Combination Of Baicalein Research Articles

Synergistic combination of baicalein and rifampicin against Staphylococcus aureus biofilms.

Staphylococcus aureus, a Gram-positive bacterium, is a predominant pathogen associated with various infections. The rapid emergence of antibiotic resistance has intensified the challenge of managing fracture-related infections in severe osteoporotic patients. Rifampicin, a potent antimicrobial agent employed against fracture and implant-related infections, necessitates combination therapies due to its susceptibility to antibiotic resistance. In this study, we explored the potential of baicalein, a bioactive flavonoid from Oroxylum indicum and Scutellaria baicalensis, in combination with rifampicin against S. aureus biofilms invitro. The minimum inhibitory concentration of baicalein and rifampicin were determined as 500 μg/mL and 12.5 ng/mL respectively. The synergistic activity of baicalein and rifampicin was determined by the fractional inhibitory concentration index (FICI) using checkerboard assay. The results showed the FICI of baicalein and rifampicin was lesser than 0.5, demonstrating synergistic effect. Furthermore, the efficacy of baicalein and rifampicin, both individually and in combination, was evaluated for biofilm inhibition and eradication. Scanning electron microscopy and confocal laser microscopy also confirmed that the synergistic combinations effectively removed most of the biofilms and partially killed pre-formed biofilms. In conclusion, the findings demonstrate that baicalein is as effective as rifampicin in inhibiting and eradicating S. aureus biofilms. Their combination exhibits synergistic effect, enhancing their bactericidal effect in completely eradicating S. aureus biofilms. The findings of this research underscore the research potential of combining baicalein and rifampicin as a novel therapeutic strategy against S. aureus biofilms, offering a promising direction for future research in the treatment of fracture-related S. aureus infections.

Synergistic antitumor activity of baicalein combined with almonertinib in almonertinib-resistant non-small cell lung cancer cells through the reactive oxygen species-mediated PI3K/Akt pathway.

Almonertinib is an important third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) exhibiting high selectivity to EGFR-sensitizing and T790M-resistant mutations. Almonertinib resistance is a major obstacle in clinical use. Baicalein possesses antitumor properties, but its mechanism of antitumor action against almonertinib-resistant non-small cell lung cancer (NSCLC) remains unelucidated. CCK-8 assay was used to examine the survival rate of H1975/AR and HCC827/AR cells following treatment for 24h with different concentrations of baicalein, almonertinib or their combination. The changes in colony formation ability, apoptosis, and intracellular reactive oxygen species (ROS) levels of the treated cells were analyzed using colony formation assay and flow cytometry. Western blotting was performed to detect the changes in protein expressions in the cells. The effects of pre-treatment with NAC on proliferation, apoptosis, and PI3K/Akt signaling pathway were observed in baicalein- and/or almonertinib-treated cells. A nude mouse model bearing subcutaneous HCC827/AR cell xenograft were treated with baicalein (20mg/kg) or almonertinib (15mg/kg), and the tumor volume and body mass changes was measured. Both baicalein and almonertinib represses the viability of HCC827/AR and H1975/AR cells in a concentration-dependent manner. Compared with baicalein or almonertinib alone, the combined application of the two drugs dramatically attenuates cell proliferation; triggers apoptosis; causes cleavage of Caspase-3, PARP, and Caspase-9; downregulates the protein expressions of p-PI3K and p-Akt; and significantly inhibits tumor growth in nude mice. Furthermore, baicalein combined with almonertinib results in massive accumulation of reactive oxygen species (ROS) and preincubation with N-acetyl-L-cysteine (ROS remover) prevents proliferation as well as inhibits apoptosis induction, with partial recovery of the decline of p-PI3K and p-Akt. The combination of baicalein and almonertinib can improve the antitumor activity in almonertinib-resistant NSCLC through the ROS-mediated PI3K/Akt pathway.

