Liposomes are the most widely studied nano drug delivery system due to their synergistic delivery system that increases drug solubility (Huang et al., 2022; Ramedani et al., 2022). It has been demonstrated that the advantage of BA-loaded nanoliposomes for treating respiratory diseases is lung targeting (Wei et al., 2016; Wei et al., 2017). Research has shown that the BA liposome (L-BA) improves oral availability and tissue distribution (Wei et al., 2014). Compared to the same dose of BA, L-BA (100 mg/kg, tail-vein injection) more significantly reduced the W/D ratio, lung injury score, pro-inflammatory factors, and protein in total bronchoalveolar lavage fluid in a mouse model of lipopolysaccharide (LPS)-induced ALI (Long et al., 2020). In particular, the daily increase in tumor weight of BALB/c nude mice injected with A549 human lung cancer tumor cells was significantly reduced by L-BA (100 mg/kg) after intravenous injection of the drug, resulting in increased the survival rate of mice (Wei et al., 2017). L-BA was modified with folic acid and polyethylene glycol to improve further tumor targeting, which exhibited higher cellular uptake than non-targeted liposomes (Chen et al., 2016).

Nano-emulsions offer unique advantages and properties that increase water solubility and dynamic stability, improve therapeutic efficacy, and reduce adverse effects and toxic reactions (Pangeni et al., 2018). Due to the sustained-release characteristics of the nano-emulsions containing BA, it is very effective in increasing oral availability. A novel nano-emulsion has been proven to improve systemic exposure to BA by promoting intestinal absorption and lymphatic transport (Wu et al., 2018). Zhao et al. (2013) prepared BA-loaded nano-emulsions by internal and external drug addition. And they found that both were superior to BA suspensions in terms of C_max and AUC_0-∞.

Micelles are synthesized from amphiphilic surfactants in the aqueous phase, which provides hydrophobic cores as reservoirs to increase the solubility of water-insoluble drugs (Gaucher et al., 2005). The carrier material containing a mixture of Pluronic P123 copolymer and sodium taurocholate in bundle gum increased the C_max and AUC in rats by 1.77 and 1.54 times more than the BA suspension, respectively (Zhang et al., 2016). The therapeutic effects of BA in micelles have been investigated in preclinical LC models. Novel carrier materials have been screened for structures targeting nano-micelles (named “nano-dandelion”) for the simultaneous delivery of curcumin and BA. The nano-dandelion improved cellular uptake and cytotoxicity in the A549 cells, exhibiting better anti-cancer effects. In addition, by aggregating more readily at the tumor site, tail vein injection nano-dandelion exerts a more effective tumor suppression effect than free drug (Wang et al., 2019).

As with liposomes, phospholipid complexes can improve the affinity of BA to solubility and cell membranes (Qin et al., 2018). It has been shown that orally administered SBG extract-phospholipid complex improves solubility and bioavailability in vivo (Chen S. et al., 2022). Although phospholipid complexes can improve bioavailability, the increased lipophilicity leads to poor solubility and dispersion of the drug in the aqueous phase (Huang et al., 2019; Wang et al., 2020b). Self-emulsifying drug delivery systems (SEDDS) are isotropic mixtures of drugs, lipids, and surfactants, which are well-suited for lipophilic drugs with limited solubility (Salawi, 2022). A preparation for improving the oral availability of BA has been developed by combining a phospholipid complex with a SEDDS, which has been shown to enhance BA transport and relative bioavailability (Wu et al., 2014).

Solid dispersions improve the bioavailability of drugs by reducing the particle size to an absolute minimum, thereby increasing the wettability of the drug (Vasconcelos et al., 2007). Li et al. (2013) have developed that the BA-polyvinylpyrrolidone coprecipitate was prepared by the solid phase dispersion technique solvent method. Compared to the BA raw material capsules, the relative bioavailability of the coprecipitate capsules was 338.2% ± 93.2%. BA mesoporous carbon nanopowder (MCN) solid dispersions offer more advantages over pure BA as an oral delivery system, including shorter time to peak concentration and higher C_max and AUC. Significantly, it improves solubility and oral bioavailability without gastrointestinal and renal toxicity (Cui et al., 2016).

