Pro-apoptotic Effects Research Articles

Araloside A alleviates sepsis-induced acute lung injury via PHD2/HIF-1α in macrophages

BackgroundAcute lung injury (ALI)-induced acute respiratory syndromes is a critical pathological sequala of sepsis. Araloside A (ARA), extracted from Aralia taibaiensis, possesses anti-oxidative and pro-apoptotic effects, as well as a protective effect against inflammatory diseases such as gastric ulcers. However, its impact on progression of ALI remains unknown. This study seeks to assess the therapeutic effect of ARA in sepsis-induced ALI, and to elucidate the underlying mechanism. MethodsSepsis-induced ALI was induced in C57BL/6 mice using lipopolysaccharide (LPS) or cecal ligation and puncture (CLP) along with simultaneous administration of ARA. In vitro, bone marrow-derived macrophages (BMDMs) and RAW264.7 cells were exposed to LPS to activate proinflammatory macrophages in the presence/absence of ARA. RNA sequencing of BMDMs was then conducted to elucidate the detailed mechanism. ResultsTreatment of mice with ARA led to a significant reduction in serum level of inflammatory cytokines, ameliorated sepsis-induced ALI (i.e., impaired barrier integrity, cell apoptosis), and increased survival of septic mice. In vitro, ARA effectively inhibited activation of proinflammatory BMDMs. In addition, RNA sequencing revealed that the PHD2/HIF-1α signaling played a critical role in the anti-inflammatory effects of ARA. ARA suppressed proinflammatory macrophages to ameliorate lung inflammation in septic mice by restoring PHD2/HIF-1α signaling. ConclusionsARA prevented mice from the fatal effects of sepsis by restoring PHD2/HIF-1α signaling, thereby inhibiting activation of proinflammatory macrophages. These findings suggest that ARA could be a promising therapy for sepsis-induced ALI.

Synergistic Inhibition of Pancreatic Cancer Cell Growth and Migration by Gemcitabine and Withaferin A.

Pancreatic cancer remains one of the most lethal malignancies due to its aggressive nature and resistance to conventional therapies. This study investigates the anti-proliferative, pro-apoptotic, and anti-migratory effects of Gemcitabine (GC) and Withaferin A (WFA) on pancreatic cancer cell lines PANC-1 and Hs766t. The MTS assay revealed that both compounds effectively inhibit cell proliferation, with WFA showing a stronger effect in Hs766t cells. Flow cytometry analysis demonstrated that GC and WFA, particularly in combination, significantly induce apoptosis in both cell lines. Migration assays confirmed the potent inhibition of cell migration by both compounds, with the combination treatment being the most effective. Furthermore, actin cytoskeleton analysis indicated substantial changes in cell morphology and stiffness, suggesting that GC and WFA disrupt the structural integrity of cancer cells. Additionally, the study highlights a ROS-mediated mechanism underlying the effects of GC and WFA, as evidenced by increased ROS levels following treatment, which were attenuated by N-acetylcysteine. Importantly, NF-κB activity was significantly modulated, with WFA reducing NF-κB activation induced by GC, potentially contributing to the synergistic pro-apoptotic effect of the combination. These findings suggest that the combination of GC and WFA may offer a synergistic therapeutic approach for treating pancreatic cancer by targeting multiple aspects of tumor cell behavior.

Rosmarinic acid attenuates glioblastoma cells and spheroids’ growth and EMT/stem-like state by PTEN/PI3K/AKT downregulation and ERK-induced apoptosis

