DTI Drug Target Insights 2024; 18: 30-46 ISSN 1177-3928 | DOI: 10.33393/dti.2024.2707 REVIEW Drug Target Insights - ISSN 1177-3928 - www.aboutscience.eu/dti © 2024 The Authors. This article is published by AboutScience and licensed under Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Commercial use is not permitted and is subject to Publisher’s permissions. Full information is available at www.aboutscience.eu Article type: Original Research Article DOI: 10.33393/dti.2024.2670 (link to https://doi.org/10.33393/ dti.2024.2670 ) Short title: (A: please provide) Molecular targets and therapeutic potential of baicalein: a review Kavita Munjal1, Yash Goel2, Vinod Kumar Gauttam 3, Hitesh Chopra 4, Madhav Singla5, Smriti 5, Saurabh Gupta 6, Rohit Sharma 7 1Department of Pharmacognosy, Amity Institute of Pharmacy, Amity University, Noida, Uttar Pradesh - India 2Department of Pharmacy, M.M. College of Pharmacy, M.M. (Deemed to be University), Mullana, Ambala, Haryana - India 3# Department of Pharmacognosy, Shiva Institute of Pharmacy, Bilaspur, Himachal Pradesh - India 4 Department of Biosciences, Saveetha School of Engineering, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu - India 5Department of Pharmacy, Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab - India 6Department of Pharmacology, Chameli Devi Institute of Pharmacy, Indore, Madhya Pradesh - India 7 Department of Rasa Shastra and Bhaishajya Kalpana, Faculty of Ayurveda, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh - India ABSTRACT Aim: Researchers using herbs and natural products to find new drugs often prefer flavonoids because of their potential as antioxidants and anti-inflammatories. The planned review addressed baicalein research findings in detail. This manuscript provides a complete review of baicalein’s potential pharmacological effects along with several molecular targets for better understanding of its therapeutic activities. Materials and methods: We targeted the review on in vitro and in vivo studies reported on baicalein. For this, the literature is gathered from the database available on search engines like PubMed, ScienceDirect, Scopus, and Google Scholar up to 21 December 2023. The keywords “Scutellaria baicalensis”, “Oroxylum indicum”, “Neuropro- tective”, “Cardioprotective”, “Toxicity studies”, and “Baicalein” were used to fetch the content. Results: Baicalein’s molecular receptor binding approach has shown anticancer, antidiabetic, antimicrobial, anti- aging, neuroprotective, cardioprotective, respiratory protective, gastroprotective, hepatic protective, and renal protective effects. The synergistic effects of this drug with other selective herbs are also contributed towards significant therapeutic potential. Conclusion: This systematic review article from a contemporary and scientific perspective offers fresh insight into S. baicalensis, O. indicum, and its bioactive component baicalein as a potential complementary medicine. Baicalein may be transformed into more efficacious and acceptable evidence-based medicine. However, we rec- ommend more clinical and mechanistic approaches to confirm safety and efficacy of baicalein. Keywords: Alzheimer’s, Baicalein, Cancer, Epilepsy, Heart failure, Hypertension, Parkinson, Stroke Received: November 6, 2023 Accepted: January 11, 2024 Published online: June 6, 2024 Corresponding author: Rohit Sharma email: rohitsharma@bhu.ac.in Hitesh Chopra email: chopraontheride@gmail.com baicalensis and Oroxylum indicum. S. baicalensis Georgi, a member of the Lamiaceae family, stands as one of the pharmacologically significant species of flowering plant. The herbaceous perennial under investigation exhibits distinct characteristics that contribute to its overall appeal. Its papery leaves, thick roots, and branching stems provide a sturdy foundation for its growth and development. Additionally, the vibrant purple-red to blue blooms add a touch of elegance and beauty to its appearance. The presence of black-brown ovoid nutlets further enhance its appearance. Traditional Chinese medicine has a rich history of utilization and contin- ues to be widely practiced. The cultivation of this particular plant species has been observed in various regions, including eastern Russia, Japan, China, Siberia, Mongolia, and Korea. In addition to the well-known Chinese medicinal ingredients, various Scutellaria species including S. viscidula, S. rehderi- ana, S. amoena, S. likiangensis, and S. hypericifolia have also Introduction Baicalein, a flavone compound, is widely recognized in Chinese traditional medicine as Huang-qin or Chinese skull- cap (1). Recent research has revealed the therapeutic signifi- cance and pharmacological findings of roots of Scutellaria https://doi.org/10.33393/dti.2024.2707 https://doi.org/dti.2022.2522 https://creativecommons.org/licenses/by-nc/4.0/legalcode https://doi.org/10.33393/dti.2024.2670 https://doi.org/10.33393/dti.2024.2670 https://orcid.org/0000-0002-9796-170X https://orcid.org/0000-0001-8867-7603 https://orcid.org/0000-0003-0720-5650 https://orcid.org/0000-0002-4783-0293 https://orcid.org/0000-0002-3682-3573 mailto:rohitsharma@bhu.ac.in mailto:chopraontheride@gmail.com Munjal et al Drug Target Insights 2024; 18: 31 © 2024 The Authors. Published by AboutScience - www.aboutscience.eu been utilized as Huang-qin in different regions (2). There are several ways available for extracting baicalein, as shown in Table 1. The auxiliary extraction methodology achieved the maximum yield while extracting from the roots of Scutellaria. O. indicum, commonly referred to as the Indian trum- pet flower, has received significant attention in the field of research. The plant in issue belongs to the Bignoniaceae family, which is well-known for its therapeutic qualities. The subject of investigation is a compact to moderate-sized decid- uous tree, characterized by presence of light grayish brown bark adorned with cory lenticels. The vibrant reddish-purple blooms grow on its outer surface, while its inner core exhib- ited the presence of pinkish yellow flowers. Additionally, the tree bears distinctive woody, winged, large, and flat fruits, which add to its visual allure. Furthermore, this remarkable tree exhibits presence of pinnately compound evergreen leaves, enhancing its overall appeal. The geographical distri- bution of this particular phenomenon primarily encompasses the countries of India, China, Thailand, Sri Lanka, Cambodia, Bangladesh, and other nations within the South Asian region. Baicalin, also known as baicalein-7-O-β-d-glucuronic acid, undergoes hydroxylation to yield a biologically active agly- cone called baicalein (CID 64982), which is chemically known as 5,6,7-trihydroxyflavone (3). Baicalein, a naturally occurring flavonoid, exhibits a chemical structure derived from the fun- damental framework of 2-phenyl chromen-4-one (also known as 2-phenyl-1-benzopyran-4-one). One intriguing aspect of bodily metabolism is the ability for certain substances to undergo a transformative process, allowing them to transition into different forms. Baicalin, a naturally occurring compound, exhibits a unique molecular structure, which contributes to the diverse biological activities and potential therapeutic applications. Understanding the structural features of baicalin is crucial for elucidating its mechanisms of action and explor- ing its potential in various fields of research (1,4). This molecule demonstrates a wide range of biologi- cal actions, including significant domains such as reduc- ing the risk of cancer, virus suppression, diabetic control, and mitigation of age-related deterioration. Additionally, it demonstrates notable protective effects on the neurological, cardiovascular, gastrointestinal (GI), hepatic, respiratory, and renal systems (5). This comprehensive review aims to consol- idate a wealth of information on the diverse pharmacological effects associated with various diseases, encompassing mul- tiple pathways, mechanisms of action, and in vitro studies (5). This review further highlight the attractive opportunities for baicalein-associated drug discovery and research across a range of therapeutic areas. Chemistry of baicalein Flavonoids, a class of