Virus ◽

Viral Spread ◽

Temporal Events

ABSTRACT Human T-lymphotropic virus type 1 (HTLV-1) infection causes adult T-cell leukemia/lymphoma (ATL) and is associated with a variety of lymphocyte-mediated disorders. HTLV-1 transmission occurs by transmission of infected cells via breast-feeding by infected mothers, sexual intercourse, and contaminated blood products. The route of exposure and early virus replication events are believed to be key determinants of virus-associated spread, antiviral immune responses, and ultimately disease outcomes. The lack of knowledge of early events of HTLV-1 spread following blood-borne transmission of the virus in vivo hinders a more complete understanding of the immunopathogenesis of HTLV-1 infections. Herein, we have used an established animal model of HTLV-1 infection to study early spatial and temporal events of the viral infection. Twelve-week-old rabbits were injected intravenously with cell-associated HTLV-1 (ACH-transformed R49). Blood and tissues were collected at defined intervals throughout the study to test the early spread of the infection. Antibody and hematologic responses were monitored throughout the infection. HTLV-1 intracellular Tax and soluble p19 matrix were tested from ex vivo cultured lymphocytes. Proviral copy numbers were measured by real-time PCR from blood and tissue mononuclear leukocytes. Our data indicate that intravenous infection with cell-associated HTLV-1 targets lymphocytes located in both primary lymphoid and gut-associated lymphoid compartments. A transient lymphocytosis that correlated with peak virus detection parameters was observed by 1 week postinfection before returning to baseline levels. Our data support emerging evidence that HTLV-1 promotes lymphocyte proliferation preceding early viral spread in lymphoid compartments to establish and maintain persistent infection.

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Human Immunodeficiency Virus Type 1 Quasispecies In Vivo and Ex Vivo

Current Topics in Microbiology and Immunology - Genetic Diversity of RNA Viruses ◽

10.1007/978-3-642-77011-1_12 ◽

1992 ◽

pp. 181-193 ◽

Cited By ~ 16

Author(s):

S. Wain-Hobson

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Ex Vivo ◽

Immunodeficiency Virus

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Microfluidics in male reproduction: is ex vivo culture of primate testis tissue a future strategy for ART or toxicology research?

MHR Basic science of reproductive medicine ◽

10.1093/molehr/gaaa006 ◽

2020 ◽

Vol 26 (3) ◽

pp. 179-192 ◽

Cited By ~ 1

Author(s):

Swati Sharma ◽

Bastien Venzac ◽

Thomas Burgers ◽

Séverine Le Gac ◽

Stefan Schlatt

Keyword(s):

Male Infertility ◽

Functional Organization ◽

Ex Vivo ◽

Significant Rise ◽

Male Reproduction ◽

Potential Applications ◽

On Chip ◽

Bio Engineering

Abstract The significant rise in male infertility disorders over the years has led to extensive research efforts to recapitulate the process of male gametogenesis in vitro and to identify essential mechanisms involved in spermatogenesis, notably for clinical applications. A promising technology to bridge this research gap is organ-on-chip (OoC) technology, which has gradually transformed the research landscape in ART and offers new opportunities to develop advanced in vitro culture systems. With exquisite control on a cell or tissue microenvironment, customized organ-specific structures can be fabricated in in vitro OoC platforms, which can also simulate the effect of in vivo vascularization. Dynamic cultures using microfluidic devices enable us to create stimulatory effect and non-stimulatory culture conditions. Noteworthy is that recent studies demonstrated the potential of continuous perfusion in OoC systems using ex vivo mouse testis tissues. Here we review the existing literature and potential applications of such OoC systems for male reproduction in combination with novel bio-engineering and analytical tools. We first introduce OoC technology and highlight the opportunities offered in reproductive biology in general. In the subsequent section, we discuss the complex structural and functional organization of the testis and the role of the vasculature-associated testicular niche and fluid dynamics in modulating testis function. Next, we review significant technological breakthroughs in achieving in vitro spermatogenesis in various species and discuss the evidence from microfluidics-based testes culture studies in mouse. Lastly, we discuss a roadmap for the potential applications of the proposed testis-on-chip culture system in the field of primate male infertility, ART and reproductive toxicology.

