Scutellarin alleviates renal ischemia-reperfusion injury by inhibiting the MAPK pathway and pro-inflammatory macrophage polarization.

Renal ischemia-reperfusion injury (IRI) is an integral process in renal transplantation, which results in compromised graft survival. Macrophages play an important role in both the early inflammatory period and late fibrotic period in response to IRI. In this study, we investigated whether scutellarin (SCU) could protect against renal IRI by regulating macrophage polarization. Mice were given SCU (5-50 mg/kg) by gavage 1 h earlier, followed by a unilateral renal IRI. Renal function and pathological injury were assessed 24 h after reperfusion. The results showed that administration of 50 mg/kg SCU significantly improved renal function and renal pathology in IRI mice. In addition, SCU alleviated IRI-induced apoptosis. Meanwhile, it reduced macrophage infiltration and inhibited pro-inflammatory macrophage polarization. Moreover, in RAW 264.7 cells and primary bone marrow-derived macrophages (BMDMs) exposed to SCU, we found that 150 µM SCU inhibited these cells to polarize to an inflammatory phenotype induced by lipopolysaccharide (LPS) and interferon-γ (IFN-γ). However, SCU has no influence on anti-inflammatory macrophage polarization in vivo and in vitro induced by in interleukin-4 (IL-4). Finally, we explored the effect of SCU on the activation of the mitogen-activated protein kinase (MAPK) pathway both in vivo and in vitro. We found that SCU suppressed the activation of the MAPK pathway, including the extracellular signal-regulated kinase (ERK), Jun N-terminal kinase (JNK), and p38. Our results demonstrated that SCU protects the kidney against IRI by inhibiting macrophage infiltration and polarization toward pro-inflammatory phenotype via the MAPK pathway, suggesting that SCU may be therapeutically important in treatment of IRI.

Hepatocyte Aquaporin 8-mediated Water Transport Facilitates Bile Dilution and Prevents Gallstone Formation in Mice.

BACKGROUND AND AIMS: Although water channel aquaporin-8 (AQP8) has been implicated in hepatic bile formation and liver diseases associated with abnormal bile flow in human and animal studies, direct evidence of its involvement in bile secretion is still lacking. This study aimed to determine the role of AQP8 in bile secretion and gallstone formation. METHODS: We generated various transgenic knock-in and knockout mouse models and assessed liver AQP8 expression by immunostaining and immunoblotting, hepatic bile secretion by cannulation of the common bile duct, cholesterol gallstone formation by feeding a high-fat lithogenic diet, and identified regulatory small molecules by screening the organic fractions of cholagogic Chinese herbs and biochemical characterization. RESULTS: We identified a novel expression pattern of AQP8 protein in the canalicular membrane of approximately 50% of the liver lobules. AQP8-deficient mice exhibited impaired hepatic bile formation, characterized by the secretion of concentrated bile with a lower flow rate and higher levels of bile lipids than that of wild-type littermates. AQP8-/- mice showed accelerated gallstone formation, which was rescued by AAV-mediated hepatic expression of AQP8 or AQP1. Moreover, we identified a small molecule, scutellarin, that upregulates hepatocyte AQP8 expression in vitro and in vivo. In AQP8+/+ mice, scutellarin significantly increased bile flow, decreased bile lipid concentrations, and prevented gallstone formation compared to AQP8-/- mice. Molecular studies revealed that scutellarin promoted the ubiquitination and degradation of HIF-1α, a transcriptional negative regulator of AQP8, by disrupting its interactions with HSP90. CONCLUSIONS: AQP8 plays a crucial role in facilitating water transport and bile dilution during hepatic bile formation, thereby mitigating gallstone formation in mice. Small-molecule intervention validated hepatocyte AQP8 as a promising drug target for gallstone therapy. IMPACT AND IMPLICATIONS: The incidence of gallstone disease is high, and current drug treatments for gallstones are very limited, necessitating the identification of novel drug targets for developing new drugs with universal applicability. To our knowledge, this is the first study to provide direct evidence that hepatic water channel AQP8 plays a key role in bile dilution and gallstone formation. Modulation of hepatic water transport may provide a universal therapeutic strategy for all types of gallstone diseases.

