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Molecular Medicine Reports Sep 2020The present study aimed to investigate the signaling pathways and the underlying molecular mechanisms involved in ethanol‑induced intestinal epithelial barrier (IEB)...
The present study aimed to investigate the signaling pathways and the underlying molecular mechanisms involved in ethanol‑induced intestinal epithelial barrier (IEB) dysfunction. Therefore, an in vitro experimental model of IEB was established using an ethanol‑treated Caco‑2 intestinal epithelial cell monolayer. The results confirmed that Rho‑associated kinases (ROCKs), namely ROCK1 and ROCK2, were involved in the underlying pathway of ethanol‑induced IEB dysfunction. Ethanol exposure significantly increased the expression of both ROCK isoforms and the activity of nuclear factor κB (NF‑κB). Furthermore, ROCK1‑ and ROCK2‑specific small interfering RNAs (siRNAs), and the NF‑κB inhibitor ammonium pyrrolidine dithiocarbamate partially inhibited transepithelial electrical resistance in Caco‑2 cells in an in vitro IEB model. In addition, ROCK1‑ and ROCK2‑specific siRNAs inhibited the activity of NF‑κB, thereby downregulating the expression of aquaporin 8 (AQP8). Taken together, the results of the present study suggested that ROCK1/ROCK2‑mediated activation of NF‑κB and upregulation of AQP8 expression levels may represent a novel mechanism of ethanol‑induced impairment of IEB function.
Topics: Aquaporins; Caco-2 Cells; Ethanol; Gene Expression Regulation; Gene Silencing; Humans; Intestinal Mucosa; NF-kappa B; Permeability; Pyrrolidines; Signal Transduction; Thiocarbamates; rho-Associated Kinases
PubMed: 32705263
DOI: 10.3892/mmr.2020.11318 -
Nature Reviews. Cancer Jul 2009Chemoprevention of lung carcinogenesis is one approach to controlling the epidemic of lung cancer caused by cigarette smoking. The target for chemoprevention should be... (Review)
Review
Chemoprevention of lung carcinogenesis is one approach to controlling the epidemic of lung cancer caused by cigarette smoking. The target for chemoprevention should be the activities of the multiple carcinogens, toxicants, co-carcinogens, tumour promoters and inflammatory compounds in cigarette smoke. At present there are many agents, both synthetic and naturally occurring, that prevent lung tumour development in well-established animal models. It seems likely that logically constructed mixtures of these agents, developed from the ground up, will be necessary for the prevention of lung carcinogenesis.
Topics: Animals; Anticarcinogenic Agents; Budesonide; Clinical Trials as Topic; Cysteine; Humans; Inositol; Lung Neoplasms; Smoking; Thiocarbamates
PubMed: 19550424
DOI: 10.1038/nrc2674 -
Proceedings of the National Academy of... Feb 2017crop species are prolific producers of indole-sulfur phytoalexins that are thought to have an important role in plant disease resistance. These molecules are...
crop species are prolific producers of indole-sulfur phytoalexins that are thought to have an important role in plant disease resistance. These molecules are conspicuously absent in the model plant , and little is known about the enzymatic steps that assemble the key precursor brassinin. Here, we report the minimum set of biosynthetic genes required to generate cruciferous phytoalexins starting from the well-studied glucosinolate pathway. In vitro biochemical characterization revealed an additional role for the previously described carbon-sulfur lyase SUR1 in processing cysteine-isothiocyanate conjugates, as well as the -methyltransferase DTCMT that methylates the resulting dithiocarbamate, together completing a pathway to brassinin. Additionally, the β-glucosidase BABG that is present in but absent in was shown to act as a myrosinase and may be a determinant of plants that synthesize phytoalexins from indole glucosinolate. Transient expression of the entire pathway in yields brassinin, demonstrating that the biosynthesis of indole-sulfur phytoalexins can be engineered into noncruciferous plants. The identification of these biosynthetic enzymes and the heterologous reconstitution of the indole-sulfur phytoalexin pathway sheds light on an important pathway in an edible plant and opens the door to using metabolic engineering to systematically quantify the impact of cruciferous phytoalexins on plant disease resistance and human health.
