scholarly journals Repurposing Lesogaberan to Promote Human Islet Cell Survival andβ-Cell Replication

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Jide Tian ◽  
Hoa Dang ◽  
Angela Hu ◽  
Willem Xu ◽  
Daniel L. Kaufman
Keyword(s):  
Cell Survival ◽  
Islet Cell ◽  
Oral Treatment ◽  
Human Islet ◽  
Drug Candidate ◽  
Gamma Aminobutyric Acid ◽  
Cell Replication ◽  
Long Term Treatment

The activation ofβ-cell’s A- and B-type gamma-aminobutyric acid receptors (GABAA-Rs and GABAB-Rs) can promote their survival and replication, and the activation ofα-cell GABAA-Rs promotes their conversion intoβ-cells. However, GABA and the most clinically applicable GABA-R ligands may be suboptimal for the long-term treatment of diabetes due to their pharmacological properties or potential side-effects on the central nervous system (CNS). Lesogaberan (AZD3355) is a peripherally restricted high-affinity GABAB-R-specific agonist, originally developed for the treatment of gastroesophageal reflux disease (GERD) that appears to be safe for human use. This study tested the hypothesis that lesogaberan could be repurposed to promote human islet cell survival andβ-cell replication.Treatment with lesogaberan significantly enhanced replication of human islet cellsin vitro, which was abrogated by a GABAB-R antagonist. Immunohistochemical analysis of human islets that were grafted into immune-deficient mice revealed that oral treatment with lesogaberan promoted humanβ-cell replication and islet cell survivalin vivoas effectively as GABA (which activates both GABAA-Rs and GABAB-Rs), perhaps because of its more favorable pharmacokinetics. Lesogaberan may be a promising drug candidate for clinical studies of diabetes intervention and islet transplantation.

scholarly journals A Clinically Applicable Positive Allosteric Modulator of GABA Receptors Promotes Human β-Cell Replication and Survival as well as GABA’s Ability to Inhibit Inflammatory T Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Jide Tian ◽  
Hoa Dang ◽  
Nataliya Karashchuk ◽  
Irvin Xu ◽  
Daniel L. Kaufman
Keyword(s):  
T Cell ◽  
Cell Survival ◽  
Islet Cell ◽  
Cell Mass ◽  
T Cell Responses ◽  
Human Islet ◽  
Cell Replication ◽  
Cell Responses ◽  
Autoreactive T Cell

A major goal of T1D research is to develop new approaches to increase β-cell mass and control autoreactive T cell responses. GABAA-receptors (GABAA-Rs) are promising drug targets in both those regards due to their abilities to promote β-cell replication and survival, as well as inhibit autoreactive T cell responses. We previously showed that positive allosteric modulators (PAMs) of GABAA-Rs could promote rat β-cell line INS-1 and human islet cell replication in vitro. Here, we assessed whether treatment with alprazolam, a widely prescribed GABAA-R PAM, could promote β-cell survival and replication in human islets after implantation into NOD/scid mice. We observed that alprazolam treatment significantly reduced human islet cell apoptosis following transplantation and increased β-cell replication in the xenografts. Evidently, the GABAA-R PAM works in conjunction with GABA secreted from β-cells to increase β-cell survival and replication. Treatment with both the PAM and GABA further enhanced human β-cell replication. Alprazolam also augmented the ability of suboptimal doses of GABA to inhibit antigen-specific T cell responses in vitro. Thus, combined GABAA-R agonist and PAM treatment may help control inflammatory immune responses using reduced drug dosages. Together, these findings suggest that GABAA-R PAMs represent a promising drug class for safely modulating islet cells toward beneficial outcomes to help prevent or reverse T1D and, together with a GABAA-R agonist, may have broader applications for ameliorating other disorders in which inflammation contributes to the disease process.

scholarly journals Antitrypanosomal Activity of Fexinidazole, a New Oral Nitroimidazole Drug Candidate for Treatment of Sleeping Sickness

