Baicalein suppresses inflammation and attenuates acute lung injury by inhibiting glycolysis via HIF‑1&alpha; signaling

Liu,Zhongyou; Zheng,Xiaona; Li,Ning; Wang,Zongyao

doi:10.3892/mmr.2024.13383

Baicalein suppresses inflammation and attenuates acute lung injury by inhibiting glycolysis via HIF‑1α signaling

Authors:
- Zhongyou Liu
- Xiaona Zheng
- Ning Li
- Zongyao Wang
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Affiliations: Department of Respiratory Diseases, Zhumadian Hospital of Traditional Chinese Medicine, Zhumadian, Henan 463000, P.R. China, Department of Scientific Research, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan 450046, P.R. China, Department of Respiratory Diseases, Zhengzhou Hospital of Traditional Chinese Medicine, Zhengzhou, Henan 450007, P.R. China
Published online on: November 5, 2024 https://doi.org/10.3892/mmr.2024.13383
Article Number: 18
Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Baicalein, a flavonoid monomer compound isolated from the dried root of the traditional Chinese herb Scutellaria baicalensis, has several pharmacological activities, such as anti‑inflammatory, anti‑angiogenic, antitumor, antimicrobial and antiviral properties. Acute lung injury (ALI) is characterized by injury of the alveolar epithelium and capillary endothelium, which results in decreased lung volume, decreased lung compliance, ventilation/perfusion mismatch, intrapulmonary edema, alveolar edema and even acute hypoxemic respiratory failure. The present study aimed to investigate the effects of baicalein on lung injury and inflammation. Bioinformatics analysis using network pharmacology predicted that the hypoxia inducible factor‑1α (HIF‑1α) and glycolysis signaling pathways were involved in the mechanism underlying the therapeutic effects of baicalein. Further in vitro and in vivo experiments, such as immunohistochemistry, immunofluorescence and PCR, verified that baicalein could inhibit HIF‑1α signaling, thus suppressing glycolysis, and improving inflammatory responses and ALI. Taken together, the results of the present study suggested that the anti‑inflammatory effects of baicalein on treating ALI were associated with its ability to suppress glycolysis via the HIF‑1α signaling pathway.

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1	Long ME, Mallampalli RK and Horowitz JC: Pathogenesis of pneumonia and acute lung injury. Clin Sci (Lond). 136:747–769. 2022. View Article : Google Scholar : PubMed/NCBI
2	Johnson ER and Matthay MA: Acute lung injury: Epidemiology, pathogenesis, and treatment. J Aerosol Med Pulm Drug Deliv. 23:243–252. 2010. View Article : Google Scholar : PubMed/NCBI
3	Schmidt GA: Managing Acute Lung Injury. Clin Chest Med. 37:647–658. 2016. View Article : Google Scholar : PubMed/NCBI
4	Fanelli V and Ranieri VM: Mechanisms and clinical consequences of acute lung injury. Ann Am Thorac Soc. 12 (Suppl 1):S3–S8. 2015. View Article : Google Scholar : PubMed/NCBI
5	Huang X, Xiu H, Zhang S and Zhang G: The Role of Macrophages in the Pathogenesis of ALI/ARDS. Mediators Inflamm. 2018:12649132018. View Article : Google Scholar : PubMed/NCBI
6	Dzopalic T, Bozic-Nedeljkovic B and Jurisic V: Function of innate lymphoid cells in the immune-related disorders. Hum Cell. 32:231–239. 2019. View Article : Google Scholar : PubMed/NCBI
7	Sakaguchi M, Marutani E, Shin HS, Chen W, Hanaoka K, Xian M and Ichinose F: Sodium thiosulfate attenuates acute lung injury in mice. Anesthesiology. 121:1248–1257. 2014. View Article : Google Scholar : PubMed/NCBI
