Molecular targets and therapeutic potential of baicalein: a review

Introduction

Baicalein, a flavone compound, is widely recognized in Chinese traditional medicine as Huang-qin or Chinese skullcap (1). Recent research has revealed the therapeutic significance and pharmacological findings of roots of Scutellaria 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 continues 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. rehderiana, S. amoena, S. likiangensis, and S. hypericifolia have also 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 trumpet 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 deciduous 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 exhibited 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 distribution 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 aglycone 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 fundamental 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 exploring its potential in various fields of research (1,4).

This molecule demonstrates a wide range of biological actions, including significant domains such as reducing 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 consolidate a wealth of information on the diverse pharmacological effects associated with various diseases, encompassing multiple 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 garnered 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 framework (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 chrysin to baicalein in recent laboratory tests; 1-(2,4,6-trihydroxyphenyl)ethanone and 1-ethyl-3-phenyl-1,3-propanedione are combined in the first synthesis technique. Chen et al completed a pioneering investigation that revealed an amazing and novel method for extracting baicalein from 3,4,5-trimethoxyphenol. This approach, which consists of a brief fourstep procedure, showed promise for a more streamlined and effective manufacture of baicalein (13,14). One of the key structural characteristics that distinguishes baicalin and baicalein is the notable existence of a di-ortho OH on ring A. The remarkable characteristic exhibited by polyphenolic compounds lies in their ability to serve as efficient markers for metal chelation, 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 phenotypically 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, mutations in the DNA or any by-products of that DNA, and dysfunction 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, synthesis, 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 gastric cancer cases and fatalities would reach its peak soon (21). The gastric cancer cell line SGC-7901 underwent a significant 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 investigation 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 activation of cyclin- CDKIs (23).

The seventh most common cause of cancer-related fatalities worldwide is pancreatic cancer. However, many developed 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 burden 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 pathophysiology, 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 inhibits 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 intracellular reactive oxygen species (ROS) and activated BNIP3 to slow down the development and hasten the apoptosis of MG-63,OS cells (38).

By reducing the levels of cyclin D1 and CDK4, which inhibits 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 progression 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 industrialized and developing nations, Alzheimer’s disease has a substantial impact on those who are affected, the caregivers, and society (40). One of the cellular disorders hypothesized to be responsible for the loss of neurons in Alzheimer’s disease is aggregation of A𝛽 (41). Baicalein exhibits neuroprotective qualities against amyloid (AN) functions by preventing 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 constituent of Lewy bodies is abnormally folded aggregates of α-syn, which manifest as intracellular inclusions in nigral dopaminergic 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 aggregation 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 demonstrated the capacity to disintegrate the preexisting α-syn fibrils (48). Additionally, by eliminating iNOS protein, mRNA, and promoter activity in endotoxin/cytokine-induced microglia, 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 disease coming in first in both categories (50). According to the Indian Global Burden of Disease Study, which was conducted between 1990 and 2019, stroke was India’s leading cause of both fatalities from neurological illnesses and disability-adjusted life years (DALYs) (51). In ischemic stroke, neuroprotection is achieved by inhibiting iNOS activity or by iNOS gene deletion. Neuroexcitotoxic and ischemic traumas 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, according 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 markedly elevated nuclear Nrf2 expression and AMPK phosphorylation 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).

Plant compound	Name of cancers	Cell lines	Cell cycle phase arrest	Mechanism	References
	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)

