Encyclopedia
Please note this is a comparison between Version 2 by Yongqiang Wen and Version 1 by Yongqiang Wen.
黄芩苷是在黄芩属黄芩（Baicalin is one of the most abundant flavonoids found in the dried roots of Scutellaria baicalensis Georgi (SBG）的干根中发现的最丰富的类黄酮之一。虽然黄芩苷被证明具有抗炎、抗病毒、抗肿瘤、抗菌、抗惊厥、抗氧化、保肝和神经保护作用，但其低亲水性和亲脂性限制了生物利用度和药理功能。因此，对黄芩苷的生物利用度和药代动力学的深入研究，有助于为疾病治疗的应用研究奠定理论基础。) belonging to the genus Scutellaria. Baicalin is demonstrated to have anti-inflammatory, antiviral, antitumor, antibacterial, anticonvulsant, antioxidant, hepatoprotective, and neuroprotective effects.
- baicalin
- bioavailability
- drug interaction
- anti-inflammatory activity
- pharmacokinetics
1. 简介Introduction
黄芩属格奥尔基（Scutellaria baicalensis Georgi (SBG）属于黄芩属，主要生长在亚洲，包括中国、蒙古、日本、韩国和西伯利亚), belonging to the genus Scutellaria, grows mainly in Asia, including China, Mongolia, Japan, Korea, and Siberia [1]。在中国，. In China, SBG被认为是一种正宗的传统药材，广泛生长在海拔60-2000米的沙漠地区和阳光充足的草坡上 is regarded as an authentic traditional medicinal herb that grows widely in desert areas and sunny grassy slopes at altitudes of 60–2000 m [2]。它主要分布在中国北方省份，如河北，山东，山西和内蒙古. It is mainly found in northern provinces of China such as Hebei, Shandong, Shanxi, and Inner Mongolia [3]。根据. Based on SBG的生长季节和周期特征，Xu等人（2020）确定秋季收获并栽培三年的SBG质量最佳’s growing season and cycle characteristics, Xu et al. (2020) determined that the quality of SBG harvested in autumn and cultivated for three years was the best [2]。. The primary active constituents of SBG的主要活性成分包括黄芩苷、黄芩素、黄芩素、黄芩素、汉黄芩素和汉黄芩素 encompass baicalin, baicalein, wogonin, Han baicalin, and Han baicalein [4]。在临床实践领域，黄芩经常用于治疗炎症性疾病、流感、腹泻、黄疸、头痛和腹痛. In the field of clinical practice, Scutellaria baicalensis Georgi is frequently employed to treat inflammatory disorders, influenza, diarrhea, jaundice, headache, and abdominal pain [5]。. The broad-spectrum pharmacological effect of SBG在减少各种疾病方面的广谱药理作用主要是通过调节宿主免疫 in diminishing various kinds of diseases is mainly through regulating host immunity [6]。此外，据报道，. In addition, SBG具有增强免疫力、抗衰老、保护肝脏和抗骨质疏松症等作用 was reported to have effects such as enhancing immunity, anti-aging, protecting the liver, and anti-osteoporosis [7，,8]。.