2011 ◽  
Vol 55 (12) ◽  
pp. 5602-5608 ◽  
Author(s):  
Marcel Kaiser ◽  
Michael A. Bray ◽  
Monica Cal ◽  
Bernadette Bourdin Trunz ◽  
Els Torreele ◽  
...  
Keyword(s):  
Oral Treatment ◽  
Sleeping Sickness ◽  
Drug Candidate ◽  
Pharmacokinetic Data ◽  
Parent Molecule ◽  
Content Type ◽  
Trypanocidal Activity ◽  
Parasite Strains

ABSTRACTFexinidazole is a 5-nitroimidazole drug currently in clinical development for the treatment of human sleeping sickness (human African trypanosomiasis [HAT]), caused by infection with species of the protozoan parasiteTrypanosoma brucei. The compound and its two principal metabolites, sulfoxide and sulfone, have been assessed for their ability to kill a range ofT. bruceiparasite strainsin vitroand to cure both acute and chronic HAT disease models in the mouse. The parent molecule and both metabolites have shown trypanocidal activityin vitroin the 0.7-to-3.3 μM (0.2-to-0.9 μg/ml) range against all parasite strains tested.In vivo, fexinidazole is orally effective in curing both acute and chronic diseases in the mouse at doses of 100 mg/kg of body weight/day for 4 days and 200 mg/kg/day for 5 days, respectively. Pharmacokinetic data indicate that it is likely that the sulfoxide and sulfone metabolites provide most, if not all, of thein vivokilling activity. Fexinidazole and its metabolites require up to 48 h exposure in order to induce maximal trypanocidal efficacyin vitro. The parent drug and its metabolites show noin vitrocross-reactivity in terms of trypanocidal activity with either themselves or other known trypanocidal drugs in use in humans. Thein vitroandin vivoantitrypanosomal activities of fexinidazole and its two principal metabolites provide evidence that the compound has the potential to be an effective oral treatment for both theT. b. gambienseandT. b. rhodesienseforms of human sleeping sickness and both stages of the disease.

Overexpression of the nuclear factor-κB subunit c-Rel protects against human islet cell death in vitro

2009 ◽  
Vol 297 (5) ◽  
pp. E1067-E1077 ◽  
Author(s):  
Dariush Mokhtari ◽  
Andreea Barbu ◽  
Ilir Mehmeti ◽  
Chantal Vercamer ◽  
Nils Welsh
Keyword(s):  
Cell Death ◽  
Islet Cell ◽  
Nuclear Translocation ◽  
Islet Cells ◽  
Human Islet ◽  
Nuclear Fraction ◽  
Nuclear Factor ◽  
Subunit C

The transcription factor nuclear factor (NF)-κB is known to modulate rates of apoptosis and may therefore play a role in the increased β-cell death that occurs in type 1 and type 2 diabetes. The aim of the present investigation was to study the expression of NF-κB subunits in human islet cells and whether overexpression of the NF-κB subunit c-Rel affects islet cell survival. We detected expression of p65, Rel-B, p50, p105, p52, and the ribosomal protein S3 (rpS3) in human islet cells. Among these, only p65 and rpS3 were translocated from the cytosolic to the nuclear fraction in response to cytokines. Interestingly, rpS3 participated in p65 binding to the κB-element in gel shift analysis experiments. We observed cytoplasmic c-Rel expression in vivo in 6J mice, and signs of nuclear translocation in β-cells of infiltrated nonobese diabetic islets. Human islet cells were also dispersed by trypsin treatment and transduced with a c-Rel adenoviral vector. This resulted in increased expression of c-Rel and inhibitory factor κB, increased κB-binding activity, and augmented protein levels of Bcl-XL, c-IAP2, and heat shock protein 72. c-Rel expression in human islet cells protected against cytokine-induced caspase 3 activation and cell death. c-Rel protected also against streptozotocin- and H2O2-induced cell death, in both intact rat islets and human islet cells. We conclude that rpS3 participates in NF-κB signaling and that a genetic increase in the activity of the NF-κB subunit c-Rel results in protection against cell death in human islets.

