Cytotoxic Effects Research Articles

Impact of Protein Corona Formation and Polystyrene NanoparticleFunctionalisationon the Interaction with Dynamic Biomimetic Membranes Comprising of Integrin.

Plastics, omnipresent in the environment, have become a global concern due to their durability and limited biodegradability, especially in the form of microparticles and nanoparticles. Polystyrene (PS), a key plastic type, is susceptible to fragmentation and surface alterations induced by environmental factors or industrial processes. With widespread human exposure through pollution and diverse industrial applications, understanding the physiological impact of PS, particularly in nanoparticle form (PS-NPs), is crucial. This study focuses on the interaction of PS-NPs with model blood proteins, emphasising the formation of a protein corona, and explores the subsequent contact with platelet membrane mimetics using experimental and theoretical approaches. The investigation involves αIIbβ3-expressing cells and biomimetic membranes, enabling real-time and label-free nanoscale precision. By employing quartz-crystal microbalance with dissipation monitoring studies, the concentration-dependent cytotoxic effects of differently functionalised ~210 nm PS-NPs on HEK293 cells overexpressing αIIbβ3 are evaluated in detail. The study unveils insights into the molecular details of PS-NP interaction with supported lipid bilayers, demonstrating that a protein corona formed in the presence of exemplary blood proteins offers protection against membrane damage, mitigating PS-NP cytotoxicity.

Efficacy and safety of novel multifunctional M10 CAR-T cells in HIV-1-infected patients: a phase I, multicenter, single-arm, open-label study

Chimeric antigen receptor T (CAR-T) cells have been proposed for HIV-1 treatment but have not yet demonstrated desirable therapeutic efficacy. Here, we report newly developed anti-HIV-1 CAR-T cells armed with endogenic broadly neutralizing antibodies (bNAbs) and the follicle-homing receptor CXCR5, termed M10 cells. M10 cells were designed to exercise three-fold biological functions, including broad cytotoxic effects on HIV-infected cells, neutralization of cell-free viruses produced after latency reversal, and B-cell follicle homing. After demonstrating the three-fold biological activities, M10 cells were administered to treat 18 HIV-1 patients via a regimen of two allogenic M10 cell infusions with an interval of 30 days, with each M10 cell infusion followed by two chidamide stimulations for HIV-1 reservoir activation. Consequently, 74.3% of M10 cell infusions resulted in significant suppression of viral rebound, with viral loads declining by an average of 67.1%, and 10 patients showed persistently reduced cell-associated HIV-1 RNA levels (average decrease of 1.15 log10) over the 150-day observation period. M10 cells were also found to impose selective pressure on the latent viral reservoir. No significant treatment-related adverse effects were observed. Overall, our study supported the potential of M10 CAR-T cells as a novel, safe, and effective therapeutic option for the functional cure of HIV-1/AIDS.

Exploring the Impact of Irradiation on Glioblastoma Blood-Brain-Barrier Permeability: Insights from Dynamic-Contrast-Enhanced-MRI and Histological Analysis

(1) Background: Glioblastoma (GB) presents a formidable challenge in neuro-oncology due to its aggressive nature, limited treatment options, and poor prognosis. The blood–brain barrier (BBB) complicates treatment by hindering drug delivery to the tumor site, particularly to the infiltrative cells in the margin of the tumor, which are mainly responsible for tumor recurrence. Innovative strategies are therefore needed to enhance drug delivery in the margins of the tumor. This study explores whether irradiation can enhance BBB permeability by assessing hemodynamic changes and the distribution of contrast agents in the core and the margins of GB tumors. (2) Methods: Mice grafted with U-87MG cells were exposed to increasing irradiation doses. The distribution of contrast agents and hemodynamic parameters was evaluated using both non-invasive magnetic resonance imaging (MRI) techniques with gadolinium–DOTA as a contrast agent and invasive histological analysis with Evans blue, a fluorescent vascular leakage marker. Diffusion–MRI was also used to assess cytotoxic effects. (3) Results: The histological study revealed a complex dose-dependent effect of irradiation on BBB integrity, with increased vascular leakage at 5 Gy but reduced leakage at higher doses (10 and 15 Gy). However, there was no significant increase in the diffusion of Gd-DOTA outside the tumor area by MRI. (4) Conclusions: The increase in BBB permeability could be an interesting approach to enhance drug delivery in glioblastoma margins for low irradiation doses. In this model, DCE-MRI analysis was of limited value in assessing the BBB opening in glioblastoma after irradiation.