polyphenolic compounds, have gar- nered significant attention in the realm of natural products due to their extensive research and exploration (11). One of the key structural components of this compound was produced using the acetate route, leading to the development of the phenolic ring chromophore (ring A) within its 15-carbon skeletal frame- work (11). One of the best examples of the most fundamental flavone molecule is chrysin, which has the unique property of retaining the necessary meta-substituted hydroxyl groups on the A-ring. The OH substitution at chrysin’s C-6 position causes it to change into the trihydroxy derivative baicalein (12) having chemical formula C15H10O5. More specifically, it is recognized as 5,6,7-trihydroxy-2-phenyl-4H-chromen-4-one, as Figure 1 illustrates. Using a multistep synthetic strategy, researchers have effectively recreated the biosynthetic transition of chry- sin to baicalein in recent laboratory tests; 1-(2,4,6-trihydroxy- phenyl)ethanone and 1-ethyl-3-phenyl-1,3-propanedione are combined in the first synthesis technique. Chen et al com- pleted a pioneering investigation that revealed an amazing and novel method for extracting baicalein from 3,4,5-trime- thoxyphenol. This approach, which consists of a brief fourstep procedure, showed promise for a more streamlined and effec- tive manufacture of baicalein (13,14). One of the key struc- tural characteristics that distinguishes baicalin and baicalein is the notable existence of a di-ortho OH on ring A. The remark- able characteristic exhibited by polyphenolic compounds lies in their ability to serve as efficient markers for metal chelation, TABLE 1 - Several methods for extraction of baicalein S. no. Species Part of the plant Extraction method Analytical technique Yield Reference 1. Oroxylum indicum Stem barks Solvent (ethanol) extraction (Reflux method) HPTLC 26.498 mg/g (6) Solvent (acetone) extraction (Reflux method) HPTLC 8.631 mg/g DMSO extract (Reflux method) HPTLC 13.883 mg/g DMF extract (Reflux method) HPTLC 20.529 mg/g Seeds Solvent (95% ethanol) extraction (maceration method) HPLC 0.72% ± 0.00% w/w (7) 2. Scutellaria baicalensis Georgi Roots Solvent (methanol) extraction (maceration method) HPLC 0.5 mg/mL (8) Auxiliary extraction method HPLC 116.8 mg/g (9) Supercritical fluid extraction HPLC-UV 2.5-80 µg/mL (10) DMF = dimethylformamide; DMSO = dimethyl sulfoxide; HPLC-UV = high-performance liquid chromatography ultraviolet; HPTLC = high-performance thin layer chromatography. Therapeutic Insights into Baicalein32 © 2024 The Authors. Drug Target Insights - ISSN 1177-3928 - www.aboutscience.eu/dti free radical scavenging properties, and enzyme inhibition. The structural features of baicalein are believed to be responsible for its reported antioxidant effects and its ability to chelate divalent metal ions (14). Anticancer effects of baicalein Cancer, uncontrolled cell proliferation, can show up phe- notypically in a number of ways, from benign to fatal. There are numerous factors that can lead to the development of cancer, including deoxyribonucleic acid (DNA) damage, muta- tions in the DNA or any by-products of that DNA, and dysfunc- tion of the regulatory and repressor mechanisms during the cell cycle. The four phases of the cell cycle in actively dividing eukaryotes occur in the sequence starting from gap 1, synthe- sis, gap 2 followed by mitosis. While entering the next phase of the cell cycle, there are a number of checkpoints available en route to ensure that the actions at each phase have been appropriately completed. Phosphorylated retinoblastoma protein (pRB), cyclin subunits, cyclin-dependent kinases (CDKs), and cyclin-dependent kinase inhibitors (CDKIs) are the components of these checkpoints (15). Cell cycle arrest occurs when cells are unable to pass cell cycle checkpoints. Cell death and growth inhibition may result from G1 arrest. G2/M arrest is linked to increased apoptosis and may increase the cytotoxicity of chemotherapy (16). It is estimated that in 2024, around 2,001,140 new cancer cases and 611,720 cancer deaths are projected to occur in the United States. With around 350 cases of lung cancer fatalities every day, lung cancer is the most common cause of cancer- related mortality (17). Baicalein induces G1/S arrest in lung squamous carcinoma (CH27) cells by downregulating CDK4 and cyclin D1, as well as upregulating cyclin E expression, a crucial regulator of the G1/S checkpoint of the cell cycle (18). Global breast cancer rates are rising, with 364,000 United States cases anticipated by 2040 (19). Baicalein inhibited 17- estradiol-induced transactivation of the estrogen recep- tor in MCF-7 human breast cancer cells in the S and G2/M stages (20). Eastern Asia currently accounts for more than 60% of cases of gastric cancer. Currently, a major problem in Eastern Asia is how to manage gastric cancer in the older population. It is anticipated that the total number of gas- tric cancer cases and fatalities would reach its peak soon (21). The gastric cancer cell line SGC-7901 underwent a sig- nificant S-phase arrest as a result of baicalein. It resulted in SGC-7901 cells going into apoptosis. Analysis of protein expression levels in SGC-7901 cells showed that when baicalein was administered, Bcl-2 was downregulated and Bax was increased (22). The third most common reason for cancer-related death worldwide is primary hepatic cancer. Most patients receive a bad prognosis at an advanced stage. In an in vitro inves- tigation using hepatoma carcinoma cells (Hep G2 and J2), baicalein therapy resulted in S-phase arrest. Some of the underlying mechanisms include early-stage DNA damage, the inhibition of growth-stimulating substances, and the acti- vation of cyclin- CDKIs (23). The seventh most common cause of cancer-related fatali- ties worldwide is pancreatic cancer. However, many devel- oped nations suffer from it more severely. Globally, there were 458,918 new cases of pancreatic cancer recorded in 2018, and 355,317 additional instances are expected to be reported before 2040 (24). Baicalein upregulates Bax while downregulating Bcl-2 and Mcl-1 to encourage apoptosis in pancreatic cancer cells (25). In PANC-1 cells, baicalein induced arrest of G0/G1 phase when studied in vitro (26). Rising death rates from colorectal cancer (CRC) are a bur- den shared by developing Asian nations. Patients with CRC may be at danger if they are underweight or overweight (27). In HCT-116 CRC cells, baicalein causes a significant arrest of S phase and promotes apoptosis by activating caspase 3 and caspase 9 (28). The most common form of male cancer in developed nations is prostate cancer (PC). In PC cells, baicalein caused G0/G1 arrest by lower down cyclins (D1 and D3) and pRB (29). Bladder cancer (BC) ranks in the top 10 most common cancers globally. Baicalein caused G2/M arrest in TSGH8301 and BFTC905 BC cells by altering two essential proteins (cyclin B1 and phospho-Cdc2) required to initiate the final stage of cell cycle (30,31). Ovarian cancer is the seventh most prevalent malignant tumor in women, gravely endangering the reproductive health of women. It has a poor prognosis, unknown pathophysiol- ogy, missed diagnoses, and a high recurrence rate (38). It only affects women and has a fatality rate of 46.2% after 5 years, making it unique to the female population (38). Baicalein inhib- its the synthesis of vascular endothelial growth factor (VEGF), HIF-1, c-Myc, and nuclear factor kappa B (NF-κB) in the G1 and S phases of ovarian cancer cell lines (OVCAR-3 and CP-70). It inhibited the growth of ovarian cancer cells by lowering the expression of matrix metalloproteinase (MMP)-2 (32-35). Osteosarcoma (OS) is the most prevalent primary bone cancer in children and adolescents. In its advanced stages, it has a low survival rate (36,37). Baicalein produced intra- cellular reactive oxygen species (ROS) and activated BNIP3 to slow down the development and hasten the apoptosis of MG-63,OS cells (38). FIGURE 1 - Structure of baicalein. Munjal et al Drug Target Insights 2024; 18: 33 © 2024 The Authors. Published by AboutScience - www.aboutscience.eu By reducing the levels of cyclin D1 and CDK4, which inhib- its the advancement