The American Journal of Chinese Medicine

Oxidative stress and pyroptosis have been established as key contributors to myocardial ischemia-reperfusion injury (MIRI). While previous studies reported that electroacupuncture (EA) preconditioning exerted cardioprotective effects, the underlying mechanisms remain elusive. Thus, this study aimed to investigate the effects of EA preconditioning on oxidative stress and pyroptosis in MIRI rats, and explore the role of nuclear factor E2-associated factor 2 (Nrf2) throughout that process. A MIRI model was constructed by ligating the left anterior descending coronary artery for 30 min, followed by 4 h of reperfusion in rats. Prior to modeling, rats were subjected to EA at the Neiguan Point for three days. Furthermore, ML385, a Nrf2 inhibitor, was administered in order to examine the role of Nrf2 in regulating oxidative stress and pyroptosis following EA preconditioning. The results revealed that EA preconditioning improved left ventricular function after MIRI and reduced both the myocardial infarction area and cTnT levels. Meanwhile, EA preconditioning alleviated MIRI-induced oxidative stress and pyroptosis, as evidenced by the downregulation of ROS, MDA, NF-κB p65, caspase-1, IL-1β, and GSDMD-N, and the upregulation of SOD and HO-1. Mechanistically, EA up-regulated enhanced the expression of Nrf2. However, its cardioprotective effects and ability to attenuate oxidative stress and pyroptosis were suppressed by the inhibition of Nrf2. Taken together, our study indicated that EA preconditioning attenuated MIRI in rats by mitigating oxidative stress and pyroptosis, with Nrf2 playing a vital role in this protective mechanism.

Traditional Chinese medicine (TCM) has protected the health of Chinese people for thousands of years. With the rapid development of artificial intelligence (AI), various fields of TCM are facing both opportunities and challenges. This review discusses the development prospects and challenges of Chinese medicine in the AI era, emphasizing that AI, as an important tool in the process of Chinese medicine healthcare services, can assist doctors in making objective, rational and professional treatment decisions, and that AI has a strong potential for development in the field of Chinese medicine. However, the emotions, complex thoughts, and humanistic values of doctors are qualities that AI is currently unable to realize, so as the dominant player, the doctor is indispensable to the medical process. By summarizing and analyzing the current development status of AI in diagnosis, drug research, health management and education in TCM, this paper reveals the development prospects and potential risks of combining TCM with AI, and suggests that AI is an important aid for modernizing and improving the quality of TCM medical care in a coordinated manner.

Endometriosis (EMS) is a chronic, estrogen-dependent inflammatory disease affecting 5–10% of women of reproductive age, characterized by the growth of endometrial tissue on the outside of the uterus. The dysregulation of iron metabolism leads to the accumulation of iron ions at the lesion sites, resulting in oxidative stress and pro-inflammatory responses that promote the progression of EMS. The mechanisms underlying ferroptosis in EMS primarily involve iron accumulation, lipid peroxidation, and loss of glutathione peroxidase 4 activity. These mechanisms confer resistance to ferroptosis within the ectopic tissues and facilitate cell survival and proliferation. Traditional Chinese medicine (TCM) has demonstrated therapeutic potential for modulating ferroptosis. Studies have shown that TCM monomers may regulate ferroptosis by modulating iron transport proteins and anti-oxidant defense mechanisms. TCM formulas employ distinct treatment strategies depending on the stage of EMS: in the early stages, they promote ferroptosis to control lesion growth, whereas in the later stages, they inhibit ferroptosis to reduce oxidative stress and inflammation in order to improve reproductive health and slow disease progression. This study provides a new perspective on potential therapeutic strategies for the management of EMS by summarizing the role of ferroptosis in its pathological mechanisms and reviewing findings on the use of TCM in regulating ferroptosis.