Characterization and Cytotoxicity Assessment of Synthesized Palladium (II) Complex-Encapsulated Zinc Oxide Nanoparticles for Cancer Treatment.

The treatment of cancer often leads to a range of adverse effects. Encapsulating drugs can mitigate these effects and enhance drug efficacy by enabling a controlled release at the site of interest. This study details the successful synthesis of zinc oxide nanoparticles (ZnONPs) through the precipitation of Zn(NO3)2·6H2O with KOH. A Pd(II) complex drug was synthesized from a Schiff base ligand derived from 2-hydroxybenzohydrazide and (E)-1-(2-(p-tolyl)hydrazono)propan-2-one using potassium tetrachloropalladate(II). This complex was subsequently incorporated into ZnONPs. Characterization of the resulting compounds was performed using Transmission Electron Microscopy (TEM), Dynamic Light Scattering (DLS), Zeta Potential, Fourier Transform Infrared (FTIR) Spectroscopy, and UV-visible spectroscopy. TEM imaging revealed particle sizes of 160.69 ± 4.74 nm for ZnONPs and 185.28 ± 2.3 nm for the Pd(II) complex-encapsulated ZnONPs. The Zeta potential values were 6.53 mV for ZnONPs and 7.36 mV for Pd(II) complex-encapsulated ZnONPs. UV-visible spectroscopy showed an absorption peak at 360 nm for ZnONPs, while the Pd(II) complex-encapsulated ZnONPs exhibited a peak at 410 nm. FTIR analysis indicated the presence of the Pd(II) complex within the ZnONPs, as evidenced by a consistent Zn-O vibrational band at 832 cm-1 and a shift in another peak from 460 to 413 cm-1. Additionally, the detection of a C = N stretching vibration at 1548 cm-1 and a carbonyl stretch at 1626 cm-1 was observed. The Encapsulation Efficiency (E.E.) of the Pd(II) complex was 97.2%. A drug release experiment conducted at pH 7 showed a steady-state release pattern after 16 h, with a cumulative release of 44.3%. The cytotoxic effects of the Pd(II) complex and its encapsulated form in ZnONPs on the MCF-7 cell line were assessed via MTT test. The Pd(II) complex encapsulated within ZnONPs exhibited decreased toxicity relative to the unencapsulated drug, as evidenced by a higher IC50 value of 418.5 μg/ml. This suggests that the encapsulation facilitates a sustained release, which allows for targeted accumulation within cells. The elevated IC50 value indicates that the drug delivery system may be engineered to modulate the release of the drug in a more controlled manner, potentially resulting in a prolonged release profile rather than an immediate therapeutic impact.

Marine Prostanoids with Cytotoxic Activity from Octocoral Clavularia spp.

Octocoral of the genus Clavularia is a kind of marine invertebrate possessing abundant cytotoxic secondary metabolites, such as prostanoids and dolabellanes. In our continuous natural product study of C. spp., two previously undescribed prostanoids [clavulone I-15-one (1) and 12-O-deacetylclavulone I (2)] and eleven known analogs (3–13) were identified. The structures of these new compounds were elucidated based on analysis of their 1D and 2D NMR, HRESIMS, and IR data. Additionally, all tested prostanoids (1 and 3–13) showed potent cytotoxic activities against the human oral cancer cell line (Ca9-22). The major compound 3 showed cytotoxic activity against the Ca9-22 cells with the IC50 value of 2.11 ± 0.03 μg/mL, which echoes the cytotoxic effect of the coral extract. In addition, in silico tools were used to predict the possible effects of isolated compounds on human tumor cell lines and nitric oxide production, as well as the pharmacological potentials.

Investigation of the role of KATP channels in the cytotoxic effect of cypermethrin on rat-derived aortic smooth muscle cells

We investigate role of ATP sensitive potassium (KATP) channel in cytotoxic effect of cypermethrin on rat aortic smooth muscle cells. Cytotoxicity analysis was performed at 0, 0.1, 0.5, 10, 50, and 100 µM concentrations of cypermethrin and the cell index (CI) was calculated. KATP currents were recorded using patch clamp technique for 50 and 100 µM concentrations and channel conductivity was determined by obtaining current-voltage characteristics. No cytotoxic effect was observed in the first 72 hours. At the 96th hour, only at 100 µM concentration, the CI value decreased significantly compared to control group and at 120 and 144th hours, it was observed that the CI value decreased significantly at all concentrations. Currents and conductivities were significantly decreased at 50 and 100 µM concentrations. Results gave clues that cypermethrin causes a cytotoxic effect on vascular smooth muscles and that KATP channels may have a role in the emergence of this effect.