类黄酮是一类广泛分布在各种蔬菜和水果中的化合物Flavonoids are a class of compounds that are widely distributed in various vegetables and fruits [9]。食用富含类黄酮的水果和蔬菜可以降低炎症性疾病的风险. The consumption of flavonoid-rich fruits and vegetables could reduce the risk of inflammatory diseases [9]。体内和体外分析证实，某些类黄酮对疾病有治疗作用。例如，黄芩苷（. In vivo and in vitro analyses have confirmed that certain flavonoids play a therapeutic effect on diseases. For example, baicalin (7-葡萄糖醛酸、5，6-二羟基黄酮、glucuronic acid, 5,6-dihydroxy-flavone, C21H18O11）近年来已广泛用于药物制剂的开发及某些疾病的治疗) has been widely used in recent years for the development of pharmaceutical formulations and the treatment of certain diseases [10]。黄芩苷，也称为黄芩素，是由黄芩素的. Baicalin, also known as begalin, is formed by combining the C7羟基与葡萄糖醛酸结合形成的 hydroxyl group of baicalein with glucuronic acid [10]（图 (Figure 1）。黄芩苷在正常情况下为淡黄色粉末). Baicalin is a light-yellow powder under normal conditions;味苦，不溶于醇类，溶于氯仿、硝基苯、二甲基亚砜等。 it is bitter in taste, insoluble in alcohols, and soluble in chloroform, nitrobenzene, dimethyl sulfoxide, etc. [11，,12，,13]. For the function of baicalin, studies have demonstrated that baicalin, containing most of the pharmacological function of SBG in modulating host immunity, plays a therapeutic role in neuroinflammation, enteritis, pneumonia, secondary inflammation, and other diseases in the clinic [14,15,16]. Inflammation is an immune response to invasiveness, which aims to clear away invasive pathogens and initiates tissue repair [17]. Although inflammation has this protective function, inappropriate inflammation can trigger damage to the body and induce the development of diseases [18]. Baicalin has been demonstrated to have anti-inflammatory and immunomodulatory functions, most of which are regulated by inhibiting the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway and nucleotide-binding oligomerization domain-like receptor pyrin domain protein 3 (NLRP3) inflammasome as well as suppressing pro-inflammatory factor expression, such as interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor α (TNF-α), cyclooxygenase 2 (COX-2), inducible nitric oxide synthase (iNOS), etc. [1,17].
图Figure 1.黄芩苷和黄芩素的化学结构.
Chemical structure of baicalin and baicalein.
In summary, the pharmacological effects of baicalin are closely related to inhibiting inflammatory reactions. In this paper, the basic physicochemical properties of baicalin and its molecular and immune regulatory mechanisms in the prevention and treatment of inflammatory diseases are reviewed.
2. 黄芩苷的生物利用度Bioavailability of Baicalin
在药理学研究中，生物利用度是指药物被体循环吸收的程度，反映胃肠道吸收的药物占口服量的百分比In pharmacological studies, bioavailability refers to the degree of drug absorbed into the systemic circulation, reflecting the percentage of drug absorbed by the gastrointestinal tract to the oral amount [19]。通常，吸收率为. Generally, the permeability coefficient of drugs with 1%的药物的渗透系数约为1.0× absorption is about 1.0 × 10−6厘米 cm/秒。药物吸收率在1%至100%之间，范围为1.0×s. The permeability coefficient of drugs absorbed between 1% and 100% ranges from 1.0 × 10−6至 to 0.1cm/s，吸收小于1%的药物和肽的渗透系数低于1.0× cm/s, and the permeability coefficient of drugs and peptides absorbed less than 1% is below 1.0 × 10−7厘米 cm/秒s [20]。.
