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Previous studies suggest baicalein, in addition to its antioxidant effects, protects against hypoxia/reoxygenation injury via its pro-oxidant properties. We hypothesize that a brief period of baicalein treatment prior to ischemia/reperfusion (I/R) may trigger preconditioning protection via a mitochondrial pro-oxidant mechanism. Using an established chick cardiomyocyte model of I/R, cells were preconditioned with baicalein (10 μM) for 10 min followed by 10-min wash prior to I/R. Intracellular oxidants were measured using 2′, 7′-dichlorofluorescin diacetate (DCFH/DA). Cell viability was assessed by propidium iodide and apoptosis determined by DNA fragmentation. Baicalein induced a transient but significant increase of DCF fluorescence within the 10-min preconditioning period, and led to significant reduction of cell death (38.9 ± 1.8% vs. 58.7 ± 1.2% in I/R control, n = 6, p < 0.001) and DNA fragmentation after I/R. Cotreatment with N-acetylcysteine (500 μM), mitochondrial complex III electron transport chain inhibitor myxothiazol (1 μM), mitochondrial K_ATP channel blocker 5-hydroxydecanoate-Na (5-HD, 500 μM) or anion channel inhibitor 4′, 4′-diisothiocyanato-stilbene-2, 2′-disulfonic acid (DIDS, 200 μM) resulted in significant abrogation of oxidant increase during induction as well as the protection conferred by baicalein preconditioning. These results suggest that baicalein preconditioning exhibits significant anti-apoptotic protection against cardiomyocyte I/R injury by mitochondrial oxidant signaling, which was in part mediated by mitochondrial K_ATP channel and anion channel opening.

Baicalein, a flavonoid derived from Scutellaria baicalensis Georgi, possesses cardioprotection against oxidant injury by scavenging reactive oxygen species (ROS). Few studies investigate whether baicalein protection is mediated by attenuating mitochondrial ROS and modulating the prosurvival and proapoptotic signaling. Primary cultured chick cardiomyocytes were used to study the role of baicalein in mitochondrial superoxide generation and signaling of Akt and JNK. Cells were exposed to H₂O₂ for 2 h and baicalein was given 2 h prior to and during 2 h of H₂O₂ exposure. Cell viability was assessed by propidium iodide and DNA fragmentation. H₂O₂ (500 μM) significantly induced 45.3 ± 6.2% of cell death compared to the control (p < 0.001) and resulted in DNA laddering. Baicalein (10, 25 or 50 μM) dose-dependently reduced the cell death to 38.7 ± 5.6% (p = 0.226); 31.2 ± 3.9% (p < 0.01); 30.3 ± 5.3% (p < 0.01), respectively. It also attenuated DNA laddering. Further, baicalein decreased intracellular ROS and mitochondrial generation that was confirmed by superoxide dismutase PEG-SOD and mitochondria electron transport chain complex III inhibitor stigmatellin. In addition, baicalein increased Akt phosphorylation and decreased JNK phosphorylation in H₂O₂-exposed cells. Moreover, baicalein augmented mitochondrial phosphorylation of Akt Thr308 and GSK3β Ser9, and prevented mitochondrial cytochrome c release assessed by cellular fractionation. Our results suggest that baicalein cardioprotection may involve an attenuation of mitochondrial and an increase in mitochondrial phosphorylation of Akt and GSK3β while decreasing JNK activation.

Myocardial dysfunction, a common complication after sepsis, significantly contributes to the death of patients with septic shock. In the search for potentially effective drugs to decrease mortality from sepsis, we investigated the cardioprotective effects of baicalein, a flavonoid present in the root of Scutellaria baicalensis, on lipopolysaccharide (LPS)-induced pro-inflammatory cytokine production and matrix metalloproteinase-2 and -9 (MMP-2/-9) expression. We found that baicalein significantly attenuated LPS-induced cardiac hypertrophy and counteracted reactive oxygen species (ROS) generation in neonatal rat cardiomyocytes. In addition, pretreatment with baicalein inhibited LPS-induced early (e.g., tumor necrosis factor-α (TNF-α) and interleukin-6) and late (e.g., high mobility group box 1 (HMGB1) pro-inflammatory cytokine release, inducible nitric oxide synthase (iNOS) expression and NO production. Finally, baicalein also significantly down-regulated the expression of MMP-2/-9 and attenuated HMGB1 translocation from the nucleus to the cytoplasm. These results suggest that baicalein can protect cardiomyocytes from LPS-induced cardiac injury via the inhibition of ROS and inflammatory cytokine production. These cardioprotective effects are possibly mediated through the inhibition of the HMGB1 and MMP-2/-9 signaling pathways.

