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CD98, also known as SLC3A2, is a multifunctional cell surface molecule consisting of amino acid transporters. CD98 is ubiquitously expressed in many types of tissues, but expressed at higher levels in cancerous tissues than in normal tissues. CD98 is also upregulated in most hepatocellular carcinoma (HCC) patients; however, the function of CD98 in HCC cells has been little studied. In this study, we generated a panel of monoclonal antibodies (MAbs) against surface proteins on human embryonic stem cells (hESCs). NPB15, one of the MAbs, bound to hESCs and various cancer cells, including HCC cells and non-small cell lung carcinoma (NSCLC) cells, but not to peripheral blood mononuclear cells (PBMCs) and primary hepatocytes. Immunoprecipitation and mass spectrometry identified the target antigen of NPB15 as CD98. CD98 depletion decreased cell proliferation, clonogenic survival, and migration and induced apoptosis in HCC cells. In addition, CD98 depletion decreased the expression of cancer stem cell (CSC) markers in HCC cells. In tumorsphere cultures, the expression of CD98 interacting with NPB15 was significantly increased, as were known CSC markers. After cell sorting by NPB15, cells with high expression of CD98 (CD98-high) showed higher clonogenic survival than cells with low expression of CD98 (CD98-low) in HCC cells, suggesting CD98 as a potential CSC marker on HCC cells. The chimeric version of NPB15 was able to induce antibody-dependent cellular cytotoxicity (ADCC) against HCC cells in vitro. NPB15 injection showed antitumor activity in an HCC xenograft mouse model. The results suggest that NPB15 may be developed as a therapeutic antibody for HCC patients. [ABSTRACT FROM AUTHOR]

Objective: In search of the better anticancer agents, fifteen bakuchiol-1,3,5-triazine derivatives were designed and synthesized through nucleophilic substitution reaction. Methods: The newly synthesized derivatives were evaluated for their in vitro cytotoxic activity against Panc-1, MDA-MB-231, A549, and UM-UC-3 using the MTT assay. Results and Discussion: The data revealed that all of the bakuchiol-1,3,5-triazine derivatives could inhibit the proliferation of Panc-1 cells. Four compounds exhibited better antiproliferative activities than that of bakuchiol. Among them, compound (IVj) displayed potent antiproliferative activity with IC50 values of 21.83 μM. Compound (IVj) also showed potent inhibitory activity against the proliferation of MDA-MB-231, A549, and UM-UC-3 cells when compared with bakuchiol. Additionally, compound (IVj) exhibited strong inhibitory effects on the migration, invasion, and adhesion of Panc-1 cells. Conclusions: The results showed that, compound (IVj) could be a promising candidate agent for the treatment of cancer. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to design and synthesize novel apigenin derivatives and evaluate their antitumor activities against NSCLC cells. Methods: A series of apigenin derivatives were synthesized and their antiproliferative effects were evaluated against the NSCLC cell line A549. The most promising compounds were identified based on their antitumor activities. Their safety was confirmed by testing them on the normal human lung cell line Beas-2B. The mechanisms of their antitumor activities were investigated by inducing apoptosis in A549 cells and inhibiting Akt protein phosphorylation. The physicochemical and ADME properties of these compounds were also predicted to evaluate their potential as PI3K inhibitors for NSCLC therapy. Results and Discussion: Compounds (Va) and (VIa) exhibited suitable antitumor activities against A549 cells, with no significant toxicity towards Beas-2B cells. They were capable of inducing apoptosis in A549 cells and inhibiting Akt protein phosphorylation, which preliminarily revealed their mechanisms for antitumor activities in vitro. The predictions of physicochemical and ADME properties showed that compound (VIa) would be a potent PI3K inhibitor for NSCLC therapy in the future. Conclusions: This study has successfully designed and synthesized apigenin derivatives with antitumor activities for NSCLC therapy. Compounds (Va) and (VIa) exhibited suitable antitumor activities with low toxicity and promising mechanisms of action. The physicochemical and ADME properties of compound (VIa) suggest its potential as a potent PI3K inhibitor for NSCLC therapy in the future. These findings provide valuable insights for the development of novel therapeutic agents against NSCLC. [ABSTRACT FROM AUTHOR]

