The Organ Protective Effects and Mechanisms of Schisandrin B

Schisandrin B is one of the main active ingredients in Schisandra chinensis, possessing a bibenzyl octahydronaphthalene structure, as shown in the following structural formula. The organ protective effect of schisandrin B was first discovered in liver research, where it showed significant efficacy in treating hepatitis through antioxidant mechanisms. Subsequent studies found that schisandrin B also has the ability to resist liver and kidney toxicity induced by exogenous substances and alleviate fibrosis in the liver, kidneys, and lungs through antioxidant and anti-fibrotic effects. In the cardiovascular system, schisandrin B can protect the myocardium from ischemia-reperfusion injury, alleviate chronic myocardial damage caused by chemotherapy drugs, enhance cognitive activities, and have sedative and hypnotic effects. Additionally, schisandrin B can relax pulmonary vascular smooth muscle, antagonize primary pulmonary hypertension, inhibit the proliferation and migration of airway smooth muscle cells, and reduce airway hyperreactivity, thus relieving asthma symptoms.

The multi-organ protective effects of schisandrin B work through different pathways, with mechanisms including antioxidant, anti-inflammatory, anti-fibrotic, promotion of heat shock response, regulation of lipid metabolism, and inhibition of apoptosis.

1. Antioxidant Effect

Schisandrin B can participate in regulating the dual antioxidant defense system, maintaining the redox balance of the body, and resisting oxidative stress damage, thus protecting the body. Schisandrin B is the best monomeric active ingredient of Schisandra chinensis to exert antioxidant effects. It can reduce the production of ROS, increase the activity of enzymatic antioxidant systems such as glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD), thereby inhibiting the occurrence of lipid peroxidation, maintaining the integrity of mitochondrial function and structure, and producing extensive protective effects on body tissues. Experiments have found that its antioxidant effect involves multiple signaling pathways, including Nrf2, AMPK, ATR, P53, TGF-β1/Smads, etc. In addition, schisandrin B also has the effect of regulating the expression of antioxidant-related genes and enhancing the activity of cytokines.

2.Anti-Inflammatory Effect

Recent studies have shown that schisandrin B possesses anti-inflammatory properties and plays a role in the treatment of various tissue and organ diseases. Its mechanisms mainly include regulating inflammation-related signaling pathways and inhibiting the differentiation of immune cells and the release of inflammatory factors. Studies have demonstrated that schisandrin B can regulate various aspects of the NF-κB pathway to alleviate inflammatory responses. Schisandrin B (4, 8 mg/L) significantly downregulates the levels of proinflammatory factors NO, TNF-α, IL-2, and IL-6, while inhibiting the Toll-like receptor 4 (TLR4)-dependent MyD88/IKK/NF-κB inflammatory signaling pathway in microglial cells, thus reducing neuroinflammation mediated by microglial cells. In a model of colitis induced by trinitrobenzene sulfonic acid (TNBS) in rats, schisandrin B was found to alleviate ulcerative colitis in rats by regulating the activity of transcription factors NF-κB and IκB, reducing the activity index of ulcerative colitis.

Oxidation-reduction is an essential component of the inflammatory response, where reactive oxygen species have potential immunomodulatory effects. Studies have found that in THP-1 cells, schisandrin B (10, 20 mg/L) can inhibit the release of inflammatory factors and immune cell differentiation by suppressing the secretion of IL-6 and IL-12 by dendritic cells. In the research on the treatment of Angiostrongylus cantonensis infection, it was discovered that after treatment with albendazole combined with 20 mg/kg of schisandrin B, the immune response of mice shifted from Th2 to Th1, thus reducing inflammation and alleviating the adverse effects of combined use of corticosteroids on brain tissue.

3.Anti-Fibrotic Effect

Fibrosis is a pathological change in the development of various chronic diseases. The progression of fibrosis can alter organ structure and impair organ function, leading to various incurable and irreversible diseases. Schisandrin B exerts its anti-fibrotic effect primarily by inhibiting the TGF-β1/Smad signaling pathway. In studies on pulmonary fibrosis, it was found that 100 mg/kg of schisandrin B can antagonize bleomycin-induced pulmonary fibrosis in male Kunming mice by inhibiting the TGF-β1/Smad2 pathway and overexpression of NOX4. Additionally, schisandrin B can inhibit the activation of Smad2/3 and mitogen-activated protein kinase pathways stimulated by TGF-β1. In vivo studies have revealed that schisandrin B can inhibit the progression of epidural fibrosis in mice after laminectomy by suppressing cell proliferation and extracellular matrix production in scar tissue.

