Structure of 5108-96-3
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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.
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Keywords: Dahuang Zhechong pill ; Liver sinusoidal endothelial cells ; Integrin ; Liver cirrhosis ; Hepatocellular carcinoma
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Midkine mediates dysfunction of liver sinusoidal endothelial cells through integrin α4 and α6
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.
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Keywords: Liver sinus endothelial cells ; Midkine ; Integrins ; Sinusoidal capillarization ; Pathological angiogenesis ; Hepatocellular carcinoma
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| 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 |
| GHS Pictogram: |
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| Signal Word: | Warning |
| Hazard Statements: | H315-H319 |
| Precautionary Statements: | P264-P280-P302+P352+P332+P313+P362+P364-P305+P351+P338+P337+P313 |
| Target |
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In Vitro:
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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:
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Species
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Animal Model
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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. |
| 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 |
|
Tags: PDTC Ammonium | Pyrrolidinedithiocarbamate | Ammonium pyrrolidinedithiocarbamate | PDTC | APDC | NF-κB | Nuclear factor-κB | Nuclear factor-kappaB | degradation of IκBα | IκBα | 5108-96-3
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| P102 | Keep out of reach of children. |
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| P221 | Take any precaution to avoid mixing with combustibles |
| P222 | Do not allow contact with air. |
| P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
| P230 | Keep wetted |
| P231 | Handle under inert gas. |
| P232 | Protect from moisture. |
| P233 | Keep container tightly closed. |
| P234 | Keep only in original container. |
| P235 | Keep cool |
| P240 | Ground/bond container and receiving equipment. |
| P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
| P242 | Use only non-sparking tools. |
| P243 | Take precautionary measures against static discharge. |
| P244 | Keep reduction valves free from grease and oil. |
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| P262 | Do not get in eyes, on skin, or on clothing. |
| P263 | Avoid contact during pregnancy/while nursing. |
| P264 | Wash hands thoroughly after handling. |
| P265 | Wash skin thouroughly after handling. |
| P270 | Do not eat, drink or smoke when using this product. |
| P271 | Use only outdoors or in a well-ventilated area. |
| P272 | Contaminated work clothing should not be allowed out of the workplace. |
| P273 | Avoid release to the environment. |
| P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
| P281 | Use personal protective equipment as required. |
| P282 | Wear cold insulating gloves/face shield/eye protection. |
| P283 | Wear fire/flame resistant/retardant clothing. |
| P284 | Wear respiratory protection. |
| P285 | In case of inadequate ventilation wear respiratory protection. |
| P231 + P232 | Handle under inert gas. Protect from moisture. |
| P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
| Code | Phrase |
| P301 | IF SWALLOWED: |
| P304 | IF INHALED: |
| P305 | IF IN EYES: |
| P306 | IF ON CLOTHING: |
| P307 | IF exposed: |
| P308 | IF exposed or concerned: |
| P309 | IF exposed or if you feel unwell: |
| P310 | Immediately call a POISON CENTER or doctor/physician. |
| P311 | Call a POISON CENTER or doctor/physician. |
| P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
| P313 | Get medical advice/attention. |
| P314 | Get medical advice/attention if you feel unwell. |
| P315 | Get immediate medical advice/attention. |
| P320 | |
| P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
| P321 | |
| P322 | |
| P330 | Rinse mouth. |
| P331 | Do NOT induce vomiting. |
| P332 | IF SKIN irritation occurs: |
| P333 | If skin irritation or rash occurs: |
| P334 | Immerse in cool water/wrap n wet bandages. |
| P335 | Brush off loose particles from skin. |
| P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
| P337 | If eye irritation persists: |
| P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
| P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
| P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
| P342 | If experiencing respiratory symptoms: |
| P350 | Gently wash with plenty of soap and water. |
| P351 | Rinse cautiously with water for several minutes. |
| P352 | Wash with plenty of soap and water. |
| P353 | Rinse skin with water/shower. |
| P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
| P361 | Remove/Take off immediately all contaminated clothing. |
| P362 | Take off contaminated clothing and wash before reuse. |
| P363 | Wash contaminated clothing before reuse. |
| P370 | In case of fire: |
| P371 | In case of major fire and large quantities: |
| P372 | Explosion risk in case of fire. |
| P373 | DO NOT fight fire when fire reaches explosives. |
| P374 | Fight fire with normal precautions from a reasonable distance. |
| P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
| P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
| P378 | |
| P380 | Evacuate area. |
| P381 | Eliminate all ignition sources if safe to do so. |
| P390 | Absorb spillage to prevent material damage. |
| P391 | Collect spillage. Hazardous to the aquatic environment |
| P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
