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Acta Pharmacologica Sinica Apr 2022Intracerebral hemorrhage (ICH) is a devastating disease, in which neuroinflammation substantially contributes to brain injury. Uncoupling protein 2 (UCP2) is a member of...
Intracerebral hemorrhage (ICH) is a devastating disease, in which neuroinflammation substantially contributes to brain injury. Uncoupling protein 2 (UCP2) is a member of the mitochondrial anion carrier family, which uncouples oxidative phosphorylation from ATP synthesis by facilitating proton leak across the mitochondrial inner membrane. UCP2 has been reported to modulate inflammation. In this study we investigated whether and how UCP2 modulated neuroinflammation through microglia/macrophages following ICH in vitro and in vivo. We used an in vitro neuroinflammation model in murine BV2 microglia to mimic microglial activation following ICH. ICH in vivo model was established in mice through collagenase infusion into the left striatum. ICH mice were treated with anetholetrithione (ADT, 50 mg· kg ·d, ip) or the classical protonophoric uncoupler FCCP (injected into hemorrhagic striatum). We showed that the expression and mitochondrial location of microglial UCP2 were not changed in both in vitro and in vivo ICH models. Knockdown of UCP2 exacerbated neuroinflammation in BV2 microglia and mouse ICH models, suggesting that endogenous UCP2 inhibited neuroinflammation and therefore played a protective role following ICH. ADT enhanced mitochondrial ROS production thus inducing mitochondrial uncoupling and activating UCP2 in microglia. ADT robustly suppressed neuroinflammation, attenuated brain edema and improved neurological deficits following ICH, and these effects were countered by striatal knockdown of UCP2. ADT enhanced AMP-activated protein kinase (AMPK) activation in the hemorrhagic brain, which was abrogated by striatal knockdown of UCP2. Moreover, striatal knockdown of AMPK abolished the suppression of neuroinflammation by ADT following ICH. On the other hand, FCCP-induced mitochondrial uncoupling was independent of UCP2 in microglia; and striatal knockdown of UCP2 did not abrogate the suppression of neuroinflammation by FCCP in ICH mice. In conclusion, the uncoupling activity is essential for suppression of neuroinflammation by UCP2. We prove for the first time the concept that activators of endogenous UCP2 such as anetholetrithione are a new class of uncouplers with translational significance.
Topics: Anethole Trithione; Animals; Cerebral Hemorrhage; Mice; Microglia; Neuroinflammatory Diseases; Uncoupling Protein 2
PubMed: 34183754
DOI: 10.1038/s41401-021-00698-1 -
ACS Omega Mar 2020Anethol trithione (ATT) has a wide range of physiological activities, but its use is limited due to its poor water solubility. To improve the solubility of ATT, we...
Anethol trithione (ATT) has a wide range of physiological activities, but its use is limited due to its poor water solubility. To improve the solubility of ATT, we synthesized and characterized a novel phosphate prodrug (ATXP) relying on the availability of the hydroxy group in 5-(4-hydroxyphenyl)-3-1,2-dithiole3-thione (ATX), which was transformed from ATT rapidly and extensively in vivo. Our results showed that ATXP significantly improved drug solubility. ATXP was rapidly converted to ATX and reached a maximum plasma concentration with a of approximately 5 min after intravenous (iv) administration. Furthermore, after the oral administration of ATXP, the was 3326.30 ± 566.50 ng/mL, which was approximately 5-fold greater than that of the parent drug form, indicating that ATXP has greater absorption than that of ATT. Additionally, the oral phosphate prodrug ATXP increased the ATX in the area under the plasma concentration vs time curves (AUC = 3927.40 ± 321.50 and AUC = 4579.0 ± 756.30), making its use in practical applications more meaningful. Finally, compared to the vehicle, ATXP was confirmed to maintain the bioactivity of the parent drug for a significant reduction in infarct volume 24 h after reperfusion. Based on these findings, the phosphate prodrug ATXP is a potentially useful water-soluble prodrug with improved pharmacokinetic properties.
PubMed: 32175506
DOI: 10.1021/acsomega.9b04129 -
Macromolecular Bioscience Nov 2015Prodrug micelles carrying 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADT-OH), a compound possessing chemopreventive properties, are prepared from amphiphilic block...
Prodrug micelles carrying 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADT-OH), a compound possessing chemopreventive properties, are prepared from amphiphilic block copolymers linking ADT-OH via an ester bond using glycine (PAM-PGlyADT) and isoleucine linkers (PAM-PIleADT). The release of ADT-OH from the PAM-PIleADT micelles is much slower than the PAM-PGlyADT micelles. The PAM-PGlyADT micelles show comparable toxicity with ADT-OH in different cancer cell lines, whereas the PAM-PIleADT micelles are not toxic up to 400 µM. This ADT-ester prodrug micelle approach enables to modulate the release rate of ADT-OH and thus might find application in cancer therapy and prevention.
