The safety of traditional Chinese medicine(TCM) has always been taken very seriously, and rich and valuable theories and experiences have been developed to ensure the safe and precise use of TCM in clinical practices. In recent years, the cognitive theory of toxicity of TCM, has undergone a profound change. TCM is characterized by the existence of intrinsic toxicity, idiosyncratic toxicity, and indirect toxicity related to organic factors. Therefore, the traditional theories and experiences of TCM, which focus on the prevention and control of intrinsic toxicity, fail to be used for the development of risk prevention and control countermeasures for newly discovered TCM with idiosyncratic toxicity and indirect toxicity. Accordingly, based on the toxicity classification and mechanism characteristics of TCM, this paper proposed a new strategy and method in TCM compatibility for detoxification based on componenttarget-effect interaction. The strategy based on component-target-effect interaction is to carry out TCM compatibility for detoxification by blocking the occurrence of drug-mediated damage and promoting damage repair through component interactions, target interactions,and/or effect interactions. Based on this theory, the paper established a strategy for TCM compatibility that aligned with the cognitive theory of toxicity of TCM, so as to achieve safe and precise use of TCM in clinical practices. The strategy based on component-targeteffect interaction has been exemplarily applied to the development of countermeasures to reduce the toxicity of TCM, including Polygonum Multiflorum, Epimedii Folium, and Psoraleae Fructus, and a new mechanism of Glycyrrhizae Radix et Rhizoma to " harmonize various medicines and detoxify myriad poisons" was illustrated, providing a scientific basis for the safe and precise use of TCM in clinical practice. This paper explained the scientific connotation, application forms, and application examples of componenttarget-effect interaction, aiming to provide a theoretical and methodological basis for guaranteeing the precise use of TCM in clinical practice and innovate the theories and methods of TCM compatibility for detoxification.
Drugs, Chinese Herbal/chemistry* ; Humans ; Medicine, Chinese Traditional/methods* ; Animals ; Drug-Related Side Effects and Adverse Reactions/prevention & control*

This study aims to explore the effects and mechanisms of the traditional Chinese medicine Cordyceps sinensis(CS) in ameliorating heart aging and injury in mice based on animal experiments and network pharmacology. A mouse model of heart aging was established by continuously subcutaneous injection of D-galactose(D-gal). Thirty mice were randomly assigned into a normal group, a model group, a low-dose CS(CS-L) group, a high-dose CS(CS-H) group, and a vitamin E(VE) group. Mice in these groups were administrated with normal saline, different doses of CS suspension, or VE suspension via gavage daily. After 60 days of treatment with D-gal and various drugs, all mice were euthanized, and blood and heart tissue samples were collected for determination of the indicators related to heart aging and injury in mice. Experimental results showed that both high and low doses of CS and VE ameliorated the aging phenotype, improved the heart index and myocardial enzyme spectrum, restored the expression levels of proteins associated with cell cycle arrest and senescence-associated secretory phenotypes(SASP), and alleviated the fibrosis and histopathological changes of the heart tissue in model mice. From the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP),259 active ingredients of CS were retrieved. From Gene Cards and OMIM, 2 568 targets related to heart aging were identified, and 133common targets shared by CS and heart aging were obtained. The Gene Ontology(GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes( KEGG) pathway enrichment revealed that the pathways related to heart aging involved oxidative stress,apoptosis, inflammation-related signaling pathways, etc. The animal experiment results showed that both high and low doses of CS and VE ameliorated oxidative stress and apoptosis in the heart tissue to varying degrees in model mice. Additionally, CS-H and VE activated the nuclear factor E2-related factor 2(Nrf2)/heme oxygenase-1(HO-1) pathway and inhibited the expression of key proteins in the nuclear factor-κB(NF-κB) pathway in the heart tissue of model mice. In conclusion, this study demonstrated based on network pharmacology and animal experiments that CS may alleviate heart aging and injury in aging mice by reducing oxidative stress,apoptosis, and inflammation in the heart via the Nrf2/HO-1/NF-κB pathway.