of the G1 phase, it slowed the growth of OS cells. By decreasing the levels of cyclin D1 and CDK4, it inhibited the growth of OS cells by inhibiting cell cycle pro- gression at the G1 phase of division (Tab. 2) (39). Baicalin for neuroprotection and cognitive enhancement Alzheimer’s disease is responsible for the more than 25 million cases of dementia that exist today. Both in indus- trialized and developing nations, Alzheimer’s disease has a substantial impact on those who are affected, the caregiv- ers, and society (40). One of the cellular disorders hypothe- sized to be responsible for the loss of neurons in Alzheimer’s disease is aggregation of A𝛽 (41). Baicalein exhibits neuro- protective qualities against amyloid (AN) functions by pre- venting AN from aggregating in PC12 neuronal cells to cause A𝛽 -induced cytotoxicity (42). By activating GABA receptors, baicalein encourages non-amyloidogenic processing of APP, which lowers the generation of A𝛽 and enhances cognitive function (43). Baicalein demonstrated a potent inhibitory effect on A𝛽 -induced cell death (43,44). The prevalence of Parkinson’s disease looks to be rising with age, and it is a global concern. Males are affected by the disease 1.5-2 times more frequently than females worldwide. The prevalence of Parkinson’s disease appears to be higher in Western nations than in Asian nations (45). Amyloid-specific proteins aggregate to cause Parkinson’s disease. In 𝛽 -sheet fibrillar aggregate, formed by several proteins including α-syn amyloid proteins are especially prevalent. The main constitu- ent of Lewy bodies is abnormally folded aggregates of α-syn, which manifest as intracellular inclusions in nigral dopami- nergic neurons in the brains of Parkinson’s disease patients (46). As a result, α-syn represents a viable therapeutic target for Parkinson’s disease treatment to stop the disease growth and spread (47). Baicalein functions by impeding the aggre- gation of disease-specific α-syn protein. Both baicalein and its oxidized counterpart prevent the production of α-syn fibrils at lower micromolar levels. Moreover, baicalein dem- onstrated the capacity to disintegrate the preexisting α-syn fibrils (48). Additionally, by eliminating iNOS protein, mRNA, and promoter activity in endotoxin/cytokine-induced microg- lia, baicalein effectively reduced NO generation and iNOS gene expression (49). Stroke ranks second globally in terms of mortality and third globally in terms of disability, with ischemic heart dis- ease coming in first in both categories (50). According to the Indian Global Burden of Disease Study, which was con- ducted between 1990 and 2019, stroke was India’s leading cause of both fatalities from neurological illnesses and dis- ability-adjusted life years (DALYs) (51). In ischemic stroke, TABLE 2 - In vitro studies of baicalin/baicalein against various types of cancer Plant compound Name of cancers Cell lines Cell cycle phase arrest Mechanism References Scutellaria baicalensis Georgi Baicalein Oroxylum indicum Lung cancer CH27 G1/S ↑sed cyclin E and ↓ sed levels of CDK4 and cyclin D1 (18) Breast cancer MCF-7 G2/S Blocked 17-estradiol- induced transactivation of the estrogen receptor (20) Gastric cancer SGC-7901 S ↓sed Bcl-2 and ↑sed Bax (22) Hepatic cancer Hep G2 and Hep J2 S Activation of CDK inhibitors like p21 or p27 (23) Pancreatic cancer PANC-1 G0/G1 ↑sed Bax and ↓sed Bcl- 2 and Mcl-1 (26) Colorectal cancer HCT-116 S Activation of Caspase 3 and 9 (28) Prostate cancer LNCaP G1/S ↓sed cyclin D1, cyclin D3, and pRB protein (29) Bladder cancer TSGH831 and BFTC905 G2/M Altering cyclin B1 and phospho-Cdc2 (31) Ovarian cancer OVCAR-3 and CP-70 G1/S ↓sed VEGF, HIF-1, c-Myc, NF-kB, and MMP-2 (34) Osteosarcoma MG-63 G1 Activating BNIP3 and ↓sed cyclin D1 and CDK4 (39) Therapeutic Insights into Baicalein34 © 2024 The Authors. Drug Target Insights - ISSN 1177-3928 - www.aboutscience.eu/dti neuroprotection is achieved by inhibiting iNOS activity or by iNOS gene deletion. Neuroexcitotoxic and ischemic trau- mas cause the production of COX-2. Specific COX-2 inhibitors reduce brain damage brought on by localized ischemia. The optimal method for treating cerebral ischemia-reperfusion (I/R) injury involves targeting the NF-κB pathway, accord- ing to numerous experts. Baicalein therapy significantly decreased the expression of COX-2 and iNOS, as well as PGE2 and NF-κB, indicating a protective effect against cerebral I/R injury. Because baicalein blocks inflammatory mediators including LOX-1, COX-2, PGE2, and NF-κB, it may have anti- inflammatory and antioxidant effects that contribute to its capacity to prevent cerebral I/R (52). Baicalein therapy mark- edly elevated nuclear Nrf2 expression and AMPK phosphory- lation in the ischemic cerebral cortex (53). Cell damage and a rise in oxidative stress are caused by an excess of ROS or by the malfunctioning of antioxidant enzymes. Basic leucine zipper transcription factor Nrf2 controls the expression of the gene that detoxifies ROS as well as the antioxidant gene (54,55). Epilepsy is a chronic, noncommunicable brain illness that affects people of all ages. One of the most prevalent neuro- logical conditions, epilepsy affects about 50 million people worldwide. More than 80% of people in low- and middle- income countries have epilepsy. FeCl3-induced post-traumatic epileptic seizures are a significant type of acquired epileptic seizures (56). Baicalein suppressed ferroptosis associated with 12/15-LOX, hence lessening the severity of post-trau- matic epileptic episodes generated by FeCl3 (57). HT22 cells were damaged by ferroptosis, which is mitigated by baicalein may be due to its lipid peroxidation inhibitor (Fig. 2) (58). Respiratory protective action of baicalein Chronic respiratory conditions are among the world’s leading causes of morbidity and mortality. They affect the lung’s airways and other structural components. Asthma is the most prevalent chronic respiratory illnesses. There are already approximately 300 million asthmatics worldwide, and by 2025, that figure may rise by an additional 100 million. Asthma is a long-term inflammatory illness of the airways characterized by thickening of the airway wall, hyper-respon- siveness and remodeling of the airways, poor relaxation, and persistent blockage of airflow by the smooth muscle of the airways (59-61). Hypersecretion of airway mucus is one of the key features of asthma pathophysiology. Baicalein ther- apy showed dramatical decrease in MUC5AC and MUC5B mRNA expression levels in the submucosal glands and the epithelium, respectively, which were significantly greater in asthma. Baicalein also exhibits anti-asthmatic properties by inhibiting tumor necrosis factor (TNF)-α-induced NF-κB acti- vation in normal bronchial epithelial (BEAS-2B) cells (62), which was mostly expressed by downstream iNOS produc- tion, IκBα phosphorylation and degradation, and nuclear translocation of p65 (63). Another structural change associated with asthma has been described as increased extracellular matrix (ECM) deposition. The primary ECM producers in the lung are myo- fibroblasts and fibroblasts. During allergic airway inflamma- tion, myofibroblasts deposit collagen types I and III. ECM’s constituents, especially collagens, are broken down and con- trolled by MMPs, which are secreted by fibroblasts. In allergic asthma, MMP-9, the main airway MMP, is upregulated, which FIGURE 2 - Baicalein regula- ting a wide range of signaling pathways linked to the etio- logy of multiple degenerative conditions. Munjal et al Drug Target Insights 2024; 18: 35 © 2024 The Authors. Published by AboutScience - www.aboutscience.eu results in airway remodeling (64). According to recent stud- ies, baicalein administration reduces the ovalbumin (OVA)- induced expression of collagen I and MMP-9 (65). Cardioprotective action of baicalein Globally, cardiovascular disease (CVD) is one of the major causes of morbidity and motility. In past few decades, changes in lifestyle and socioeconomic conditions that have an impact on the progression of CVDs have been observed. Hypertension is a significant contributor to CVD and fatalities globally, par- ticularly in low- and middle-income nations. As