Topics: Anethole Trithione; Antineoplastic Agents; Humans; Hydrolysis; Micelles; Neoplasms; Prodrugs
PubMed: 26102371
DOI: 10.1002/mabi.201500156 -
Nature Communications Aug 2022Inefficient tumour treatment approaches often cause fatal tumour metastases. Here, we report a biomimetic multifunctional nanoplatform explicitly engineered with a...
Inefficient tumour treatment approaches often cause fatal tumour metastases. Here, we report a biomimetic multifunctional nanoplatform explicitly engineered with a Co-based metal organic framework polydopamine heterostructure (MOF-PDA), anethole trithione (ADT), and a macrophage membrane. Co-MOF degradation in the tumour microenvironment releases Co, which results in the downregulation of HSP90 expression and the inhibition of cellular heat resistance, thereby improving the photothermal therapy effect of PDA. HS secretion after the enzymatic hydrolysis of ADT leads to high-concentration gas therapy. Moreover, ADT changes the balance between nicotinamide adenine dinucleotide/flavin adenine dinucleotide (NADH/FAD) during tumour glycolysis. ATP synthesis is limited by NADH consumption, which triggers a certain degree of tumour growth inhibition and results in starvation therapy. Potentiated 2D/3D autofluorescence imaging of NADH/FAD is also achieved in liquid nitrogen and employed to efficiently monitor tumour therapy. The developed biomimetic nanoplatform provides an approach to treat orthotopic tumours and inhibit metastasis.
Topics: Biomimetic Materials; Biomimetics; Energy Metabolism; Flavin-Adenine Dinucleotide; Humans; Hypothermia; NAD; Neoplasms; Tumor Microenvironment
PubMed: 35931744
DOI: 10.1038/s41467-022-32349-2 -
Drug Metabolism and Disposition: the... Oct 2018A study of the metabolism of anethole dithiolethione (ADT, 5-(p-methoxyphenyl)-3-1,2-dithiole-3-thione) by rat and human liver microsomes showed the formation of the...
Metabolism of Anethole Dithiolethione by Rat and Human Liver Microsomes: Formation of Various Products Deriving from Its -Demethylation and -Oxidation. Involvement of Cytochromes P450 and Flavin Monooxygenases in These Pathways.
A study of the metabolism of anethole dithiolethione (ADT, 5-(p-methoxyphenyl)-3-1,2-dithiole-3-thione) by rat and human liver microsomes showed the formation of the corresponding -oxide and the -oxide of desmethyl-ADT (dmADT, 5-(p-hydroxyphenyl)-3-1,2-dithiole-3-thione), and of p-methoxy-acetophenone (pMA) and p-hydroxy-acetophenone (pHA), in addition to the previously described metabolites, dmADT, anethole dithiolone (ADO, 5-(p-methoxyphenyl)-3-1,2-dithiole-3-one) and its demethylated derivative dmADO [5-(p-hydroxyphenyl)-3-1,2-dithiole-3-one]. The microsomal metabolism of ADO under identical conditions led to dmADO and to pMA and pHA. The metabolites of ADT derive from two competing oxidative pathways: an -demethylation catalyzed by cytochromes P450 and an -oxidation mainly catalyzed by flavin-dependent monooxygenases (FMO) and, to a minor extent, by CYP enzymes. The most active human CYP enzymes for ADT demethylation appeared to be CYP1A1, 1A2, 1B1, 2C9, 2C19, and 2E1. ADT -oxidation is catalyzed by FMO 1 and 3, and to a minor extent by CYP enzymes such as CYP3A4.
Topics: Anethole Trithione; Animals; Cytochrome P-450 Enzyme System; Demethylation; FMN Reductase; Humans; Male; Metabolomics; Microsomes, Liver; Mixed Function Oxygenases; Oxidation-Reduction; Rats; Rats, Sprague-Dawley
PubMed: 30018103
DOI: 10.1124/dmd.118.082545 -
Bioorganic & Medicinal Chemistry Letters Sep 2022Oxidative stress and inflammation were considered to be the major mechanisms in liver damage caused by clofibrate (CF). In order to obtain lipid-lowering drugs with less...
