Liver disease (LD) is a global health problem caused by multiple factors. At present, there are still obvious problems with limited efficacy and strong side effects of drugs used in the clinical treatment of LD. Therefore, it is of great significance to search for effective hepatoprotective drugs from natural products. Geniposide (GS) is a cyclic ether terpenoid compound and a key component in the traditional Chinese medicine Gardenia jasminoides. It has a significant inhibitory effect on LD. However, there is currently no literature systematically analyzing its mechanism of action. To adapt to the environment of new drug research and the need for precision medication, this article summarizes the pathways and possible mechanisms of action discovered by GS in the treatment of LD, based on recent research literature: regulating bile stasis, antioxidant and anti-apoptosis, improving amino acid metabolism, improving energy metabolism, regulating lipid metabolism, anti-inflammatory and analgesic effects, etc. It also summarizes the pharmacokinetics of GS in vivo and discusses the liver toxicity of GS that is positively correlated with dosage. In addition, the existing problems in current research and possible future development directions were also discussed, to lay the foundation for the clinical development of natural product GS.

Chinese herbal medicine (CHM), with a range of pharmacological and molecular targets, has unique advantages in the comprehensive treatment of colorectal cancer (CRC); however, its clinical application remains limited owing to undetermined anti-CRC mechanisms. Recent studies have shown that gut microbes mediate the intestinal barrier, metabolism, and immunity, which, in turn, affect CRC initiation, progression, and CHM therapy. Here, we summarize the mechanisms and clinical applications of the gut microbiota involved in CRC, together with the latest studies of CHM in CRC therapy and its anti-tumor molecular basis from the gut microbiota perspective. This review highlights the gut microbiota as a “bridge” to clarify the scientific of CHM in treating CRC. More efforts should be focused on how the gut microbiome interacts with CHM to elucidate the mechanism of action of CHM and provide a more applicable basis for CHM- and microbiota-related therapies for the treatment of CRC.

Objective: A complex relationship exists between obstructive sleep apnea syndrome and diabetes mellitus (DM). Chronic intermittent hypoxia (CIH), which is a core pathological feature of obstructive sleep apnea syndrome, may play an important role in the onset and development of DM-related atherosclerosis (DM-AS). This study aimed to investigate the mechanism of action of tetramethylpyrazine (TMP) in CIH-associated DM-AS.

Methods: In vivo, a DM-AS mouse model was established by intraperitoneal injection of streptozotocin combined with a high-fat diet. They were exposed to CIH or normoxic conditions for 8 weeks and received different doses of TMP, rosuvastatin, toyocamycin, and purified water. Glycolipid metabolism, inflammation levels, degree of aortic AS, and expression levels of endoplasmic reticulum stress (ERS) and autophagy proteins were examined in mice. In vitro, human umbilical vein endothelial cells (HUVECs) were treated with high glucose and fat in combination with insulin to establish an insulin-resistant cell model (HUVEC-IR). After pretreatment with 4μ8C (IRE1 inhibitor) and different doses of TMP, intermittent hypoxic intervention was performed. Changes in cell morphology, proliferative activity, glucose consumption, and ability to migrate were observed, and the expression levels of ERS and autophagy proteins were detected.

Results: In vivo experiments showed that CIH significantly increased blood glucose levels and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) (P < 0.001 or P < 0.05), low-density lipoprotein cholesterol (LDL-C) content (P < 0.001), and the levels of three inflammatory factors [interleukin-1 beta (IL-1β), IL-6, and tumor necrosis factor-alpha (TNF-α)] in the mice (P < 0.001) compared with those of the mice with DM alone; moreover, the aortic atherosclerotic (AS) plaque area in CIH mice was significantly enlarged (P < 0.001). Western blotting results showed that the expressions of aortic IRE1α, XBP1s, Beclin1, and LC3A proteins were significantly increased in CIH mice compared with DM mice (P < 0.05). After treatment with different doses of TMP, rosuvastatin calcium, and toyocamycin, serum inflammation and lipid levels and plaque area were significantly reduced in mice (P < 0.001 and P < 0.001, respectively). The expression levels of aortic XBP1s, Beclin1, and LC3A were reduced in TMP- and toyocamycin-treated mice (P < 0.05). In the in vitro experiments, compared with normoxic cells, the cells treated with intermittent hypoxia (IH) showed a significant decrease in cell migration distance (P < 0.05), a significant increase in apoptosis rate (P < 0.001), a substantial increase in proliferation inhibition rate (P < 0.001), a significant increase in the levels of XBP1s and LC3A proteins (P < 0.05), and an increase in the number of autophagic vesicles/lysosomes, as observed under transmission electron microscopy. After treatment with different doses of TMP and 4μ8C, cell morphology was significantly restored, apoptosis rate significantly reduced (P < 0.001), and XBP1s, Beclin1, and LC3A expressions significantly inhibited (P < 0.05).