Topics: Arabidopsis; Brassica rapa; Carbon-Sulfur Lyases; Disease Resistance; Glucosinolates; Indoles; Metabolic Engineering; Methylation; Methyltransferases; Plant Physiological Phenomena; Plant Proteins; Plants, Genetically Modified; Sesquiterpenes; Thiocarbamates; Nicotiana; beta-Glucosidase; Phytoalexins
PubMed: 28154137
DOI: 10.1073/pnas.1615625114 -
European Review For Medical and... Jan 2017This study aimed to explore the role of NF-κB/P65 signaling pathway in postoperative cognitive dysfunction (POCD) after sevoflurane anesthesia.
OBJECTIVE
This study aimed to explore the role of NF-κB/P65 signaling pathway in postoperative cognitive dysfunction (POCD) after sevoflurane anesthesia.
MATERIALS AND METHODS
A total of 120 male Sprague-Dawley (SD) rats were selected and assigned into five groups (24 rats in each group): the control, sevoflurane, sevoflurane + splenectomy, pyrrolidine dithiocarbamate (PDTC, a specific inhibitor of NF-κB), and sevoflurane + splenectomy + PDTC groups. Electrocardiogram (ECoG) and behavior changes of rats were monitored before and after anesthesia/operation. Ionized calcium-binding adapter molecules 1 (Iba-1) in the hippocampal zones were observed by immunofluorescence staining. Blood-brain barrier (BBB) permeability was determined by immunohistochemistry. The mRNA and protein expressions of NF-κB/P65 signaling pathway-related proteins and inflammatory cytokines were detected by qRT-PCR assay and Western blotting.
RESULTS
During the anesthesia/operation, the vital signs of rats were stable, but the ECoG in the sevoflurane and sevoflurane + splenectomy groups mainly presented slow waves. The ECoG arousal response in the sevoflurane + splenectomy + PDTC group was observed. At 24 h after the anesthesia/operation, the expressions of NF-κB and P65 in the hippocampal zone, the expressions of IκBα and inflammatory cytokines (IL-1β, IL-6 and TNF-α), the expression of Iba-1 in rat hippocampal dentate gyrus (DG) zone and CA3 zone, and the permeability of BBB were significantly increased and the behavior of rats changed dramatically (all p < 0.05), while PDTC treatments could eliminate these changes induced by the anesthesia/operation (all p < 0.05). No changes were observed in the expressions of NF-κB, P65, IκBα, Iba-1 and inflammatory cytokines (IL-1β, IL-6 and TNF-α), and the permeability of BBB and the behavior of rats in the sevoflurane and the PDTC groups (all p > 0.05).
CONCLUSIONS
These results suggest that the inhibition of NF-κB/P65 signaling pathway may relieve POCD after sevoflurane anesthesia.
Topics: Anesthetics, Inhalation; Animals; Blood-Brain Barrier; Cognitive Dysfunction; Cytokines; Male; Methyl Ethers; Pyrrolidines; Rats; Rats, Sprague-Dawley; Sevoflurane; Signal Transduction; Thiocarbamates; Transcription Factor RelA; Tumor Necrosis Factor-alpha
PubMed: 28165545
DOI: No ID Found -
Molecules (Basel, Switzerland) Jun 2021Three novel gold(III) complexes (-) of general composition [Au(Bipydc)(SCNR)]Cl (Bipydc = 2,2'-bipyridine-3,3'-dicarboxylic acid and R = methyl for...
Three novel gold(III) complexes (-) of general composition [Au(Bipydc)(SCNR)]Cl (Bipydc = 2,2'-bipyridine-3,3'-dicarboxylic acid and R = methyl for dimethyldithiocarbamate (DMDTC), ethyl for diethyldithiocarbamate (DEDTC), and benzyl for dibenzyldithiocarbamate (DBDTC)) have been synthesized and characterized by elemental analysis, FTIR and NMR spectroscopic techniques. The spectral results confirmed the presence of both the Bipydc and dithiocarbamate ligands in the complexes. The in vitro cytotoxic studies demonstrated that compounds - were highly cytotoxic to A549, HeLa, MDA-231, and MCF-7 cancer cells with activities much higher (about 25-fold) than cisplatin. In order to know the possible mode of cell death complex , [Au(Bipydc)(DEDTC)]Cl was further tested for induction of apoptosis towards the MCF-7 cells. The results indicated that complex induces cell death through apoptosis.
