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Chemical Structure| 314054-00-7 Chemical Structure| 314054-00-7

Structure of C-176
CAS No.: 314054-00-7

Chemical Structure| 314054-00-7

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C-176 is a STING inhibitor with anti-inflammatory effection.

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Product Citations

Product Citations

Wu, Yu-tong ; Xu, Wen-ting ; Zheng, Li ; Wang, Sheng ; Wei, Juan ; Liu, Mei-yun , et al.

Abstract: Acute respiratory distress syndrome (ARDS) is a high-mortality pulmonary disorder characterized by an intense inflammatory response and a cytokine storm. As of yet, there is no proven effective therapy for ARDS. Itaconate, an immunomodulatory derivative accumulated during inflammatory macrophage activation, has attracted widespread attention for its potent anti-inflammatory and anti-oxidative properties. This study pointed to explore the protective impacts of 4-octyl itaconate (4-OI) on ARDS. The results showed that lung injury was attenuated markedly after 4-OI pre-treatment, as represented by decreased pulmonary edema, inflammatory cell infiltration, and production of inflammatory factors. LPS stimulation induced NLRP3-mediated pyroptosis in vitro and in vivo, as represented by the cleavage of gasdermin D (GSDMD), IL-18 and IL-1β release, and these changes could be prevented by 4-OI pretreatment. Mechanistically, 4-OI eliminated mitochondrial reactive oxygen species (mtROS) and mtDNA escaping to the cytosol through the opening mitochondrial permeability transition pore (mPTP) in alveolar macrophages (AMs) under oxidative stress. In addition, 4-OI pretreatment markedly down_x005f_x0002_regulated cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING) expression, and interferon regulatory factor 3 (IRF3) phosphorylation in vitro and in vivo. Meanwhile, inhibition of STING/IRF3 pathway alleviated NLRP3-mediated pyroptosis induced by LPS in vitro. Taken together, this study indicated that 4-OI ameliorated ARDS by rescuing mitochondrial dysfunction and inhibiting NLRP3-mediated macrophage pyroptosis in a STING/IRF3-dependent manner, which further revealed the potential mechanism of itaconate in preventing inflammatory diseases.

Keywords: 4-octyl itaconate ; Acute respiratory distress syndrome ; NLRP3 inflammasome ; Macrophage pyroptosis ; Mitochondrial dysfunction ; cGAS/STING pathway

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Product Details of C-176

CAS No. :314054-00-7
Formula : C11H7IN2O4
M.W : 358.09
SMILES Code : O=C(C1=CC=C([N+]([O-])=O)O1)NC2=CC=C(I)C=C2
MDL No. :MFCD00784208
InChI Key :JBIKQXOZLBLMKI-UHFFFAOYSA-N
Pubchem ID :1103958

Safety of C-176

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Isoform Comparison

Biological Activity

In Vitro:

Cell Line
Concentration Treated Time Description References
HK-2 cells 3 μM 48 h Inhibited STING signaling pathway, alleviated hypoxia-induced fibrosis and inflammatory responses Cell Death Discov. 2024 Jul 7;10(1):314.
dTHP-1 cells 1 μM 1 h Pretreatment with C-176 significantly decreased the mRNA expression of IFN-β and IL-1β and slightly reduced the phosphorylation of NF-κB p65. Additionally, C-176 pretreatment suppressed the cleavage of caspase-1 and GSDMD, indicating that the STING signaling pathway is not involved in noncanonical inflammasome activation during HAdV infection. Front Immunol. 2023 Apr 18;14:1169968.
MPC5 mouse podocytes 1 µM C176 ameliorated palmitic acid (PA)-induced podocyte injury, as evidenced by restored protein levels of nephrin and podocin, reduced apoptosis, decreased phosphorylation of TBK1 and NF-κB p65, and reduced levels of IL-6 and TNF-α. iScience. 2022 Sep 16;25(10):105145.
H446 cells 1 μM 48 h To detect the expression levels of STING pathway-related proteins. The results showed that the protein expression levels of p-IRF3 and p-STING decreased after treatment with C-176 Cell Death Discov. 2023 Aug 5;9(1):289.
H1688 cells 1 μM 48 h To detect the expression levels of STING pathway-related proteins. The results showed that the protein expression levels of p-IRF3 and p-STING decreased after treatment with C-176 Cell Death Discov. 2023 Aug 5;9(1):289.
BV2 cells 0.5 μM 1 h To investigate the anti-inflammatory effects and mechanisms of C-176 in an in vitro SAH model, results showed that C-176 significantly decreased the expression of M1 microglial markers and upregulated AMPK phosphorylation. J Neuroinflammation. 2020 May 25;17(1):165.