BackgroundGlioblastoma (GB) is a highly malignant type of brain cancer with a poor prognosis. Therapeutic strategies for GB are still limited. Rosmarinic acid (RA), a polyphenolic compound, is a promising experimental anticancer agent, but its specific protein targets for GB remain unclear. PurposeThis study aimed to elucidate the anticancer effects of RA in 2D- and 3D-GB cells and the underlying mechanisms. Methods3D-tumor spheroids (mimics in vivo tumors) were obtained by the hanging-drop/agarose method. RA's anti-glioma activity on U-87MG (p53-wt/PTEN-mt) and LN229 (p53-mt/PTEN-wt) cells was evaluated through cell viability, colony-formation, migration/invasion/angiogenesis assays, fluorescence imaging, and spheroid growth analysis. The underlying mechanism of the anticancer effects of RA was investigated by Western blot and immunofluorescence analysis. The MEK inhibitor U0126 was used to block ERK phosphorylation. ResultsRA treatments exerted anti-proliferative and pro-apoptotic effects on human GB cells. RA dose-dependently reduced angiogenesis and intracellular ROS levels, suppressed glioma growth, and migration/invasion in 2D-culture and cancer stem cell (CSC)-like 3D-spheroid culture (SPC). Repeated therapy in SPC was more effective by leading to disrupted structure than a single treatment. Treatments in SPC also suppressed epithelial-mesenchymal transition (EMT) and CSC-like properties. Strikingly, RA downregulated the SIRT1/FOXO1/NF-κB axis independently of p53 or PTEN function in both gliomas. Immunofluorescence labeling revealed decreased SIRT1 and NF-κB-p65 and increased FOXO1 and GAPDH proteins in nuclear location (associated with apoptosis). Surprisingly, RA increased p-ERK1/2 levels, but priming with U0126 abolished RA-mediated p-ERK upregulation; thus, autophagy and apoptosis induction in GB cells were prevented, and the growth of GB spheroids accelerated. Specifically, RA also inhibited the PTEN/PI3K/AKT pathway in U-87MG cells. Due to genetic differences in cells, U-87MG cells were more sensitive to RA treatments than LN229 cells. Meanwhile, our positive control drug trial results with FDA-approved temozolomide (TMZ) used in GB treatment showed that our test compound rosmarinic acid exhibited higher therapeutic effects than TMZ at lower doses. ConclusionSuppression of EMT, downregulation of SIRT1/FOXO1/NF-κB axis, inhibition of PTEN/PI3K/AKT signaling pathway, and ERK-induced apoptosis and autophagy were determined to be involved in stopping glioma progression. Our findings for the first time, revealed that RA may have potential therapeutic use by having multiple targets in human brain cancer with further clinical studies.

Arctium lappaL. polysaccharides alleviate oxidative stress and inflammation in the liver and kidney of aging mice by regulating intestinal homeostasis

Arctium lappa L. polysaccharide (ALP) is a prominent bioactive compound renowned for its multifaceted functional properties, including anti-inflammatory, antioxidant, antifibrotic, immunomodulatory, and pro-apoptotic effects. This study evaluated the aging-delaying effect of ALP and its mechanisms using a D-galactose (D-gal)-induced aging model. After an 8-week treatment, ALP significantly ameliorated D-gal-induced inflammation and oxidative stress in the liver, kidneys, and intestines. Notably, ALP administration led to a marked reduction of the pathogenic bacterium Desulfovibrio and a substantial increase in the beneficial bacterium Muribaculum. These microbial shifts were associated with upregulated expression of intestinal tight junction proteins and intestinal mucins, leading to enhanced intestinal barrier integrity. Consequently, the leakage of enterotoxins and inflammatory mediators was effectively reduced. The findings indicate that ALP alleviates tissue inflammation and oxidative stress, while also delaying aging in mice. This effect is achieved through the regulation of intestinal ecological homeostasis and the repair of the intestinal immune barrier.

From 2D to 3D In Vitro World: Sonodynamically-Induced Prooxidant Proapoptotic Effects of C60-Berberine Nanocomplex on Cancer Cells.

The primary objective of this research targeted the biochemical effects of SDT on human cervix carcinoma (HeLa) and mouse Lewis lung carcinoma (LLC) cells grown in 2D monolayer and 3D spheroid cell culture. HeLa and LLC monolayers and spheroids were treated with a 20 µM C60-Ber for 24 h, followed by irradiation with 1 MHz, 1 W/cm2 US. To evaluate the efficacy of the proposed treatment on cancer cells, assessments of cell viability, caspase 3/7 activity, ATP levels, and ROS levels were conducted. Our results revealed that US irradiation alone had negligible effects on LLC and HeLa cancer cells. However, both monolayers and spheroids irradiated with US in the presence of the C60-Ber exhibited a significant decrease in viability (32% and 37%) and ATP levels (42% and 64%), along with a notable increase in ROS levels (398% and 396%) and caspase 3/7 activity (437% and 246%), for HeLa monolayers and spheroids, respectively. Similar tendencies were observed with LLC cells. In addition, the anticancer effects of C60-Ber surpassed those of C60, Ber, or their mixture (C60 + Ber) in both cell lines. The detected intensified ROS generation and ATP level drop point to mitochondria dysfunction, while increased caspase 3/7 activity points on the apoptotic pathway induction. The combination of 1 W/cm2 US with C60-Ber showcased a promising platform for synergistic sonodynamic chemotherapy for cancer treatment.