per the 2017 guidelines from the American College of Cardiology and American Heart Association, hypertension is defined as a systolic blood pressure over 130 mm Hg or a diastolic blood pressure above 80 mm Hg (66-70). Baicalin assisted in lower- ing high-sensitivity C-reactive protein (CRP), interleukin (IL)-6, and IL-1 levels in the serum, which served to forcibly lower blood pressure (71). Baicalin altered the expression of miR- 145 and increased TNF-α levels in human aortic endothelial cells (HAECs), thereby reducing the inflammatory effects of TNF-α (72). Angiotensin II (Ang II) may activate apoptosis-related proteins, encourage the production of ROS, and inhibit the synthesis of NO, which results in endothelial dysfunction that may lead to hypertension. Therefore, lowering cell apoptosis, suppressing oxidative stress, and preventing Ang II-induced endothelial dysfunction are effective ways to treat hyperten- sion. Baicalin has been shown in a study utilizing the human umbilical vein endothelial cell (HUVEC) model of Ang II injury to significantly reduce oxidative stress and endothelial dys- function caused by Ang II. The primary strategies employed to produce these beneficial effects include modulating the expression of Bax, Bcl-2, and cleaved caspase-3, activating the ACE2/Ang-(1-7)/mas axis, and upregulating the PI3K/ AKT/eNOS pathway. They also found that baicalin raised NO level and total antioxidant capacity, and decreased markers of oxidative stress such as malondialdehyde (MDA) and ROS (73,74). It was also shown that the combination of baicalin and berberine relaxed blood arteries by acting on the volt- age-dependent Ca2+ channel (VDCC) (75). By boosting endogenous NO synthesis, which is produced by the enzyme endothelial nitric oxide synthase (eNOS), baicalin may also lower blood pressure (76). Heart failure is a complicated clinical condition that arises when the heart is unable to pump enough blood to meet the body’s needs. It arises from any ailment that impacts the ventricles’ ability to fill or the blood’s ability to be ejected into the systemic circulation (77). Baicalin seems to be very useful in treatment of CHF as it has an anti-fibrosis property. Baicalin may be able to treat myocardial fibrosis by inhibiting the expression of the fibrosis genes (type I and III collagen) and connective tissue growth factor (CTGF). Baicalin can effi- ciently induce endothelial cell migration and greatly boost the expression of VEGF when the concentration is between 10 and 50 g/mL, which aids in promoting angiogenesis. This outcome can be achieved by over-activating the ERR/PGC-1a pathway (78). Baicalin also decreased caspase-3 and the Bax/Bcl-2 ratio, which lowered apoptosis. This suggests that apoptosis inhibition could lessen adverse remodeling and the eventual development of heart failure (79). Gastroprotective activity of baicalein Peptic ulcer disease (PUD), as determined by hospi- talization statistics and diagnosed by physicians, had an incidence rate of 0.03%-0.17% and 0.10%-0.19% per year, respectively. Although most research indicated that PUD incidence or prevalence had decreased over time, still it is a serious and life-threatening disease (80). Acetylsalicylic acid (ASA), Helicobacter pylori infection, and non-steroidal anti- inflammatory drugs (NSAIDs) are the major causes of PUD. While there has been a significant improvement in H. pylori infection therapy recently, ASA and NSAID prescriptions have grown within the same time frame (81). According to reports, inhibiting gastric acid output and exhibiting a reduc- tion in gastric mucosal damage are both effects of activating α2-adrenergic receptors (82). The gastroprotective proper- ties of baicalein may be mediated through these receptors. In contrast to the formation of free radicals, glutathione (GSH) protects the stomach mucosa from damage (82). Baicalein was found to exert protective effects via raising the tissue’s GSH concentration, signaling to an antioxidant mechanism (83). Baicalein exhibited cytoprotective effects by inducing the secretion of more gastric mucus, acting as an anti-secretory by suppressing hydrogen-potassium-ATPase activity, and acting as an antioxidant by raising GSH levels (83). By raising the SH compound, which naturally regulates mucus production, and the NO level, which is involved in maintenance of the integrity of the gastric mucosa, and regulates the secretions like acid, alkaline, mucus, and blood flow in gastric mucosa, baicalein demonstrated a gastroprotective effect against lesions (83). The stomach mucosa showed significant reductions in MDA, IL-8, and TNF-α contents, as well as increases in superoxide dismutase (SOD) activity and glutathione peroxidase (GPx) level due to inhibition of inflammation and ROS scavenging actions of the baicalein-Zn complex (84). Hepatoprotective activity of baicalein Worldwide, the prevalence and incidence of nonalcoholic fatty liver disease (NAFLD), the main cause of liver-related morbidity and mortality, have increased as a result of the obesity epidemic (85). Men and aging both increase the risk of NAFLD and fibrosis. Despite the fact that obesity is a major risk factor for NAFLD, current studies have revealed that slim individuals can also develop the condition (86). NAFLD is defined as the condition in which 5% or more hepatic cells develop macro-vesicular steatosis, when there is no second- ary etiology like alcohol or drugs (86). An excessive buildup of lipids in the liver results from the increased hepatic lipogen- esis and serum non-esterified fatty acids, which causes fatty liver, decreased liver function, and ultimately liver failure (87). Baicalein has several effects against FLD, suggesting that it may be used therapeutically. In order to improve lipid metab- olism and reduce hepatic de novo lipogenesis, baicalein inhib- its the Ca2+/CaM-dependent protein kinase/AMP-activated protein kinase/acetyl-CoA carboxylase (CaMKK/AMPK/ACC) Therapeutic Insights into Baicalein36 © 2024 The Authors. Drug Target Insights - ISSN 1177-3928 - www.aboutscience.eu/dti pathway (88). Baicalein also has the capacity to reduce liver fibrosis, oxidative stress, and systemic inflammation in FLD. In order to reverse fibrosis, baicalein consequently inhibits the synthesis of collagen (type I and α-1) chain and transforming growth factor (TGF)-β1 (88,89). Additionally, it inhibits the TGF-1/Smad3 pathway in vitro to reverse the epithelial-mes- enchymal transition and stop the progression of liver fibro- sis (90). Baicalein also has an indirect antioxidant effect by decreasing MDA levels while increasing hepatic GSH and SOD (91). By inhibiting the TGF-β/Smad pathway, baicalein slowed down the epithelial-mesenchymal transition. Additionally, it decreased high levels of inflammatory factors such TNF-α, IL-1 and -6, inhibited the apoptotic proteins caspase-3 and -9, and B-cell lymphoma-2, and hindered the IκB kinase/IκB/ NF-κB pathway. These all helped to lessen liver disorders (92). Because of its inhibitory influence on the production of p-p38, MAPK, p-CREB, FoxO1, PGC-1, PEPCK, and G6Pase, baicalein considerably reduces insulin concentrations brought on by a high-fat meal. Thus, because of its numerous pharmacological actions, baicalein may prevent FLD (93). Baicalein action as a renal protective agent Chronic kidney disease (CKD) prevalence is acknowledged as a major public health concern on a global scale. It is esti- mated that 13.4% (11.7%-15.1%) of the global population has KD and that 4.902-7.083 million have end-stage kidney disease (ESKD), requiring renal replacement therapy (94). The incapacity of the kidneys to perform their excretory duties, which results in the retention of nitrogenous waste products in the blood, is known as renal failure. Kidney failure comes in two flavors: acute and chronic (95). One of the main causes of renal failure is diabetes mellitus (DM), which is why many diabetic individuals continue to struggle with diabetic nephropathy (DN), which is a serious condition (96). Patients with DN typically have elevated urine microalbumin, urine β2-MG, and Urinary albumin excretion rate in Diabetic neu- ropathy. Among these, an increase in urine