Ellagic acid inhibits dihydrotestosterone-induced ferroptosis and promotes hair regeneration by activating the wnt/ß-catenin signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Androgenic alopecia (AGA) is the most prevalent form of hair loss in clinical practice and affects the physical and psychological well-being of adolescents. Paeonia lactiflora Pallas (PL), which is widely used in traditional Chinese medicine, enhances blood function and promotes hair growth, and ellagic acid (EA), a polyphenol in PL extract, shows strong antioxidant, anti-aging, and anti-inflammatory properties and also plays a role in the treatment of various skin conditions. However, its role and mechanism of action in AGA remain unclear. AIM OF THE STUDY: To determine whether EA can rescue slow hair regeneration by regulating dihydrotestosterone (DHT)-induced ferroptosis in AGA mice and clarify the effect of EA on DHT-induced ferroptosis in dermal papilla cells (DPCs). MATERIALS AND METHODS: Male C57BL/6 mice were used to establish a DHT-induced AGA mouse model, whereas DPCs were used to establish a DHT-induced cellular model. Thereafter, we investigated the therapeutic mechanism of action of EA via immunofluorescence, western blot analysis, immunohistochemistry, electron microscopy, and molecular docking. RESULTS: EA stimulated hair regeneration in mice and reversed DHT-induced increases in iron content, lipid peroxidation, and DHT-induced mitochondrial dysfunction by activating the Wnt/ß-catenin signaling pathway. Further, ß-catenin knockdown suppressed the inhibitory effect of EA on DHT-induced ferroptosis in DPCs. CONCLUSION: EA inhibits DHT-induced ferroptosis and promotes hair regrowth in mice by activating the Wnt/ß-catenin signaling pathway. Thus, it has potential for use as a treatment option for AGA.

Ethanol extract of Eclipta prostrata induces multiple myeloma ferroptosis via Keap1/Nrf2/HO-1 axis.

BACKGROUND: Multiple myeloma (MM) is an incurable hematological malignancy with limited therapeutic efficacy. Eclipta prostrata is a traditional Chinese medicinal plant reported to possess antitumor properties. However, the effects of E. prostrata in MM have not been explored. PURPOSE: The aim of this study was to define the mechanism of the ethanol extract of E. prostrata (EEEP) in treating MM and identify its major components. METHODS: The pro-ferroptotic effects of EEEP on cell death, cell proliferation, iron accumulation, lipid peroxidation, and mitochondrial morphology were determined in RPMI-8226 and U266 cells. The expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2), kelch-like ECH-associated protein 1 (Keap1), heme oxygenase-1 (HO-1), glutathione peroxidase 4 (GPX4), and 4-hydroxynonenal (4HNE) were detected using western blotting during EEEP-mediated ferroptosis regulation. The RPMI-8226 and U266 xenograft mouse models were used to explore the in vivo anticancer effects of EEEP. Finally, high performance liquid chromatography (HPLC) and ultra-high-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry system (UPLC-Q/TOF-MS) were used to identify the major constituents of EEEP. RESULTS: EEEP inhibited MM cell growth and induced cell death in vitro and in vivo. By promoting malondialdehyde and Fe2+ accumulation, lipid peroxidation, and GSH suppression, EEEP triggers ferroptosis in MM. Mechanistically, EEEP regulates the Keap1/Nrf2/HO-1 axis and stimulates ferroptosis. EEEP-induced lipid peroxidation and malondialdehyde accumulation were blocked by the Nrf2 activator NK-252. In addition, HPLC and UPLC-Q/TOF-MS analysis elucidated the main components of EEEP, including demethylwedelolactone, wedelolactone, chlorogenic acid and apigenin, which may play important roles in the anti-tumor function of EEEP. CONCLUSION: In summary, EEEP exerts its anti-MM function by inducing MM cell death and inhibiting tumor growth in mice. We also showed that EEEP can induce lipid peroxidation and accumulation of ferrous irons in MM cells both in vivo and in vitro, leading to ferroptosis. In addition, this anti-tumor function may be achieved by the EEEP activation of Keap1/Nrf2/HO-1 axis. This is the first study to reveal that EEEP exerts anti-MM activity through the Keap1/Nrf2/HO-1-dependent ferroptosis regulatory axis, making it a promising candidate for MM treatment.

Sesamin attenuates UVA-induced keratinocyte injury via inhibiting ASK-1-JNK/p38 MAPK pathways.

BACKGROUND: Ultraviolet (UV) exposure-stimulated reactive oxygen species (ROS) formation in keratinocytes is a crucial factor in skin aging. Phytochemicals have become widely popular for protecting the skin from UV-induced cell injury. Sesamin (SSM) has been shown to play a role in extensive pharmacological activity and exhibit photoprotective effects. AIM: To assess the protective effect of SSM on UVA-irradiated keratinocytes and determine its potential antiphotoaging effect. METHODS: HaCaT keratinocytes pretreated with SSM were exposed to UVA radiation at 8 J/cm2 for 10 min. Cell viability and oxidative stress indicators were evaluated using a cell counting kit-8 and lactate dehydrogenase (LDH), malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) assay kits. Apoptosis and intracellular ROS levels were analyzed using annexin V-fluorescein isothiocyanate/propyridine iodide and dichlorodihydrofluorescein diacetate staining, respectively. Protein levels of matrix metalloprotein-1 (MMP-1), MMP-9, Bax/Bcl-2, and mitogen-activated protein kinase (MAPK) pathway proteins, phospho-apoptosis signal-regulating kinase-1 (p-ASK-1)/ASK-1, phospho-c-Jun N-terminal protein kinase (p-JNK)/JNK, and p-p38/p38 were determined using western blotting. RESULTS: Sesamin showed no cytotoxicity until 160 µmol/L on human keratinocytes. Sesamin pretreatment (20 and 40 µM) reversed the suppressed cell viability, increased LDH release and MDA content, decreased cellular antioxidants GSH and SOD, and elevated intracellular ROS levels, which were induced by UVA irradiation. Additionally, SSM inhibited the expression of Bax, MMP-1, and MMP-9 and stimulated Bcl-2 expression. In terms of the regulatory mechanisms, we demonstrated that SSM inhibits the phosphorylation of ASK-1, JNK, and p38. CONCLUSION: The results suggest that SSM attenuates UVA-induced keratinocyte injury by inhibiting the ASK-1-JNK/p38 MAPK pathways.

