TNF-α is an important cytokine involved in metabolic diseases such as obesity, insulin resistance, hyperlipidemia, and NAFLD [59]. The production of TNF-α in the process of liver injury causes the release of IL-1β and IL-6, which mediates inflammatory response [60]. Hepatotoxicity could activate the toll-like receptor 4 (TLR4) through excessive lipid accumulation in hepatocytes [61]. Upon activation of TLR4, a large amount of MyD88 aggregates NF-κB and MAPK [62]. The aggregations of NF-κB and MAPK promote the expression of TNF-α, IL-1β, IL-6, and other pro-inflammatory factors and the infiltration of pro-inflammatory cells, which further aggravates liver injury [63]. For instance, studies showed that baicalin could reduce the expressions levels of TNF-α and NF-κB in liver tissue and the production of TNF-α, IL-1β, and IL-6 in plasma, thus reducing the degree of liver inflammation [64,65]. In line with this, baicalin reduced systemic inflammation by blocking the NLR pyrin domain containing 3-Gasdermin D signal transduction and by inhibiting TLR4 signal cascade in mice, reducing the release of pro-inflammatory factors (TNF-α, IL-8, and IL-6) [36,37,66]. In addition, studies found that baicalin can initiate the repair of liver injury caused by acetaminophen (APAP) [67]. The main mechanism is to promote liver regeneration after APAP-induced acute liver injury in mice by inducing the accumulation of nuclear factor erythroid2-related factor 2 (NRF2) in the cytoplasm and the activation of NLRP3 inflammasome, which in turn leads to the increase in IL-18 expression and the proliferation of hepatocytes, thus achieving liver-regeneration function [36,67].

Rheumatoid arthritis (RA) is a chronic inflammatory disease in the synovium, which can lead to cartilage and bone damage and disability [68]. Factors involved in the development of diseases include genetic factors, infections, and immune dysfunction [69,70]. Currently, RA is managed clinically with non-steroidal anti-inflammatory drugs (NSAIDs), anti-rheumatic drugs (DMARDs), immunosuppressive drugs, etc. [71]. During the onset and spread of RA, immune T and B lymphocytes activate the effector cells and then release pro-inflammatory mediators such as IL-1, IL-6, IL-17, and TNF-α, which are primarily responsible for synovial joint inflammation and bone erosion [71]. IL-17 is an important cytokine produced by T helper 17 cells (Th17) [72]. As a potent inflammatory cytokine, it could induce the production of a variety of pro-inflammatory factors such as IL-6, TNF-α, and IL-1β, all of which can lead to an inflammatory response in tissues and cells [73] and a significant increase in IL-17 in both the serum and joint fluid of RA patients relative to osteoarthritis [74]. The production of a range of chemokines induced by IL-17 led to the recruitment of T cells, B cells, monocytes, and neutrophils in diseased joints [75]. Matrix metalloproteinases (MMPS), nitric oxide (NO), and nuclear factor-κB (RANK)/RANK ligand (RANKL) receptor activators can be upregulated by IL-17 in both cartilage and osteoblasts, leading to damage in bone and articular cartilage and promoting the development of RA [76,77]. Therefore, inhibition of IL-17 expression might be an important target to improve RA (Figure 2).

Inactivated Mycobacterium tuberculosis adjuvant-induced arthritis in mice showed that intraperitoneal administration of 100 mg/kg baicalin significantly inhibited the expansion of the spleen Th17 cell population (40%) and attenuated arthritic symptoms such as paw and ankle swelling [79]. A molecular mechanism study showed that baicalin inhibited the expression of the retinoid-related orphan nuclear receptor γt (RORγt) gene, a key transcription factor for Th17 cell differentiation [80]. Furthermore, baicalin treatment in IL-17-contaminated synovial cells for 24 h significantly inhibited lymphocyte adhesion to synovial cells, blocked IL-17-induced inflammatory cascade, and reduced the expression of intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule (VCAM-1), IL-6, and TNF-α [79]. Additionally, Tong et al. (2018) found that baicalin reduced TLR2 and MyD88 gene expression and the toll-like receptor 2 (TLR2), myeloid differentiation factor 88 (MyD88), and NF-κB-p65 protein expression in RA synovial fibroblasts (RA-FLS) [81], suggesting that the mechanism of baicalin’s action might be related to the inhibition of the TLR2/MyD88/NF-κB signaling pathway. The above studies suggest that baicalin has a positive effect in alleviating RA disease, but more detailed mechanisms of action need to be further investigated.