Highly Efficient Synergistic Chemotherapy and Magnetic Resonance Imaging for Targeted Ovarian Cancer Therapy Using Hyaluronic Acid-Coated Coordination Polymer Nanoparticles.

The diagnosis and treatment of ovarian cancer (OC) are still a grand challenge, more than 70% of patients are diagnosed at an advanced stage with a dismal prognosis. Magnetic resonance imaging (MRI) has shown superior results to other examinations in preoperative assessment, while cisplatin-based chemotherapy is the first-line treatment for OC. However, few previous studies have brought together the two rapidly expanding fields. Here a technique is presented using cisplatin prodrug (Pt-COOH), Fe3+, and natural polyphenols (Gossypol) to construct the nanoparticles (HA@PFG NPs) that have a stable structure, controllable drug release behavior, and high drug loading capacity. The acidic pH values in tumor sites facilitate the release of Fe3+, Pt-COOH, and Gossypol from HA@PFG NPs. Pt-COOH with GSH consumption and cisplatin-basedchemotherapy plus Gossypol with pro-apoptotic effects displays asynergisticeffect forkillingtumorcells. Furthermore, the release of Fe3+ at the tumor sites promotes ferroptosis and enables MRI imaging of OC. Inthe patient-derived tumor xenograft (PDX)model, HA@PFG NPs alleviate the tumor activity. RNA sequencing analysis reveals that HA@PFG NPs ameliorate OC symptoms mainly through IL-6 signal pathways. This work combines MRI imaging with cisplatin-based chemotherapy, which holds great promise for OC diagnosis and synergistic therapy.

Effect of Sodium-Glucose Co-Transporter 2 Inhibitors Combined with Metformin on Pancreatic Cancer Cell Lines.

Pancreatic cancer (PC) is the ninth-leading cause of cancer-related deaths worldwide. Diabetic patients have an increased risk and mortality rates for PC. Sodium-glucose co-transporter 2 (SGLT2) inhibitors and metformin (Met) are widely used anti-diabetic medications. Both Met and SGLT2 inhibitors have anticancer properties in PC, but nothing is known concerning their combined effect. So, we investigated the in vitro effect of SGLT2 inhibitors combined with Met. Canagliflozin and dapagliflozin possessed cytotoxic, antiproliferative, and pro-apoptotic properties in the tested PC cell lines. In PANC-1 cells, the antimigratory and pro-apoptotic effects were enhanced when dapagliflozin was combined with Met, and G1 cell cycle arrest was enhanced when dapagliflozin or canagliflozin was combined with Met. In AsPC-1 cells, the cytotoxic effect and the G1 cell cycle arrest were enhanced when canagliflozin and dapagliflozin, respectively, were combined with Met. Only the cytotoxic effects of SGLT2 inhibitors, but not the combination treatments, involved PI3K and JNK-dependent pathways in AsPC-1 cells. In conclusion, combination treatments increased the anticancer effects in a cell type-dependent way in the two investigated cell lines. Additionally, the cytotoxic effect of SGLT2 inhibitors was dependent on the PI3K and JNK pathways in AsPC-1 cells, but Met appears to act via a distinct mechanism.

Design and comprehensive characterization of dry powder inhalation aerosols of simvastatin DPPC/DPPG lung surfactant-mimic nanoparticles/microparticles for pulmonary nanomedicine.