Erratum: Corrigendum: Water extract of cacumen platycladi promotes hair growth through the Akt/GSK3ß/ß-catenin signaling pathway.

[This corrects the article DOI: 10.3389/fphar.2023.1038039.].

Andrographolide induced ferroptosis in multiple myeloma cells by regulating the P38/Nrf2/HO-1 pathway.

Andrographis paniculata is used as a functional food in Asia. Andrographolide (Andro), a diterpene lactone isolated from Andrographis paniculata, has been reported to have potent anticancer activity. Multiple myeloma (MM), the second most common malignant tumor in hematology, is incurable. Ferroptosis, a type of cell death driven by iron-dependent lipid peroxidation, has shown potential in the treatment of various cancers. However, previous studies have not demonstrated whether Andro inhibits the development of MM via ferroptosis or any other mechanism. In the present study, we observed that Andro induced cell death, G0/G1 cell cycle arrest and evoked oxidative stress in MM cells. Interestingly, these phenomena were accompanied by increases in intracellular and mitochondrial Fe2+ and lipid peroxidation levels. Furthermore, treatment with ferroptosis inhibitors rescued Andro-induced cell death, which indicated that ferroptosis contributed to this phenomenon. Mechanistic examination showed that Andro may block the Nrf2/HO-1 signaling pathway by activating P38, thereby inducing ferroptosis. Moreover, inhibition of P38 expression rescued Andro-induced cell death, changes in the level of Nrf2 and HO-1 expression, Fe2+ and lipid peroxidation. Taken together, our findings suggest that Andro induces ferroptosis in MM cells via the P38/Nrf2/HO-1 pathway, providing a potential preventative and therapeutic approach for MM.

Water extract of cacumen platycladi promotes hair growth through the Akt/GSK3ß/ß-catenin signaling pathway.

Cacumen Platycladi (CP) consists of the dried needles of Platycladus orientalis L.) Franco. It was clinically demonstrated that it effectively regenerates hair, but the underlying mechanism remains unknown. Thus, we employed shaved mice to verify the hair growth-promoting capability of the water extract of Cacumen Platycladi (WECP). The morphological and histological analyses revealed that WECP application could significantly promote hair growth and hair follicles (HFs) construction, in comparison to that of control group. Additionally, the skin thickness and hair bulb diameter were significantly increased by the application of WECP in a dose-dependent manner. Besides, the high dose of WECP also showed an effect similar to that of finasteride. In an in vitro assay, WECP stimulated dermal papilla cells (DPCs) proliferation and migration. Moreover, the upregulation of cyclins (cyclin D1, cyclin-dependent kinase 2 (CDK2), and cyclin-dependent kinase 4 (CDK4)) and downregulation of P21 in WECP-treated cell assays have been evaluated. We identified the ingredients of WECP using ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS) and endeavored to predict their relevant molecular mechanisms by network analysis. We found that the Akt (serine/threonine protein kinase) signaling pathway might be a crucial target of WECP. It has been demonstrated that WECP treatment activated the phosphorylation of Akt and glycogen synthase kinase-3-beta (GSK3ß), promoted ß-Catenin and Wnt10b accumulation, and upregulated the expression of lymphoid enhancer-binding factor 1 (LEF1), vascular endothelial growth factor (VEGF), and insulin-like growth factor 1 (IGF1). We also found that WECP significantly altered the expression levels of apoptosis-related genes in mouse dorsal skin. The enhancement capability of WECP on DPCs proliferation and migration could be abrogated by the Akt-specific inhibitor MK-2206 2HCl. These results suggested that WECP might promote hair growth by modulating DPCs proliferation and migration through the regulation of the Akt/GSK3ß/ß-Catenin signaling pathway.

Shikonin induces ferroptosis in multiple myeloma via GOT1-mediated ferritinophagy.

Multiple myeloma (MM) is an incurable hematological malignancy that lacks effective therapeutic interventions. Ferroptosis is a newly discovered form of cell death that has shown great potential for MM therapy. As a proteasome inhibitor and necroptosis inducer, shikonin (SHK) performs dual functions in MM cells. However, whether SHK inhibits the development of MM via ferroptosis or any other mechanism remains elusive. Here, we provide evidence that SHK treatment was capable of inducing ferroptosis and immunogenic cell death (ICD) in MM. The results showed that SHK treatment induced lactate dehydrogenase release, triggered cell death, evoked oxidative stress, and enhanced ferrous iron and lipid peroxidation levels. Furthermore, treatment with ferroptosis inhibitors reversed SHK-induced cell death, which indicated that ferroptosis contributed to this phenomenon. Meanwhile, ferroptosis was accompanied by the extracellular release of Adenosine 5'-triphosphate (ATP) and High mobility group protein B1 (HMGB1), which are characteristics of ICD. Further investigation showed that glutamic-oxaloacetic transaminase 1 (GOT1) acted as a critical mediator of SHK-induced ferroptosis by promoting ferritinophagy. In conclusion, our findings suggest that SHK exerts ferroptotic effects on MM by regulating GOT1-mediated ferritinophagy. Thus, SHK is a potential therapeutic agent for MM.