Animals ; Cordyceps/chemistry* ; Mice ; NF-E2-Related Factor 2/genetics* ; NF-kappa B/genetics* ; Aging/genetics* ; Male ; Signal Transduction/drug effects* ; Network Pharmacology ; Drugs, Chinese Herbal/pharmacology* ; Heme Oxygenase-1/genetics* ; Heart/drug effects* ; Humans ; Myocardium/metabolism* ; Membrane Proteins/genetics*

To investigate the effects and mechanisms of Yougui Pills(YGP) on oxidative damage induced by hydrogen peroxide(H_2O_2) in human ovarian granulosa cells(KGN). The components in serum with low-and high-doses of YGP were analyzed and compared through ultra-high performance liquid chromatography-quadrupole electrostatic field orbitrap mass spectrometry(UHPLC-QEMS), and selected the serum containing YGP high-dose group to follow-up experiments. To stimulated KGN with 200 μmol·L~(-1) H_2O_2to establish an oxidative damage model, which was divided into normal group, model group, low-, medium-, and high-dose of YGP groups, and the efficacy was further verified on the basis of silencing or overexpressing serine protease inhibitor(Serpina3k), further validating the efficacy based on the silencing or overexpression of Serpina3k. TUNEL staining was used to detect cell apoptosis,enzyme-linked immunosorbent assay(ELISA) was employed to measure the secretion levels of estradiol(E_2) and 17β-E_2 in KGN, and Western blot was utilized to assess the expression of Serpina3k and proteins related to the Keap1/Nrf2 signaling pathway. The results show that compared to the model group, each dose group of YGP not only significantly reduces granulocyte apoptosis and upregulates the secretion levels of E_2 and 17β-E_2, but also significantly upregulates Serpina3k and Nrf2 pathway. Further research has found that overexpression of Serpina3k not only enhances the therapeutic effect of YGP but also increases the expression of Nrf2 and inhibits the expression of Keap1. Conversely, interfering with Serpina3k partially reverses the therapeutic effect of YGP, while also partially. The results indicate that the mechanism by which YGP improves oxidative stress in KGN may be related to its upregulation of Serpina3k expression, which affects the conduction of the Keap1/Nrf2 signaling pathway. This study reveals the mechanism by which YGP protects granular cells, providing a certain theoretical basis for its clinical application.
NF-E2-Related Factor 2/genetics* ; Kelch-Like ECH-Associated Protein 1/genetics* ; Humans ; Female ; Signal Transduction/drug effects* ; Oxidative Stress/drug effects* ; Granulosa Cells/cytology* ; Drugs, Chinese Herbal/pharmacology* ; Apoptosis/drug effects* ; Serpins/genetics*

This study aimed to compare the ameliorative effects of Lycii Fructus and Chrysanthemi Flos at different ratios on retinal damage in mice and to elucidate the underlying mechanisms. A retinal injury model was established by intraperitoneal injection of sodium iodate(NaIO_3) solution. The mice were divided into the following groups: blank group, model group, positive drug(AREDS 2) group, low-and high-dose groups of Lycii Fructus and Chrysanthemi Flos at 1∶1, low-and high-dose groups at 3∶1, and low-and high-dose groups at 1∶3. Administration was carried out 15 days after modeling. The visual acuity of the mice was assessed using the black-and-white box test. The fundus was observed using an optical coherence tomography device, and retinal thickness was measured. HE staining was used to observe the morphology and pathological changes of the retina. The levels of oxidative factors in serum and ocular tissues were measured using assay kits. The levels of inflammatory factors in serum and ocular tissues were detected by enzyme-linked immunosorbent assay(ELISA), and the expression of Nrf2, HO-1, and NF-κB proteins in ocular tissues was analyzed by Western blot. The results showed that after administration of Lycii Fructus and Chrysanthemi Flos at different ratios, the model group showed improved retinal thinning and disordered arrangement of retinal layers, elevated content of SOD and GSH in the serum and ocular tissues, and reduced levels of MDA, TNF-α, IL-1β, and IL-6. Lycii Fructus and Chrysanthemi Flos at 1∶1 and 1∶3 showed better improvement effects. The combination significantly upregulated the expression levels of Nrf2 and HO-1 and downregulated the expression of NF-κB p65. These results indicate that Lycii Fructus and Chrysanthemi Flos at different ratios can improve retinal damage, reduce oxidative stress, and alleviate inflammation in both the body and ocular tissues of mice. The mechanism may be related to the regulation of the Nrf2/HO-1 and NF-κB signaling pathways in ocular tissues. These findings provide a theoretical basis for the clinical application of Lycii Fructus and Chrysanthemi Flos in the treatment of dry age-related macular degeneration.