Epilepsy is a chronic, noncommunicable brain illness that affects people of all ages. One of the most prevalent neurological 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-traumatic 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-responsiveness 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 therapy 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 activation in normal bronchial epithelial (BEAS-2B) cells (62), which was mostly expressed by downstream iNOS production, 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 myofibroblasts and fibroblasts. During allergic airway inflammation, myofibroblasts deposit collagen types I and III. ECM’s constituents, especially collagens, are broken down and controlled by MMPs, which are secreted by fibroblasts. In allergic asthma, MMP-9, the main airway MMP, is upregulated, which results in airway remodeling (64). According to recent studies, 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, particularly 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 lowering 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 hypertension. 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 dysfunction 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 voltage-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 efficiently 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 hospitalization 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 reduction in gastric mucosal damage are both effects of activating α2-adrenergic receptors (82). The gastroprotective properties 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 secondary etiology like alcohol or drugs (86). An excessive buildup of lipids in the liver results from the increased hepatic lipogenesis 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 metabolism and reduce hepatic de novo lipogenesis, baicalein inhibits the Ca2+/CaM-dependent protein kinase/AMP-activated protein kinase/acetyl-CoA carboxylase (CaMKK/AMPK/ACC) 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-mesenchymal transition and stop the progression of liver fibrosis (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 estimated 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 neuropathy. 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 considerably 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 anticancer drug cisplatin. Increased ROS generation from cisplatin 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 peroxynitrite 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 peroxynitrite-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 antibiotics on germs and resulted in ongoing difficulties, despite notable advancements in the treatment of microbial infections (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 bacterial resistance to antibiotics has motivated the creation of innovative antibacterial drugs for the treatment of infectious disorders. People from many cultures have used a variety of herbal remedies for many generations, and some of these natural medicines are crucial for the treatment and prevention of infectious diseases (105,106). Baicalein’s function as an antibacterial agent is crucial. Baicalin inhibits pro-inflammatory cytokine release, MAPK activation, NF-κB pathway activation, 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 phosphorylation 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 bacillus. Through a number of mechanisms, such as enhancing the host immune system, preventing the formation of biofilms, lowering antimicrobial medicine resistance, suppressing bacterial 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 pathway, 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 transaminase (ALT), aspartate aminotransferase (AST), and total bilirubin 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 antifungal 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 substantial inhibitory effect on CaEno1’s enolase activity (115). Baicalein inhibits TSLP/TSLPR pathway activity, which suppresses inflammatory response and protects against A. fumigatus keratitis by preventing fungal growth, biofilm formation, 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 consistently 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 encourages insulin production (118). Baicalein is used to treat diabetes, 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 synthesis of glucose after meal digestion may minimize hyperglycemia. It was discovered that baicalein had α-glucosidase inhibitory effects comparable to those of the commonly prescribed, clinically effective α-glucosidase inhibitor, acarbose (120). The synergistic impact of baicalein and acarbose treatment 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 complicated 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 glycation rates. This can lead to nonfunctional proteins and further activate several signaling pathways, increasing the risk of beta-cell damage, insulin resistance, and diabetes complications. 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 genetically determined) factors, such as exposure to ultraviolet (UV) radiation, high intake of alcohol, and pollution. UV radiation 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 baicalein 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, nucleic acids, and cell membranes. ROS have a major contribution 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 considerably elevated MDA levels in fibroblasts and significantly decreased SOD and GSH-Px activities. Additionally, baicalin therapy by itself dramatically reduced MDA levels in fibroblasts and increased SOD and GSH-Px activity (125).

Pharmacokinetics

Patents on baicalein

The patents related to pharmacological activity of baicalein have been tabulated in Table 4.

Conclusion

This systematic review provides a new scientific and modern perspective on the traditional Chinese medicine baicalein as a possible supplementary therapy. Baicalein contains anticancer, antimicrobial, antidiabetic, and antiaging properties 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 was no impairment seen in liver and renal function; however, 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 critical 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 clinical 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.

Financial support: Nil

Author contributions: Kavita Munjal, YashGoel, Vinod Kumar Gauttam: conceptualization, methodology, investigation, data collection, and writing—original manuscript. Hitesh Chopra, Madhav Singla, Smriti, Saurabh Gupta, Rohit Sharma: editing and proofreading. Hitesh Chopra, Rohit Sharma: supervision. All authors approved the submission of the final manuscript.