Tamarix articulata (T. articulata) - An Important Halophytic Medicinal Plant with Potential Pharmacological Properties

2019 ◽  
Vol 20 (4) ◽  
pp. 285-292 ◽  
Author(s):  
Abdullah M. Alnuqaydan ◽  
Bilal Rah
Keyword(s):  
Medicinal Plant ◽  
Biological Activities ◽  
Wide Spectrum ◽  
Biological Properties ◽  
In Vivo Model ◽  
Drug Candidate ◽  
Phytochemical Analysis ◽  
Pharmacological Properties

Background:Tamarix Articulata (T. articulata), commonly known as Tamarisk or Athal in Arabic region, belongs to the Tamaricaece species. It is an important halophytic medicinal plant and a good source of polyphenolic phytochemical(s). In traditional medicines, T. articulata extract is commonly used, either singly or in combination with other plant extracts against different ailments since ancient times.Methods:Electronic database survey via Pubmed, Google Scholar, Researchgate, Scopus and Science Direct were used to review the scientific inputs until October 2018, by searching appropriate keywords. Literature related to pharmacological activities of T. articulata, Tamarix species, phytochemical analysis of T. articulata, biological activities of T. articulata extracts. All of these terms were used to search the scientific literature associated with T. articulata; the dosage of extract, route of administration, extract type, and in-vitro and in-vivo model.Results:Numerous reports revealed that T. articulata contains a wide spectrum of phytochemical(s), which enables it to have a wide window of biological properties. Owing to the presence of high content of phytochemical compounds like polyphenolics and flavonoids, T. articulata is a potential source of antioxidant, anti-inflammatory and antiproliferative properties. In view of these pharmacological properties, T. articulata could be a potential drug candidate to treat various clinical conditions including cancer in the near future.Conclusion:In this review, the spectrum of phytochemical(s) has been summarized for their pharmacological properties and the mechanisms of action, and the possible potential therapeutic applications of this plant against various diseases discussed.

In Vitro and In Vivo Investigations into the Carbene Copper Bromide Anticancer Drug Candidate WBC4

2014 ◽  
Vol 11 (7) ◽  
pp. 825-832 ◽  
Author(s):  
Wolfgang Walther ◽  
Iduna Fichtner ◽  
Frauke Hackenberg ◽  
Wojciech Streciwilk ◽  
Matthias Tacke
Keyword(s):  
Anticancer Drug ◽  
Drug Candidate ◽  
Copper Bromide

MESENCHYMAL TNFR1 EXPRESSION PRESERVES THE COLONIC EPITHELIAL STEM CELL NICHE

2021 ◽  
Vol 27 (Supplement_1) ◽  
pp. S7-S8
Author(s):  
Safina Gadeock ◽  
Cambrian Liu ◽  
Brent Polk
Keyword(s):  
Stem Cell ◽  
Stem Cell Niche ◽  
Mesenchymal Cells ◽  
Epithelial Stem Cells ◽  
Epithelial Stem Cell ◽  
Long Term Treatment ◽  
Lgr5 Expression ◽  
Cell Niche

Abstract Tumor necrosis factor (TNF) is a highly expressed cytokine in inflammatory bowel disease (IBD). Although TNF can induce colonic epithelial dysfunction and apoptosis, recent studies suggest that TNF signalling promotes epithelial wound repair and stem cell function. Here we investigated the role of TNF receptor 1 (TNFR1) in mediating TNF’s effects on colonic epithelial stem cells, integral to mucosal healing in colitis. We demonstrate that Tnfr1-/- mice exhibit loss in Lgr5 expression (-52%, p<0.02; N=6) compared to wildtype (WT) controls. However, the opposite result was found in vitro, wherein murine Tnfr1-/- colonoids demonstrated a significant increase in Lgr5 expression (66%, p<0.007; N=6) compared to WT colonoids. Similarly, human colonoids treated with an anti-TNFR1 antibody also demonstrated an increase in Lgr5 expression, relative to IgG controls. To resolve the contradiction in the in vivo versus in vitro environment, we hypothesized that mesenchymal TNFR1 expression regulates the epithelial stem cell niche. To determine the relationships between these cell types, we co-cultured WT or Tnfr1-/- colonoids with WT or Tnfr1-/- colonic myofibroblasts (CMFs). We found that epithelial Lgr5 expression was significantly higher (by 52%, p<0.05; N=3) when co-cultured with WT compared to TNFR1-/- myofibroblasts. The loss of TNFR1 expression in vivo increases the number of αSMA+ mesenchymal cells by nearly 56% (N=6) but considerably reduces the pericryptal PDGFRα+ cells, suggesting modifications in mesenchymal populations that contribute to the epithelial stem cell niche. Functionally, primary Tnfr1-/--CMFs displayed PI3k (p<0.001; N=3) and MAPK (p<0.01; N=3)-dependent increases in migration, proliferation, and differentiation, but RNA profiling demonstrated by diminished levels of stem cell niche factors, Rspo3 (-80%, p<0.0001; N=6) and Wnt2b (-63%, p<0.008; N=6) compared to WT-CMFs. Supplementation with 50ng recombinant Rspo3 for 5 d to Lgr5-GFP organoids co-cultured with TNFR1-/--CMFs restored Lgr5 expression to wildtype levels. Therefore, TNFR1-mediated TNF signalling in mesenchymal cells promotes their ability to support an epithelial stem cell niche. These results should motivate future studies of the stem cell niche in the context of long-term treatment with anti-TNF therapies.

