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Nature Communications Nov 2022Nonalcoholic steatohepatitis (NASH) has been linked with the gut-liver axis. Here, we investigate the potential for repurposing disulfiram (DSF), a drug commonly used to... (Clinical Trial)
Clinical Trial
Nonalcoholic steatohepatitis (NASH) has been linked with the gut-liver axis. Here, we investigate the potential for repurposing disulfiram (DSF), a drug commonly used to treat chronic alcoholism, for NASH. Using a mouse model, we show that DSF ameliorates NASH in a gut microbiota-dependent manner. DSF modulates the gut microbiota and directly inhibits the growth of Clostridium. Administration of Clostridium abolishes the ameliorating effects of DSF on NASH. Mechanistically, DSF reduces Clostridium-mediated 7α-dehydroxylation activity to suppress secondary bile acid biosynthesis, which in turn activates hepatic farnesoid X receptor signaling to ameliorate NASH. To assess the effect of DSF on human gut microbiota, we performed a self-controlled clinical trial (ChiCTR2100048035), including 23 healthy volunteers who received 250 mg-qd DSF for 7 days. The primary objective outcomes were to assess the effects of the intervention on the diversity, composition and functional profile of gut microbiota. The pilot study shows that DSF also reduces Clostridium-mediated 7α-dehydroxylation activity. All volunteers tolerated DSF well and there were no serious adverse events in the 7-day follow-up period. Transferring fecal microbiota obtained from DSF-treated humans into germ-free mice ameliorates NASH. Collectively, the observations of similar ameliorating effects of DSF on mice and humans suggest that DSF ameliorates NASH by modulating the gut microbiota and bile acid metabolism.
Topics: Humans; Bile Acids and Salts; Clostridium; Disulfiram; Gastrointestinal Microbiome; Liver; Non-alcoholic Fatty Liver Disease; Pilot Projects
PubMed: 36369291
DOI: 10.1038/s41467-022-34671-1 -
International Journal of Molecular... Jan 2022Dithiocarbamate ligands have the ability to form stable complexes with transition metals, and this chelating ability has been utilized in numerous applications. The... (Review)
Review
Dithiocarbamate ligands have the ability to form stable complexes with transition metals, and this chelating ability has been utilized in numerous applications. The complexes have also been used to synthesize other useful compounds. Here, the up-to-date applications of dithiocarbamate ligands and complexes are extensively discussed. Some of these are their use as enzyme inhibitor and treatment of HIV and other diseases. The application as anticancer, antimicrobial, medical imaging and anti-inflammatory agents is examined. Moreover, the application in the industry as vulcanization accelerator, froth flotation collector, antifouling, coatings, lubricant additives and sensors is discussed. The various ways in which they have been employed in synthesis of other compounds are highlighted. Finally, the agricultural uses and remediation of heavy metals via dithiocarbamate compounds are comprehensively discussed.
Topics: Anti-Bacterial Agents; Enzyme Inhibitors; Humans; Ligands; Metals, Heavy; Thiocarbamates; Transition Elements
PubMed: 35163241
DOI: 10.3390/ijms23031317 -
Molecules (Basel, Switzerland) Jan 2020Interest in the synthesis of Bi(III) and Sb(III) dithiocarbamate complexes is on the rise, and this has been attributed to their wide structural diversity and their... (Review)
Review
Interest in the synthesis of Bi(III) and Sb(III) dithiocarbamate complexes is on the rise, and this has been attributed to their wide structural diversity and their interesting application as biological agents and in solid state/materials chemistry. The readily available binding sites of the two sulphur atoms within the dithiocarbamate moiety in the complexes confers a wide variety of geometry and interactions that often leads to supramolecular assemblies. Although none of the bismuth or antimony metals are known to play any natural biological function, their dithiocarbamate complexes, however, have proven very useful as antibacterial, antileishmanial, anticancer, and antifungal agents. The dithiocarbamate ligands modulate the associated toxicity of the metals, especially antimony, since bismuth is known to be benign, allowing the metal ion to get to the targeted sites; hence, making it less available for side and other damaging reactions. This review presents a concise chemistry and some known biological potentials of their trivalent dithiocarbamate complexes.