The Rho Kinase (ROCK) pathway is recognized to be involved in changes that lead to remodeling in pulmonary hypertension (PH), particularly cellular processes including signaling, contraction, migration, proliferation, differentiation, and apoptosis. Simvastatin (Sim) has a potent anti-proliferative and pro-apoptotic effect on vasculature smooth muscle cells through the inhibition of the synthesis of isoprenoids intermediates which are essential for the post-translational isoprenylation of Rho, Rac, and Ras family GTPases. Sim targets the underlying mechanism in vascular remodeling. Using bionanomaterials and particle engineering design, this innovative study reports on the advanced inhalable dry powders composed of sim with synthetic phospholipid bionanomaterials, DPPC/DPPG, as a lung surfactant-mimic. These were successfully designed and produced as co-spray dried (Co-SD) nanoparticles and microparticles for nanomedicine delivery as dry powder inhalers (DPIs). Different techniques were used to comprehensively characterize the physicochemical properties of the resulting Co-SD particles. The Next Generation ImpactorTM (NGI™) was used with three different FDA-approved human DPI devices with varying shear stress which were the HandiHaler®, Neohaler®, Aerolizer® DPI devices for aerosol dispersion performance. The formulation-device interactions were examined and correlated. Using human lung cells from different lung regions, in vitro cell viability and transepithelial electrical resistance (TEER) at the air-liquid interface showed biocompatibility of the formulations as a function of dose.

Effect of a Phytochemical-Rich Olive-Derived Extract on Anthropometric, Hematological, and Metabolic Parameters.

Extra virgin olive oil is a fundamental component of the Mediterranean diet. It contains several molecules that sustain human well-being by modulating cellular metabolism and exerting antioxidant, anti-inflammatory, and anti-ageing effects to protect normal tissues, and it can exert anti-angiogenic and pro-apoptotic effects on cancer cells. Metabolites found in different parts of the olive tree, including leaves, also possess properties that might help in cancer prevention and promote wellness in aging. Olive mill wastewater (OMWW), a liquid residue produced during olive oil extraction, represents an environmental issue. However, it is rich in phytochemicals with potential beneficial properties. Dietary supplements based on OMWW can be produced for nutritional supplementation with advantages to the ecology. This work aims to measure hematochemical, anthropometric, and metabolomic parameters in volunteers taking an OMWW dietary supplement, Oliphenolia® (OMWW-OL). The supplementation of OMWW-OL 25 mL twice daily for 30 days was tested on a pilot cohort of volunteers with characteristics close to metabolic syndrome. Hematochemical, anthropometric, serum biomarkers and serum metabolomic parameters were analyzed before the intervention, at 30 days, and 30 days after stopping consumption. A total of 29 volunteers were enrolled, and 23 completed the study. The participants' parameters at baseline were measured, and then twice daily at 30 days of treatment and 30 days after assumption discontinuation. Although treatment was with an olive derivative, their weight did not increase. Their body mass index, instead of augmenting, slightly decreased, particularly in the women. Also, hydration increased, especially in the women, while blood pressure, glycemia, and insulin decreased. Cholesterol, high-density lipoproteins, and triglycerides were stable, and LDL levels decreased, while vitamin D levels, alongside calcium, perceptibly increased. Albumin also increased. All the values were in support of an equilibrium, with no damaging effects. By mass spectrometry analysis, we also found favorable changes in the vitamin D/histamine and homocysteine/methionine ratios, an increase in a new metabolite of unknown formula, and the vitamin D/unknown metabolite ratio. Supplementation of OMWW-OL has no detrimental effects and might imply the beneficial modulation of several biological parameters. Although this is a small pilot study, with limited potency, it preliminarily suggests that the OMWW extract use could be potentially valuable for people at risk of metabolic syndrome. Some of these parameters could also be relevant in supporting healthy ageing and in cancer prevention.

New drug combination regimen based on pharmacokinetic characteristics—Erdafitinib combined with sertraline or duloxetine

The aim of this study is to investigate novel strategies for reducing adverse reactions caused by erdafitinib through a drug combination based on its pharmacokinetic characteristics. The spectrum and characterizations of drugs that can inhibit the metabolism of erdafitinib are examined both in vitro and in vivo. The efficacy of combination regimens are then evaluated using subcutaneous xenograft tumor models. The results demonstrated that sertraline and duloxetine, out of more than 100 screened drugs, inhibited the metabolism of erdafitinib through mixed and non-competitive inhibition, respectively. This inhibition primarily occurred via the CYP2C9 and CYP2D6 pathways. The primary alleles of CYP2C9 and CYP2D6 not only determine the metabolic characteristics of erdafitinib but also influence the strength of drug-drug interactions. Co-administration of sertraline or duloxetine with erdafitinib in rats and mice resulted in nearly a three-fold increase in the blood exposure of erdafitinib and its major metabolite M6. When sertraline or duloxetine was combined with 1/3 of the erdafitinib dosage, the anti-proliferative and pro-apoptotic effects on SNU-16 xenografts were comparable to those of the original full dose of erdafitinib. However, the combination regimen significantly mitigated hyperphosphatemia, retinal damage, intestinal villus damage, and gut microbiome dysbiosis. This study utilized pharmacokinetic methods to propose a new formulation of erdafitinib combined with sertraline or duloxetine. The findings suggest that this combination has potential for clinical co-administration based on a database analysis, thereby providing a novel strategy for anti-tumor treatment with fibroblast growth factor receptor (FGFR) inhibitors.