Obesity refers to excessive total or local fat in the body, which is a “metabolic syndrome” with indicators such as abnormal blood glucose, blood fat, blood pressure, and insulin resistance (IR) [82]. Excessive nutrient intake and lack of exercise are likely to cause obesity, which is associated with insulin resistance and an increased risk of type 2 diabetes [83]. It was established that excessive white adipose tissue (WAT) is associated with the occurrence of chronic, low-grade, and systemic inflammation [84]. NF-κB, as a major pro-inflammatory nuclear transcription factor, directly increases the expression level of pro-inflammatory cytokines and chemokines [85]. The inactive state of NF-κB is chelated with a complex of inhibitor-κB (IKB) inhibitor protein family members in the cytoplasm [85]. Upon cellular activation, IκB kinase β (IKK-β) phosphorylates IκB, leading to its ubiquitination and proteolytic degradation. This in turn releases and translocates NF-κB to the nucleus and further activates target gene transcription in the nucleus [85]. Thus, inhibition of the NF-κB signaling pathway in adipose tissue reduces the incidence of chronic, low-grade, and systemic inflammation and confers a protective mechanism against the development and progression of insulin resistance and type 2 diabetes [85].

In most cases, obesity develops from regularly eating a high-fat diet (HFD), and excess obesity can lead to fatty liver disease, known as “NAFLD” [86]. Overexpression of adiponectin, leptin, and TNF-α is a major factor increasing the risk of liver fat accumulation, insulin resistance, pancreatic beta cell dysfunction, and fibrosis [87,88]. Baicalin was shown to reduce the degree of fatty liver degeneration and obesity in a dose-dependent manner, which was attributed to baicalin-dependent inhibition of the hepatic calmodulin-dependent protein kinase kinase beta (CaMKKβ)/Adenosine 5‘-monophosphate -activated protein ki-nase (AMPK)/acetyl-CoA carboxylase (ACC) pathway [12]. Therefore, AMPK activators may be an effective target for the treatment of obesity and type 2 diabetes. Diabetes is an important cause of endocrine and metabolic disorders. Long-term hyperglycemia can cause a variety of chronic complications such as diabetic nephropathy and diabetic retinopathy [89,90]. Studies have shown that baicalin can effectively improve diabetic nephropathy, mainly by activating the NRF2-mediated antioxidant signaling pathway and inhibiting the MAPK-mediated inflammatory signaling pathway [89,90]. In support of this, baicalin was reported to significantly reduce the expression of pro-inflammatory factors IL-1β, IL-6, and TNF-α through the MAPK pathway [89,90]. Because of the important clinical significance of baicalin in the prevention and treatment of obesity and diabetes, more and more attention is focused on baicalin in obesity and diabetes.

