Aldehyde Dehydrogenase Inhibitor Research Articles

Selected markers of ovarian cancer and their relation to targeted therapy (Review).

Despite advances in surgical treatment techniques and chemotherapy-including anti-angiogenic and immune poly (ADP-ribose) polymerase inhibitors, the 5-year survival rate in ovarian cancer (OC) remains low. The reasons for this are the diagnosis of cancer in advanced clinical stages, chemoresistance and cancer recurrence. New therapeutic approaches are being developed, including the search for new biomarkers that are also targets for targeted therapy. The present review describes new molecular markers with relevance to targeted therapy, which to date have been studied only in experimental research. These include the angiogenic protein angiopoietin-2, the transmembrane glycoprotein ectonucleotide pyrophosphatase/phosphodiesterase 1, the adhesion protein E-cadherin, the TIMP metallopeptidase inhibitor 1 and Kruppel-like factor 7. Drugs affecting cancer stem cells (CSCs) in OC, such as metformin and salinomycin, as well as inhibitors of CSCs markers aldehyde dehydrogenase 1 (with the drug ATRA) and the transcription factor Nanog homeobox (microRNA) are also discussed. A new approach to prevention and possible therapies under investigation such as development of vaccines containing a subpopulation of CD117(+) and CD44(+) stem cells with a promising option for use in women with OC was described.

Aldehyde Dehydrogenases as Promising Targets for Treating Toxic Alde-hyde-related Diseases.

<p>Background: Mammals are exposed to various endogenous and exogenous aldehydes, and aldehyde dehydrogenases (ALDHs) function to metabolize these aldehydes to acids to counteract aldehyde over-load. ALDHs therefore play important roles in a series of physiological and pathophysiological process-es. ALDHs activators and inhibitors are not only important probes for exploring ALDHs functions, but promising for the treatment of toxic aldehyde-related diseases. </p> <p> Methods: This review comprehensively summarized the categories and characteristics of 19 human ALDHs, elaborated their related biological pathways, such as alcohol metabolism, retinoic acid (RA) production, neurotransmitter metabolism, etc. Especially, reported ALDHs activators and inhibitors were summarized by listing their target, inhibition form and clinical application. </p> <p> Results: On the one hand, summarization of the types and relative functions is useful for further re-search on aldehyde metabolic pathways and related diseases. On the other hand, review of existing acti-vators and inhibitors of ALDHs contributes to discovering new leading compounds and provide new insights. </p> <p> Conclusion: In consideration of the important role ALDH plays in toxic aldehyde-related diseases, ALDHs are promising targets for the treatment of toxic aldehyde-related diseases, and advocate more research efforts to explore their pathophysiology and to develop new regulators. </p>.

Latamoxef dosing regimen adjustments and pharmaceutical care in pediatrics.

Latamoxef is a semi-synthetic, broad-spectrum oxacephem antibiotic used primarily to treat infectious diseases, but the adverse drug reactions, such as the risk of fatal bleeding, once caused physicians to use it less frequently. However, with the rise of antibiotic-resistant bacterial strains, latamoxef is being used again to treat infectious diseases, especially in pediatrics. The pharmacokinetic parameters of latamoxef are highly variable, given the changes in body composition, organ maturation, and development that occurs in pediatrics. Therefore, an appropriate dosing regimen is essential. Latamoxef dosing optimization in pediatrics should adequately account for current body weight, postnatal age, postmenstrual age, and different minimum inhibitory concentration (MIC) values. In addition, attention should also be paid to some of the adverse reactions associated with latamoxef, such as coagulation disorders and bleeding risks, disulfiram-like reactions, as well as hypersensitivity and anaphylactic shock. This review summarizes the dosing regimens and some key points of pharmaceutical care for latamoxef in pediatrics in order to provide a better reference for its application in clinical practice.

