Chenodeoxycholic Acid Pharmacology in Biotechnology and Transplantable Pharmaceutical Applications for Tissue Delivery: An Acute Preclinical Study

Introduction. Primary bile acids (PBAs) are produced and released into human gut as a result of cholesterol catabolism in the liver. A predominant PBA is chenodeoxycholic acid (CDCA), which in a recent study in our laboratory, showed significant excipient-stabilizing effects on microcapsules carrying insulinoma β-cells, in vitro, resulting in improved cell functions and insulin release, in the hyperglycemic state. Hence, this study aimed to investigate the applications of CDCA in bio-encapsulation and transplantation of primary healthy viable islets, preclinically, in type 1 diabetes. Methods. Healthy islets were harvested from balb/c mice, encapsulated in CDCA microcapsules, and transplanted into the epididymal tissues of 6 syngeneic diabetic mice, post diabetes confirmation. Pre-transplantation, the microcapsules’ morphology, size, CDCA-deep layer distribution, and physical features such as swelling ratio and mechanical strength were analyzed. Post-transplantation, animals’ weight, bile acids’, and proinflammatory biomarkers’ concentrations were analyzed. The control group was diabetic mice that were transplanted encapsulated islets (without PBA). Results and Conclusion. Islet encapsulation by PBA microcapsules did not compromise the microcapsules’ morphology or features. Furthermore, the PBA-graft performed better in terms of glycemic control and resulted in modulation of the bile acid profile in the brain. This is suggestive that the improved glycemic control was mediated via brain-related effects. However, the improvement in graft insulin delivery and glycemic control was short-term.

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Antidiabetic activity of tannin fraction of Bridelia ferruginea (Benth) leaf extract on fructose-induced diabetic mice

Journal of Herbmed Pharmacology ◽

10.34172/jhp.2021.06 ◽

2020 ◽

Vol 10 (1) ◽

pp. 68-74

Author(s):

Sabrina Sanvee ◽

Oudjaniyobi Simalou ◽

Gneiny Whad Tchani ◽

Hèzouwè Kagnou ◽

Batomayena Bakoma ◽

...

Keyword(s):

Condensed Tannins ◽

Reducing Power ◽

Antidiabetic Activity ◽

Control Group ◽

Diabetic Mice ◽

Leaf Extracts ◽

Frap Assay ◽

Antioxidant Power ◽

Bridelia Ferruginea

Introduction: Bridelia ferruginea is a plant known for its antidiabetic properties. However, few studies on leaf extracts have induced anti-hyperglycemic activity on normal mice subjected to carbohydrate overload. The current study was designed to assess the effect of the leaf extracts’ fraction on fructose-induced diabetic mice. Methods: The in vitro ferric-reducing antioxidant power (FRAP) assay were carried out and the condensed tannins quantified. The vanillin-HCl method was used to characterize the condensed tannins. The antidiabetic effect on fructose-induced diabetic mice was evaluated for 28 days using a fructose-enriched fat diet approach. Results: The fraction confirmed the antioxidant activity with a reducing power of 800 μg/mL comparable to ascorbic acid at 200 μg/mL. The condensed tannins were estimated at 79.6 ± 3.4 mg catechin equivalent per gram of sample. Significant decreases in blood sugar levels of 6.25% at the 7th day, 11.04% at the 14th day, 12.61% at the 21th day, and 11.35% at the 28th day were obtained in mice treated with the extract dose of 200 mg/kg of body weight, compared to the positive control group. The decreases of 37.11% of triglycerides and 40.16% of total cholesterol were also obtained. Conclusion: The investigated fraction showed notable antidiabetic activity and might be a good candidate in the treatment of diabetes.

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PPARα/γ, adiponectin and GLUT4 overexpression induced by moronic acid methyl ester influenced on glucose and triglycerides levels of experimental diabetic mice

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2021-0526 ◽

2021 ◽

Author(s):

Samuel Estrada-Soto ◽

Litzia Cerón-Romero ◽

Gabriel Navarrete-Vázquez ◽

Edgar Rosales-Ortega ◽

Jaime H. Gómez-Zamudio ◽

...

