The study aims to examine the effects and potential mechanisms of disulfiram (DSF) on cardiac hypertrophic injury, focusing on the role of transforming growth factor-β-activated kinase 1 (TAK1)-mediated pan-apoptosis (PANoptosis). H9C2 cardiomyocytes were treated with angiotensin II (Ang II, 1 µmol/L) to establish an in vitro model of myocardial hypertrophy. DSF (40 µmol/L) was used to treat cardiomyocyte hypertrophic injury models, either along or in combination with the TAK1 inhibitor, 5z-7-oxozeaenol (5z-7, 0.1 µmol/L). We assessed cell damage using propidium iodide (PI) staining, measured cell viability with CCK8 assay, quantified inflammatory factor levels in cell culture media via ELISA, detected TAK1 and RIPK1 binding rates using immunoprecipitation, and analyzed the protein expression levels of key proteins in the TAK1-mediated PANoptosis pathway using Western blot. In addition, the surface area of cardiomyocytes was measured with Phalloidin staining. The results showed that Ang II significantly reduced the cellular viability of H9C2 cardiomyocytes and the binding rate of TAK1 and RIPK1, significantly increased the surface area of H9C2 cardiomyocytes, PI staining positive rate, levels of inflammatory factors [interleukin-1β (IL-1β), IL-18, and tumor necrosis factor α (TNF-α)] in cell culture media and p-TAK1/TAK1 ratio, and significantly up-regulated key proteins in the PANoptosis pathway [pyroptosis-related proteins NLRP3, Caspase-1 (p20), and GSDMD-N (p30), apoptosis-related proteins Caspase-3 (p17), Caspase-7 (p20), and Caspase-8 (p18), as well as necroptosis-related proteins p-MLKL, RIPK1, and RIPK3]. DSF significantly reversed the above changes induced by Ang II. Both 5z-7 and exogenous IL-1β weakened these cardioprotective effects of DSF. These results suggest that DSF may alleviate cardiac hypertrophic injury by inhibiting TAK1-mediated PANoptosis.
Animals ; MAP Kinase Kinase Kinases/physiology* ; Rats ; Myocytes, Cardiac/pathology* ; Disulfiram/pharmacology* ; Cardiomegaly ; Apoptosis/drug effects* ; Cell Line ; Angiotensin II ; Necroptosis/drug effects* ; Interleukin-1beta/metabolism* ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism* ; Lactones ; Resorcinols ; Zearalenone/administration & dosage*

A series of chemotherapeutic drugs that induce DNA damage, such as cisplatin (DDP), are standard clinical treatments for ovarian cancer, testicular cancer, and other diseases that lack effective targeted drug therapy. Drug resistance is one of the main factors limiting their application. Sensitizers can overcome the drug resistance of tumor cells, thereby enhancing the antitumor activity of chemotherapeutic drugs. In this study, we aimed to identify marketable drugs that could be potential chemotherapy sensitizers and explore the underlying mechanisms. We found that the alcohol withdrawal drug disulfiram (DSF) could significantly enhance the antitumor activity of DDP. JC-1 staining, propidium iodide (PI) staining, and western blotting confirmed that the combination of DSF and DDP could enhance the apoptosis of tumor cells. Subsequent RNA sequencing combined with Gene Set Enrichment Analysis (GSEA) pathway enrichment analysis and cell biology studies such as immunofluorescence suggested an underlying mechanism: DSF makes cells more vulnerable to DNA damage by inhibiting the Fanconi anemia (FA) repair pathway, exerting a sensitizing effect to DNA damaging agents including platinum chemotherapy drugs. Thus, our study illustrated the potential mechanism of action of DSF in enhancing the antitumor effect of DDP. This might provide an effective and safe solution for combating DDP resistance in clinical treatment.
Female ; Male ; Humans ; Cisplatin/pharmacology* ; Disulfiram/pharmacology* ; Testicular Neoplasms/drug therapy* ; Fanconi Anemia/drug therapy* ; Alcoholism/drug therapy* ; Drug Resistance, Neoplasm ; Cell Line, Tumor ; Substance Withdrawal Syndrome/drug therapy* ; Apoptosis ; Antineoplastic Agents/therapeutic use* ; Cell Proliferation