Topics: Animals; Anti-Bacterial Agents; Antifungal Agents; Antimony; Antineoplastic Agents; Antiprotozoal Agents; Bismuth; Coordination Complexes; Humans; Models, Chemical; Thiocarbamates
PubMed: 31940910
DOI: 10.3390/molecules25020305 -
International Journal of Molecular... Mar 2022Tricyclodecan-9-yl xanthogenate (D609) is a synthetic tricyclic compound possessing a xanthate group. This xanthogenate compound is known for its diverse pharmacological... (Review)
Review
Tricyclodecan-9-yl xanthogenate (D609) is a synthetic tricyclic compound possessing a xanthate group. This xanthogenate compound is known for its diverse pharmacological properties. Over the last three decades, many studies have reported the biological activities of D609, including antioxidant, antiapoptotic, anticholinergic, anti-tumor, anti-inflammatory, anti-viral, anti-proliferative, and neuroprotective activities. Its mechanism of action is extensively attributed to its ability to cause the competitive inhibition of phosphatidylcholine (PC)-specific phospholipase C (PC-PLC) and sphingomyelin synthase (SMS). The inhibition of PCPLC or SMS affects secondary messengers with a lipidic nature, i.e., 1,2-diacylglycerol (DAG) and ceramide. Various in vitro/in vivo studies suggest that PCPLC and SMS inhibition regulate the cell cycle, block cellular proliferation, and induce differentiation. D609 acts as a pro-inflammatory cytokine antagonist and diminishes Aβ-stimulated toxicity. PCPLC enzymatic activity essentially requires Zn, and D609 might act as a potential chelator of Zn, thereby blocking PCPLC enzymatic activity. D609 also demonstrates promising results in reducing atherosclerotic plaque formation, post-stroke cerebral infarction, and cancer progression. The present compilation provides a comprehensive mechanistic insight into D609, including its chemistry, mechanism of action, and regulation of various pharmacological activities.
Topics: Bridged-Ring Compounds; Norbornanes; Thiocarbamates; Thiones; Type C Phospholipases
PubMed: 35328726
DOI: 10.3390/ijms23063305 -
CNS Neuroscience & Therapeutics Dec 2023Many studies have recently highlighted the role of photobiomodulation (PBM) in neuropathic pain (NP) relief after spinal cord injury (SCI), suggesting that it may be an...
BACKGROUND
Many studies have recently highlighted the role of photobiomodulation (PBM) in neuropathic pain (NP) relief after spinal cord injury (SCI), suggesting that it may be an effective way to relieve NP after SCI. However, the underlying mechanisms remain unclear. This study aimed to determine the potential mechanisms of PBM in NP relief after SCI.
METHODS
We performed systematic observations and investigated the mechanism of PBM intervention in NP in rats after SCI. Using transcriptome sequencing, we screened CXCL10 as a possible target molecule for PBM intervention and validated the results in rat tissues using reverse transcription-polymerase chain reaction and western blotting. Using immunofluorescence co-labeling, astrocytes and microglia were identified as the cells responsible for CXCL10 expression. The involvement of the NF-κB pathway in CXCL10 expression was verified using inhibitor pyrrolidine dithiocarbamate (PDTC) and agonist phorbol-12-myristate-13-acetate (PMA), which were further validated by an in vivo injection experiment.
RESULTS
Here, we demonstrated that PBM therapy led to an improvement in NP relative behaviors post-SCI, inhibited the activation of microglia and astrocytes, and decreased the expression level of CXCL10 in glial cells, which was accompanied by mediation of the NF-κB signaling pathway. Photobiomodulation inhibit the activation of the NF-κB pathway and reduce downstream CXCL10 expression. The NF-κB pathway inhibitor PDTC had the same effect as PBM on improving pain in animals with SCI, and the NF-κB pathway promoter PMA could reverse the beneficial effect of PBM.
CONCLUSIONS
Our results provide new insights into the mechanisms by which PBM alleviates NP after SCI. We demonstrated that PBM significantly inhibited the activation of microglia and astrocytes and decreased the expression level of CXCL10. These effects appear to be related to the NF-κB signaling pathway. Taken together, our study provides evidence that PBM could be a potentially effective therapy for NP after SCI, CXCL10 and NF-kB signaling pathways might be critical factors in pain relief mediated by PBM after SCI.