Oxidative stress and inflammation were considered to be the major mechanisms in liver damage caused by clofibrate (CF). In order to obtain lipid-lowering drugs with less liver damage, the structure of clofibrate was optimized by O-desmethyl anetholtrithione and got the target compound clofibrate-O-desmethyl anetholtrithione (CF-ATT). CF-ATT significantly reduced the levels of plasma triglycerides (TG), total cholesterol (TC) in hyperlipidemia mice induced by Triton WR-1339. In addition, CF-ATT has a significantly protective effect on the liver compared with CF. The liver weight and liver coefficient were reduced. The hepatic function indexes were also decreased, such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP). Histopathological examination of the liver revealed that inflammatory cell infiltration, nuclear degeneration, cytoplasmic loosening and hepatocyte necrosis were ameliorated by administration with CF-ATT. The hepatoprotective mechanism showed that CF-ATT significantly up-regulated Nrf2 and HO-1 protein expression and down-regulated p-NF-κB P65 expression in the liver. CF-ATT has obviously antioxidant and anti-inflammatory activity. These findings suggested that CF-ATT has significant hypolipidemia activity and exact hepatoprotective effect possibly through the Nrf2/NF-κB-mediated signal pathway.
Topics: Anethole Trithione; Animals; Antioxidants; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Clofibrate; Liver; Liver Diseases; Mice; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress
PubMed: 35697180
DOI: 10.1016/j.bmcl.2022.128844 -
Nitric Oxide : Biology and Chemistry Apr 2015H2S donor molecules have the potential to be viable therapeutic agents. The aim of this current study was (i) to investigate the effects of a novel triphenylphosphonium...
Effects of AP39, a novel triphenylphosphonium derivatised anethole dithiolethione hydrogen sulfide donor, on rat haemodynamic parameters and chloride and calcium Cav3 and RyR2 channels.
H2S donor molecules have the potential to be viable therapeutic agents. The aim of this current study was (i) to investigate the effects of a novel triphenylphosphonium derivatised dithiolethione (AP39), in the presence and absence of reduced nitric oxide bioavailability and (ii) to determine the effects of AP39 on myocardial membrane channels; CaV3, RyR2 and Cl(-). Normotensive, L-NAME- or phenylephrine-treated rats were administered Na2S, AP39 or control compounds (AP219 and ADT-OH) (0.25-1 µmol kg(-1)i.v.) and haemodynamic parameters measured. The involvement of membrane channels T-type Ca(2+) channels CaV3.1, CaV3.2 and CaV3.3 as well as Ca(2+) ryanodine (RyR2) and Cl(-) single channels derived from rat heart sarcoplasmic reticulum were also investigated. In anaesthetised Wistar rats, AP39 (0.25-1 µmol kg(-1) i.v) transiently decreased blood pressure, heart rate and pulse wave velocity, whereas AP219 and ADT-OH and Na2S had no significant effect. In L-NAME treated rats, AP39 significantly lowered systolic blood pressure for a prolonged period, decreased heart rate and arterial stiffness. In electrophysiological studies, AP39 significantly inhibited Ca(2+) current through all three CaV3 channels. AP39 decreased RyR2 channels activity and increased conductance and mean open time of Cl(-) channels. This study suggests that AP39 may offer a novel therapeutic opportunity in conditions whereby (•)NO and H2S bioavailability are deficient such as hypertension, and that CaV3, RyR2 and Cl(-) cardiac membrane channels might be involved in its biological actions.
Topics: Anethole Trithione; Animals; Blood Pressure; Caveolin 3; Hydrogen Sulfide; NG-Nitroarginine Methyl Ester; Organophosphorus Compounds; Phenylephrine; Pulse Wave Analysis; Rats; Rats, Wistar; Ryanodine Receptor Calcium Release Channel
PubMed: 25555533
DOI: 10.1016/j.niox.2014.12.012 -
The American Journal of Pathology Jan 2024Benign prostate hyperplasia (BPH) is caused by the nonmalignant enlargement of the transition zone of the prostate gland, leading to lower urinary tract symptoms....
Benign prostate hyperplasia (BPH) is caused by the nonmalignant enlargement of the transition zone of the prostate gland, leading to lower urinary tract symptoms. Although current medical treatments are unsatisfactory in many patients, the limited understanding of the mechanisms driving disease progression prevents the development of alternative therapeutic strategies. The probasin-prolactin (Pb-PRL) transgenic mouse recapitulates many histopathological features of human BPH. Herein, these alterations parallel urodynamic disturbance reminiscent of lower urinary tract symptoms. Single-cell RNA-sequencing analysis of Pb-PRL mouse prostates revealed that their epithelium mainly includes low-androgen signaling cell populations analogous to Club/Hillock cells enriched in the aged human prostate. These intermediate cells are predicted to result from the reprogramming of androgen-dependent luminal cells. Pb-PRL mouse prostates exhibited increased vulnerability to oxidative stress due to reduction of antioxidant enzyme expression. One-month treatment of Pb-PRL mice with anethole trithione (ATT), a specific inhibitor of mitochondrial ROS production, reduced prostate weight and voiding frequency. In human BPH-1 epithelial cells, ATT decreased mitochondrial metabolism, cell proliferation, and stemness features. ATT prevented the growth of organoids generated by sorted Pb-PRL basal and LSC cells, the two major BPH-associated, androgen-independent epithelial cell compartments. Taken together, these results support cell plasticity as a driver of BPH progression and therapeutic resistance to androgen signaling inhibition, and identify antioxidant therapy as a promising treatment of BPH.