Enhanced systemic antitumor efficacy of PD-1/PD-L1 blockade with immunological response induced by photodynamic therapy.

Photodynamic therapy (PDT) is an antitumor therapy and has traditionally been regarded as a localized therapy in itself. However, recent reports have shown that it not only exerts a direct cytotoxic effect on cancer cells but also enhances body's tumor immunity. We hypothesized that the immunological response induced by PDT could potentially enhance the efficacy of programmed death-1 (PD-1) / programmed death-ligand 1 (PD-L1) blockade. The cytotoxic effects of PDT on colon 26 cells were investigated in vitro using the WST assay. We investigated whether the antitumor effect of anti-PD-1 antibodies could be amplified by the addition of PDT. We performed combination therapy by randomly allocating tumor-bearing mice to four treatment groups: control, anti-PD-1 antibodies, PDT, and a combination of anti-PD-1 antibodies and PDT. To analyze the tumor microenvironment after treatment, the tumors were resected and pathologically evaluated. The viability rate of colon 26 cells decreased proportionally with the laser dose. In vivo experiments for combined PDT and anti-PD-1 antibody treatment, combination therapy showed an enhanced antitumor effect compared with the control. Immunohistochemical findings of the tumor microenvironment 10 days after PDT indicated that the number of CD8+ cells, the area of Iba-1+ cells and the area expressing PD-L1 were significantly higher in tumors treated with combination therapy than in tumors treated with anti-PD-1 antibody alone, PDT alone, or the control. PDT increased immune cell infiltration into the tumor microenvironment. The immunological response induced by PDT may enhance the efficacy of PD-1/PD-L1 blockade.

Assessment of chemotherapeutic effects on cancer cells using adhesion noise spectroscopy

With cancer as one of the leading causes of death worldwide, there is a need for the development of accurate, cost-effective, easy-to-use, and fast drug-testing assays. While the NCI 60 cell-line screening as the gold standard is based on a colorimetric assay, monitoring cells electrically constitutes a label-free and non-invasive tool to assess the cytotoxic effects of a chemotherapeutic treatment on cancer cells. For decades, impedance-based cellular assays extensively investigated various cell characteristics affected by drug treatment but lack spatiotemporal resolution. With progress in microelectrode fabrication, high-density Complementary Metal Oxide Semiconductor (CMOS)-based microelectrode arrays (MEAs) with subcellular resolution and time-continuous recording capability emerged as a potent alternative. In this article, we present a new cell adhesion noise (CAN)-based electrical imaging technique to expand CMOS MEA cell-biology applications: CAN spectroscopy enables drug screening quantification with single-cell spatial resolution. The chemotherapeutic agent 5-Fluorouracil exerts a cytotoxic effect on colorectal cancer (CRC) cells hampering cell proliferation and lowering cell viability. For proof-of-concept, we found sufficient accuracy and reproducibility for CAN spectroscopy compared to a commercially available standard colorimetric biological assay. This label-free, non-invasive, and fast electrical imaging technique complements standardized cancer screening methods with significant advances over established impedance-based approaches.

Polyvinylpyrrolidone‐functionalized graphene oxide as a nanocarrier for dual‐drug delivery of quercetin and curcumin against HeLa cancer cells