Animals ; Mice ; Retina/injuries* ; Male ; Lycium/chemistry* ; Drugs, Chinese Herbal/administration & dosage* ; Chrysanthemum/chemistry* ; NF-kappa B/genetics* ; Humans ; Retinal Diseases/metabolism* ; NF-E2-Related Factor 2/metabolism* ; Oxidative Stress/drug effects* ; Flowers/chemistry* ; Heme Oxygenase-1/genetics*

Because of the unclear active substances, metabolic pathways, and targets of new drugs of traditional Chinese medicine(TCM), non-clinical safety evaluation often fails to accurately locate the target organs and tissue exposed to medicinal toxicity. The human use experience(HUE) contains important safety information of TCM, while the clinical safety data in the past HUE are few and have not been effectively applied. Standardized prospective HUE studies should be carried out to collect the clinical safety data, in which appropriate physical and chemical indicators(including blood, urine, and stool routine), liver biochemical indicators, kidney biochemical indicators, and cardiovascular biochemical indicators should be selected for safety evaluation, and the detection time point and sample size should be rationally designed. Importance should be attached to the observation of symptoms and signs of adverse events/reactions in patients as well as the safety information of special groups such as the elderly, children, and pregnant women. The adverse events of TCM should be observed, judged, and treated according to the theory and the diagnosis and treatment mode of TCM. The clinical safety information about the HUE should be comprehensively collected for new drugs of TCM to make up for the lack of extrapolation of toxicological test results to humans. The unique advantages of clinical origin of new drugs of TCM should be given full play for cross-reference of the results of toxicological research and the conclusions of HUE safety evaluation. In addition, benefit-risk assessment should be conducted based on HUE, and a panoramic safety evaluation system characterized by macro and micro combination and in line with the characteristics of TCM should be established to improve the success rate in the research and development of new drugs of TCM.
Humans ; Drugs, Chinese Herbal/adverse effects* ; Medicine, Chinese Traditional/adverse effects* ; Drug-Related Side Effects and Adverse Reactions ; Female

The purpose of this study was to clarify the effect of Huotan Jiedu Tongluo Decoction on atherosclerosis(AS) injury in ApoE~(-/-) mice by regulating the ferroptosis pathway. Seventy-five ApoE~(-/-) mice were randomly divided into model group, low-, medium-, and high-dose of Huotan Jiedu Tongluo Decoction groups, and evolocumab group(n=15), and 15 C57BL/6J mice were selected as the blank group. Mice in the blank group were fed with a normal diet, and those in the other groups were fed with a high-fat diet to induce AS. From the 9th week, mice in Huotan Jiedu Tongluo Decoction groups were administrated with Huotan Jiedu Tongluo Decoction at corresponding doses by gavage, and those in the blank group and the model group were given an equal volume of distilled water. Mice in the evolocumab group were treated with evolocumab 18.2 mg·kg~(-1 )by subcutaneous injection every 2 weeks. After 8 weeks of continuous intervention, oil red O staining and hematoxylin-eosin(HE) staining