Biomolecules & Therapeutics最新文献

Cynaropicrin, a sesquiterpene lactone found in artichoke leaves exerts diverse pharmacological effects. This study investigated whether cynaropicrin has a paraptosis-like cell death effect in human hepatocellular carcinoma Hep3B cells in addition to the apoptotic effects reported in several cancer cell lines. Cynaropicrin-induced cytotoxicity and cytoplasmic vacuolation, a key characteristic of paraptosis, were not ameliorated by inhibitors of necroptosis, autophagy, or pan caspase inhibitors in Hep3B cells. Our study showed that cynaropicrin-induced cytotoxicity was accompanied by mitochondrial dysfunction and endoplasmic reticulum stress along with increased cellular calcium ion levels. These effects were significantly mitigated by endoplasmic reticulum stress inhibitor or protein synthesis inhibitor. Moreover, cynaropicrin treatment in Hep3B cells increased reactive oxygen species generation and downregulated apoptosis-linked gene 2-interacting protein X (Alix), a protein that inhibits paraptosis. The addition of the reactive oxygen species scavenger N-acetyl-L-cysteine (NAC) neutralized cynaropicrin-induced changes in Alix expression and endoplasmic reticulum stress marker proteins counteracting endoplasmic reticulum stress and mitochondrial impairment. This demonstrates a close relationship between endoplasmic reticulum stress and reactive oxygen species generation. Additionally, cynaropicrin activated p38 mitogen activated protein kinase and a selective p38 mitogen activated protein kinase blocker alleviated the biological phenomena induced by cynaropicrin. NAC pretreatment showed the best reversal of cynaropicrin induced vacuolation and cellular inactivity. Our findings suggest that cynaropicrin induced oxidative stress in Hep3B cells contributes to paraptotic events including endoplasmic reticulum stress and mitochondrial damage.

Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme that plays a pivotal role in immune regulation by metabolizing tryptophan into kynurenine, leading to T cell suppression and promoting immune tolerance. However, persistent activation of IDO1 can lead to prolonged immune stimulation in inflammatory conditions such as skin diseases and chronic inflammation. In this study, we developed modified peptide nucleic acids (PNAs) conjugated with cationic lipid chains to target IDO1 pre-mRNA and evaluated their anti-inflammatory effects in human keratinocytes. The modified PNAs demonstrated enhanced solubility, robust binding affinity, and effective penetration into keratinocytes. Quantitative PCR results showed significant downregulation of IDO1 and pro-inflammatory cytokines such as IL-6, IL-8, and PTGS2 in interferon γ (IFNγ)-treated keratinocytes. These findings suggest that cell-penetrating PNAs targeting IDO1 hold potential as a therapeutic approach for inflammatory skin disorders and chronic inflammation.

Triple-negative breast cancer (TNBC) is an aggressive cancer subtype lacking targeted therapies and is characterized by high recurrence rates and poor prognosis. Recent advances in targeting DNA damage response (DDR) pathways using poly (ADP‒ribose) polymerase (PARP) inhibitors offer promising therapeutic strategies, especially for TNBC patients with BRCA1/2 mutations. This study reports the development and characterization of ART-446, a novel and selective CHK2 inhibitor. ART-446 showed potent activity against TNBC, regardless of BRCA deficiency, and it also reversed PARP inhibitor resistance. ART-446 potently inhibited CHK2 (IC₅₀: 9.06 nM) with high selectivity over other kinases; it synergized with the PARP inhibitor olaparib, enhancing DNA damage, inducing G2/M cell cycle arrest, and promoting apoptosis in both BRCA-mutant and wild-type TNBC cells. Mechanistic analyses revealed that ART-446 sensitized BRCA mutant and WT cells to PARP inhibitors by impairing DNA repair and increasing the accumulation of DNA damage. Importantly, ART-446 disrupted both homologous recombination and nonhomologous end-joining repair pathways, addressing a key limitation of PARP inhibitor monotherapy-resistance in BRCA-proficient cancers. In vivo, the combination of ART-446 and olaparib significantly reduced tumor growth in TNBC xenograft models without noticeable toxicity. The combined treatment increased DNA damage signaling, as evidenced by elevated γH2AX levels, and enhanced the sensitivity of BRCA2-deficient cells to ART-446. These findings underscore the potential of ART-446 to exploit DNA repair deficiencies and overcome resistance mechanisms associated with PARP inhibitors. By addressing the limitations of current treatments and expanding the utility of PARP inhibitors, ART-446 represents a promising candidate for DDR-targeted therapies, offering a novel approach to improve the outcomes of patients with TNBC.

