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Chemical Structure| 5108-96-3 Chemical Structure| 5108-96-3

Structure of 5108-96-3

Chemical Structure| 5108-96-3

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Pyrrolidinedithiocarbamate ammonium (Ammonium pyrrolidinedithiocarbamate) is a selective NF-κB inhibitor that can cross the blood-brain barrier (BBB).

Synonyms: Pyrrolidinedithiocarbamate ammonium; Ammonium pyrrolidinedithiocarbamate; MUN 08963

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Fu, Chuankui ; Zhang, Yiheng ; jie Xi, Wen ; Xu, Kejia ; Meng, Fansheng ; Ma, Tianle , et al.

Abstract: Ethnopharmacological relevance: Dahuang Zhechong pill (DHZCP), a traditional Chinese medicine, was derived from the famous book Unk “Synopsis of Prescriptions of the Golden Chamber” during the Han dynasty. Owing to its ability to invigorate the circulation of blood in Chinese medicine, DHZCP is usually used for treating liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Clinical application have shown that DHZCP exhibits satisfactory therapeutic effects in HCC adjuvant therapy; however, little is known about its underlying mechanisms. Aim of the study: We aimed to clarify the mechanism of DHZCP against hepatic sinusoidal capillarization in rats with LC and HCC by inhibiting the MK/integrin signaling pathway of liver sinusoidal endothelial cells (LSECs). Materials and methods: The contents of 29 characteristic components in DHZCP were determined by ultraperformance liquid chromatography-tandem mass spectrometry. DEN (Diethylnitrosamine)-induced LC and HCC rat models were constructed, and DHZCP was administered when the disease entered the LC stage. After 4 or 12 weeks of administration, hematoxylin and eosin staining, Masson staining, Metavir score, and SSCP (Single strand conformation polymorphism) gene mutation detection were used to confirm tissue fibrosis and cancer. The levels of NO, ET-1 and TXA2, which can regulate vasomotor functions and activate the MK/Itgα6/Src signaling pathway were evaluated by using immunohistochemistry, chemiluminescence, immunofluorescence, Western blot analysis, and enzyme-linked immunosorbent assay (ELISA). Similar methods were also used to evaluate the levels of VEGF, VEGFR, Ang-2 and Tie, which can promote pathological angiogenesis and activate the MK/Itgα4/NF-κB signaling pathway. In vitro cell experiments were performed using potential pharmacodynamic molecules targeting integrins in DHZCP were selected by molecular docking, and the effects of these molecules on the function of LSECs were studied by Itgα4+ and Itgα6+ cell models. Results: At the stage of LC, the animal experiments demonstrated that DHZCP mainly inhibited the MK/Itgα6 signaling pathway to increase the number and size of hepatic sinus fenestration, reversed the ET-1/NO and TXA2/NO ratios, regulated hepatic sinus relaxation and contraction balance, reduced the portal vein pressure, and inhibited cirrhotic carcinogenesis. At the HCC stage, DHZCP could also significantly inhibit the MK/Itgα4 signaling pathway, reduce pathological angiogenesis, and alleviate disease progression. The results of the cell experiments showed that Rhein, Naringenin, Liquiritin and Emodin-8-O-β-D-glucoside (PMEG) were involved in vascular regulation by affecting the MK/integrin signaling pathway. Liquiritin and PMEG mainly blocked the MK/α6 signal, which is important in regulating the vasomotor function of the liver sinus. Naringenin and Rhein mainly acted by blocked the signaling of MK/α4 action signal, which are potent molecules that inhibit pathological angiogenesis. Conclusions: DHZCP could improve the hepatic sinusoidal capillarization of LC and HCC by inhibiting the MK/Itgα signaling pathway and inhibited disease progression. Rhein, Naringenin, Liquiritin and PMEG were the main active molecules that affected the MK/Itgα signaling pathway.

Keywords: Dahuang Zhechong pill ; Liver sinusoidal endothelial cells ; Integrin ; Liver cirrhosis ; Hepatocellular carcinoma

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Wu, Li ; Chen, Honglin ; Fu, Chuankui ; Xing, Mulan ; Fang, Huihua ; Yang, Furong , et al.

Abstract: Midkine (MK)2 is an important regulatory molecule that promotes pathological angiogenesis of hepatocellular carcinoma (HCC). Although some studies have shown that its expression is increased in chronic liver disease, its effect on sinusoidal vasculopathy are still unclear. In this study, we demonstrated that MK was mainly secreted by liver sinus endothelial cells (LSECs) during the stage of precancerous lesions. Increased expression of its receptor integrin was an important mechanism by which MK participated in sinusoidal vasculopathy through autocrine and positive feedback effects. LSECs with high expression of integrin α6 (Itgα6+) and integrin α4 (Itgα4+) were used to study the mechanism of MK, and it was found that the effect of MK on LSECs was closely related to the integrin subtypes. The activation of MK /integrin α6/Src/Shc signaling pathway promoted the expression of ET-1, TXA2 and reduced the production of NO, and then induced the capillary vascularization of liver sinusoids, while the activation of MK/integrin α4/NF-κB pathway mainly induced angiogenesis by promoting the production of VEGF and Ang2. In the three-dimensional co-culture system of hepatocytes (BRL-3A) and LSECs, MK significantly increased the production of reactive oxygen species (ROS) in the co-culture system of highly expressed integrin LSECs and decreased the expression of tumor suppressor gene P53 in hepatocytes. These results suggested that MK /integrin signaling pathway, especially MK /integrin α6, was an important mechanism leaded to persistent sinusoidal hepatic vasculopathy in chronic liver disease and induced HCC, while MK/integrin α4 activation was more involved in pathological angiogenesis.