Disulfiram has been used for the treatment of alcohol dependence for nearly 65 years and is approved by the Food and Drug Administration. It causes negative reinforcement by accumulating toxic acetaldehyde due to irreversible inhibition of aldehyde dehydrogenase. Disulfiram has very few side effects when taken without alcohol. Epileptic seizure induction is a rare side effect in therapeutic doses, and its mechanism is unknown. We present a patient with a single epileptic seizure which was thought to be due to disulfiram used in the treatment of alcohol dependence. We did not find it ethical to administer disulfiram again because the patient discontinued alcohol use and was afraid of epileptic seizures.
Acetaldehyde ; Alcoholism ; Aldehyde Dehydrogenase ; Disulfiram ; Epilepsy ; Humans ; Reinforcement (Psychology) ; United States Food and Drug Administration

PURPOSE: Glioblastoma, the most common brain tumor in adults, has poor prognosis. The purpose of this study was to determine the effect of disulfiram (DSF), an aldehyde dehydrogenase inhibitor, on in vitro radiosensitivity of glioblastoma cells with different methylation status of O⁶-methylguanine-DNA methyltransferase (MGMT) promoter and the underlying mechanism of such effect. MATERIALS AND METHODS: Five human glioblastoma cells (U138MG, T98G, U251MG, U87MG, and U373MG) and one normal human astrocyte (NHA) cell were cultured and treated with DSF or 6MV X-rays (0, 2, 4, 6, and 8 Gy). For combined treatment, cells were treated with DSF before irradiation. Surviving fractions fit from cell survival based on colony forming ability. Apoptosis, DNA damage repair, and cell cycle distributionwere assayed bywestern blot for cleaved caspase-3, γH2AX staining, and flow cytometry, respectively. RESULTS: DSF induced radiosensitization in most of the glioblastoma cells, especially, in the cells with radioresistance as wildtype unmethylated promoter (MGMT-wt), but did not in normal NHA cell. DSF augmented or induced cleavage of caspase-3 in all cells after irradiation. DSF inhibited repair of radiation-induced DNA damage in MGMT-wt cells, but not in cells with methylated MGMT promoter. DSF abrogated radiation-induced G2/M arrest in T98G and U251MG cells. CONCLUSION: Radiosensitivity of glioblastoma cells were preferentially enhanced by pre-irradiation DSF treatment compared to normal cell, especially radioresistant cells such as MGMT-wt cells. Induction of apoptosis or inhibition of DNA damage repair may underlie DSF-induced radiosensitization. Clinical benefit of combining DSF with radiotherapy should be investigated in the future.
Adult ; Aldehyde Dehydrogenase ; Apoptosis ; Astrocytes ; Brain Neoplasms ; Caspase 3 ; Cell Cycle ; Cell Survival ; Disulfiram ; DNA Damage ; Flow Cytometry ; Glioblastoma ; Humans ; In Vitro Techniques ; Methylation ; Prognosis ; Radiation Tolerance ; Radiotherapy

BACKGROUND: NUP98 has numerous partner genes of which plant homeodomain (PHD) finger protein 23 (PHF23) fusion with NUP98 (NP23) can be detected by RT-PCR in patients with cytogenetically normal acute myelogenous leukemia (AML). In this fusion transcript of NP23 PHD of PHF23 is known to specifically bind H3K4me3 residues and act as a chromatic modifier. Disulfiram (DSF) which inhibits the binding of PHD to H3K4me3 residues selectively killed NP23 myeloblasts in vitro and therefore, we planned to evaluate the efficacy of DSF in vivo. METHODS: Cultured 961C cells (CD45.2), NP23 myeloblast cells were transplanted into B57BL/6 mice (CD45.1). Using limit dilution assay the number of leukemic stem cells (LSCs) could be calculated. A certain amount of 961C cells were transplanted into B57BL/6 mice and DSF was treated after 1 week. The engraftment level was monitored with CD45.2. Kaplan Meier survival curve was used to compare the survival between therapeutic and control group. RESULTS: 961C cells could be transplanted without radiation in recipient mice. Calculated LSC was estimated to be 1 out of 184 cells (95% CI range, 56–609). When treated with DSF of different doses and administration routes in 961C recipient mice no survival advantage of DSF was observed in 961C transplanted immunocompetent mouse, however it was evident that engraftment level was consistent in both groups. CONCLUSION: No survival advantage of DSF in 961C transplanted immunocompetent mouse was observed, however it was evident that 961C cells shared niche with normal hematopoietic stem cells (HSCs). We expect that 961C cells and transplanted recipient mice have the potential to be used as in vivo system for new drugs development as well as for research dealing with niche for normal HSCs and LSCs.
Animals ; Disulfiram ; Fingers ; Granulocyte Precursor Cells ; Hematopoietic Stem Cells* ; Humans ; In Vitro Techniques ; Leukemia, Myeloid, Acute ; Mice ; Plants ; Stem Cells