Targeting abatacept-resistant T-helper-17 cells by aldehyde dehydrogenase inhibition

IL-17-producing helper T (Th17) cells are long-lived and serve as central effector cells in chronic autoimmune diseases. The underlying mechanisms of Th17 persistence remain unclear. We demonstrated that abatacept, a CD28 antagonist, effectively prevented the development of skin disease in a Th17-dependent experimental autoimmune dermatitis model. Abatacept selectively inhibited the emergence of IL-7R-negative effector-phenotype Tcells while allowing the survival and proliferation of IL-7R+ memory-phenotype cells. The surviving IL-7R+ Th17 cells expressed genes associated with alcohol/aldehyde detoxification and showed potential to transdifferentiate into IL-7R-negative effector cells. Inhibiting aldehyde dehydrogenase reduced IL-7R+ Th17 cells invivo, independently of CD28, and exhibited additive effects when combined with abatacept. Our findings suggest that CD28 blockade prevents inflammation without eliminating persistent memory cells. These remaining memory cells can be targeted by other drugs, such as aldehyde dehydrogenase inhibitors, to limit their survival, thereby facilitating the treatment of chronic autoimmune diseases.

RADT-28. DISRUPTION OF BIOENERGETICS ENHANCES RADIO-SENSITIVITY OF PATIENT-DERIVED GLIOBLASTOMA TUMORSPHERES

Abstract INTRODUCTION Glioblastoma (GBM), the most common primary brain tumor, has been associated with poor prognosis despite various treatment modalities, the surgical resection accompanied by chemotherapy and radiotherapy. Although the importance of radiotherapy is well known, its combination with bioenergetics regulators has not been established in clinical practice. Here, we hypothesized that bioenergetics regulators improve the radio-sensitivity of GBM-tumorspheres (TS). METHODS Gene expression profiles of GBM patient-derived TSs were obtained from microarray. In vitro efficacies of the treatment were evaluated using clonogenic assay, 3D invasion assay, neurosphere-formation assay, and apoptosis-analysis. Protein expression was evaluated by western blot, and immunofluorescence was performed for detection of γH2AX foci. In vivo efficacies were confirmed using a mouse orthotopic-xenograft model. RESULTS GBM TSs with high-radioresistant or low-radioresistant were selected according to expression levels of radiation response associated genes. In order to select the bioenergetics regulators that significantly increased the radiotherapy effect of GBM-TSs, five bioenergetics regulators were combined which are oxidative-phosphorylation (OxPhos) inhibitor (IM156A), aldehyde-dehydrogenase inhibitor (gossypol) + OxPhos inhibitor (phenformin), fatty acid oxidation inhibitor (etomoxir), pentose-phosphate pathway inhibitor (dehydroepiandrosterone; DHEA) and glycolysis inhibitor (2-deoxy-D-glucose; 2DG). Amongst of these five bioenergetics regulators, DHEA and 2DG significantly augmented the therapeutic efficacies of ionizing radiation (IR) by reducing the survival fraction, stemness, and invasiveness in both high-radioresistant and low-radioresistant GBM TSs. IR combined with bioenergetics regulators (DHEA or 2DG) induced DNA damage response and apoptosis in low-radioresistant GBM TSs. In vivo experiments using a mouse orthotopic-xenograft model confirmed the tendency to prolong survival period and reduced the size in tumor after the combined treatment of 2DG with IR in low-radioresistant GBM TS. CONCLUSION These data proposes that the combination of bioenergetics regulators and radiotherapy is more effective than IR monotherapy itself. We expect that this combination regimen can strategically establish as a future treatment practice of GBM.

Hydrogen cyanamide exposure: a case series from Pavia Poison Control Centre.