其低水溶性Its low water solubility （(67.03 ± 1.60 μg/mL） 和渗透率 （) and permeability (0.037 × 10−6CM cm/M）确定黄芩苷不能通过被动扩散到宿主细胞脂质双层中，这导致黄芩苷的吸收不良和生物利用度低m) determine that baicalin cannot be transported by passive diffusion into the host cell lipid bilayer, which results in poor absorption and the low bioavailability of baicalin [21]。相反，黄芩素是一种黄芩苷，具有良好的渗透性和亲脂性，可被胃肠道很好地吸收. Contrarily, baicalein, a glycoside form of baicalin with good permeability and lipophilicity, can be well absorbed by the gastrointestinal tract [22]。研究表明，黄芩苷和黄芩素在黄芩苷的吸收过程中存在相互转化. Studies have shown that there is an interconversion between baicalin and baicalein during the absorption process of baicalin [22，,23，,24]。特别是，在动物中给药后，黄芩素可以通过源自肠道细菌的. In particular, after drug administration in animals, baicalin could be hydrolyzed to baicalein by β-葡糖醛酸酶水解为黄芩素，黄芩素可以通过体内循环的尿苷5′-二磷酸（UDP）葡糖苷酸转移酶（UGT）回收为黄芩苷glucuronidase derived from intestinal bacteria, and baicalein could be recovered to baicalin by uridine 5′-diphosphate (UDP) glucuronide transferase (UGT) circulating in vivo [25]。这种相互转化最大限度地发挥了黄芩苷的全部药效学功能. This mutual conversion maximizes the full pharmacodynamic functions of baicalin [25]。由于黄芩素比黄芩素吸收更好，黄芩素转化为黄芩素是黄芩素在肠道中吸收的关键步骤。此外，据报道，肠道微生物群与黄芩苷转化为黄芩素有关. Due to the better absorption of baicalein compared to baicalin, the conversion of baicalin to baicalein is a key step for the absorption of baicalin in the intestine. Furthermore, the intestinal microbiota was reported to be associated with the conversion of baicalin to baicalein [26]。例如，与常规大鼠相比，无菌大鼠对黄芩素的肠道吸收显着降低. For instance, the intestinal absorption of baicalin in germ-free rats was significantly reduced compared to conventional rats [26]，表明肠道菌群的存在有利于人体对黄芩素的吸收和利用。也就是说，只有一小部分黄芩苷作为原料被人体吸收，大部分被细菌水解成黄芩素，被肉体吸收。人血清白蛋白（, suggesting that the presence of intestinal flora was conducive to the body’s absorption and utilization of baicalin. In other words, only a small proportion of baicalin is absorbed by the physical body as a raw component, and most of it is hydrolyzed into baicalein by bacteria and absorbed by the physical body. Human serum albumin (HSA）是人体吸收和利用类黄酮（例如黄芩素、儿茶素、槲皮素等）的主要转运介质) is the main transport medium through which flavonoids (for example, baicalin, catechin, quercetin, etc.) are absorbed and utilized by the physical body [27]。黄芩苷在宿主中的转运速率和体积分布取决于黄芩苷与. The rate of transport and volume distribution of baicalin in the host depends on the binding degree of baicalin to HSA的结合程度 [28]。特别是，根据时间-浓度曲线下的面积，黄芩苷的相对吸收率约为. Especially, it was confirmed that, based on the area under the time–concentration curve, the relative absorption rate of baicalin was approximately 65% [29]。进一步的药代动力学分析表明，大鼠血清中黄芩苷的峰浓度低于黄芩素. Further pharmacokinetic analysis showed that the peak concentration of baicalin in rat serum was lower than that of baicalein [30]。为了提高黄芩苷的生物利用度，研究人员专注于黄芩苷新配方的开发，如固体纳米晶纳米乳液、固液纳米颗粒、脂质体制剂、磷脂复合物水凝胶等。. To improve the bioavailability of baicalin, investigators focused on the development of new formulations of baicalin, such as solid nanocrystal nano-emulsions, solid–liquid nanoparticles, liposome formulations, phospholipid complex hydrogels, etc. [31，,32，,33]。这些新技术和产品的应用开发旨在提高黄芩苷的溶解度和吸收性。. The application development of these new technologies and products aims to improve the solubility and absorption of baicalin.
