scutellarein and Inflammation

The side effects of chemotherapy drugs have been hindering the progress of tumor treatment. The liver is the metabolic site of most drugs, which leads to the frequent occurrence of liver injury. Classical chemotherapy drugs such as pirarubicin (THP) can also cause dose‑dependent hepatotoxicity, and the related mechanism is closely related to liver inflammation. Scutellarein (Sc) is a potential Chinese herbal monomer exhibiting liver protection activity, which can effectively alleviate the liver inflammation caused by obesity. In the present study, THP was used to establish a rat model of hepatotoxicity, and Sc was used for treatment. The experimental methods used included measuring body weight, detecting serum biomarkers, observing liver morphology with H&E staining, observing cell apoptosis with TUNEL staining, and detecting the expression of PTEN/AKT/NFκB signaling pathways and inflammatory genes with PCR and western blotting. However, whether Sc can inhibit the liver inflammation induced by THP has not been reported. The experimental results showed that THP led to the upregulation of PTEN and the increase of inflammatory factors in rat liver, while Sc effectively alleviated the aforementioned changes. It was further identified in primary hepatocytes that Sc can effectively inhabited PTEN, regulate AKT/NFκB signaling pathway, inhibit liver inflammation and ultimately protect the liver.

Topics: Animals; Apoptosis; Chemical and Drug Induced Liver Injury; Inflammation; NF-kappa B; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Rats; Signal Transduction

Inflammation is a severe topic in the immune system and play a role as pro-inflammatory mediators. In response to such inflammatory substances, immune cells release cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Lipopolysaccharide (LPS) is known as an endotoxin in the outer membrane of Gram-negative bacteria, and it catalyzes inflammation by stimulating the secretion of inflammatory-mediated cytokines such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) by stimulated immune cells. Among the pathways involved in inflammation, nuclear factor kappa (NF-кB) and mitogen-activated protein kinases (MAPKs) are important. NF-kB is a diploid composed of p65 and IkBα and stimulates the pro- gene. MAPKs is a family consisting of the extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38, JNK and p38 play a role as proinflammatory mediators. Thus, we aim to determine the scutellarein (SCU) effect on LPS stimulated RAW264.7 cells. Furthermore, since scutellarein has been shown to inhibit the SARS coronavirus helicase and has been used in Chinese medicine to treat inflammatory disorders like COVID-19, it would be required to examine scutellarein's anti-inflammatory mechanism. We identified inflammation-inducing substances using western blot with RAW264.7 cells and SCU. And we discovered that was reduced by treatment with SCU in p-p65 and p-IκBα. Also, we found that p-JNK and p-ERK were also decreased but there was no effect in p-p38. In addition, we have confirmed that the iNOS was also decreased after treatment but there is no change in the expression of COX-2. Therefore, this study shows that SCU can be used as a compound to treat inflammation.

Topics: Animals; Apigenin; COVID-19; Cyclooxygenase 2; Cytokines; Extracellular Signal-Regulated MAP Kinases; Inflammation; Lipopolysaccharides; Mice; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; RAW 264.7 Cells; Signal Transduction

Atopic dermatitis (AD) is one of the most common chronic inflammatory cutaneous diseases with unmet clinical needs. As a common ingredient found in several medicinal herbs with efficacy on cutaneous inflammatory diseases, Scutellarein (Scu) has been shown to possess anti-inflammatory and anti-proliferative activities. We aimed to evaluate the therapeutic efficacy of Scu against AD and its underlying molecular mechanism.. Efficacy of Scu on AD was evaluated in 2,4-dinitrofluorobenzene (DNFB) and carvacrol-induced dermatitis mouse models. Cytokine mRNA and serum IgE levels were examined using qPCR and ELISA, respectively. Voltage clamp recordings were used to measure currents mediated by transient receptor potential (TRP) channels. In silico docking, site-direct mutagenesis, and covalent modification were used to explore the binding pocket of Scu on TRPV3.. Subcutaneous administration of Scu efficaciously suppresses DNFB and carvacrol-induced pruritus, epidermal hyperplasia and skin inflammation in wild type mice but has no additional benefit in Trpv3 knockout mice in the carvacrol model. Scu is a potent and selective TRPV3 channel allosteric negative modulator with an apparent affinity of 1.18 μM. Molecular docking coupled with site-direct mutagenesis and covalent modification of incorporated cysteine residues demonstrate that Scu targets the cavity formed between the pore helix and transmembrane helix S6. Moreover, Scu attenuates endogenous TRPV3 activity in human keratinocytes and inhibits carvacrol-induced proliferative and proinflammatory responses.. Collectively, these data demonstrate that Scu ameliorates carvacrol-induced skin inflammation by directly inhibiting TRPV3, and TRPV3 represents a viable therapeutic target for AD treatment.