Liver cirrhosis is a critical stage in the progression of various chronic liver diseases, often leading to severe complications such as ascites, hepatic encephalopathy, and a high mortality rate, and it thus poses a serious threat to patient life. The activation of hepatic stellate cells is a central driver of disease progression. Cellular autophagy, a lysosome-mediated degradation process, plays a key role in maintaining cellular function and dynamic homeostasis. Research has shown that autophagy is closely associated with proteins like LC3, Beclin-1, P62, and mTOR, and is regulated through signaling pathways such as PI3K/Akt/mTOR, Ras/Raf/MEK/ERK, and AMPK/mTOR. Additionally, the relationship between autophagy and apoptosis, as well as between autophagy and exosomes, has been further demonstrated. While modern medicine has made progress in treating cirrhosis, it still faces significant limitations. By contrast, numerous studies have demonstrated the efficacy of traditional Chinese medicine in preventing and treating liver cirrhosis by regulating autophagy, with fewer adverse effects. Chinese herbal monomers and formulations can modulate various autophagy-related signaling pathways, including PI3K/Akt/mTOR, Ras/Raf/MEK/ERK, and AMPK/mTOR, and influence key autophagy proteins such as LC3 and Beclin-1. This modulation inhibits hepatic stellate cell activation, reduces extracellular matrix deposition, and exerts anticirrhotic effects. Moreover, Chinese medicine appears to reduce adverse reactions in cirrhosis treatment and lower the risk of disease recurrence. This review explores the mechanisms of autophagy in the prevention and treatment of liver cirrhosis through Chinese medicine, offering new insights for the development of Chinese medicinal therapies for cirrhosis and their rational clinical application.

Ulcerative colitis (UC) is a chronic, nonspecific inflammatory disorder characterized by symptoms such as abdominal pain, diarrhea, hematochezia, and urgency during defecation. While the primary site of involvement is the colon, UC can extend to encompass the entire rectum and colon. The causes and development mechanisms of UC are still not well understood; nonetheless, it is currently held that factors including environmental influences, genetic predispositions, intestinal mucosal integrity, gut microbiota composition, and immune dysregulation contribute to its development. Dysregulated immune responses are pivotal in the pathophysiology of UC, and these aberrant responses are considered key contributors to the disease onset. In patients with UC, immune cells become hyperactive and erroneously target normal intestinal tissue, resulting in inflammatory cascades and damage to the intestinal mucosa. The therapeutic strategies currently employed for UC include immunosuppressive agents such as aminosalicylates and corticosteroids. However, these treatments often prove costly and carry significant adverse effects — imposing a considerable burden on patients. Traditional Chinese Medicine (TCM) has attracted worldwide attention because of its multi-target approach, minimal side effects, cost-effectiveness, and favorable efficacy profiles. In this review, the ways in which TCM modulates inflammatory responses in the treatment of ulcerative colitis have been outlined. Research into TCM modalities for modulating inflammatory pathways in the treatment of UC, which has yielded promising advancements, including individual herbs, herbal formulations, and their derivatives, has been summarized. TCM has been utilized to treat UC and the immune system plays a key role in regulating intestinal homeostasis. It is imperative to facilitate large-scale evidence-based medical research and promote the clinical application of TCM in the management of UC.

Myocardial infarction (MI) is a significant threat to human health worldwide. Following MI, cardiomyocytes (CMs) undergo pyroptosis, exacerbating the damage caused by infarction. Ginseng may play a role in alleviating CM pyroptosis. However, further exploration is needed regarding its main active ingredients and effects. By employing network pharmacology on the active ingredients of ginseng, MI and pyroptosis, and employing molecular docking between such ingredients and pyroptosis-related proteins, we screened for the main ingredient of ginseng. Through network pharmacology and molecular docking, we identified ginsenoside Rh2, which acts on MI and cell pyroptosis, as the most likely active ingredient that stably binds to pyroptosis-related proteins. We subsequently constructed a neonatal rat CM oxygen–glucose deprivation (OGD) model in vitro and an MI mouse model in vivo. Ginsenoside Rh2 was administered, with losartan used as a positive control. In the in vitro OGD model, ginsenoside Rh2 increased the viability of primary rat CMs and mitigated OGD-induced pyroptosis. In the in vivo MI model, ginsenoside Rh2 reduced CM pyroptosis, decreased infarct size, and subsequently improved cardiac function. Our study provides a novel therapeutic strategy for MI by attenuating CM pyroptosis.