Conclusion: CIH promoted the onset of DM-AS, whereas TMP attenuated ERS and excessive autophagy by modulating the IRE1α-XBP1 signaling pathway and inhibiting XBP1 splicing, thereby ameliorating DM-AS exacerbated by CIH.

Objective: Unlike for drug-drug interactions, rigorous guidelines for assessing herb-drug interactions are nonexistent. GuHong is an intravenous herbal formulation used as adjunct therapy for the management of ischemic stroke. This investigation aimed to evaluate its potential to precipitate pharmacokinetic drug interactions. To facilitate the potential assessment, a human multi-compound pharmacokinetic study, along with associated supportive studies, was conducted to pinpoint GuHong compounds for testing.

Methods: After analyzing the chemical composition of GuHong, a pharmacokinetic study was conducted in healthy subjects who received GuHong intravenously to identify its significantly exposed compounds and their pharmacokinetics. In addition, supportive rat and in vitro studies were conducted to assess the hepatic and renal disposition of these compounds, including their metabolism and transport. The potential of GuHong to precipitate drug interactions was evaluated in vitro using significantly exposed compounds, which were tested for their effects on drug-metabolizing enzymes and drug transporters listed in the ICH M12 Guideline (2024), with a focus on inhibition and induction. Samples were analyzed by liquid chromatography-mass spectrometry.

Results: A total of 54 constituents (0.01-27.18 μmol/day) derived from Carthamus tinctorius flowers (Honghua) and N-acetyl-L-glutamine (3,090 μmol/day) were detected in GuHong. Following intravenous administration of GuHong, hydroxysafflor yellow A emerged as the principal circulating compound from Honghua. Saffloquinoside D, kaempferol-3-O-rutinoside, kaempferol-3-O-sophoroside, 8-hydroxycinnamic acid-8-O-glucoside, coumaric acid-4-O-glucoside, and chlorogenic acid, also from Honghua, were detected but at low plasma levels. Hydroxysafflor yellow A, primarily eliminated via glomerular filtration-based renal excretion, exhibited the characteristics of an intravenous “hard drug.” N-Acetyl-L-glutamine was another major circulating compound of GuHong and was eliminated through renal excretion and hydrolysis to L-glutamine. GuHong had a low potential to precipitate pharmacokinetic drug interactions.

Conclusions: The low drug interaction potential of GuHong is advantageous for its use in the treatment of ischemic stroke in the context of polypharmacy. The methodology developed here can be applied to the study of other complex herbal medicines for their pharmacokinetic drug interaction potential.

Objective: Soluble epoxide hydrolase (sEH) emerges as a target of interest for inflammatory diseases. Piperine is a natural amide alkaloid from Piper nigrum and displays an inhibitory effect toward sEH, its chemical structural transformation was carried out in order to obtain a library of sEH inhibitors based on its skeleton.

Methods: Structural transformation of piperine was carried out by chemical methods, and piperine derivatives were assayed for their sEH potentials. A mouse acute lung injury model was constructed by lipopolysaccharide (LPS). Hematoxylin and eosin (H&E) staining, immunofluorescence staining, Western Blot, and enzyme-linked immunosorbent assay were used for investigating the protective potential of sEH inhibitor 11h.

Results: Piperine derivatives 11e, 11h, 11j, and 11o showed inhibitory potentials toward sEH with values of half maximal inhibitory concentration (IC₅₀) from 20 to 70 nM. Compound 11h attenuated the pathological course of LPS-mediated acute lung injury (ALI) in vivo. Furthermore, levels of cytokines tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), myeloperoxidase (MPO), and lactate dehydrogenase (LDH) were decreased after administration of 11h. The LPS-mediated inflammation and redox unbalance, including expressions of cyclooxygenase-2 (COX-2), heme oxygenase-1 (HO-1), intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), p-p65/p65, glutamate-cysteine ligase modifier subunit (GCLM), and nuclear factor erythroid-2-related factor 2 (Nrf2), were ameliorated through nuclear factor kappa B (NF-κB) and Nrf2 pathways via enhancing levels of epoxyeicosatrienoic acids (EETs) in LPS-exposed ALI mice after compound 11h treatment. Molecular docking demonstrated that the aromatic unsaturated group of 11h occupied a hydrophobic pocket and its urea group formed three hydrogen bonds with Asp333, Tyr381, and Tyr465, which stabilized the active conformation of the ligand.

