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Experimental Neurology May 2024Cerebral small vessel disease (CSVD) is a cerebral vascular disease with insidious onset and poor clinical treatment effect, which is related to neuroinflammation. This...
Cerebral small vessel disease (CSVD) is a cerebral vascular disease with insidious onset and poor clinical treatment effect, which is related to neuroinflammation. This study investigated whether lipopolysaccharide-induced intestinal inflammation enhanced the level of pyroptosis in the brain of rats with CSVD. The bilateral carotid artery occlusion (BCAO) model was selected as the object of study. Firstly, behavioral tests and Hematoxylin-eosin staining (HE staining) were performed to determine whether the model was successful, and then the AIM2 inflammasome and pyroptosis indexes (AIM2, ASC, Caspase-1, IL-1β, GSDMD, N-GSDMD) in the brain were detected by Western blotting and Immunohistochemistry (IHC). Finally, a single intraperitoneal injection of lipopolysaccharide (LPS) was used to induce intestinal inflammation in rats, the expression of GSDMD and N-GSDMD in the brain was analyzed by Western blotting and to see if pyroptosis caused by intestinal inflammation can be inhibited by Disulfiram, an inhibitor of pyroptosis. The results showed that the inflammatory response and pyroptosis mediated by the AIM2 inflammasome in BCAO rats were present in both brain and intestine. The expression of N-GSDMD, a key marker of pyroptosis, in the brain was significantly increased and inhibited by Disulfiram after LPS-induced enhancement of intestinal inflammation. This study shows that AIM2-mediated inflammasome activation and pyroptosis exist in both brain and intestine in the rat model of CSVD. The enhancement of intestinal inflammation will increase the level of pyroptosis in the brain. In the future, targeted regulation of the AIM2 inflammasome may become a new strategy for the clinical treatment of CSVD.
Topics: Animals; Rats; Brain; Cerebral Small Vessel Diseases; Disulfiram; DNA-Binding Proteins; Inflammasomes; Inflammation; Lipopolysaccharides; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis
PubMed: 38428714
DOI: 10.1016/j.expneurol.2024.114746 -
Substance Abuse Treatment, Prevention,... Feb 2024Combinations of alcohol use disorder (AUD) medications have been investigated, but few if any reports describe patients maintained on more than two options at the same...
BACKGROUND
Combinations of alcohol use disorder (AUD) medications have been investigated, but few if any reports describe patients maintained on more than two options at the same time.
CASE PRESENTATION
We report a case of a middle-aged man hospitalized with gastrointestinal bleeding and acute kidney injury who had been maintained on four AUD medications (naltrexone, acamprosate, disulfiram, and gabapentin) and multiple psychiatric medications simultaneously as an outpatient. Direct quotations of his experiences with each AUD medication are included, revealing some deviations from what was prescribed as well as nuanced perceptions of effects. Overall, he tolerated the regimen well, but its AUD effects were insufficient to prevent several episodes of returning to alcohol use. He had very high hospital utilization. This prompted the initiation of an involuntary commitment, which began a period of at least six months of sobriety.
CONCLUSIONS
Quadruple pharmacotherapy for AUD may be well tolerated and supportive of recovery for an extended period of time. However, for our patient the regimen ultimately failed to prevent multiple episodes of returning to alcohol use and serious medical complications. In refractory cases like this, more intensive interventions such as involuntary commitment can be considered.
Topics: Male; Middle Aged; Humans; Alcoholism; Acamprosate; Disulfiram; Naltrexone; Alcohol Drinking
PubMed: 38424567
DOI: 10.1186/s13011-024-00599-6 -
Respiratory Research Feb 2024Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS) as common life-threatening lung diseases with high mortality rates are...
BACKGROUND
Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS) as common life-threatening lung diseases with high mortality rates are mostly associated with acute and severe inflammation in lungs. Recently, increasing evidence supports activated inflammation and gasdermin D (GSDMD)-mediated pyroptosis in macrophage are closely associated with ALI. Basic helix-loop-helix family member e40 (Bhlhe40) is a transcription factor that is comprehensively involved in inflammation. However, there is little experimental evidence connecting Bhlhe40 and GSDMD-driven pyroptosis. The study sought to verify the hypothesis that Bhlhe40 is required for GSDMD-mediated pyroptosis in lipopolysaccharide (LPS)-induced inflammatory injury.