Electrospun membranes (EMs) have a wide range of applications, including use as local delivery systems. In this study, we manufactured a polyurethane Tecoflex™ EM loaded with bismuth-based lipophilic nanoparticles (Tecoflex™ EMs-BisBAL NPs). The physicochemical and mechanical characteristics, along with the antitumor and bactericidal effects, were evaluated using a breast cancer cell line and methicillin-susceptible and resistant Staphylococcus aureus (MRSA). Drug-free Tecoflex™ EMs and Tecoflex™ EMs-BisBAL NPs had similar fiber diameters of 4.65 ± 1.42 µm and 3.95 ± 1.32 µm, respectively. Drug-free Tecoflex™ EMs did not negatively impact a human fibroblast culture, indicating that the vehicle is biocompatible. Tecoflex™ EMs-BisBAL NPs increased 94% more in size than drug-free Tecoflex™ EMs, indicating that the BisBAL NPs enhanced hydration capacity. Tecoflex™ EMs-BisBAL NPs were highly bactericidal against both methicillin-susceptible S. aureus and MRSA clinical isolates, inhibiting their growth by 93.11% and 61.70%, respectively. Additionally, Tecoflex™ EMs-BisBAL NPs decreased the viability of MCF-7 tumor cells by 86% after 24 h exposure and 70.1% within 15 min. Regarding the mechanism of action of Tecoflex™ EMs-BisBAL NPs, it appears to disrupt the tumor cell membrane. In conclusion, Tecoflex™ EMs-BisBAL NPs constitute an innovative low-cost drug delivery system for human breast cancer and postoperative wound infections. [ABSTRACT FROM AUTHOR]

The zelkovamycin family is a class of cyclic octapeptides with potent antibacterial and antiviral activity. Due to their unique chemical structures and excellent bioactivity, zelkovamycins have consistently attracted the interest of synthetic chemists. However, only the total synthesis of zelkovamycin and zelkovamycin G has been reported until now. The current work presents, for the first time, the synthesis of zelkovamycin analogues, along with their anticancer activity assessment. Firstly, the corresponding chain peptide based on the amino acid sequence of zelkovamycin H was synthesized using the Fmoc solid-phase peptide strategy. This was followed by cyclization under high dilution conditions to obtain compound 21, and its structure was elucidated by NMR analysis. The results confirm that compound 21 is not the natural product of zelkovamycin H. We deduced that during the synthesis of peptide 12, the D-Abu residue epimerized to the L-Abu form, leading to the formation of peptide 20, which blocked our efforts during the synthesis of zelkovamycin H. Two more analogues, 22 and 23, were synthesized by changing the structure of amino acid residues using the same strategy. The anticancer activity of analogues 21–23 against Huh-7 cells was evaluated in vitro; however, their IC50 values were >50 μM. [ABSTRACT FROM AUTHOR]

Cancer continues to be a major global health issue, ranking among the top causes of death worldwide. To develop novel antitumor agents, this study focused on the synthesis of a series of 21 novel furanopyridinone derivatives through structural modifications and functional enhancements. The in vitro anti-tumor activities of these compounds were investigated through the cytotoxicity against KYSE70 and KYSE150 and led to the identification of compound 4c as the most potent compound. At a concentration of 20 µg/mL, compound 4c demonstrated a remarkable 99% inhibition of KYSE70 and KYSE150 cell growth after 48 h. IC50 was 0.655 µg/mL after 24 h. Additionally, potential anti-tumor cellular mechanisms were explored through molecular docking, which was used to predict the binding mode of 4c with METAP2 and EGFR, suggesting that the C=O part of the pyridone moiety likely played a crucial role in binding. This study provided valuable insights and guidance for the development of novel anticancer drugs with novel structural scaffolds. [ABSTRACT FROM AUTHOR]

Stimulus-responsive materials hold significant promise for antitumor applications due to their variable structures and physical properties. In this paper, a series of peptides with a responsive viologen derivative, Pep-CnV (n = 1, 2, 3) were designed and synthesized. The process and mechanism of the interaction were studied and discussed. An ultraviolet–visible (UV) spectrophotometer and fluorescence spectrophotometer were used to study their redox responsiveness. Additionally, their secondary structures were measured by Circular Dichroism (CD) in the presence or absence of the reductant, Na2SO3. DPPC and DPPG liposomes were prepared to mimic normal and tumor cell membranes. The interaction between Pep-CnV and biomembranes was investigated by the measurements of surface tension and cargo leakage. Results proved Pep-CnV was more likely to interact with the DPPG liposome and destroy its biomembrane under the stimulus of the reductant. And the destruction increased with the length of the hydrophobic tail chain. Pep-CnV showed its potential as an intelligent antitumor agent. [ABSTRACT FROM AUTHOR]