Ovarian cancer usually metastasizes from the ovary to adjacent organs through direct invasion with blood vessels formed by endothelial cells. Targeting apoptosis of ovarian cancer and angiogenesis is promising for anticancer therapy. Leaves of Ipomoea sp. have reportedly shown promise in treating ovarian cancer. Here, we investigated the apoptosis-inducing and anti-angiogenic effects of compounds isolated from Ipomoea batatas vines (IBV). Phytochemical examination of IBV led to the isolation and verification of eight compounds (1-8): chlorogenic acid (1), 3,4-dicaffeoylquinic acid (2), 3,5-dicaffeoylquinic acid (3), 4,5-dicaffeoylquinic acid (4), 1,3,5-tricaffeoylquinic acid (5), N-trans-feruloyltyramine (6), scopoletin (7), and esculetin (8). Of these, 1,3,5-tricaffeoylquinic acid (5) showed the highest cytotoxicity in A2780 human ovarian cancer cells, inducing apoptotic death in more than 37% cells and decreasing viability to less than 25% at 100 μM. Compound 5 increased the levels of cleaved caspase-8, Bax, cleaved PARP, and caspase-3/9, and decreased the levels of cleaved Bcl-2. Further, 5 inhibited tubule formation in HUVECs. VEGFR2, ERK, PI3K, Akt, and mTOR protein expression was also suppressed by 5. Then, a simple, rapid, and reliable LC-MS/ MS method was developed to determine the contents of the isolated compounds from IBV. Overall, 5 has potential for treating ovarian cancer as it induces apoptosis in ovarian cancer cells and inhibits tube formation.

The incidence of cutaneous squamous cell carcinoma (CSCC) is increasing rapidly. This study discussed the effects of artesunate (ART) on CSCC cell proliferation and migration via the solute carrier family 7 member 11 (SLC7A11)-glutathione peroxidase 4 (GPX4) pathway. MTT assessed cell viability and analyzed the IC₅₀ value (69.26 μM). Accordingly, human CSCC cells (A431) were cultured in vitro, and treated with 70 μM ART, Ferrostatin-1, oe-SLC7A11, and C646, with cell biological behavior assessed. The potential targets of ART were predicted. p53 acetylation and protein stability and ART-p300 binding were examined. Thymusless nude mice were subcutaneously inoculated with A431 cells, and treated with ART and C646. ART-treated A431 cells showed weakened proliferation, migration, lactate dehydrogenase levels, oxidized glutathione/glutathione ratio, reactive oxygen species, malondialdehyde, and active Fe²⁺ levels, which could be reversed by suppressing ferroptosis. ART promoted p53 acetylation and protein stability and curbed the SLC7A11-GPX4 pathway by targeting p300. ART stimulated ferroptosis via the SLC7A11-GPX4 pathway, thereby repressing CSCC cell proliferation and migration, which were counteracted by p300 inhibition. ART regulated the SLC7A11-GPX4 pathway by up-regulating the p300-p53 axis, thereby hindering tumor growth in vivo. Collectively, ART inhibits CSCC proliferation and migration by modulating the SLC7A11-GPX4 pathway through the p300-p53 axis.

