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Cell Death & Disease Sep 2023Gasdermin D (GSDMD)-mediated pyroptosis has a significant pro-inflammation characteristic due to dramatic secretion of pro-inflammatory substances. However, its role...
Gasdermin D (GSDMD)-mediated pyroptosis has a significant pro-inflammation characteristic due to dramatic secretion of pro-inflammatory substances. However, its role remains unclear in psoriasis as one chronic inflammatory skin disorder with high prevalence. We found that N-terminal GSDMD (N-GSDMD) was aberrantly expressed in epidermis of skin lesion in psoriasis patients and imiquimod-induced psoriasis-like dermatitis (IIPLD) mice. In epidermis of IIPLD mice and M5 (simulating psoriatic inflammatory challenge)-treated keratinocytes cultured in vitro, cleavage products of caspase-1, GSDMD and IL-1β were increased. M5-stimulated keratinocyte presented typical pyroptosis morphology accompanied with PI-staining. Gsdmd keratinocytes could not present pyroptosis morphology while stimulated with M5. Electroporation of recombinant N-GSDMD could make the pyroptosis morphology reappear. In Gsdmd mice or keratinocyte-specific Gsdmd conditional knockout mice, we observed the alleviation of psoriatic inflammation and epidermal aberrant expression of Ki-67 and differentiation markers (loricrin and keratin 5) after imiquimod stimulation. Transplanting skin tissue from control mice to Gsdmd mice can evoke the response to imiquimod stimulation in the background of Gsdmd mice (not limited in transplanting area). In M5-stimulated keratinocytes, disulfiram or GSDMD siRNA transfection can inhibit pyroptosis and eliminate disproportionate increases of Ki-67 and PI. We further validated that topically application of disulfiram (pyroptosis inhibitor) also alleviated IIPLD in mice. These findings indicate a novel mechanism that GSDMD-mediated keratinocyte pyroptosis facilitates hyperproliferation and aberrant differentiation induced by immune microenvironment in psoriatic skin inflammation, which contributes to pathogenesis of psoriasis. Our study provides an innovative insight that targeting pyroptosis can be considered as a therapeutic strategy against psoriasis.
Topics: Animals; Mice; Gasdermins; Disulfiram; Imiquimod; Ki-67 Antigen; Pyroptosis; Keratinocytes; Psoriasis; Dermatitis; Inflammation
PubMed: 37673869
DOI: 10.1038/s41419-023-06094-3 -
Theranostics 2023Disulfiram (DSF), a Food and Drug Administration (FDA)-approved drug for chronic alcohol addiction, has anti-inflammatory effects that help prevent various cancers, and...
Disulfiram (DSF), a Food and Drug Administration (FDA)-approved drug for chronic alcohol addiction, has anti-inflammatory effects that help prevent various cancers, and Cu can enhance the effects of DSF. Inflammatory bowel diseases (IBD) are characterized by chronic or recurrent relapsing gastrointestinal inflammation. Many drugs targeting the immune responses of IBD have been developed, but their application has many problems, including side effects and high costs. Therefore, there is an urgent need for new drugs. In this study, we investigated the preventive effects of DSF+Cu on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice. The anti-inflammatory effects were investigated using the DSS-induced colitis mouse model and lipopolysaccharide (LPS)-induced macrophages. DSS-induced TCRβ mice were used to demonstrate the effect of DSF in conjunction with Cu on CD4 T cell-secreted interleukin 17 (IL-17). In addition, the effect of DSF+Cu on intestinal flora was studied by 16S rRNA microflora sequencing. DSF and Cu could significantly reverse the symptom of DSS-induced UC in mice, such as weight loss, disease activity index score, colon length shortening, and reversal of colon pathological changes. DSF and Cu could inhibit colonic macrophage activation by blocking the nuclear factor kappa B (NF-κB) pathway, reducing nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3)-inflammasome-derived interleukin 1 beta (IL-1β) secretion and caspase-1 (CASP1) activation, and decreasing IL-17 secretion by CD4 T cells. Moreover, the treatment of DSF and Cu could protect the intestinal barrier by reversing the expression of tight junction proteins, zonula occluden-1 (ZO-1), occludin, and mucoprotein-2 (MUC2). Additionally, DSF+Cu could reduce the abundance of harmful bacteria and increase beneficial bacteria in the intestinal tract of mice, effectively improving intestinal microecology. Our study evaluated the effect of DSF+Cu on the immune system and gut microbiota in colonic inflammation and highlighted its potential to treat UC in the clinic.