Keyword(s):

Methyl Ester ◽

Acid Methyl Ester ◽

Control Group ◽

Oral Glucose ◽

Acute Administration ◽

Diabetic Mice ◽

Ppar Γ ◽

Acid Methyl

The current study aimed to determine the antidiabetic and antidyslipidemic activities of moronic acid methyl ester (1) by in vivo, in vitro, in silico and molecular biology studies. Compound 1 was evaluated to establish its dose-dependent antidiabetic and antihyperglycemic (50 mg/kg) activities, in diabetic and normoglycemic male CD1 mice, respectively. Also, compound 1 was subjected to a sub-acute study (50 mg/kg/day for eight days) to determine blood biochemical profiles and the expression of PTP-1B, GLUT4, PPAR-α, PPAR-γ, adiponectin, IL-1β, and MCP1 in adipose tissue of animals after treatment. Different doses in acute administration of 1 decreased glycemia (p < 0.05), compared with vehicle, showing greater effectiveness in the range 50-160 mg/kg. Also, the oral glucose tolerance test (OGTT) showed that 1 induced a significant antihyperglycemic action by opposing the hyperglycemic peak (p < 0.05). Moreover, 1 subacute administration decrease glucose and triglycerides levels after treatment (p < 0.05); while the expression of PPAR-α and γ, adiponectin and GLUT4 displayed an increase (p< 0.05) compared with the diabetic control group. In conclusion, compound 1 showed antihyperglycemic, antidiabetic and antidyslipidemic effects in normal and diabetic mice, probably due to insulin sensitization through increase mRNA expression of GLUT4, PPAR-α, PPAR-γ and adiponectin genes.

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Rosiglitazone impairs proliferation of human adrenocortical cancer: preclinical study in a xenograft mouse model

Endocrine Related Cancer ◽

10.1677/erc-09-0170 ◽

2010 ◽

Vol 17 (1) ◽

pp. 169-177 ◽

Cited By ~ 24

Author(s):

Michaela Luconi ◽

Monica Mangoni ◽

Stefania Gelmini ◽

Giada Poli ◽

Gabriella Nesi ◽

...

Keyword(s):

Tumor Growth ◽

Day Treatment ◽

Xenograft Model ◽

Preclinical Study ◽

Histological Evaluation ◽

Control Group ◽

Adrenocortical Cancer ◽

Ki 67

Adrenocortical carcinoma (ACC) is a rare aggressive tumor with a poor prognosis. The lack of a specific and effective medical treatment is due to the poor knowledge of the mechanisms underlying tumor growth. Research on potential drugs able to specifically interfere with tumor proliferation is essential to develop more efficacious therapies. We evaluated for the first time the in vivo effect of rosiglitazone (RGZ), an anti-diabetic drug with in vitro anti-tumor properties, on ACC proliferation in a xenograft model obtained by s.c. injection of human ACC H295R cells in athymic mice. When the tumor size reached 5 mm, animals were allocated to 5 mg/kg RGZ- or water-treated groups. Tumor volume was measured twice a week. A significant reduction of tumor growth in RGZ versus control (control) group was observed and was already maximal following 17 day treatment (1−T/C=75.4% (43.7–93.8%)). After 31 days of treatment, mice were killed and tumor analyzed. Tumor histological evaluation revealed characteristics of invasiveness, richness in small vessels and mitotic figures in control group, while RGZ group tumors presented non infiltrating borders, few vessels, and many apoptotic bodies. Tumor immunohistochemistry showed that Ki-67 was reduced in RGZ versus control group. Quantitative real-time RT-PCR demonstrated a significant reduction in the expression of angiogenic (VEGF), vascular (CD31), proliferation (BMI-1), and anti-apoptotic (Bcl-2) genes in RGZ versus control group tumors. The same inhibitory effects were confirmed in in vitro RGZ-treated H295R. Our findings support and expand the role of RGZ in controlling ACC proliferation and angiogenesis in vivo and in vitro.