Disulfiram is the commonly prescribed drug for the treatment of alcohol dependence. It's major metabolite (diethyldithiocarbamate) is an inhibitor of dopamine-betahydroxylase, an enzyme that catalyzes the metabolism of dopamine to norepinephrine resulting in psychosis. We recommend that disulfiram should be used at the lowest effective dose, possibly 250 mg daily and caution should be taken while prescribing disulfiram for patients with personal and familial antecedents of psychosis.
Alcoholism ; Disulfiram* ; Dopamine ; Humans ; Metabolism ; Norepinephrine ; Psychotic Disorders*

No abstract available.
Disulfiram* ; Psychotic Disorders*

Underweight and specific nutrient deficiencies are frequent in adult patients with inflammatory bowel disease (IBD). In addition, a significant number of children with IBD, particularly Crohn's disease (CD) have impaired linear growth. Nutritional support is important in patients with IBD and nutritional problems. Enteral nutrition (EN) can reduce CD activity and maintain remission in both adults and children. Given that the ultimate goal in the treatment of CD is mucosal healing, this advantage of EN over corticosteroid treatment is valuable in therapeutic decision-making. EN is indicated in active CD, in cases of steroid intolerance, in patient's refusal of steroids, in combination with steroids in undernourished individuals, and in patients with inflammatory stenosis of the small intestine. EN should be the first choice compared to total parenteral nutrition. However, EN does not have a primary therapeutic role in ulcerative colitis. In conclusion, it appears that the role of nutrition as supportive care in patients with IBD should not be underestimated. The aim of this comprehensive review is to provide the reader with an update on the role of nutritional support in IBD patients.
Adult ; Child ; Colitis, Ulcerative ; Constriction, Pathologic ; Crohn Disease ; Disulfiram ; Enteral Nutrition ; Humans ; Inflammatory Bowel Diseases* ; Intestine, Small ; Nutritional Support* ; Parenteral Nutrition, Total ; Steroids ; Thinness

PURPOSE: A survey was conducted to assess the impact of a TED-like educational session on participants' willingness to accept dental implant therapy. MATERIALS AND METHODS: Volunteers interested in having information about dental implant therapies were recruited and asked to complete a two-part survey before and after an educational session. The initial survey elicited demographic information, self-perceived knowledge on dental implants and willingness to this kind of treatment. A "TED-style" presentation that provided information about dental implant treatments was conducted before asking the participants to complete a second set of questions assessing the impact of the session. RESULTS: The survey was completed by 104 individuals, 78.8% were women and the mean age was 66.5+/-10.8. Before the educational session, 76.0% of the participants refused dental implants mainly due to lack of knowledge. After the educational session, the rejection of dental implants decreased by almost four folds to 20.2%. CONCLUSION: This study proved that an educational intervention can significantly increase willingness to accept treatment with dental implants in a segment of the population who is interested in having information about dental implant therapy. Furthermore, educational interventions, such as TED-like talks, might be useful to increase popular awareness on dental implant therapy.
Dental Implants* ; Disulfiram ; Education, Dental ; Female ; Humans ; Volunteers

Eating behaviour disorder during early childhood is a common pediatric problem. Many terminologies have been used interchangeably to describe this condition, hindering implementation of therapy and confusing a common problem. The definition suggests an eating behaviour which has consequences for family harmony and growth. The recent Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition does not cover the entire spectrum seen by pediatricians. Publications are substantive but level of evidence is most of the time low. This purpose of this review is to clarify terminology of eating behaviour problems during early childhood; including benign picky eating, limited diets, sensory food aversion, selective eating, food avoidance emotional disorder, pervasive refusal syndrome, tactile defensiveness, functional dysphagia, neophobia and toddler anorexia. This tool is proposed only to ease the clinical management for child care providers. Diagnostic criteria are set and management tools are suggested. The role of dietary counselling and, where necessary, behavioural therapy is clarified. It is hoped that the condition will make its way into mainstream pediatrics to allow these children, and their families, to receive the help they deserve.
Anorexia ; Child ; Child Care ; Deglutition Disorders ; Diagnostic and Statistical Manual of Mental Disorders ; Diet ; Disulfiram ; Feeding and Eating Disorders ; Eating* ; Hope ; Humans ; Meals ; Pediatrics