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AMF alleviated the inflammatory response in pleural exudate and lung tissue. (A) Representative microphotographs of lung sections stained with F4/80. (B–D) TNF-α, IL-1β, and IL-10 levels in exudates were measured by ELISA. The data are expressed as the mean ± SEM. n = 5 per group. *p < 0.05 and **p < 0.01 Car group vs. control group; #p < 0.05 and ##p < 0.01 Car + AMF group vs. Car group.
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Many natural flavonoids can activate nuclear factor erythroid 2-related factor 2 (Nrf2), which is pivotal for alleviating various diseases related to inflammation and oxidative stress, including pleurisy. Amentoflavone (AMF), a biflavonoid extracted from many plants, has some beneficial bioactivities, especially anti-inflammatory and antioxidative...
Citations
... Thus, the ability of GXEA and GXM to reduce DCF fluorescence intensity underscores its role as an antioxidant. Morelloflavone (Gil et al. 1997) and amentoflavone (Hou et al. 2022) present in GXEA and GXM were reported to scavenge ROS and exhibit antioxidant activity. ...
Pro-oxidants play a crucial role in cancer by causing oxidative stress that leads to apoptosis. The present study demonstrates the prooxidant and anti-inflammatory potential of ethyl acetate and methanolic extracts of Garcinia xanthochymus fruit. Oxidation of Trolox and NADH activity indicated the pro-oxidant capacity of the extracts. Significant decrease in cell viability in B16F10 and MDA-MB-231 cancer cell lines and significant increase in caspase 3 activity after treatment with extracts indicated pro-oxidant induced apoptosis. Pre-treatment with the extracts significantly inhibited ROS, reduced NO production, inhibited LPS-induced COX-2 and suppressed IL-6 and TNF-α expression. HRMS analysis showed the presence of compounds like biflavonoids, xanthones, phloroglucinols, benzophenones, etc. The fruit is rich in total phenolic and flavonoid contents, and have DPPH radical scavenging, ferric reducing antioxidant and metal chelating potential. This study report for the first time about the anticancer and anti-inflammatory properties of G. xanthochymus whole fruit.
... Of note, our network pharmacology study, RNA-seq analysis and Nrf2 intervene experiments indicate that the Keap1-Nrf2 pathway is the predominant enriched pathway associated with the protective effects of CTS on AAA. In fact, a Nrf2-ROS-NF-κB pathway (84,85), a Nrf2-NF-κB/STAT3 pathway (86,87) and a NF-κB-pyroptosis pathway (88,89) have been well established previously. Collectively, combined with our findings and others, it can be concluded that Nrf2 activation plays a central role in CTS-mediated inhibition of NF-κB/STAT3 signaling, inflammatory response, pyroptosis and AAA formation. ...
Rationale: Abdominal aortic aneurysm (AAA) is an inflammatory, fatal aortic disease that currently lacks any effective drugs. Cryptotanshinone (CTS) is a prominent and inexpensive bioactive substance derived from Salvia miltiorrhiza Bunge, a well-known medicinal herb for treating cardiovascular diseases through its potent anti-inflammatory properties. Nevertheless, the therapeutic effect of CTS on AAA formation remains unknown.
Methods: To investigate the therapeutic effect of CTS in AAA, variety of experimental approaches were employed, majorly including AAA mouse model establishment, real-time polymerase chain reaction (PCR), RNA sequencing, western blot, co-immunoprecipitation, scanning/transmission electron microscopy (SEM/TEM), enzyme-linked immunosorbent assay (ELISA), seahorse analysis, immunohistochemistry, and confocal imaging.
Results: In this study, we demonstrated that CTS suppressed the formation of AAA in apolipoprotein E knock-out (ApoE-/-) mice infused with Ang II. A combination of network pharmacology and whole transcriptome sequencing analysis indicated that activation of the Keap1-Nrf2 pathway and regulation of programmed cell death in vascular smooth muscle cells (VSMCs) are closely linked to the anti-AAA effect of CTS. Mechanistically, CTS promoted the transcription of Nrf2 target genes, particularly Hmox-1, which prevented the activation of NLRP3 and GSDMD-initiated pyroptosis in VSMCs, thereby mitigating VSMC inflammation and maintaining the VSMC contractile phenotype. Subsequently, by utilizing molecular docking, together with the cellular thermal shift assay (CETSA) and isothermal titration calorimetry (ITC), a particular binding site was established between CTS and Keap1 at Arg415. To confirm the binding site, site-directed mutagenesis was performed, which intriguingly showed that the Arg415 mutation eliminated the binding between CTS and the Keap1-Nrf2 protein and abrogated the antioxidant and anti-pyroptosis effects of CTS. Furthermore, VSMC-specific Nrf2 knockdown in mice dramatically reversed the protective action of CTS in AAA and the inhibitory effect of CTS on VSMC pyroptosis.