Topics: A549 Cells; Antineoplastic Agents; Coordination Complexes; Gold; HeLa Cells; Humans; MCF-7 Cells; Pyridines; Thiocarbamates
PubMed: 34209921
DOI: 10.3390/molecules26133973 -
Journal of Pharmacological Sciences Jan 2006Tubulointerstitial fibrosis is a common feature of many progressive renal diseases and is a main determinant that leads to an irreversible loss of renal function. In... (Review)
Review
Tubulointerstitial fibrosis is a common feature of many progressive renal diseases and is a main determinant that leads to an irreversible loss of renal function. In chronic cyclosporin A nephrotoxicity, we previously reported that inflammatory responses such as macrophage infiltration preceded interstitial fibrosis. This inflammation was accompanied by an elevation in renal nuclear factor kappaB (NF-kappaB) activity. Similar findings were obtained in chronic tacrolimus nephrotoxicity and obstructive nephropathy. Inhibition of NF-kappaB markedly attenuated renal inflammation and interstitial fibrosis in these models. Furthermore, administration of oral adsorbent (Kremezin) significantly attenuated the increase in renal NF-kappaB activity and concomitantly reduced interstitial inflammation and renal fibrosis in chronic renal failure rats. Elimination of indoxyl sulfate by this adsorbent is likely involved in this mechanism since it is known that indoxyl sulfate activates NF-kappaB in renal tubular cells. It is suggested that strategy aiming at NF-kappaB inhibition is important to prevent the progression of renal fibrosis.
Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Anti-Inflammatory Agents; Carbon; Disease Models, Animal; Fibrosis; Inflammation; Kidney Diseases; NF-kappa B; Oxides; Pyrrolidines; Rats; Renin-Angiotensin System; Thiocarbamates
PubMed: 16397373
DOI: 10.1254/jphs.fmj05003x4 -
Bioscience Reports May 2020To investigate the relationship between PI3K/Akt/NF-κB cellular signal pathway and the expression of P-gp and LRP in multidrug resistance (MDR) cell of nasopharyngeal...
AIM
To investigate the relationship between PI3K/Akt/NF-κB cellular signal pathway and the expression of P-gp and LRP in multidrug resistance (MDR) cell of nasopharyngeal carcinoma.
METHOD
The PI3K, p-Akt and NF-κB/p65 as the activity of PI3K/Akt/NF-κB were detected by Western blot. The expressions of LRP and P-gp were detected by Western blot and real-time PCR.
RESULT
The RIs of CNE/DDP group to DDP, 5-Fu, VCR, ADR and PTX were 35.04, 18.14, 24.13, 12.00 and 10.18, respectively. The RIs of LY-294002 group were 11.77, 5.83, 3.07, 3.86 and 3.34, and PDTC group were 11.08, 6.55, 7.66, 2.18 and 4.05. The expressions of PI3K, p-Akt and NF-κBp65, LRP and P-gp were increased and mRNA of LRP and P-gp were up-regulated in CNE/DDP. The expression of p-Akt in LY-294002 group was down-regulated. The expression of NF-κB p65 in PDTC group was decreased. The mRNA of LRP and P-gp in LY-294002 group and PDTC group were decreased.
CONCLUSION
MDR of nasopharyngeal carcinoma cell can be regulated by activating PI3K/Akt/NF-κB signal pathway and then increase the expression of P-gp and LRP. The MDR of nasopharyngeal carcinoma cell can be reversed by inhibiting PI3K/Akt/NF-κB signal pathway.
Topics: ATP Binding Cassette Transporter, Subfamily B; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrrolidines; Signal Transduction; Thiocarbamates; Transcription Factor RelA; Vault Ribonucleoprotein Particles
PubMed: 32400857
DOI: 10.1042/BSR20190239 -
Canadian Medical Association Journal Oct 1977
Topics: Alcoholism; Disulfiram; Humans; Placebos
PubMed: 907942
DOI: No ID Found -
Journal of the American Chemical Society May 2017Botulinum neurotoxin serotype A (BoNT/A) causes a debilitating and potentially fatal illness known as botulism. The toxin is also a bioterrorism threat, yet no...