Hydrogen cyanamide is a plant growth regulator introduced in Italy as Dormex in 2000, but recalled from the market in 2008. It's currently not authorized in Europe. Inhalation/dermal contact may cause irritation/caustic burns, ingestion of severe organ damage and concomitant alcohol consumption disulfiram-like reaction due to aldehyde-dehydrogenase inhibition by hydrogen cyanamide. To study all exposure cases referred to our centre, evaluating temporal and geographic distribution and analysing clinical manifestations, including the ones after alcohol consumption. We retrospectively evaluated all hydrogen cyanamide exposures referred to our Poison Control Centre (January 2007-December 2021). For each case, age, sex, exposure route/year, geographical location, intent of exposure, alcohol co-ingestion, emergency department-admission Poison Severity Score, signs/symptoms and treatment were analysed. Thirty subjects were included. Median case/year was 1 [1; 2]: 79% occurred after market withdrawal, 92% in Sicily. All exposures were unintentional and work related; 41% of patients also co-ingested alcohol. Mean poison severity score at emergency department admission was 1.54, more severe when ingestion occurred. The most common signs/symptoms were flushing, secondary to peripheral vasodilation (41%), hyperaemia/erythema (29%), dyspnoea (25%), nausea (20%), vomiting (12%), oedema (12%), II-III degrees burns (12%) and pharyngodynia (12%). All patients were treated symptomatically and fully recovered. Hydrogen cyanamide exposure can lead to severe clinical manifestations. Despite its withdrawal from the Italian market, hydrogen cyanamide is still used: through PCC's crucial role in monitoring exposure to agricultural products efforts should be made to contrast illegal trade and increase awareness of its potential toxicity in those countries in which it's still legal.

The Myth that Metronidazole and Alcohol Cause a Disulfiram-Like Reaction

The Myth that Metronidazole and Alcohol Cause a Disulfiram-Like Reaction

Reakcja disulfiramowa i disulfiramopodobna – niewyjaśnione do końca interakcje leków z etanolem

Reakcja disulfiramowa (ang. disulfiram-ethanol reaction, DER) i reakcja disulfiramopodobna (ang. disulfiram-like reaction, DLR) definiowane jako ostre zatrucie aldehydem octowym po ekspozycji na etanol wciąż pozostają problemem współczesnej farmakoterapii. Nazwy reakcji pochodzą od leku o nazwie disulfiram, po raz pierwszy zarejestrowanego w Stanach Zjednoczonych do leczenia alkoholizmu w latach 40. ubiegłego wieku. DER będąca efektem działania disulfiramu polega na blokowaniu dehydrogenazy aldehydu octowego (ALDH) powodując kumulację aldehydu octowego towarzyszącą ostrej nietolerancji alkoholu etylowego i awersję do jego spożywania. Wiele popularnie stosowanych leków wykazuje zdolność do interakcji z etanolem pod postacią DLR, której przebieg kliniczny cechuje się wysokim zróżnicowaniem, w rzadkich przypadkach prowadząc nawet do śmierci pacjenta. W przypadku leków tj. abakawir, niektórych cefalosporyn i prokarbazyny obserwowano zarówno objawy jak i mechanizm charakterystyczny dla DER. Wiele substancji czynnych tj. chloramfenikol, gryzeofulwina, metronidazol i propranolol, niegdyś uważanych za wywołujące DLR na podstawie objawów klinicznych występujących u pacjentów w przebiegu zatrucia, charakteryzuje inny mechanizm interakcji, często nieprowadzący do wzrostu poziomu aldehydu octowego we krwi, ale związany ze zmianami stężenia neurotransmiterów w ośrodkowym układzie nerwowym (OUN). W przypadku innych leków, omówionych w przedstawionym artykule, mechanizm nie jest poznany. Wspólną cechą wymienionych leków jest występowanie objawów, które przypominają DER. Z tych powodów przedstawione interakcje leków (innych niż disulfiram) z etanolem określane są mianem DLR. Dostępne dane dla wielu leków są ograniczone, a dla wybranych substancji opisywano jedynie pojedyncze przypadki kliniczne ostrej nietolerancji etanolu bez weryfikacji jej mechanizmu, co dodatkowo utrudnia wnioskowanie i wskazuje na konieczność dalszych badań w tym zakresie. W opisie poszczególnych leków zawarto również informacje o potencjalnym ryzyku występowania reakcji disulfiramowej pozyskane z Charakterystyki Produktu Leczniczego (ChPL) danego, dostępnego na rynku polskim preparatu.