AbstractThis study is to develop a nanocarrier based on polyvinylpyrrolidone (PVP)‐functionalized graphene oxide (GO–PVP), loaded with both curcumin (CUR) and quercetin (QSR), and then its performance compared with nanocarriers carrying the drugs separately. The study also aimed to investigate the cytotoxic effects of these nanocarriers on HeLa cancer cells. To achieve this, GO was synthesized using a modified version of Hummer's method and subsequently functionalized with PVP. Drug loading onto the GO and GO–PVP nanocarriers was achieved through hydrophobic interactions. Furthermore, the ability of the nanocarriers to accommodate a single drug or a combination of drugs was examined. In our study, combined system shows higher drug loading, that is, 28.1% of QSR and 24.34% of CUR onto GO–PVP–QSR–CUR nanocarrier in comparison to single drug nanocarrier systems GO–PVP–QSR and GO–PVP–CUR which loaded 22.5% of QSR and 18.73% of CUR, respectively. Notably, the synthesized nanocarrier exhibited a pH‐sensitive drug release pattern. These results collectively suggest that GO–PVP–CUR–QSR displayed significantly higher cytotoxicity against HeLa cancer cells compared to both single‐drug nanocarrier systems at the specified concentrations. In addition, future pre‐clinical and clinical studies to evaluate the safety and efficacy of GO–PVP–CUR–QSR for cancer treatment are strongly recommended.Highlights Developed nanocarrier based on polyvinylpyrrolidone functionalized GO (GO–PVP). The GO–PVP nanocarrier was loaded with both curcumin (CUR) and quercetin (QSR). GO–PVP displays a higher loading capacity for both QSR and CUR compared to GO. QSR‐ and CUR‐loaded GO–PVP nanocarriers exhibited higher cytotoxic effects.

Asparagine transport through SLC1A5/ASCT2 and SLC38A5/SNAT5 is essential for BCP-ALL cell survival and a potential therapeutic target.

B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) blasts strictly depend on the transport of extra-cellular asparagine (Asn), yielding a rationale for L-asparaginase (ASNase) therapy. However, the carriers used by ALL blasts for Asn transport have not been identified yet. Exploiting RS4;11 cells as BCP-ALL model, we have found that cell Asn is lowered by either silencing or inhibition of the transporters ASCT2 or SNAT5. The inhibitors V-9302 (for ASCT2) and GluγHA (for SNAT5) markedly lower cell proliferation and, when used together, suppress mTOR activity, induce autophagy and cause a severe nutritional stress, leading to a proliferative arrest and a massive cell death in both the ASNase-sensitive RS4;11 cells and the relatively ASNase-insensitive NALM-6 cells. The cytotoxic effect is not prevented by coculturing leukaemic cells with primary mesenchymal stromal cells. Leukaemic blasts of paediatric ALL patients express ASCT2 and SNAT5 at diagnosis and undergo marked cytotoxicity when exposed to the inhibitors. ASCT2 expression is positively correlated with the minimal residual disease at the end of the induction therapy. In conclusion, ASCT2 and SNAT5 are the carriers exploited by ALL cells to transport Asn, and ASCT2 expression is associated with a lower therapeutic response. ASCT2 may thus represent a novel therapeutic target in BCP-ALL.

Mangrove mud clam as an effective sentinel species for monitoring changes in coastal microplastic pollution

The worldwide mangrove shorelines are experiencing considerable contamination from microplastics (MPs). Finding an effective sentinel species in the mangrove ecosystem is crucial for early warning of ecological and human health risks posed by coastal microplastic pollution. This study collected 186 specimens of the widely distributed mangrove clam (Geloina expansa, Solander, 1786) from 18 stations along the Leizhou Peninsula, the largest mangrove coast in Southern China. This study discovered that mangrove mud clams accumulated a relatively high abundance of MPs (2.96 [1.61 – 6.03] items · g-1) in their soft tissue, wet weight, as compared to previously reported levels in bivalves. MPs abundance is significantly (p < 0.05 or 0.0001) influenced by coastal urban development, aquaculture, and shell size. Furthermore, the aggregated MPs exhibit a significantly high polymer risk index (Level III, H = 353.83). The estimated annual intake risk (EAI) from resident consumption, as calculated via a specific questionnaire survey, was at a moderate level (990 – 2,475, items ·g -1 ·Capita -1). However, the EAI based on suggested nutritional standards is very high, reaching 113,990 (79,298 – 148,681), items · g -1 · Capita -1. We recommend utilizing the mangrove mud clam as sentinel species for the monitoring of MPs pollution changing across global coastlines. Environmental ImplicationMicroplastics are pervasive pollutants in the marine environment, posing a threat to ecological and human food safety. In addition to physical impacts such as gut blockage, there is growing evidence of the cytotoxic and genotoxic effects of microplastics. The mangrove mud clam, which lives in the landward frontiers of coastlines around the world, is exposed to relatively high environmental concentrations of microplastics. This study found significant effects of coastal human activities on the accumulation of microplastics in mangrove mud clams. The mangrove mud clam can serve as an effective sentinel species for early detection of microplastic accumulation risks in coastlines worldwide.