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Biliary Secretion of Quasi-Enveloped Human Hepatitis A Virus

mBio ◽

10.1128/mbio.01998-16 ◽

2016 ◽

Vol 7 (6) ◽

Cited By ~ 31

Author(s):

Asuka Hirai-Yuki ◽

Lucinda Hensley ◽

Jason K. Whitmire ◽

Stanley M. Lemon

Keyword(s):

Life Cycle ◽

Bile Acids ◽

Neutralizing Antibodies ◽

Hepatitis A ◽

Hepatitis A Virus ◽

Acute Infection ◽

Cell Culture Supernatant ◽

Particle Type ◽

Human Bile

ABSTRACTHepatitis A virus (HAV) is an unusual picornavirus that is released from cells cloaked in host-derived membranes. These quasi-enveloped virions (eHAV) are the only particle type circulating in blood during infection, whereas only nonenveloped virions are shed in feces. The reason for this is uncertain. Hepatocytes, the only cell type known to support HAV replicationin vivo, are highly polarized epithelial cells with basolateral membranes facing onto hepatic (blood) sinusoids and apical membranes abutting biliary canaliculi from which bile is secreted to the gut. To assess whether eHAV and nonenveloped virus egress from cells via vectorially distinct pathways, we studied infected polarized cultures of Caco-2 and HepG2-N6 cells. Most (>99%) progeny virions were released apically from Caco-2 cells, whereas basolateral (64%) versus apical (36%) release was more balanced with HepG2-N6 cells. Both apically and basolaterally released virions were predominantly enveloped, with no suggestion of differential vectorial release of eHAV versus naked virions. Basolateral to apical transcytosis of either particle type was minimal (<0.02%/h) in HepG2-N6 cells, arguing against this as a mechanism for differences in membrane envelopment of serum versus fecal virus. High concentrations of human bile acids converted eHAV to nonenveloped virions, whereas virus present in bile from HAV-infectedIfnar1−/−Ifngr1−/−andMavs−/−mice banded over a range of densities extending from that of eHAV to that of nonenveloped virions. We conclude that nonenveloped virions shed in feces are derived from eHAV released across the canalicular membrane and stripped of membranes by the detergent action of bile acids within the proximal biliary canaliculus.IMPORTANCEHAV is a hepatotropic, fecally/orally transmitted picornavirus that can cause severe hepatitis in humans. Recent work reveals that it has an unusual life cycle. Virus is found in cell culture supernatant fluids in two mature, infectious forms: one wrapped in membranes (quasi-enveloped) and another that is nonenveloped. Membrane-wrapped virions circulate in blood during acute infection and are resistant to neutralizing antibodies, likely facilitating HAV dissemination within the liver. On the other hand, virus shed in feces is nonenveloped and highly stable, facilitating epidemic spread and transmission to naive hosts. Factors controlling the biogenesis of these two distinct forms of the virus in infected humans are not understood. Here we characterize vectorial release of quasi-enveloped virions from polarized epithelial cell cultures and provide evidence that bile acids strip membranes from eHAV following its secretion into the biliary tract. These results enhance our understanding of the life cycle of this unusual picornavirus.

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PTH Modulation by Aldosterone and Angiotensin II is Blunted in Hyperaldosteronism and Rescued by Adrenalectomy

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2019-00143 ◽

2019 ◽

Vol 104 (9) ◽

pp. 3726-3734 ◽

Cited By ~ 8

Author(s):

Livia Lenzini ◽

Selene Prisco ◽

Paul Emmanuel Vanderriele ◽

Silvia Lerco ◽

Francesca Torresan ◽

...

Keyword(s):

Angiotensin Ii ◽

Ex Vivo ◽

Primary Cultures ◽

Zona Glomerulosa ◽

Before And After ◽

Bilateral Adrenal Hyperplasia ◽

Aldosterone Producing Adenoma ◽

Serum Pth

Abstract Context Accumulating evidence suggests a link between adrenocortical zona glomerulosa and parathyroid gland through mechanisms that remain unexplored. Objectives To test the hypothesis that in vivo angiotensin II blockade affects PTH secretion in patients with hypertension and that aldosterone and angiotensim II directly stimulate PTH secretion ex vivo. Design and Setting We investigated the changes of serum PTH levels induced by oral captopril (50 mg) administration in patients with primary essential hypertension (EH) and with primary aldosteronism (PA) caused by bilateral adrenal hyperplasia (BAH) or aldosterone-producing adenoma (APA), the latter before and after adrenalectomy. We also exposed primary cultures of human parathyroid cells from patients with primary hyperparathyroidism to angiotensin II (10−7 M) and/or aldosterone (10−7 M). Results Captopril lowered PTH levels (in nanograms per liter) both in patients with EH (n = 63; 25.9 ± 8.3 baseline vs 24.4 ± 8.0 postcaptopril, P < 0.0001) and in patients with APA after adrenalectomy (n = 27; 26.3 ± 11.6 vs 24.0 ± 9.7 P = 0.021). However, it was ineffective in patients with full-blown PA caused by APA and BAH. In primary culture of human parathyroid cells, both aldosterone (P < 0.001) and angiotensin II (P = 0.002) markedly increased PTH secretion from baseline, by acting through mineralocorticoid receptor and angiotensin type 1 receptor, as these effects were abolished by canrenone and irbesartan, respectively. Conclusion These results collectively suggest an implication of the renin-angiotensin-aldosterone system in PTH regulation in humans, at least in PTH-secreting cells obtained from parathyroid tumors. Moreover, they further support the concept that mild hyperparathyroidism is a feature of human PA that is correctable with adrenalectomy.