A putative role for ALDH inhibitors and chemoprevention of BRCA-mutation-driven tumors

Aldehyde dehydrogenase (ALDH) enzymatic activity is a marker of cancer-initiating cells (CIC) in many tumor types. Our group and others have found that ALDH1A family inhibitors (ALDHi) can preferentially induce death of ovarian CIC in established ovarian cancer. We sought to determine if ALDHi, by targeting CIC at the time of tumor initiation, could function as a chemopreventive for ovarian cancer. As BRCA1/2 mutation carriers represent a population who could benefit from an ovarian cancer chemopreventive, we focused on BRCA mutation-associated tumor cell lines and murine tumor models. We found that, compared to BRCA wild-type cells, BRCA mutant ovarian cancer cells are more sensitive to the ALDHi673A. Similarly, while 673A treatment of wild-type fallopian tube epithelial (FTE) cells is non-toxic, 673A induces death in FTE cells with BRCA1 knockdown. Using a murine fallopian tube organoid model of ovarian carcinogenesis, we show that 673A reduced organoid complexity and significantly reduce colony formation of BRCA-mutant cells. Organoids that persisted after 673A treatment were predominantly BRCA1wt, but NF1 mutant, suggesting a resistance mechanism. Finally, using the BPRN (Brca1, Trp53, Rb1, Nf1 inactivated) mouse model of tubo-ovarian cancer, we evaluated the impact of intermittent 673A therapy on carcinogenesis. 673A treatment resulted in a significant reduction in serous tubal intraepithelial carcinoma (STIC) lesions and carcinomas. Collectively, the findings suggest that ALDHi, such as 673A, could serve as chemopreventive agents for BRCA1/2 mutation carriers.

The Relationship between Antibiotics and Disulfiram-like Reaction

Drinking without antibiotics has become the consensus of more and more people. On this phenomenon this paper will introduce the principle of this. The article will briefly introduce the structure of the medication principle and partial historical development. Partial historical development of two different kinds of mainstream antibiotics, cephalosporin and metronidazole. Understand these two mainstream antibiotics from scratch, and understand the principle of the reason why we cannot have them with alcohol fundamentally. Furthermore, the article will briefly analyze the principle and phenomenon of the same side reaction produced by two antibiotics with different structures, namely, a disulfiramlike reaction, to explain and show what will happen if people have these two kinds of antibiotics after drinking the alcohol. In this way, this work will popularize the hazards and precautions of drug use after drinking to more nonprofessionals

Advancing Cancer Therapy with Copper/Disulfiram Nanomedicines and Drug Delivery Systems.

Disulfiram (DSF) is a thiocarbamate based drug that has been approved for treating alcoholism for over 60 years. Preclinical studies have shown that DSF has anticancer efficacy, and its supplementation with copper (CuII) significantly potentiates the efficacy of DSF. However, the results of clinical trials have not yielded promising results. The elucidation of the anticancer mechanisms of DSF/Cu (II) will be beneficial in repurposing DSF as a new treatment for certain types of cancer. DSF's anticancer mechanism is primarily due to its generating reactive oxygen species, inhibiting aldehyde dehydrogenase (ALDH) activity inhibition, and decreasing the levels of transcriptional proteins. DSF also shows inhibitory effects in cancer cell proliferation, the self-renewal of cancer stem cells (CSCs), angiogenesis, drug resistance, and suppresses cancer cell metastasis. This review also discusses current drug delivery strategies for DSF alone diethyldithocarbamate (DDC), Cu (II) and DSF/Cu (II), and the efficacious component Diethyldithiocarbamate-copper complex (CuET).

Identification and characterisation of the tegument-expressed aldehyde dehydrogenase SmALDH_312 of Schistosoma mansoni, a target of disulfiram.

