Ferula sesquiterpenes, ferutinin, galbanic acid and karatavic acid, suppress thymocyte volume regulation and proliferation by blocking the volume-sensitive anion channel

Article

Author: Fayziev, Diyor D ; Rustamova, Sarvinoz I ; Syrov, Vladimir N ; Merzlyak, Petr G ; Inogamov, Utkir K ; Kurbannazarova, Ranokhon Sh ; Tsiferova, Nargiza A ; Khojiboev, Sirojbek A ; Toshtemirova, Gulnoza A ; Sabirov, Ravshan Z

BACKGROUNDT cell development and maturation requires efficient cell volume regulation (CVR) system. Although the molecular basis of CVR is being rapidly elucidated, pharmacology of its key components remains poorly developed. Biopharmaceuticals specifically targeting CVR and its central player, the volume-sensitive outwardly rectifying anion channel (VSOR/VRAC), are necessary to uncover relationships between the channel, CVR and cell proliferation and survival.METHODSThe effects of three Ferula sesquiterpenes, ferutinin, galbanic acid and karatavic acid on the regulatory volume decrease (RVD) of freshly isolated thymocytes by light transmittance, on proliferation of primary cultured thymocytes by cell counting and on the VSOR/VRAC by patch-clamp were evaluated.RESULTSFerutinin, galbanic acid and karatavic acid exerted a profound inhibitory effect on RVD of thymocytes, leading to proliferation arrest. All three sesquiterpenes blocked VSOR/VRAC in a voltage-independent "cork-in-bottle" manner with half-maximal efficiencies comparable to those for RVD. Hill coefficients of 2.0-3.3 imply that positively cooperated binding of 2-3 molecules of the Ferula sesquiterpenes to VSOR/VRAC is required to suppress cell proliferation via inhibition of CVR. The Ferula sesquiterpenes were not apoptogenic, but induced necrotic cell death, which was pronounced for ferutinin and less manifested for galbanic and karatavic acids. VSOR/VRAC and RVD inhibition did not correlate with necrotic cell death induction.CONCLUSIONThe VSOR/VRAC channel blockage by Ferula sesquiterpenes was found to impair the CVR machinery of thymocytes, resulting in suppression of cell proliferation. The necrotic cell death is not a direct consequence of VSOR/VRAC and RVD inhibition, likely involving other cellular pathways.

01 Mar 2025·Value in Health

Use of Real-World Evidence in Health Technology Reassessments Across 6 Health Technology Assessment Agencies

Article

Author: Hanisch, Melinda ; Arena, Patrick Joseph ; Jaksa, Ashley ; Marsico, Mark

OBJECTIVESTo review health technology assessment reassessments (HTARs) and characterize the use of real-world evidence (RWE) in HTARs.METHODSSix agencies were chosen for inclusion in this targeted review: Canadian Agency for Drugs and Technologies in Health, National Institute for Health and Care Excellence, Haute Autorité de Santé, Gemeinsamer Bundesausschuss/Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen, Zorginstituut Nederland, and Pharmaceutical Benefits Advisory Committee. Each agency's assessment was screened to identify their 8 most recent HTARs, which were evaluated to determine if they used RWE. If for a given agency less than half of the screened HTARs used RWE, we identified an additional 4 HTARs for evaluation. For each reassessment, we extracted drug characteristics, HTAR details, initial assessment details, and if/how the RWE was used. Narrative synthesis in conjunction with descriptive statistics were used to characterize the findings.RESULTSWe identified 40 HTARs across the agencies. Over half of the HTARs were for oncology therapies. Additionally, 55% used RWE; these reassessments tended to be for orphan therapies. RWE was submitted to address at least 1 clinical uncertainty, with the most common being related to the primary/secondary endpoints. The majority of RWE studies came from registry data (57.1%). Moreover, the proportion of HTARs resulting in no change in patient access was similar between HTARs that did and did not use RWE. Lastly, no de novo RWE comparative effectiveness studies were identified.CONCLUSIONSOur findings imply that RWE can play a role in addressing uncertainties identified at launch, especially in addition to clinical trial evidence; agencies and sponsors should collaborate/align on evidence needs and study feasibility to ensure RWE can be effectively used in reassessments.

01 Mar 2025·Neuroscience Letters

Galbanic acid delays the development of seizures by modulating the expression of TNFα, IL1β, and TLR4 genes and reducing hippocampal nitrite levels and may be useful in the treatment of epilepsy

Article

Author: Lorigooini, Zahra ; Mardani, Marzieh ; Bijad, Elham ; Amini-Khoei, Hossein ; Shahrani, Diana ; Asgharzadeh, Najmeh ; Ghavamnia, Saeid ; Shahrani, Mohamad ; Korrani, Mehrdad Shahrani

INTRODUCTION AND OBJECTIVEEpilepsy is one of the most common chronic brain disorders worldwide. This study aimed to determine the effect of Galbanic acid on seizures.MATERIALS AND METHODSIn this study, 40 NMRI mice were used and divided into 4 groups. The control group received 10 mg/kg normal saline. Three groups received Galbanic acid at doses of 10, 20, and 40 mg/kg. The positive control group received diazepam with a dose of 10 mg/kg. All injections were made intraperitoneally for one week. Seizures were induced in all mice by injection of 90 mg/kg Pentylenetetrazole (PTZ). Then the latency of seizure onset in each of the experimental groups was recorded. After anesthesia with Ketamine 100 mg/kg and Xylazine 10 mg/kg, blood samples were taken and after decapitation, the hippocampus was isolated and the expression of αTNF-, IL1β, and TLR4 genes in this region was measured.RESULTSGalbanic acid increased the delay in seizure onset, decreased brain and serum nitrite levels, and decreased the expression of αTNF-, IL1β, and TLR4 genes in brain tissue compared to the control group (P < 0.01, p < 0.001).CONCLUSIONGalbanic acid reduced nitrite and the expression of αTNF-, IL1β, and TLR4, leading to a decrease in neuroinflammation and, as a result, a delay in seizure onset in mice.

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Indication	Highest Phase	Country/Location	Organization	Date
Melanoma	Preclinical	Iran	Mashhad University of Medical Sciences	07 Feb 2024

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