4.Promotion of Heat Shock Response

Heat shock proteins (HSPs) are expressed under stressful conditions such as excessive heat, ischemia, hypoxia, and mechanical injury. They enhance cells' tolerance to adverse stimuli, serving as a type of molecular chaperone protein that is widely distributed in various cells and participates in cell growth, development, and death. HSPs possess the function of reducing cell apoptosis and promoting cell repair. In mouse models of liver injury and myocardial ischemia-reperfusion induced by CCl4, HgCl2, and acetaminophen, it was discovered that 0.8 g/kg of schisandrin B can upregulate heat shock proteins 25/70 (Hsp25/70) to enhance mitochondrial glutathione redox reactions and maintain this effect for 72 hours. On the other hand, it upregulates the expression of heat shock proteins 27/70 (Hsp27/70) to exert protective effects on the liver and myocardium.

5.Regulation of Lipid Metabolism

Schisandrin B can inhibit fatty acid synthase activity and upregulate the expression of fat differentiation-related proteins, sterol regulatory element-binding protein 1, and TNF-α, suppressing palmitic acid expression, steatosis, and liver fibrosis. Additionally, schisandrin B activates hormone-sensitive lipase to accelerate lipolysis in 3T3-L1 adipocytes and diet-induced obese C57BL/6 mouse subcutaneous adipocytes. It also enhances the expression of fatty acid oxidation genes in these adipocytes and reduces lipid levels. Schisandrin B can reduce the size of subcutaneous adipocytes and subcutaneous tissue mass in mice, indicating its potential therapeutic effect for weight loss. However, studies have shown that long-term low doses and rapid high doses of schisandrin B in the treatment of non-alcoholic fatty liver disease may lead to increased lipid levels in the serum and liver of mice.

6.Inhibition of Cell Apoptosis

Oxidative stress and excessive inflammatory response are also causes of cell apoptosis. Schisandrin B can reduce cell apoptosis by lowering oxidative stress and inflammatory response. In a model of ischemia-reperfusion injury established by ligating the left anterior descending coronary artery of SD male rats for 40 minutes and reperfusion for 1 hour, it was found that schisandrin B (20, 40, 80 mg/kg) inhibited endoplasmic reticulum stress-induced cardiomyocyte apoptosis by suppressing the transcription factor 6, PERK, and PI3K/AKT signaling pathways. In studies on cyclosporine A [sc, 30 mg/(kg·d), 6 weeks] induced renal injury in SD rats and 10 μmol/L cisplatin-induced HK-2 cell injury, 20 mg/kg of schisandrin B exerted an anti-renal tissue injury effect by inhibiting the release of lactate dehydrogenase and apoptosis in renal tubular epithelial cells.

Schisandrin B exhibits protective effects on the liver, kidneys, lungs, and cardiovascular system, and its multi-organ protective effect is the result of a combined action through different pathways.

① Protection for the Liver: Schisandrin B is clinically recognized as a hepatoprotective agent with extensive effects. Non-alcoholic fatty liver disease (NAFLD) comprises a series of liver conditions including non-alcoholic steatohepatitis, hepatic steatosis, cirrhosis, and hepatocellular carcinoma. The pathogenesis of NAFLD involves oxidative stress, endoplasmic reticulum (ER) stress, abnormal accumulation of free fatty acids, and a proinflammatory state in the liver. Numerous studies have demonstrated that schisandrin B possesses anti-inflammatory, anti-oxidative, anti-fibrotic, lipid-regulating, and anti-ER stress effects in the liver. In traditional Chinese medicine, schisandrin B has been used in the treatment of hepatitis. Experiments have shown that schisandrin B can reduce collagen deposition, delay the progression of CCL4-induced liver fibrosis in rats, and effectively improve liver function. Its mechanisms involve redox reactions, endoplasmic reticulum stress, and apoptosis. Pretreatment with schisandrin B significantly inhibits CCL4-induced plasma alanine aminotransferase (ALT) activity and reduces plasma SDH activity in CCL4-poisoned mice, indicating its hepatoprotective effect. This is related to the enhancement of hepatic mitochondrial glutathione redox status and mitochondrial glutathione reductase activity. Further research has found that the antioxidant mechanism of schisandrin B in the liver is by inhibiting the TGF-β/Smad signaling pathway to inhibit hepatic stellate cell activation and activating the Nrf2-mediated antioxidant signaling pathway.