Schistosomiasis is an infectious disease caused by blood flukes of the genus Schistosoma and affects approximately 200 million people worldwide. Since Praziquantel (PZQ) is the only drug for schistosomiasis, alternatives are needed. By a biochemical approach, we identified a tegumentally expressed aldehyde dehydrogenase (ALDH) of S. mansoni, SmALDH_312. Molecular analyses of adult parasites showed Smaldh_312 transcripts in both genders and different tissues. Physiological and cell-biological experiments exhibited detrimental effects of the drug disulfiram (DSF), a known ALDH inhibitor, on larval and adult schistosomes in vitro. DSF also reduced stem-cell proliferation and caused severe tegument damage in treated worms. In silico-modelling of SmALDH_312 and docking analyses predicted DSF binding, which we finally confirmed by enzyme assays with recombinant SmALDH_312. Furthermore, we identified compounds of the Medicine for Malaria Venture (MMV) pathogen box inhibiting SmALDH_312 activity. Our findings represent a promising starting point for further development towards new drugs for schistosomiasis.

Targeting aldehyde dehydrogenase enzymes in combination with chemotherapy and immunotherapy: An approach to tackle resistance in cancer cells.

Modern cancer chemotherapy originated in the 1940s, and since then, many chemotherapeutic agents have been developed. However, most of these agents show limited response in patients due to innate and acquired resistance to therapy, which leads to the development of multi-drug resistance to different treatment modalities, leading to cancer recurrence and, eventually, patient death. One of the crucial players in inducing chemotherapy resistance is the aldehyde dehydrogenase (ALDH) enzyme. ALDH is overexpressed in chemotherapy-resistant cancer cells, which detoxifies the generated toxic aldehydes from chemotherapy, preventing the formation of reactive oxygen species and, thus, inhibiting the induction of oxidative stress and the stimulation of DNA damage and cell death. This review discusses the mechanisms of chemotherapy resistance in cancer cells promoted by ALDH. In addition, we provide detailed insight into the role of ALDH in cancer stemness, metastasis, metabolism, and cell death. Several studies investigated targeting ALDH in combination with other treatments as a potential therapeutic regimen to overcome resistance. We also highlight novel approaches in ALDH inhibition, including the potential synergistic employment of ALDH inhibitors in combination with chemotherapy or immunotherapy against different cancers, including head and neck, colorectal, breast, lung, and liver.

Cefotaxime: A Reappraisal in Lower Respiratory Tract Infections

Lower respiratory Tract Infection (LRTI) is one of the fourth most common cause of mortality across the globe, and constitutes to be a major portion in critically ill patients associated with prolonged hospitalisation. Apart from age factor, other risk factors which predispose to the LRTI include poor sanitization, severe malnutrition, and lack of breast feeding for infants, HIV infection, lack of immunization, chronic illness, family history of LRTI and exposure to tobacco smoke/air pollutants. The third generation cephalosporins are used in management and treatment of gram-negative and gram-positive organism. Common bacteria implicated in these infections include S. pneumoniae, H. influenzae, Chlamydia pneumoniae, and Staphylococcus aureus. Third generation cephalosporins also target respiratory ailments like acute bronchitis, pneumonia, acute exacerbation of chronic lung diseases (such as COPD or bronchiectasis).  Cefotaxime and ceftriaxone have been widely recommended in guidelines to be used for many infections and diseases, but, some serious adverse effects have been seen in past few years with ceftriaxone like cholelithiasis, encephalopathy, memory impairment, tonic- clonic seizures, neurotoxicity and auto-immune haemolytic anaemia. This fact compels us to revisit the clinically safer and efficacious drug Cefotaxime which have been used since decades but have not developed any resistance till date. Cefotaxime has been found to be well tolerated and not associated with hypo-prothrombinemia/coagulopathies, disulfiram-like reactions, as with other cephalosporins. It can readily cross the blood-brain barrier when administered intravenously and may treat gram-negative infections resistant to previous generations of cephalosporins. Cefotaxime, demonstrates good efficacy and safety in the management of LRTIs including CAP, hospital acquired/nosocomial acquired pneumonia, acute exacerbation of pneumonia and acute bronchitis caused by both gram positive as well as gram negative bacteria. Keywords: LRTI, Cefotaxime, cephalosporins, CAP, pneumonia, respiratory tract

Disulfiram-like reaction with cefixime

Disulfiram-like reaction with cefixime

Comparison of Quantitative Values of Headspace Gas Chromatography--Mass Spectrometry and a Formate Quantification Kit in Blood Formate Quantification.

