scholarly journals Modulating Innate and Adaptive Immunity by (R)-Roscovitine: Potential Therapeutic Opportunity in Cystic Fibrosis

2016 ◽  
Vol 8 (4) ◽  
pp. 330-349 ◽  
Author(s):  
Laurent Meijer ◽  
Deborah J. Nelson ◽  
Vladimir Riazanski ◽  
Aida G. Gabdoulkhakova ◽  
Geneviève Hery-Arnaud ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Therapeutic Agent ◽  
Drug Candidate ◽  
Innate And Adaptive Immunity ◽  
Animal Pain ◽  
Pain Models ◽  
Therapeutic Opportunity ◽  
Induction Of Apoptosis ◽  
Preclinical Safety ◽  
Phase I And Ii

(R)-Roscovitine, a pharmacological inhibitor of kinases, is currently in phase II clinical trial as a drug candidate for the treatment of cancers, Cushing's disease and rheumatoid arthritis. We here review the data that support the investigation of (R)-roscovitine as a potential therapeutic agent for the treatment of cystic fibrosis (CF). (R)-Roscovitine displays four independent properties that may favorably combine against CF: (1) it partially protects F508del-CFTR from proteolytic degradation and favors its trafficking to the plasma membrane; (2) by increasing membrane targeting of the TRPC6 ion channel, it rescues acidification in phagolysosomes of CF alveolar macrophages (which show abnormally high pH) and consequently restores their bactericidal activity; (3) its effects on neutrophils (induction of apoptosis), eosinophils (inhibition of degranulation/induction of apoptosis) and lymphocytes (modification of the Th17/Treg balance in favor of the differentiation of anti-inflammatory lymphocytes and reduced production of various interleukins, notably IL-17A) contribute to the resolution of inflammation and restoration of innate immunity, and (4) roscovitine displays analgesic properties in animal pain models. The fact that (R)-roscovitine has undergone extensive preclinical safety/pharmacology studies, and phase I and II clinical trials in cancer patients, encourages its repurposing as a CF drug candidate.

Identification of 2-Fluoropalmitic Acid as a Potential Therapeutic Agent Against Glioblastoma

2020 ◽  
Vol 26 (36) ◽  
pp. 4675-4684 ◽  
Author(s):  
Shabierjiang Jiapaer ◽  
Takuya Furuta ◽  
Yu Dong ◽  
Tomohiro Kitabayashi ◽  
Hemragul Sabit ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Drug Screening ◽  
Therapeutic Agent ◽  
Gelatin Zymography ◽  
Therapeutic Agents ◽  
Drug Candidate ◽  
Potential Therapeutic Agent ◽  
Sphere Formation ◽  
Improve Patient

Background: Glioblastomas (GBMs) are aggressive malignant brain tumors. Although chemotherapy with temozolomide (TMZ) can extend patient survival, most patients eventually demonstrate resistance. Therefore, novel therapeutic agents that overcome TMZ chemoresistance are required to improve patient outcomes. Purpose: Drug screening is an efficient method to find new therapeutic agents from existing drugs. In this study, we explored a novel anti-glioma agent by drug screening and analyzed its function with respect to GBM treatment for future clinical applications. Methods: Drug libraries containing 1,301 diverse chemical compounds were screened against two glioma stem cell (GSC) lines for drug candidate selection. The effect of selected agents on GSCs and glioma was estimated through viability, proliferation, sphere formation, and invasion assays. Combination therapy was performed to assess its ability to enhance TMZ cytotoxicity against GBM. To clarify the mechanism of action, we performed methylation-specific polymerase chain reaction, gelatin zymography, and western blot analysis. Results: The acyl-CoA synthetase inhibitor 2-fluoropalmitic acid (2-FPA) was selected as a candidate anti-glioma agent. 2-FPA suppressed the viability and stem-like phenotype of GSCs. It also inhibited proliferation and invasion of glioma cell lines. Combination therapy of 2-FPA with TMZ synergistically enhanced the efficacy of TMZ. 2-FPA suppressed the expression of phosphor-ERK, CD133, and SOX-2; reduced MMP-2 activity; and increased methylation of the MGMT promoter. Conclusion: 2-FPA was identified as a potential therapeutic agent against GBM. To extend these findings, physiological studies are required to examine the efficacy of 2-FPA against GBM in vivo.

scholarly journals Photocontrolled apoptosis induction using precursor miR-664a and an RNA carrier-conjugated with photosensitizer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kazunori Watanabe ◽  
Tomoko Nawachi ◽  
Ruriko Okutani ◽  
Takashi Ohtsuki
Keyword(s):  
Cancer Therapy ◽  
Cell Types ◽  
Drug Candidate ◽  
Apoptosis Induction ◽  
Delivery Method ◽  
Apoptotic Pathway ◽  
Photochemical Internalization ◽  
Therapeutic Uses ◽  
Induction Of Apoptosis ◽  
Nucleic Acid Drug