Topics: Animals; Rats; Neuralgia; NF-kappa B; Spinal Cord; Spinal Cord Injuries; Thiocarbamates
PubMed: 37475184
DOI: 10.1111/cns.14325 -
Accounts of Chemical Research Sep 2019In addition to nitric oxide and carbon monoxide, hydrogen sulfide (HS) has been recently recognized as an important biological signaling molecule with implications in a... (Review)
Review
In addition to nitric oxide and carbon monoxide, hydrogen sulfide (HS) has been recently recognized as an important biological signaling molecule with implications in a wide variety of processes, including vasodilation, cytoprotection, and neuromodulation. In parallel to the growing number of reports highlighting the biological impact of HS, interest in developing HS donors as both research tools and potential therapeutics has led to the growth of different HS-releasing strategies. Many HS investigations in model systems use direct inhalation of HS gas or aqueous solutions of NaSH or NaS; however, such systems do not mimic endogenous HS production. This stark contrast drives the need to develop better sources of caged HS. To address these limitations, different small organosulfur donor compounds have been prepared that release HS in the presence of specific activators or triggers. Such compounds, however, often lack suitable control compounds, which limits the use of these compounds in probing the effects of HS directly. To address these needs, our group has pioneered the development of carbonyl sulfide (COS) releasing compounds as a new class of HS donor motifs. Inspired by a commonly used carbamate prodrug scaffold, our approach utilizes self-immolative thiocarbamates to access controlled release of COS, which is rapidly converted to HS by the ubiquitous enzyme carbonic anhydrase (CA). In addition, this design enables access to key control compounds that release CO/HO rather than COS/HS, which enables delineation of the effects of COS/HS from the organic donor byproducts. In this Account, we highlight a library of first-generation COS/HS donors based on self-immolative thiocarbamates developed in our lab and also highlight challenges related to HS donor development. We showcase the release of COS in the presence of specific triggers and activators, including biological thiols and bio-orthogonal reactants for targeted applications. We also demonstrate the design and development of a series of HO/reactive oxygen species (ROS)-triggered donors and show that such compounds can be activated by endogenous levels of ROS production. Utilizing approaches in bio-orthogonal activation, we establish that donors functionalized with an -nitrobenzyl photocage can enable access to light-activated donors. Similar to endogenous production by cysteine catabolism, we also prepared a cysteine-selective COS donor activated by a Strongin ligation mechanism. In efforts to help delineate potential differences in the chemical biology of COS and HS, we also report a simple esterase-activated donor, which demonstrated fast COS-releasing kinetics and inhibition of mitochondrial respiration in BEAS-2B cells. Additional investigations revealed that COS release rates and cytotoxicity correlated directly within this series of compounds with different ester motifs. In more recent and applied applications of this HS donation strategy, we also highlight the development of donors that generate either a colorimetric or fluorescent optical response upon COS release. Overall, the work described in this Account outlines the development and initial application of a new class of HS donors, which we anticipate will help to advance our understanding of the rapidly emerging chemical biology of HS and COS.
Topics: Animals; Carbonic Anhydrases; Cell Survival; HeLa Cells; Humans; Hydrogen Peroxide; Hydrogen Sulfide; Mice; Molecular Structure; RAW 264.7 Cells; Sulfur Oxides; Thiocarbamates
PubMed: 31390174
DOI: 10.1021/acs.accounts.9b00315 -
European Journal of Medicinal Chemistry Apr 2021Colchicine shows very high antimitotic activity, therefore, it is used as a lead compound for generation of new anticancer agents. In the hope of developing novel,...
Colchicine shows very high antimitotic activity, therefore, it is used as a lead compound for generation of new anticancer agents. In the hope of developing novel, useful drugs with more favourable pharmacological profiles, a series of doubly modified colchicine derivatives has been designed, synthesized and characterized. These novel carbamate or thiocarbamate derivatives of 10-demethoxy-10-methylaminocolchicine have been tested for their antiproliferative activity against four human cancer cell lines. Additionally, their mode of action has been evaluated as colchicine binding site inhibitors, using molecular docking studies. Most of the tested compounds showed greater cytotoxicity (IC in a low nanomolar range) and were characterized by a higher selectivity index than standard chemotherapeutics such as cisplatin and doxorubicin as well as unmodified colchicine. Their pharmacological use in cancer therapy could possibly be accomplished with lower dosages and result in less acute toxicity problems than in the case of colchicine. In addition, we present a QSAR model for predicting the antiproliferative activity of doubly modified derivatives for two tumour cell lines.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Colchicine; Drug Screening Assays, Antitumor; Humans; Molecular Docking Simulation; Molecular Structure; Protein Binding; Quantitative Structure-Activity Relationship; Thiocarbamates; Tubulin; Tubulin Modulators
PubMed: 33611191
DOI: 10.1016/j.ejmech.2021.113282 -
The American Journal of Medicine Jun 1990For 40 years, disulfiram has been the alcohol-aversive drug used most frequently by American physicians in the treatment of alcohol dependency disorders. We reviewed the... (Review)
Review
PURPOSE
For 40 years, disulfiram has been the alcohol-aversive drug used most frequently by American physicians in the treatment of alcohol dependency disorders. We reviewed the clinical literature regarding the risks, benefits, indications, and efficacy of this controversial drug and summarized current knowledge of this therapy.
