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

OBJECTIVES: The purpose of this study is to determine methods of dental caries prevention by investigating the use of compounds of Diospyros kaki (D. kaki) peel, Momordica charantia (M. charantia), and Canavalia gladiata (C. gladiata) extracts to limit the cariogenic traits of Streptococcus mutans (S. mutans), such as their ability to proliferate and adhere to the tooth surface. METHODS: Broth microdilution and the agar spreading assay were used to determine the antimicrobial effect and minimum inhibitory concentration (MIC) of S. mutans extracts. In order to identify the adhesive ability of S. mutans at varying concentrations, culture plates were first stained with 1 ml of 0.01% crystal violet for 15 minutes at room temperature, and then eluted with 1 ml of EtOH:Acetone (8:2) solution for 15 minutes in a 37℃ incubator. Eluted solutions were then evaluated by use of a spectrophotometer at 575 nm. RESULTS: Experiments were conducted in order to investigate the effectiveness of D. kaki peel, M. charantia, and C. gladiata extracts on limiting the proliferation of S. mutans. The MIC was measured as an indication of whether the antibacterial activity of D. kaki peel, M. charantia, and C. gladiata extracts had a significant bacteriostatic effect on S. mutans. M. charantia extract was effective for growth inhibition on S. mutans at a minimum concentration of 0.25%. From the adhesion ability assay, M. charantia extract had an anti-adhesive effect. CONCLUSIONS: These results indicate that M. charantia extract demonstrates antibacterial activity and has an anti-adhesive effect on S. mutans. Due to these properties, M. charantia extract may be used to prevent dental caries.
Adhesives ; Agar ; Canavalia ; Dental Caries ; Diospyros ; Gentian Violet ; Incubators ; Microbial Sensitivity Tests ; Momordica charantia ; Momordica ; Streptococcus mutans ; Streptococcus ; Thiram ; Tooth

BACKGROUND/AIMS: Among irritants causing gastric ulcer, Helicobacter pylori (H. pylori) might be pivotal, after which eradication became essential way in either inhibiting ulcerogenesis or preventing ulcer recurrence. Since threonine is essential in either mucus synthesis or cytoprotection, we hypothesized that the dietary threonine from Corynebacterium glutamicum (C. glutamicum) can mitigate the cytotoxicity of H. pylori infection.MATERIALS AND METHODS: RGM-1 cells were challenged with 100 multiplicity of infection H. pylori for 6 hours, during which threonine alone or combination with Corynebacterium sp. was administered and compared for anti-Helicobacter, anti-inflammation, anti-oxidative, and cytoprotective actions.RESULTS: Threonine alone or combination of threonine and C. glutamicum yielded significant bacteriostatic outcomes. The increased expressions of interleukin (IL)-1β, IL-8, Cox-2, and iNOS mRNA after H. pylori infection were significantly decreased with either threonine alone or the combination of threonine and C. glutamicum. The elevated expressions of NF-kB, HIF-1a, and c-jun after H. pylori infection were all significantly decreased with the combination of threonine and broth from C. glutamicum (P < 0.05), leading to significant decreases in 2′,7′-dichlorofluorescein-diacetate (P < 0.01). Tracing further host antioxidative response, the attenuated expression of heme oxygenase-1, Nrf2, and dehydrogenase quinone-1 after H. pylori infection was significantly preserved with combination of threonine and C. glutamicum. H. pylori infection led to significant increases in apoptosis accompanied with Bcl-2 decreases and Bax increases, while the combination of threonine and C. glutamicum significantly attenuated apoptosis, in which attenuated EGF, TGF-β, and VEGF were significantly regulated, while β-catenin did not change.CONCLUSIONS: Threonine synthesized from C. glutamicum significantly alleviated the cytotoxicity of H. pylori in gastric epithelial cells.
Apoptosis ; Corynebacterium glutamicum ; Corynebacterium ; Cytoprotection ; Epidermal Growth Factor ; Epithelial Cells ; Helicobacter pylori ; Heme Oxygenase-1 ; Interleukin-8 ; Interleukins ; Irritants ; Mucus ; NF-kappa B ; Oxidative Stress ; Oxidoreductases ; Recurrence ; RNA, Messenger ; Stomach Ulcer ; Thiram ; Threonine ; Ulcer ; Vascular Endothelial Growth Factor A

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

PURPOSE: A case of a transient visual field defect and a change in spectral-domain optical coherence tomography (SD-OCT) after an overdose of sildenafil citrate is described. CASE SUMMARY: A 67-year-old male with no previous medical history presented with a bluish tinge and visual field defect in both eyes. He had consumed eight tablets of sildenafil citrate (800 mg) 3 days before the visit. His best-corrected visual acuity was 14/20 in the right eye and 20/20 in the left eye. No specific finding was noted on slit-lamp examination. Fundus examination and fundus photography revealed focal foveal hypopigmentation in both eyes. He underwent SD-OCT imaging with the Cirrus HD-OCT (Carl Zeiss Meditec, Oberkochen, Germany), and thickening of the ellipsoid zone and choroid was revealed by SD-OCT scans. He was advised not to take any more sildenafil citrate and was followed for 1 week after the first visit. Central scotomas of both eyes were revealed by a visual field test, and thickening of the ellipsoid zone and choroid remained. His eyes were re-evaluated 1 and 3 months after the first visit, and although the symptoms nearly disappeared, abnormalities in the visual field test and on SD-OCT remained, albeit with some degree of improvement. He revisited us 4 months after the first visit, at which time the visual field test and SD-OCT scans showed results within normal ranges. CONCLUSIONS: Sildenafil citrate overdose can result in a color anomaly (bluish tinge), visual field defects, and thickening of the ellipsoid zone and choroid on SD-OCT scans.
Aged ; Choroid ; Humans ; Hypopigmentation ; Male ; Photography ; Reference Values ; Scotoma ; Sildenafil Citrate ; Tablets ; Tolnaftate ; Tomography, Optical Coherence ; Visual Acuity ; Visual Field Tests ; Visual Fields