Programmed death of cardiomyocytes in cardiovascular disease and new therapeutic approaches.

Cardiovascular diseases (CVDs) have a complex pathogenesis and pose a major threat to human health. Cardiomyocytes have a low regenerative capacity, and their death is a key factor in the morbidity and mortality of many CVDs. Cardiomyocyte death can be regulated by specific signaling pathways known as programmed cell death (PCD), including apoptosis, necroptosis, autophagy, pyroptosis, and ferroptosis, etc. Abnormalities in PCD can lead to the development of a variety of cardiovascular diseases, and there are also molecular-level interconnections between different PCD pathways under the same cardiovascular disease model. Currently, the link between programmed cell death in cardiomyocytes and cardiovascular disease is not fully understood. This review describes the molecular mechanisms of programmed death and the impact of cardiomyocyte death on cardiovascular disease development. Emphasis is placed on a summary of drugs and potential therapeutic approaches that can be used to treat cardiovascular disease by targeting and blocking programmed cell death in cardiomyocytes.

Scutellarin inhibits oleic acid induced vascular smooth muscle foam cell formation via activating autophagy and inhibiting NLRP3 inflammasome activation.

Abnormalities in vascular smooth muscle cells (VSMCs) are pivotal in the pathogenesis of cardiovascular pathologies such as atherosclerosis and hypertension. Scutellarin (Scu), a flavonoid derived from marigold flowers, exhibits a spectrum of biological activities including anti-inflammatory, antioxidant, antitumor, immunomodulatory and antimicrobial effects. Notably, Scu has demonstrated the capacity to mitigate vascular endothelial damage and prevent atherosclerosis via its antioxidative properties. Nevertheless, the influence of Scu on the formation of VSMC-derived foam cells remains underexplored. In this study, Scu was evidenced to efficaciously attenuate oleic acid (OA)-induced lipid accumulation and the upregulation of adipose differentiation-associated protein Plin2 in a dose- and time-responsive manner. We elucidated that Scu effectively diminishes OA-provoked VSMC foam cell formation. Further, it was established that Scu pretreatment augments the protein expression of LC3B-II and the mRNA levels of Map1lc3b and Becn1, concurrently diminishing the protein levels of the NLRP3 inflammasome compared to the OA group. Activation of autophagy through rapamycin attenuated NLRP3 inflammasome protein expression, intracellular lipid droplet content and Plin2 mRNA levels. Scu also counteracted the OA-induced decrement of LC3B-II levels in the presence of bafilomycin-a1, facilitating the genesis of autophagosomes and autolysosomes. Complementarily, in vivo experiments revealed that Scu administration substantially reduced arterial wall thickness, vessel wall cross-sectional area, wall-to-lumen ratio and serum total cholesterol levels in comparison to the high-fat diet model group. Collectively, our findings suggest that Scu attenuates OA-induced VSMC foam cell formation through the induction of autophagy and the suppression of NLRP3 inflammasome activation.

Research progress on anti-tumor mechanisms of scutellarin.

Scutellarin, one of natural flavonoids from Scutellaria barbata D. Don and Erigeron breviscapus (vant) Hand.-Mazz. Modern pharmacological studies have shown that scutellarin has a good anti-tumor effect. According to the literature review at home and abroad, scutellarin can inhibit the growth and metastasis of tumor cells, block the cell cycle at various stages, induce apoptosis and autophagy, interfere with tumor metabolism, reverse drug resistance of tumor cells and enhance the sensitivity of chemotherapy drugs. In this paper, the anti-tumor mechanism of scutellarin was reviewed, and the shortcomings of current studies and future research directions were analyzed, so as to provide a basis for further exploration of the anti-tumor potential of scutellarin and its further development and utilization.

Mechanism of scutellarin inhibition of astrocyte activation to type A1 after ischemic stroke.