Revealing active constituents within traditional Chinese Medicine used for treating bacterial pneumonia, with emphasis on the mechanism of baicalein against multi-drug resistant Klebsiella pneumoniae

Ethnopharmacological relevanceThe emergence of antibiotic-resistant bacteria has rendered it more challenging to treat bacterial pneumonia. Traditional Chinese medicine (TCM) has superior efficacy in the treatment of pneumonia, and it has the unique advantage of antibacterial resistance against multi-drug resistant (MDR) bacteria, but the medication rule and pharmacological mechanism of its antibacterial activity are not clear. Aim of the studyThis study aims to reveal Chinese medication patterns in treating bacterial pneumonia to select bioactive constituents in core herbs, predict their pharmacological mechanisms and further explore their antibacterial ability against clinically isolated MDR Klebsiella pneumoniae (KP) and their antibacterial mechanisms. Materials and methodsThe high-frequency medicinal herbs to treat lung diseases were first screened from Pharmacopoeia of the People's Republic of China (ChP.), and then bioactive compounds in core herbs and targets for compounds and disease were collected. Potential targets, signaling pathways, and drugs' core components were determined by constructing protein-protein interaction network, enrichment analysis and "component-target-pathway-disease" network were mapped by Cytoscape 3.8.2, and the potential therapeutic value of selected core components was verified by comparing the disease targets in the GEO database with the herbal component targets in the ITCM database. The clinically isolated KP were screened by drug sensitivity tests with meropenem (MEM), polymyxin E (PE), and tigecycline and biofilm-forming assay; broth microdilution, chessboard methods and biofilm morphology and permeability experiments were employed to determine the antibacterial, bactericidal and biofilm inhibition ability of selected bioactive constituents alone and in combination with antibiotics; The mechanism of bioactive components on quorum sensing (QS) genes LuxS and LuxR was predicted by molecular docking and tested by RT-PCR. ResultsThe 13 core Chinese medicines were obtained by mining ChP., and 615 potential targets of core herbal medicine were screened, and the PI3K-Akt signaling pathway might play crucial roles in the therapeutic process. In-vitro experiments revealed that the selected core compounds, including forsythoside B, baicalin, baicalein, and forsythin, all have antibacterial activity, in which baicalein had the strongest ability and a synergistic effect in combination with MEM or PE. Their synergy exhibited a stronger effect on biofilms of MDR KP, inhibiting biofilm formation, disrupting formed biofilms, and removing the residual structures of dead bacteria. Baicalein was predicted to have stable binding capacity to LuxS and LuxR genes by molecular docking, and RT-PCR results verified that the combination of baicalein with MEM or PE was effective in inhibiting the expression of QS genes (LuxS and LuxR) and consequently suppressing biofilm formation. ConclusionThe core Chinese herbal medicine in the ChP. to treat lung diseases has a multi-component, multi-target, and multi-pathway synergy to improve bacterial pneumonia. Experimental studies have confirmed that the bioactive compound baicalein was able to combat MDR KP alone and synergistic with MEM or PE, inhibited and disrupted biofilms via regulating LuxS and LuxR genes, and further disturbed quorum sensing system to promote the therapeutic efficacy, which provides a new pathway and rationale for treating MDR KP-induced bacterial pneumonia.

Baicalein Resensitizes Multidrug-Resistant Gram-Negative Pathogens to Doxycycline.

As multidrug-resistant pathogens emerge and spread rapidly, novel antibiotics urgently need to be discovered. With a dwindling antibiotic pipeline, antibiotic adjuvants might be used to revitalize existing antibiotics. In recent decades, traditional Chinese medicine has occupied an essential position in adjuvants of antibiotics. This study found that baicalein potentiates doxycycline against multidrug-resistant Gram-negative pathogens. Mechanism studies have shown that baicalein causes membrane disruption by attaching to phospholipids on the Gram-negative bacterial cytoplasmic membrane and lipopolysaccharides on the outer membrane. This process facilitates the entry of doxycycline into bacteria. Through collaborative strategies, baicalein can also increase the production of reactive oxygen species and inhibit the activities of multidrug efflux pumps and biofilm formation to potentiate antibiotic efficacy. Additionally, baicalein attenuates the lipopolysaccharide-induced inflammatory response in vitro. Finally, baicalein can significantly improve doxycycline efficacy in mouse lung infection models. The present study showed that baicalein might be considered a lead compound, and it should be further optimized and developed as an adjuvant that helps combat antibiotic resistance. IMPORTANCE Doxycycline is an important broad-spectrum tetracycline antibiotic used for treating multiple human infections, but its resistance rates are recently rising globally. Thus, new agents capable of boosting the effectiveness of doxycycline need to be discovered. In this study, it was found that baicalein potentiates doxycycline against multidrug-resistant Gram-negative pathogens in vitro and in vivo. Due to its low cytotoxicity and resistance, the combination of baicalein and doxycycline provides a valuable clinical reference for selecting more effective therapeutic strategies for treating infections caused by multidrug-resistant Gram-negative clinical isolates.