3.黄芩苷的毒性 Toxicity of Baicalin
清除药物的安全剂量范围和作用时间对药物特性至关重要，因为这些直接威胁动物的安全。确定黄芩苷的安全剂量范围及其作用持续时间在不同的动物和细胞模型中具有至关重要的意义Clearing the safe dose range and action time of drugs is crucial for drug properties, as these directly threaten animals’ safety. The determination of baicalin’s safe dosage range and its duration of action holds paramount significance across diverse animal and cellular models [34]。为了研究黄芩苷是否参与肝胰岛素抵抗和糖异生活性的调节，一项体外研究表明，腹腔注射黄芩苷（. To investigate whether baicalin was involved in the regulation of hepatic insulin resistance and gluconeogenic activity, an ex in vivo study showed that intraperitoneal injection of baicalin (50mg / kg）不仅导致肥胖小鼠（C57BL / 6J）的体重减轻和胰岛素抵抗（胰岛素抵抗的稳态模型评估，HOMA-IR），而且还降低了葡萄糖耐受不良和高血糖症。在这项研究中，他们还表明黄芩苷对小鼠的肝脏没有毒性 mg/kg) not only resulted in body weight loss and insulin resistance (Homeostatic model assessment for insulin resistance, HOMA-IR) in obese mice (C57BL/6J) but also reduced glucose intolerance and hyperglycemia. In this study, they also showed that baicalin was not toxic to mice’s liver [35]。结果表明，黄芩苷通过抑制肥胖小鼠肝脏中. In line, baicalin was found to effectively alleviate the development of obesity by inhibiting the expression of p-p38丝裂原活化蛋白激酶（MAPK）、磷酸化环腺苷3′，5′-单磷酸（cAMP）反应结合蛋白（ mitogen-activated protein kinase (MAPK), phosphorylation cyclic adenosine 3′,5′-monophosphate (cAMP) response binding protein (p-CREB）、叉头转录因子叉头盒O1A（Foxo1）、过氧化物酶体增殖物激活受体γ共激活剂1α（), forkhead transcription factor forkhead box O1A (Foxo1), peroxisome proliferator-activated receptor γ coactivators 1α (PGC-1α）、磷酸烯醇丙酮酸羧激酶（PEPCK）和葡萄糖-6-磷酸酶（), phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G6Pase）的表达，可有效缓解肥胖的发展。 肝细胞) in the liver of obese mice and hepatocytes [35]。. Another study performed by Shi等人（2020）进行的另一项研究表明，对乙酰氨基酚（APAP）诱导的小鼠肝毒性在给予黄芩素后6 h、12 h和18 h有效降低，给予 et al. (2020) demonstrated that liver toxicity induced by acetaminophen (APAP) in mice was effectively reduced at 6 h, 12 h, and 18 h after baicalin administration, and the necrotic area of liver cells was significantly reduced in mice administrated with 40 mg/kg黄芩素的小鼠肝细胞坏死面积显着减少 baicalin [36]。这些结果表明，安全剂量的黄芩苷不仅对小鼠没有细胞毒性，而且可以降低脂毒性。与此一致，据报道，黄芩苷可有效抑制用. These results indicate that baicalin at a safe dose not only has no cytotoxicity in mice but can also reduce lipotoxicity. In line with this, baicalin was reported to effectively inhibit the occurrence of lipopolysaccharide (LPS)-induced hepatitis in chickens treated with 50、100和200mg/kg黄芩素治疗的鸡LPS诱导的肝炎的发生, 100, and 200 mg/kg baicalin [37]。一项针对非酒精性脂肪性肝病（. An oxidative stress study in non-alcoholic fatty liver disease (NAFLD）的氧化应激研究显示，根据CCK-0测定法测定，浓度范围为01.100nM至2μM的黄芩苷在24小时和48小时对HepG8细胞没有任何细胞毒性作用), revealed that baicalin at concentrations ranging from 0.01 nM to 100 μM did not exhibit any cytotoxic effects on HepG2 cells at 24 h and 48 h, as determined by the cholecystokinin (CCK)-8 assay [38]。.