OBJECTIVE: The aim of this study was to investigate the effects of scutellarin on the activation of astrocytes into the A1 type following cerebral ischemia and to explore the underlying mechanism. METHODS: In vivo, a mouse middle cerebral artery wire embolism model was established to observe the regulation of astrocyte activation to A1 type by scutellarin, and the effects on neurological function and brain infarct volume. In vitro, primary astrocytes were cultured to establish an oxygen-glucose deprivation model, and the mRNA and protein expression of C3, a specific marker of A1-type astrocytes pretreated with scutellarin, were examined. The neurons were cultured in vitro to detect the toxic effects of ischemia-hypoxia-activated A1 astrocyte secretion products on neurons, and to observe whether scutellarin could reduce the neurotoxicity of A1 astrocytes. To validate the signaling pathway-related proteins regulated by scutellarin on C3 expression in astrocytes. RESULTS: The results showed that scutellarin treatment reduced the volume of cerebral infarcts and attenuated neurological deficits in mice caused by middle cerebral artery embolism. Immunofluorescence and Western blot showed that treatment with scutellarin down-regulated middle cerebral artery embolism and OGD/R up-regulated A1-type astrocyte marker C3. The secretory products of ischemia-hypoxia-activated A1-type astrocytes were toxic to neurons and induced an increase in neuronal apoptosis, and astrocytes treated with scutellarin reduced the toxic effects on neurons. Further study revealed that scutellarin inhibited the activation of NF-κB signaling pathway and thus inhibited the activation of astrocytes to A1 type.

Scutellarin inhibits the glioma cell proliferation by downregulating BIRC5 to promote cell apoptosis.

The expression changes of baculovirus inhibitor of apoptosis repeat-containing protein5 in brain glioma after administration of Scutellarin was detected. To explore the effort of scutellarin on anti-glioma by downregulating BIRC5.The effect of scutellarin on tumour growth and animal survival was detected by administering scutellarin to nude mice subcutaneous tumour formation and SD rats in situ tumour formation models. A significantly different gene BIRC5 was found by using the combination of TCGA databases and network pharmacology. And then qPCR was performed to detect the expression of BIRC5 in glioma tissues, cells and normal brain tissues and glial cells. CCK-8 was used to detect the IC50 of scutellarin on glioma cells. The wound healing assay, flow cytometry and MTT test were used to detect the effect of scutellarin on the apoptosis and proliferation of glioma cells. The expression of BIRC5 in glioma tissues was significantly higher than that in normal brain tissues. Scutellarin can significantly reduce tumour growth and improve animal's survival. After scutellarin was administered, the expression of BIRC5 in U251 cells was significantly reduced. And after same time, apoptosis increased and cell proliferation was inhibited. This original research showed that scutellarin can promote the apoptosis of glioma cells and inhibit the proliferation by downregulating the expression of BIRC5.

Scutellarin ameliorates diabetic nephropathy via TGF-ß1 signaling pathway.

Breviscapine, a natural flavonoid mixture derived from the traditional Chinese herb Erigeron breviscapus (Vant.) Hand-Mazz, has demonstrated a promising potential in improving diabetic nephropathy (DN). However, the specific active constituent(s) responsible for its therapeutic effects and the underlying pharmacological mechanisms remain unclear. In this study, we aimed to investigate the impact of scutellarin, a constituent of breviscapine, on streptozotocin-induced diabetic nephropathy and elucidate its pharmacological mechanism(s). Our findings demonstrate that scutellarin effectively ameliorates various features of DN in vivo, including proteinuria, glomerular expansion, mesangial matrix accumulation, renal fibrosis, and podocyte injury. Mechanistically, scutellarin appears to exert its beneficial effects through modulation of the TGF-ß1 signaling pathway, as well as its interaction with the Erk and Wnt/ß-catenin pathways.

Scutellarin Attenuates Doxorubicin-Induced Cardiotoxicity by Inhibiting Myocardial Fibrosis, Apoptosis and Autophagy in Rats.