The Combination of Baicalein and Memantine Reduces Oxidative Stress and Protects against β-amyloid-Induced Alzheimer’s Disease in Rat Model

Alzheimer's disease (AD) is a neuronal condition causing progressive loss of memory and cognitive dysfunction particularly in elders. An upsurge in the global old age population has led to a proportionate increase in the prevalence of AD. The current treatments for AD are symptomatic and have debilitating side effects. A literature review and current research have directed scientists to explore natural products with better safety and efficacy profiles as new treatment options for AD. Baicalein, belonging to the flavone subclass of flavonoids, has been reported for its anti-oxidant, anti-inflammatory, AChE enzyme inhibitory activity and anti-amyloid protein aggregation activity, which collectively demonstrates its benefits as a neuroprotective agent. Presently, memantine, a NMDAR antagonist, is one of the important drugs used for treatment of Alzheimer's disease. The current study aims to investigate the effect of baicalein in combination with memantine in β-amyloid-induced AD in albino Wistar rats. Baicalein (10 mg/kg) alone, 5 mg/kg and 10 mg/kg in combination with memantine (20 mg/kg) was administered for 21 days. Treatment with baicalein in combination with memantine showed significant improvement in behavioural studies. The combination treatment decreased oxidative stress, β-amyloid plaque formation and increased the expression of brain-derived neurotrophic factor (BDNF) in the brain. From the results, it can be concluded that treatment with baicalein and memantine could be beneficial for reducing the progression of neurodegeneration in rats. Baicalein has an additive effect in combination with memantine, making it a potential option for the treatment of AD.

Effects of baicalein with memantine on aluminium chloride-induced neurotoxicity in Wistar rats.

Alzheimer's disease is a progressive neurodegenerative condition. It is one of the most common 28 forms of dementia accounting for 60-80% of people suffering from dementia. There are very few medications that are approved for the treatment of Alzheimer's disease. Baicalein, belonging to the flavone subclass of flavonoids, has been reported to have a neuroprotective effect by reducing oxidative stress and neuroinflammation, inhibiting the AChE enzyme, and reducing amyloid protein aggregation and toxicity. Memantine is one of the most important drugs used for treating Alzheimer's disease. The purpose of this work was to study the effect of baicalein with memantine on aluminum chloride-induced neurotoxicity in Wistar rats. Aluminum chloride (100mg/kg p.o.) was administered for 42days in male Wistar rats to induce neurotoxicity. Baicalein alone (10mg/kg) and a combination of baicalein (5mg/kg and 10mg/kg) with memantine (20mg/kg) were administered for 42days. Treatment of baicalein with memantine showed significant improvement in behavioral parameters. The combination reduced oxidative stress and the formation of β-Amyloid plaques and increased brain-derived neurotrophic factor (BDNF) expression. Based on findings, it can be concluded that treatment with baicalein and memantine may slow the progression of neurodegeneration in rats.

Cytotoxic Evaluation of Doxorubicin Combination with Baicalein and Resveratrol Against Hct116 and Hepg2 Cancer Cell Lines (Conference Paper) #

Combination of natural poly-phenolic compounds with chemotherapeutic agents is recently being a novel strategy in cancer therapy researches owing to their potential antioxidant and anti-inflammatory properties that modulate several intracellular signaling pathways.
 Resveratrol and Baicalein are well known poly-phenolic compounds that belong to stilbene and flavone subclasses, respectively.
 This study aims to investigate the possible enhancement effect of resveratrol and Baicalein when combined with doxorubicin using a different combination ratio and applied on two cancer cell lines: HCT116 (colorectal cancer cells) and HepG2 (hepatocellular cancer cells). It also investigates the possibility of such natural compounds to provide a protection effect on cardiocytes (H9C2) when resveratrol and Baicalein treatment followed by doxorubicin is used. 
 The two cancer cell lines were treated with different combination groups, including the combination between doxorubicin and Baicalein or resveratrol and the combination between the three compounds using a different combination ratio for both treatment groups (i.e., two drugs or three drugs combination). Treatment applied on cells, using cell density of 7000 cells /well and incubation time was 48 hrs. MTT test was performed to assay the cell viability.
 The results obtained showed that the cytotoxicity of doxorubicin in the two cancer cell lines has increased when combined with Baicalein and resveratrol. Doxorubicin IC50 decreased from 4.99 µg/ml to 0.3657 µg/ml and from 7.3 µg/ml to 0.676 µg/ml on HCT116 and HepG2 cells, respectively, using constant combination ratio (1:1:1).
 The combination of doxorubicin, Baicalein, and resveratrol has resulted in a less cardiotoxic effect compared to treatment with doxorubicin alone. This decrease was obviously seen when the three compounds were combined using a low concentration range and with a constant combination ratio.
 Conclusion: combinations of Baicalein and resveratrol with doxorubicin chemotherapeutic drug In Vitro had enhanced the cytotoxic activity of such a chemotherapeutic drug, while simultaneously eliminating its cardio-toxicity side effect.