Topics: Animals; Mice; Colitis, Ulcerative; Disulfiram; Dextran Sulfate; Interleukin-17; RNA, Ribosomal, 16S; Colitis; Colon; NF-kappa B; Inflammation; Inflammatory Bowel Diseases; Anti-Inflammatory Agents; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 37284442
DOI: 10.7150/thno.81571 -
Proceedings of the National Academy of... Aug 2023Toll-like receptor 4 (TLR4) sensing of lipopolysaccharide (LPS), the most potent pathogen-associated molecular pattern of gram-negative bacteria, activates NF-κB and...
Toll-like receptor 4 (TLR4) sensing of lipopolysaccharide (LPS), the most potent pathogen-associated molecular pattern of gram-negative bacteria, activates NF-κB and Irf3, which induces inflammatory cytokines and interferons that trigger an intense inflammatory response, which is critical for host defense but can also cause serious inflammatory pathology, including sepsis. Although TLR4 inhibition is an attractive therapeutic approach for suppressing overexuberant inflammatory signaling, previously identified TLR4 antagonists have not shown any clinical benefit. Here, we identify disulfiram (DSF), an FDA-approved drug for alcoholism, as a specific inhibitor of TLR4-mediated inflammatory signaling. TLR4 cell surface expression, LPS sensing, dimerization and signaling depend on TLR4 binding to MD-2. DSF and other cysteine-reactive drugs, previously shown to block LPS-triggered inflammatory cell death (pyroptosis), inhibit TLR4 signaling by covalently modifying Cys133 of MD-2, a key conserved residue that mediates TLR4 sensing and signaling. DSF blocks LPS-triggered inflammatory cytokine, chemokine, and interferon production by macrophages in vitro. In the aggressive N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease (PD) in which TLR4 plays an important role, DSF markedly suppresses neuroinflammation and dopaminergic neuron loss, and restores motor function. Our findings identify a role for DSF in curbing TLR4-mediated inflammation and suggest that DSF and other drugs that target MD-2 might be useful for treating PD and other diseases in which inflammation contributes importantly to pathogenesis.
Topics: Animals; Mice; Disulfiram; Toll-Like Receptor 4; Lipopolysaccharides; Signal Transduction; Alcoholism; Cytokines
PubMed: 37487070
DOI: 10.1073/pnas.2306399120 -
Antibiotics (Basel, Switzerland) Mar 2023: Since disulfiram's discovery in the 1940s and its FDA approval for alcohol use disorder, other indications have been investigated. This review describes potential... (Review)
Review
: Since disulfiram's discovery in the 1940s and its FDA approval for alcohol use disorder, other indications have been investigated. This review describes potential clinical applications, associated risks, and challenges. : For this narrative review, a PubMed search was conducted for articles addressing in vivo studies of disulfiram with an emphasis on drug repurposing for the treatment of human diseases. The key search terms were "disulfiram" and "Antabuse". Animal studies and in vitro studies highlighting important mechanisms and safety issues were also included. : In total, 196 sources addressing our research focus spanning 1948-2022 were selected for inclusion. In addition to alcohol use disorder, emerging data support a potential role for disulfiram in the treatment of other addictions (e.g., cocaine), infections (e.g., bacteria such as Staphylococcus aureus and Borrelia burgdorferi, viruses, parasites), inflammatory conditions, neurological diseases, and cancers. The side effects range from minor to life-threatening, with lower doses conveying less risk. Caution in human use is needed due to the considerable inter-subject variability in disulfiram pharmacokinetics. : While disulfiram has promise as a "repurposed" agent in human disease, its risk profile is of concern. Animal studies and well-controlled clinical trials are needed to assess its safety and efficacy for non-alcohol-related indications.
PubMed: 36978391
DOI: 10.3390/antibiotics12030524 -
Journal of Addiction MedicineWe aimed to determine medications' comparative efficacy and safety for adults with alcohol use disorders. (Meta-Analysis)
Meta-Analysis
BACKGROUND
We aimed to determine medications' comparative efficacy and safety for adults with alcohol use disorders.
METHODS
We searched eleven electronic data sources for randomized clinical trials with at least 4 weeks of treatment reporting on alcohol consumption (total abstinence and reduced heavy drinking), dropouts, and dropouts due to adverse events. We conducted network meta-analyses using random-effects, frequentist models, and calculated summary rate ratios (RRs) with 95% confidence intervals (CIs).