Conclusion: Naturally derived CTS exhibits promising efficacy as a treatment drug for AAA through its targeting of the Keap1-Nrf2-GSDMD-pyroptosis axis in VSMCs.
... The number of F4/80 + cells significantly increases after the mice are injected with Car in pleural cavity [36]. In this model, oxidative stress emerges as a crucial factor that accelerates inflammation by stimulating substantial inflammatory cell infiltration and the release of inflammatory mediators, which worsens lung injury [37]. ...
... In this model, oxidative stress emerges as a crucial factor that accelerates inflammation by stimulating substantial inflammatory cell infiltration and the release of inflammatory mediators, which worsens lung injury [37]. Neutrophil aggregation and macrophage activation lead to the production of pro-inflammatory cytokines, such as IL-1β, IL-6, IL-17, TNF-α, IFN-γ, iNOS, and COX2, which are closely linked to the severity of pleurisy and lung injury induced by Car [36,38]. Therefore, oxidative stress and subsequent inflammation are identified as the primary causes of Car-induced pleurisy and lung injury. ...
Pleurisy can be categorized as primary or secondary, arising from immunological, tumorous, or microbial conditions. It often results in lung structure damage and the development of various respiratory issues. Among the different types, tuberculous pleurisy has emerged as a prominent focus for both clinical and scientific investigations. The IL-10 family, known for its anti-inflammatory properties in the human immune system, is increasingly being studied for its involvement in the pathogenesis of pleurisy. This review aims to present a detailed overview of the intricate role of IL-10 family members (specifically IL-10, IL-22, and IL-26) in human and animal pleuritic diseases or relevant animal models. These insights could serve as valuable guidance and references for further studies on pleurisy and potential therapeutic strategies.
... A study revealed that amentoflavone suppressed myocarditis response stimulated by ischemia-reperfusion by the NF-κB pathway (Li et al. 2021a), and it also inhibited NLRP3 inflammasome to exert neuroprotective effects on epileptogenesis (Rong et al. 2019). Amentoflavone also promoted Nrf2 activation through suppressing NF-κB/STAT3 (signal transducer and activator of transcription 3) pathways and ameliorated carrageenan-stimulated pleurisy and lung injury (Hou et al. 2022). A report in 2019 showed that amentoflavone was considered to be a lead compound for the treatment of monoiodoacetate (MIA)-stimulated OA model (Vasconcelos et al. 2019). ...
The role of amentoflavone on cartilage injury in knee osteoarthritis (KOA) rats and the underlying mechanism were explored. KOA rat and IL-1β-stimulated chondrocyte models were constructed. MTT, colony formation, and ELISA were performed to determine the cytotoxicity, cell proliferation, and inflammatory factors. The role of PTGS2 in IL-1β-stimulated chondrocytes was also confirmed through transfecting PTGS2 overexpression and silencing plasmids. Further, we analyzed how amentoflavone regulated PTGS2 to improve IL-1β-stimulated chondrocytes in vitro. Additionally, we analyzed the expression of PTGS2 after amentoflavone treatment. In vivo, HE and Safranin-O staining were carried out, and the inflammatory response was detected by ELISA and HE staining. In addition, we also analyzed the regulatory effect of amentoflavone on PTGS2 and explored the mechanism effect of PTGS2 in vitro and in vivo. The results indicated that PTGS2 was the downstream molecule of amentoflavone, which was highly expressed in IL-1β-stimulated chondrocytes and KOA rats, and amentoflavone decreased PTGS2 expression. We also confirmed the potential role of amentoflavone on KOA, which was also characterized by the repair of cartilage injury, reduction of inflammatory infiltration, and improvement of functional disability. Consistent with in vivo results, in vitro experiments gave the same conclusions. Amentoflavone reduced PTGS2 expression in IL-1β-stimulated chondrocytes and inhibited inflammation of chondrocytes via PTGS2. Collectively, the results confirmed that this drug was the potential targeted drug for KOA, whose repair effect on cartilage injury was partly related to PTGS2.