The anthracycline antibiotic doxorubicin (DOX) is an effective anticancer agent, but its clinical use is limited by dose-dependent cardiotoxicity. Scutellarin (SCU), a natural polyphenolic flavonoid, is used as a cardioprotective agent for infarction and ischemia-reperfusion injury. This study investigated the beneficial effect of SCU on DOX-induced chronic cardiotoxicity. Rats were injected intraperitoneally (i. p.) with DOX (2.5 mg/kg) twice a week for four weeks and then allowed to rest for two weeks to establish the chronic cardiotoxicity animal model. A dose of 10 mg/kg/day SCU was injected i. p. daily for six weeks to attenuate cardiotoxicity. SCU attenuated DOX-induced elevated oxidative stress levels and cardiac troponin T (cTnT), decreased left ventricular ejection fraction (LVEF) and fractional shortening (LVFS), elevated isovolumic relaxation time (IVRT), electrophysiology and histopathological alterations. In addition, SCU significantly attenuated DOX-induced cardiac fibrosis and reduced extracellular matrix (ECM) accumulation by inhibiting the TGF-ß1/Smad2 signaling pathway. Furthermore, SCU also prevented against DOX-induced apoptosis and autophagy as evidenced by upregulation of Bcl-2, downregulation of Bax and cleaved caspase-3, inhibited the AMPK/mTOR pathway. These results revealed that the cardioprotective effect of SCU on DOX-induced chronic cardiotoxicity may be attributed to reducing oxidative stress, myocardial fibrosis, apoptosis and autophagy.

Scutellarin alleviates lipopolysaccharide-provoked septic nephrotoxicity via attenuation of inflammatory and oxidative events and mitochondrial dysfunction.

BACKGROUND: Sepsis-associated acute kidney injury (AKI) is highlighted by high incidence of mortality and morbidity. Scutellarin is a flavone extracted from certain medicinal plants with anti-inflammatory and anti-oxidative properties. This research study was done to investigate the beneficial effect of scutellarin on lipopolysaccharide (LPS) murine model of AKI. MATERIALS AND METHODS: Five groups of mice were used including control (without LPS injection), LPS group (LPS injection, 10 mg/kg), and LPS + Scutellarin25, 50, and/or 100 groups (receiving scutellarin orally at different doses of 25, 50, or 100 mg/kg before LPS injection). RESULTS: Scutellarin pretreatment effectively lowered kidney function markers (BUN, creatinine, and cystatin C), improved superoxide dismutase (SOD) besides enhancement of level, and/or gene expression for nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase 1 (HO-1) and also reduced oxidative stress factors including reactive oxygen species (ROS) and malondialdehyde (MDA). In addition, scutellarin reduced tissue level and/or gene expression of inflammatory markers comprising toll-like receptor 4 (TLR4), nuclear factor-kappaB (NF-κB), and tumor necrosis factor α (TNF-α) and properly raised anti-inflammatory factor IL-10. Moreover, scutellarin enhanced mitochondrial membrane potential (MMP) and attenuated histopathological changes in renal tissue subsequent to LPS challenge. Beneficial effects of scutellarin was associated with improvement of gene expression regarding peroxisome proliferator-activated receptor gamma (PPARγ) and its coactivator PGC-1α as specific markers of mitochondrial biogenesis. CONCLUSION: These results indicate that scutellarin could protect against LPS-provoked AKI through restraining inflammation and oxidative stress and maintenance of mitochondrial health and biogenesis which is partly mediated through its regulation of Nrf2/PPAR-γ/PGC-1α/NF-kB/TLR4.

Scutellarin Alleviates Ischemic Brain Injury in the Acute Phase by Affecting the Activity of Neurotransmitters in Neurons.