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Bile acids inhibit duodenal secretin expression via orphan nuclear receptor small heterodimer partner (SHP)

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00094.2009 ◽

2009 ◽

Vol 297 (1) ◽

pp. G90-G97 ◽

Cited By ~ 9

Author(s):

Ian P. Y. Lam ◽

Leo T. O. Lee ◽

Hueng-Sik Choi ◽

Gianfranco Alpini ◽

Billy K. C. Chow

Keyword(s):

Gene Expression ◽

Bile Acids ◽

Nuclear Receptor ◽

Target Genes ◽

In Vivo Studies ◽

Control Group ◽

Orphan Nuclear Receptor ◽

Small Heterodimer Partner

Small heterodimer partner (SHP) is an orphan nuclear receptor in which gene expression can be upregulated by bile acids. It regulates its target genes by repressing the transcriptional activities of other nuclear receptors including NeuroD, which has been shown to regulate secretin gene expression. Here, we evaluated the regulation on duodenal secretin gene expression by SHP and selected bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA). In vitro treatment of CDCA or fexaramine elevated the SHP transcript level and occupancy on secretin promoter. The increase in the SHP level, induced by bile acid treatment or overexpression, reduced secretin gene expression, whereas this gene inhibitory effect was reversed by silencing of endogenous SHP. In in vivo studies, double-immunofluorescence staining demonstrated the coexpression of secretin and SHP in mouse duodenum. Feeding mice with 1% CA-enriched rodent chow resulted in upregulation of SHP and a concomitant decrease in secretin transcript and protein levels in duodenum compared with the control group fed with normal chow. A diet enriched with 5% cholestyramine led to a decrease in SHP level and a corresponding increase in secretin expression. Overall, this study showed that bile acids via SHP inhibit duodenal secretin gene expression. Because secretin is a key hormone that stimulates bile flow in cholangiocytes, this pathway thus provides a novel means to modulate secretin-stimulated choleresis in response to intraduodenal bile acids.

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A Multiparametric Assessment of Human Islets Predicts Transplant Outcomes in Diabetic Mice

Cell Transplantation ◽

10.1177/09636897211052291 ◽

2021 ◽

Vol 30 ◽

pp. 096368972110522

Author(s):

Hirotake Komatsu ◽

Meirigeng Qi ◽

Nelson Gonzalez ◽

Mayra Salgado ◽

Leonard Medrano ◽

...

Keyword(s):

Oxygen Consumption ◽

Oxygen Consumption Rate ◽

Consumption Rate ◽

Single Cells ◽

Human Islets ◽

In Vitro Assays ◽

Diabetic Mice ◽

Post Transplantation

Prior to transplantation into individuals with type 1 diabetes, in vitro assays are used to evaluate the quality, function and survival of isolated human islets. In addition to the assessments of these parameters in islet, they can be evaluated by multiparametric morphological scoring (0–10 points) and grading (A, B, C, D, and F) based on islet characteristics (shape, border, integrity, single cells, and diameter). However, correlation between the multiparametric assessment and transplantation outcome has not been fully elucidated. In this study, 55 human islet isolations were scored using this multiparametric assessment. The results were correlated with outcomes after transplantation into immunodeficient diabetic mice. In addition, the multiparametric assessment was compared with oxygen consumption rate of isolated islets as a potential prediction factor for successful transplantations. All islet batches were assessed and found to score: 9 points ( n = 18, Grade A), 8 points ( n = 19, Grade B), and 7 points ( n = 18, Grade B). Islets that scored 9 (Grade A), scored 8 (Grade B) and scored 7 (Grade B) were transplanted into NOD/SCID mice and reversed diabetes in 81.2%, 59.4%, and 33.3% of animals, respectively ( P < 0.0001). Islet scoring and grading correlated well with glycemic control post-transplantation ( P < 0.0001) and reversal rate of diabetes ( P < 0.05). Notably, islet scoring and grading showed stronger correlation with transplantation outcome compared to oxygen consumption rate. Taken together, a multiparametric assessment of isolated human islets was highly predictive of transplantation outcome in diabetic mice.

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Alleviating Effects of Active Fraction of Euonymus alatus Abundant in Flavonoids on Diabetic Mice

The American Journal of Chinese Medicine ◽

10.1142/s0192415x08005643 ◽

2008 ◽

Vol 36 (01) ◽

pp. 125-140 ◽

Cited By ~ 13

Author(s):

Xian-Kang Fang ◽

Yuan Gao ◽

Hai-Yan Yang ◽

Su-Mei Lang ◽

Qiu-Juan Wang ◽

...