Baicalein is a component of the root of Scutellaria baicalensis Georgi, which has traditionally been used to treat liver disease in China. In the present study, we investigated baicalein’ ability to reduce the liver injury induced by myocardial ischemia and reperfusion (I/R). Myocardial I/R was induced in this experiment by a 40min occlusion of the left anterior descending coronary artery and a 3h reperfusion in rats. The induced myocardial I/R significantly increased the serum levels of aspartate transaminase (AST) and alanine transaminase (ALT), indicating the presence of liver injury. Hepatic apoptosis was significantly increased. The serum levels of tumor necrosis factor-$\alpha$ (TNF-$\alpha$), interleukin-1$\beta$ (IL-1$\beta$), and interleukin-6 (IL-6) were significantly elevated, as was the TNF-$\alpha$ level in the liver. Intravenous pretreatment with baicalein (3, 10, or 30mg/kg) 10min before myocardial I/R significantly reduced the serum level increase of AST and ALT, apoptosis in the liver, and the elevation of TNF-$\alpha$, IL-1$\beta$, and IL-6 levels. Moreover, baicalein increased Bcl-2 and decreased Bax in the liver. Phosphorylation of the prosurvival kinases, including Akt and extracellular signal-regulated kinases 1 and 2 (ERK1/2), was also increased. In conclusion, we found that baicalein can reduce the liver injury induced by myocardial I/R. The underlying mechanisms are likely related to the inhibition of the extrinsic and intrinsic apoptotic pathways, possibly via the inhibition of TNF-$\alpha$ production, the modulation of Bcl-2 and Bax, and the activation of Akt and ERK1/2. Our findings may provide a rationale for the application of baicalein or traditional Chinese medicine containing large amounts of baicalein to prevent liver injury in acute myocardial infarction and cardiac surgery.

Interest in the health benefits of flavonoids, particularly their effects on neurodegenerative disease, is increasing. This study evaluated the role of baicalein, a flavonoid compound isolated from the traditional Chinese medicine Scutellaria baicalensis, in glutamate release and glutamate neurotoxicity in the rat hippocampus. In the rat hippocampal nerve terminals (synaptosomes), baicalein inhibits depolarization-induced glutamate release, and this phenomenon is prevented by chelating the extracellular Ca${}^{2+}$ ions and blocking presynaptic Cav2.2 (N-type) and Cav2.1 (P/Q-type) channel activity. In slice preparations, whole cell patch-clamp experiments revealed that baicalein reduced the frequency of miniature excitatory postsynaptic currents, without affecting their amplitude. In a kainic acid rat model, intraperitoneally administering baicalein to rats before the kainic acid intraperitoneal injection substantially attenuated kainic acid-induced neuronal cell death, c-Fos expression, and the activation of the mammalian target of rapamycin in the hippocampus. This study is the first to demonstrate that the natural compound baicalein inhibits glutamate release from hippocampal nerve terminals, and executes a protective action against kainic acid-induced excitotoxicity in vivo. The findings enhance the understanding of baicalein’s action in the brain, and suggest that this natural compound is valuable for treating brain disorders related to glutamate excitotoxicity.