| P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
| P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
| P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
| P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
| P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
| P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
| P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
| P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
| P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
| P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
| P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
| P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
| P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
| P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
| P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
| P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
| P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
| P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
| P370 + P376 | In case of fire: Stop leak if safe to Do so. |
| P370 + P378 | In case of fire: |
| P370 + P380 | In case of fire: Evacuate area. |
| P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
| P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
| Code | Phrase |
| P401 | |
| P402 | Store in a dry place. |
| P403 | Store in a well-ventilated place. |
| P404 | Store in a closed container. |
| P405 | Store locked up. |
| P406 | Store in corrosive resistant/ container with a resistant inner liner. |
| P407 | Maintain air gap between stacks/pallets. |
| P410 | Protect from sunlight. |
| P411 | |
| P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
| P413 | |
| P420 | Store away from other materials. |
| P422 | |
| P402 + P404 | Store in a dry place. Store in a closed container. |
| P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
| P403 + P235 | Store in a well-ventilated place. Keep cool. |
| P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
| P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
| P411 + P235 | Keep cool. |
Disposal | |
| Code | Phrase |
| P501 | Dispose of contents/container to ... |
| P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
| Code | Phrase |
| H200 | Unstable explosive |
| H201 | Explosive; mass explosion hazard |
| H202 | Explosive; severe projection hazard |
| H203 | Explosive; fire, blast or projection hazard |
| H204 | Fire or projection hazard |
| H205 | May mass explode in fire |
| H220 | Extremely flammable gas |
| H221 | Flammable gas |
| H222 | Extremely flammable aerosol |
| H223 | Flammable aerosol |
| H224 | Extremely flammable liquid and vapour |
| H225 | Highly flammable liquid and vapour |
| H226 | Flammable liquid and vapour |
| H227 | Combustible liquid |
| H228 | Flammable solid |
| H229 | Pressurized container: may burst if heated |
| H230 | May react explosively even in the absence of air |
| H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
| H240 | Heating may cause an explosion |
| H241 | Heating may cause a fire or explosion |
| H242 | Heating may cause a fire |
| H250 | Catches fire spontaneously if exposed to air |
| H251 | Self-heating; may catch fire |
| H252 | Self-heating in large quantities; may catch fire |
| H260 | In contact with water releases flammable gases which may ignite spontaneously |
| H261 | In contact with water releases flammable gas |
| H270 | May cause or intensify fire; oxidizer |
| H271 | May cause fire or explosion; strong oxidizer |
| H272 | May intensify fire; oxidizer |
| H280 | Contains gas under pressure; may explode if heated |
| H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
| H290 | May be corrosive to metals |
Health hazards | |
| Code | Phrase |
| H300 | Fatal if swallowed |
| H301 | Toxic if swallowed |
| H302 | Harmful if swallowed |
| H303 | May be harmful if swallowed |
| H304 | May be fatal if swallowed and enters airways |
| H305 | May be harmful if swallowed and enters airways |
| H310 | Fatal in contact with skin |
| H311 | Toxic in contact with skin |
| H312 | Harmful in contact with skin |
| H313 | May be harmful in contact with skin |
| H314 | Causes severe skin burns and eye damage |
| H315 | Causes skin irritation |
| H316 | Causes mild skin irritation |
| H317 | May cause an allergic skin reaction |
| H318 | Causes serious eye damage |
| H319 | Causes serious eye irritation |
| H320 | Causes eye irritation |
| H330 | Fatal if inhaled |
| H331 | Toxic if inhaled |
| H332 | Harmful if inhaled |
| H333 | May be harmful if inhaled |
| H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
| H335 | May cause respiratory irritation |
| H336 | May cause drowsiness or dizziness |
| H340 | May cause genetic defects |
| H341 | Suspected of causing genetic defects |
| H350 | May cause cancer |
| H351 | Suspected of causing cancer |
| H360 | May damage fertility or the unborn child |
| H361 | Suspected of damaging fertility or the unborn child |
| H361d | Suspected of damaging the unborn child |
| H362 | May cause harm to breast-fed children |
| H370 | Causes damage to organs |
| H371 | May cause damage to organs |
| H372 | Causes damage to organs through prolonged or repeated exposure |
| H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
| Code | Phrase |
| H400 | Very toxic to aquatic life |
| H401 | Toxic to aquatic life |
| H402 | Harmful to aquatic life |
| H410 | Very toxic to aquatic life with long-lasting effects |
| H411 | Toxic to aquatic life with long-lasting effects |
| H412 | Harmful to aquatic life with long-lasting effects |
| H413 | May cause long-lasting harmful effects to aquatic life |
| H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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