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Cytochrome C (Cyt C) is a central mediator of intrinsic apoptosis, whereas its heme-free precursor, apocytochrome C (APO-Cyt C), competitively inhibits this process. Sodium aescinate (SA), a natural triterpene saponin, is known to facilitate the endosomal escape of protein drugs. We initially aimed to investigate the effects of enhancing endosomal escape efficiency on protein activity through the combination of SA and Cyt C. However, this study investigates an cytotoxicity observed when APO-Cyt C is combined with SA and aims to elucidate the underlying molecular mechanism. Contrary to its established anti-apoptotic function, APO-Cyt C, when co-administered with a non-toxic concentration of SA, induced potent, caspase-dependent mitochondrial apoptosis in cancer cells. This pro-apoptotic switch was not primarily triggered by BCL-2 family protein modulation, ROS generation, or calcium overload. Instead, the primary mechanism is the induction of excessive and lethal autophagy. SA was found to induce lysosomal membrane damage, evidenced by Galectin-9 recruitment, which initiates lysophagy. The addition of APO-Cyt C significantly amplified the autophagic flux, leading to decreased p62 levels and enhanced LC3-II turnover. Mechanistically, this synergy is driven by a dual impact on the AKT-mTOR-TFEB pathway: APO-Cyt C treatment decreased mTOR phosphorylation, while the combination promoted the nuclear translocation of the autophagy regulator, TFEB. Inhibition of autophagic flux using Bafilomycin A1 or Tetrandrine rescued cells from apoptosis, confirming that excessive autophagy is the direct cause of cell death. This study reveals a novel therapeutic strategy wherein an anti-apoptotic protein is converted into a potent pro-apoptotic agent. The combination of APO-Cyt C and SA triggers apoptosis by overwhelming the cell with excessive autophagic flux, driven by synergistic inhibition of the mTOR-TFEB axis. These findings highlight the therapeutic potential of modulating autophagy and suggest that combining mTOR inhibitors with lysosome-targeting agents like SA could be an effective anti-cancer strategy. Summary This study reveals a novel strategy to combat cancer by repurposing an endogenous anti-apoptotic protein into a potent therapeutic agent. We demonstrate that apocytochrome C (APO-Cyt C), when combined with the natural compound sodium aescinate (SA), triggers cancer cell death through excessive autophagy rather than conventional apoptotic pathways. The discovery that this combination induces lethal autophagy by synergistically targeting both mTOR signaling and lysosomal function provides important insights for overcoming drug resistance. These findings highlight the promising therapeutic potential of combining mTOR inhibitors with lysosome-targeting saponins, establishing a new paradigm for cancer treatment through coordinated regulation of autophagic processes.
Salidroside, one of the main active compounds extracted from Rhodiola, has shown promising potential for the treatment of osteoporosis. Our previous study demonstrated that salidroside alleviated cognitive dysfunction in senescence-accelerated mouse prone 8(SAMP8) mice. In this study, we further investigated the effect of salidroside on osteoporosis in SAMP8 mice and explored the mechanism. The results of micro-computed tomography(micro-CT) and histology showed that salidroside significantly increased trabecular bone formation and improved bone microstructure in senile osteoporotic SAMP8 mice, and upregulated the protein expression levels of phosphatidylinositol-3-kinase(PI3K), glutathione peroxidase 4(GPX4), and Runt-related transcription factor 2(RUNX2) in the distal femur. Cell-based assays, including the Cell Counting Kit-8(CCK-8) assay, senescence-associated β-galactosidase (SA-β-galactosidase) staining, alkaline phosphatase (ALP) staining, Alizarin Red staining, and lipid peroxide detection, demonstrated that salidroside significantly promoted the proliferation and osteogenic differentiation of senile osteoporotic bone marrow stromal cells (BMSCs) and decreased lipid peroxide levels. Furthermore, real-time polymerase chain reaction (RT-PCR) and Western blotting analysis showed that salidroside increased protein and gene expression levels of solute carrier family 7 member 11(SLC7A11), GPX4, and ferroptosis suppressor protein 1(FSP1). Additionally, salidroside also increased the phosphorylation of PI3K, AKT, and mTOR, an effect reversed by LY294002.In conclusion, our investigation showed that salidroside could prevent ferroptosis, promote proliferation, and enhance osteogenic differentiation in senile osteoporotic BMSCs, thereby alleviating senile osteoporosis in SAMP8 mice. The PI3K/AKT/mTOR signaling pathway might play a crucial role in this mechanism. These findings suggest that salidroside has the potential to prevent senile osteoporosis and may serve as a candidate for therapeutic development.