Acute lung injury (ALI) can lead to severe respiratory system damage, characterized by extensive inflammation and lung tissue injury. Ophiopogonin D (OD), from Ophiopogon japonicus, has pharmacological effects such as anti-inflammatory and anti-oxidant, hypoglycemic, anti-aging, and immune regulation properties. This study attempts to identify the protective mechanism of OD against ALI by the inhibition of ferroptosis of macrophages. The tissue-specific expression of USP25 in patients with COVID-19 was evaluated using single-cell data from the China National GeneBank and the GSE147507 dataset from Gene Expression Omnibus (GEO). C57BL/6 mice, Murine bone marrow derived macrophages (BMDM) or RAW264.7 cells were induced by Lipopolysaccharide (LPS). OD prevented ALI, and reduced inflammation levels and oxidative stress in mice models. OD significantly decreased the number of monocyte/macrophages (CD11b $+$Ly6G-cells) in the peritoneal cavity after ALI induction. OD-mitigated inflammation and oxidative stress of macrophages in the ALI model. OD-reduced ferroptosis of macrophages in a model of ALI through the inhibition of ROS-induced mitochondrial damage. USP25 is significantly expressed in macrophages in patients with COVID-19 using single-cell analysis. OD-suppressed Rac1/NOX1-derived ROS to reduce the mitochondrial damage of macrophages in a model of ALI by the induction of USP25 activity. OD-identified USP25 at 907-VAL and 975-ARG in an ALI model to suppress USP25 Ubiquitination. OD from Ophiopogon japonicus induces USP25 activity to reduce ferroptosis of macrophages in ALI by binding the Rac1 and Nox1 complex. Therefore, it can be concluded that OD may be a potential therapeutic drug for the treatment of ALI.

Acetaminophen (APAP)-induced liver injury (AILI) is a universal liver disease and the predominant cause of acute liver failure in clinical practice. Autophagy is a highly conserved intracellular degradation pathway, with accumulating evidence indicating its involvement in APAP hepatotoxicity. Notably, the serine/threonine AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/unc-51-like kinase 1 (ULK1) pathway serves as the most classical autophagy pathway and engages in autophagy activation. Thus, pharmacological activation of the AMPK/mTOR/ULK1 pathway has emerged as a critical strategy for addressing AILI. Chlorogenic acid (CGA), a main bioactive constituent isolated from Lonicera japonica Thunb., is an autophagy regulator with potential for AILI therapy. However, whether and how CGA modulates autophagy to antagonize AILI has not yet been elucidated. In the present study, we aim to explore the impact of CGA on AILI, as well as the underlying mechanisms in vitro and in vivo. The results demonstrated that CGA could protect the mice and LO2 cells from oxidative stress and liver injury induced by APAP. Regarding mechanisms, CGA activated the AMPK/mTOR/ULK1 pathway, thereby promoting autophagy. This was evidenced by the degradation of p62/SQSTM1 (hereafter referred to as p62), as well as the up-regulation of LC3B, ATG5, and Beclin1. It is worth noting that the aforementioned, CGA-provided beneficial effects were abrogated by pharmacological inhibition of AMPK with Compound C (CC, an AMPK inhibitor). These $\mathrm{\text{findings}}=\mathrm{\text{illustrated}}$ that CGA alleviates oxidative stress and liver injury induced by APAP, which is contingent upon the regulatory effect of CGA on the AMPK/mTOR/ULK1 axis.

The intestinal absorption of active herbal constituents plays an important role in the biomedical efficacy of Traditional Chinese Medicine (TCM) formulations after oral administration. TCM compounds with low oral bioavailability can reach the distal intestine and then interact with intestinal flora, influencing the botanical pharmacological effects. In this study, in vitro digestion and an ex vivo Ussing chamber model were utilized to evaluate the intestinal absorption behavior of Forsythiae Fructus-Lonicerae Japonicae Flos-containing Yinqiao Jiedu Granule (YQJDG). It was found that the jejunum exhibited active absorption effects for some components of the formula, while the oral bioavailability of other herbal ingredients was low. Through further research using a combined UPLC-MS/MS and 16S rDNA sequencing technique, we studied the existence of the reciprocal interactions between YQJDG and gut microbiome. The in vitro fecal fermentation results showed that YQJDG significantly impacted the microbial community composition. The YQJDG markedly increased the abundance of beneficial microorganisms, such as Parabacteroides distasonis and Streptococcus gallolyticus subsp. Macedonicus, and suppressed the abundance of conditional pathogens including Prevotella steorerea, Haemophilus parainfluenzae, and Bacteroides. These effects may potentially contribute to the body’s immune functions and anti-inflammatory capacities. UPLC-MS/MS analysis suggested that the fecal microbiota chemically transformed constituents with low bioavailability to more readily absorbed potentially active metabolites. These findings provided valuable insights into the absorption characteristics of YQJDG and its interaction with the gut microbiome, further facilitating our understanding of precise pharmacological mechanisms of action of this Chinese herbal formulation.

