Phytomedicine最新文献

Background: Pyrrolizidine alkaloids (PAs), particularly monocrotaline (MCT), are common phytotoxins known to induce pulmonary arterial hypertension (PAH), a progressive and fatal cardiopulmonary disease. However, the specific mechanism initiating PAH and the basis for the differing toxic potencies among PAs, such as MCT and retrorsine (RTS), remain undefined.

Purpose: This study aimed to investigate the mechanistic basis for the marked difference in pulmonary toxicity between two representative PAs, MCT and RTS. We specifically tested the hypothesis that the severity of PA-induced lung injury is determined by the extent of hemoglobin adduction within red blood cells (RBCs) and the consequent impairment of oxygen transport.

Study design: We employed a comparative toxicological design using rat models, treating them with equimolar doses of MCT and RTS, to assess and compare their respective toxicological pathways and resulting pulmonary injury.

Methods: Rats were administered MCT or RTS. Dehydropyrrolizidine alkaloid (DHPA) adduct formation on RBC hemoglobin was profiled using proteomics. Pulmonary hemodynamics, pulmonary vascular remodeling, and systemic hypoxia levels were subsequently measured.

Results: DHPAs selectively and covalently bound to specific residues (D74, E91, H93, K133) on the hemoglobin β-1 chain, critically impairing the oxygen-carrying capacity of RBCs. MCT exposure resulted in significantly higher levels of pyrrole-hemoglobin adducts (approximately 95% binding) compared to RTS (approximately 70% binding). This higher adduction rate led to more severe systemic hypoxia, which was consistently associated with greater pulmonary arterial endothelial activation and more severe PAH in the MCT group.

Conclusion: The severity of PA-induced PAH is directly correlated with the degree of hemoglobin adduction and resulting hypoxia. Hemoglobin adduction and impaired oxygen transport are critical, upstream events that define the etiology of PA-induced pulmonary arterial hypertension.

Background: Sepsis-induced acute liver injury (SALI) remains a major challenge with limited effective treatments. Although Corydalis saxicola Bunting (CSB) exhibits anti-inflammatory and hepatoprotective properties, its role in SALI remains poorly understood.

Purpose: To identify the active components and molecular mechanisms of CSB in protecting against SALI.

Methods: In vivo LPS-induced rat liver injury and in vitro cytokine-induced HepG2 injury models were established, treated with CSB extract or dehydrocavidine (DC). A series of advanced techniques including ferroptosis PCR array, super-resolution stimulated emission depletion (STED) microscopy, assay for transposase-accessible chromatin with sequencing (ATAC-seq), cellular thermal shift assay (CETSA), surface plasmon resonance (SPR), molecular dynamics simulation, and site-directed mutation were employed to investigate the underlying mechanisms.

Results: DC significantly mitigated LPS-induced liver injury, microcirculatory disorder, and leukocyte adhesion. It also alleviated liver ferroptosis under LPS challenge. In vitro studies revealed that LPS-activated macrophages secreted tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), which triggered hepatocyte ferroptosis. DC countered this process by inhibiting the production of these cytokines and correcting cytokine-induced mitochondrial abnormalities in hepatocytes. Mechanistically, DC bound to Kelch-like ECH-associated protein 1 (Keap1) at arginine 415 (R415), disrupting the formation of the Keap1/nuclear factor erythroid 2-related factor 2 (Nrf2) complex. This enabled Nrf2 nuclear translocation and promoted antioxidant gene expression, thereby correcting LPS-induced redox imbalance in hepatocytes.

Conclusions: In addition to inhibiting LPS-induced macrophage activation, DC activates the Nrf2 signaling pathway in hepatocytes to alleviate inflammation-enhanced liver ferroptosis. It provides potential therapeutic strategies for sepsis and Gram-negative bacteria-associated liver injury.

Background: Endothelial-to-mesenchymal transition (EndMT) is a potential therapeutic target for hypertension-induced vascular injury. Andrographolide (AGP) is a bioactive labdane diterpenoid that confers cardiovascular protective effects. However, the role of AGP in regulating EndMT during hypertension-related vascular injury is not clear.

Purpose: In this study, we investigated the effect of AGP on EndMT in vascular injury and elucidated its underlying mechanism in hypertension.

Methods: Angiotensin II (Ang II)-induced hypertensive mice were used to evaluate the vascular protective effects of AGP. Mechanistic experiments were performed in Ang II-stimulated endothelial cells. We detected EndMT markers both in vitro and in vivo. We also conducted a small-scale clinical trial to assess the effects of AGP on vascular damage in patients with hypertension.