Cerebral ischemic stroke is a common neuron loss disease that is caused by the interruption of the blood supply to the brain. In order to enhance the CIS outcome, both identifying the treatment target of ischemic brain damage in the acute phase and developing effective therapies are urgently needed. Scutellarin had been found to be beneficial to ischemic injuries and has been shown to have potent effects in clinical application on both stroke and myocardial infarction. However, whether scutellarin improves ischemic brain damage in the acute phase remains unknown. In this study, the protective effects of scutellarin on ischemic brain damage in the acute phase (within 12 h) were illustrated. In middle cerebral artery occlusion and reperfusion (MCAO/R) modeling rats, the Z-Longa score was significantly down-regulated by 25% and 23.1%, and the brain infarct size was reduced by 26.95 ± 0.03% and 25.63 ± 0.02% when responding to high-dose and low-dose scutellarin treatments, respectively. H&E and TUNEL staining results indicated that the neuron loss of the ischemic region was improved under scutellarin treatment. In order to investigate the mechanism of scutellarin's effects on ischemic brain damage in the acute phase, changes in proteins and metabolites were analyzed. The suppression of scutellarin on the glutamate-inducing excitatory amino acid toxicity was strongly indicated in the study of both proteomics and metabolomics. A molecular docking experiment presented strong interactions between scutellarin and glutamate receptors, which score much higher than those of memantine. Further, by performing a parallel reaction monitoring-mass spectrometry (PRM-MS) study on both the cortex and hippocampus tissue of the ischemic region, we screened the scutellarin-regulating molecules that are involved in both the release and transportation of neurotransmitters. It was found that the aberrant levels of glutamate receptors, including EAAT2, GRIN1, GRIN2B, and GRM1, as well as of other glutamatergic pathway-involving proteins, including CAMKK2, PSD95, and nNOS, were significantly regulated in the ischemic cortex. In the hippocampus, EAAT2, GRIN1, nNOS, and CAM were significantly regulated. Taken together, scutellarin exerts potent effects on ischemic brain damage in the acute phase by regulating the activity of neurotransmitters and reducing the toxicity of excitatory amino acids in in neurons.

Intravenous Administration of Scutellarin Nanoparticles Augments the Protective Effect against Cerebral Ischemia-Reperfusion Injury in Rats.

This study investigates the protective effect of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with scutellarin (SCU), a flavone isolated from the traditional Chinese medicineErigeron breviscapus (Vant.) Hand.-Mazz., in reducing cerebral ischemia/reperfusion (I/R) injury in vivo. The focal cerebral I/R injury model was established by occluding the middle cerebral artery for 1 h in male Sprague-Dawley (SD) rats. Our SCU-PLGA NPs exhibited an extended in vitro release profile and prolonged blood circulation in rats with cerebral ischemia. More importantly, when administered intravenously once a day for 3 days, SCU-PLGA NPs increased the SCU level in the ischemic brain, compared to free SCU, resulting in a significant reduction of the cerebral infarct volume after cerebral I/R. Furthermore, SCU-PLGA NPs reversed the histopathological changes caused by cerebral I/R injury, as well as attenuated cell apoptosis in the brain tissue, as confirmed by hematoxylin and eosin, and TUNEL staining. Our findings have revealed that our injectable SCU-PLGA NPs provide promising protective effects against cerebral I/R injury, which could be used in combination with the existing conventional thrombolytic therapies to improve stroke management.

Scutellarin-mediated autophagy activates exosome release of rat nucleus pulposus cells by positively regulating Rab8a via the PI3K/PTEN/Akt pathway.

To provide a basis for promising exosome-based therapies against intervertebral disc degeneration (IDD), our present research aimed to identify a mechanism underlying the vesicle release from nucleus pulposus cells (NPCs). Scutellarin (SC) is a natural chemotherapeutic agent isolated from Erigeron breviscapus with a variety of biological activities. Here, we observed the significantly elevated autophagy levels in rat NPCs under the stimulation of SC, leading to a concomitant enhancement of intracellular vesicle release, which could be attributed to the inactivation of the phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/protein kinase B (Akt) pathway. To ensure that exosome release was driven by SC via the autophagic pathway, we implemented gain-of-function and loss-of-function studies by additionally using insulin-like growth factor-1 (IGF-1) and small-interfering RNA of autophagy-related gene 5 (ATG5), and the exosome secretion decreased in the case of attenuated autophagy. Evidently, the treatment with SC exerted the remarkable upregulation of Rab8a through the overexpression of ATG5. After the respective knockdown of ATG5 and Rab8a, the increased release of exosomes induced by SC was reversed, whereas the number of intracellular vesicles was restored. Overall, it can be concluded that SC contributes to the autophagy activation in NPCs by acting on the PI3K/PTEN/Akt pathway, which upregulates the expression of Rab8a and promotes the release of exosomes, inspiring novel therapeutic strategies in preventing IDD that might be fruitfully investigated.