Baicalein sensitizes triple negative breast cancer MDA-MB-231 cells to doxorubicin via autophagy-mediated down-regulation of CDK1.

Triple negative breast cancer (TNBC) is a kind of refractory cancer with poor response to conventional chemotherapy. Recently, the combination of baicalein and doxorubicin was reported to exert a synergistic antitumor effect on breast cancer. However, the underlying mechanism how baicalein sensitizes breast cancer cells to doxorubicin remains to be elucidated. Here, it was found that 20μM baicalein increased the autophagy markers including the ratio of LC3B II/I, GFP-LC3 punctate aggregates and down-regulation of p62 expression, and up-regulated mitophagy marker PINK1 and Parkin in TNBC MDA-MB-231 cells as well. In contrast, doxorubicin decreased the levels of autophagy markers, and significantly up-regulated CDK1 in MDA-MB-231 cells. Pretreatment with baicalein markedly inhibited the doxorubicin-induced decrease in autophagy markers and up-regulation of CDK1, which was reversed by the autophagy inhibitor 3-Methyladenine. Moreover, baicalein alleviated the doxorubicin-induced expression and phosphorylation (at Ser616) of mitochondrial fission protein Drp1. Intriguingly, the autophagy inhibitor 3-Methyladenine also significantly weakened the effect of baicalein on doxorubicin-induced viability decrease and apoptosis in MDA-MB-231 cells. Taken together, our data indicate that baicalein improves the chemosensitivity of TNBC cells to doxorubicin through promoting the autophagy-mediated down-regulation of CDK1, also suggest a novel strategy for prevention of TNBC in the future.

Baicalein activates 5’ adenosine monophosphate-activated protein kinase, inhibits the mammalian target of rapamycin, and exhibits antiproliferative effects in pancreatic neuroendocrine tumors in vitro and in vivo

BackgroundThe mammalian target of rapamycin inhibition has been shown to prolong progression-free survival in patients with pancreatic neuroendocrine tumors. The natural compound baicalein indirectly inhibits the mammalian target of rapamycin, but it is unknown if baicalein exhibits such effects at physiologically achievable concentrations or exhibits synergy. MethodsPancreatic neuroendocrine tumor cell lines were cultured with baicalein, everolimus, and/or a synthetic 5’ adenosine monophosphate-activated protein kinase activating agent alone and in combination. Cell viability assays and immunoblotting were performed. Female severe combined immunodeficient-beige mice were injected with BON-1 cells and treated with baicalein and COH-SR4 solutions via oral gavage. Tumor volumes were compared at 30 days. ResultsImmunoblotting revealed that treatment of baicalein induced 5’ adenosine monophosphate-activated protein kinase activation and the mammalian target of rapamycin inhibition. Treatment with baicalein alone led to a significant decrease in the ratio of viable cells compared with controls at 72 hours at concentrations ≥5 μM (P = .021). The addition of COH-SR4 led to significantly greater effect on cell viability than with baicalein alone (P < .001, P < .001). The combination of baicalein with everolimus resulted in significantly lower cell viability than with everolimus alone (P = .005, P < .001). Tumor volume in vivo was significantly decreased with the combination of baicalein and COH-SR4 compared with controls (P = .003). ConclusionBaicalein exhibits antiproliferative effects against pancreatic neuroendocrine tumor cell lines at doses ≥5 μM and demonstrates synergy.