... By combining diferent in vivo and in vitro models (Tables 2 and 3), a study indicates that extracts obtained from A. corniculatum, specifcally methanol and ethyl acetate extracts, exhibit notable inhibitory efects on the chronic infammatory phase and these efects are observed through the suppression of mononuclear cell infltration, fbroblast proliferation, collagen fber production, and connective tissue formation, all of which contribute to the development of granuloma [45]. Carrageenan-induced pleurisy is a very common method used to test anti-infammatory therapeutics [49]. Methanol and ethyl acetate extract of A. corniculatum protects against acute lung infammation by lowering nitrate/nitrite concentrations and MPO enzyme levels and also decreases neutrophils and mononuclear infltration at a higher dose (100 mg/kg) in a mice model of pleurisy [47] ( Table 3). ...
Aegiceras corniculatum, commonly referred to as Khalsi, is a member of the mangrove Myrsinaceae family. The various parts of this plant have been used in traditional medicinal systems for their potential therapeutic effects in conditions such as asthma, microbial infections, diabetes, pain relief, inflammation, cancer, and arthritis. A diverse array of bioactive phytochemicals such as flavonoids, benzoquinones, triterpenes, polyphenolic acids, stilbenes, tannins, and macrolides have been identified in different parts of this plant. The aim of this review was to summarize the bioactive phytoconstituents reported from this plant that are accountable for the observed different pharmacological effects of the plant and further elucidate the possible underlying mechanisms by which these chemicals exert their actions. The search was conducted on various widely used database platforms, including Google Scholar, Scopus, Web of Science, SciFinder, and PubMed. Articles published until July 2023 were extracted and all the information was sorted based on the inclusion and exclusion criteria. The data revealed that anti-inflammatory compounds from this plant suppress iNOS, myeloperoxidase, COX, LOX, and cytokines (like TNF-alpha, IL-1ß, LTB4, IL-12, and IL-6) to reduce inflammation. 5-O-Butyl-embelin, 2-hydroxy-5-ethoxy-3-nonyl1, 4-benzoquinone, 5-O-methylembelin, 5-O-methyl-rapanone, s-saponin, and 5-O-ethylembelin are some phytochemicals of A. corniculatum with anticancer properties, although their mechanism is unclear. A. corniculatum has antibacterial, parasitic, and antifungal effects, but no antiviral effects were reported. The plant-isolated coumaric acid and fatty acids interact with bacterial DNA/RNA and limit protein formation, making them antibacterial. Gallocatechin, epicatechin, epigallocatechin-3-O-gallate, epigallocatechin, and other tannins, as well as flavonoids like kaempferol, quercetin, and isorhamnetin, are some of the compounds in A. corniculatum that may depolarize and change bacterial membranes, showing antibacterial effect. These phenolic chemicals also reduce oxidative stress and help treat cancer and other inflammatory diseases. The extract of this plant activates the κ-opioid receptor, causing central antinociception. Catechol components, such as epigallocatechin-3-O-gallate, protect against CNS illnesses including Parkinson’s disease and amnesia. Despite numerous studies demonstrating various pharmacological advantages of this plant and its constituents, the number of clinical trials conducted on humans remains significantly limited.
... Interestingly, these characteristic effects of SIRT1 inhibition by CPA were dose-dependently mitigated in the present work with the administration of AMV. These favorable effects may be attributed to the ability of AMV to increase the genetic expression of SIRT1 with a subsequent increase in Nrf2 content in the pulmonary tissues, which restores the prooxidant/antioxidant balance to normal values [16,42]. In addition, the enhancement of the histone deacetylase activity of SIRT1 mediated by AMV may underlie the mitigating effects of AMV detected in the present study on the inflammatory cascade [16,43]. ...
Background and objectives: Cyclophosphamide (CPA) is an alkylating agent that is used for the management of various types of malignancies and as an immunosuppressive agent for the treatment of immunological disorders. However, its use is limited by its potential to cause a wide range of pulmonary toxicities. Amentoflavone (AMV) is a flavonoid that had proven efficacy in the treatment of disease states in which oxidative stress, inflammation, and apoptosis may play a pathophysiologic role. This study investigated the potential ameliorative effects of the different doses of AMV on CPA-induced pulmonary toxicity, with special emphasis on its antioxidant, anti-inflammatory, and apoptosis-modulating effects. Materials and methods: In a rat model of CPA-induced pulmonary toxicity, the effect of AMV at two dose levels (50 mg/kg/day and 100 mg/kg/day) was investigated. The total and differential leucocytic counts, lactate dehydrogenase activity, and levels of pro-inflammatory cytokines in the bronchoalveolar lavage fluid were estimated. Also, the levels of oxidative stress parameters, sirtuin-1, Keap1, Nrf2, JAK2, STAT3, hydroxyproline, matrix metalloproteinases 3 and 9, autophagy markers, and the cleaved caspase 3 were assessed in the pulmonary tissues. In addition, the histopathological and electron microscopic changes in the pulmonary tissues were evaluated. Results: AMV dose-dependently ameliorated the pulmonary toxicities induced by CPA via modulation of the SIRT-1/Nrf2/Keap1 axis, mitigation of the inflammatory and fibrotic events, impaction of JAK-2/STAT-3 axis, and modulation of the autophagic and apoptotic signals. Conclusions: AMV may open new horizons towards the mitigation of the pulmonary toxicities induced by CPA.