Keyword(s):

Plasma Glucose ◽

Ethyl Acetate Fraction ◽

Control Group ◽

Oral Glucose ◽

Diabetic Mice ◽

Active Fraction ◽

Active Components ◽

Euonymus Alatus ◽

Significant Difference

Euonymus alatus (E. alatus) has been used as a folk medicine for diabetes in China for more than one thousand years. In order to identify major active components, effects of different fractions of E. alatus on the plasma glucose levels were investigated in normal mice and alloxan-induced diabetic mice. Our results show that ethyl acetate fraction (EtOAc Fr.) displayed significant effects on reducing plasma glucose. In oral glucose tolerance, EtOAc Fr. at 17.2 mg/kg could significantly decrease the blood glucose of both normal mice and diabetic mice. After 4 weeks administration of the EtOAc Fr, when compared with the diabetic control, there were significant difference in biochemical parameters, such as glycosylated serum protein, superoxide dismutase and malondial dehyde, triglyceride, and total cholesterol, between alloxan-induced diabetic mice and the control group. Additional histopathological studies of pancreatic islets also showed EtOAc Fr. has beneficial effects on diabetic mice. Chemical analysis with three-dimensional HPLC demonstrated that the major components from EtOAc Fr were flavonoids and phenolic acids, which had anti-oxidative effects on scavenging DPPH-radical in vitro. All these experimental results suggest that EtOAc Fr. is an active fraction of E. alatus and can prevent the progress of diabetes. The mechanism of E. alatus for glucose control may be by stimulating insulin release, improving glucose uptake and improving oxidative-stress.

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IL-10 Is a Novel Ligand for Hematopoietic Stem Cell Self-Renewal.

Blood ◽

10.1182/blood.v104.11.2164.2164 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2164-2164 ◽

Cited By ~ 1

Author(s):

Il-Hoan Oh ◽

Young-Ju Kang ◽

Bin Cho

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell ◽

Biological Effects ◽

Control Group ◽

Post Transplantation ◽

Self Renewal ◽

Hematopoietic Stem ◽

Limiting Dilution ◽

Cells Cultured

Abstract IL-10 has been known to play a major role in modulating inflammatory and immune response. However, the anemia sign in targeted disruption of IL-10 (IL-10KO) and supportive effects of IL-10 during in-vitro culture of hematopoietic progenitor cells implicated potential role of IL-10 for hematopoietic function. To delineate the physiological significance of IL-10 for normal hematopoiesis, first, we undertook study to examine the various hematopoietic compartments in IL-10 KO mice in comparison to wild type (WT) counterparts. In the phenotypic analysis, the bone marrow cells (BMC) of IL-10 KO mice showed modest hypocellularity including TER119+ cells, but no difference were observed in the assay for in-vitro colony forming cells (CFC) (3 Exp.). In contrast, the number of more primitive hematopoietic cells as defined by long term culture (LTC-IC) was 2-fold lower in the BMCs of IL-10 KO mice compared to WT, and further decrease (7-fold) were observed in those IL-10 KO mice that had enterocolitis (2 Exp). Similarly, when equivalent numbers of BMCs from IL-10 KO or WT were transplanted into irradiated congeneic recipient (Pep3b-Ly5.1), IL-10 KO BMC showed 2-fold lower level of engraftment (88% vs 44%) than WT over the span of post-transplantation 3 to 12 weeks (2 exp, n=7 ea,). In the limiting dilution analysis to measure the HSC contents, the frequency of competitive repopulating unit (CRU) in the IL-10 KO BMC was also two fold lower than WT (1/2164 vs. 1/5931, respectively) with further decreasse in CRU frequency being observed for those from IL-10 KO with enterocolitis (< 1/17380), suggesting that IL-10 KO mice has decreased content of hematopoietic stem cell (HSC). To exclude possible indirect biological effects in IL-10 KO mice, and see if IL-10 have direct effect on quantity of HSCs, normal 5-FU prestimulated BMCs were cultured for 5 days on stromal cells that had been retrovirally transduced with IL-10 or control vector (MIG) along with TPO, SCF and FL. When the cells were transplanted into the recipients, cells cultured in the IL-10 secreting stroma exhibited significantly higher level engraftment compared to those cultured in the control stroma (23% vs 54% for PB, 16% vs 49% for BM engraftment, respectively, n=4). Secondary transplantation of these primary recipients at post-transplantation 9 month showed that the BM cells grown in IL-10 secreting stroma had 663 donor-derived CRUs, while those transplanted with control group had 215 donor-derived CRUs, a 3-fold higher CRU contents in the presence of IL-10. In further studies to see if IL-10 could be a direct ligand for primitive HSCs, first, expression of IL-10 receptor on those cells were confirmed by RT-PCR. Next, purified HSCs (c-kit+Sca-1+Lin-) without accessory cells were cultured in the stroma-free condition with or without exogeneous addition of IL-10 for 5 days, and transplanted into recipients in limiting dilution. The result showed that CRU frequency of cells cultured with IL-10 was 3-fold higher than those cultured in the absence of IL-10 (1/525 vs. 1/1465), thus suggesting that IL-10 is a direct ligand for HSC self-renewal. These results may implicate significance of IL-10 for pathogenesis and treatment of autoimmune diseases by stem cell transplantation as well as for improved ex-vivo expansion of HSCs.