AbstractMethods to spatially induce apoptosis are useful for cancer therapy. To control the induction of apoptosis, methods using light, such as photochemical internalization (PCI), have been developed. We hypothesized that photoinduced delivery of microRNAs (miRNAs) that regulate apoptosis could spatially induce apoptosis. In this study, we identified pre-miR-664a as a novel apoptosis-inducing miRNA via mitochondrial apoptotic pathway. Further, we demonstrated the utility of photoinduced cytosolic dispersion of RNA (PCDR), which is an intracellular RNA delivery method based on PCI. Indeed, apoptosis is spatially regulated by pre-miR-664a and PCDR. In addition, we found that apoptosis induced by pre-miR-664a delivered by PCDR was more rapid than that by lipofection. These results suggest that pre-miR-664a is a nucleic acid drug candidate for cancer therapy and PCDR and pre-miR-664a-based strategies have potential therapeutic uses for diseases affecting various cell types.

scholarly journals Analgesic Interaction Between Morphine with Fentanyl In Experimental Murine Pain

2021 ◽  
Author(s):  
Hugo F Miranda ◽  
Viviana Noriega ◽  
Fernando Sierralta ◽  
Ramon Sotomayor-Zarate ◽  
Juan Carlos Prieto
Keyword(s):  
Phase I ◽  
Dose Response ◽  
Multimodal Treatment ◽  
Binding Capacity ◽  
Tail Flick ◽  
Pharmacological Interaction ◽  
Isobolographic Analysis ◽  
Antinociceptive Action ◽  
Animal Pain ◽  
Pain Models

Abstract Opioids are among the most effective pain relievers available, however multimodal antinociception between opioids, has not been extensively studied in diverse animal pain models.In this study the pharmacological interaction of morphine with fentanyl was evaluated in different murine pain models by means of isobolographic analysis. In control animals, morphine and fentanyl produced a dose-related antinociceptive action in the murine assays and the rank of potency was: formalin hind paw phase I > formalin phase II > tail flick. Coadministration of morphine with fentanyl, in a fixed relation 1:1 of their ED50, produces a dose response in all tests and the isobologram resulted in synergism. Fentanyl was more effective than morphine which could be explained according the suggestion that opioids could be acting through other targets, with different binding capacity thru the regulation or activation of non-opioid receptors. Co-administration of morphine with fentanyl induces synergism in all murine trials, confirming the antinociceptive capacity of both opioids which would constitute a promisory idea to multimodal treatment of pain.

Animal pain models

2004 ◽  
Vol 5 (3) ◽  
pp. S17
Author(s):  
V. Smith ◽  
C. Beyer ◽  
M. Brandt
Keyword(s):  
Animal Pain ◽  
Pain Models

Animal pain models

2004 ◽  
Vol 5 (3) ◽  
pp. S17
Author(s):  
P. Robinson ◽  
K. Smith ◽  
A. Loescher ◽  
F. Boissonade ◽  
S. Atkins ◽  
...  
Keyword(s):  
Animal Pain ◽  
Pain Models

230 TAPENTADOL: EFFICACY PROFILE OF A NOVEL CENTRALLY ACTIVE ANALGESIC WITH A DUAL MODE OF ACTION IN ANIMAL PAIN MODELS

2006 ◽  
Vol 10 (S1) ◽  
pp. S62c-S62 ◽  
Author(s):  
J. Vry ◽  
T.M. Tzschentke ◽  
T. Christoph ◽  
M. Méen ◽  
B. Kögel ◽  
...  
Keyword(s):  
Mode Of Action ◽  
Dual Mode ◽  
Animal Pain ◽  
Pain Models ◽  
Efficacy Profile

Preclinical Safety Assessment of Drug Candidate-Induced Pancreatic Toxicity

2016 ◽  
pp. 242-260
Author(s):  
Karrie A. Brenneman ◽  
Shashi K. Ramaiah ◽  
Lauren M. Gauthier
Keyword(s):  
Safety Assessment ◽  
Drug Candidate ◽  
Pancreatic Toxicity ◽  
Preclinical Safety

scholarly journals GABAPENTIN IS EFFECTIVE IN VISCERAL & BIPHASIC ANIMAL PAIN MODELS: AN EXPERIMENTAL STUDY

2015 ◽  
Vol 4 (5) ◽  
pp. 276-279
Author(s):  
Arunim swarup ◽  
Dhanesh Kumar ◽  
Saurabh Kansal ◽  
Priti Sinha
Keyword(s):  
Experimental Study ◽  
Animal Pain ◽  
Pain Models
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