8	Kosutova P, Kolomaznik M, Calkovska A, Mokra D and Mikolka P: Nitric-Oxide-releasing dexamethasone derivative NCX-1005 improves lung function and attenuates inflammation in experimental lavage-induced ARDS. Pharmaceutics. 13:20922021. View Article : Google Scholar : PubMed/NCBI
9	Xia L, Zhang C, Lv N, Liang Z, Ma T, Cheng H, Xia Y and Shi L: AdMSC-derived exosomes alleviate acute lung injury via transferring mitochondrial component to improve homeostasis of alveolar macrophages. Theranostics. 12:2928–2947. 2022. View Article : Google Scholar : PubMed/NCBI
10	Gopalakrishnan A, Joseph J, Shirey KA, Keegan AD, Boukhvalova MS, Vogel SN and Blanco JCG: Protection against influenza-induced Acute Lung Injury (ALI) by enhanced induction of M2a macrophages: Possible role of PPARγ/RXR ligands in IL-4-induced M2a macrophage differentiation. Front Immunol. 13:9683362022. View Article : Google Scholar : PubMed/NCBI
11	Wu S, Tang W, Liu L, Wei K, Tang Y, Ma J, Li H and Ao Y: Obesity-induced downregulation of miR-192 exacerbates lipopolysaccharide-induced acute lung injury by promoting macrophage activation. Cell Mol Biol Lett. 29:362024. View Article : Google Scholar : PubMed/NCBI
12	Zhong WJ, Yang HH, Guan XX, Xiong JB, Sun CC, Zhang CY, Luo XQ, Zhang YF, Zhang J, Duan JX, et al: Inhibition of glycolysis alleviates lipopolysaccharide-induced acute lung injury in a mouse model. J Cell Physiol. 234:4641–4654. 2019. View Article : Google Scholar : PubMed/NCBI
13	Wang L, Cao Y, Gorshkov B, Zhou Y, Yang Q, Xu J, Ma Q, Zhang X, Wang J, Mao X, et al: Ablation of endothelial Pfkfb3 protects mice from acute lung injury in LPS-induced endotoxemia. Pharmacol Res. 146:1042922019. View Article : Google Scholar : PubMed/NCBI
14	Jurisic V, Radenkovic S and Konjevic G: The Actual Role of LDH as tumor marker, biochemical and clinical aspects. Adv Exp Med Biol. 867:115–124. 2015. View Article : Google Scholar : PubMed/NCBI
15	Soto-Heredero G, Gómez de Las Heras MM, Gabande-Rodriguez E, Oller J and Mittelbrunn M: Glycolysis-a key player in the inflammatory response. FEBS J. 287:3350–3369. 2020. View Article : Google Scholar : PubMed/NCBI
16	Jurisic V, Bumbasirevic V, Konjevic G, Djuricic B and Spuzic I: TNF-alpha induces changes in LDH isotype profile following triggering of apoptosis in PBL of non-Hodgkin's lymphomas. Ann Hematol. 83:84–91. 2004. View Article : Google Scholar : PubMed/NCBI
17	Corcoran SE and O'Neill LA: HIF1α and metabolic reprogramming in inflammation. J Clin Invest. 126:3699–3707. 2016. View Article : Google Scholar : PubMed/NCBI
18	Dang B, Gao Q, Zhang L, Zhang J, Cai H, Zhu Y, Zhong Q, Liu J, Niu Y, Mao K, et al: The glycolysis/HIF-1α axis defines the inflammatory role of IL-4-primed macrophages. Cell Rep. 42:1124712023. View Article : Google Scholar : PubMed/NCBI
19	Zhuang H, Lv Q, Zhong C, Cui Y, He L, Zhang C and Yu J: Tiliroside ameliorates ulcerative colitis by restoring the M1/M2 Macrophage Balance via the HIF-1α/glycolysis Pathway. Front Immunol. 12:6494632021. View Article : Google Scholar : PubMed/NCBI
20	Sowndhararajan K, Deepa P, Kim M, Park SJ and Kim S: Baicalein as a potent neuroprotective agent: A review. Biomed. Pharmacother. 95:1021–1032. 2017. View Article : Google Scholar : PubMed/NCBI
21	Liu BY, Li L, Liu GL, Ding W, Chang WG, Xu T, Ji XY, Zheng XX, Zhang J and Wang JX: Baicalein attenuates cardiac hypertrophy in mice via suppressing oxidative stress and activating autophagy in cardiomyocytes. Acta Pharmacol Sin. 42:701–714. 2021. View Article : Google Scholar : PubMed/NCBI
22	Ren M, Zhao Y, He Z, Lin J, Xu C, Liu F, Hu R, Deng H and Wang Y: Baicalein inhibits inflammatory response and promotes osteogenic activity in periodontal ligament cells challenged with lipopolysaccharides. BMC Complement Med Ther. 21:432021. View Article : Google Scholar : PubMed/NCBI