Osteoporosis (OP) is a major systemic bone disease leading to an imbalance in bone homeostasis which remains a challenge in the current treatment of bone defects. Our previous studies on strontium (Sr) doping apparently stimulated osteogenesis of bioceramics, which suggested a promising strategy for the treatment of bone defects. However, the potential effects and the underlying mechanisms of Sr-doping on osteoporotic bone defects still remain unclear. Autophagy is a conventional self-degradation process of cells involved in bone homeostasis and regeneration under physiological and pathological conditions. Therefore, it is essential to design appropriate biomaterials and investigate the associated osteogenic mechanisms via autophagy. Based on this hypothesis, Sr-doped 45S5 bioglass (Sr/45S5) was fabricated, and ovariectomy bone marrow-derived mesenchymal stem cells (OVX-BMSCs) were applied as the in vitro cell culture model. First, the optimal Sr-doping concentration of 10 mol% was screened by cell proliferation, ALP staining, alizarin red S staining and the real-time PCR assay. Then, the results of western blot (WB) analysis showed that Sr-induced osteogenic differentiation of OVX-BMSCs was associated with time-dependent modulation of autophagy and related to the AKT/mTOR signaling pathway. Meanwhile, the autophagy in Sr-induced osteogenic differentiation of OVX-BMSCs was detected by WB, immunofluorescence staining and transmission electron microscopy. Furthermore, the effect of osteogenic differentiation of OVX-BMSCs has been significantly inhibited by the administration of autophagy inhibitors and the AKT/mTOR pathway inhibitors, respectively, in the early and late periods of osteogenic differentiation. Finally, the results of the model of femoral condyle defects in OVX-rats indicated that Sr10/45S5 granules remarkably enhanced bone regeneration which provided the evidences in vivo. Our research indicates that Sr-doping provides a promising strategy to promote osteogenic differentiation of OVX-BMSCs and bone regeneration in osteoporotic bone defects via early improvement of autophagy and late activation of the Akt/mTOR signaling pathway.
Depression is a common psychological disease with high morbidity and mortality. Recently, the involvement of synaptic plasticity in the pathogenesis of depression has shed light on the direction of developing novel antidepressants. Levomilnacipran is a newly approved medication for the treatment of adult major depressive disorder. However, the detailed mechanisms underlying its antidepressant-like effects have yet to be illuminated. In this study, we aimed to investigate the role of levomilnacipran in regulating synaptic plasticity and explore the possible molecular mechanisms of its antidepressant effects using a rat model of depression induced by lipopolysaccharide (LPS). The results demonstrated that levomilnacipran (30 mg/kg, i.p.) significantly ameliorated depression-like behaviors in rats, alleviated the dysregulation of synaptic plasticity, and suppressed neuroinflammation within hippocampus induced by LPS-treatment. Levomilnacipran increased the expression of postsynaptic dense 95 (PSD-95) and synaptophysin (Syn) and reversed the imbalance between pro- and anti-inflammatory cytokines within hippocampus of depressed rats. Additionally, levomilnacipran elevated expression level of brain-derived neurotrophic factor (BDNF), accompanied by increased tyrosine kinase B (TrkB), phosphorylated phosphatidylinositol 3-kinase (PI3K), phosphorylated protein kinase B (p-Akt), and phosphorylated mammalian target of rapamycin (p-mTOR). Taken together, these results suggest that levomilnacipran may exert antidepressant effects via upregulating BDNF/TrkB mediated PI3K/Akt/mTOR signaling pathway to improve synaptic plasticity. These findings reveal potential mechanisms for the antidepressant effects of levomilnacipran and offer new insights into the treatments for depression. Graphical Abstract
The preventive role of polysaccharide from the seeds of Plantago asiatica L. (PLCP) against reproductive system injury induced by nonylphenol (NP) was investigated. Male Sprague-Dawley rats were exposed orally to NP 1 h after PLCP intragastric administration continuously for 45 days. The results showed that NP induced significant decrease in relative weight of testes and epididymis, changed testicular histomorphology, and disrupted hormone secretions. Moreover, oxidative stress occurred after NP exposure by overproduction of Malondialdehyde, lipid peroxidation, inducible nitric oxide synthase, and low activities of superoxide dismutase and catalase. Furthermore, the induction of apoptosis and disturbance of PI3K/Akt/mTOR pathway by NP were also proved. Interestingly, PLCP alleviated NP toxicity by improving antioxidant enzymes, recovering hormone secretions, inhibiting apoptosis and autophagy, which involves PI3K/Akt/mTOR pathway. These findings provide a good direction that PLCP may be a good candidate to help body defend against toxic substance, particularly endocrine disrupting chemicals induced reproductive toxicity.