Design, synthesis and evaluation of novel scutellarin and scutellarein-N,N-bis-substituted carbamate-l-amino acid derivatives as potential multifunctional therapeutics for Alzheimer's disease.

In this study, we designed, synthesized and evaluated a series of scutellarin and scutellarein-N,N-bis-substituted carbamate-l-amino acid derivatives as multifunctional therapeutic agents for the treatment of Alzheimer's disease (AD). Compounds containing scutellarein as the parent nucleus (6a-l) had good inhibitory activity against acetyl cholinesterase (AChE), with compound 6 h exhibiting the most potent inhibition of electric eel AChE and human AChE enzymes with IC50 values of 6.01 ± 1.66 and 7.91 ± 0.49 µM, respectively. In addition, compound 6 h displayed not only excellent inhibition of self- and Cu2+-induced Aß1-42 aggregation (89.17% and 86.19% inhibition) but also induced disassembly of self- and Cu2+-induced Aß fibrils (84.25% and 78.73% disaggregation). Moreover, a neuroprotective assay demonstrated that pre-treatment of PC12 cells with 6 h significantly decreased lactate dehydrogenase levels, increased cell viability, enhanced expression of relevant apoptotic proteins (Bcl-2, Bax, and caspase-3) and inhibited RSL3 induced PC12 cell ferroptosis. Furthermore, hCMEC/D3 and hPepT1-MDCK cell line permeability assays indicated that 6 h would have optimal blood-brain barrier and intestinal absorption characteristics. The in vivo experimental data suggested that 6 h ameliorated learning and memory impairment in mice by decreasing AChE activity, increasing ACh levels and alleviating pathological damage of hippocampal tissue cells. These multifunctional properties highlight compound 6 h as a promising candidate for development as a multifunctional drug against AD.

Scutellarin suppresses triple-negative breast cancer metastasis by inhibiting TNFα-induced vascular endothelial barrier breakdown.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high vascularity and frequent metastasis. Tumor-associated abnormal vasculature was reported to accelerate TNBC metastasis. Scutellarin (SC) is a natural flavonoid with a cardiovascular protective function. In this study, SC reduced TNBC metastasis and alleviated tumor-associated vascular endothelial barrier injury in vivo. SC rescued the tumor necrosis factor-α (TNFα)-induced diminishment of endothelial junctional proteins and dysfunction of the endothelial barrier in vitro. SC reduced the increased transendothelial migration of TNBC cells through a monolayer composed of TNFα-stimulated human mammary microvascular endothelial cells (HMMECs) or human umbilical vein endothelial cells (HUVECs). TNFα induced the nuclear translocation of enhancer of zeste homolog-2 (EZH2), and its chemical inhibitor GSK126 blocked TNFα-induced endothelial barrier disruption and subsequent TNBC transendothelial migration. TNF receptor 2 (TNFR2) is the main receptor by which TNFα regulates endothelial barrier breakdown. Extracellular signal-regulated protein kinase (ERK)1/2 was found to be downstream of TNFα/TNFR2 and upstream of EZH2. Additionally, SC abrogated the TNFR2-ERK1/2-EZH2 signaling axis both in vivo and in vitro. Our results suggest that SC reduced TNBC metastasis by suppressing TNFα-initiated vascular endothelial barrier breakdown through rescuing the reduced expression of junctional proteins by regulating the TNFR2-ERK1/2-EZH2 signaling pathway.