Baicalein is an active flavonoid extracted from the root of Scutellaria baicalensis that has anticancer and anti-inflammatory properties; its effects on osteoblastic and angiogenic potential are controversial. The aim of this study was to investigate the effects of baicalein on odontoblastic differentiation and angiogenesis and the underlying mechanism in human dental pulp cells (HDPCs). Baicalein (1–10$\mu$M) had no cytotoxic effects and promoted alkaline phosphatase (ALP) activity, mineralization assayed by Alizarin Red-S staining, and the mRNA expression of marker genes, in a concentration-dependent manner. In addition, baicalein upregulated angiogenic factors and increased in vitro capillary-like tube formation. Moreover, baicalein upregulated bone morphogenetic protein (BMP)-2 mRNA and phosphorylation of Smad 1/5/8 and Wnt ligand mRNA, glycogen synthase kinase-3, and nuclear $\beta$-catenin. The odontogenic and angiogenic effects of baicalein were abolished by the BMP antagonist noggin and the Wnt/$\beta$-catenin receptor antagonist DKK-1. These results demonstrate that baicalein promoted odontoblastic differentiation and angiogenesis of HDPCs by activating the BMP and Wnt/$\beta$-catenin signal pathways. Our findings suggest that baicalein may contribute to dental pulp repair and regenerative endodontics.

Baicalein (BA), one of the major compounds isolated from the root of Scutellaria baicalensis Gerogi, exhibits various pharmacological effects, such as anti-oxidant, anti-inflammatory, and anticancer effects. In this study, we found that BA reduced cell viability and increased apoptosis in ovarian cancer cells. Treatment of cells with BA enhanced microtubule-associated protein light chain 3-II (LC3-II) expression, acidic vesicular organelle and GFP-LC3 fluorescence dot accumulation. Combined treatment with chloroquine and BA apparently reduced cell viability and increased the cleavage of poly (ADPribose) polymerase (PARP) in both HEY and A2780 ovarian cancer cell lines, indicating that BA induces a protective autophagy in these cells. Knockdown of Beclin 1 by siRNA remarkably decreased BA-induced LC3-II lipidation. In addition, we found an increase in the phosphorylation of extracellular signal-regulated kinase (ERK, Thr202/Thr204) and AKT (Ser473) after BA treatment, and inhibition of ERK activation by the pharmacological inhibitor U0126 or ERK siRNA blocked BA-induced autophagy. Taken together, these results suggest that BA induces Beclin 1- and ERK-dependent autophagy in ovarian cancer cells.

In this study, we investigated the effect of the two flavonoids, baicalin (baicalein 7-O-$\beta$- d-glucuronic acid) and its aglycone, baicalein (5,6,7-trihydroxyflavone), after encapsulation into amorphous calcium polyphosphate (Ca-polyP) microparticles on mineralization of primary human osteoblasts (phOSB). Both flavonoids, which come from root extracts of Scutellaria baicalensis Georgi, are used in Traditional Chinese Medicine, and are nontoxic in cells up to a concentration of 3$\mu$g/ml. The morphogenetically active, energy-rich Ca-polyP particles with a stoichiometric P:Ca ratio of 1:2 are degraded by cellular alkaline phosphatase (ALP) to ortho-phosphate used for bone hydroxyapatite formation. Here we show that the flavone-loaded Ca-polyP microparticles are readily taken up by phOSB, resulting in the accumulation of polyP around the nuclei and the formation of intracellular vesicles containing the ALP. In addition, we demonstrate that baicalin/baicalein causes a rise of the intracellular calcium [Ca${}^{2+}$]_i a level which markedly is augmented after encapsulation into Ca-polyP, through activation of the phospholipase C. Moreover, both flavones, either alone or associated with Ca-polyP microparticles, upregulate the expression of the osteoblast calcium efflux channel, the plasma membrane Ca${}^{2+}$-ATPase (PMCA), while the expression of ALP, which promotes bone mineralization, is induced by Ca-polyP and by the flavones only if present in the Ca-polyP-microparticle-associated form. As a result, the extent of bone mineralization is markedly enhanced. Based on the two-armed activating function, new applications of baicalin/baicalein as a component of nutriceuticals for osteoporosis prevention or bone implants can be envisaged.