Reactions of a chromone‐based hydrazone (SalHFC; HL) with Ni(II), Co(II), and Cd(II) ions yielded new solid chelates with the general formula [M(L)X].nZ, M = Ni(II), Co(II) and Cd(II), X = NO3− or OAc−, n = 0.5–2, Z = H2O or EtOH for complexes 1, 3, 4, 6, 7, 8 and [M2(L)(OAc)3X].0.5EtOH.nH2O, M = Ni(II) and Co(II), X = H2O or EtOH, n = 1 or zero for complexes 2 and 5. The synthesized chelates have been successfully characterized by means of different analytical and spectroscopic tools. SalHFC performs as a monoanionic tridentate in all chelates except chelate 2 and 5 (monoanionic tetradentate). Molar conductivity measurements demonstrated a non‐electrolytic manner of all chelates. Nickel(II) and cobalt(II)‐SalHFC chelates displayed tetrahedral geometries whereas cadmium(II) chelates (7 and 8) were octahedral. TG was employed to inspect the thermal degradation patterns of SalHFC‐complexes, and the Coats‐Redfern equations were employed to estimate the kinetic parameters of the thermal degradation steps. Density functional theory (DFT) level implementation in the Gaussian 09 program at B3LYP/6‐311G(d,p) level was efficaciously used to predict the molecular structural properties of SalHFC and its chelates and the theoretical data and experimental findings were then integrated. SalHFC and its chelates displayed anticancer action against the HepG2 cell line and the results were verified by molecular docking studies. [ABSTRACT FROM AUTHOR]

Eight novel clerodane diterpenoids (1 − 8) were isolated from the twigs of Casearia graveolens. Their structures were elucidated through comprehensive nuclear magnetic resonance (NMR), high-resolution electrospray ionization mass spectrometry (HR-ESI-MS), and electronic circular dichroism (ECD) analyses. In addition to structural determination, surface plasmon resonance (SPR) assays were conducted to investigate molecular interactions, revealing that compound 8 exhibited high affinity for vascular endothelial growth factor receptor 2 (VEGFR2), a key regulator of tumor angiogenesis. Subsequent in vivo experiments demonstrated that compound 8 effectively inhibited angiogenesis and displayed significant antitumor activity by suppressing tumor proliferation and metastasis in zebrafish xenograft models. These findings suggest that compound 8 holds promise as an anticancer lead compound targeting VEGFR-2 to obstruct tumor angiogenesis. [ABSTRACT FROM AUTHOR]

The objective of this study was to develop a nanoformulation of 5-fluorouracil (5-FU) combined with Andrographolide (AG) to synergize their anticancer activity, reduce the dose of 5-FU, and minimize the side effects of 5-FU. Solid lipid nanoparticles (SLNs) of 5-FU and AG were synthesized and characterized separately for average particle size, EE, DL, TEM, DSC, and FTIR. In vitro cytotoxicity was assessed in A549 lung cancer cells, and in vivo experiments were conducted using Ehrlich Ascites Carcinoma (EAC)-induced tumors in Balb/c mice, evaluating tumor regression parameters (TRP) and lifespan analysis (LSA). The average particle size of the SLNs was below 150 nm. The combination nanoformulation of AG and 5-FU exhibited enhanced cytotoxicity in A549 cell lines, with an IC50 value of 18.45 ± 1.03 (p < 0.05). In the in vivo study, the combination nanoformulation showed a decrease in tumor size, an increase in mean survival time, and a significant increment in lifespan compared to the toxic control and AG-SLNs treated groups (p < 0.05). These effects were almost comparable to those observed in the 5-FU-treated group. The combination of nanoformulations, AG, at a dose of 10 mg/kg body weight and 5-FU at 10 mg/kg body weight, demonstrated a synergistic anticancer effect, reduced dose of 5-FU, improved aqueous solubility of both drugs, and increased oral bioavailability. Additionally, nanoparticles were almost found to be stable and they showed potential for reducing side effects such as anemia or myelosuppression. These findings support the potential of combining AG-based chemotherapy with 5-FU for effective cancer prevention and treatment. Figure showing schematic diagram representing research work performed in this study. Abbreviations: SLN, solid-lipid nanoparticles; TEM, transmission electron microscopy; DSC, differential scanning calorimetry; FTIR, Fourier transform infrared spectroscopy. [ABSTRACT FROM AUTHOR]