Cyclodextrins have been widely used as functional excipients in inclusion formulations (Gandhi et al., 2020). Li et al. (2017) synthesized β-cyclodextrin (β-CD) and BA host-guest inclusion complexes to exert better therapeutic effects. And the inclusion complex found that the AUC_0-t, AUC_0-∞, and the relative oral bioavailability increased by 2.65, 2.53, and 2 times compared with free BA. To further improve the solubility and stability of the complexation of BA with β-CD, researchers structurally modified the BA complex to synthesize hydroxypropyl-β-CD to enhance antioxidant capacity, which is the most reactive form (Li et al., 2009a).

Due to the low bioavailability of BA, researchers have synthesized various novel formulations of BA to increase its solubility, bioavailability, targeting, cellular uptake, and retention time in vivo, increasing the therapeutic effect of BA. However, studies of these novel formulation forms are still in the pre-clinical stage, and further evaluation is needed to determine whether they can be used in the clinic.

In 2019, the unprecedented COVID-19 was caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has become a global public health concern (Kciuk et al., 2022; Murali et al., 2022). BA has been shown to inhibit SARS-CoV-2 RNA-dependent RNA polymerase activity and exhibited significant antiviral activity against SARS-CoV-2 in vitro (Zandi et al., 2021). Evidence shows that cytokine storm (CS) was a pivotal stage in the advancement of COVID-19 (Hach et al., 2022; Jing et al., 2022; Shevtsova et al., 2022). You et al. (2022) used the method of network pharmacology to analyze the possible pathway of BA inhibiting CS. The enrichment analysis results showed that the tumor necrosis factor-α (TNF-α) pathway and IL (interleukin)-17 pathway might be potentially significant pathways for BA to inhibit CS. Furthermore, BA (200 mg/kg, gavage) exerts an anti-inflammatory effect by decreasing the expression of TNF-α, which alleviates CS against lung injury in vivo. As is well known, SARS-CoV-2 uses the ACE2 to enter cells, and ACE2 cleaves angiotensin (Ang) II into Ang 1–7, which is thought to exert a cellular response primarily through the receptor Mas to counteract RAS activation in several organs (Letko et al., 2020; South et al., 2020). A study by Wei reported that BA inhibits Ang II-induced oxidative damage and dysfunction in endothelial cells through activation of the ACE2/Ang-(1–7)/Mas axis and upregulation of the PI3K/AKT/eNOS pathway, thereby exerting a protective effect on endothelial cells (Wei et al., 2015).

From the above summary, we found that BA prevented COVID-19 through antiviral activity, inhibiting CS and protecting against endothelial cell dysfunction and oxidative damage (Figure 1; Table 3). In the future, clinical evaluation of BA for the treatment of COVID-19 needs to be performed.

ALI is a life-threatening disease with a high fatality rate in a clinical setting (Guo et al., 2022). Severe lung infection, pulmonary contusion, and pulmonary embolism are the direct causes of ALI (He et al., 2021). The main pathological features are acute inflammation and apoptosis of alveolar epithelial cells (Allen and Kurdowska, 2014; Liu et al., 2020; Gao et al., 2021).

Using the LPS-induced ALI model, BA might be a novel strategy for lung protection, mainly due to BA (200 mg/kg, orally administration) inhibited the expression of TNF-α, IL-1β, IL-6, and malondialdehyde (MDA) and restored antioxidative enzyme activities, including superoxide dismutase (SOD) and catalase (CAT). The suppression of inflammatory and oxidant responses was mediated by activation of the nuclear erythroid factor 2 (Nrf2)-mediated heme oxygenase-1 (HO-1) pathway (Meng et al., 2019). In addition, another similar model study conducted by Zhu et al. demonstrated that 50 mg/kg and 100 mg/kg of BA (gavage) significantly alleviated the permeability of the alveolocapillary membrane and tissue injury through the toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor-kappa B (NF-κB)/nod-like receptor pyrin containing 3 (NLRP3) pathway and the mitogen-activated protein kinase (MAPK) pathway (Changle et al., 2022). The BA-induced attenuation of lung injury via the NF-κB anti-inflammatory pathway was confirmed in another lung injury model. Peng showed that BA (80 mg/kg, oral gavage) might alleviate lung injury in an avian pathogenic E. coli-induced model by inhibiting the phosphorylation of NF-κB (Peng et al., 2019). The findings demonstrated that BA modulated the NF-κB anti-inflammatory pathway, suggesting that it may contribute to reversing pulmonary injury. In a study of the air embolism-induced ALI model, BA (1, 2, and 4 mg/kg) was added into the lung perfusate, alleviating lung injury in isolated lungs by suppressing the proinflammatory cytokines, oxygen radicals, and NF-κB activity (Li et al., 2009b).