Baicalein is an active component of Scutellaria baicalensis Georgi, which has traditionally been used to treat cardiovascular diseases in China. In this study, we investigated if treatment with baicalein can attenuate the lung injury induced by myocardial ischemia and reperfusion (I/R). Myocardial I/R, induced by a 40-min occlusion of the left anterior descending coronary artery and a 3-h reperfusion, significantly increased histological damage and the wet-to-dry weight ratio of lungs in rats. The terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive nuclei and caspase-3 activation was significantly increased in the lungs. Serum and bronchoalveolar lavage fluid levels of tumor necrosis factor-$\alpha$ (TNF-$\alpha$), interleukin-1$\beta$ (IL-1$\beta$), and interleukin-6 (IL-6) were significantly elevated, as were TNF-$\alpha$ levels in the lung. Intravenous administration with baicalein at doses of 3, 10, and 30mg/kg for ten minutes before myocardial I/R significantly reduced histological damage, the wet-to-dry weight ratio, and apoptosis in the lung. Baicalein also significantly inhibited the increase in levels of TNF-$\alpha$, IL-1$\beta$, and IL-6. Moreover, baicalein increased Bcl-2 and decreased p53, Bax, and cytochrome $c$ in lungs. Phosphorylation of the prosurvival kinases, including Akt and extracellular signal-regulated kinases 1 and 2 (ERK1/2), was increased, while the phosphorylation of the pro-apoptotic mitogen-activated protein kinases, including p38 and c-Jun N-terminal kinase (JNK), was decreased. In conclusion, treatment with baicalein attenuates the lung injury induced by myocardial I/R. The mechanisms might be related to the limiting of apoptosis, possibly via the inhibition of both the extrinsic and intrinsic pathways of apoptosis, including the inhibition of TNF-$\alpha$ production and modulation of pro- and anti-apoptotic signaling elements.

Baicalein is a flavonoid with excellent oxidant scavenging capability. It has been reported to protect against a variety of oxidative injuries including ischemia/reperfusion (I/R). However, the optimal treatment strategy for I/R injury and the protective mechanisms are not fully understood. In this study we employed an established chick cardiomyocyte model of I/R and investigated the effects of three baicalein treatment strategies on reactive oxygen species (ROS) scavenging, nitric oxide (NO) production and cell viability. The molecular signaling pathways were also explored. Compared to the I/R control (cell death 52.2$\pm$2.0%), baicalein preventive treatment (25$\mu$M, pretreated for 72h and continued through I/R) conferred the best protection (19.5$\pm$3.9%, $p<0.001$), followed by I/R treatment (treated during I/R) and reperfusion treatment (treated at reperfusion only). Preventive and I/R treatments almost completely abolished ROS generation during both ischemic and reperfusion phases, and increased NO production and Akt phosphorylation. Reperfusion treatment reduced the ROS burst in the early reperfusion phase only, and had no effect on NO production and Akt activation. Further, the phosphorylation of phosphatase and tensin homolog (PTEN), a phosphatase negatively regulating Akt activation, was significantly increased by baicalein preventive treatment and slightly by the I/R treatment. PTEN protein expression was reduced in the same trend accordingly. Baicalein reperfusion treatment had no effects on PTEN phosphorylation and expression. Our results indicate that baicalein preventive treatment confers optimal cardioprotection against I/R injury, and this protection involves effective oxidant scavenging and the activation of PTEN/Akt/NO pathway.

Scutellaria baicalensis (Huangqin in Chinese) is a major traditional Chinese medicine (TCM) herb, which has a long history of use in the treatment of a variety of symptoms correlated with cancer. In the past decade, the potential of S. baicalensis and single compounds derived from it as anticancer agents targeting various pathways has received extensive research attention. Specifically, the proliferation and metastases inhibiting properties of the single compounds in cancer have been studied; however, the underlying mechanisms remain unclear. This review summarizes the various mechanisms, pathways and molecular targets involved in the anticancer activity of S. baicalensis and its single compounds. However, the aim of this review is to provide a more thorough view of the last 10 years to link traditional use with modern research and to highlight recently discovered molecular mechanisms. Extracts and major flavonoids derived from S. baicalensis have been found to possess anticancer effects in multiple cancer cell lines both in vitro and in vivo. Further investigation is warranted to better understand the underlying mechanisms and to discover novel targets and cancer therapeutic drugs that may improve both the survival and quality of life of cancer patients.