METHOD
We performed studies using Bhlhe40-knockout (Bhlhe40 ) mice, small interfering RNA (siRNA) targeting Bhlhe40 and pyroptosis inhibitor disulfiram to investigate the potential roles of Bhlhe40 on LPS-induced ALI and the underlying mechanisms.
RESULTS
Bhlhe40 was highly expressed in total lung tissues and macrophages of LPS-induced mice. Bhlhe40 mice showed alleviative lung pathological injury and inflammatory response upon LPS stimulation. Meanwhile, we found that Bhlhe40 deficiency significantly suppressed GSDMD-mediated pyroptosis in macrophage in vivo and in vitro. By further mechanistic analysis, we demonstrated that Bhlhe40 deficiency inhibited GSDMD-mediated pyroptosis and subsequent ALI by repressing canonical (caspase-1-mediated) and non-canonical (caspase-11-mediated) signaling pathways in vivo and in vitro.
CONCLUSION
These results indicate Bhlhe40 is required for LPS-induced ALI. Bhlhe40 deficiency can inhibit GSDMD-mediated pyroptosis and therefore alleviate ALI. Targeting Bhlhe40 may be a potential therapeutic strategy for LPS-induced ALI.
Topics: Animals; Mice; Lipopolysaccharides; Pyroptosis; Macrophages; Acute Lung Injury; Caspases; Inflammation; RNA, Small Interfering; Homeodomain Proteins; Basic Helix-Loop-Helix Transcription Factors
PubMed: 38402153
DOI: 10.1186/s12931-024-02740-2 -
Molecular Medicine Reports Apr 2024Acetaminophen (APAP) overdose is the primary cause of drug‑induced acute liver failure in numerous Western countries. NLR family pyrin domain containing 3 (NLRP3)...
Acetaminophen (APAP) overdose is the primary cause of drug‑induced acute liver failure in numerous Western countries. NLR family pyrin domain containing 3 (NLRP3) inflammasome activation serves a pivotal role in the pathogenesis of various forms of acute liver injury. However, the cellular source for NLRP3 induction and its involvement during APAP‑induced hepatotoxicity have not been thoroughly investigated. In the present study, hematoxylin and eosin staining was performed to assess histopathological changes of liver tissue. Immunohistochemistry staining(NLRP3, Caspase‑1, IL‑1β, GSDMD and Caspase‑3), western blotting (NLRP3, Caspase‑1, IL‑1β, GSDMD and Caspase‑3) and RT‑qPCR (NLRP3, Caspase‑1 and IL‑1β) were performed to assess the expression of NLRP3/GSDMD signaling pathway. TUNEL staining was performed to assess apoptosis of liver tissue. The serum expression levels of inflammatory factors (IL‑6, IL‑18, IL‑1β and TNF‑α) were assessed using ELISA and inflammation of liver tissue was assessed using immunohistochemistry (Ly6G and CD68) and RT‑qPCR (TNF‑α, Il‑6, Mcp‑1, Cxcl‑1, Cxcl‑2). A Cell Counting Kit‑8 was performed to assess cell viability and apoptosis. Protein and gene expression were analyzed by western blotting (PCNA, CCND1) and RT‑qPCR (, and ). Through investigation of an APAP‑induced acute liver injury model (AILI), the present study demonstrated that APAP overdose induced activation of NLRP3 and cleavage of gasdermin D (GSDMD) in hepatocytes, both and . Additionally, mice with hepatocyte‑specific knockout of exhibited reduced liver injury and lower mortality following APAP intervention, accompanied by decreased infiltration of inflammatory cells and attenuated inflammatory response. Furthermore, pharmacological blockade of NLRP3/GSDMD signaling using MCC950 or disulfiram significantly ameliorated liver injury and reduced hepatocyte death. Notably, hepatocyte deficiency promoted liver recovery by enhancing hepatocyte proliferation. Collectively, the present study demonstrated that inhibition of the NLRP3 inflammasome protects against APAP‑induced acute liver injury by reducing hepatocyte pyroptosis and suggests that targeting NLRP3 may hold therapeutic potential for treating AILI.