Exploring In Vitro Immunomodulatory Properties of Moss Atrichum undulatum Extracts

Bryophytes are rich sources of diverse secondary metabolites with a wide range of biological activities, including anti-inflammatory, antitumor and antimicrobial effects. The aim of this study was to investigate the chemical composition of extracts from two different genotypes (Serbian and Hungarian) of the axenic moss Atrichum undulatum and evaluate the immunomodulatory potential of the prepared extracts in vitro. Both genotypes of moss samples were cultivated in vitro and subsequently extracted in a Soxhlet apparatus with methanol or ethyl acetate. The highest concentration of total phenolic compounds was found in the methanolic extract of the Serbian genotype (54.25 mg GAE/g extract), while the ethyl acetate extract of the Hungarian genotype showed the highest concentration of phenolic acids (163.20 mg CAE/extract), flavonoids (35.57 mg QE/extract), and flavonols (2.25 mg QE/extract). The extracts showed anti-neuroinflammatory properties by reducing the production of reactive oxygen species, nitric oxide, and tumor necrosis factor alpha by lipopolysaccharide-stimulated microglial cells. Moreover, they mitigated the cytotoxic effects of the pro-inflammatory mediators produced by activated microglia on neurons. The data obtained suggest that extracts from A. undulatum moss have promising anti-neuroinflammatory and neuroprotective properties, making them interesting candidates for further research to combat neuroinflammation.

In Vitro Evaluation of Antioxidant, Antiglycation and Anti-Protein Denaturation Potentials of Indigenous Myanmar Medicinal Plant Extracts

ABSTRACT The antioxidant, anti-glycation and anti-protein denaturation potential of test extracts were assessed by hemolysis, antioxidant, antiglycation, and anti-protein denaturation assays. The cytotoxic effect of the tested extracts ranged from 6.18 ± 0.15 to 29.33 ± 1.47%. The highest effect was noted in C. carandas, H. cannabinus, T. chebula and H. indicum in antioxidant assay. The phenolic content ranged from 84.73 to 238.23 mg GAE g−1 of extract and the flavonoid was 36.05 to 184.26 mgRE g−1 of extracts. Antiglycation activity exhibited in M. longifolia, T. chebula, H. cannabinus and H. indicum (leaf). C. carandas, H. cannabinus and H. indicum showed significant IC50 value in protein denaturation.

Lactic Acid Bacteria-Derived Postbiotics as Adjunctive Agents in Breast Cancer Treatment to Boost the Antineoplastic Effect of a Conventional Therapeutic Comprising Tamoxifen and a New Drug Candidate: An Aziridine–Hydrazide Hydrazone Derivative

Breast cancer is associated with high mortality and morbidity rates. As about 20–30% of patients exhibiting ER-positive phenotype are resistant to hormonal treatment with the standard drug tamoxifen, finding new therapies is a necessity. Postbiotics, metabolites, and macromolecules isolated from probiotic bacteria cultures have been proven to have sufficient bioactivity to exert prohealth and anticancer effects, making them viable adjunctive agents for the treatment of various neoplasms, including breast cancer. In the current study, postbiotics derived from L. plantarum and L. rhamnosus cultures were assessed on an in vitro breast cancer model as potential adjunctive agents to therapy utilizing tamoxifen and a candidate aziridine–hydrazide hydrazone derivative drug. Cell viability and cell death processes, including apoptosis, were analyzed for neoplastic MCF-7 cells treated with postbiotics and synthetic compounds. Cell cycle progression and proliferation were analyzed by PI-based flow cytometry and Ki-67 immunostaining. Postbiotics decreased viability and triggered apoptosis in MCF-7, modestly affecting the cell cycle and showing a lack of negative impact on normal cell viability. Moreover, they enhanced the cytotoxic effect of tamoxifen and the new candidate drug toward MCF-7, accelerating apoptosis and the inhibition of proliferation. This illustrates postbiotics’ potential as natural adjunctive agents supporting anticancer therapy based on synthetic drugs.