Scutellarin protects the kidney from ischemia/reperfusion injury by targeting Nrf2.

BACKGROUND: Acute kidney injury (AKI) results in high morbidity and mortality among inpatients, while effective treatment and intervention are still absent. Therefore, this study aims to explore the effects of Scutellarin (Scu) in experimental models in vivo and in vitro. METHODS: In vivo experiment, we employed a total of 30 Wistar rats, which further were modelled by a bilateral renal pedicle clip for 45 min, then received 50 mg/kg/day Scu. In vitro, HK-2 cells were administered with 20µΜ Scu and then incubated in hypoxia/reoxygenation (H/R) conditions for 24 h. The knockdown of Nrf2 expression was conducted by small interfering RNA (siRNA) transfection. RESULTS: As a result, the AKI model was well established with an increased SCr, BUN, KIM-1 level, and histological injury score, while Scu treatment reduced the levels above and increased the antioxidative enzyme HO-1. H/R induced an increase of ROS in HK-2 cells, while Scu decreased the ROS level. Bioinformatics results showed the transcription factor Nrf2 was a hub protein during the AKI, which also bound to Scu with low binding energy, indicating that the downstream effect of Scu might be mediated by Nrf2. To verify the suppose above, we employed siRNA against Nrf2, which shows a significant increase in ROS after Nrf2 was blocked. Meanwhile, the HO-1 showed similar expression compared with the 'H/R + Nrf2 siRNA' and 'H/R + Nrf2 siRNA + Scu' group, implying the protective effect of Scu was mediated by the Nrf2/HO-1 pathway. CONCLUSION: Scu led to up-regulation of HO-1 through activating the Nrf2 signalling pathway, protecting the kidneys from ischemia/reperfusion (I/R)-induced oxidative damage.

Scutellarin ameliorates hepatic lipid accumulation by enhancing autophagy and suppressing IRE1α/XBP1 pathway.

Nonalcoholic fatty liver disease is the most prevalent liver disease characterized by excessive lipid accumulation in hepatocytes. Endoplasmic reticulum (ER) stress and autophagy play an important role in lipid accumulation. In this study, scutellarin (Scu) was examined in palmitic acid-treated HepG2 cells and C57/BL6 mice fed a high-fat diet (HFD). Scu reduced intracellular lipid content and inhibited sterol regulatory element binding protein-1c (SREBP-1c)-mediated lipid synthesis and fatty acid translocase-mediated lipid uptake in HepG2 cells. Additionally, Scu restored impaired autophagy and inhibited excessive activation of ER stress in vivo and in vitro. Moreover, Scu upregulated forkhead box O transcription factor 1-mediated autophagy by inhibiting inositol-requiring enzyme 1α (IRE1α)/X-box-binding protein 1 (XBP1) branch activation, while XBP1s overexpression exacerbated the lipid accumulation and impaired autophagy in HepG2 cells and also weakened the positive effects of Scu. Furthermore, Scu attenuated ER stress by activating autophagy, ultimately downregulating SREBP-1c-mediated lipid synthesis, and autophagy inhibitors offset these beneficial effects. Scu inhibited the crosstalk between autophagy and ER stress and downregulated saturated fatty acid-induced lipid accumulation in hepatocytes. These findings demonstrate that Scu ameliorates hepatic lipid accumulation by enhancing autophagy and suppressing ER stress via the IRE1α/XBP1 pathway.

Protective Effects of Scutellarin on Acute Alcohol Intestinal Injury.