Mechanisms of action of Sappan lignum for prostate cancer treatment: network pharmacology, molecular docking and experimental validation.

Prostate cancer (PCa) is the most common non-cutaneous malignancy in men globally. Sappan lignum, which exists in the heartwood of Caesalpinia sappan L., has antitumor effects; however, its exact mechanism of action remains unclear. This study elucidated the underlying mechanisms of Sappan lignum in PCa through network pharmacology approaches and molecular docking techniques. Moreover, the therapeutic effects of Sappan lignum on PCa were verified through in vitro experiments. The constituent ingredients of Sappan lignum were retrieved from the HERB database. Active plant-derived compounds of Sappan lignum were screened based on gastrointestinal absorption and gastric drug properties. Disease targets for PCa were screened using unpaired and paired case datasets from the Gene Expression Omnibus. Intersection targets were used for gene ontology and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis. Core targets were identified through topological analysis parameters and their clinical relevance was validated through The Cancer Genome Atlas database. The affinity between the phytochemicals of Sappan lignum and core proteins was verified using the molecular docking technique. Validation experiments confirmed the significant potential of Sappan lignum in treating PCa. Twenty-one plant-derived compounds of Sappan lignum and 821 differentially expressed genes associated with PCa were collected. Among 32 intersection targets, 8 were screened according to topological parameters. KEGG analysis indicated that the antitumor effects of Sappan lignum on PCa were primarily associated with the p53 pathway. The molecular docking technique demonstrated a strong affinity between 3-deoxysappanchalcone (3-DSC) and core proteins, particularly cyclin B1 (CCNB1). CCNB1 expression correlated with clinicopathological features in patients with PCa. Experimental results revealed that 3-DSC exhibited anti-proliferative, anti-migratory, and pro-apoptotic effects on 22RV1 and DU145 cells while also causing G2/M phase cell cycle arrest, potentially through modulating the p53/p21/CDC2/CCNB1 pathway. This research highlights the promising therapeutic potential of Sappan lignum in treating PCa, with a particular focus on targeting the p53 pathway.

Amorphous silica nanoparticles exhibit antitumor activity in triple-negative breast cancer cells.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is mainly treated with cytotoxic chemotherapy. However, this treatment is not always effective, and an important percentage of patients develop recurrence. Nanomaterials are emerging as alternative treatment options for various diseases, including cancer. This work reports the synthesis, characterization, antitumor activity evaluation, and sub-acute toxicity studies of two formulations based on amorphous silica nanoparticles (SiNPs). They are functionalized with 3-aminopropyltriethoxisilane (Si@NH2) and folic acid (FA; Si@FA). The results show that SiNPs reduce the viability and migration of TNBC MDA-MB-231 and 4T1 cell lines and Si@FA do not affect the growth of the mammary nonmalignant HC11 cells. In addition, Si@FA induces reactive oxygen species (ROS) generation and displays antiproliferative and subsequently proapoptotic effects in MDA-MB-231 cells. Moreover, none of the SiNPs cause signs of sub-acute toxicity in mice when administered at 30 mg/kg over a month. In conclusion, these nanosystems display intrinsic antitumor activity without causing toxic in vivo effects, being a promising therapeutic alternative for TNBC.

Elevated concentrations of amyloid-β oligomers and their proapoptotic effects on age-related cataract.

Recently, amyloid-β oligomers (AβOs) have been studied as the primary pathogenic substances in Alzheimer's disease (AD). Our previous study revealed that the Aβ expression level is closely related to ARC progression. Here, we demonstrated that the accumulation of AβOs in the lens epithelium of age-related cataract (ARC) patients increased during ARC progression and that this alteration was consistent with the changes in mitochondrial function, oxidative stress, and cellular apoptosis. Invitro, human lens epithelial cells (HLECs) treated with AβOs exhibited Ca2+ dyshomeostasis, impaired mitochondrial function, elevated oxidative stress levels, and increased apoptosis. Moreover, the proapoptotic effect of AβOs was alleviated after the uptake of mitochondrial Ca2+ was inhibited. These results establish that AβOs may promote HLEC apoptosis by inducing mitochondrial Ca2+ overload, thus preliminarily revealing the possible association between the accumulation of AβOs and other pathological processes in ARC.