23	Li B, Chen K, Qian N, Huang P, Hu F, Ding T, Xu X, Zhou Q, Chen B, Deng L, et al: Baicalein alleviates osteoarthritis by protecting subchondral bone, inhibiting angiogenesis and synovial proliferation. J Cell Mol Med. 25:5283–5294. 2021. View Article : Google Scholar : PubMed/NCBI
24	Wang R, Wang C, Lu L, Yuan F and He F: Baicalin and baicalein in modulating tumor microenvironment for cancer treatment: A comprehensive review with future perspectives. Pharmacol. Res. 199:1070322024.PubMed/NCBI
25	Ning B, Shen J, Liu F, Zhang H and Jiang X: Baicalein Suppresses NLRP3 and AIM2 Inflammasome-Mediated Pyroptosis in Macrophages Infected by Mycobacterium tuberculosis via Induced Autophagy. Microbiol Spectr. 11:e4711222023. View Article : Google Scholar
26	Szapiel SV, Elson NA, Fulmer JD, Hunninghake GW and Crystal RG: Bleomycin-induced interstitial pulmonary disease in the nude, athymic mouse. Am Rev Respir. 120:893–899. 1979.PubMed/NCBI
27	Li Q, Peng J, Luo Y, Zhou J, Li T, Cao L, Peng S, Zuo Z and Wang Z: Far infrared light irradiation enhances Aβ clearance via increased exocytotic microglial ATP and ameliorates cognitive deficit in Alzheimer's disease-like mice. J Neuroinflammation. 19:1452022. View Article : Google Scholar : PubMed/NCBI
28	Jurisic V: Multiomic analysis of cytokines in immuno-oncology. Expert Rev Proteomics. 17:663–674. 2020. View Article : Google Scholar : PubMed/NCBI
29	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
30	Chin CH, Chen SH, Wu HH, Ho CW, Ko MT and Lin CY: cytoHubba: Identifying hub objects and sub-networks from complex interactome. BMC Syst Biol. 8 (Suppl 4):S112014. View Article : Google Scholar : PubMed/NCBI
31	Xie WM, Su W, Liu XY, Zhou J, Wang M, Wang Y, Wang W, Bai X, Li Z and Li T: FTO Deficiency Alleviate LPS-induced ALI by TXNIP/NLPR3-mediated alveolar epithelial cell pyroptosis. Am J Respir Cell Mol Biol. 70:351–363. 2024. View Article : Google Scholar : PubMed/NCBI
32	Kligerman S: Pathogenesis, imaging, and evolution of acute lung injury. Radiol Clin North Am. 60:925–939. 2022. View Article : Google Scholar : PubMed/NCBI
33	Rubenfeld GD and Herridge MS: Epidemiology and outcomes of acute lung injury. Chest. 131:554–562. 2007. View Article : Google Scholar : PubMed/NCBI
34	Hu Q, Hou S, Xiong B, Wen Y, Wang J, Zeng J, Ma X and Wang F: Therapeutic effects of baicalin on diseases related to gut-brain axis dysfunctions. Molecules. 28:65012023. View Article : Google Scholar : PubMed/NCBI
35	Li J, Deng SH, Li J, Li L, Zhang F, Zou Y, Wu DM and Xu Y: Obacunone alleviates ferroptosis during lipopolysaccharide-induced acute lung injury by upregulating Nrf2-dependent antioxidant responses. Cell Mol Biol Lett. 27:292022. View Article : Google Scholar : PubMed/NCBI
36	Li J, Lu K, Sun F, Tan S, Zhang X, Sheng W, Hao W, Liu M, Lv W and Han W: Panaxydol attenuates ferroptosis against LPS-induced acute lung injury in mice by Keap1-Nrf2/HO-1 pathway. J Transl Med. 19:962021. View Article : Google Scholar : PubMed/NCBI
37	Fukatsu M, Ohkawara H, Wang X, Alkebsi L, Furukawa M, Mori H, Fukami M, Fukami SI, Sano T, Takahashi H, et al: The suppressive effects of Mer inhibition on inflammatory responses in the pathogenesis of LPS-induced ALI/ARDS. Sci Signal. 15:d25332022. View Article : Google Scholar : PubMed/NCBI
38	Luo L, Huang F, Zhong S, Ding R, Su J and Li X: Astaxanthin attenuates ferroptosis via Keap1-Nrf2/HO-1 signaling pathways in LPS-induced acute lung injury. Life Sci. 311((Pt A)): 1210912022. View Article : Google Scholar : PubMed/NCBI