Reducing the intestinal side effects of acarbose by baicalein through the regulation of gut microbiota: An in vitro study

Combination of dietary flavonoid-baicalein and acarbose reduces the risk that prediabetes will develop into type 2 diabetes mellitus; however, the mechanism underlying this effect has not been clarified. In this study, the in vitro culture conditions of intestinal microorganisms from prediabetic mice were optimized to increase over 30% similarity between in vitro cultured and fecal samples. Baicalein and acarbose alone and in combination, and their corresponding starch hydrolysate were assayed by the in vitro model. The results indicated that the combination of baicalein with acarbose decreased gas production by reducing the residual starch ratio in starch hydrolysate and decreasing the dosage of acarbose, and that reducing the relative abundance of gut bacteria correlated with gas production is the main mechanism. This study provided a theoretical foundation for the development of flavonoid dietary supplements to enhance the efficacy of oral hypoglycemic agents with fewer side effects and higher efficacy.

Inhibitory effect of a combination of baicalein and quercetin flavonoids against Candida albicans strains isolated from the female reproductive system

Flavonoids are a diverse group of compounds originating from several natural plant sources. Various biological effects of flavonoids have been reported, including antimicrobial and antifungal activities. In this study, we showed the possibility of using commercial flavonoids, i.e. baicalein and quercetin, based on natural equivalents as compounds with antifungal properties against Candida albicans species. The effects of baicalein and/or quercetin were investigated using reference C. albicans strain and 50 clinical strains isolated from vulvovaginal candidiasis (VVC) patients. Baicalein and quercetin MIC values against C. albicans strains ranged between 0.5 and 256 μg/ml. We observed predominantly indifferent, synergistic, or partially synergistic interactions between both flavonoids and between the flavonoids and fluconazole in the treatment of planktonic cells of the C. albicans strains. Treatment with the flavonoid complex inhibited adhesion and aggregation of cells, cell surface hydrophobicity (CSH), flocculation, biofilm formation and reduced hyphal growth. Real-time RT-PCR revealed that baicalein and quercetin in combination down-regulated the expression of biofilm-specific genes. Finally, we observed increase in the cell membrane permeability of C. albicans and its physical destruction as a result of the synergistic activity of baicalein and quercetin. Our research evidences the effectiveness of baicalein and quercetin applied in combination as potential anti-Candida agents.

Combination of baicalein and trans‐chalcone synergistically reduces amyloid beta and its toxicity in yeast

AbstractBackgroundThere has been a long quest to uncover effective therapeutic strategy to prevent or cure AD as current strategies only support as palliative care. This study utilizes unmodified and genetically modified Saccharomyces cerevisiae as model organisms to screen and find potential natural bioactive compounds that can reduce the levels of amyloid beta and associated toxicity.MethodsEleven selected naturally occurring bioactive compounds namely mangiferin, quercetin, rutin, resveratrol, epigallocatechin gallate (EGCG), urolithin A, oleuropein, rosmarinic acid, salvianolic acid B, baicalein and trans‐chalcone at specific concentration (50µM) were screened for their ability to change intracellular green fluorescent protein (GFP) tagged Aβ42 levels, in vivo anti‐amyloid properties using thioflavin‐S fluorescent dye and induce heat stress response using the yeast heat stress reporter that expresses mCherry red fluorescent protein under control of a heat shock promoter containing heat shock elements (HSEs). Furthermore, the two compounds with highest activity in all three screens were combined together in varying concentrations of each to study the underlying combination ability to reduce GFP‐Aβ42, their effect on growth, turnover of native Aβ42 and reactive oxygen species.ResultsThe bioactive compounds reduced intracellular GFP‐Aβ42 levels (except mangiferin) and intracellular amyloid fibrils (except resveratrol and EGCG) in yeast models significantly with highest effect shown by baicalein and trans‐chalcone. Among the bioactive compounds, quercetin, rutin, rosmarinic acid, baicalein and trans‐chalcone significantly induced heat stress reporter with highest effect demonstrated by baicalein and trans‐chalcone. Furthermore, the combinations of baicalein and trans‐chalcone showed synergistic ability to reduce GFP‐Aβ42. Although some of the combinations were found growth inhibitory, a combination of 50μM trans‐chalcone and 30μM baicalein was found to be cytoprotective as well as an effective reducer of GFP‐Aβ42. In addition, the combination of the two compounds showed synergy in reducing ROS in yeast cells expressing native Aβ42 and reduced the Aβ42 protein levels by nearly 80%.ConclusionThe findings of the study suggest that the combination of baicalein and trans‐chalcone can be a therapeutic strategy to cure or at least prevent AD. However, further studies are recommended to ascertain that similar cytoprotective activity is observed in humans and optimization of dosage to observe best effect.