Biodegradable Zn-2Cu-0.5Zr alloy promotes the bone repair of senile osteoporotic fractures via the immune-modulation of macrophages

Delayed bone-healing of senile osteoporotic fractures remains a clinical challenge due to the alterations caused by aging in bone and immune systems. The novel biomaterials that address the deficiencies in both skeletal cells and immune systems are required to effectively treat the bone injuries of older patients. Zinc (Zn) has shown promise as a biodegradable material for use in orthopedic implants. To address the bone-healing deficiencies in elderly patients with bone injuries, we developed a biodegradable Zn-based alloy (Zn–2Cu-0.5Zr) with enhanced mechanical properties, including a yield strength of 198.7 MPa and ultimate tensile strength of 217.6 MPa, surpassing those of pure Zn and Zn–2Cu alloys. Cytotoxicity tests conducted on bone marrow mesenchymal stem cells (BMSCs) and MC3T3-E1 cells demonstrated that the extracts from Zn–2Cu-0.5Zr alloy exhibited no observable cytotoxic effects. Furthermore, the extracts of Zn–2Cu-0.5Zr alloy exhibited significant anti-inflammatory effects through regulation of inflammation-related cytokine production and modulation of macrophage polarization. The improved immune-osteo microenvironment subsequently contributed to osteogenic differentiation of BMSCs. The potential therapeutic application of Zn–2Cu-0.5Zr in senile osteoporotic fracture was tested using a rat model of age-related osteoporosis. The Zn–2Cu-0.5Zr alloy met the requirements for load-bearing applications and accelerated the healing process in a tibial fracture in aged rats. The imaging and histological analyses showed that it could accelerate the bone-repair process and promote the fracture healing in senile osteoporotic rats. These findings suggest that the novel Zn–2Cu-0.5Zr alloy holds potential for influencing the immunomodulatory function of macrophages and facilitating bone repair in elderly individuals with osteoporosis.

Naringenin ameliorates cytotoxic effects of bisphenol A on mouse Sertoli cells by suppressing oxidative stress and modulating mitophagy: An experimental study

Background: Bisphenol A (BPA), an endocrine-disrupting agent, is widely used as polycarbonate plastics for producing food containers. BPA exposure at environmentally relevant concentrations can cause reproductive disorders. Objective: The effect of Naringenin (NG) on BPA-induced Sertoli cell toxicity and its mechanism was examined in the present study. Materials and Methods: In this experimental-laboratory study, the mouse TM4 cells were treated to BPA (0.8 μm) or NG for 24 hr at concentrations of 10, 20, and 50 μg/ml. Cell viability, reactive oxygen species (ROS) production, malondialdehyde (MDA) content, antioxidant level, and mitochondrial membrane potential (MMP) were examined. The expression of mitophagy-related genes, including Parkin and PTEN-induced putative kinase 1 (Pink1), was also evaluated. Results: BPA significantly lowered the viability of the Sertoli cells (p = 0.004). Pink1 and Parkin levels of the BPA group were significantly increased (p &lt; 0.001), while the MMP was considerably decreased (p &lt; 0.001). BPA raised MDA and ROS levels (p &lt; 0.001) and reduced antioxidant biomarkers (p = 0.003). NG at the 20 and 50 μg/ml concentrations could significantly improve the viability and MMP of TM4 cells (p = 0.034). NG depending on concentration, could decrease Pink1 and Parkin at mRNA and protein levels compared to the BPA group (p = 0.024). NG enhanced antioxidant factors, while ROS and MDA levels were decreased in the BPA-exposed cells. Conclusion: The beneficial impacts of NG on BPA-exposed Sertoli cells are related to the suppression of mitophagy and the reduction of oxidative stress. Key words: Mitophagy, Naringenin, Sertoli cells, Bisphenol A, Reactive oxygen species, Pink1, Parkin.

Oleanolic acid inhibits cholesterol synthesis by suppressing the expression and enzymatic activity of HMGCR

ABSTRACT This study investigated the impact of Oleanolic Acid (OA) on cholesterol metabolism and. MTT assays demonstrated that OA had no cytotoxic effects on HepG2 cells at concentrations below 20 μM. Subsequent experiments focused on 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR), a key enzyme in cholesterol biosynthesis. OA significantly reduced HMGCR protein expression without affecting other enzymes. Further investigations revealed that OA reduced the protein and mRNA expression of HMGCR and its upstream regulator Sterol regulatory element binding protein-2 (SREBP-2) in HepG2 cells. OA activated Adenosine 5’-monophosphate (AMP)-activated protein kinase (AMPK), enhancing HMGCR phosphorylation and inhibiting its activity. Molecular docking experiments suggested that OA could suppress HMGCR enzymatic activity through hydrophobic interactions, reducing catalytic efficiency. Overall, OA downregulated HMGCR expression and activity, leading to decreased cholesterol synthesis. These findings highlight OA’s regulatory role in cholesterol metabolism and its potential for improving atherosclerosis (AS), supporting its application in functional food development.