Natural killer (NK) cells are innate immune cells that are crucial for anticancer activity and have been developed as an immune cell therapy for leukemia. However, their limited effectiveness against solid tumors has prompted research into methods to enhance NK cell activity through combination therapies. Health supplements capable of boosting immune surveillance against tumor cells are gaining attention owing to their potential benefits. Resveratrol, a stilbenoid produced by several plants including peanuts and grapes, reportedly exerts anticancer effects and can activate immune cells. The peanut sprout extract cultivated with fermented sawdust medium (PSEFS) is rich in resveratrol, leveraging its health benefits in terms of the dry weight of herbal products, thus maximizing the utilization of resveratrol's beneficial properties. Our study compared the efficacy of resveratrol and PSEFS and revealed that PSEFS significantly enhanced NK cell activation compared with an equivalent dose of resveratrol. We investigated the ability of PSEFS to potentiate NK cell anticancer activity, focusing on NK cell survival, tumor cell lysis, and NK cell activation in PSEFS-administered mice. Our findings suggest that PSEFS could be a potential NK cell booster for cancer immunotherapy.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is challenging to treat and lacks targeted therapeutic drugs in the clinic. Natural active ingredients provide promising opportunities for discovering and developing targeted therapies for TNBC. This study investigated the effects of daurisoline on TNBC and elucidated its potential mechanisms. Using network pharmacology, a correlation was identified between daurisoline, derived from Menispermum dauricum, and breast cancer, particularly involving the Notch signaling pathway. The effects of daurisoline on the proliferation, migration, and apoptosis of MDA-MB-231 and MDA-MB-468 cells were evaluated in vitro. Additionally, the impact of daurisoline on the growth of MDA-MB-231 xenograft tumors in nude mice was assessed through in vivo experiments. Expression levels of Notch signaling pathway-related proteins, including Notch-1, NICD, PSEN-1, Bax, and Bcl-2, were examined using molecular docking and Western blotting to explore the underlying mechanisms of daurisoline's anti-breast cancer effects. It was revealed that daurisoline could effectively inhibit the proliferation and migration of MDA-MB-231 and MDA-MB-468 cells and promote apoptosis. Furthermore, it significantly reduced the growth of subcutaneous tumors in nude mice. Notably, daurisoline could reduce the hydrolytic activity of γ-secretase by binding to the catalytic core PSEN-1, thereby inhibiting activation of the γ-secretase/Notch axis and contributing to its anti-TNBC effects. This study supported the development of naturally targeted drugs for TNBC and provided insights into the research on dibenzylisoquinoline alkaloids, such as daurisoline.

Melanin is a bio-pigment molecule synthesized by melanocytes. Its role is to shield the skin from ultraviolet radiation. Nonetheless, aberrant melanin production, whether excessive or deficient, can lead to conditions such as vitiligo, freckles, melanocytic nevi, and even melanoma. The biosynthetic pathway of melanin is known as melanogenesis, which is regulated by various transcription factors and enzymatic processes. Piperine (PPN), an alkaloid compound extracted from Piper retrofractum Vahl., was investigated for its potential anti-fungal and anti-inflammatory effects. Our hypothesis centered on the inhibition of melanin biosynthesis in response to PPN treatment. Subsequently, it was observed that PPN treatment resulted in a dose-dependent reduction in melanin production, accompanied by a decrease in tyrosinase activity. Furthermore, PPN was found to downregulate the protein levels of key melanogenesis-related genes. Additionally, PPN was observed to elevate the phosphorylation levels of ERK. To assess the role of ERK signaling in PPN-induced melanogenesis regulation, PD98059, an ERK inhibitor, was used. When Melan-A cells were treated with PD98059, the reduced expression level of MITF and melanin content induced by piperine were restored. Additionally, phosphorylation of ERK increased the phosphorylation of MITF at Ser73. This phosphorylated MITF leads to ubiquitination, and ultimately, the protein level of MITF decreases through proteasomal degradation. Likewise, when Melan-A cells were treated with MG132, a proteasomal inhibitor, the reduced expression level of MITF and melanin content induced by piperine were restored. Consequently, PPN can be a potential candidate for application as a skin whitening agent or in formulations to mitigate hyperpigmentation.

Depression is a widespread psychiatric disorder with complex pathogenesis and unsatisfactory therapeutic effects. As a native flavonoid, Isorhamnetin (ISO) has been deemed to exert neuroprotective effects by antioxidation and regulation of immunity. However, no reports of anti-depressed effect of ISO have yet been found. The present study was conducted to clarify the mechanism basis of anti-depressed effect of ISO utilizing behavioral, biochemical, molecular approaches in vitro and in vivo and bio-informatics analysis. The effects of ISO on depressed mice was investigated through the SPT and FST, and the lesions were examined by H&E staining. Besides, the inflammatory factor and indicator in kynurenine pathway were assessed through detection kits, and the microbiota were checked by 16sRNA. Molecular docking study was performed to investigate the target of ISO. Additionally, Western blot was used to test the activation of PI3K/AKT signaling pathway. The results indicated that ISO could enhance the sugar water preference of mice in SPT and reduce immobility time in FST. Further more, ISO suppressed peripheral and central inflammation, regulated the changes in kynurenine pathway and gut microbiota, inhibited activation of PI3K/AKT pathway, and presented good binding patterns with target proteins on PI3K/AKT signaling pathway. Collectively, these findings demonstrate that ISO alleviated depression-like behaviour by normalizing inflammation-induced dysregulation of the crosstalk between KP and gut microbiota disorder through regulated PI3K/AKT/NF-κB pathway.