In Vivo:

Species
Animal Model
Administration Dosage Frequency Description References
Mice Oxidative stress-induced retina degeneration model Intraperitoneal injection 10 mg/kg Once daily for 3 days C176 inhibited SI-induced cGAS-STING activation and reduced retina destruction and subretinal immune cell infiltration. Cell Death Differ. 2022 Sep;29(9):1816-1833
Mice Unilateral ureteral obstruction (UUO) model Intraperitoneal injection 750 nM/mouse Once daily for 14 days Inhibited STING signaling pathway, alleviated UUO-induced renal fibrosis and inflammation Cell Death Discov. 2024 Jul 7;10(1):314.
Mice LLC lung metastasis model Intraperitoneal injection 13.4 mg/kg Once daily for 24 days STING inhibition significantly reversed the STING-activated DC maturation and migration in Tfam-/- mice and promoted tumor progression and metastasis J Immunother Cancer. 2023 Mar;11(3):e005430
Mice Subcutaneous xenograft model Intraperitoneal injection 5 mg/kg Once daily for 7 days To evaluate the effect of C-176 on the GPR162-STING signaling pathway induced by radiotherapy, results showed that C-176 significantly reduced the anti-tumor effect of radiotherapy Signal Transduct Target Ther. 2023 Feb 1;8(1):48
Mice CKD/ApoE−/− mice Intraperitoneal injection 4 mg/kg Every other day for 12 weeks Significantly retarded AS progression and improved plaque vulnerability Adv Sci (Weinh). 2021 Jan 6;8(5):2002738.
Mice Db/db mice Intraperitoneal injection 5 mg/kg Once daily for 21 consecutive days C176 inhibited the cGAS-STING pathway and ameliorated podocyte injury in db/db mice, as evidenced by reduced microalbuminuria, alleviated glomerular hypertrophy and mesangial expansion, restored nephrin levels, and reduced podocyte apoptosis. iScience. 2022 Sep 16;25(10):105145.
C57BL/6J mice Subarachnoid hemorrhage (SAH) model Intraperitoneal injection 750 nM, 200 μL Single dose, 30 minutes post-modeling To investigate the neuroprotective effects and mechanisms of C-176 in an SAH model, results showed that C-176 significantly attenuated brain edema, neuronal injury, and improved both short-term and persistent neurological dysfunction, with its anti-inflammatory effects partially mediated by AMPK signaling. J Neuroinflammation. 2020 May 25;17(1):165.

Clinical Trial:

NCT Number Conditions Phases Recruitment Completion Date Locations
NCT01308658 Healthy Phase 1 Completed - Germany ... More >> Berlin, Germany Less <<

Protocol

Bio Calculators
Preparing Stock Solutions 1mg 5mg 10mg

1 mM

5 mM

10 mM

2.79mL

0.56mL

0.28mL

13.96mL

2.79mL

1.40mL

27.93mL

5.59mL

2.79mL

Dissolving Methods
Please choose the appropriate dissolution scheme according to your animal administration guide.For the following dissolution schemes, clear stock solution should be prepared according to in vitro experiments, and then cosolvent should be added in turn:

in order to ensure the reliability of the experimental results, the clarified stock solution can be properly preserved according to the storage conditions; The working fluid for in vivo experiment is recommended to be prepared now and used on the same day;

The percentage shown in front of the following solvent refers to the volume ratio of the solvent in the final solution; If precipitation or precipitation occurs in the preparation process, it can be assisted by heating and/or ultrasound.
Protocol 1
Protocol 2

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