From the above summary, BA exerts anti-oxidative stress and anti-inflammatory effects through the Nrf2-mediated HO-1 pathway. CAT antioxidant enzyme, transforming growth factor-β (TGF-β), and granulocyte-macrophage colony-stimulating factor (GM-CSF) are involved in relieving ALI regulated by BA. And the inhibition of lung inflammation via the NF-κB pathway might play a pivotal role in attenuating pulmonary damage by BA (Table 3).

Bronchial asthma is a chronic airway disease predominantly characterized by chronic inflammation and hyperresponsiveness, leading to cough, wheezing, shortness of breath, and chest tightness (Olin and Wechsler, 2014; Banno et al., 2020; Yasuda et al., 2020). It is widely believed that cytokines and inflammatory cells such as eosinophils, neutrophils, lymphocytes, and mast cells are involved in asthma (Yasuda et al., 2020; Zhang et al., 2020).

Ma et al. (2014) confirmed that BA (10–40 mg/kg, gavage) alleviated ovalbumin (OVA)-induced allergic asthma by inhibiting airway resistance, eosinophil count, and IL-4 level, recovering lung compliance, and increasing the expression of IFN-γ. And the study of molecular mechanisms might be associated with the decrease of IL-17A. Another similar model also confirmed the importance of immune regulation in asthma. Xu et al. (2017a) demonstrated that intragastric gavage (i.g.) administration of BA at a dose of 10, 25, and 65 mg/kg protected OVA and LPS-induced allergic asthma in mice models by maintaining Th17/Treg balance. In the study of Sun, researchers administered BA (gavage) dosages ranging from 25 to 100 mg/kg/day to mice with OVA-induced allergic asthma. The result demonstrated that BA reduced the expression of TGF-β1, IL-13, and vascular endothelial growth factor in tissue remodeling by suppressing the activation of the extracellular signal-regulated kinase (ERK) pathway and RAS expressions (Sun et al., 2013). Liu et al. (2016) found BA (10, 25, and 50 mg/kg, i.g. administration) could reduce the expression of immunoglobulin E (IgE), IL-6, TNF-α, CC-chemokine receptor (CCR) 7, C-C chemokine ligand (CCL)19/CCL21 in the OVA-induced mice model, inhibiting airway inflammation via the NF-κB pathway.

According to above research, immune modulation and inhibition of inflammatory responses appear to be important mechanisms for BA to treat asthma. It is critical for BA to relieve asthma by inhibiting the ERK pathway and inhibiting CCR7, CCL19/CCL21, and NF-κB pathway (Table 4).

COPD is characterized by airway remodeling and progressive lung inflammation, which are the main features of an increase in the number of alveolar macrophages, neutrophils, and T lymphocytes (Barnes, 2014; Chang et al., 2014). Cigarette smoking is one of the primary causes of COPD, resulting in 5 million deaths annually (Jones et al., 2017; Labaki and Rosenberg, 2020).

Hao et al. (2021) utilized cigarette smoke extract-induced mouse lung epithelial cell model and cigarette smoke and LPS-induced mouse model to investigate the anti-inflammatory effect of BA in COPD. They found that BA (25, 50, and 100 mg/kg, i.g. administration) inhibited inflammatory cell infiltration and the secretion of pro-inflammatory factors by regulating the heat shock protein 72 (HSP72)-mediated c-Jun N-terminal kinases (JNK) pathway. In addition, Zhang et al. showed that BA (i.g. administration) dosages ranging from 40 to 160 mg/kg suppressed the expression of inflammatory factors in cigarette smoke (extract)-induced human bronchial epithelial cells and airway tissues through suppressing the inflammatory response, enhancing histone deacetylase 2 protein expression, and inhibiting the activation of NF-κB and its downstream target of PAI-1 (Zhang et al., 2021). Using the same model, a study by Zeng et al. indicated that BA (20, 40, and 80 mg/kg, i.g. administration) reduced cigarette smoke-induced inflammation in human type II pneumocytes and rats by suppressing IL-6, IL-8, and TNF-α via the inhibition of NF-κB activation (Lixuan et al., 2010).