黄芩苷对内质网（Baicalin has a significant inhibitory effect on endoplasmic reticulum (ER）应激有显著的抑制作用。例如，发现黄芩苷（12.5μM和25μM）可有效抑制ER应激标志物磷酸化肌醇需要酶1α（) stress. For instance, baicalin (12.5 μM and 25 μM) was found to effectively inhibit the expression of ER stress marker phosphorylated inositol-requiring enzyme 1α (p-IRE1α）和反向棕榈酸（PA）诱导的细胞凋亡和活性氧（ROS）的表达) and reverse palmitic acid (PA)-induced apoptosis and reactive oxygen species (ROS) production [38]。主要机制可能是黄芩苷通过抑制. The main mechanism might be because baicalin reduced PA-induced cytotoxicity by inhibiting ER应激和硫氧还蛋白相互作用蛋白（Txnip） stress and the activation of thioredoxin-interacting protein (Txnip)/NLRP12炎症小体的活化来降低PA诱导的细胞毒性 inflammasome [39]。这些研究为黄芩苷的临床应用提供了新的理论依据，进一步完善了黄芩苷的细胞毒性研究。从毒理学角度来看，黄芩苷比黄芩苷毒性更大. These studies provide a new theoretical basis for the clinical application of baicalin and further improve the cytotoxicity study of baicalin. From a toxicological point of view, baicalin is more toxic than baicalein [39]。有趣的是，肠道微生物可能对黄芩苷引起的肝毒性有保护作用. Interestingly, intestinal microorganisms might have a protective effect on hepatotoxicity caused by baicalin [39]。为了支持这一点，黄芩素与粪便酶孵育以剂量依赖性方式降低了对肝癌细胞（. To support this, incubation of baicalin with fecal enzymes diminished the cytotoxicity to hepatocellular carcinoma (HepG2）细胞的细胞毒性，这表明人粪便酶从黄芩苷转化为黄芩素可防止黄芩苷诱导的对HepG2细胞的细胞毒性) cells in a dose-dependent manner, suggesting that the conversion from baicalin to baicalein by human fecal enzymes protects against baicalin-induced cytotoxicity to HepG2 cells [40，,41]。这些研究为黄芩苷的临床应用铺平了新的理论基础，进一步完善了黄芩苷的细胞毒性研究。. These studies pave a new theoretical basis for the clinical application of baicalin and further improve the cytotoxicity studies of baicalin.
4. 黄芩苷的治疗效果
4.1. 黄芩苷对肝炎的影响
Therapeutic Effects of Baicalin
4.1. Effect of Baicalin on Hepatitis
TNF-α是一种重要的细胞因子，参与肥胖、胰岛素抵抗、高脂血症和 is an important cytokine involved in metabolic diseases such as obesity, insulin resistance, hyperlipidemia, and NAFLD等代谢性疾病 [59]。肝损伤过程中. The production of TNF-α的产生导致IL-1β和IL-6的释放，IL 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-60β和IL-like receptor 4介导炎症反应[4]。肝毒性可通过肝细胞中脂质过度积累来激活 (TLR614) through excessive lipid accumulation in hepatocytes [461]。. Upon activation of TLR88激活后，大量的MyD62聚集了NF-κB和MAPK4, a large amount of MyD88 aggregates NF-κB and MAPK [162]。. The aggregations of NF-κB和MAPK的聚集促进TNF-α、IL-6 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等促炎因子的表达和促炎细胞的浸润，进一步加重肝损伤-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]。4.2. Role of Baicalin in Rheumatoid Arthritis
.
4.2. Role of Baicalin in Rheumatoid Arthritis
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).4.3. Anti-Inflammatory Role of Baicalin in Obesity and Type 2 Diabetes
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.
4.3. Anti-Inflammatory Role of Baicalin in Obesity and Type 2 Diabetes
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].4.4. 黄芩苷在呼吸系统相关炎症中的作用
在过去几年中，呼吸系统疾病变得更加普遍，对人类健康和安全构成重大威胁。常见的呼吸系统疾病包括哮喘、
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.
4.4. Role of Baicalin in Respiratory-Related Inflammation
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和), and pulmonary arterial hypertension (PAH) [91]。哮喘被认为是由持续性气道炎症引起的可逆性气道阻塞，由空气污染物和遗传易感因素引起. Asthma, which is recognized as reversible airway obstruction induced by persistent airway inflammation, is caused by airborne pollutants and genetic predisposition factors [92]。. IPF或肺纤维化（PF）是以成纤维细胞增殖和胶原沉积在肺组织结构中为特征的，是一种由肺炎、过度吸烟和/或其他因素引起的慢性间质性肺疾病，可导致结构破坏和呼吸衰竭 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]。4.5. 黄芩苷在炎症性肠病中的治疗作用
. 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].