Over the past few years, respiratory diseases have become more prevalent, posing a significant threat to human health and safety. The commonly occurring respiratory diseases include asthma, idiopathic pulmonary fibrosis (IPF), and pulmonary arterial hypertension (PAH) [91]. Asthma, which is recognized as reversible airway obstruction induced by persistent airway inflammation, is caused by airborne pollutants and genetic predisposition factors [92]. IPF or pulmonary fibrosis (PF), characterized by fibroblast proliferation and collagen deposition in lung tissue structure, is a chronic interstitial lung disease caused by pneumonia, excessive smoking, and/or other factors, leading to structural destruction and respiratory failure [93]. Relevant studies reported that a class of small non-coding RNA molecules, such as microRNA-21 (miR-21) [94], miR-29, and miR-155, all involving the progression of IPF, is upregulated by pro-inflammatory cytokines and transforming growth factor β-1 (TGF-β1) [28,91,95]. Baicalin is an effective treatment in patients with respiratory tract diseases [96]. A study in bleomycin (5 U/kg)-induced PF mice showed that intraperitoneal injection of baicalin (120 mg/kg/d) reduced lung fibrosis, collagen deposition, and hydroxyproline levels in lung tissue through reducing TGFβ1-induced extracellular signal-regulated kinaes 1/2 (ERK1/2) signaling compared with the control [96]. To investigate baicalin’s anti-fibrosis effect, a study in mice with knocked-out adenosine A2a receptor (A2aR), which is an inflammatory regulatory receptor, found that, compared with A2aR-positive mice, A2aR-knockout mice had more severe pulmonary fibrosis and higher expression levels of TGF-β1 and phosphorylated ERK1/2 protein [96]. Based on these results, the authors proposed that baicalin might exert its antifibrotic effect by downregulating the elevated levels of TGFβ1 and pERK1/2 and promoting the expression of inflammatory regulatory gene A2aR [96]. The A2aR gene expressed in macrophages, dendritic cells, T cells, B cells, and epithelial cells is considered a novel regulator of inflammation and tissue repair [97]. PAH is characterized by right ventricular hypertrophy and dysfunction due to the deposition of extracellular matrix (ECM) protein collagen fibers on the walls of pulmonary arterioles, which further leads to constriction of pulmonary blood vessels [98]. In a related baicalin study, the results in rats with chronic hypoxia pretreated with baicalin (30 mg/kg) showed inhibition of p38 MAPK and a downregulation of matrix metalloproteinase 9 (MMP-9) expression in pulmonary arterioles, thus alleviating PAH and pulmonary heart disease (right-side cardiac dysfunction) [97]. In addition, baicalin was reported to reduce the expression levels of IL-1β, IL-6, and TNF-α in lung tissue by regulating the p38 MAPK signaling pathway, suggesting an anti-inflammatory role of baicalin [99].

Inflammatory bowel disease (IBD) is a chronic immune disorder characterized by recurrent episodes of abdominal pain, diarrhea, and purulent stool [100]. IBD mainly includes Crohn’s disease (CD) and ulcerative colitis (UC) [101,102,103]. Baicalin plays a protective role in IBD by inhibiting oxidative stress, immune regulation, and anti-inflammatory properties [104]. To support this, baicalin was found to affect inflammatory processes by regulating autophagy and the NF-κB signaling pathway in intestinal epithelial cells, thereby improving paracellular permeability [105]. In line with this, baicalin was reported to attenuate the inflammatory response by modulating the polarization of M1 macrophages towards the M2 phenotype in a dextran sodium sulfate (DSS)-induced ulcerative colitis model [101]. Similarly, it was found that baicalin downregulated inflammatory cytokines’ expression of IL-1β, TNF-α, apoptotic genes Bcl-2, and caspase-9 in the colon of 2,4,6-trinitrobenzesulfonic acid (TNBS)-induced UC rats in a dose-dependent fashion [106]. The treatment of baicalin in inflammation is mainly mediated by suppressing the inhibitor-κB (IKB) kinase complex (IKK)/IKB/NF-κB signaling pathway [106]. Especially, the administration of baicalin (5–20 mg/kg) in TNBS-induced UC rats downregulated the expression of TNF-α and IL-6 and inhibited the TLR4/NF-κB signaling pathway, thereby alleviating UC [107]. Consistently, baicalin (30–120 mg/kg) was reported to have a therapeutic effect in TNBS-induced UC by promoting the activities of antioxidant enzymes such as superoxide dismutase (SOD), catalase, and glutathione peroxidase (GSH-PX) and by reducing the content of malondialdehyde (MDA) [108]. This study further found that baicalin (100 mg/kg) reduced the production of IL-6, IL-1β, and IL-17 in serum and inhibited the activation of SOD, GSH-PX, and MDA in the UC model under high temperature and humidity [108]. These results suggest that the anti-inflammatory effect of baicalin is attributed to inhibiting the activation of the NF-κB and MAPK signaling pathways.