According to recent advances, the mechanism of COPD mitigation by BA revolves around inhibition of the inflammatory response, mainly through tight regulation of the HSP72-mediated JNK pathway, HDAC2/NF-κB/PAI-1 pathway, and NF-κB pathway (Table 4).

PAH is a progressive and fatal disease with rapid onset and mortality in 7 people for every 100 person-years in Asian countries (Chung et al., 2015). Pulmonary endothelial cell dysfunction, pulmonary artery smooth muscle proliferation, and right ventricular hypertrophy are all involved in the development and formation of PAH (Xu et al., 2022b).

In a study by Luan et al. (2015), the rats with monocrotaline (MCT)-induced PAH were administered BA (i.g. administration) at a daily dose of 100 mg/kg. The results showed that BA downregulated the mRNA levels of TNF-α, IL-13, IL-6, and ET-1 in pulmonary tissues via blocking the activation of the NF-κB signaling pathway to attenuate PAH. Utilizing the same model, Xue et al. (2021) found that BA (20, 50, and 200 mg/kg, i.g. administration) profoundly reduced the mRNA and protein levels of inflammatory factors, excessive proliferation, migration of pulmonary artery smooth muscle cells, and vascular remodeling via the TNF‐α/bone morphogenetic protein receptor 2 (BMPR2) signaling pathway. In an MCT-induced rat model, BA (20, 100, and 200 mg/kg, i.p. injection) protected the rats from the severity of pulmonary vascular remodeling and cardiorespiratory injury via AKT/ERK/NF-κB signaling pathways and p-eNOS protein (Yan et al., 2019). In another PAH model, the relief of chronic hypoxia-induced PAH by BA (60 mg/kg, i.p. injection) through the AKT pathway was confirmed. In addition, the results of in vivo studies suggested that BA performed a therapeutic role via the attenuation of the adenosine A_2A receptor-induced SDF-1/CXCR4/PI3K/AKT pathway (Huang et al., 2017). Yan et al. (2016) demonstrated that 30 mg/kg of BA (i.p. injection) relieved the hypoxia-induced PAH model by mitigating pulmonary hypertension, pulmonary arteriole, and right ventricular remodeling and ameliorating hypoxic cor pulmonale by suppressing the p38 MAPK pathway and the expression of matrix metalloprotein (MMP)-9.

In conclusion, the suppression of inflammatory factors, the TNF‐α/BMPR2 pathway, the SDF-1/CXCR4/PI3K/AKT pathway, and the p38 MAPK pathway seem to be essential to the regulation of PAH by BA (Table 4).

PF is a chronic, progressive, and deadly lung disease primarily affecting middle-aged and older people (Sharif, 2017). It is generally accepted that the occurrence of PF is abnormal wound healing after repeated alveolar injury in genetically susceptible individuals, leading to the destruction of the lung parenchyma, and deposition of extracellular matrix in fibroblasts and alveolar epithelium. In addition, improperly activated alveolar epithelial cells (AECs) and fibroblasts cause the fibrotic response (King et al., 2011; Ptasinski et al., 2021).

A recent study indicated that 50 mg/kg BA (i.p. administration) effectively suppresses bleomycin (BLM)-induced PF in rats by decreasing the expression of hydroxyproline, TGF-β, collagen I, collagen III, and TNF-α, enhancing the function of anti-oxidative stress, and inhibiting apoptotic protein expression. Moreover, this study also showed that 80 μg/mL BA reverses BLM-induced fibroblast proliferation, regulating the expression of phosphoinositide 3-kinase (PI3K)/AKT and calcium/calmodulin-dependent kinase II in vitro (Zhao et al., 2020). Another in vivo study revealed that 120 mg/kg BA (i.p. administration) was found to block the TGF-β1-induced ERK1/2 signaling pathway via the adenosine A_2A receptor, leading to the alleviation of fibrosis caused by BLM (Huang et al., 2016). In recent years, the targeted omics approach for biomarkers discovery has been an effective approach for evaluating the effectiveness and mechanisms of BA (Ullah et al., 2022). In the study of Chang et al. (2021), the researchers administered 25–100 mg/kg BA to rat models with PF caused by BLM. The results demonstrated that BA ameliorated the levels of MDA and SOD to relieve oxidative stress. Furthermore, BA was identified to potentially alleviate PF by regulating four vital metabolic markers, including taurine, hypotaurine, glutathione, and glycerophospholipid metabolism.