4.5. Therapeutical Effects of Baicalin in Inflammatory Bowel Disease
Inflammatory bowel disease (IBD是一种慢性免疫性疾病，其特征是反复发作腹痛、腹泻和化脓性粪便) is a chronic immune disorder characterized by recurrent episodes of abdominal pain, diarrhea, and purulent stool [100]。. IBD主要包括克罗恩病（CD）和溃疡性结肠炎（UC） mainly includes Crohn’s disease (CD) and ulcerative colitis (UC) [101，101,102，103,103]。黄芩苷通过抑制氧化应激、免疫调节和抗炎特性在. Baicalin plays a protective role in IBD中起保护作用 by inhibiting oxidative stress, immune regulation, and anti-inflammatory properties [104]。为了支持这一点，发现黄芩苷通过调节肠上皮细胞中的自噬和. To support this, baicalin was found to affect inflammatory processes by regulating autophagy and the NF-κB信号通路来影响炎症过程，从而改善细胞旁通透性 signaling pathway in intestinal epithelial cells, thereby improving paracellular permeability [105]。与此一致，据报道，在葡聚糖硫酸钠（DSS）诱导的溃疡性结肠炎模型中，黄芩苷通过调节. In line with this, baicalin was reported to attenuate the inflammatory response by modulating the polarization of M1巨噬细胞向M2表型的极化来减弱炎症反应 macrophages towards the M2 phenotype in a dextran sodium sulfate (DSS)-induced ulcerative colitis model [101]。同样，黄芩苷以剂量依赖性方式下调了黄芩苷在1，2，9-三硝基苯磺酸（TNB. S）诱导的UC大鼠结肠中IL-2β、TNF-α、凋亡基因Bcl-4和半胱天冬酶-6的表达imilarly, 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]。黄芩苷在炎症中的治疗主要通过抑制抑制剂. The treatment of baicalin in inflammation is mainly mediated by suppressing the inhibitor-κB（IKB）激酶复合物（IKK） (IKB) kinase complex (IKK)/IKB/NF-κB信号通路介导 signaling pathway [106]。特别是，在TNBS诱导的UC大鼠中给予黄芩苷（. Especially, the administration of baicalin (5-20mg/kg）下调了TNF-α和IL-6的表达，并抑制了–20 mg/kg) in TNBS-induced UC rats downregulated the expression of TNF-α and IL-6 and inhibited the TLR4/NF-κB信号通路，从而缓解了UC signaling pathway, thereby alleviating UC [107]。据报道，黄芩苷（. Consistently, baicalin (30-120mg/kg）通过促进超氧化物歧化酶（SOD）、过氧化氢酶和谷胱甘肽过氧化物酶（–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）等抗氧化酶的活性，以及降低丙二醛（MDA）的含量，对TNBS诱导的UC具有治疗作用) and by reducing the content of malondialdehyde (MDA) [108]。该研究进一步发现，黄芩苷（. This study further found that baicalin (100mg/kg）可降低血清中IL-6、IL-1β和IL-17的产生，并抑制高温高湿下UC模型中SOD、 mg/kg) reduced the production of IL-6, IL-1β, and IL-17 in serum and inhibited the activation of SOD, GSH-PX和MDA的活化, and MDA in the UC model under high temperature and humidity [108]。这些结果表明，黄芩苷的抗炎作用归因于抑制. These results suggest that the anti-inflammatory effect of baicalin is attributed to inhibiting the activation of the NF-κB和MAPK信号通路的激活。4.6. 黄芩苷在心血管疾病中的抗炎作用
炎症是与心肌纤维化、 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].