Phospholipid-Anchored Ligand Conjugation on Extracellular Vesicles for Enhanced Cancer Targeting.

Extracellular vesicles (EVs) are recognized as potential candidates for next-generation drug delivery systems. However, the inherent cancer-targeting efficiency is unsatisfactory, necessitating surface modification to attach cell-binding ligands. By utilizing phospholipase D from Streptomyces in combination with maleimide-containing primary alcohol, the authors successfully anchored ligands onto milk-derived EVs (mEVs), overcoming the issues of ligand leakage or functional alteration seen in traditional methods. Quantitative nano-flow cytometry demonstrated that over 90% of mEVs are effectively modified with hundreds to thousands of ligands. The resulting mEV formulations exhibited remarkable long-term stability in conjugation proportion, ligand number, size distribution, and particle concentration, even after months of storage. It is further shown that conjugating transferrin onto mEVs significantly enhanced cellular uptake and induced pronounced cytotoxic effects when loaded with paclitaxel. Overall, this study presents a highly efficient, stable, cost-effective, and scalable ligand conjugation approach, offering a promising strategy for targeted drug delivery of EVs.

Effect of Pyridoxine Derivative B6NO on Transcription Factor Nrf2 Activity and Cytotoxic Properties of Doxorubicin In Vitro.

The effect of a new pyridoxine derivative B6NO on doxorubicin cytotoxicity and Nrf2-dependent cellular processes in vitro was studied. Antioxidant B6NO enhances the cytotoxic effect of doxorubicin on tumor cells, which is associated with G2/M cell division arrest and an increase in activity of proapoptotic enzyme caspase-3. The antioxidant promotes intracellular accumulation and nuclear translocation of Nrf2 transcription factor in non-tumor and tumor cells. In non-tumor cells, B6NO increases the expression of antioxidant system proteins and reduces ROS generation in the presence of doxorubicin. In tumor cells, no activation of Nrf2-dependent processes occurs under the action of the antioxidant. Our findings demonstrate the prospect of further studies of pyridoxine derivatives as antioxidants to reduce adverse reactions during chemotherapy.

Evaluation of the cytotoxic activities of the essential oil from Pistacia atlantica Desf. oleoresin on human gastric cancer cell lines.

Numerous herbal products have been the subject of research regarding their potential role in cancer prevention or adjuvant therapy. Pistacia atlantica and its main phytochemicals have garnered significant attention for their potential anti-cancer effects. The study aimed to assess the growth inhibitory effects of P. atlantica essential oil (PAEO) on MKN-45 and AGS cells. This study quantified the volatile compounds in PAEO using Gas Chromatography-Mass Spectrometry (GC-MS). Subsequently, MKN-45 and AGS cells were treated with varying concentrations of PAEO (5%, 2.5%, 1.25%, 0.625%, 0.3125%, 0.156%, 0.0781%, 0.0391%, 0.0195%) for 24h. Cell viability was evaluated through the MTT assay. The impact of PAEO on gene expression was investigated by quantifying the mRNA levels of Bax and Bcl2 in the various experimental groups using quantitative Real-Time PCR (qRT-PCR) analysis. Additionally, flow cytometry was utilized to evaluate apoptosis in the treated cells. The analysis of PAEO revealed that α-pinene was the predominant monoterpene, constituting 87.9% of the oil composition. The cytotoxic effects of PAEO were evaluated, and it was found that the oil significantly reduced the viability of MKN-45 and AGS cells. The IC50 for MKN-45 cells was determined to be 1.94 × 10-3% after 24h of treatment, while for AGS cells the IC50 was 2.8 × 10-3% after 24h. Additionally, the research revealed that PAEO triggered a notable rise in apoptotic cells in both AGS and MKN-45 cell lines. Moreover, at the molecular level, the findings indicated an increase in Bax expression and a decrease in Bcl2 mRNA expression, providing further evidence of the induction of apoptosis in both MKN-45 and AGS cell lines following PAEO treatment. The findings of this study offer evidence supporting the cytotoxic effects of PAEO on gastric cancer cell lines by promoting apoptosis. The findings suggest that PAEO may offer potential as a therapeutic candidate in managing and treating gastric cancer.