TGF-β acts as a potent driver of PF progression by induction of epithelial-mesenchymal transition (EMT) (Qian et al., 2018). At doses of 2–50 μM, BA appears to be implicated in the radiation-induced EMT of AECs by inhibiting TGF-β and ERK/GSK signaling pathways mediated fibrosis (Lu et al., 2017). In terms of immunoregulatory mechanisms, i.p. injection of 100 mg/kg BA decreased PF in mouse models caused by silica by altering the Th17/Treg responses by lowering Th17 cells, activating Treg cells, and inhibiting IL-6 and IL-23 (Liu et al., 2015).

In summary, BA alleviates PF through a variety of mechanisms, including inhibition of the inflammatory response, oxidative stress, EMT, apoptosis and immune modulation (Table 5).

LC remains the primary cause of cancer deaths in the world (Wei et al., 2015; Saman et al., 2022). As the most common subtype of LC, non-small cell lung cancer (NSCLC) accounts for around 85% of LC cases (Fiero et al., 2019). Currently, surgery, chemotherapy, radiation, and targeted molecular treatment are the main treatment options for LC patients (South et al., 2020). However, the side effects and toxicity of these techniques have become limiting factors in the clinical treatment of lung cancer (Luan et al., 2015; Yamamoto et al., 2022).

Sui et al. (2020) found that 20 mg/kg of BA can trigger apoptosis and block cell cycle G1/S transition in carcinoma of the lung cells via the AKT/mechanistic target of rapamycin (mTOR) pathway. NSCLC is highly prone to invasion and metastasis, which are closely associated with the occurrence of EMT (Xia et al., 2014). In this regard, Chen reported that BA inhibited the EMT of NSCLC through the PDK1/AKT pathway (Chen et al., 2021). Recently, the importance of miRNAs in cancer progression has been reported (He et al., 2005; Lee and Dutta, 2007). Zhao et al. (2021) discovered that BA (60 μg/mL) restrained cell proliferation and invasion, promoted apoptosis, and arrested the G1/S phase via the miR-340-5p/NET1 axis, exerting anti-lung cancer effects. In an in vitro study, BA (20–80 μmol/L) inhibited cell viability, triggered apoptosis, and decreased cell migration and invasion by inhibiting the activation of the sirtuin 1 (SIRT1)/adenosine monophosphate-activated protein kinase (AMPK) signaling pathway (You et al., 2018). In several studies, overexpression of PDZ-binding kinase/T-LAK cell-originated protein kinase (PBK/TOPK) has been related to a poor prognosis and is a crucial target for anticancer drugs (Lei et al., 2013; Han et al., 2021). Diao et al. (2019) found that BA inhibited PBK/TOPK activities by directly binding with PBK/TOPK in vitro and in vivo.

Despite the successful efficacy of chemotherapy, there is growing concerned about chemotherapeutic agents developing resistance (Siddik, 2003; Apps et al., 2015; Pan et al., 2019). Considering this, researchers found that combining BA and DDP (cisplatin) inhibited tumor cells significantly more than DDP or BA alone in A549 and A549/DDP cells (DDP-resistant cells). The attenuation of the resistance of DDP was connected with downregulating MARK2 and p-Akt proteins (Xu et al., 2017b). In addition, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising target for overcoming cancer cell resistance (von Karstedt et al., 2017). BA (75 μM) can increase TRAIL-induced apoptosis and intracellular reactive oxygen species generation in cancer cells via activating p38 MAPK, enhancing the antitumor effectiveness of TRAIL (Zhang et al., 2017). The findings of the current investigations suggested that targeting MAPK is a significant pathway to reduce drug resistance in cancer. The AKT/mTOR, the PDK1/AKT, the SIRT1/AMPK pathways, and the regulation of active MMP-2, active MMP-9, vimentin, and E-cadherin are connected with the relief of LC (Table 5).