Topics: Mice; Animals; NLR Family, Pyrin Domain-Containing 3 Protein; Inflammasomes; Acetaminophen; Pyroptosis; Caspase 3; Tumor Necrosis Factor-alpha; Chemical and Drug Induced Liver Injury, Chronic; Interleukin-6; Hepatocytes
PubMed: 38391117
DOI: 10.3892/mmr.2024.13185 -
Journal of Cancer 2024Metastasis has been one of the most important causes of death from breast cancer, and chemotherapy remains the major option for metastatic breast cancer. However, drug...
Metastasis has been one of the most important causes of death from breast cancer, and chemotherapy remains the major option for metastatic breast cancer. However, drug resistance and higher toxicity from chemotherapy have been an obstacle for clinical practice, and the combination of chemotherapy with immunotherapy has emerged as a promising treatment strategy. Here, we describe a therapy based on the combination of disulfiram (DSF) and Cu with widely used cytotoxic docetaxel (DTX). DSF/Cu-induced immunogenic cell death promoted the release of type I interferon and human monocyte-induced dendritic cell maturation, which established a foundation for the combination with chemotherapy. Consequently, the combination of DSF/Cu and DTX resulted in significantly more potent anti-tumor effects in 4T1-bearing mice than in single therapy. The present study has shed new light on combining DSF/Cu-induced immune responses with traditional chemotherapeutic agents to achieve greater benefits for patients with metastasis.
PubMed: 38370371
DOI: 10.7150/jca.89120 -
Frontiers in Pediatrics 2024Latamoxef 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... (Review)
Review
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.
PubMed: 38362000
DOI: 10.3389/fped.2024.1302087 -
Journal of Molecular Medicine (Berlin,... Apr 2024Acute leukemia continues to be a major cause of death from disease worldwide and current chemotherapeutic agents are associated with significant morbidity in survivors....
Acute leukemia continues to be a major cause of death from disease worldwide and current chemotherapeutic agents are associated with significant morbidity in survivors. While better and safer treatments for acute leukemia are urgently needed, standard drug development pipelines are lengthy and drug repurposing therefore provides a promising approach. Our previous evaluation of FDA-approved drugs for their antileukemic activity identified disulfiram, used for the treatment of alcoholism, as a candidate hit compound. This study assessed the biological effects of disulfiram on leukemia cells and evaluated its potential as a treatment strategy. We found that disulfiram inhibits the viability of a diverse panel of acute lymphoblastic and myeloid leukemia cell lines (n = 16) and patient-derived xenograft cells from patients with poor outcome and treatment-resistant disease (n = 15). The drug induced oxidative stress and apoptosis in leukemia cells within hours of treatment and was able to potentiate the effects of daunorubicin, etoposide, topotecan, cytarabine, and mitoxantrone chemotherapy. Upon combining disulfiram with auranofin, a drug approved for the treatment of rheumatoid arthritis that was previously shown to exert antileukemic effects, strong and consistent synergy was observed across a diverse panel of acute leukemia cell lines, the mechanism of which was based on enhanced ROS induction. Acute leukemia cells were more sensitive to the cytotoxic activity of disulfiram than solid cancer cell lines and non-malignant cells. While disulfiram is currently under investigation in clinical trials for solid cancers, this study provides evidence for the potential of disulfiram for acute leukemia treatment. KEY MESSAGES: Disulfiram induces rapid apoptosis in leukemia cells by boosting oxidative stress. Disulfiram inhibits leukemia cell growth more potently than solid cancer cell growth. Disulfiram can enhance the antileukemic efficacy of chemotherapies. Disulfiram strongly synergises with auranofin in killing acute leukemia cells by ROS induction. We propose testing of disulfiram in clinical trial for patients with acute leukemia.
Topics: Humans; Disulfiram; Reactive Oxygen Species; Auranofin; Cell Line, Tumor; Leukemia, Myeloid, Acute
PubMed: 38349407
DOI: 10.1007/s00109-023-02414-4 -
Cancers Feb 2024Copper, an essential element for various biological processes, demands precise regulation to avert detrimental health effects and potential cell toxicity. This paper... (Review)
Review
Copper, an essential element for various biological processes, demands precise regulation to avert detrimental health effects and potential cell toxicity. This paper explores the mechanisms of copper-induced cell death, known as cuproptosis, and its potential health and disease implications, including cancer therapy. Copper ionophores, such as elesclomol and disulfiram, increase intracellular copper levels. This elevation triggers oxidative stress and subsequent cell death, offering potential implications in cancer therapy. Additionally, copper ionophores disrupt mitochondrial respiration and protein lipoylation, further contributing to copper toxicity and cell death. Potential targets and biomarkers are identified, as copper can be targeted to those proteins to trigger cuproptosis. The role of copper in different cancers is discussed to understand targeted cancer therapies using copper nanomaterials, copper ionophores, and copper chelators. Furthermore, the role of copper is explored through diseases such as Wilson and Menkes disease to understand the physiological mechanisms of copper. Exploring cuproptosis presents an opportunity to improve treatments for copper-related disorders and various cancers, with the potential to bring significant advancements to modern medicine.