... In the current study, DOX administration caused remarkable oxidative stress, evidenced by a substantial elevation in MDA levels and significant down-regulation of SOD activity in the cardiac tissue. While treatment with AMF effectively mitigated oxidative stress conditions, these results keep with other reports [23,27,28]. NOX enzymes are an important source of cardiac ROS generation that mediates the Dox semiquinone radical formation by transferring one electron from the NADPH to Dox [1,3]. ...
... In this finding, AMF exerted significant anti-inflammatory effects as manifested by substantial down-regulation of productions and proinflammatory cytokines IL-6 expressions and inhibition of NF-κB signal transduction pathways. These effects are consistent with previous reports [27,28]. Also, AMF's anti-inflammatory effect is confirmed by in vitro studies in which AMF inhibited inflammation via inhibition of NF-κB and inflammatory cytokines such as IL-6, IL-1β, and TNF-α in LPS-induced RAW264.7 cells [34][35][36]. ...
Doxorubicin (DOX) is an available chemotherapeutic drug for treating various tumors. However, its effectiveness is limited by cardiotoxicity. Amentoflavone (AMF), a natural biflavonoid separated from Cycas thouarsii ethyl acetate fraction, displays promising anticancer, anti-inflammatory, and antioxidant effects. Thus, our research aims to explore whether AMF could boost cardioprotective effects against DOX cardiotoxicity and reveal the potential underlying mechanisms of cardioprotection. Mice were classified into four groups; Normal control, Untreated DOX group, and DOX groups treated with AMF (40 and 80 mg/kg, respectively) intraperitoneal injection daily for four days before doxorubicin administration and for additional three days following DOX administration to assess cardiotoxicity. Echocardiography showed that AMF 80 treated group was protected from DOX cardiotoxicity. Additionally, it alleviated histopathological structural alterations and effectively restored heart weight and body weight ratio. These effects were confirmed biochemically by a substantially reduced serum creatine kinase-MB (CK-MB) and aspartate aminotransferase (AST) levels. AMF effectively restored nuclear respiratory factor-1(NRF-1), mitochondrial transcription factor A (TFAM), and normalized heat shock protein − 27(HSP-27) expression levels compared to the DOX group. Moreover, AMF mitigated oxidative stress conditions and significantly suppressed NADPH oxidase (NOX) expression levels. It also showed significant anti-inflammatory effects via suppressing interleukin-6 (IL-6) expression and decreasing nuclear factor Kabba B (NF-κb) immune-staining. In addition, AMF markedly reduced FAS ligand (FASL) expression and p53 immune staining in cardiac tissue. This study is the first for the in vivo potential beneficial effects of AMF against acute DOX cardiotoxicity, possibly via exerting antioxidant, anti-inflammatory, and anti-apoptotic effects and restoring mitochondrial function.
... Persistently activated STAT3 is associated with the proliferation, survival, and invasiveness of tumor cells, including those of breast, lung, pancreatic, and head and neck origin. Recent studies suggested the possibility of the interplay or cross talk between Nrf2 and STAT3 [40,41]. In our studies, RT restrained the phosphorylation of STAT3 and decreased Nrf2 in protein levels, suggesting that the STAT3/Nrf-2 signaling axis might be involved in the mechanism of RT repressing migration and invasion. ...
As one of marine tetrahydroisoquinoline alkaloids, renieramycin T plays a significant role in inhibiting tumor metastasis and invasion. However, the effect of renieramycin T on inflammation-related tumor metastasis and invasion is still unknown, and its mechanisms remain unclear. Here we established an inflammation-related tumor model by using the supernatant of RAW264.7 cells to simulate B16F10 mouse melanoma cells. The results indicate that renieramycin T suppressed RAW264.7 cell supernatant-reduced B16F10 cell adhesion to a fibronectin-coated substrate, migration, and invasion through the matrigel in a concentration-dependent manner. Moreover, Western blot results reveal that renieramycin T attenuated the phosphorylation of STAT3 and down-regulated the expression of Nrf2. Together, the above findings suggest a model of renieramycin T in suppressing B16F10 cancer cell migration and invasion. It may serve as a promising drug for the treatment of cancer metastasis.