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Type 1 diabetic cardiomyopathy in the Akita (Ins2WT/C96Y) mouse model is characterized by lipotoxicity and diastolic dysfunction with preserved systolic function

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00452.2009 ◽

2009 ◽

Vol 297 (6) ◽

pp. H2096-H2108 ◽

Cited By ~ 105

Author(s):

Ratnadeep Basu ◽

Gavin Y. Oudit ◽

Xiuhua Wang ◽

Liyan Zhang ◽

John R. Ussher ◽

...

Keyword(s):

Sarcoplasmic Reticulum ◽

Diastolic Dysfunction ◽

Diabetic Cardiomyopathy ◽

Ex Vivo ◽

Systolic Function ◽

Doppler Imaging ◽

Hemodynamic Measurements ◽

Long Chain

Diabetic cardiomyopathy is an important contributor to diastolic and systolic heart failure. We examined the nature and mechanism of the cardiomyopathy in Akita ( Ins2WT/C96Y) mice, a model of genetic nonobese type 1 diabetes that recapitulates human type 1 diabetes. Cardiac function was evaluated in male Ins2WT/C96Y and their littermate control ( Ins2WT/WT) mice using echocardiography and tissue Doppler imaging, in vivo hemodynamic measurements, as well as ex vivo working heart preparation. At 3 and 6 mo of age, Ins2WT/C96Y mice exhibited preserved cardiac systolic function compared with Ins2WT/WT mice, as evaluated by ejection fraction, fractional shortening, left ventricular (LV) end-systolic pressure and maximum rate of increase in LV pressure in vivo, cardiac work, cardiac power, and rate-pressure product ex vivo. Despite the unaltered systolic function, Ins2WT/C96Y mice exhibited significant and progressive diastolic dysfunction at 3 and 6 mo of age compared with Ins2WT/WT mice as assessed by tissue and pulse Doppler imaging (E-wave velocity, isovolumetric relaxation time) and by in vivo hemodynamic measurements (LV end-diastolic pressure, time constant of LV relaxation, and maximum rate of decrease in LV pressure). We found no evidence of myocardial hypertrophy or fibrosis in the Ins2WT/C96Y myocardium. Consistent with the lack of fibrosis, expression of procollagen-α type I, procollagen-α type III, and fibronectin were not increased in these hearts. Ins2WT/C96Y hearts showed significantly reduced sarcoplasmic reticulum Ca2+-ATPase 2a (cardiac sarcoplasmic reticulum Ca2+ pump) levels, elevated β-myosin heavy chain isoform, increased long-chain fatty acids, and triacylglycerol with evidence of lipotoxicity, as indicated by a significant rise in ceramide, diacylglycerol, and lipid deposits in the myocardium. Consistent with metabolic perturbation, and a switch to fatty acid oxidation from glucose oxidation in Ins2WT/C96Y hearts, expression of mitochondrial long-chain acyl-CoA dehydrogenase and pyruvate dehydrogenase kinase isoform 4 were increased. Insulin treatment reversed the diastolic dysfunction, the elevated B-type natriuretic peptide and β-myosin heavy chain, and the reduced sarcoplasmic reticulum Ca2+-ATPase 2a levels with abolition of cardiac lipotoxicity. We conclude that early type 1 diabetic cardiomyopathy is characterized by diastolic dysfunction associated with lipotoxic cardiomyopathy with preserved systolic function in the absence of interstitial fibrosis and hypertrophy.

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β-Cell Generation: Can Rodent Studies Be Translated to Humans?

Journal of Transplantation ◽

10.1155/2011/892453 ◽

2011 ◽

Vol 2011 ◽

pp. 1-15 ◽

Cited By ~ 11

Author(s):

Françoise Carlotti ◽

Arnaud Zaldumbide ◽

Johanne H. Ellenbroek ◽

H. Siebe Spijker ◽

Rob C. Hoeben ◽

...

Keyword(s):

Ex Vivo ◽

Cell Mass ◽

Cell Types ◽

Organ Donors ◽

Cell Replacement Therapy ◽

Β Cell ◽

Cell Replacement ◽

Therapeutic Alternatives

β-cell replacement by allogeneic islet transplantation is a promising approach for patients with type 1 diabetes, but the shortage of organ donors requires new sources ofβcells. Islet regenerationin vivoand generation ofβ-cellsex vivofollowed by transplantation represent attractive therapeutic alternatives to restore theβ-cell mass. In this paper, we discuss different postnatal cell types that have been envisaged as potential sources for futureβ-cell replacement therapy. The ultimate goal being translation to the clinic, a particular attention is given to the discrepancies between findings from studies performed in rodents (bothex vivoon primary cells andin vivoon animal models), when compared with clinical data and studies performed on human cells.

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