The present study aims to investigate the roles of scutellarin (SCU) on acute alcohol intestinal injury. Mice were divided into six groups: alcohol, three administration, negative control and positive drug bifendate control. The administration group mice were intraperitoneally injected with SCU for 3 consecutive days followed by alcohol gavage at an interval of 1 h. After the mice were sacrificed, colon tissue damage was evaluated by histopathological examination; the activities of inducible nitric oxide synthase (iNOS) and catalase (CAT), as well as the content of malondialdehyde (MDA) were detected using biochemical kits; the levels of inflammatory cytokines mRNA were determined by real-time fluorescence quantitative PCR; the protein expression levels of hemeoxygenase-1 (HO-1) and phosphorylated nuclear factor-ĸB p65 were measured via western blotting. The results showed that alcohol induced severe colon morphological degradation, epithelia atrophy, and more inflammatory cells infiltration in the submucosa. SCU treatment prevented this process, especially in the middle and high dose groups. Alcohol treatment caused excessive lipid peroxidation product accumulation of MDA, restrained the activity of antioxidant enzyme CAT, induced HO-1 expression in the colon, whereas low dose SCU treatment significantly down-regulated the MDA level, enhanced the CAT level, and accelerated HO-1 signals. SCU prevented alcohol stimulation triggered inflammatory response in colon tissues through significantly downregulating the iNOS activity, transcript levels of Tnf-α, Il-1ß and Il-6, and phosphorylation levels of NF-κB p65. These findings suggest that SCU protects the colon via antioxidant and anti-inflammatory mechanisms, making it a promising drug against alcohol-induced colon damage.

Protective Activities of Scutellarin against Alcohol-Induced Acute Kidney Injury.

Acute alcohol consumption has adverse effects in the kidney, resulting in kidney damage and disease, which are typically accompanied by oxidation and inflammation. Scutellarin (SCU) is the major effective ingredient of breviscapine and its anti-inflammation and antioxidant efficacy has been previously reported. The present study revealed the protective effective of SCU as therapeutic medicine against alcohol-induced inflammation and oxidative stress, leading to acute kidney injury (AKI). The AKI model was established by giving 50 % ethanol (12 mL/kg) via lavage. Kidney tissues were collected and used for histopathology analysis, biochemical assays and qRT-PCR analysis. The therapeutic effects of SCU were evaluated by observing pathological changes from HE-stained kidney tissues. Additionally, the anti-inflammation activity of SCU was evaluated by measuring the relative mRNA expression levels of Tnf-α, Il-1ß, Il-6 and the activity of iNOS. The antioxidant capacity was assessed by measuring the lipid peroxidation marker 'MDA' and antioxidant enzymes activity of SOD, CAT and GSH-Px. The results showed that serious swelling and damage occurred in the renal tubular epithelium of alcohol intake group, accompanying with glomerular atrophy, necrosis and increase of inflammatory infiltration. SCU treatment significantly reduced the damage of diseased renal tubular epithelium and glomerular, and less inflammatory cell emerged. The inflammation cytokines expression levels were elevated and oxidative stress index decreased after alcohol intake compared to the control group. In conclusion, inflammation and oxidative stress occur in the kidney after acute and excessive alcohol intake, SCU exhibited protective roles via its anti-inflammation and antioxidant activity in AKI.

Scutellarin alleviates cerebral ischemia/reperfusion by suppressing oxidative stress and inflammatory responses via MAPK/NF-κB pathways in rats.

Neuroinflammation contributes to the progression of cerebral ischemia/reperfusion (I/R) damage. Scutellarin (SL) is a glucuronide flavonoid that has apoptotic, anti-inflammatory, and anti-tumor properties. It is anti-oxidant and anti-inflammatory mechanism as a neuroprotective against ischemic brain injury is unknown. The purpose of the study was to examine the role and mechanism of SL in preventing I/R damage in a rat model. SL (40 and 80 mg/kg) was given to the rats for 14 days before the ischemic stroke. SL administration prevented I/R mediated brain injury, and neuronal apoptosis. Malondialdehyde, superoxide dismutase, glutathione, IL-6, and IL-1ß and nitric oxide were modulated by SL. SL suppressed the p65 and p38 expressions in particular. The findings show that SL protects rats from cerebral damage caused by I/R through the nuclear factor kappa-B p65 and p38 mitogen-activated protein kinase signaling pathway. Thus, SL protected the brain of rats from ischemic injury by inhibiting the inflammatory process.