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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 -
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 -
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 -
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 -
Drug Metabolism and Disposition: the... Jun 2020It has been reported that microsomal metabolism of ADT (5-(p-methoxyphenyl)-3H-1,2-dithiole-3-thione, anetholedithiolethione, Sulfarlem) and ADO...
It has been reported that microsomal metabolism of ADT (5-(p-methoxyphenyl)-3H-1,2-dithiole-3-thione, anetholedithiolethione, Sulfarlem) and ADO (5-(p-methoxyphenyl)-3H-1,2-dithiole-3-one, anetholedithiolone) led to formation of HS mainly derived from oxidations catalyzed by cytochrome P450-dependent monooxygenases and that ADO was a better HS donor than ADT under these conditions. This article compares the HS donor abilities of 18 dithiolethione and dithiolone analogs of ADT and ADO upon incubation with rat liver microsomes. It shows that, for all the studied compounds, maximal HS formation was obtained after incubation with microsomes and NADPH and that this formation greatly decreased in the presence of -benzylimidazole, a known inhibitor of cytochrome P450. This indicates that HS formation from all the studied compounds requires, as previously observed in the case of ADT and ADO, oxidations catalyzed by cytochrome P450-dependent monooxygenases. Under these conditions, the studied dithiolones were almost always better HS donors than the corresponding dithiolethiones. Interestingly, the best HS yields (up to 75%) were observed in microsomal oxidation of ADO and its close analogs, pCl-Ph-DO and Ph-DO, in the presence of glutathione (GSH), whereas only small amounts of HS were formed in microsomal incubations of those compounds with GSH but in the absence of NADPH. A possible mechanism for this effect of GSH is proposed on the basis of results obtained from reactions of GSH with 5-(p-methoxyphenyl)-3H-1,2-dithiole-3-one-1-sulfoxide, the ADO metabolite involved in HS formation in microsomal oxidation of ADO. SIGNIFICANCE STATEMENT: A series of 18 dithiolethiones and dithiolones were compared for their ability to form hydrogen sulfide (HS) in oxidations catalyzed by microsomal monooxygenases. The studied dithiolones were better HS donors than the corresponding dithiolethiones, and the addition of glutathione to the incubations strongly increased HS formation. A possible mechanism for this effect of GSH is proposed on the basis of results obtained from reactions of GSH with 5-(p-methoxyphenyl)-3H-1,2-dithiole-3-one-1-sulfoxide, a metabolite of the choleretic and sialologic drug Sulfarlem.
Topics: Anethole Trithione; Animals; Aryl Hydrocarbon Hydroxylases; Glutathione; Heterocyclic Compounds, 1-Ring; Hydrogen Sulfide; Microsomes, Liver; Oxidation-Reduction; Rats; Thiones
PubMed: 32234734
DOI: 10.1124/dmd.119.090274 -
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 -
Oxidative Medicine and Cellular... 2020Anethole dithiolethione (ADT) is a marketed drug to treat xerostomia. Its mechanism of action is still unknown, but several preclinical studies indicate that it is able...
AIMS
Anethole dithiolethione (ADT) is a marketed drug to treat xerostomia. Its mechanism of action is still unknown, but several preclinical studies indicate that it is able to increase intracellular glutathione (GSH) and protect against oxidative stress. Here, we investigated the molecular mechanisms behind these effects.
RESULTS
Oral treatment of rats confirmed the GSH enhancing properties of ADT; among the different organs examined in this study, only the kidney showed a significant GSH increase that was already observed at low-dose treatments. The increase in GSH correlated with a decrease in -glutamyltranspeptidase (-GT) activity of the different tissues. and experiments with tubular renal cells and isolated perfused rat kidney showed that the cellular uptake of intact GSH was correlated with the extracellular concentrations of GSH.
CONCLUSION
s. The prominent pharmacological effect of ADT was a marked increase of GSH concentration in the kidney and a decrease of some systemic and renal biomarkers of oxidative stress. In particular, by inhibition of -GT activity, it decreased the production cysteinylglycine, a thiol that has prooxidant effects as the consequence of its autooxidation. The activity of ADT as GSH enhancer in both the circulation and the kidney was long-lasting. All these characteristics make ADT a promising drug to protect the kidney, and in particular proximal tubule cells, from xenobiotic-induced damage.
Topics: Anethole Trithione; Animals; Cell Line; Cysteine; Dipeptides; Disulfides; Glutathione; Humans; Kidney; Kidney Tubules, Proximal; Male; Malondialdehyde; Oxidative Stress; Rats; Rats, Sprague-Dawley; gamma-Glutamyltransferase
PubMed: 33062138
DOI: 10.1155/2020/3562972 -
Drug Metabolism and Disposition: the... Oct 2019The drug anetholedithiolethione (ADT) and its analogs have been extensively used as HS donors. However, the mechanism of HS formation from ADT under biologic conditions...
The drug anetholedithiolethione (ADT) and its analogs have been extensively used as HS donors. However, the mechanism of HS formation from ADT under biologic conditions remains almost completely unknown. This article shows that only small amounts of HS are formed during incubation of ADT and of its metabolite anetholedithiolone (ADO) with rat liver cytosol or with rat liver microsomes (RLM) in the absence of NADPH, indicating that HS formation under these conditions is of hydrolytic origin only to a minor extent. By contrast, much greater amounts of HS are formed upon incubation of ADT and ADO with RLM in the presence of NADPH and dioxygen, with a concomitant formation of HS and -methoxy-acetophenone (pMA). Moreover, HS and pMA formation under those conditions are greatly inhibited in the presence of -benzyl-imidazole indicating the involvement of cytochrome P450-dependent monooxygenases. Mechanistic studies show the intermediate formation of the ADT-derived 1,2-dithiolium cation and of the ADO sulfoxide during microsomal metabolism of ADT and ADO, respectively. This article proposes the first detailed mechanisms for the formation of HS from microsomal metabolism of ADT and ADO in agreement with those data and with previously published data on the metabolism of compounds involving a C=S bond. Finally, this article shows for the first time that ADO is a better HS donor than ADT under those conditions. SIGNIFICANCE STATEMENT: Incubation of anetholedithiolethione (ADT) or its metabolite anetholedithiolone (ADO) in the presence of rat liver microsomes, NADPH, and O leads to HS. This article shows for the first time that this HS formation involves several steps catalyzed by microsomal monooxygenases and that ADO is a better HS donor than ADT. We propose the first detailed mechanisms for the formation of HS from the microsomal metabolism of ADT and ADO.
Topics: Anethole Trithione; Animals; Anisoles; Cytochrome P-450 Enzyme System; Cytosol; Hydrogen Sulfide; Imidazoles; Microsomes, Liver; NADP; Rats
PubMed: 31213461
DOI: 10.1124/dmd.119.087205