PubMed: 38339398
DOI: 10.3390/cancers16030647 -
Chinese Medical Journal Jun 2024Cancer is a major global health issue. Effective therapeutic strategies can prolong patients' survival and reduce the costs of treatment. Drug repurposing, which... (Review)
Review
Cancer is a major global health issue. Effective therapeutic strategies can prolong patients' survival and reduce the costs of treatment. Drug repurposing, which identifies new therapeutic uses for approved drugs, is a promising approach with the advantages of reducing research costs, shortening development time, and increasing efficiency and safety. Disulfiram (DSF), a Food and Drug Administration (FDA)-approved drug used to treat chronic alcoholism, has a great potential as an anticancer drug by targeting diverse human malignancies. Several studies show the antitumor effects of DSF, particularly the combination of DSF and copper (DSF/Cu), on a wide range of cancers such as glioblastoma (GBM), breast cancer, liver cancer, pancreatic cancer, and melanoma. In this review, we summarize the antitumor mechanisms of DSF/Cu, including induction of intracellular reactive oxygen species (ROS) and various cell death signaling pathways, and inhibition of proteasome activity, as well as inhibition of nuclear factor-kappa B (NF-κB) signaling. Furthermore, we highlight the ability of DSF/Cu to target cancer stem cells (CSCs), which provides a new approach to prevent tumor recurrence and metastasis. Strikingly, DSF/Cu inhibits several molecular targets associated with drug resistance, and therefore it is becoming a novel option to increase the sensitivity of chemo-resistant and radio-resistant patients. Studies of DSF/Cu may shed light on its improved application to clinical tumor treatment.
Topics: Disulfiram; Humans; Drug Repositioning; Neoplasms; Antineoplastic Agents; Reactive Oxygen Species; Neoplastic Stem Cells; Signal Transduction; NF-kappa B
PubMed: 38275022
DOI: 10.1097/CM9.0000000000002909 -
Frontiers in Pharmacology 2023Fungal infections have become clinically challenging owing to the emergence of drug resistance in invasive fungi and the rapid increase in the number of novel pathogens....
Fungal infections have become clinically challenging owing to the emergence of drug resistance in invasive fungi and the rapid increase in the number of novel pathogens. The development of drug resistance further restricts the use of antifungal agents. Therefore, there is an urgent need to identify alternative treatments for (). Disulfiram (DSF) has a good human safety profile and promising applications as an antiviral, antifungal, antiparasitic, and anticancer agent. However, the effect of DSF on Cryptococcus is yet to be thoroughly investigated. This study investigated the antifungal effects and the mechanism of action of DSF against to provide a new theoretical foundation for the treatment of infections. studies demonstrated that DSF inhibited growth at minimum inhibitory concentrations (MICs) ranging from 1.0 to 8.0 μg/mL. Combined antifungal effects have been observed for DSF with 5-fluorocytosine, amphotericin B, terbinafine, or ketoconazole. DSF exerts significant protective effects and synergistic effects combined with 5-FU for infected with . Mechanistic investigations showed that DSF dose-dependently inhibited melanin, urease, acetaldehyde dehydrogenase, capsule and biofilm viability of . Further studies indicated that DSF affected by interfering with multiple biological pathways, including replication, metabolism, membrane transport, and biological enzyme activity. Potentially essential targets of these pathways include acetaldehyde dehydrogenase, catalase, ATP-binding cassette transporter (ABC transporter), and iron-sulfur cluster transporter. These findings provide novel insights into the application of DSF and contribute to the understanding of its mechanisms of action in .
PubMed: 38273827
DOI: 10.3389/fphar.2023.1268649