Keywords: Liver sinus endothelial cells ; Midkine ; Integrins ; Sinusoidal capillarization ; Pathological angiogenesis ; Hepatocellular carcinoma

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Alternative Products

Product Details of Ammonium pyrrolidine-1-carbodithioate

CAS No. :5108-96-3
Formula : C5H12N2S2
M.W : 164.29
SMILES Code : [S-]C(N1CCCC1)=S.[NH4+]
Synonyms :
Pyrrolidinedithiocarbamate ammonium; Ammonium pyrrolidinedithiocarbamate; MUN 08963
MDL No. :MFCD00012720

Safety of Ammonium pyrrolidine-1-carbodithioate

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H315-H319
Precautionary Statements:P264-P280-P302+P352+P332+P313+P362+P364-P305+P351+P338+P337+P313

Related Pathways of Ammonium pyrrolidine-1-carbodithioate

pyroptosis

Isoform Comparison

Biological Activity

Target
  • NF-κB

In Vitro:

Cell Line
Concentration Treated Time Description References
ADSCs 30 μM PDTC was used to block p-p65 activity to reduce ROS production and cell apoptosis. Burns Trauma. 2022 Mar 14;10:tkac001.
AGS cells 20 or 40 μM 4 h PDTC significantly reduced DCF fluorescence in H. pylori-infected or hydrogen peroxide-treated cells, indicating that PDTC inhibited STAMBPL1 degradation. Cell Mol Life Sci. 2022 Jan 23;79(2):86.
A549 cells 10, 50, 100, 300, 500 μM 4 h To investigate the role of PDTC on the NF-κB signaling pathway in A549 cells, results showed that PDTC pretreatment significantly increased the frequency of CD4+T cells and decreased the frequencies of Tregs and CD45RA+Tregs. J Transl Med. 2014 Nov 11;12:304.
peripheral blood leukocytes (PBLs) 0.5 μM 6 h to investigate the inhibitory effect of PDTC on the mRNA expressions of IL-1β and CXCL11 induced by rPf_IL-17A/F1, 2, and 3 proteins Front Immunol. 2021 Jun 29;12:626895.
mouse primary astrocytes 200 nM 6 h To investigate the effect of PDTC on tau PFF-induced inflammatory response in astrocytes, results showed that PDTC significantly inhibited tau PFF-induced NFκB signaling activation. Cell Biosci. 2023 Sep 27;13(1):179.
Caco-2 cells 50 μM 4 h To verify whether the elevation of AANAT expression resulting from gut microbiota alterations depends on NF-κB signaling Gut Microbes. 2024 Jan-Dec;16(1):2313769.
Bone marrow-derived macrophages (BMDMs) 5 µg/ml 24 h To investigate the inhibitory effect of PDTC on NF-ĸB p65 phosphorylation. The results showed that PDTC could inhibit N-protein-induced NF-ĸB p65 phosphorylation, thereby alleviating the inflammatory response. Front Immunol. 2021 Dec 7;12:791753.
RAW264.7 cells 100 μM 1 h PDTC, as a positive control, significantly suppressed TNF-α and IL-6 production in LPS-stimulated RAW264.7 cells, with inhibition rates of 90% and 55%, respectively. J Biomed Sci. 2009 Jul 14;16(1):64.

In Vivo:

Species
Animal Model
Administration Dosage Frequency Description References
Mice Colorectal cancer xenograft model Intraperitoneal injection 250 mg/kg Single dose PDTC enhanced the activity of 5-FU in a colorectal cancer xenograft model and reduced gastrointestinal toxicity associated with 5-FU therapy in the large bowel but not in the small bowel. Br J Cancer. 2006 Jul 3;95(1):35-41
Mice Myd88ΔIEC mice Drinking water 1 g/L Two weeks To investigate how gut microbiota regulates host melatonin production through MyD88 signaling Gut Microbes. 2024 Jan-Dec;16(1):2313769.
Mice Acute lung injury model Intraperitoneal injection 50 mg/kg Single injection, lasting 24 hours To investigate the inhibitory effect of PDTC on N-protein-induced acute lung injury. The results showed that PDTC could alleviate N-protein-induced lung injury, reducing total protein concentration, total cell count, and neutrophil infiltration in the bronchoalveolar lavage fluid. Front Immunol. 2021 Dec 7;12:791753.
BALB/c mice LPS-induced acute inflammation model Intraperitoneal injection 50 mg/kg Once, 1 hour before LPS challenge The PDTC group significantly reduced serum levels of TNF-α, IL-6, and IL-1β at 9 hours after LPS challenge and significantly increased the survival rate. J Biomed Sci. 2009 Jul 14;16(1):64.

Protocol

Bio Calculators
Preparing Stock Solutions 1mg 5mg 10mg

1 mM

5 mM

10 mM

6.09mL

1.22mL

0.61mL

30.43mL

6.09mL

3.04mL

60.87mL

12.17mL

6.09mL

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