② Protection for the Kidneys: Schisandrin B has certain therapeutic effects on nephrotic syndrome and diabetic nephropathy, and can inhibit renal tubular interstitial fibrosis in end-stage renal disease. Inflammation and oxidative stress are key pathogenic factors in nephrotic syndrome and diabetic nephropathy. Studies have shown that schisandrin B can improve renal function in adriamycin-induced nephrotic syndrome rat models, reduce serum MDA and NO levels, enhance SOD activity, and induce the expression levels of glutamate-cysteine ligase catalytic subunit, NQO1 quinone NADH dehydrogenase 1, and HO-1 proteins. Its mechanism of action is related to the activation of the Nrf2/ARE signaling pathway. Research has shown that diabetic mouse models fed with schisandrin B can significantly reduce renal injury caused by hyperglycemia, significantly inhibiting renal cell apoptosis and fibrosis.

③ Protection for the Lungs: In pulmonary fibrosis, there is excessive accumulation of extracellular matrix and overproliferation of fibroblasts, leading to inflammatory injury and tissue destruction. Oxidative stress is involved in the process of pulmonary fibrosis, and increased ROS levels disrupt DNA structure, causing lipid and protein denaturation. Experiments have demonstrated that schisandrin B can reduce lung collagen accumulation after 2 weeks of bleomycin administration and reduce histological and biochemical parameters. When schisandrin B is used together with glycyrrhizic acid, it can reduce inflammatory reactions, decrease Bml accumulation in lung collagen, and exert antioxidant effects. Oxidative stress imbalance participates in the pathogenesis of asthma, and ROS may cause damage to the body through the NF-κB pathway, leading to protein and lipid peroxidation. Schisandrin B can inhibit alveolar epithelial cell proliferation in these models, inhibit inflammatory factor expression, and have good anti-inflammatory effects. Its mechanism is by regulating the NF-κB signaling pathway and downregulating the expression of IL-8, COX-2, and other inflammation-related factors, thereby improving the inflammatory microenvironment.

④ Protection for the Cardiovascular System: The occurrence of cardiovascular diseases is closely related to oxidative stress, which leads to mitochondrial dysfunction and apoptosis, affects endothelial cell function, and promotes the development of endothelial-to-mesenchymal transition (EndMT), ultimately leading to fibrosis and vascular remodeling. Schisandrin B can inhibit ROS production, inhibit vascular EndMT and fibrosis, and play a positive role in preventing the progression of cardiovascular diseases. In a mouse model of myocardial hypertrophy induced by aortic banding, schisandrin B was found to improve cardiac function, reduce myocardial hypertrophy and fibrosis. Further research has shown that schisandrin B inhibits myocardial hypertrophy and fibrosis induced by angiotensin II by inhibiting the MAPK signaling pathway in cardiomyocytes. At the same time, schisandrin B can inhibit apoptosis and mitochondrial membrane potential (MMP) depolarization in rat aortic endothelial cells (RAEC), inhibit angiotensin II-induced ROS production, and induce antioxidant responses in RAEC. Its antioxidant activity involves the regulation of the Keap1-Nrf2 pathway, and Keap1 is its target in this process.

Schisandrin B is a typical natural small molecule compound with enormous clinical application potential in terms of its protective effect on organs in inflammatory reactions and tumor treatment. Schisandrin B can alleviate myocardial injury caused by anthracycline chemotherapeutic drugs, opening up a new approach to preventing the cardiac toxicity of chemotherapy drugs. Its anti-inflammatory effect is expected to replace corticosteroid hormones in the combined treatment of parasites. With the development of research methods and technologies for small molecule drugs, the pharmacological effects and mechanisms of Schisandrin B have been further clarified, which will provide strong theoretical basis and broader clinical application scenarios for its evidence-based medical effects.

References

[1] Ma Junchi, Zhao Jintong, Gao Shiyong, Jia Shaohua, Zhang Xiujuan. Research Progress on the Purification Process and Pharmacological Effects of Schisandrin B [J]. Modern Chinese Medicine, 2022, 24(03): 533-541. DOI: 10.13313/j.issn.1673-4890.20201130004.

[2] Zhang Lingling, Wang Piao, Fang Yanhua, Wang Ruoyu, Liang Shanshan. Research Progress on the Molecular Mechanism of Organ Protective Effects of Schisandrin B [J]. Modern Drugs and Clinical, 2022, 37(04): 896-900.

[3] Wang Ruiqi, Bai Jie. Research Progress on the Antioxidant Stress Injury Effect and Mechanism of Schisandrin B [J]. Hebei Medical Journal, 2022, 44(05): 767-771.

About the Author

Xiaomichong, a pharmaceutical quality researcher, has been committed to pharmaceutical quality research and drug analysis method validation for a long time. Currently employed by a large domestic pharmaceutical research and development company, she is engaged in drug inspection and analysis as well as method validation.