Botulinum neurotoxin serotype A (BoNT/A) causes a debilitating and potentially fatal illness known as botulism. The toxin is also a bioterrorism threat, yet no pharmacological antagonist to counteract its effects has reached clinical approval. Existing strategies to negate BoNT/A intoxication have looked to antibodies, peptides, or organic small molecules as potential therapeutics. In this work, a departure from the traditional drug discovery mindset was pursued, in which the enzyme's susceptibility to metal ions was exploited. A screen of a series of metal salts showed marked inhibitory activity of group 11 and 12 metals against the BoNT/A light chain (LC) protease. Enzyme kinetics revealed that copper (I) and (II) cations displayed noncompetitive inhibition of the LC (K ≈ 1 μM), while mercury (II) cations were 10-fold more potent. Crystallographic and mutagenesis studies elucidated a key binding interaction between Cys165 on BoNT/A LC and the inhibitory metals. As potential copper prodrugs, ligand-copper complexes were examined in a cell-based model and were found to prevent BoNT/A cleavage of the endogenous protein substrate, SNAP-25, even at low μM concentrations of complexes. Further investigation of the complexes suggested a bioreductive mechanism causing intracellular release of copper, which directly inhibited the BoNT/A protease. In vivo experiments demonstrated that copper (II) dithiocarbamate and bis(thiosemicarbazone) complexes could delay BoNT/A-mediated lethality in a rodent model, indicating their potential for treating the harmful effects of BoNT/A intoxication. Our studies illustrate that metals can be therapeutically viable enzyme inhibitors; moreover, enzymes that share homology with BoNT LCs may be similarly targeted with metals.
Topics: Animals; Botulinum Toxins, Type A; Coordination Complexes; Copper; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Induced Pluripotent Stem Cells; Kinetics; Mice; Neurons; Protease Inhibitors; Structure-Activity Relationship; Thiocarbamates; Thiosemicarbazones
PubMed: 28475321
DOI: 10.1021/jacs.7b01084 -
BMC Pharmacology & Toxicology Jul 2022Liver fibrosis is a wound-healing response to chronic injury, featuring with excess accumulation of extracellular matrix secreted by the activated hepatic stellate cells...
BACKGROUND
Liver fibrosis is a wound-healing response to chronic injury, featuring with excess accumulation of extracellular matrix secreted by the activated hepatic stellate cells (HSC). Disulfiram (DSF), also known as Antabuse, has been used for the treatment of alcohol addiction and substance abuse. Recently, overwhelming studies had revealed anti-cancer effects of DSF in multiple cancers, including liver cancer. But the actual effects of DSF on liver fibrosis and liver function remain unknown.
METHODS
In this study, we evaluated the effects of low-dose DSF in CCl4- and Bile Duct Ligation (BDL)-induced hepatic fibrosis rat models. Cell proliferation was detected by using the Cell-Light™ EdU Apollo®567 Cell Tracking Kit. Cell apoptosis was analyzed using a TdT-mediated dUTP nick end labeling (TUNEL) kit, viability was measured with Cell Counting Kit-8(CCK8). Relative mRNA expression of pro-fibrogenic was assessed using quantitative RT-PCR. The degree of liver fibrosis, activated HSCs, were separately evaluated through Sirius Red-staining, immunohistochemistry and immunofluorescence. Serum alanine aminotransferase (ALT) and asparagine aminotransferase (AST) activities were detected with ALT and AST detecting kits using an automated analyzer.
RESULTS
Liver fibrosis was distinctly attenuated while liver functions were moderately ameliorated in the DSF-treated group. Activation and proliferation of primary rat HSCs isolated from rat livers were significantly suppressed by low-dose DSF. DSF also inhibited the viability of in vitro cultured rat or human HSC cells dose-dependently but had no repressive role on human immortalized hepatocyte THLE-2 cells. Interestingly, upon DSF treatment, the viability of LX-2 cells co-cultured with THLE-2 was significantly inhibited, while that of THLE-2 co-cultured with LX-2 was increased. Further study indicated that HSCs apoptosis was increased in DSF/CCl4-treated liver samples. These data indicated that DSF has potent anti-fibrosis effects and protective effects toward hepatocytes and could possibly be repurposed as an anti-fibrosis drug in the clinic.
CONCLUSIONS
DSF attenuated ECM remodeling through suppressing the transformation of quiet HSCs into proliferative, fibrogenic myofibroblasts in hepatic fibrosis rat models. DSF provides a novel approach for the treatment of liver fibrosis.
Topics: Animals; Bile Ducts; Cell Proliferation; Disulfiram; Hepatic Stellate Cells; Humans; Liver; Liver Cirrhosis; Rats
PubMed: 35864505
DOI: 10.1186/s40360-022-00583-5