Conclusions: These findings demonstrated that compound 11h may serve as a lead compound for developing sEH inhibitors and treating inflammation related to diseases, such as ALI.

Objective: To investigate the mechanism by which moxibustion regulates the expression of inflammatory cytokines in ulcerative colitis (UC) rats through the P2X7 receptor (P2X7R)/nuclear factor-kappa B (NF-κB) pathway.

Methods: UC was induced using dextran sulfate sodium (DSS) in both wild-type (WT) and P2X7R knockout (KO) mice. General health conditions, pathological changes, and periodic acid-Schiff (PAS) staining of the colonic tissues were analyzed. Immunohistochemistry was used to detect NF-κB p65 protein expression in colonic tissues. Male Sprague-Dawley (SD) rats were randomly assigned to four groups: normal, model, normal + herb-partitioned moxibustion, and model + herb-partitioned moxibustion. UC was induced in rats by cyclic DSS administration. Rats in the herb-partitioned moxibustion group received moxibustion at the bilateral Tianshu (ST25) and Qihai (RN6) acupoints. The effects of herb-partitioned moxibustion were evaluated regarding general health conditions and histopathological alterations in colon tissue. The protein expression of P2X7R and NF-κB p65 in colonic tissues was determined by immunohistochemistry, whereas interleukin (IL)-10 mRNA levels were quantified using real-time quantitative polymerase chain reaction (RT-qPCR). Furthermore, enzyme-linked immunosorbent assay (ELISA) was used to measure serum concentrations of tumor necrosis factor-alpha (TNF-α) and IL-6.

Results: Colonic epithelial damage and inflammatory cell infiltration were significantly reduced in P2X7R KO mice compared to WT mice, along with reduced expression of NF-κB p65 protein in colonic tissues (P < 0.05). Moxibustion improves histopathological damage, goblet cell number, and intestinal mucus secretion in rats with UC. Compared to the normal group, the model group exhibited increased histopathological scores, serum TNF-α, and IL-6 levels, as well as elevated P2X7R and NF-κB p65 protein expression in colonic tissues (P < 0.05). In comparison to the model group, the model + herb-partitioned moxibustion group demonstrated significantly lower histopathological scores, reduced serum TNF-α and IL-6 levels, and decreased P2X7R and NF-κB p65 protein expression (P < 0.05).

Conclusions: Moxibustion at “Tianshu” and “Qihai” acupoints may inhibit the levels of IL-6 and TNF-α inflammatory factors and reduce inflammation in the UC colonic mucosa by regulating the P2X7R/NF-κB p65 pathway in UC colonic tissues.

Objective: Preventing the transition from acute to chronic pain (pain transition) is a new strategy for treating chronic pain. The present study aimed to investigate the role of K⁺-Cl⁻ Cotransporter Isoform 2 (KCC2) and γ-aminobutyric acid receptor type A (GABAAR) in the spinal cord dorsal horn (SCDH) in pain transition and the intervention effect of electroacupuncture (EA), and to understand the mechanism of EA in preventing acute and chronic pain transition in the spinal center.

Methods: A rat model of hyperalgesic priming (HP) was established by injecting carrageenan (Car) into the plantar area of rats, followed by the injection of prostaglandin E₂ (PGE₂) into the dorsal foot 7 days later. The GABAAR agonist (muscimol) and KCC2 activator (CLP257) were intrathecally injected for three consecutive days after PGE₂ injection. EA was applied at a frequency of 2/100 Hz to the bilateral foot Zusanli (ST36) and Kunlun (BL60). A von Frey filament was used to detect the pain threshold in each group of rats. Western blotting (WB) and immunofluorescence (IF) were used to detect GABAAR and KCC2 expression in each rats group. By combining EA intervention with a KCC2 inhibitor (VU0240551), we explored the mechanism of pain transition of EA regulation of GABAAR and KCC2 expression in SCDH.