Bile acid metabolism mediated by gut microbiota is significantly related to immunity regulation that plays an important role in the development and treatment of inflammatory bowel disease (IBD). Our previous study has demonstrated that Panax notoginseng saponins (PNS) alleviate colitis due to the regulation of T helper 17/Regulatory T cells (Th17/Treg) balance via gut microbiota. However, the effects and mechanism of PNS on colitis pertinent to bile acid metabolism mediated by gut microbiota remain elusive. This study aims to investigate the anti-colitis mechanism of PNS by regulating the Th17/Treg balance pertinent to gut microbiota–bile acid metabolism. Results showed that PNS significantly decreased the relative abundance of Allobaculum, Dubosiella, Muribaculum, and Alistipes, and up-regulated the relative contents of conjugated bile acids, such as TCA and TCDCA. Fecal microbiota transplantation (FMT) showed that the gut microbiota remodeled by PNS had a regulatory effect on bile acid metabolism, and up-regulated the relative contents of TCA and TCDCA, which alleviated IBD and promoted Treg cell expression in vivo and in vitro. Taken together, PNS could reshape the profiling of gut microbiota to generate more TCA and TCDCA, which improve the balance of Th17/Treg to exert anti-IBD effects.

Non-small cell lung cancer (NSCLC) is a malignancy that faces serious resistance challenges in treatment. In this study, we identified Piperlongumine as a promising therapeutic candidate to overcome Osimertinib resistance in NSCLC. We systematically investigated the inhibitory effect of Piperlongumine on NSCLC cells and confirmed that it could effectively inhibit the in vitro kinase activity of wild-type (WT), exon 19 deletion, and L858R/T790M-mutated EGFR. We also found that Piperlongumine-induced intrinsic apoptosis by interfering with the EGFR signaling pathway, which was characterized by the down-regulation of the anti-apoptotic protein Mcl-1. Further mechanistic studies revealed that Piperlongumine-induced degradation of Mcl-1 was dependent on the Akt-GSK3β signaling pathway. Additionally, Piperlongumine-promoted interaction between Mcl-1 and β-TRCP, thereby enhancing β-TRCP-mediated ubiquitination and the degradation of Mcl-1. Furthermore, Piperlongumine significantly inhibited tumor growth in both Osimertinib-sensitive and resistant NSCLC xenograft models. These findings highlight the potential of Piperlongumine as an effective agent in overcoming EGFR-targeted therapy resistance and suggest new avenues for its clinical application in NSCLC treatment.

Platinum-based chemotherapy remains a mainstay of clinical practice in the standard treatment of epithelial ovarian cancer (EOC). Most patients who receive this treatment, however, develop relapse and drug resistance. Ginsenoside Rg6 (G-Rg6), one of the anticarcinogenic active components in the American ginseng berry, may hold promise in the adjuvant chemotherapy of EOC. In this study, the correlation between fucosylation and cisplatin (cDDP) resistance in EOC cells was validated by gene expression profile analysis and lectin blot. We found that G-Rg6 derived from the American ginseng berry inhibits the cell viability and protein fucosylation of cDDP-resistant EOC cells. G-Rg6-induced G₂/M-cell cycle arrest was proven to result from the autophagy of cDDP-resistant EOC cells. In addition, we observed that G-Rg6 initiates autophagy in cDDP-resistant EOC cells by inhibiting the GRB2–ERK1/2–mTOR axis, and that high concentration of G-Rg6 treatment leads to cell apoptosis. G-Rg6 also enhances cDDP uptake in A2780CP cells by promoting CTR1 expression and suppressing its core fucosylation. Therapies combining cDDP and G-Rg6 display higher efficacy in inhibiting the cDDP-resistant EOC cells in comparison with the sole application of cDDP, exhibiting strong potential for clinical application. G-Rg6 derived from the American ginseng berry can improve cDDP resistance in EOC cells via suppressing fucosylation and inducing autophagy, suggesting its potential in the adjuvant chemotherapy of EOC patients.