microalbumin and urinary 2-MB indicates renal tubular injury, while an increase in UAER indicates glomerular injury (97). It was discovered that baicalin significantly reduced the patient’s urine 2-MG, UAER, and microalbumin levels. Additionally, it was discovered to con- siderably enhance the patient’s quality of life, reduce the rate at which DN progresses, and enhance kidney function (98-100). Acute renal injury is a serious adverse effect of the anti- cancer drug cisplatin. Increased ROS generation from cispla- tin damages endogenous intracellular targets like proteins, lipids, and DNA, resulting in cellular malfunction and death (101). Additionally, the toxic effects of cisplatin are made worse by the activation of various signaling pathways, such as MAPKs, NF-κB, and p53, by cisplatin-induced ROS (114). A key factor in the pathophysiology of cisplatin-induced kidney injury is the production of iNOS and strong cytotoxic peroxyni- trite through the interaction of superoxide radical and NO (102). Baicalein has been demonstrated to have a significant antioxidant impact. Baicalein has been shown to adequately remove peroxynitrite anion radicals and inhibit peroxyni- trite-induced cell death in LLC-PK1 cells. Pretreatment with baicalein significantly decreased these changes. Therefore, baicalein’s capacity to lessen cisplatin-induced nephrotoxicity is probably due, at least in part, to the attenuation of renal oxidative and/or nitrative stress (Fig. 3) (102). Baicalein as an antimicrobial agent Across the world, infectious diseases are a leading source of morbidity and mortality (103). The emergence of drug- resistant forms of bacteria has diminished the impact of anti- biotics on germs and resulted in ongoing difficulties, despite notable advancements in the treatment of microbial infec- tions (104). Combination therapy was developed in response to this problem, and as a result of the expanding prevalence of antibiotic resistance, it has improved treatment efficacy and partially reduced drug resistance. Furthermore, the bac- terial resistance to antibiotics has motivated the creation of innovative antibacterial drugs for the treatment of infectious FIGURE 3 - The healing poten- tial of baicalein by modulating several signaling pathways miti- gating the symptoms of certain illnesses such as cardiac, renal, respiratory, and gastric. Munjal et al Drug Target Insights 2024; 18: 37 © 2024 The Authors. Published by AboutScience - www.aboutscience.eu disorders. People from many cultures have used a variety of herbal remedies for many generations, and some of these nat- ural medicines are crucial for the treatment and prevention of infectious diseases (105,106). Baicalein’s function as an anti- bacterial agent is crucial. Baicalin inhibits pro-inflammatory cytokine release, MAPK activation, NF-κB pathway activa- tion, and NLRP3 to diminish inflammation in periodontal cells. By promoting the expression of interferon regulatory factor (IRF)4 and inhibiting the expression of IRF5, baicalin also lessens inflammation by regulating the transition of M1 to M2 macrophages. Baicalin inhibited NF-κB and p38 phos- phorylation as well as mRNA expression, which decreases pro-inflammatory cytokines TNF-α, IL-β, and IL-6 levels (107). Bacterial growth occurs naturally as biofilms, which are abundant in the environment (108). Biofilm production leads to an increase in resistance to antibiotics and antimicrobial agents. Quorum sensing (QS), a mechanism responsible for the intercellular exchanges of information, is essential to the production of biofilms (109). Baicalin suppresses the QS system, which inhibits inflammatory responses. Baicalein has been shown to have antimicrobial properties against Meningococcus, Staphylococcus aureus, Corynebacterium diphtheriae, Pseudomonas aeruginosa, and dysentery bacil- lus. Through a number of mechanisms, such as enhancing the host immune system, preventing the formation of biofilms, lowering antimicrobial medicine resistance, suppressing bac- terial secretions, and upsetting microbial morphology, baicalin acts as a herbal antimicrobial agent against several microbial infections (110). Baicalin has also been shown to suppress apoptosis, decrease FAS protein expression, block the caspase-8 path- way, and decrease Bax protein production. These actions are all thought to contribute to its antiviral efficacy (111). Baicalin lowers the raised levels of hepatic markers alanine transami- nase (ALT), aspartate aminotransferase (AST), and total bili- rubin along with hepatitis B virus (HBV)-DNA in patients with chronic hepatitis B. It can also be used in conjunction with other medications to treat viral infections in patients with an H1N1 influenza infection. Baicalin regulates the numbers of T-lymphocyte subsets and upregulates CD3+, CD4+/CD8+, and other positive lymphocyte subsets (112). Invasive fungal infections increase morbidity and death of patients who have impaired immune systems (113). Currently, polyenes, echinocandins, and azoles are the three primary classes of frontline clinical antifungal agents used to treat such infections (114). However, each of these groups has drawbacks that may restrict their clinical use for the management of invasive fungal infections, and it is urgently necessary to identify new antifungal medicines that target novel targets. Baicalein has demonstrated potential antifun- gal activity. It significantly inhibits the growth of Aspergillus fumigatus, Cryptococcus neoformans, and Candida species. Because it targets Eno1, BE (baicalein) has anti-C. albicans action via preventing glycolysis. BE (baicalein) has a sub- stantial inhibitory effect on CaEno1’s enolase activity (115). Baicalein inhibits TSLP/TSLPR pathway activity, which sup- presses inflammatory response and protects against A. fumigatus keratitis by preventing fungal growth, biofilm for- mation, and adhesion (Tab. 3) (116,117). Antidiabetic property of baicalein DM is the most prevalent endocrine disorder in the 21st century, and is spreading all over the world. Diabetes increases blood sugar levels. Neglecting to manage it consis- tently and carefully increases the risk of significant adverse effects, including stroke and heart failure. Type 1, type 2, and gestational diabetes are the three most prevalent forms of the disease. By preventing islet cell death, baicalein reduces hyperglycemia, improves glucose intolerance, and encour- ages insulin production (118). Baicalein is used to treat dia- betes, which lowers total cholesterol, plasma triglyceride plasma levels along with sugar lowering effect (119). Baicalein additionally showed antihyperglycemic effects in both in vivo and in vitro models via blocking the α-glucosidase action in 3T3-L1 adipocyte cell line. The main function of the enzyme α-glucosidase is to catalyze the breakdown of starches and carbs in food to produce glucose that may be absorbed through the digestive tract (120). As a result, delaying the syn- thesis of glucose after meal digestion may minimize hyper- glycemia. It was discovered that baicalein had α-glucosidase inhibitory effects comparable to those of the commonly pre- scribed, clinically effective α-glucosidase inhibitor, acarbose (120). The synergistic impact of baicalein and acarbose treat- ment is reported for showing reduced harmful hepatic side effects associated with using high dosages of the acarbose alone to treat diabetes by lowering the dosage from high (20 mg/kg) to low (4 mg/kg) levels (121). Glycation of bovine serum albumin (BSA) is a compli- cated chain of events wherein reducing sugars like glucose alter the structure of the protein. Due to the excess glucose molecules in their serum, diabetics usually have greater gly- cation rates. This can lead to nonfunctional proteins and fur- ther activate several signaling pathways, increasing the risk of beta-cell damage, insulin resistance, and diabetes complica- tions. Baicalein also has the potential to cure hyperglycemia by reducing BSA glycation (122). Baicalein action as an antiaging agent Skin aging is a natural process that is defined by the skin’s progressive physiologic and anatomical changes. The dermis experiences striking alterations including