Topics: Animals; Anti-Inflammatory Agents; Apigenin; Cymenes; Cysteine; Cytokines; Dermatitis, Atopic; Dinitrofluorobenzene; Humans; Immunoglobulin E; Inflammation; Mice; Mice, Knockout; Molecular Docking Simulation; RNA, Messenger; Transient Receptor Potential Channels; TRPV Cation Channels

Acute kidney injury (AKI) is a clinical syndrome that usually caused by ischemia/reperfusion (I/R). Previous studies have revealed the protection of scutellarein against ischemia in nervous system. This study aimed to demonstrate the potential of scutellarein in ischemic AKI.. Animal model of ischemic AKI was established by clamping bilateral kidney pedicles in Sprague-Dawley rats. HK-2 cells were exposed to oxygen glucose deprivation/reoxygenation (OGD/R) to induce a cell model of AKI. The effects of scutellarein pre-treatment were detected by H&E staining, TUNEL, ELISA, CCK-8, LDH activity assay, ROS generation, flow cytometry, qRT-PCR and western blotting. Bioinformatic analysis was performed to probe the targets of scutellarein.. The blood urea nitrogen (BUN) and serum creatinine (SCr) levels in rats treated with scutellarein were lower than that in model groups. Scutellarein suppressed the pathological injury of kidney, and dose-dependently inhibited the apoptosis and pro-inflammatory cytokines release (IL-1β, IL-6 and IL-18). Scutellarein prevented OGD/R-induced HK-2 cell loss and cytotoxicity. ROS generation, apoptosis, and inflammation induced by OGD/R were all inhibited by scutellarein. By searching on the TCMSP and Symmap databases, COX-2 was screened out as a target of scutellarein. Scutellarein has no significant impacts on COX-2 mRNA expression, but could inhibit its protein level. Scutellarein promoted COX-2 protein degradation via enhancing autophagy. Furthermore, overexpression of COX-2 partly eliminated the renal protection of scutellarein in HK-2 cells.. Scutellarein was suggested as a renal protective agent against ischemia-induced damage in AKI. The protective properties of scutellarein may be through inhibition of COX-2.

Topics: Acute Kidney Injury; Animals; Apigenin; Cell Death; Cell Line; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Humans; Inflammation; Ischemia; Kidney Tubules, Proximal; Male; Rats; Rats, Sprague-Dawley

Scutellarein (Sc), a natural compound and an active ingredient of Erigeron breviscapus (vant.), shows anti-inflammatory and antioxidant properties and has the potential for obesity treatment. However, no previous in vivo study has been conducted to assess the role of Sc in obesity. This study investigated the effects of Sc on obesity and associated hyperlipidemia and fatty liver and explores the underlying mechanisms of action in a mouse model.. The study was conducted using a well-established mouse model of obesity induced by high-fat diet (HFD) feeding. Anti-obesity effects were assessed using body weight, abdominal circumference, white adipose tissue, adiposity index, and fatty liver index. Lipid lowering and liver protective effects were examined by blood sample analysis. Lipid dystopia deposition was confirmed by liver pathological sections. The signaling pathways of lipid metabolism and cytokine/inflammatory mediator were evaluated using Real-Time PCR and Western blot.. Central obesity, dyslipidemia, inflammation, and hepatic steatosis were developed in mice fed with HFD. Administration of Sc at a dose of 50 mg/kg for 16 weeks effectively attenuated all obesity indicators tested. Further studies revealed the antagonistic effect of Sc on hyperlipidemia was a result of the repression of the lipid synthesis pathway, de novo pathway, HMGCR, promoting fatty acid oxidation (PPARα, CPT-1a) and increased cholesterol output (PPARγ-LXRα-ABCA1). The anti-inflammatory effect was attributed to blocking the expression of inflammatory genes, including TNF-α, IL-6, NF-κB.. These results suggest that Sc possesses important novel anti-obesity effects accompanying lipid lowering and anti-inflammation-based liver protective effects. These favorable effects are causally associated with the suppression of gene expression of inflammatory cytokines and fine regulation of genes responsible for energy metabolism. Our results advance the understanding of the pharmacological actions of Sc, and provides a role for Sc in effective management of obesity.

Topics: Animals; Anti-Obesity Agents; Apigenin; Body Weight; Cytokines; Diet, High-Fat; Energy Metabolism; Gene Expression Regulation; Hyperlipidemias; Inflammation; Lipid Metabolism; Lipids; Liver; Male; Mice, Inbred C57BL; Obesity; Organ Size

Six flavonoid derivatives were tested for their influence on Naja naja and human recombinant synovial phospholipase A2. They showed a selectivity for the last enzyme with IC50 = 14.3, 17.6, 12.2 and 28.2 microM for quercetagetin, kaempferol-3-O-galactoside, scutellarein and scutellarein-7-O-glucuronide, respectively, while reduced effects were observed for hispidulin and hibifolin. After topical application all the flavonoids inhibited 12-O-tetradecanoylphorbol-13-acetate-induced ear oedema in mice with a potency comparable to that of indomethacin and they were also able to inhibit carrageenan-induced mouse paw oedema at a dose of 150 mg/kg p.o. The blockade of the free hydroxyl at C-7 or C-6 reduced the anti-inflammatory activity and also the inhibitory effect on human recombinant synovial phospholipase A2. These results are in accordance with the notion that group II phospholipases A2 may play a role in experimental inflammation, although several mechanisms seems to be involved in the anti-inflammatory effect of this group of flavonoids.

Topics: Animals; Chromones; Edema; Flavanones; Flavones; Flavonoids; Galactosides; Humans; Inflammation; Kaempferols; Male; Mice; Phospholipases A; Phospholipases A2; Quercetin; Recombinant Proteins; Snakes; Tetradecanoylphorbol Acetate