In this study, we synthesized zinc selenide (ZnSe)-polyacrylamide (PAM) nanomaterials for their potential application in treating knee osteoarthritis (KOA). Initially, we characterized the newly prepared material through various techniques including Fourier-transform infrared spectroscopy, scanning electron microscopy, transmission electron microscopy, and nitrogen adsorption–desorption to confirm its identity as the desired product. The results demonstrated that ZnSe-PAM nanomaterial exhibited excellent water solubility, biocompatibility, and stability, along with a large surface area, making it suitable for use as a drug carrier. Subsequently, the material was loaded with the drug 1 to obtain ZnSe-PAM@1. Cellular and thermosensitive experiments were then conducted, revealing that this nanomaterial could facilitate drug release by generating heat, thereby reducing the level of microRNA-146a-5P and blocking the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin/extracellular (PI3K/Akt/mTOR/ERK) signal-regulated kinase signaling pathway, thus alleviating the symptoms of KOA. These findings present a new direction for drug intervention in KOA and highlight the potential of developing ZnSe-PAM nanomaterials as novel drug carriers.
Nonylphenol (NP) is known to damage the intestinal epithelial barrier (IEB), although its mechanisms remain unclear. Arabinogalactan (AG) is a natural polysaccharide with intestinal protective properties. This study explored the mechanisms of NP-induced IEB damage and evaluated the protective potential of AG in a Caco-2 cell monolayer model. The results revealed that NP induces inflammation and oxidative stress through the PI3K/AKT/mTOR signaling pathway, thereby inhibiting tight junction (TJ) gene and protein expression and ultimately leading to IEB damage. Conversely, AG enhanced TJ expression and suppressed inflammation and oxidative stress by activating the PI3K/AKT/mTOR signaling pathway, thus alleviating NP-induced IEB damage. This research provides new insights into the molecular mechanisms of NP-induced IEB damage and highlights the potential of AG as a functional food ingredient for promoting intestinal health. Moreover, our study provides a theoretical basis for supporting policies aimed at restricting NP residues in food and offers a potential dietary reference for high-risk populations exposed to NP-contaminated environments.
Autophagy, a lysosomal degradative pathway, is crucial for the pathogenesis of Alzheimer’s disease (AD). Schizandrol A (SchA) shows multiple pharmacological effects. However, the potential effects and mechanisms of SchA on amyloid-β (Aβ)-induced autophagy remain unclear. In this study, differentiated SH-SY5Y cells or primary hippocampal neurons were pretreated with SchA (2 μg/ml) for 1 h before subjected to Aβ 1–42 (10 μM) for 24 h to test its effects on cell viability, apoptosis, oxidative stress, and autophagy. Then an mTOR inhibitor (rapamycin) and a PI3K inhibitor (LY294002) were employed to explore the role of PI3K/AKT/mTOR pathway. The results showed that SchA significantly inhibited Aβ 1–42 -triggered reduction of viable cells, increases of apoptotic cell number and pro-apoptotic protein expressions, as well as alterations of oxidative stress markers. In addition, the increases of LC3-II/LC3-I and Beclin-1 and decrease of p62 were suppressed by SchA. At the molecular level, we found that the inactivation of PI3K/AKT/mTOR pathway was ameliorated by SchA. Inhibition of PI3K/AKT/mTOR pathway deteriorated the protective effects of SchA against Aβ 1–42 -induced autophagy activation, cell death, and apoptosis. In conclusion, we demonstrate that SchA attenuates Aβ 1–42 -induced autophagy through activating PI3K/AKT/mTOR signaling pathway. SchA may be a novel drug for the prevention and treatment of AD.