the huge deposition of irregular elastic fibers, collagen deterioration, and hyaluronic acid loss. Skin aging is caused by a variety of extrinsic (usually linked to aging) and natural (mostly genet- ically determined) factors, such as exposure to ultraviolet (UV) radiation, high intake of alcohol, and pollution. UV radi- ation is the main cause of photoaging in human skin (123). Baicalein may find use in skin care products and as a photoprotective agent. UV radiation significantly raised the activities of MMP-1 mRNA (123), while baicalin treatment inhibited this UV radiation-induced action of MMP-1 and resulted in the formation of procollagen type 1. Rich baica- lein inhibited collagen fiber loss, wrinkle formation, and skin thickness brought on by UV radiation. UV causes high levels of ROS to be produced in the skin tissues. This can cause increase of oxidative stress to a variety of cellular macro and micro molecules, including proteins, Therapeutic Insights into Baicalein38 © 2024 The Authors. Drug Target Insights - ISSN 1177-3928 - www.aboutscience.eu/dti nucleic acids, and cell membranes. ROS have a major contri- bution in both the onset and development of skin aging. MDA is a result of lipid peroxidation whose quantity reveals the extent of oxidative stress on cells. The antioxidant defense of the normal cell against ROS is carried out by SOD and GSH-Px enzymes (125). The results demonstrate that UV rays cause oxidative damage and slow down the dermal tissue capacity to eliminate ROS. It was also revealed that UVA radiation con- siderably elevated MDA levels in fibroblasts and significantly decreased SOD and GSH-Px activities. Additionally, baicalin therapy by itself dramatically reduced MDA levels in fibro- blasts and increased SOD and GSH-Px activity (125). Pharmacokinetics Clinical and toxicological studies It has been shown that baicalein is a unique, potentially effective medicinal agent for treating a range of illnesses. Therefore, clinical trials are required to ensure the therapeu- tic role of baicalein. Several studies are designed by various research groups for the purpose. Two phase I clinical trials were conducted on healthy adults in China to evaluate the safety and efficacy using chewable baicalein pills. Seventy-two healthy Chinese adults participated in a phase I (2014) random, double-blind investigation to examine the pharmacokinetic (PK) characteristics of baicalein using a single-dose trial (100-2800 mg) (126). Blood, urine, and feces samples were obtained at fixed schedules for up to 48 hours post drug administration. After that, baicalein was inves- tigated by the spectrometric analysis of samples through liquid chromatography with tandem mass spectrometry (LC/MS/MS). The PK profile of baicalein was found to be mul- tiphasic, with a median Tmax of 0.75-3.5 hours and a t1/2 of 1.90-15.01 hours. The proportionality coefficient (90% CI) estimates for Cmax, AUC0-t, and AUC0 were 0.83 (0.70-0.96), 0.91 (0.81-1.00), and 0.92 (0.82-1.02), in that order. The predefined ranges of 0.89-1.11, 0.93-1.07, and 0.93-1.07, respectively, encompass all values. It was unclear what the dose proportionality was for a baicalein dose range of 100- 2800 mg. Baicalein excreted in urine makes up 1% of the total. Baicalein was eliminated as a medication in approxi- mately 27% of the feces. Baicalein’s Cmax and Cavg values at 800 mg single dose and 800 mg multiple dose, respec- tively, were higher than the in vitro effective concentration (0.1 μM) against SARS-CoV-2 (127). Baicalein was highly tol- erable. Eleven adverse treatment-related occurrences were detected; all were considered “minor” and retreated on their own. There were no significant adverse occurrences. As a result, healthy volunteers tolerated single oral dosages of baicalein of 100-2800 mg without any adverse effects (127). The study by Li M, Shi A, Pang H, et al. published in the Journal of Ethnopharmacology in 2014 investigated the safety, tolerability, and pharmacokinetics of a single ascend- ing dose of baicalein chewable tablets in healthy subjects. The research found that single oral doses of 100-2800 mg of baicalein were safe and well tolerated by healthy individu- als, with no serious adverse events occurring. The study con- cluded that baicalein chewable tablets were generally safe and well-tolerated, supporting the further exploration of baicalein in clinical studies due to its favorable safety profile and pharmacokinetic properties (128). Baicalein suppressed the generation of mid-late mRNA, hence suppressing the H1N1 and H3N2 influenza viruses, A/FM1/1/47, and A/ Beijing/32/92, respectively (163). Baicalein and its metabo- lites were found at higher concentrations, but not in a dose- proportionate way. In healthy Chinese volunteers, baicalein tablets within the studied dosage range were well-tolerated and safe, with no severe or potentially fatal side effects (128). In order to assess the safety and efficacy of capecitabine (CAP) in conjunction with PHY906, a combination of four traditional Chinese herbs—Scutellaria baicalensis Georgi, Glycyrrhiza uralensis Fisch., Ziziphus jujuba Mill., and Paeonia lactiflora Pall.—in the treatment of advanced pan- creatic carcinoma (APC), another study was carried out in 2006. Preclinical studies indicate that PHY906 is a potent inhibitor of NF-κB and that it works in concert with CAP to exhibit synergistic antitumor effects in PANC-1 cell lines. PHY906 does not alter the PK of CAP, as studies on several tumor types have shown, but it may reduce the GI toxicities associated with chemotherapy, especially diarrhea. These data have motivated the phase I/II study of the safety and tolerability of a weekly (7/7) dose-intense schedule for CAP plus PHY906. Patients with advanced solid tumors (STs) who did not respond to conventional therapy were recruited for the phase I research. On days 1-4, patients were given 800 mg of PHY906 twice a day, and for 14 days, they were given 1,500 mg/m2 of CAP every day. Patients with gemcitabine- refractory APC will be recruited for the phase II research. The study’s findings show that CAP and PHY906 together have tolerable toxicity in patients with ST (130). In phase I/II clinical trials oral administration of baica- lein has been shown to be safe for humans (130). However, more detailed research on baicalein’s therapeutic potential in patients with various diseases is required. Nano-formulations of baicalein Srivastava et al created baicalein-loaded mixed micelles to improve the solubility and bioavailability of baicalein oral prep- aration to treat breast cancer. Micelles encapsulating baicalein in pluronic F127 (F127) and D-tocopherol polyethylene glycol 1000 succinate (TPGS) were investigated for their anticancer properties. The micelles in the optimal formulation exhibited a zeta potential of 4.01 mV and a mean particle size of 25.04 nm. Baicalein was released from micelles in vitro with a sustained release profile at pH 7.4, and an 83.43% computed entrapment efficiency percentage was obtained. In vitro cell culture studies showed a significant increase in the absorption and cytotox- icity of baicalein formulation and performance evaluation of polymeric in-loaded micelles targeting MDAMB-231 cell lines. The cell cycle analysis findings demonstrated that cells were halted in the G0/G1 phase of the cell cycle and that baicalein micelles had a greater capacity to induce apoptosis than did baicalein in its free form. The results of the ROS and mitochon- drial membrane potential experiment demonstrate that the novel formulation suppresses cell growth through the ROS- dependent mitochondrial-mediated apoptotic pathway (131). Munjal et al Drug Target Insights 2024; 18: 39 © 2024 The Authors. Published by AboutScience - www.aboutscience.eu Majumdar et al developed baicalein-loaded nanolipo- some gel formulation, which was easy to apply to the skin’s surface because it has a high degree of homogeneity, a pH that is about equivalent to that of the skin, and an appropri- ate thixotropic characteristic. Baicalein’s release was greatly extended and concentration-independent after the develop- ment of nanoliposomal gel. In contrast to commercially avail- able