Results: The HP model was established by injecting mice with Car/PGE₂. Compared to the normal saline (NS) + NS and NS + PGE₂ groups, the pain threshold of the Car + PGE₂ group decreased significantly 48 hours after PGE₂ injection (P < 0.01). The WB results indicated that intrathecal injection of a GABAAR agonist upregulated GABAAR expression in the SCDH of HP model rats (P < 0.05). WB and IF results revealed that intrathecal injection of the KCC2 activator significantly increased GABAAR and KCC2 expression in the SCDH of HP model rats (P < 0.01) and that GABAAR and KCC2 were co-expressed in the same SCDH cells. Compared to the Car + PGE₂ group, EA intervention significantly increased MWTs from 48 to 72 hours after the first injection and 4, 24, and 48 hours after the second injection (P < 0.01). EA upregulated GABAAR and KCC2 expression in the SCDH of rats with HP (P < 0.05). Intrathecal injection of the KCC2 inhibitor blocked the analgesic effect of EA in HP model rats (P < 0.01).

Conclusions: In SCDH, KCC2 expression was downregulated, causing downregulation of GABAAR expression and resulting in pain transition. EA upregulates KCC2 and GABAAR expression and prevents pain transition.

Objective: The effectiveness of chemotherapy is affected by tumor heterogeneity and drug resistance mechanisms; however, there are certain limitations. Electroacupuncture can regulate the tumor immune response and restore bone marrow hematopoietic function, which is affected by chemotherapy. This study investigated the efficacy and mechanism of electroacupuncture combined with cisplatin in the treatment of non-small-cell lung cancer mice.

Methods: To establish a mouse model of non-small-cell lung cancer, gene sequencing combined with bioinformatics analysis, flow cytometry, and liquid-phase chips was used to observe the expression of immune cells and related factors in the mouse tumor microenvironment. Flow cytometry was used to observe subpopulations of mouse bone marrow hematopoietic stem cells and progenitor cells. PAC1 receptor agonists were used to observe mouse tumor immunity and bone marrow hematopoiesis-related indicators.

Results: The combination of electroacupuncture with high- and low-dose chemotherapy had a better tumor-suppressive effect. Electroacupuncture can affect the gene expression profile of immune cells, especially the expression levels of Ccr1, Cxcr5, Zbp1, and CamkIIα, and increases the levels of interferon-γ (IFN-γ) and interleukin (IL)-2 protein, upregulating the levels of cytokines Ccl4, Ccl3, and IL-6 in the tumor tissue. Additionally, electroacupuncture enhanced the infiltration of CD8⁺ T cells, dendritic cells, and M1-type macrophages at the tumor site, and reduced the proportion of Th17 and Treg cells. Furthermore, electroacupuncture remodels the bone marrow hematopoietic microenvironment after chemotherapy by increasing the number of bone marrow hematopoietic stem cell subsets, leukocytes, and subpopulations in the peripheral blood. PAC1 receptor agonists have similar effects to those of electroacupuncture on hematopoietic protection and tumor immunity after chemotherapy.

Conclusions: Electroacupuncture may improve chemotherapy-induced bone marrow suppression, reshape the tumor microenvironment immune response affected by chemotherapy, and change the tumor immune microenvironment to an anti-tumor mode by regulating tumor local immune-related cytokines. The PAC1 receptor may be a drug target for the treatment of myelosuppression and immunosuppression in patients with tumors.

This article conducts a comprehensive review of both traditional therapeutic application knowledge and contemporary literature pertaining to Choerospondias axillaris (Roxb.) Burtt et Hill. Traditional application information was gathered from relevant reports, books, and classic material medica. Research literature and dissertations on C. axillaris chemical constituents and pharmacological activities, available up to 2023, were sourced from electronic databases. Pharmaceutical components such as flavonoids, phenolic acids, triterpenes, lignans, and organic acids were identified in C. axillaris and categorized based on their relevance to cardiovascular roles. Examining the material basis for C. axillaris efficacy in addressing cardiovascular diseases, an analysis of 27 Chinese patent medicines containing Choerospondiatis Fructus (CF) highlighted Myristicae Semen as the most frequently utilized and strongly associated with CF in prescriptions. C. axillaris exhibited notable pharmacological effects, encompassing anti-myocardial ischemia-reperfusion injury, anti-arrhythmic properties, anti-myocardial fibrosis, and hemorheological effects linked to cardiovascular diseases. This review aspires to provide valuable insights for translating traditional applications into modern pharmaceuticals and offers guidance for clinical applications in cardiovascular interventions.