Elucidating hydroxysafflor yellow A's multi-target mechanisms against alcoholic liver disease through integrative pharmacology.
Alcoholic liver disease (ALD) significantly contributes to global liver-related morbidity and mortality. Natural products play a crucial role in the prevention and treatment of ALD. Hydroxysafflor yellow A (HSYA), a unique and primary component of Safflower (Carthamus tinctorius l.), exhibits diverse pharmacological activities. However, the impact and mechanism of HSYA on ALD have not been fully elucidated.
The purpose of this study was to employ an integrative pharmacology approach to assess the multi-targeted mechanism of HSYA against ALD.
Network pharmacology and molecular docking techniques were used to analyze the potential therapeutic signaling pathways and targets of HSYA against ALD. An ALD model in zebrafish larvae was established. Larvae were pretreated with HSYA and then exposed to ethanol. Liver injury was measured by fluorescence expression analysis in the liver-specific transgenic zebrafish line Tg (fabp10a:DsRed) and liver tissue H&E staining. Liver steatosis was determined by whole-mount oil red O staining and TG level. Additionally, an ethanol-induced hepatocyte injury model was established in vitro to observe hepatocyte damage (cell viability, ALT level), lipid accumulation (oil red O staining, TC and TG), and oxidative stress (ROS, MDA, GPx and SOD) in HepG2 cells treated with or without HSYA. Finally, qRT-PCR combined with network pharmacology and molecular docking was employed to validate the effects of HSYA on targets.
HSYA exhibited a significant, dose-dependent improvement in ethanol-induced liver injury in zebrafish larvae and HepG2 cells. Network pharmacology analysis revealed that HSYA may exert pharmacological effects against ALD through 341 potential targets. These targets are involved in various signaling pathways, including lipid metabolism and atherosclerosis, PI3K-Akt signaling pathway, MAPK signaling pathway, and ALD itself. Molecular docking studies displayed that HSYA had a strong binding affinity toward the domains of IL1B, IL6, TNF, PPARA, PPARG, HMGCR and ADH5. qRT-PCR assays demonstrated that HSYA effectively reversed the ethanol-induced aberrant gene expression of SREBF1, FASN, ACACA, CPT1A, PPARA, IL1B, IL6, TNFα, ADH5, and ALDH2 in vivo and in vitro.
This study offers a comprehensive investigation into the anti-ALD mechanisms of HSYA using an integrative pharmacology approach. The potential targets of HSYA may be implicated in enhancing ethanol catabolism, reducing lipid accumulation, mitigating oxidative stress, and inhibiting inflammatory response.
Yu HC
，Bai QR
，Guo JJ
，Chen MY
，Wang L
，Tong FC
，Zhang SL
，Wu J
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Hydroxysafflor yellows alleviate thrombosis and acetaminophen-induced toxicity in vivo by enhancing blood circulation and poison excretion.
Hydroxysafflor yellow A (HSYA) from the flower of Carthamus tinctorius (Safflower) has been reported to have various pharmacological effects. However, little is known about the bioactivities of other chemical constituents in Safflower and the relationship between enhancement of blood circulation and hepatoprotection by HSYA.
The present research was to evaluate the antithrombotic and hepatoprotective activities of HSYA and C, examine their mechanisms of actions, including influence on the excretion velocity of acetaminophen, and the relationship between the antithrombotic, hepatoprotective, and other bioactivities.
The hepatoprotective activities were examined by acetaminophen (APAP)-induced zebrafish toxicity and carbon tetrachloride (CCl4)-induced mouse liver injury. The concentrations of APAP in zebrafish and APAP that was excreted to the culture media were quantified by UHPLC-MS. The anti-thrombosis effect of HSYA and C were examined by the phenylhydrazine (PHZ)-induced zebrafish thrombosis.
HSYA and HSYC showed robust protection on APAP-induced toxicity and PHZ-induced thrombosis. The hepatoprotective effects of HSYA and C were more potent than that of the positive control, acetylcysteine (61.7% and 58.0%, respectively, vs. 56.9% at 100 µM) and their antithrombosis effects were more robust than aspirin (95.1% and 86.2% vs. 52.7% at 100 µM). HSYA and C enhanced blood circulation, rescued APAP-treated zebrafish from morphological abnormalities, and mitigated APAP-induced toxicity in liver development in liver-specific RFP-expressing transgenic zebrafish. HSYC attenuated CCl4-induced mouse liver injury and regulated the levels of HIF-1α, iNOS, TNF-α, α-SMA, and NFκB in liver tissues. HSYA was also protective in a dual thrombotic and liver toxicity zebrafish model. By UHPLC-MS, HSYA accelerated the excretion of APAP.
HSYA and C are the bioactive constituents of Safflower that are responsible for the herbal drug's traditional use in promoting blood circulation to remove blood stasis. Safflower and its chalcone constituents may protect from damage due to exogenous or disease-induced endogenous toxins by enhancing the excretion velocity of toxins.
Wang LW
，Cui XY
，He JF
，Duan S
，Liu CR
，Shan CB
，Wang Y
，Ma CM
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The raw and vinegar-processed Curcuma phaeocaulis Val. ameliorate TAA-induced zebrafish liver injury by inhibiting TLR4/MyD88/NF-κB signaling pathway.
Liver injury, the main factor in the pathogenesis of most liver diseases, is a known contributor to acute liver failure, liver fibrosis, or liver cancer. Curcuma phaeocaulis Val. (PEZ) has been broadly used in treating liver injury with satisfying therapeutic effects; however, the mechanism is still unclear.
This study aimed to explore the mechanism of PEZ in ameliorating thioacetamide (TAA)-induced zebrafish liver injury based on a comprehensive method integrating network-based computational prediction and experimental validations.
Ultrahigh-performance liquid chromatography-quadrupole exactive mass spectrometry/mass spectrometry (UPLC-Q-Exactive MS/MS) analysis was used to analyze components in raw and vinegar-processed PEZ (VPEZ). Network pharmacology was used to construct a compound-target network for liver injury to predict the possible biological targets of PEZ along with potential signaling pathways. TAA-induced zebrafish larvae liver injury model was established, and the anti-liver injury effect of PEZ by a series of indexes was measured, including liver phenotype analysis, histopathological analysis of liver tissues, and biochemical indexes analysis. Remarkably, the predicted pathway by network pharmacology was further validated using RT-qPCR and Western blotting analyzes in animal experiments.
40 chemical constituents derived from PEZ were identified, while 45 chemical components derived from VPEZ were identified. Based on it, 565 genes related to these identified compounds in PEZ and 1023 genes linked to liver injury were collected by network pharmacology. Critically, KEGG analysis indicated that the TLR4/MyD88/NF-κB signaling pathway was recommended as one of the main pathways related to the anti-liver injury effect of PEZ. Experimentally, PEZ could alleviate TAA-induced liver injury. Compared to the liver injury model group without any treatment, the treatment of PEZ significantly reduced the expression of both mRNA and protein targets in the TLR4/MyD88/NF-κB signaling pathway. In addition, the effect of VPEZ was more significant than that of the raw one.
The raw and vinegar-processed PEZ could ameliorate TAA-induced zebrafish liver injury through TLR4/MyD88/NF-κB signaling pathway.
Gao T
，Lin L
，Yang Q
，Zhu Z
，Wang S
，Xie T
，Liao W
... -
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ResearchGate
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