Development of Mitoxantrone-Loaded Quercetin Nanoparticles for Breast Cancer Therapy with Potential for Synergism with Bioactive Natural Products

Nanoparticle (NP)-based drug delivery systems have caused a paradigm shift in cancer treatment by enabling drug targeting, sustaining drug release, and reducing systemic toxicity of chemotherapy. Here we developed a novel NP formulation for the anticancer drug mitoxantrone (MTZ) by loading it into an emerging nanomaterial derived from the plant polyphenol quercetin (QCT). QCT was partially oxidized to produce amphiphilic oxQCT which was co-assembled with poly(ethylene glycol) (PEG) and MTZ by nanoprecipitation to form MTZ NPs. The optimal NPs exhibited an average diameter of 128 nm, a polydispersity index of 0.22, and a drug loading efficiency of 76%. While only a small fraction of the loaded drug was released at physiologic pH, a significantly higher fraction was released at acidic pH. The anticancer activity of MTZ NPs was assessed in MCF-7 and MDA-MB-231 breast cancer cell lines, alone and in combination with the bioactive natural products curcumin (CUR) and thymoquinone (TQ). In cell viability assays, MTZ NPs were slightly less potent than free MTZ, most likely due to their sustained release properties, but their cytotoxicity was greatly enhanced in the presence of TQ (in MCF-7 cells) as well as CUR (in MDA-MB-231 cells). The results were corroborated by apoptosis assays such as mitochondrial membrane potential measurement, acridine orange/ethidium bromide staining, in addition to caspase activity assays. The assays revealed that the NPs’ proapoptotic effect was enhanced in the presence of CUR or TQ, depending on the cell line. Our work presents a promising nanocarrier platform for MTZ with the potential to enhance its bioactivity against breast cancer when combined with bioactive natural products.

Enhanced anti-tumor and anti-metastatic activity of quercetin using pH-sensitive Alginate@ZIF-8 nanocomposites:in vitroandin vivostudy.

Quercetin (Qc) possesses anti-cancer properties, such as cell signaling, growth suppression, pro-apoptotic, anti-proliferative, and antioxidant effects. In this study, we developed an alginate-modified ZIF-8 (Alg@ZIF-8) to enhance the anti-tumor efficacy of Qc. The developed alginate-modified quercetin-loaded ZIF-8 (Alg@Qc@ZIF-8) was characterized using scanning electron microscope (SEM), dynamic light scattering (DLS), fourier transform infrared spectroscopy Thermogravimetric analysis, Brunauer-Emmett-Teller, and x-ray diffraction. The drug release pattern was evaluated at pH 5.4 and 7.4. The cytotoxicity of nanoparticles was assessed on the 4T1 cell line. Finally, the anti-tumor activity of Alg@Qc@ZIF-8 was evaluated in 4T1 tumor-bearing mice. SEM showed that the nanoparticles were spherical with a diameter of mainly below 50 nm. The DLS showed that the developed nanoparticles' hydrodynamic diameter, zeta potential, and polydispersity index were 154.9 ± 7.25 nm, -23.8 ± 5.33 mV, and 0.381 ± 0.09, respectively. The drug loading capacity was 10.40 ± 0.02%. Alg@Qc@ZIF-8 exhibited pH sensitivity, releasing more Qc at pH 5.4 (about 3.62 times) than at pH 7.4 after 24 h. Furthermore, the IC50value of Alg@Qc@ZIF-8 on the 4T1 cell line was 2.16 times lower than net Qc. Importantly, in tumor-bearing mice, Alg@Qc@ZIF-8 demonstrated enhanced inhibitory effects on tumor growth and lung metastasis compared to net Qc. Considering thein vitroandin vivooutcomes, Alg@Qc@ZIF-8 might hold great potential for effective breast cancer management.

Mechanistic insights into Retama raetam's anti-proliferative and pro-apoptotic effects in A549 lung cancer cells: targeting PI3K/Akt pathway and ROS production.