Baicalein (BE) extracted from Scutellaria baicalensis Georgi is able to alleviate various cardiovascular and inflammatory diseases. However, the effects of BE on pulmonary arterial hypertension (PAH) remain unknown. Therefore, the present study aimed to examine whether BE ameliorates pneumonectomy and monocrotaline-induced PAH in rats and further investigate the underlying molecular mechanisms. Administration of BE greatly attenuated the development of PAH as evidenced by an improvement of its characteristic features, including elevation of right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling. Moreover, the increased protein expression of endothelin-1 (ET-1) and ET_A receptor (ET_AR), superoxide overproduction, and activation of Akt/ERK1/2/GSK3$\beta$/$\beta$-catenin pathway that occurred in the lungs of PAH rats were markedly reversed by BE treatment. Compared with the untreated PAH rats, higher expression of endothelial nitric oxide synthase (eNOS), but lower levels of inducible nitric oxide synthase and vWF were observed in BE-treated PAH rats. Collectively, treatment with BE remarkably attenuates the pathogenesis of PAH, and the protection of BE may be associated with suppressing Akt/Erk1/2/GSK3$\beta$/$\beta$-catenin/ET-1/ET_AR signaling and preventing endothelial dysfunction. These results suggest that BE is a potential agent for treatment of PAH.

Baicalein is a natural flavonoid with anti-oxidant activities protecting against ischemia/reperfusion (I/R) injury. Previous studies suggest that oxidative burst early after reperfusion accelerates cell death. We therefore investigated the critical therapeutic window of baicalein by examining the timing of baicalein treatment in relation to its oxidant modulating and cytoprotective effects. Using an established chick cardiomyocyte model of I/R, we administered baicalein at various time points after reperfusion and assessed cell viability and the profiles of reactive oxygen species (ROS), nitric oxide (NO), and Akt phosphorylation. Baicalein administered at the onset of reperfusion resulted in a concentration-dependent reduction of cell death (25 $\mu$M $48.2\pm 1.9$%, 50$\mu$M $43.8\pm 1.5$%, 100$\mu$M $36.6\pm 2.1$%, vs. I/R control $57.3\pm 1.4$%, all $p<0.05$). Baicalein (100$\mu$M) timely and effectively scavenged ROS burst and enhanced NO production in the early reperfusion phase. Cotreatment with NO synthase (NOS) inhibitor l-NAME (200$\mu$M) partially abrogated the cytoprotective effect. Baicalein (100$\mu$M) given after reperfusion lost protective effect in a time-dependent manner with cytoprotection completely lost if $>60$min. Even with only 15-min delay after reperfusion, the ROS scavenging effect was abolished and the NO enhancing effect markedly reduced. The phosphorylation of Akt, an upstream regulator of eNOS, also diminished as the delay lengthened. In conclusion, baicalein treatment after reperfusion confers cardioprotection in a concentration- and time-dependent manner. The critical therapeutic window lies in the early reperfusion phase, during which ROS scavenging and Akt-eNOS mediated NO signaling are most effective.

Baicalein (BAI) is a natural flavonoid. It has been shown that BAI has anticancer effects, but the molecular mechanism is still unclear. The aim of the current study was to confirm whether or not BAI triggers autophagy and induces AMPK activation in glioma U251 cells. The Ad-mcherry-GFP-LC3B adenovirus experiments indicated that BAI induces glioma cell autophagy. Western blotting showed that the level of LC3II expression increased with the time and concentration of BAI. Following treatment with chloroquine, the expression of LC3 was enhanced Immunofluorescence also confirmed this result. At the same time, cleaved caspase-3, DAPI staining, and JC-1 staining revealed that apoptosis was also induced in the induction of autophagy. In addition, we found that BAI activates phosphorylation of AMPK, which is further confirmed using compound C in this process. When the phosphorylation of AMPK was inhibited, autophagy, and apoptosis were also inhibited. In conclusion, BAI induces autophagy and apoptosis through AMPK pathway. Surprisingly, our research provides new insight with the function of anticancer of BAI, and the potential of the promotion in glioma cell apoptosis might be related to autophagy activation. These results demonstrate the anticancer activity of BAI, which can be used as potential therapeutic agents for cancer therapy.