Methanol poisoning is caused by the toxicity of formate, a by-product of methanol metabolism. Measurement of blood formate concentrations is required for emergency treatment and investigation of the cause of death. In this study, we measured concentrations of formate in the plasma of a patient with methanol poisoning using headspace gas chromatography--mass spectrometry (HS-GC--MS) and a formate assay kit. Results showed a discrepancy as the quantitative values of the kit were higher than those of HS-GC--MS. Metabolic profiling of low-molecular-weight organic compounds in patient plasma samples showed that the concentrations of lactate were correlated with the values obtained using the kit. We observed a progression when lactate and lactate dehydrogenase were added to the kit reaction simultaneously, even in the absence of formate. Moreover, disulfiram, an aldehyde dehydrogenase inhibitor, suppressed the values of patient plasma samples in the formate assay kit, implying that formate production from remaining methanol in patient plasma samples via formaldehyde occurred during the kit reaction. The reactions of the kit with lactate and methanol were undesirable for accurate measurement of formate concentration in the sample. However, considering that elevated concentrations of lactate and remaining methanol both cause acidosis and are dangerous to the body, cross-reactions with lactate and methanol in the formate assay kit may be acceptable for rapid diagnosis in facilities where HS-GC--MS and other physical and chemical equipment are unavailable.

Targeting aldehyde dehydrogenase for prostate cancer therapies.

Prostate cancer (PCa) is the most common cancer in men in the United States. About 10 – 20% of PCa progress to castration-resistant PCa (CRPC), which is accompanied by metastasis and therapeutic resistance. Aldehyde dehydrogenase (ALDH) is famous as a marker of cancer stem-like cells in different cancer types, including PCa. Generally, ALDHs catalyze aldehyde oxidation into less toxic carboxylic acids and give cancers a survival advantage by reducing oxidative stress caused by aldehyde accumulation. In PCa, the expression of ALDHs is associated with a higher tumor stage and more lymph node metastasis. Functionally, increased ALDH activity makes PCa cells gain more capabilities in self-renewal and metastasis and reduces the sensitivity to castration and radiotherapy. Therefore, it is promising to target ALDH or ALDHhigh cells to eradicate PCa. However, challenges remain in moving the ALDH inhibitors to PCa therapy, potentially due to the toxicity of pan-ALDH inhibitors, the redundancy of ALDH isoforms, and the lack of explicit understanding of the metabolic signaling transduction details. For targeting PCa stem-like cells (PCSCs), different regulators have been revealed in ALDHhigh cells to control cell proliferation and tumorigenicity. ALDH rewires essential signaling transduction in PCa cells. It has been shown that ALDHs produce retinoic acid (RA), bind with androgen, and modulate diverse signaling. This review summarizes and discusses the pathways directly modulated by ALDHs, the crucial regulators that control the activities of ALDHhigh PCSCs, and the recent progress of ALDH targeted therapies in PCa. These efforts will provide insight into improving ALDH-targeted treatment.