Trans-Chalcone Plus Baicalein Synergistically Reduce Intracellular Amyloid Beta (Aβ42) and Protect from Aβ42 Induced Oxidative Damage in Yeast Models of Alzheimer's Disease.

Finding an effective therapeutic to prevent or cure AD has been difficult due to the complexity of the brain and limited experimental models. This study utilized unmodified and genetically modified Saccharomyces cerevisiae as model organisms to find potential natural bioactive compounds capable of reducing intracellular amyloid beta 42 (Aβ42) and associated oxidative damage. Eleven natural bioactive compounds including mangiferin, quercetin, rutin, resveratrol, epigallocatechin gallate (EGCG), urolithin A, oleuropein, rosmarinic acid, salvianolic acid B, baicalein and trans-chalcone were screened for their ability to reduce intracellular green fluorescent protein tagged Aβ42 (GFP-Aβ42) levels. The two most effective compounds from the screens were combined in varying concentrations of each to study the combined capacity to reduce GFP-Aβ42. The most effective combinations were examined for their effect on growth rate, turnover of native Aβ42 and reactive oxygen species (ROS). The bioactive compounds except mangiferin and urolithin A significantly reduced intracellular GFP-Aβ42 levels. Baicalein and trans-chalcone were the most effective compounds among those that were screened. The combination of baicalein and trans-chalcone synergistically reduced GFP-Aβ42 levels. A combination of 15 μM trans-chalcone and 8 μM baicalein was found to be the most synergistic combination. The combination of the two compounds significantly reduced ROS and Aβ42 levels in yeast cells expressing native Aβ42 without affecting growth of the cells. These findings suggest that the combination of baicalein and trans-chalcone could be a promising multifactorial therapeutic strategy to cure or prevent AD. However, further studies are recommended to look for similar cytoprotective activity in humans and to find an optimal dosage.

Combination of baicalein and miR-106a-5p mimics significantly alleviates IL-1β-induced inflammatory injury in CHON-001 cells.

Osteoarthritis (OA) induces inflammation and degeneration of all joint components, and as such, is a considerable source of disability, pain and socioeconomic burden worldwide. Baicalein (BAI) and microRNA (miR)-106a-5p suppress the progression of OA; however, the effects of BAI and miR-106a-5p for the combined treatment of OA are not completely understood. An in vitro OA model was established by treating CHON-001 cells with 20 ng/ml interleukin (IL)-1β. Cell Counting Kit-8 and flow cytometry assays were conducted to evaluate cell viability and apoptosis, respectively. Western blotting was performed to determine the expression levels of Bax, active caspase-3, Bcl-2, collagen I, collagen III, aggrecan, matrix metallopeptidase (MMP)-13, MMP-9, active Notch1 and transcription factor hes family bHLH transcription factor 1 (Hes1). The levels of IL-6 and tumor necrosis factor-α in the cell culture medium were quantified via ELISA. The present study revealed that treatment with BAI or miR-106a-5p mimic alleviated IL-1β-induced apoptosis, and BAI + miR-106a-5p combination treatment exerted enhanced anti-inflammatory effects compared with monotherapy. Furthermore, IL-1β-induced accumulation of collagen, collagen III, MMP-13 and MMP-9 in CHON-001 cells was reversed to a greater degree following combination treatment compared with monotherapy. Likewise, IL-1β-induced aggrecan degradation was markedly reversed by combination treatment. IL-1β-induced upregulation of active Notch1 and Hes1 in CHON-001 cells was also significantly attenuated by combined BAI + miR-106a-5p treatment. In conclusion, the results of the present study revealed that the combination of BAI and miR-106a-5p mimic significantly decreased IL-1β-induced inflammatory injury in CHON-001 cells, which may serve as a novel therapeutic strategy for OA.