were employed to observe the lipid deposition and plaque formation in the aortic root. Masson staining was used to evaluate the collagen content in the aortic root. The serum levels of total cholesterol(TC), triglycerides(TG), high-density lipoprotein cholesterol(HDL-C), and low-density lipoprotein cholesterol(LDL-C) were determined by biochemical kits. The levels of Fe~(2+), superoxide dismutase(SOD), malondialdehyde(MDA), and glutathione(GSH) in the aorta were measured by colorimetry. The protein and mRNA levels of nuclear factor erythroid 2-related factor 2(Nrf2), glutathione peroxidase 4(GPX4), solute carrier family 7 member 11(SLC7A11), and acyl-CoA synthetase long chain family member 4(ACSL4) in the aorta were detected by Western blot and RT-qPCR, respectively. The expression of Nrf2, GPX4, and SLC7A11 was localized by immunofluorescence. The results showed that low-, medium-, and high-dose Huotan Jiedu Tongluo Decoction reduced the plaque formation of aortic root and increased the collagen content in AS mice. At the same time, Huotan Jiedu Tongluo Decoction improved the lipid metabolism by lowering the levels of TC, LDL-C, and TG and elevating the level of HDL-C in the serum. Huotan Jiedu Tongluo Decoction enhanced the antioxidant capacity by elevating the levels of GSH and SOD and lowering the level of MDA in the aorta and inhibiting the accumulation of Fe~(2+) in the aorta. In addition, Huotan Jiedu Tongluo Decoction up-regulated the protein and mRNA levels of Nrf2, GPX4, and SLC7A11, while down-regulating the protein and mRNA levels of ACSL4. In summary, Huotan Jiedu Tongluo Decoction can effectively alleviate AS lesions in ApoE~(-/-) mice by activating the Nrf2/GPX4 pathway, reducing lipid peroxidation, and inhibiting ferroptosis.
Animals ; Ferroptosis/drug effects* ; Atherosclerosis/metabolism* ; Drugs, Chinese Herbal/administration & dosage* ; NF-E2-Related Factor 2/genetics* ; Mice ; Mice, Inbred C57BL ; Apolipoproteins E/metabolism* ; Male ; Phospholipid Hydroperoxide Glutathione Peroxidase/genetics* ; Signal Transduction/drug effects* ; Humans ; Mice, Knockout

Macroporous resin adsorption column chromatography, silica gel column chromatography, ODS column chromatography, and semi-preparative high-performance liquid chromatography, combined with analytical methods such as NMR and MS, were employed to separate and identify compounds from the 70% ethanol extract of Ajania purpurea. A total of 30 compounds were isolated and identified, including 13 phenolic acids, 7 coumarins, 2 lignans, 1 flavonoid, 2 sesquiterpenes, 1 steroid, and 4 others. Among them, compounds 1 and 2 were newly discovered compounds, and compounds 4, 6, 8, 12, 14-23, 25, 28, and 30 were isolated from Ajania plants for the first time. Bioactivity screening showed that multiple compounds significantly inhibited the production of nitric oxide in lipopolysaccharide-stimulated RAW264.7 cells in a dose-dependent manner. Furthermore, compound 2 elevated the levels of glutathione in LPS-induced BEAS-2B cells, reduced the expression of pro-inflammatory cytokines such as tumor necrosis factor(TNF)-α, interleukin(IL)-6, and IL-1β, enhanced the mRNA of GPX4, HMOX1, NFE2L2, and enhanced protein levels of GPX4, HO-1, Nrf2, and SLC7A11, demonstrating potential anti-ferroptotic effect.