scholarly journals Long-Acting Risperidone Dual Control System: Preparation, Characterization and Evaluation In Vitro and In Vivo

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1210
Author(s):  
Xieguo Yan ◽  
Shiqiang Wang ◽  
Kaoxiang Sun
Keyword(s):  
Drug Loading ◽  
Entrapment Efficiency ◽  
In Vitro Dissolution ◽  
Dissolution Behavior ◽  
In Vivo Evaluation ◽  
Long Term Treatment ◽  
Long Acting

Schizophrenia, a psychiatric disorder, requires long-term treatment; however, large fluctuations in blood drug concentration increase the risk of adverse reactions. We prepared a long-term risperidone (RIS) implantation system that can stabilize RIS release and established in-vitro and in-vivo evaluation systems. Cumulative release, drug loading, and entrapment efficiency were used as evaluation indicators to evaluate the effects of different pore formers, polymer ratios, porogen concentrations, and oil–water ratios on a RIS implant (RIS-IM). We also built a mathematical model to identify the optimized formulation by stepwise regression. We also assessed the crystalline changes, residual solvents, solubility and stability after sterilization, in-vivo polymer degradation, pharmacokinetics, and tissue inflammation in the case of the optimized formulation. The surface of the optimized RIS microspheres was small and hollow with 134.4 ± 3.5 µm particle size, 1.60 SPAN, 46.7% ± 2.3% implant drug loading, and 93.4% entrapment efficiency. The in-vitro dissolution behavior of RIS-IM had zero-order kinetics and stable blood concentration; no lag time was released for over three months. Furthermore, the RIS-IM was not only non-irritating to tissues but also had good biocompatibility and product stability. Long-acting RIS-IMs with microspheres and film coatings can provide a new avenue for treating schizophrenia.

scholarly journals Macropinocytosis requires Gal-3 in a subset of patient-derived glioblastoma stem cells

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Laetitia Seguin ◽  
Soline Odouard ◽  
Francesca Corlazzoli ◽  
Sarah Al Haddad ◽  
Laurine Moindrot ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Survival ◽  
Small Gtpases ◽  
Molecular Signature ◽  
Carbohydrate Binding ◽  
Pancreatic Cancers ◽  
Galectin 3 ◽  
Pharmacologic Inhibition

AbstractRecently, we involved the carbohydrate-binding protein Galectin-3 (Gal-3) as a druggable target for KRAS-mutant-addicted lung and pancreatic cancers. Here, using glioblastoma patient-derived stem cells (GSCs), we identify and characterize a subset of Gal-3high glioblastoma (GBM) tumors mainly within the mesenchymal subtype that are addicted to Gal-3-mediated macropinocytosis. Using both genetic and pharmacologic inhibition of Gal-3, we showed a significant decrease of GSC macropinocytosis activity, cell survival and invasion, in vitro and in vivo. Mechanistically, we demonstrate that Gal-3 binds to RAB10, a member of the RAS superfamily of small GTPases, and β1 integrin, which are both required for macropinocytosis activity and cell survival. Finally, by defining a Gal-3/macropinocytosis molecular signature, we could predict sensitivity to this dependency pathway and provide proof-of-principle for innovative therapeutic strategies to exploit this Achilles’ heel for a significant and unique subset of GBM patients.