Inhibition of Autophagy Amplifies Baicalein-Induced Apoptosis in Human Colorectal Cancer

Baicalein is a Chinese herbal compound extracted from Scutellaria baicalensis that has anti-tumor properties. The aim of this study was to elucidate the mechanisms of action of baicalein against human colorectal cancer cell lines and to assess whether the anti-proliferative effects of baicalein may be amplified with autophagy inhibition. Human colon cancer cell lines (HT-29, HCT-116, SW480, and SW620) were treated with baicalein alone and in combination with the autophagy inhibitor chloroquine (CQ). Baicalein reduced cell viability in all four colon cancer lines in a dose-dependent fashion. Combination treatment of baicalein and the autophagy inhibitor CQ significantly decreased cell viability compared with baicalein alone in HT-29 and HCT-116 cell lines. Western blot analysis of the HCT-116 cell line treated with both baicalein and CQ demonstrated increased expression of LC3-II, a component of autophagy. The combination of baicalein with CQ culminated in activation of caspase-3-mediated apoptosis. These findings demonstrate that inhibition of autophagy enhanced apoptotic cell death induced by baicalein treatment in colon cancer cell lines. Future work will assess other targetable apoptotic pathways activated by baicalein and autophagy inhibition.

Baicalein enhanced cisplatin sensitivity of gastric cancer cells by inducing cell apoptosis and autophagy via Akt/mTOR and Nrf2/Keap 1 pathway

Baicalein is a natural flavonoid with various pharmacological activities including antitumor. The synergistic anti-cancer effect of the combination of baicalein and Cisplatin (DDP) on gastric cancer (GC) has not been reported. MTT assay and colony formation assay were used to determine the inhibitory effect of the combination of baicalein and DDP on cell survival. Invasive assay was performed to test the effects of baicalein and DDP on cell invasive capability. A flow cytometric analysis was conducted to determine the apoptosis-induced effects of baicalein on GC cells, especially SGC-7901/DDP (resistant to DDP). Confocal laser microscope and real-time PCR were used to test autophagy-induced effects of baicalein on SGC-7901 and SGC-7901/DDP cells. Western blotting was performed to investigate the molecular mechanisms of baicalein inducing apoptosis and autophagy. Our study showed that baicalein could inhibit cell proliferation of MGC-803, HGC-27, SGC-7901 and SGC-7901/DDP, and the inhibitory effect was extremely enhanced when combining with DDP. Additionally, combination of baicalein and DDP suppressed the invasive capability and induced apoptosis and autophagy in both SGC-7901 and SGC-7901/DDP, and the effect was stronger than that of DDP or baicalein alone. The further molecular mechanism analysis indicated that baicalein modulated the activities of Akt/mTOR and Nrf2/Keap 1 signaling. Our study demonstrated that baicalein enhanced DDP sensitivity of SGC-7901/DDP gastric cancer cells by inducing apoptosis and autophagy via Akt/mTOR and Nrf2/Keap 1 pathway.

Antibacterial synergy between linezolid and baicalein against methicillin-resistant Staphylococcus aureus biofilm in vivo

Methicillin-resistant Staphylococcus aureus (MRSA) can form biofilms, which prevents the penetration of antibiotics, decreasing their efficacy. This study investigated whether baicalein has synergistic antibacterial effects with linezolid in vivo. We cultivated MRSA 17546 biofilms on silicone implants and inserted them into the air pouches of rat models. The rats were treated with linezolid, baicalein, or a combination therapy for three consecutive days. All treatments reduced the number of colony-forming units (CFU) in the biofilms compared to the control (p < 0.05). However, by day two, the CFU counts were significantly lower in the combination group than in the individual treatment groups (p < 0.05). Histological analysis of the air pouches showed that the severity of the inflammatory cell infiltration was severe in the combination therapy group. In the combination group, the biofilm structure on the implant's surface was sparse and more free colonies could be seen by scanning electron microscopy (SEM); by day three, no obvious biofilm was observed. The serum levels of Staphylococcus enterotoxin A (SEA), C-reactive protein (CRP), and procalcitonin (PCT) were the lowest in the group where rats were treated with the combination of baicalein and linezolid (p < 0.05) compared to other groups. The results suggest that baicalein may inhibit the accessory gene regulator system, reducing the expression of SEA, thus lowering CRP and PCT levels. Furthermore, the inhibitory effect was more pronounced when baicalein was combined with linezolid. These results provide an important basis for the development of a new combination regimen to treat patients with biofilm-associated MRSA infections.