formulations, the nanoliposomes loaded with baicalein demonstrated remarkable anti-inflammatory effectiveness throughout testing. Accordingly, the engineered nanoliposo- mal gel filled with baicalein may be employed as an effec- tive carrier for baicalein topical administration to suppress inflammatory reactions (132). The efficacy of baicalein-loaded iron oxide nanoparticles (NPs) against the triple-negative breast cancer (TNBC) cell line MDA-MB-231 was examined by Kavithaa et al. Using an electron microscope to analyze a subset of cancer cells, it was revealed that the particles were absorbed by the vari- ous subcellular components of the cells. Furthermore, the assessment of mitochondrial membrane potential was con- ducted using flow cytometry employing JC-1 labeling. The results indicated the presence of significant aggregates in cells treated with iron oxide NPs loaded with baicalein, indi- cating a considerable reduction in mitochondrial membrane potential. Baicalein-loaded iron oxide NPs elevated apop- totic genes such as Bad, Bax, GADD45, and poly(ADP-ribose) polymerase (PARP) cleavage in a dose-dependent manner while downregulating anti-apoptotic genes. Comprehensive kit-based flow cytometric analysis confirms that nano con- jugates may clearly induce apoptosis, DNA damage, and cell cycle arrest, as well as reduce the rate of cell proliferation in TNBC cells (133). Li et al investigated the releasing patterns and loading efficiencies of baicalein (BE) and baicalin (BA) enclosed in mesoporous silica nanoparticles (MSNs) that were produced and modified with amines (Nano-BA and Nano-BE, respec- tively). Using primary human gingival epithelial cells (hGECs), the cytotoxicity of Nano-BA and Nano-BE was examined, and a transmission electron microscope was used to observe the cells’ uptake of the compounds. Their anti-inflammatory effects in IL-1-treated hGECs were measured using the cyto- kine array and the enzyme-linked immunosorbent test. This study shows that amine-modified MSNs are capable of encapsulating BA and BE, and that this nano-encapsulation greatly increases the rate of drug delivery and prolongs the release of BA and BE for up to 216 hours. Furthermore, when exposed to a solution devoid of NPs, hGECs were able to inter- nalize Nano-BA and Nano-BE and maintain them inside the cells for at least 24 hours. It is noteworthy that IL-1-induced expression of IL-6 and IL-8 in hGECs is effectively suppressed by pretreatment with Nano-BE. To summarize, BE encapsu- lated in a NP may efficiently release its contents and be taken up by cells, which has major anti-inflammatory effects (134). Researchers created a pH-responsive drug delivery system (DDS) encapsulating baicalein zeolite imidazole framework-8 (ZIF-8). The synthesized nanocomposite exhib- ited a drug-loading capacity of 40.32%. The in vitro drug release kinetics from the nanocomposite showed excel- lent stimuli-responsive drug release capabilities in an acidic environment. The growth of E. coli, S. aureus, P. aeruginosa, and Staphylococcus epidermidis was significantly inhibited by the nanocomposite. The synergistic effect of zinc (II) ions and baicalein molecules was demonstrated to be the antibacte- rial mechanism of the BA@ZIF-8 nanocomposite. According to in vitro biocompatibility tests, BA@ZIF-8 did not cause any cytotoxicity in L929 fibroblast cells. The created nanocom- posite dramatically enhanced the number of proliferating and migrating cells in the wounded area, according to tests conducted on a scratch wound. According to the findings of the pH-responsive drug release mechanism, the synthesized nanocomposite exhibited greater stability at a neutral pH. The nanocomposite demonstrated rapid baicalein release (65.8%) in acidic conditions, indicating that it is a great choice for pH-responsive drug delivery (135). This investigation of the anticancer properties of BSA- baicalein @Zn-Glu nanostructure-mediated GluRs was con- ducted using human glioblastoma U87 cells. The transport of baicalein active component was studied with hybrid NPs of BSA-Ba@Zn-Glu. BSA-Ba@Zn-Glu NPs were effectively synthesized in a single reduction process. The cytotoxic efficacy and apoptotic rate of the nanostructures on U87 glioblastoma cells were assessed using 3-(4,5-dimethylthi- azol-a-yl)-2,5 diphenyltetrazolium bromide (MTT) assays and flow cytometry, respectively. The synthesized BSA-Ba@ Zn-Glu nanostructures, with diameters ranging from 142.40 to 177.10 nm and zeta potentials between 10.57 and 35.77 mV, have the potential to extravasate into cancer cells. The drug release of BSA-Ba@Zn NPs was both pH-dependent and pH-controlled. In vitro, it was demonstrated that BSA-Ba@ Zn-Glu NPs significantly reduced cell viability and increased apoptosis in U87 cancer cells. A green manufacturing approach was used to create Zn NPs, and it was shown that these particles had a deadly effect in addition to increasing the uptake of NPs by cells via Glu receptors. Glu conjuga- tion and drug delivery of baicalein were achieved through the use of BSA NPs as a nano-platform. BSA-Ba@Zn-Glu NPs can cause dose-dependent cytotoxicity and death in human brain cancer cells (U87). Finally, future research on targeted medication delivery in vivo may make use of this nanostruc- ture. It may also be paired with other treatments, such as x-ray irradiation (Table 3) (136). Patents on baicalein The patents related to pharmacological activity of baica- lein have been tabulated in Table 4. Conclusion This systematic review provides a new scientific and mod- ern perspective on the traditional Chinese medicine baica- lein as a possible supplementary therapy. Baicalein contains anticancer, antimicrobial, antidiabetic, and antiaging prop- erties in addition to protective effects on the brain, heart, lungs, stomach, hepatic, and renal systems, based on the published data reviewed. Repeatedly administering baicalein orally, at dosages ranging from 200 to 600 mg, was shown to be safe and well-tolerated by healthy individuals. There Therapeutic Insights into Baicalein40 © 2024 The Authors. Drug Target Insights - ISSN 1177-3928 - www.aboutscience.eu/dti TABLE 3 - Studies of nano-formulated baicalein/baicalin in several disorders S. no. Disorder Formulation Combination Application Outcome Reference 1. Diabetes NLC No In vitro and in vivo B-NLCs possess favorable physical stability and enhanced capability for drug retention along with improved antidiabetic effectiveness (137) Selenium NPs Naringenin + baicalin In vitro and in vivo Maintain optimal blood glucose levels by enhancing insulin sensitivity, production, and mitigating the dysfunction of pancreatic β-cells in T2DM (138) 2 Breast cancer Iron oxide NPs No In vitro At a very low dose, it inhibits antiapoptotic protein and increases apoptotic proteins (139) Nanoemulsion Paclitaxel + baicalein In vitro and in vivo Improved permeability and retention effects (140) 3. Human lung cancer cells Nanoparticles (prodrug) Paclitaxel + baicalein In vitro and in vivo Exhibited synergism and anticancer potential and reduction of multidrug resistance of paclitaxel occurs (142) 4. Cervical tumor Nanoliposomes No In vivo This formulation demonstrated significant antitumor efficacy (142) 5. Cerebral ischemia SLN OX26 antibody + baicalin In vivo It regulates amino acid levels, which are responsible for the therapeutic effect of treating excitotoxic neuronal damage (143) NLC = nanostructured lipid carriers; NP = nanoparticle; SLN = solid lipid nanoparticles; T2DM = type 2 diabetes mellitus. TABLE 4 - Patents related to baicalein S. no. Patent number Year of publishing/grant Details of patent 1. CN1411815A 2003 The current innovation relates to the preparation method for baicalin eye drops. The root of the natural Chinese medicinal plant Scutellaria is the source of baicalin, the main active element in the product. It exhibits a robust therapeutic effect in the management of pathogen- induced ophthalmopathy without causing ocular discomfort or deleterious side effects. 