An anti-alcoholism drug, disulfiram and copper complex improves radio-resistance of tumor-initiating cells in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a malignant cancer with a poor prognosis. Chemoradiotherapy is one of the most important strategies for patients with locally advanced unresectable ESCC; however, its therapeutic effect is unsatisfactory. Tumor-initiating cells (TICs) have been reported to be resistant to conventional chemotherapy and radiotherapy so far. Therefore, we aimed to develop a treatment strategy targeting TICs in ESCC to improve radiosensitivity. First, we validated aldehyde dehydrogenase 1 (ALDH1) as a TIC marker and investigated its ability to mediate resistance in human ESCC cell lines using flow cytometry, Western blotting, and functional analyses. Then, we focused on disulfiram (DSF), an aldehyde dehydrogenase inhibitor, used to treat alcohol use disorder. We investigated the effect of DSF and copper (II) D-gluconate (Cu) on the radiosensitivity of ESCC in xenograft mouse models. ALDH1-positive cells showed an upregulation of SOX2 and Nanog, exhibiting much stronger tumor-initiating properties than ALDH1-negative cells. Furthermore, inhibition of ALDH1 attenuated the tumor-initiating properties of ESCC cell lines. Our results also showed that ALDH1-positive cells were resistant to chemotherapy and radiotherapy, and the inhibition of ALDH1 led to the mitigation of therapeutic resistance. Our in vitro and in vivo studies revealed that the DSF/Cu complex could radiosensitize ALDH1-positive ESCC cells and downregulate the phosphoinositide 3-kinase/Akt pathway. ALDH1 inhibition by the DSF/Cu complex enhances the radiosensitivity of TICs in ESCC. The drug repositioning approach using disulfiram is a potential treatment option to overcome radioresistance in patients with locally advanced ESCC.

Anti-metastatic breast cancer potential of novel nanocomplexes of diethyldithiocarbamate and green chemically synthesized iron oxide nanoparticles

Mortality rate of metastatic breast cancer is linked to cancer stem cells (CSCs)’ aggressive features (chemoresistance to apoptosis and redox imbalance). Therefore, unique dual therapeutic strategy compacts CSCs with inducing oxidative stress-mediated nonapoptosis (ferroptosis), confers effective malignant tumor eradication. Diethyldithiocarbamate (DDC) is a potent inhibitor of CSC aldehyde dehydrogenase and lowers glutathione (GSH) which aggravate iron-dependent ferroptosis. Herein, nanoformulations of DDC with green chemically synthesized ferrous oxide nanoparticles (FeO NPs) and ferric oxide (Fe2O3 NPs) were prepared. Due to nanoparticle characters and synergistic effect between iron oxide NPs and DDC, nanocomplexes (DFeO NPs and DFe2O3 NPs, respectively) exhibited the strongest anti-metastatic cancer potency in vitro. Because of corresponding iron oxide nature, DFeO NPs demonstrated better therapeutic efficacy than DFe4O3 NPs, in mammary tumor liver metastasis-bearing mice, in terms of tumor size, histological analysis, immunostaining % of ki-67+ and caspase 3+, and gene expression of p53 and BCl2. The potent anti-tumor effect of DFeO nanocomplex is attributed to the maximum elevation of reactive oxygen species and lipid peroxidation (ferroptosis hall marker) with severe depletion of GSH and Nrf2 selectively in both tumor tissues, causing CSC eradication with halting metastatic activity. The latters were confirmed by lowering CD44+ % and gene expression of HIF-α, β-catenin, Notch, ABCG2-mediated chemoresistance, and MMP9 with diminishing liver tumor marker. Moreover, this nanocomplex did not cause any abnormal alterations in histological and biochemical parameters, compared to healthy group. Therefore, the selective apoptotic and ferroptotic with anti-CSC effects of DFeO NPs open new safe avenue for metastatic tumor therapy.

35361 Disulfiram-like reactions to topical tacrolimus: A case series

A 20-year-old Caucasian man presented to our clinic with pink papules coalescing into thin scaly plaques on the bilateral upper and lower eyelids, temples, and upper and lower cutaneous lips. He was diagnosed with periorificial dermatitis and prescribed topical tacrolimus 0.1% ointment. A 22-year-old Caucasian woman presented to our clinic with scattered monomorphic pink papules on the bilateral alar creases and lower cutaneous lip. She was diagnosed with periorificial dermatitis and prescribed tacrolimus 0.1% ointment.