CONCLUSIONS
Disulfiram will produce an aversive reaction with ethanol, usually at a dose between 250 mg/day and 500 mg/day, although some patients may not have an aversive reaction at this level. Cardiac, hepatic, and neurologic toxicity can also occur within this dosage range. If disulfiram is to be used, the patient must clearly understand the risks of drinking while taking the drug, and the physician and patient must agree about the need for continued clinical supervision and monitoring for efficacy and side effects. The physician must also recognize that disulfiram is only an adjunctive therapy and that continued support, supervision, and other therapeutic measures are required. Disulfiram is probably effective in reducing the frequency of alcohol consumption in the compliant patient over the short term (e.g., 6 months). Certain subgroups of patients, such as those who are older, those who are more socially stable, and those who are well-motivated, may experience a beneficial effect for longer periods. The drug may be most effective in reducing short-term alcohol consumption when the compliance of the patient is supervised, although consideration of this kind of therapy includes the practical problems of supervising the patient and concerns that the supervising person may be placed in a difficult position. Prescription of disulfiram without accompanying education, counseling, and concomitant alcoholism therapy is not beneficial. Disulfiram has no proven effect on the long-term outcome of alcoholism.
Topics: Alcoholism; Disulfiram; Ethanol; Humans
PubMed: 2189310
DOI: 10.1016/0002-9343(90)90534-k -
Signal Transduction and Targeted Therapy Mar 2020Accumulated oxidative damage may lead to irreversible retinal pigmented epithelium (RPE) cell death, which is considered to be the primary cause of dry age-related...
Accumulated oxidative damage may lead to irreversible retinal pigmented epithelium (RPE) cell death, which is considered to be the primary cause of dry age-related macular degeneration (AMD), leading to blindness in the elderly. However, an effective therapy for this disease is lacking. Here, we described a robust high-content screening procedure with a library of 814 protective compounds and found that D609 strongly protected RPE cells from sodium iodate (SI)-induced oxidative cell death and prolonged their healthy survival. D609 effectively attenuated excessive reactive oxygen species (ROS) and prevented severe mitochondrial loss due to oxidative stress in the RPE cells. Surprisingly, the potent antioxidative effects of D609 were not achieved through its own reducibility but were primarily dependent on its ability to increase the expression of metallothionein. The injection of this small water-soluble molecule also showed an explicit protective effect of the RPE layer in an SI-induced AMD mouse model. These findings suggested that D609 could serve as a novel antioxidative protector of RPE cells both in vitro and in vivo and unveiled a novel antioxidative mechanism of D609, which may ultimately have clinical applications for the treatment of AMD.
Topics: Animals; Cell Death; Disease Models, Animal; Humans; Macular Degeneration; Mitochondria; Norbornanes; Oxidative Stress; Reactive Oxygen Species; Retinal Pigment Epithelium; Thiocarbamates
PubMed: 32296021
DOI: 10.1038/s41392-020-0122-1 -
ACS Chemical Biology Feb 2019Hydrogen sulfide (HS) is an important gasotransmitter and biomolecule, and many synthetic small-molecule HS donors have been developed for HS-related research. One...
Hydrogen sulfide (HS) is an important gasotransmitter and biomolecule, and many synthetic small-molecule HS donors have been developed for HS-related research. One important class of triggerable HS donors is self-immolative thiocarbamates, which function by releasing carbonyl sulfide (COS), which is rapidly converted to HS by the ubiquitous enzyme carbonic anhydrase (CA). Prior studies of esterase-triggered thiocarbamate donors reported significant inhibition of mitochondrial bioenergetics and toxicity when compared to direct sulfide donors, suggesting that COS may function differently than HS. Here, we report a suite of modular esterase-triggered self-immolative COS donors and include the synthesis, HS release profiles, and cytotoxicity of the developed donors. We demonstrate that the rate of ester hydrolysis correlates directly with the observed cytotoxicity in cell culture, which further supports the hypothesis that COS functions as more than a simple HS shuttle in certain biological systems.
Topics: Esterases; HeLa Cells; Humans; Sulfur Oxides; Thiocarbamates
PubMed: 30640440
DOI: 10.1021/acschembio.8b00981