scholarly journals Development of Physiologically Based Pharmacokinetic Model for Orally Administered Fexuprazan in Humans

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 813
Author(s):  
Yoo-Seong Jeong ◽  
Min-Soo Kim ◽  
Nora Lee ◽  
Areum Lee ◽  
Yoon-Jee Chae ◽  
...  
Keyword(s):  
Gastric Acid ◽  
Pbpk Model ◽  
Pbpk Modeling ◽  
Drug Candidate ◽  
Metabolite Formation ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

Fexuprazan is a new drug candidate in the potassium-competitive acid blocker (P-CAB) family. As proton pump inhibitors (PPIs), P-CABs inhibit gastric acid secretion and can be used to treat gastric acid-related disorders such as gastroesophageal reflux disease (GERD). Physiologically based pharmacokinetic (PBPK) models predict drug interactions as pharmacokinetic profiles in biological matrices can be mechanistically simulated. Here, we propose an optimized and validated PBPK model for fexuprazan by integrating in vitro, in vivo, and in silico data. The extent of fexuprazan tissue distribution in humans was predicted using tissue-to-plasma partition coefficients in rats and the allometric relationships of fexuprazan distribution volumes (VSS) among preclinical species. Urinary fexuprazan excretion was minimal (0.29–2.02%), and this drug was eliminated primarily by the liver and metabolite formation. The fraction absorbed (Fa) of 0.761, estimated from the PBPK modeling, was consistent with the physicochemical properties of fexuprazan, including its in vitro solubility and permeability. The predicted oral bioavailability of fexuprazan (38.4–38.6%) was within the range of the preclinical datasets. The Cmax, AUClast, and time-concentration profiles predicted by the PBPK model established by the learning set were accurately predicted for the validation sets.

scholarly journals Preclinical Studies in Anti-Trypanosomatidae Drug Development

2021 ◽  
Vol 14 (7) ◽  
pp. 644
Author(s):  
Cintya Perdomo ◽  
Elena Aguilera ◽  
Ileana Corvo ◽  
Paula Faral-Tello ◽  
Elva Serna ◽  
...  
Keyword(s):  
Rural Communities ◽  
Chagas Disease ◽  
Murine Model ◽  
Mammalian Cells ◽  
Drug Candidate ◽  
Murine Macrophages ◽  
Causative Agents ◽  
Trypanosomatid Parasites

The trypanosomatid parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania are the causative agents of human African trypanosomiasis, Chagas Disease and Leishmaniasis, respectively. These infections primarily affect poor, rural communities in the developing world, and are responsible for trapping sufferers and their families in a disease/poverty cycle. The development of new chemotherapies is a priority given that existing drug treatments are problematic. In our search for novel anti-trypanosomatid agents, we assess the growth-inhibitory properties of >450 compounds from in-house and/or “Pathogen Box” (PBox) libraries against L. infantum, L. amazonensis, L.braziliensis, T. cruzi and T. brucei and evaluate the toxicities of the most promising agents towards murine macrophages. Screens using the in-house series identified 17 structures with activity against and selective toward Leishmania: Compounds displayed 50% inhibitory concentrations between 0.09 and 25 μM and had selectivity index values >10. For the PBox library, ~20% of chemicals exhibited anti-parasitic properties including five structures whose activity against L. infantum had not been reported before. These five compounds displayed no toxicity towards murine macrophages over the range tested with three being active in an in vivo murine model of the cutaneous disease, with 100% survival of infected animals. Additionally, the oral combination of three of them in the in vivo Chagas disease murine model demonstrated full control of the parasitemia. Interestingly, phenotyping revealed that the reference strain responds differently to the five PBox-derived chemicals relative to parasites isolated from a dog. Together, our data identified one drug candidate that displays activity against Leishmania and other Trypanosomatidae in vitro and in vivo, while exhibiting low toxicity to cultured mammalian cells and low in vivo acute toxicity.

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