Topics: Male; Humans; Mice; Animals; Aged; Androgens; Prostate; Prostatic Hyperplasia; Antioxidants; Cell Plasticity; Hyperplasia; Lead; Mice, Transgenic; Prolactin; Epithelial Cells; Lower Urinary Tract Symptoms
PubMed: 37827216
DOI: 10.1016/j.ajpath.2023.09.010 -
Nanoscale Oct 2019To address the thereapeutic challenges in clinical cancer treatment and guarantee efficient and rapid intracellular delivery of drugs while evading efflux and...
To address the thereapeutic challenges in clinical cancer treatment and guarantee efficient and rapid intracellular delivery of drugs while evading efflux and chemotherapy resistance, herein, we designed a liposomal nanostructure equipped with superparamagnetic iron oxide nanoparticles (SPIOs) and anethole trithione (ADT, a hydrogen sulfide (HS) donor drug). At first, by spatially focused manipulation of the external static magnetic field (SMF), the SPIOs and ADT-loaded liposomes (SPIOs-ADT-LPs) could rapidly overcome the cell membrane barrier to enter the cytoplasm, which could be imaged by magnetic resonance imaging (MRI). Sequentially, the intracellular release of ADT drugs was triggered by enzymatic catalysis to generate acoustic-sensitive HS gas. At the beginning, during the production of HS at low concentrations, the cell membrane could be permeabilized to further increase the cellular uptake of SPIOs-ADT-LPs. The continued generation of HS gas bubbles, imaged by ultrasound (US) imaging, further enhanced the intracellular hydrostatic pressure (above 320 pN per cell) to physically unfold the cytoskeleton, leading to complete cell death. The magneto-acoustic approach based on SPIO-ADT-LPs as intracellular bubble reactors leads to improved anticancer cell efficacy and has potential applications for novel MRI/US dual image-guided bubble bursting of cancer cells.
Topics: Anethole Trithione; Hep G2 Cells; Humans; Hydrogen Sulfide; Liposomes; Magnetic Fields; Magnetic Resonance Imaging; Microbubbles; Nanoparticles; Neoplasms; Ultrasonography
PubMed: 31596307
DOI: 10.1039/c9nr07021d -
BMC Medical Research Methodology Jun 2022Real-life data consist of exhaustive data which are not subject to selection bias. These data enable to study drug-safety profiles but are underused because of their...
A data-driven pipeline to extract potential adverse drug reactions through prescription, procedures and medical diagnoses analysis: application to a cohort study of 2,010 patients taking hydroxychloroquine with an 11-year follow-up.
CONTEXT
Real-life data consist of exhaustive data which are not subject to selection bias. These data enable to study drug-safety profiles but are underused because of their temporality, necessitating complex models (i.e., safety depends on the dose, timing, and duration of treatment). We aimed to create a data-driven pipeline strategy that manages the complex temporality of real-life data to highlight the safety profile of a given drug.
METHODS
We proposed to apply the weighted cumulative exposure (WCE) statistical model to all health events occurring after a drug introduction (in this paper HCQ) and performed bootstrap to select relevant diagnoses, drugs and interventions which could reflect an adverse drug reactions (ADRs). We applied this data-driven pipeline on a French national medico-administrative database to extract the safety profile of hydroxychloroquine (HCQ) from a cohort of 2,010 patients.
RESULTS
The proposed method selected eight drugs (metopimazine, anethole trithione, tropicamide, alendronic acid & colecalciferol, hydrocortisone, chlormadinone, valsartan and tixocortol), twelve procedures (six ophthalmic procedures, two dental procedures, two skin lesions procedures and osteodensitometry procedure) and two medical diagnoses (systemic lupus erythematous, unspecified and discoid lupus erythematous) to be significantly associated with HCQ exposure.
CONCLUSION
We provide a method extracting the broad spectrum of diagnoses, drugs and interventions associated to any given drug, potentially highlighting ADRs. Applied to hydroxychloroquine, this method extracted among others already known ADRs.
Topics: Antirheumatic Agents; Cohort Studies; Drug-Related Side Effects and Adverse Reactions; Follow-Up Studies; Humans; Hydroxychloroquine; Prescriptions
PubMed: 35676635
DOI: 10.1186/s12874-022-01628-3