Lung cancer, particularly non-small cell lung cancer (NSCLC), is a leading cause of cancer-related deaths worldwide. This study investigates the molecular mechanisms behind the anti-cancer effects of the tropical desert plant Retama raetam (R. raetam) on the A549 NSCLC cell line. The research examined R. raetam's anti-proliferative effects, cytotoxicity, apoptosis, reactive oxygen species (ROS) generation, mitochondrial membrane potential, and cell morphology in NSCLC A549 and L-132 cells. In addition, the influence of R. raetam on DNA fragmentation, apoptotic signaling, and PI3K/Akt pathways for its anti-cancer mechanism was examined. Our results indicated that R. raetam's effects were dose- and time-dependent to exhibit anti-proliferative effects on A549 cells. R. raetam treatment promoted apoptotic cell death cycle arrest, increased apoptotic cells, depolarized the mitochondrial membrane, and induced morphological alterations in cells and nuclei. It also inhibited A549 cell migration (P < 0.05), colonization, and invasiveness. Moreover, the study demonstrated that R. raetam treatment resulted in the upregulation of Bax expression, downregulation of Bcl-2 expression, and apoptotic fragmented DNA in A549 cells. The top five bioactive compounds derived from R. raetam exhibited molecular interactions that inhibit PIK3CA and AKT1. This inhibition leads to an increased frequency of apoptosis and subsequent death of cancer cells. Additionally, R. raetam extract induced an increase in ROS formation and cytochrome c levels, indicating that its toxic effects on A549 cells involve both ROS-dependent cytotoxicity through the disruption of mitochondrial transmembrane potential ΔΨm and ROS-independent cell cycle arrest through downregulation BCL-2, PARP, E-Cadherin, PI3K, and Akt expressions pathways.

Synthesis and Molecular Dynamic Simulation of Novel Cationic and Non-cationic Pyrimidine Derivatives as Potential G-quadruplex-ligands.

Drug resistance has been a problem in cancer chemotherapy, which often causes shortterm effectiveness. Further, the literature indicates that telomere G-quadruplex could be a promising anti-cancer target. We synthesized and characterized two new pyrimidine derivatives as ligands for G-quadruplex DNA. The interaction of novel non-cationic and cationic pyrimidine derivatives (3a, b) with G-quadruplex DNA (1k8p and 3qsc) was explored by circular dichroism (CD) and ultraviolet-visible spectroscopy and polyacrylamide gel electrophoresis (PAGE) methods. The antiproliferative activity of desired compounds was evaluated by the MTT assay. Apoptosis induction was assessed by Propidium iodide (P.I.) staining and flow cytometry. Computational molecular modeling (CMM) and molecular dynamics simulation (MD) were studied on the complexes of 1k8p and 3qsc with the compounds. The van der Waals, electrostatic, polar solvation, solventaccessible surface area (SASA), and binding energies were calculated and analyzed. The experimental results confirmed that both compounds 3a and 3b interacted with 1k8p and 3qsc and exerted cytotoxic and proapoptotic effects on cancer cells. The number of hydrogen bonds and the RMSD values increased in the presence of the ligands, indicating stronger binding and suggesting increased structural dynamics. The electrostatic contribution to binding energy was higher for the cationic pyrimidine 3b, indicating more negative binding energies. Both experimental and MD results confirmed that 3b was more prone to form a complex with DNA G-quadruplex (1k8p and 3qsc), inhibit cell growth, and induce apoptosis, compared to the non-cationic pyrimidine 3a.

Prenylated xanthones from mangosteen (Garcinia mangostana) target oxidative mitochondrial respiration in cancer cells