RESULTS
We included 156 trials (N = 27,334). Nefazodone (RR = 2.11; 95% CI, 1.42-3.13), aripiprazole (RR = 1.97; 95% CI, 1.36-2.88), carbamazepine (RR = 1.85; 95% CI, 1.03-3.32), and nalmefene (RR = 1.17; 95% CI, 1.01-1.35) were associated with the most dropouts. Baclofen (RR = 0.83; 95% CI, 0.70-0.97) and pregabalin (RR = 0.63; 95% CI, 0.43-0.94) caused fewer dropouts than placebo. Nalmefene (RR = 3.26; 95% CI, 2.34-4.55), fluvoxamine (RR = 3.08; 95% CI, 1.59-5.94), and topiramate (RR=2.18; 95% CI, 1.36-3.51) caused more dropouts from adverse events over placebo. Gamma-hydroxy-butyrate (RR = 1.90; 95% CI, 1.03-3.53), baclofen (RR = 1.80; 95% CI, 1.39-2.34), disulfiram (RR = 1.71; 95% CI, 1.39-2.10), gabapentin (RR = 1.66; 95% CI, 1.04-2.67), acamprosate (RR = 1.33; 95% CI, 1.15-1.54), and oral naltrexone (RR = 1.15; 95% CI, 1.01-1.32) improved total abstinence over placebo (Fig. 3C). For reduced heavy drinking, disulfiram (RR = 0.19; 95% CI, 0.10-0.35), baclofen (RR = 0.72; 95% CI, 0.57-0.91), acamprosate (RR = 0.78; 95% CI, 0.70-0.86), and oral naltrexone (RR = 0.81; 95% CI, 0.73-0.90) were efficacious against placebo.
CONCLUSIONS
The current meta-analyses provide evidence that several medications for AUDs are effective and safe and encourage the expanded use of these medications in the clinical setting. Our review found that acamprosate (2-3 g/d), disulfiram (250-500 mg/d), baclofen (30 mg/d), and oral naltrexone (50 mg/d) had the best evidence for improving abstinence and heavy drinking for patients with AUD.
PROSPERO
CRD42020208946.
Topics: Adult; Humans; Acamprosate; Alcoholism; Baclofen; Disulfiram; Naltrexone; Network Meta-Analysis; Randomized Controlled Trials as Topic
PubMed: 35653782
DOI: 10.1097/ADM.0000000000000992 -
Antibiotics (Basel, Switzerland) Jan 2023Lyme disease caused by infection with a multitude of vector-borne organisms can sometimes be successfully treated in its very early stages. However, if diagnosis is... (Review)
Review
Lyme disease caused by infection with a multitude of vector-borne organisms can sometimes be successfully treated in its very early stages. However, if diagnosis is delayed, this infection can become disseminated and, like another spirochetal infection syphilis, can affect multiple organ systems in the body, causing a wide variety of life-altering symptoms. Conventional antibiotic therapy may not be effective in eradicating the symptoms of the disease we know as Lyme disease. The recent literature has suggested that disulfiram (DSM) may be a potent drug in the armamentarium of physicians who treat chronic Lyme disease. The use of disulfiram in the treatment of Lyme disease started with a researcher who determined that DSM is bactericidal to spirochete. Encouraged by published case reports of apparent recovery from chronic Lyme disease, having prescribed DSM ourselves in the past for alcoholics who had a desire to stop drinking and prescribing it now for patients with chronic Lyme disease, we observed both predictable and potentially avoidable side effects not necessarily related to the ingestion of alcohol. We reviewed the published literature in PubMed and Google Scholar, using the following key words: Lyme Disease; Borrelia burgdorferi treatment; and disulfiram toxicity. This paper outlines the results of that research to help avoid some of the pitfalls inherent in this novel use of an old and established medication in the practice of clinical medicine.
PubMed: 36830172
DOI: 10.3390/antibiotics12020262 -
BMJ Case Reports Mar 2021Disulfiram has been widely used for over six decades in the treatment of alcohol dependence, as an aversive therapeutic agent. Despite having very few side effects when...
Disulfiram has been widely used for over six decades in the treatment of alcohol dependence, as an aversive therapeutic agent. Despite having very few side effects when taken without concurrent alcohol consumption, some of these may underlie serious clinical complications. Epileptic seizure induction is a rare adverse effect of disulfiram and its aetiological mechanism is unknown. We present a hospitalised 47-year-old male patient with two episodes of generalised tonic-clonic seizures during treatment with disulfiram while abstinent from alcohol.
Topics: Anticonvulsants; Carbamazepine; Disulfiram; Epilepsies, Partial; Epilepsy, Generalized; Epilepsy, Tonic-Clonic; Humans; Male; Middle Aged; Seizures
PubMed: 33731397
DOI: 10.1136/bcr-2020-236296