In addition, baicalin (50–150 mg/kg) administration decreased myeloperoxidase (MPO) activity, NO content, and the expression of TNF and IL-6 in the colon of DSS-induced UC rats [109]. Another study showed that baicalin (100 mg/kg) attenuated DSS-induced UC by blocking the TLR-4/NF-κB-p65/IL-6 signaling pathway and inhibiting inflammatory cytokines’ expression of TNF-α, IL-6, and IL-13 [110]. Consistently, baicalin (10 mg/kg) downregulated the expression of macrophage migration inhibitors monocyte chemoattractant protein (MCP)-1 and macrophage inflammatory protein (MIP)-3a in rat colons of a TNBS-induced UC model [111]. The balance of Th17/regulatory T cells (Treg) has been demonstrated to be associated with UC [112]. For instance, baicalin (20–100 mg/kg) regulated the balance of Th17/Treg by inhibiting MDA and ROS production, reducing GSH and SOD levels, and downregulating the expression of Th17-related factors IL-6 and IL-17 in TNBS-induced UC rats [113,114]. In clinical studies of UC patients, baicalin regulated immune balance and relieved the UC-induced inflammation reaction by promoting the proliferation of CD4(+) CD29(+) cells and modulating immunosuppressive pathways [115].

Inflammation is an important link with the pathogenesis of cardiovascular diseases such as myocardial fibrosis, atherosclerosis (AS), and myocardial depression, and it plays a crucial role in the further development of disease [116]. AS, the pathological basis of cardiovascular disease, could cause angina pectoris and myocardial infarction, etc. [117]. The main pathological mechanism involved is an endothelial function, lipid deposition, oxidative stress damage, immune inflammation, etc. [118,119]. Baicalin is widely used in lipid-lowering studies because of its effectiveness in reducing serum total cholesterol (TC), triacylglycerol (TG), and low-density lipoprotein cholesterol (LDL-C) levels [120]. In an apolipoprotein E (APOE)^−/− mouse model of a high-cholesterol diet, baicalin reduced the expression of TG and LDL-C [121]. Their further analysis showed that baicalin promoted the proliferation and viability of Treg cells and the expression of TGF-β and IL-10, which improved the progression of atherosclerotic lesions through lipid regulation and immunomodulation [122]. In the development of AS-induced inflammation, activation of NF-κB increased the production of inflammatory factors and chemokines [123]. Therefore, baicalin has a beneficial effect on the development of AS by inhibiting the NF-κB signaling pathway [124]. It was also shown that baicalin mediated the Wnt1/dickkopf-related protein 1 (DKK1) signaling pathway to prevent AS [125]. In addition, the Th17/Treg balance is inextricably linked to the development of AS, and IL-17A secreted by Th17 triggers the onset of AS-induced inflammation and Treg, a protective T cell, which effectively attenuates the inflammatory response [126]. Patients with AS commonly have a Th17/Treg imbalance; specifically, Th17 cells increase, and Treg cells decrease [127]. Studies conducted by Jiang et al. (2019) and Yang et al. (2012) showed that baicalin had a protective effect on Th17/Treg homeostasis, which is associated with its anti-AS role [128,129]. In hypertension studies, baicalin reduced hypertension-induced inflammation (significant reduction in IL-1β and IL-6) by increasing the expression of tight-junction proteins that could maintain intestinal integrity [130]. Baicalin could also lower blood pressure by lowering calcium levels and causing vascular smooth muscle diastole [131]. In summary, baicalin has a combined effect on the prevention and treatment of cardiovascular disease.