Critical care medicine is a medical specialty engaging the diagnosis and treatment of critically ill patients who have or are likely to have life-threatening organ failure. Sepsis, a life-threatening condition that arises when the body responds to infection, is currently the major cause of death in intensive care units (ICU). Although progress has been made in understanding the pathophysiology of sepsis, many drawbacks in sepsis treatment remains unresolved. For example, antimicrobial resistance, controversial of glucocorticoids use, prolonged duration of ICU care and the subsequent high cost of the treatment. Recent years have witnessed a growing trend of applying traditional Chinese medicine (TCM) in sepsis management. The TCM application emphasizes use of herbal formulation to balance immune responses to infection, which include clearing heat and toxin, promoting blood circulation and removing its stasis, enhancing gastrointestinal function, and strengthening body resistance. In this paper, we will provide an overview of the current status of Chinese herbal formulations, single herbs, and isolated compounds, as an add-on therapy to the standard Western treatment in the sepsis management. With the current trajectory of worldwide pandemic eruption of newly identified Coronavirus Disease-2019 (COVID-19), the adjuvant TCM therapy can be used in the ICU to treat critically ill patients infected with the novel coronavirus.

Gastric cancer is a common malignancy worldwide and is associated with high morbidity and mortality rates. However, very little is known about the underlying mechanism in human gastric cancer cells. Baicalein (BAI), a widely used Chinese herbal medicine, has shown anticancer effects on many types of human cancer cell lines. Here, we investigated the molecular mechanisms underlying BAI action on gastric cancer cell proliferation and migration. The results showed that BAI can expressively inhibit cell proliferation, colony-forming ability and migration ability in a dose-dependent manner, while in the meantime inducing cell apoptosis. Additionally, we found that BAI can suppress FAK and the phosphorylation of PI3K, AKT and mTOR in a dose-dependent manner. Furthermore, BAI significantly inhibited tumor growth in a xenograft model. Also, BAI can inhibit the proliferation and migration of gastric cancer cells and the expression of the pathway by downregulating the expression of FAK. In short, we demonstrated that BAI inhibited gastric cancer cell proliferation and migration through FAK interaction via downregulation in AKT/mTOR signaling, which signifies that BAI may be a latent therapeutic factor for the treatment of gastric cancer patients and that FAK might be a hopeful therapy target for the disease.

Objective: The objective of this study is to preliminarily evaluate the efficacy of the combination of baicalein and docetaxel on non-small cell lung cancer (NSCLC) in vivo.

Methods: The subcutaneous model was established by inoculation of A549 cells, and then these tumor-bearing mice were randomly assigned to eight groups to receive normal saline (NS) as control, baicalein alone, Taxotere${}^{\text{®}}$ (docetaxel injection) alone or the combination of baicalein and Taxotere${}^{\text{®}}$. The effect of the combination treatment was evaluated by $q$ value. Tumors were harvested for TUNEL and CD31 immunohistochemical staining and important organs for H&E staining.

Results: Baicalein 50mg/kg plus docetaxel 10mg/kg significantly reduced tumor weight and inhibited the growth rate of tumor, displaying the additive effect indicated by the $q$ value. Increased apoptosis and decreased tumor angiogenesis also provided pathological evidence. Additionally, baicalein 50mg/kg plus docetaxel 10mg/kg did not increase toxicity in lung, liver and kidney.

Conclusion: Baicalein 50mg/kg plus docetaxel 10mg/kg additively inhibits the growth of NSCLC in vivo, and the mechanism underlying remains to be discovered.

Scutellaria baicalensis (Huangqin in Chinese) is a major traditional Chinese medicine (TCM) herb, which has a long history of use in the treatment of a variety of symptoms correlated with cancer. In the past decade, the potential of S. baicalensis and single compounds derived from it as anticancer agents targeting various pathways has received extensive research attention. Specifically, the proliferation and metastases inhibiting properties of the single compounds in cancer have been studied; however, the underlying mechanisms remain unclear. This review summarizes the various mechanisms, pathways and molecular targets involved in the anticancer activity of S. baicalensis and its single compounds. However, the aim of this review is to provide a more thorough view of the last 10 years to link traditional use with modern research and to highlight recently discovered molecular mechanisms. Extracts and major flavonoids derived from S. baicalensis have been found to possess anticancer effects in multiple cancer cell lines both in vitro and in vivo. Further investigation is warranted to better understand the underlying mechanisms and to discover novel targets and cancer therapeutic drugs that may improve both the survival and quality of life of cancer patients.