Combination of baicalein and docetaxel additively inhibits the growth of non-small cell lung cancer in vivo

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[Formula: see text] (docetaxel injection) alone or the combination of baicalein and Taxotere[Formula: see text]. The effect of the combination treatment was evaluated by [Formula: see text] value. Tumors were harvested for TUNEL and CD31 immunohistochemical staining and important organs for H&amp;E staining. Results: Baicalein 50[Formula: see text]mg/kg plus docetaxel 10[Formula: see text]mg/kg significantly reduced tumor weight and inhibited the growth rate of tumor, displaying the additive effect indicated by the [Formula: see text] value. Increased apoptosis and decreased tumor angiogenesis also provided pathological evidence. Additionally, baicalein 50[Formula: see text]mg/kg plus docetaxel 10[Formula: see text]mg/kg did not increase toxicity in lung, liver and kidney. Conclusion: Baicalein 50[Formula: see text]mg/kg plus docetaxel 10[Formula: see text]mg/kg additively inhibits the growth of NSCLC in vivo, and the mechanism underlying remains to be discovered.

Combined Effects of Baicalein and Docetaxel on Apoptosis in 8505c Anaplastic Thyroid Cancer Cells via Downregulation of the ERK and Akt/mTOR Pathways.

BackgroundAnaplastic thyroid cancer (ATC) is one of the most lethal human malignancies. Docetaxel, a microtubule stabilizer, is a common chemotherapeutic agent used to treat various metastatic cancers. However, prolonged use results in various side effects and drug resistance. Flavonoids, such as baicalein, are accepted chemotherapeutic and dietary chemopreventive agents with many advantages, such as greater accessibility, affordability, and lower toxicity, compared with traditional chemotherapy agents. In this study, we evaluated whether baicalein enhances the effects of docetaxel on apoptosis and metastasis in 8505c ATC cells.MethodsThe 8505c cells were treated with baicalein or docetaxel individually and in combination. Cell viability was measured by MTT (thiazolyl blue tetrazolium bromide) assay, and apoptosis was detected by fluorescence microscopy of Hoechst-stained cells. The expression of apoptotic (Bax and caspase-3), anti-apoptotic (Bcl-2), angiogenic (vascular endothelial growth factor [VEGF], transforming growth factor β [TGF-β], E-cadherin, and N-cadherin), and signaling (extracellular signal-regulated kinase [ERK] mitogen activated protein kinase [MAPK], Akt, and mammalian target of rapamycin [mTOR]) proteins was determined by Western blot analysis.ResultsThe combination of baicalein (50 or 100 µM) and docetaxel (10 nM) significantly inhibited proliferation and induced apoptosis compared with monotherapies. The combination treatment significantly inhibited the expression of Bax, caspase-3, VEGF, TGF-β1, E-cadherin, N-cadherin, and mTOR, but decreased the expression of Bcl-2 and significantly decreased the phosphorylation of ERK and Akt.ConclusionThe combination of baicalein and docetaxel effectively induced apoptosis and inhibited metastasis in 8505c cells through downregulation of apoptotic and angiogenic protein expression and blocking of the ERK and Akt/mTOR pathways in 8505c cells. These results suggest that baicalein enhances the anticancer effects of docetaxel in ATC.

Synergistic effects of baicalein with gemcitabine or docetaxel on the proliferation, migration and apoptosis of pancreatic cancer cells

Baicalein, a type of flavonoids extracted from Scutellaria baicalensis Georgi, has been reported to be a very promising drug for pancreatic cancer. However, it is unclear whether combination of baicalein with gemcitabine or docetaxel is synergistic to the treatment for pancreatic cancer (PC). We investigated the combinational effects of baicalein with gemcitabine or docetaxel on proliferation, cell cycle, migration and apoptosis of human PC cells. Administration of baicalein alone significantly inhibit the proliferation of PC cells. Notably, when it is combined with gemcitabine or docetaxel, combination index (CI) values calculated by Calcusyn software are smaller than 1, indicating the synergism of baicalein with gemcitabine or docetaxel for the treatment of PC cells. Consistently, EdU assay showed that administration of baicalein significantly enhanced the capacity of gemicitabine to inhibit proliferation of PC cells. Cell cycle analysis showed that high-concentration of baicalein was able to arrest PC cells in the Sphase. Furthermore, low concentration of baicalein in combination with either gemcitabine or docetaxel exhibited strong suppression on the migration of PC cells. A further study using transmission electron microscope (TEM), DAPI staining and western blot showed that baicalein induced-apoptosis of PC cells might be via caspase-3/PARP signaling pathway. Notably, combination treatment was able to induce more severe cell apoptosis of PC cells. In conclusion, baicalein exhibited synergistic effects with gemcitabine or docetaxel on the treatment of PC cells.