Mice ; Animals ; Lignans/isolation & purification* ; RAW 264.7 Cells ; Humans ; Nitric Oxide ; Tumor Necrosis Factor-alpha/immunology* ; Drugs, Chinese Herbal/isolation & purification* ; NF-E2-Related Factor 2/metabolism* ; Macrophages/metabolism* ; Interleukin-6/immunology*

This article investigated the effect and mechanism of salidroside(SAL) on the expression of adhesion molecules in oxidized low-density lipoprotein(oxLDL)-induced mouse aortic endothelial cell(MAEC). The oxLDL-induced endothelial cell injury model was constructed, and the safe concentration and action time of SAL were screened. The cells were divided into control group, oxLDL group, low and high concentration groups of SAL, and ferrostatin-1(Fer-1) group. The cell viability was detected by CCK-8 assay; lactate dehydrogenase(LDH) leakage was measured by colorimetry; the expression of intercellular adhesion molecule 1(ICAM-1) and recombinant vascular cell adhesion molecule 1(VCAM-1) were detected by immunofluorescence; Fe~(2+),glutathione(GSH),malondialdehyde(MDA),and 4-hydroxynonenal(4-HNE) levels were detected by kit method; reactive oxygen species(ROS) was detected by DCFH-DA probe; the levels of glutathione peroxidase 4(GPX4),silent mating type information regulation 2 homolog 1(SIRT1), and nuclear factor erythroid 2-related factor 2(Nrf2) were determined by using Western blot. The inhibitors of Nrf2 and SIRT1 were used, and endothelial cell were divided into control group, oxLDL group, SAL group, ML385 group(Nrf2 inhibitor), and EX527 group(SIRT1 inhibitor). The ultrastructure of mitochondria was observed by electron microscope; mitochondrial membrane potential(MMP) was detected by flowcytometry; the expressions of SIRT1,Nrf2,solute carrier family 7 member 11(SLC7A11),GPX4,ferroportin 1(FPN1),ferritin heavy chain 1(FTH1),ICAM-1, and VCAM-1 were detected by Western blot. The results showed that similar to Fer-1,low and high concentrations of SAL could improve cell viability, inhibit LDH release and the expression of ICAM-1 and VCAM-1 in oxLDL-induced endothelial cells(P<0.05 or P<0.01). It was related to increase in GSH level, decrease in Fe~(2+),ROS,MDA, and 4-HNE level, and up-regulation of SIRT1,Nrf2, and GPX4 expression to inhibit ferroptosis(P<0.05 or P<0.01). The intervention effect of high concentration SAL was the most significant. ML385 and EX527 could partially offset the protection of SAL on mitochondrial structure and MMP and reverse the ability of SAL to up-regulate the expression of SIRT1,Nrf2,SLC7A11,GPX4,FPN1, and FTH1 and down-regulate the expression of ICAM-1 and VCAM-1(P<0.05 or P<0.01).To sum up, SAL could reduce the expression of ICAM-1 and VCAM-1 in oxLDL-induced endothelial cell, which may relate to activation of SLC7A11/GPX4 antioxidant signaling pathway mediated by SITR1/Nrf2, up-regulation of FPN1 and FTH1 expression, and inhibition of ferroptosis.
Sirtuin 1/genetics* ; Animals ; Ferroptosis/drug effects* ; Lipoproteins, LDL/metabolism* ; NF-E2-Related Factor 2/genetics* ; Mice ; Endothelial Cells/cytology* ; Glucosides/pharmacology* ; Phenols/pharmacology* ; Cell Adhesion Molecules/genetics* ; Reactive Oxygen Species/metabolism* ; Intercellular Adhesion Molecule-1/genetics* ; Vascular Cell Adhesion Molecule-1/genetics* ; Cell Survival/drug effects*

Parkinson's disease(PD) is a neurodegenerative disorder characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra and the accumulation of Lewy bodies. While conventional drugs like levodopa can improve early symptoms, their efficacy diminishes over time, and they may cause severe side effects. Traditional Chinese medicine(TCM), with its multi-target therapeutic approach, has shown unique advantages in PD treatment, particularly in slowing disease progression and improving clinical symptoms. The nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase-1(HO-1) signaling pathway plays a critical role in cellular antioxidation, anti-inflammation, and cellular repair mechanisms, which are crucial for neuroprotection against PD. Studies indicate that TCM regulates the Nrf2/HO-1 pathway to enhance neuronal antioxidative capacity, inhibit neuroinflammation, promote dopaminergic neuron repair and survival, and slow pathological progression. This review explores the neuroprotective role of the Nrf2/HO-1 pathway in PD patients, including alleviating oxidative stress, suppressing neuroinflammation, promoting neuronal repair, and regulating iron metabolism and autophagy. It also discusses the mechanisms by which TCM active ingredients(flavonoids, alkaloids, terpenes, saponins, polyphenols, etc.), single herbs(Cistanche deserticola, Uraria crinite, and Melissa officinalis, etc.), and formulas(Bushen Jianpi Decoction, Didang Decoction, and Gancao Yangyin Decoction, etc.) modulate the Nrf2/HO-1 pathway in PD treatment, providing a theoretical basis for the clinical application and new drug development of TCM in PD prevention and treatment.
