Pharmacological targeting cGAS/STING/NF-κB axis by tryptanthrin induces microglia polarization toward M2 phenotype and promotes functional recovery in a mouse model of spinal cord injury

Article

Author: Jia, Mengxian ; Fan, Ziwei ; Lin, Xiaowu ; Fang, Zheyu ; Chen, Sibing ; Lian, Jiashu ; Wang, Ying ; Yue, Juanqing ; Dong, Jianhong ; Zhu, Zhoule ; Huang, Zhihui ; Xue, Xiumin ; Liu, Yuqing ; Qian, Yiming ; Teng, Honglin ; Zhou, Jian ; Hua, Xin ; Zhu, Minyu ; Wu, Yumin

JOURNAL/nrgr/04.03/01300535-202511000-00031/figure1/v/2025-03-16T134409Z/r/image-tiff The M1/M2 phenotypic shift of microglia after spinal cord injury plays an important role in the regulation of neuroinflammation during the secondary injury phase of spinal cord injury. Regulation of shifting microglia polarization from M1 (neurotoxic and proinflammatory type) to M2 (neuroprotective and anti-inflammatory type) after spinal cord injury appears to be crucial. Tryptanthrin possesses an anti-inflammatory biological function. However, its roles and the underlying molecular mechanisms in spinal cord injury remain unknown. In this study, we found that tryptanthrin inhibited microglia-derived inflammation by promoting polarization to the M2 phenotype in vitro. Tryptanthrin promoted M2 polarization through inactivating the cGAS/STING/NF-κB pathway. Additionally, we found that targeting the cGAS/STING/NF-κB pathway with tryptanthrin shifted microglia from the M1 to M2 phenotype after spinal cord injury, inhibited neuronal loss, and promoted tissue repair and functional recovery in a mouse model of spinal cord injury. Finally, using a conditional co-culture system, we found that microglia treated with tryptanthrin suppressed endoplasmic reticulum stress–related neuronal apoptosis. Taken together, these results suggest that by targeting the cGAS/STING/NF-κB axis, tryptanthrin attenuates microglia–derived neuroinflammation and promotes functional recovery after spinal cord injury through shifting microglia polarization to the M2 phenotype.

01 Jul 2025·Journal of Molecular Structure

Synthesis and anticancer evaluation of tryptanthrin appended spiro1-nitropyrrolizidine derivatives by the three-component reaction of tryptanthrin, l-proline and β-nitrostyrene

Author: Sandhya, K. S. ; Gouri, R. ; Deepthi, Ani ; Meenakshy, C. B. ; Lekshmi, D. K. S.

Tryptanthrin incorporated 1-nitropyrrolizidines were synthesized with high regiospecificity in diastereomerically pure forms by the one-pot three component reaction of tryptanthrin, L-proline and β-nitrostyrene.The cis-relationship between the protons in carbons 1, 2 and 8 of the products 4a-p was confirmed by 1D NOE anal. and further support for the cis-cycloadduct formation, through endo attack of S-shaped ylide, was gained computationally.In silico docking studies, revealed that compounds 4j and 4k were the best candidates for anticancer screening and further in vitro anal. of these compounds against human breast cancer cell line-MCF-7 indicated mild activity with IC₅₀ values 41.57 ± 0.41 μg/mL and 65.94 ± 0.34 μg/mL resp.from ADMET-AI web server indicated the higher bioavailability value with a good BBB (Blood Brain Barrier) penetration score of 0.80 and 0.77 for 4j and 4k resp.Also, both the compounds exhibited good human intestinal absorption (HIA) value, less carcinogenicity (0.41 and 0.42) and high excretion rate (91.55 % and 89.96 %).

01 May 2025·Toxicology and Applied Pharmacology

Tryptanthrin alleviate lung fibrosis via suppression of MAPK/NF-κB and TGF-β1/SMAD signaling pathways in vitro and in vivo

Article

Author: Niu, Min ; Deng, Xiang-Min ; Lv, Ting-Ting ; Hua, Zheng-Ying ; Wu, Xin ; Wang, Yong-Zhi

Idiopathic pulmonary fibrosis (IPF), a progressive interstitial lung disease of unknown etiology, remains a therapeutic challenge with limited treatment options. This study investigates the therapeutic potential and molecular mechanisms of Tryptanthrin, a bioactive indole quinazoline alkaloid derived from Isatis tinctoria L., in pulmonary fibrosis. In a bleomycin-induced murine IPF model, Tryptanthrin administration (5 and 10 mg/kg/day for 28 days) significantly improved pulmonary function parameters and attenuated histological evidence of fibrosis. Mechanistic analysis revealed dual pathway modulation: Tryptanthrin suppressed MAPK/NF-κB signaling through inhibition of phosphorylation events, subsequently reducing pulmonary levels of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). Concurrently, it attenuated TGF-β1/Smad pathway activation by decreasing TGF-β1 expression and Smad2/3 phosphorylation, thereby downregulating fibrotic markers including COL1A1, α-smooth muscle actin (α-SMA), and fibronectin in lung tissues. Complementary in vitro studies using Lipopolysaccharide (LPS) or TGF-β1-stimulated NIH3T3 fibroblasts confirmed these anti-inflammatory and anti-fibrotic effects through analogous pathway inhibition. Our findings demonstrate that Tryptanthrin exerts therapeutic effects against pulmonary fibrosis via coordinated modulation of both inflammatory (MAPK/NF-κB) and fibrotic (TGF-β1/Smad) signaling cascades, suggesting its potential as a novel multi-target therapeutic agent for IPF management.

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Indication	Highest Phase	Country/Location	Organization	Date
Inflammation	Preclinical	China	Shaanxi University of Traditional Chinese Medicine	03 Jul 2024
Pressure Ulcer	Preclinical	China	The First Affiliated Hospital of Wenzhou Medical College	01 Mar 2024

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