Results: In Ang II-induced hypertensive mice, AGP improved endothelial function, alleviated arterial stiffness, and decreased aortic remodeling while also lowering blood pressure. It also suppressed EndMT in hypertensive mice and Ang II-treated endothelial cells. Quantitative co-immunofluorescence staining of aortic sections revealed that the percentage of CD31/vimentin double-positive cells was significantly higher in Ang II-induced hypertensive mice, whereas AGP treatment considerably decreased this proportion. Endothelial Notch1 expression was upregulated during EndMT, whereas genetic or pharmacological inhibition of Notch1 blocked Ang II-induced EndMT. Ang II downregulated the expression of Sp1, whereas the overexpression of Sp1 mitigated Ang II-induced EndMT; moreover, knocking down Sp1 abrogated the protective effects of AGP. In mice, the overexpression of Sp1 via adeno-associated virus 9 or Notch1 inhibition attenuated vascular injury by suppressing EndMT. Moreover, AGP improved flow-mediated dilation and reduced brachial-ankle pulse wave velocity in hypertensive patients (ChiCTR2300071970).

Conclusions: We found that AGP ameliorates hypertension-induced vascular injury by inhibiting EndMT through the Sp1-Notch1 pathway. These findings suggest that AGP may serve as a promising therapeutic candidate for restoring vascular homeostasis in patients suffering from hypertension.

Background: Primary dysmenorrhea is associated with aberrant uterine contractility, inflammatory activation, and oxidative stress, resulting in nociceptive hypersensitivity and impaired quality of life. Lycopodium serratum Thunb. var. longipetiolatum Spring. (LS), a fern endemic to Taiwan, has been traditionally used to alleviate menstrual disorders; however, its mechanistic basis remains undefined.

Purpose: This study aimed to investigate the chemical constituents, uterine relaxant, and antinociceptive effects of LS extracts, and to elucidate their molecular mechanisms in dysmenorrhea.

Methods: Ethanolic extracts of LS and their solvent-partitioned fractions, ethyl acetate (LSE-EA), n-butanol (LSE-BuOH), and aqueous (LSE-H₂O) were characterized by LC-MS/MS for phenolic constituents. The relaxant and antinociceptive effects were assessed in ex vivo uterine contraction assays induced by prostaglandin F₂α (PGF₂α), oxytocin, acetylcholine, and carbachol, and in acetic acid- and oxytocin-induced pain models in ICR mice. Western blot, biochemical, and histopathological analyses were performed to delineate molecular and oxidative pathways.

Results: LSE-EA exhibited the strongest inhibition of uterine contraction and pain responses. LC-MS/MS identified ferulic acid, caffeic acid, and chlorogenic acid as major metabolites. Mechanistically, LSE-EA downregulated oxytocin receptor (OTR) and myosin light chain kinase (MLCK), suppressed TLR-4/NF-κB/COX-2 and ERK activation, reduced uterine IL-6 expression, and attenuated oxidative stress, as evidenced by decreased malondialdehyde levels and restoration of redox balance.

Conclusion: Lycopodium serratum extract confers protection against dysmenorrhea through concurrent suppression of Ca²⁺-dependent uterine contraction, inflammatory signaling, and oxidative stress. These findings identify LSE-EA as a novel bioactive fraction with therapeutic potential in redox-mediated uterine dysfunction.

Background: Traditional Chinese medicine (TCM) compatibility (TCMC) is an important form of clinical application of TCM, and proper compatibility are key to ensuring the safe use of TCM. However, reports of liver injury associated with the combination of Epimedii Folium (EF) and Psoraleae Fructus (PF), a commonly used pair of TCM in clinical, have gradually increased in recent years. The mechanism underlying this phenomenon remains unclear, which significantly hinders the development of risk prevention and control strategies for the EF and PF combination.

Methods: Bone marrow-derived macrophages (BMDMs) were employed to establish an in vitro inflammasome activation model for screening susceptibility factors of idiosyncratic liver injury exacerbated by the combination of EF and PF. Subsequently, a classical idiosyncratic liver injury evaluation model was utilized to objectively assess the susceptibility of the combined treatment in aggravating liver injury. Finally, mechanisms underlying the combined use of EF and PF in exacerbating idiosyncratic liver injury were systematically evaluated through RNA-seq, flow cytometry, immunofluorescence, and immunohistochemistry.