39	Zhang P, Zhang D, Zhou W, Wang L, Wang B, Zhang T and Li S: Network pharmacology: Towards the artificial intelligence-based precision traditional Chinese medicine. Brief Bioinform. 25:bbad5182023. View Article : Google Scholar : PubMed/NCBI
40	Nogales C, Mamdouh ZM, List M, Kiel C, Casas AI and Schmidt HHHW: Network pharmacology: Curing causal mechanisms instead of treating symptoms. Trends Pharmacol Sci. 43:136–150. 2022. View Article : Google Scholar : PubMed/NCBI
41	Palomer X, Salvado L, Barroso E and Vazquez-Carrera M: An overview of the crosstalk between inflammatory processes and metabolic dysregulation during diabetic cardiomyopathy. Int J Cardiol. 168:3160–3172. 2013. View Article : Google Scholar : PubMed/NCBI
42	O'Neill LA and Hardie DG: Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature. 493:346–355. 2013. View Article : Google Scholar : PubMed/NCBI
43	Jha MK, Song GJ, Lee MG, Jeoung NH, Go Y, Harris RA, Park DH, Kook H, Lee IK and Suk K: Metabolic connection of inflammatory pain: Pivotal role of a pyruvate dehydrogenase kinase-pyruvate dehydrogenase-lactic acid axis. J Neurosci. 35:14353–14369. 2015. View Article : Google Scholar : PubMed/NCBI
44	Chen Z, Liu M, Li L and Chen L: Involvement of the Warburg effect in non-tumor diseases processes. J Cell Physiol. 233:2839–2849. 2018. View Article : Google Scholar : PubMed/NCBI
45	Gan P, Zhang S and Fred Wong WS: Targeting reprogrammed metabolism as a therapeutic approach for respiratory diseases. Biochem. Pharmacol. 228:1161872024.PubMed/NCBI
46	Chen J, Li G, Sun D, Li H and Chen L: Research progress of hexokinase 2 in inflammatory-related diseases and its inhibitors. Eur J Med Chem. 264:1159862024. View Article : Google Scholar : PubMed/NCBI
47	Webb BA, Dosey AM, Wittmann T, Kollman JM and Barber DL: The glycolytic enzyme phosphofructokinase-1 assembles into filaments. J Cell Biol. 216:2305–2313. 2017. View Article : Google Scholar : PubMed/NCBI
48	Israelsen WJ and Vander Heiden MG: Pyruvate kinase: Function, regulation and role in cancer. Semin Cell Dev Biol. 43:43–51. 2015. View Article : Google Scholar : PubMed/NCBI
49	Puleston DJ, Villa M and Pearce EL: Ancillary Activity: Beyond core metabolism in immune cells. Cell Metab. 26:131–141. 2017. View Article : Google Scholar : PubMed/NCBI
50	Wang C, Wang Y, Song D, Su J and Zhang F: Therapeutic Effects of Modified Si-Miao-Yong-An Decoction in the Treatment of Rat Myocardial Ischemia/Reperfusion Injury. Evid Based Complement Alternat Med. 2022:14424052022.PubMed/NCBI
51	Gomez A, Serrano A, Salero E, Tovar A, Amescua G, Galor A, Keane RW, de Rivero Vaccari JP and Sabater AL: Tumor necrosis factor-alpha and interferon-gamma induce inflammasome-mediated corneal endothelial cell death. Exp Eye Res. 207:1085742021. View Article : Google Scholar : PubMed/NCBI
52	Fang Y, Li Z, Yang L, Li W, Wang Y, Kong Z, Miao J, Chen Y, Bian Y and Zeng L: Emerging roles of lactate in acute and chronic inflammation. Cell Commun Signal. 22:2762024. View Article : Google Scholar : PubMed/NCBI
53	Qiu B, Yuan P, Du X, Jin H, Du J and Huang Y: Hypoxia inducible factor-1α is an important regulator of macrophage biology. Heliyon. 9:e171672023. View Article : Google Scholar : PubMed/NCBI
54	Azzam HN, El-Derany MO, Wahdan SA, Faheim RM, Helal GK and El-Demerdash E: The role of mitochondrial/metabolic axis in development of tamoxifen resistance in breast cancer. Hum Cell. 36:1877–1886. 2023. View Article : Google Scholar : PubMed/NCBI
55	Kierans SJ and Taylor CT: Regulation of glycolysis by the hypoxia-inducible factor (HIF): Implications for cellular physiology. J Physiol. 599:23–37. 2021. View Article : Google Scholar : PubMed/NCBI