Mangosteen (Garcinia mangostana) is well-known for its nutritional value and health benefits. Breast cancer is the most common cancer and the leading cause of cancer-related mortality among females worldwide. Here we show that the prenylated xanthones, α-mangostin, γ-mangostin, 9-hydroxycalabaxanthone (9-HCX), and garcinone E from the mangosteen pericarp exhibit cytotoxicity against a panel of human cancer cell lines including lung adenocarcinoma (A549), cervical carcinoma (HeLa), prostatic carcinoma (DU 145), pancreatic carcinoma (MIA PaCa-2), hepatocellular carcinoma (Hep G2), bladder urothelial cancer (5637), as well as the triple-negative breast cancer cells MDA-MB-231. In line with its higher predicted bioactivity score compared to other prenylated xanthones, 9-HCX induced the strongest antiproliferative and proapoptotic effects in MDA-MB-231 breast cancer xenografts in vivo. In different in vitro models, we demonstrate that prenylated xanthones from G. mangostana target mitochondria in cancer cells by inhibition of the mitochondrial respiratory chain complex II (α-mangostin, γ-mangostin, and garcinone E) and complex III (9-HCX) as shown in isolated mitochondria. Accordingly, oxidative mitochondrial respiration (OXPHOS) was inhibited, mitochondrial proton leak increased, and adenosine triphosphate (ATP) synthesis decreased as analyzed by Seahorse assay in MDA-MB-231 cells. Hence, the prenylated xanthones increased mitochondrial superoxide levels, induced mitochondrial membrane permeabilization, and initiated caspase 3/7-mediated apoptosis in MDA-MB-231 triple-negative breast cancer cells. Thus, prenylated xanthones from Garcinia mangostana exhibit anticancer activity based on interference with the mitochondrial respiration.

CYTOTOXICITY OF ALOE VERA EXTRACT ON CHRONIC MYELOID LEUKEMIA CELLS; IN VITRO STUDY ON CYTOTOXICITY ON HL-60 CELLS

Aloe vera has been traditionally used for its various therapeutic properties, but its potential anticancer effects have not been thoroughly explored. Understanding its efficacy against leukemia could significantly impact care recommendations for leukemia patients. Objective: This in-vitro study aims to establish the anti-cancerous effects of Aloe vera on the Human Leukemia HL-60 cell line. Methods: Following approval from the Ethical Review Committee, this study involved culturing the HL-60 cell line and treating it with increasing concentrations of Aloe vera extract to determine the half-maximal inhibitory concentration (IC50). The MTT assay was employed to assess cell viability, and the absorbance was measured using an ELISA reader. Gene expression levels of pro-apoptotic biomarkers, Caspase-3 and Caspase-9, were also quantified to gauge apoptosis induction. Results: Aloe vera demonstrated a relatively low IC50 value of 13.1 µM in the HL-60 cell line, indicating potent cytotoxicity. Notably, pro-apoptotic biomarkers were highly expressed, with Caspase-3 and Caspase-9 recording gene expression levels of 11.1 and 13.7, respectively. Conclusion: Aloe vera exhibited significant pro-apoptotic effects against the leukemia HL-60 cell line, suggesting its potential as an anti-cancer agent. Further in-vivo and clinical studies are warranted to elucidate the specific pathways through which Aloe vera exerts these effects and to validate its use in clinical settings.

THE COMPARATIVE STUDY OF THE EFFECT OF LOW-INTENSITY BROADBAND AND LOW-INTENSITY PULSED ULTRASOUND ON B16 MELANOMA CELLS IN VITRO

Aim. To evaluate the effect of low-intensity broadband ultrasound (UMUS) and low-intensity pulsed ultrasound (LIPUS) on B16 melanoma cells in vitro. Methods. The research was conducted on B16 melanoma cells under two modes of low-intensity ultrasonic sounding of cells, for which an SDG 2082 X Siglent generator (USA) with an ultrasonic emitter diameter of 20 mm was used; with a frequency for UMUS of 1-7 MHz, intensity of 30 mW/cm, pulse duration of 50 μs, and for LIPUS with a frequency of 1.5 MHz, intensity of 30 mW/cm, pulse duration of 200 μs. Both modes of cell sounding were carried out with threefold irradiation, once a day after which the distribution of cells by cycle phases, the level of apoptosis and proliferative activity was determined by the method of ductal cytofluorimetry. Results. Under the influence of UMUS ultrasonic sounding, the inhibition of the proliferation of melanoma cells by 1.6 times (P&lt;0.05), a 2-fold decrease in the content of aneuploid cells, compared to the control, was found, however, cytostatic and proapoptotic effects were not recorded. Under the influence of LIPUS sounding, an anti-proliferative effect, an increase in the content of dead and apoptotic cells and a decrease in the DI-index compared to the corresponding control were found. Conclusions. Under the action of low-intensity broadband ultrasound (UMUS) and low-intensity pulsed ultrasound (LIPUS), a cytotoxic/cytostatic and pro-apoptotic effect and a decrease in the content of the aneuploid cell population were revealed.