Results: The combined use of EF and PF significantly enhanced the activation of the inflammasome. Specifically, Icariside I, a main compound of EF, synergistically promoted the activation of the NLRP3 inflammasome induced by bavachinin, a main compound of PF, while bavachinin directly activated inflammasome components such as NLRP3, NLRC4, and AIM2, leading to enhanced inflammasome activation, increased inflammation, increased apoptosis, and exacerbated oxidative stress, ultimately exacerbating liver injury. In addition, RNA-seq and GSEA analyses further confirm the association between the exacerbation of liver injury and abnormal activation of inflammasomes. Therefore, inflammasome-promoting TCM, such as EF, and inflammasome-activating TCM, such as PF, should be avoided in combination with immune-activated populations, and co-administration with drugs that downregulate inflammasome activation can reduce toxicity.

Conclusion: In summary, this study proposes a precision toxicity control strategy represented by exacerbate idiosyncratic liver injury caused by the combination of EF and PF, offering new insights to ensure its clinical safety and thereby reduce the occurrence of TCM-related liver injury events.

Background: Isodeoxyelephantopin (IDET) is a sesquiterpene lactone isolated from traditional herb Elephantopus scaber, which is known for its anti-inflammatory activities. While our previous study demonstrated that IDET inhibits NLRP3 expression in an acute peritonitis model, its therapeutic potential in chronic inflammatory diseases such as ulcerative colitis (UC), as well as the underlying mechanisms involving inflammasome signaling, have not yet been fully elucidated.

Purpose: This research was designed to explain the protective capacity of IDET in UC and to clarify how IDET modulates IL-1β-mediated inflammatory responses through the TXNIP/NLRP3 signaling pathway, by integrating in vitro and in vivo experimental systems.

Results: IDET significantly reduced dextran sulfate sodium (DSS)-induced colitis in mice, improving disease scores, reducing inflammation, and preserving colon histology. Mechanistically, IDET exerted a multi-tiered suppression of the inflammasome pathway, which suppresses IL-1β-driven inflammation. Firstly, it disrupted the upstream priming signal by downregulating NLRP3 expression through NF-κB signaling pathway. Secondly, it inhibited inflammasome assembly, as evidenced by reduced ASC oligomerization and NLRP3-ASC interaction. Consequently, IDET reduced the cleavage of pro-caspase-1 and pro-IL-1β, resulting in an approximately 4-fold reduction in mature IL-1β secretion. A key finding was that IDET interfered with the activation signal by attenuating the TXNIP-NLRP3 interaction, according to immunoprecipitation and molecular docking results.

Conclusions: Extending our previous findings on its anti-acute inflammatory activity, this study demonstrates that IDET alleviates experimental ulcerative colitis by targeting multiple stages of NLRP3 inflammasome activation. The results highlight the translational potential of IDET, a natural compound, for treating chronic intestinal inflammation.

Background: Diabetic retinopathy (DR) pathogenesis is driven by the dysregulation of an interconnected network of regulated cell death (RCD) modalities, including apoptosis, autophagy-dependent cell death, pyroptosis, and ferroptosis. Current therapies often fail to address this upstream cellular damage. Natural products (NPs), with their inherent polypharmacology, offer a promising strategy to modulate this complex network.

Purpose: This review advances a framework conceptualizing DR as the collapse of a dynamic RCD network and positions NPs as "RCD network modulators". We delineate how these agents can restore homeostasis and overcome the limitations of existing mono-target therapies.

Methods: A systematic literature search was conducted using Web of Science and PubMed, integrating keywords related to "natural products", "diabetic retinopathy", and specific "regulated cell death" modalities. All animal experiments adhered to ethical guidelines and complied with both international and institutional ethical standards.

Results: NPs simultaneously engage the master regulatory nodes-mitochondrial dysfunction, hyperactivation of the inflammasome, and oxidative stress. By modulating the Bcl-2 rheostat, normalizing autophagic flux, suppressing NLRP3 assembly, and activating Nrf2/SIRT1 pathways, NPs orchestrate a "network rewiring" to halt DR progression. However, clinical translation is significantly constrained by pharmacokinetic challenges, including low oral bioavailability and poor ocular penetration.

Conclusion: DR pathology emerges from network-level RCD dysregulation. NPs, which function as modulators of the RCD network, represent a compelling therapeutic shift toward addressing the root drivers of retinal degeneration.