2. CN103720650A 2014 The innovation is an injection of baicalin that has anti-influenza viral properties. Baicalin, 2.16 g of disodium hydrogen phosphate, 0.6 g of sodium dihydrogen phosphate, and 100 mL of injection water make up this mixture. The injection is sterilized by applying high pressure while keeping the sodium hydroxide pH at 7.0. The medication blocks neuraminidase action, which prevents the virus from releasing its infection. It is highly bioavailable and rarely causes negative side effects. 3. CN101642426B 2009 The innovation is a technique for making nanoscale eye drops of the baicalein adhesion type. Baicalein (w/w) = 0.001%-3%, lipid (w/w) = 0.1%-20%, surfactant (w/w) = 0.1%- 10%, preservative (w/w) = 0.001%-3%, isotonic regulator (w/w) = 0.1%-10%, penetration enhancer (w/w) = 0.005%-10%. The remaining volume of deionized water is used to create the baicalin adhesion type nanoscale eye drops, with the pH being kept between 5 and 9. 4. CN101856350A 2010 The use of baicalein in the preparation of medications for the treatment and prevention of PD is disclosed in the invention. The formulation has the ability to improve and treat PD symptoms while also lowering the trembling frequencies and amplitudes. By preventing damage to dopaminergic neurons, the formulation can effectively prevent and treat pathological changes and the development of PD. Baicalein, on the other hand, inhibits Parkinson’s symptoms by acting on nervous systems and protects dopaminergic neurons through apoptosis resistance, inflammatory resistance, and antioxidation. 5. CN101701245A 2010 The innovation offers a way to extract the major proteinase inhibitor of the SARS coronavirus from a traditional Chinese remedy. The steps in the procedure are as follows: (1) Determining the exosomatic suppressive activities of different extractives from a single traditional Chinese medicine that are main proteinase inhibitors of the SARS coronavirus; (2) choosing the extractive that has the highest exosomatic suppressive activity; and (3) sorting and choosing the extractives chosen in step (2) at least once. The substance that the procedure separated has exosomatic inhibitory actions on the major proteinase of the SARS coronavirus, making it a potentially ideal medication or a viable prodrug for commercialization. (Continued) Munjal et al Drug Target Insights 2024; 18: 41 © 2024 The Authors. Published by AboutScience - www.aboutscience.eu S. no. Patent number Year of publishing/grant Details of patent 6. CN102068452A 2011 The invention relates to a pharmaceutical composition with a synergistic antiviral ratio of 20:1 to 1:10 for baicalein and ribavirin. It lessens the minimum medicine tolerance as well as the adverse effects and side effects. Moreover, the antiviral component works by inhibiting viral replication. It has great advantages and looks to have a bright future in treating and preventing influenza viruses. 7. CN105560177A 2016 The invention discloses the veterinary mixed suspension containing amoxicillin and baicalein, as well as the manufacturing process. The suspension is made by dispersing the active components, amoxicillin and baicalein, 1:1, in a dispersion medium. The problems of amoxicillin being easily broken down in an aqueous solution and the medication being slowly released in an oily mixed suspension are both solved for time-dependent antibiotics. T>MIC is prolonged, effective acting time is prolonged, and a user only needs to take the medication three times consecutively at intervals of 12 hours. 8. CN112007023A 2020 According to the invention, baicalein alpha, beta, or (beta 0+ beta 1) mixed crystal form can be used for preventing and/or treating obesity and its related conditions. More precisely, to the administration of a drug in the range of 0.001-2000 mg/kg/day/po as an active element in the management of obesity and its by-products, including hyperlipidemia, insulin resistance, and blood sugar. 9. CN108653206B 2020 The innovation, which falls under the category of pharmaceutical preparations, describes how to prepare a baicalein nanosuspension. The following elements comprise the baicalein nanosuspension prescription, expressed as a percentage by mass: phospholipid (0.05%-10%), F-68 (0.1-3%), glycerol (1%-10%), and the rest water. 0.1%-2% of the phospholipid compound is called baicalein. The invention offers a low cost and energy consumption, excellent safety, enhanced stability, better medication loading rate, and a straightforward and convenient operation. 10. CN112691102A 2021 The invention describes using baicalein to make a medication that treats and prevents PD as well as the depressive symptoms of Parkinson’s syndrome. The invention finds that baicalein can clearly increase the levels of neurotransmitters like DA, NE, and 5-HT in the brain and metabolites thereof, decrease the level of neuroinflammation factors in blood plasma, and improve the symptoms of a rotenone-induced depression mood model of a PD/Parkinson syndrome mouse. Consequently, baicalein can be utilized to make medications that prevent and treat PD as well as the symptoms of depression associated with the condition. 11. CN113244216A 2021 The innovation reveals the use of baicalein in the development of a medication to suppress a novel coronavirus and reveals that baicalein and SARS-CoV-2Mpro can be coupled, also preventing SARS-CoV-2Mpro from functioning as an enzyme in vitro. The protease activity, which impedes the new coronavirus’s ability to replicate, has promising applications in the field of creating new coronavirus drugs. 12. WO2021159570A1 2021 This invention involves using baicalein to make a drug that will either treat or prevent a disease caused by a novel coronavirus infection. The invention in question pertains specifically to the use of baicalein and a pharmaceutical composition containing baicalein in the preparation of a drug intended to prevent and/or treat diseases caused by novel coronavirus infections (SARS-CoV-2). These infections can range in severity from mild to severe, and they include novel coronavirus pneumonia. 13. CN113925861A 2022 The invention describes the use of a Scutellaria flavone active ingredient and its preparation in the manufacturing of a medication intended to cure or prevent inflammatory storm. Wogonin, oroxylin A, and baicalein are the components from which the active ingredient of baicalein is chosen. Reducing the frequency of inflammatory storms, particularly in patients who are severely ill, helps to lessen organ damage and halt the disease’s course. The innovation finds that wogonin, baicalein, and oroxylin A all operate to varying degrees to block the mouse cytokine storm. Lung damage and inflammatory cell infiltration brought on by an inflammatory storm can be lessened by baicalein. Thus, the medication for both preventing and treating the inflammatory storm can be made using the active ingredient of baicalein. DA = dopamine; MIC = minimum inhibitory concentration; NE = norepinephrine; PD = Parkinson’s disease; SARS-CoV = severe acute respiratory syndrome coro- navirus. TABLE 4 - (Continued) Therapeutic Insights into Baicalein42 © 2024 The Authors. Drug Target Insights - ISSN 1177-3928 - www.aboutscience.eu/dti was no impairment seen in liver and renal function; how- ever, it may affect the metabolism of triglycerides. Baicalein is rapidly and extensively metabolized in the body, resulting in the production of several metabolites. Out of the seven metabolites, 7-BS and BGG exhibited a significantly larger amount in the plasma. The scientific literature has shown the antiviral activity of baicalein and baicalin (7-BG). There are direct and indirect consequences among them. It is criti- cal to know each mode of action in order to maximize this flavonoid’s efficacy in treating diseases. There are direct and indirect consequences among them. Clinical research on this natural substance’s efficacy, however, did not provide enough information. Consequently, additional evidence-based clini- cal trials are required to verify the safety and effectiveness of baicalein as a potential therapeutic agent for a range of human illnesses and for the good of humanity. Acknowledgment The images were created using Biorender software. Disclosures Conflict of interest: The authors declare no conflict of interest. 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