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The bile acid chenodeoxycholic acid directly modulates metabolic pathways in white adipose tissue in vitro : insight into how bile acids decrease obesity

NMR in Biomedicine ◽

10.1002/nbm.3583 ◽

2016 ◽

Vol 29 (10) ◽

pp. 1391-1402 ◽

Cited By ~ 8

Author(s):

João Soeiro Teodoro ◽

Anabela Pinto Rolo ◽

Ivana Jarak ◽

Carlos Marques Palmeira ◽

Rui Albuquerque Carvalho

Keyword(s):

Adipose Tissue ◽

Bile Acid ◽

Bile Acids ◽

White Adipose Tissue ◽

Chenodeoxycholic Acid ◽

Metabolic Pathways ◽

Adipose Tissue In Vitro ◽

Insight Into

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Lactoferrin interacts with bile acids and increases fecal cholesterol excretion in rats

Biochemistry and Cell Biology ◽

10.1139/bcb-2016-0052 ◽

2017 ◽

Vol 95 (1) ◽

pp. 142-147 ◽

Cited By ~ 9

Author(s):

Kanae Nakamura ◽

Satoru Morishita ◽

Tomoji Ono ◽

Michiaki Murakoshi ◽

Keikichi Sugiyama ◽

...

Keyword(s):

Bile Acids ◽

Cholesterol Absorption ◽

Control Group ◽

High Cholesterol Diet ◽

Hepatic Cholesterol ◽

Intestinal Cholesterol Absorption ◽

Cationic Protein ◽

Cholesterol Levels ◽

Cholesterol Excretion

Lactoferrin (LF) is a multifunctional cationic protein (pI 8.2–8.9) in mammalian milk. We previously reported that enteric-LF prevented hypercholesterolemia and atherosclerosis in a diet-induced atherosclerosis model using Microminipig, although the underlying mechanisms remain unclear. Because LF is assumed to electrostatically interact with bile acids to inhibit intestinal cholesterol absorption, LF could promote cholesterol excretion. In this study, we assessed the interaction between LF and taurocholate in vitro, and the effect of LF on cholesterol excretion in rats. The binding rate of taurocholate to LF was significantly higher than that to transferrin (pI 5.2–6.3). When rats were administered a high-cholesterol diet (HCD) containing 5% LF, LF was detected using ELISA in the upper small intestine from 7.5 to 60 min after the administration. Rats were fed one of the following diets: control, HCD, or HCD + 5% LF for 21 days. Fecal neutral steroids and hepatic cholesterol levels in the HCD group were significantly higher than those in the control group. The addition of LF to a HCD significantly increased fecal neutral steroids levels (22% increase, p < 0.05) and reduced hepatic cholesterol levels (17% decrease, p < 0.05). These parameters were inversely correlated (R = −0.63, p < 0.05). These results suggest that LF promotes cholesterol excretion via interactions with bile acids.

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