... Fascinatingly, these compounds could cross the blood-brain barrier and are known to ameliorate mitochondrial dysfunctions, inflammation, and oxidative stress via modulating different cell signalling pathways (Cao et al. 2017;Chetia Phukan et al. 2022;Siddique and Jyoti 2017;Bitu Pinto et al. 2015;Pan et al. 2020;Wang et al. 2017;Siddique 2021;Liu et al. 2019;Ohia et al. 2001). Prevention of dopaminergic neuronal loss was shown in both cell culture and animal models with these compounds by upregulation of Nrf2 and PI3K/ Akt signaling pathways, thereby reducing the oxidant and inflammatory responses and promoting cell survival and growth (Chung et al. 2019;Chetia Phukan et al. 2022;Hou et al. 2022;Cao et al. 2017;Li et al. 2020;Cheng et al. 2016;Liu et al. 2019;Pan et al. 2020;Xiao et al. 2018;Tsai et al. 2011;Ma et al. 2020;Antala et al. 2012). The referred compounds from G. morella were also reported to provide neuroprotection by suppressing the NF-κB and MAPK signaling pathways and subsequent inflammatory processes (Hou et al. 2022;Chung et al. 2019;Lv et al. 2016;Xiao et al. 2017;Ajiboye et al. 2019;Ma et al. 2020;Li et al. 2020;Kim et al. 2004;Wang et al. 2020). ...
... Prevention of dopaminergic neuronal loss was shown in both cell culture and animal models with these compounds by upregulation of Nrf2 and PI3K/ Akt signaling pathways, thereby reducing the oxidant and inflammatory responses and promoting cell survival and growth (Chung et al. 2019;Chetia Phukan et al. 2022;Hou et al. 2022;Cao et al. 2017;Li et al. 2020;Cheng et al. 2016;Liu et al. 2019;Pan et al. 2020;Xiao et al. 2018;Tsai et al. 2011;Ma et al. 2020;Antala et al. 2012). The referred compounds from G. morella were also reported to provide neuroprotection by suppressing the NF-κB and MAPK signaling pathways and subsequent inflammatory processes (Hou et al. 2022;Chung et al. 2019;Lv et al. 2016;Xiao et al. 2017;Ajiboye et al. 2019;Ma et al. 2020;Li et al. 2020;Kim et al. 2004;Wang et al. 2020). Therefore, it can be suggested that by virtue of these compounds, GME might have controlled the mitochondrial dysfunctions and inflammatory processes via modulating the Nrf2/PI3K/Akt/NF-κB/MAPK signaling pathways. ...
Dopaminergic neuroprotection is the main interest in designing novel therapeutics against Parkinson’s disease (PD). In the process of dopaminergic degeneration, mitochondrial dysfunctions and inflammation are significant. While the existing drugs provide symptomatic relief against PD, a therapy conferring total neuroprotection by targeting multiple degenerative pathways is still lacking. Garcinia morella is a common constituent of Ayurvedic medication and has been used for the treatment of inflammatory disorders. The present study investigates whether administration of G. morella fruit extract (GME) in MPTP mouse model of PD protects against dopaminergic neurodegeneration, including the underlying pathophysiologies, and reverses the motor behavioural abnormalities. Administration of GME prevented the loss of dopaminergic cell bodies in the substantia nigra and its terminals in the corpus striatum of PD mice. Subsequently, reversal of parkinsonian behavioural abnormalities, viz. akinesia, catalepsy, and rearing, was observed along with the recovery of striatal dopamine and its metabolites in the experimental model. Furthermore, reduced activity of the mitochondrial complex II in the nigrostriatal pathway of brain of the mice was restored after the administration of GME. Also, MPTP-induced enhanced activation of Glial fibrillary acidic protein (GFAP) and neuronal nitric oxide synthase (nNOS) in the nigrostriatal pathway, which are the markers of inflammatory stress, were found to be ameliorated on GME treatment. Thus, our study presented a novel mode of dopaminergic neuroprotection by G. morella in PD by targeting the mitochondrial dysfunctions and neuroinflammation, which are considered to be intricately associated with the loss of dopaminergic neurons.