Humans ; Parkinson Disease/genetics* ; NF-E2-Related Factor 2/genetics* ; Signal Transduction/drug effects* ; Drugs, Chinese Herbal/pharmacology* ; Animals ; Heme Oxygenase-1/genetics* ; Medicine, Chinese Traditional

This study employed a mouse model of coronary artery ligation to assess the effect and mechanism of Jiming Powder on mitochondrial autophagy in mice with myocardial infarction. The mouse model of heart failure post-myocardial infarction was established by ligating the left anterior descending coronary artery. The pharmacological efficacy of Jiming Powder was evaluated through echocardiographic imaging, hematoxylin-eosin(HE) staining, and Masson staining. The levels of malondialdehyde(MDA), Fe~(2+), reduced glutathione(GSH), and superoxide dismutase(SOD) in heart tissues, as well as MDA immunofluorescence of heart tissues, were measured to assess lipid peroxidation and Fe~(2+) levels in the hearts of mice in different groups. Ferroptosis levels in the groups were evaluated using scanning electron microscopy and Prussian blue staining. Western blot analysis was conducted to detect the levels of key ferroptosis-related proteins, including nuclear factor erythroid 2-related factor 2(NRF2), ferritin heavy chain(FTH), glutathione peroxidase 4(GPX4), solute carrier family 7 member 11(SLC7A11), heme oxygenase 1(HO-1), and Kelch-like ECH-associated protein 1(KEAP1). The results showed that compared with the model group, both the high-and low-dose Jiming Powder groups exhibited significantly reduced left ventricular internal diameter in systole(LVIDs) and left ventricular internal diameter in diastole(LVIDd), while the left ventricular ejection fraction(EF) and left ventricular fractional shortening(FS) were significantly improved, effectively enhancing cardiac function in mice post-myocardial infarction. HE staining revealed that Jiming Powder attenuated myocardial inflammatory cell infiltration post-infarction, and Masson staining indicated that Jiming Powder effectively reduced fibrosis in the infarct margin area. Treatment with Jiming Powder reduced the levels of MDA and Fe~(2+), indicators of lipid peroxidation post-myocardial infarction, while increasing GSH and SOD levels, thus protecting ischemic myocardium. Western blot results demonstrated that Jiming Powder reduced KEAP1 protein accumulation, activated the NRF2/HO-1/GPX4 pathway, and up-regulated the protein expression of FTH and SLC7A11, exerting an inhibitory effect on ferroptosis. This study reveals that Jiming Powder exerts a therapeutic effect on myocardial infarction by inhibiting ferroptosis through the NRF2/HO-1/GPX4 pathway, providing a foundation for subsequent research on the pharmacological effects of Jiming Powder.
Animals ; Ferroptosis/drug effects* ; Myocardial Infarction/physiopathology* ; NF-E2-Related Factor 2/genetics* ; Mice ; Drugs, Chinese Herbal/administration & dosage* ; Male ; Heme Oxygenase-1/genetics* ; Phospholipid Hydroperoxide Glutathione Peroxidase/genetics* ; Humans ; Mice, Inbred C57BL ; Signal Transduction/drug effects* ; Disease Models, Animal