Fibroblasts excessive proliferation was considered as a decisive reason for epidural fibrosis , which was known as a serious complication of lumbar laminectomy. As a traditional Chinese medicine , triptolide (TP) was used to be proved effective in preventing several fibrosis scar formation diseases. However, little is known about the effect of TP on preventing epidural fibrosis and its possible mechanism. Here, we performed in vitro and in vivo experiments to detect the possible mechanism of TP in preventing epidural fibrosis. In vitro, the effect of TP on impacting fibroblasts proliferation activities was detected by CCK-8, cell cycle assay and EdU incorporation assay. Also, the expressions of cell proliferation protein markers and the expressions of p-PI3K, p-AKT, p-mTOR were detect by Western blot . Besides, the effect of TP on inducing fibroblast apoptosis and autophagy was tested by Western blots, flow cytometry, TUNEL staining , Transmission electron microscope (TEM) analysis and LC3 immunofluorescent staining. The results suggested that TP could suppress the activation of PI3K/AKT/mTOR signaling pathway. Meanwhile, TP could inhibit fibroblast proliferation and induce fibroblast apoptosis as well as autophagy, which was known as two cellular self-destructions. Furthermore, we speculated the possible molecular pathway, through which that TP could inhibit fibroblast proliferation, induce fibroblast apoptosis and autophagy. We used PI3-kinase activator (740Y-P) to activate the PI3K/AKT/mTOR signaling. Activation of PI3K/AKT/mTOR signaling pathway increase the proliferation of fibroblasts and suppressed the autophagy and apoptosis induced by TP. In vivo, we built epidural fibrosis models in rats and locally applied TP of various concentrations. Hematoxylin–eosin (HE) and Masson's trichrome were used to detect the effect of TP on reducing epidural fibrosis. And the results showed that TP could significantly reduce the surgery-induced epidural fibrosis. In conclusion, the results above shown that TP could reduce epidural fibrosis formation, and the potential mechanism might through inhibiting fibroblast proliferation and stimulating apoptosis and autophagy via suppressing PI3K/AKT/mTOR signaling pathway. It might provide a novel thought for reducing surgery-induced epidural fibrosis.
Oxidative stress is a critical cause for the progression of neurodegenerative diseases, indicating that screening natural antioxidant and pharmacological targeting of mechanism need more attention. Natural plant polysaccharides are the primary group of natural antioxidants showing mighty antioxidant activity. Therefore, a polysaccharide (AFP-2) from flowers of Apios americana Medik was isolated, purified and characterized. Then, a H 2 O 2 -induced PC12 cells oxidative stress model was established to investigate the neuroprotective role of AFP-2 and to clarify the potential mechanism of action against H 2 O 2 -induced neurotoxicity. It was found that AFP-2 reduced ROS production and mitochondrial damage caused by hydrogen peroxide in PC12 cells. In addition, data from transmission electron microscope and western blot displayed that AFP-2 significantly activated autophagy in PC12 cells via Akt-mTOR pathway. These results together qualify AFP-2 as an interesting natural polysaccharide worth further investigation as a neuroprotective agent.
In the following study, a series of new lupeol-3-carbamate derivatives were synthesized, and the structures of all the newly derived compounds were characterized. The new compounds were screened to determine their anti-proliferative activity against human lung cancer cell line A549, human liver cancer cell line HepG2, and human breast cancer cell line MCF-7. Most of the compounds were found to show better anti-proliferative activity in vitro than lupeol. Among them, obvious anti-proliferation activity (IC50= 5.39~9.43 μM) was exhibited by compound3iagainst all three tumor cell lines. In addition, a salt reaction was performed on compound3k(IC50= 13.98 μM) and it was observed that the anti-proliferative activity and water solubility of compound3k·CH3I(IC50= 3.13 μM), were significantly enhanced subsequent to the salt formation process. The preliminary mechanistic studies demonstrated that apoptosis in HepG2 cells was induced by compound3k·CH3Ithrough the inhibition of the PI3K/AKT/mTOR pathway. In conclusion, a series of new lupeol-3-carbamate derivatives were synthesized via the structural modification of the C-3 site of lupeol, thus laying a theoretical foundation for the design of this new anticancer drug.
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