Chronic silica nephropathy has been associated with tubulointerstitial disease, immune-mediated multisystem disease, chronic kidney disease, and end-stage renal disease. On the other hand, acute intentional exposure is extremely rare. The authors' experienced a 44-year-old man who took rapid cement hardener (sodium silicate) in a suicide attempt whilst in a drunken state. He visited the emergency department approximately 1 hour after ingestion. Information on the material was obtained after 3 L gastric lavage. The patient complained of a sore throat, epigastric pain, and swollen to blood tinged vomitus. Proton pump inhibitors, hemostats, steroid, and fluids were administered. Nine hours after ingestion, he was administered 200 mL hematochezia. Immediately after, a gastroenterologist performed an endoscopic procedure that revealed diffuse hyperemic mucosa with a color change and variable sized ulceration in the esophagus, whole stomach, and duodenal 2(nd) portion. Approximately 35 hours later, persistent oligouria and progressive worsening of the renal function parameters (BUN/Cr from 12.2/1.2 to 67.5/6.6 mg/dL) occurred requiring hemodialysis. The patient underwent 8 sessions of hemodialysis for 1 month and the BUN/Cr level increased to 143.2/11.2 mg/dL and decreased to 7.6/1.5 mg/dL. He was discharged safely from the hospital. Follow up endoscopy revealed a severe esophageal stricture and he underwent endoscopic bougie dilatation. Acute cement hardener (sodium silicate) intoxication can cause renal failure and strong caustic mucosal injury. Therefore, it is important to consider early hemodialysis and treatment to prevent gastrointestinal injury and remote esophageal stricture.
Acute Kidney Injury* ; Adult ; Caustics ; Dilatation ; Drug Overdose ; Eating ; Emergency Service, Hospital ; Endoscopy ; Esophageal Stenosis ; Esophagus ; Follow-Up Studies ; Gastric Lavage ; Gastrointestinal Hemorrhage ; Hand ; Humans ; Kidney ; Kidney Failure, Chronic ; Mucous Membrane ; Pharyngitis ; Proton Pump Inhibitors ; Renal Dialysis ; Renal Insufficiency ; Renal Insufficiency, Chronic ; Silicates ; Silicon Dioxide ; Stomach ; Suicide ; Tolnaftate ; Ulcer

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

Tibial dyschondroplasia (TD) cases has not been reported in Tibetan chickens (TBCs), but it is commonly seen in commercial broilers characterized by lameness. The underlying mechanism remains unclear. Hypoxia-inducible factors (HIFs) are important regulators of cellular adaptation to hypoxic conditions. In this study, we investigated the role of HIF-1α,
Anoxia ; Blotting, Western ; Chickens ; Growth Plate ; Osteochondrodysplasias ; Poultry ; Reverse Transcriptase Polymerase Chain Reaction ; RNA ; Thiram

Tetanic stimulation of the sciatic nerve (TSS) triggers long-term potentiation in the dorsal horn of the spinal cord and long-lasting pain hypersensitivity. CX3CL1-CX3CR1 signaling is an important pathway in neuronal-microglial activation. Nuclear factor κB (NF-κB) is a key signal transduction molecule that regulates neuroinflammation and neuropathic pain. Here, we set out to determine whether and how NF-κB and CX3CR1 are involved in the mechanism underlying the pathological changes induced by TSS. After unilateral TSS, significant bilateral mechanical allodynia was induced, as assessed by the von Frey test. The expression of phosphorylated NF-κB (pNF-κB) and CX3CR1 was significantly up-regulated in the bilateral dorsal horn. Immunofluorescence staining demonstrated that pNF-κB and NeuN co-existed, implying that the NF-κB pathway is predominantly activated in neurons following TSS. Administration of either the NF-κB inhibitor ammonium pyrrolidine dithiocarbamate or a CX3CR1-neutralizing antibody blocked the development and maintenance of neuropathic pain. In addition, blockade of NF-κB down-regulated the expression of CX3CL1-CX3CR1 signaling, and conversely the CX3CR1-neutralizing antibody also down-regulated pNF-κB. These findings suggest an involvement of NF-κB and the CX3CR1 signaling network in the development and maintenance of TSS-induced mechanical allodynia. Our work suggests the potential clinical application of NF-κB inhibitors or CX3CR1-neutralizing antibodies in treating pathological pain.
Animals ; Antibodies ; therapeutic use ; Antioxidants ; therapeutic use ; CX3C Chemokine Receptor 1 ; immunology ; metabolism ; Cytokines ; metabolism ; Disease Models, Animal ; Enzyme Inhibitors ; therapeutic use ; Ganglia, Spinal ; drug effects ; metabolism ; Hyperalgesia ; etiology ; metabolism ; Nerve Tissue Proteins ; metabolism ; Pain Threshold ; physiology ; Physical Stimulation ; adverse effects ; Proline ; analogs & derivatives ; therapeutic use ; Rats ; Rats, Sprague-Dawley ; Sciatic Nerve ; physiology ; Signal Transduction ; physiology ; Spinal Cord ; drug effects ; metabolism ; Thiocarbamates ; therapeutic use ; Up-Regulation ; drug effects ; physiology