Abstract In this study, a novel magnetic and pH-responsive nanocarrier was developed, incorporating both natural and synthetic polymers, for delivering curcumin (CUR) to breast cancer cells. For this purpose, CuFe2O4@poly(methacrylic acid) (CuFe2O4@PMAA) nanogel was developed and conjugated with amino-modified lignin (Lignin-adipic acid dihydrazide conjugate, Lig-ADH) to achieve the CuFe2O4@PMAA@Lig-ADH nanocarrier. The morphology, structure, and physical properties of the synthesized nanomaterials were examined using a range of techniques, including transmission electron microscopy (TEM), field emission scanning electron microscopy (FESEM), Fourier transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), energy dispersive X-ray (EDX), and vibrating sample magnetometer (VSM). The synthesized nanocarrier exhibited a spherical shape, with an average diameter of approximately 15 nm, and demonstrated good magnetic responsiveness. Moreover, the in vitro drug release was found to be pH-dependent, with an increased release rate in acidic conditions. To evaluate cytotoxicity, the survival of MCF-7 cells was measured using the MTT assay for 24 h. Notably, the synthesized CuFe2O4@PMAA@Lig-ADH@CUR and CUR exhibited significant cytotoxic effects, effectively eliminating MCF-7 cells with IC50 values of 39.80 µg/mL and 4.27 µg/mL, respectively. Also, the significant intracellular uptake of NPs was confirmed by FITC and DAPI staining after 4 h. This research highlighted the potential of CuFe2O4@PMAA@Lig-ADH@CUR as a highly effective nano-delivery system and demonstrated a straightforward method for utilizing renewable lignin.

Abstract The growth of material science and technology places high importance on creating better processes for synthesizing copper nanoparticles. Thus, an easy, ecological, and benign process for producing copper nanoparticles (CuNPs) has been developed using Priestia sp. bacteria utilizing a variety of low-cost agro-industrial wastes and byproducts. The biosynthesis of CuNPs was conducted using glucose medium and copper ions salt solution, then it was replaced by utilizing low-cost agro-industrial wastes. UV–visible spectroscopy, dynamic light scattering (DLS), X-ray diffraction (XRD), High-resolution transmission electron microscope (HR-TEM), Attenuated Total Reflectance and Fourier transform infrared (ATR-FTIR), and zeta potential were used to characterize the biosynthesized CuNPs. The cytotoxicity of CuNPs using Vero -CCL-81 cell lines, and antibacterial and antitumor properties using human colon epithelial colorectal adenocarcinoma Caco-2-HTB-37 cell lines were assessed. The UV–visible and DLS studies revealed CuNPs formation, with a maximum concentration of 6.19 ppm after 48 h, as indicated by a 0.58 Surface plasmon resonance (SPR) within 450 nm and 57.73 nm particle size. The 16S rRNA gene analysis revealed that Priestia sp. isolate is closely related to Priestia megaterium and has been deposited in the NCBI GenBank with accession number AMD 2024. The biosynthesis with various agro-industrial wastes indicated blackstrap sugar cane molasses being the most effective for reducing CuNPs size to 3.12 nm owing to various reducing and stabilizing active compounds. The CuNPs were free of contaminants, with a sphere-shaped structure and a cytotoxicity assessment with an IC50 of 367.27 μg/mL. The antibacterial activity exhibited by the most susceptible bacteria were Bacillus cereus ATCC 11788 and Staphylococcus aureus ATCC 6538 with inhibition zones of 26.0 mm and 28.0 mm, respectively. The antitumor effect showed an IC50 dose of 175.36 μg/mL. Based on the findings, the current work sought to lower product costs and provide a practical solution to the environmental contamination issues brought on by the buildup of agricultural wastes. In addition, the obtained CuNPs could be applied in many fields such as pharmaceuticals, water purification, and agricultural applications as future aspects.

Algal metabolites have been extensively studied as potential anticancer therapeutics. Among them, polysaccharides have attracted much attention because of their beneficial biological effects and safety. In the present research, the chemical characteristics, antitumor, and proapoptotic activities of extracellular polysaccharides (EPS) isolated from a new Bulgarian strain of the green microalga Coelastrella sp. BGV were investigated. A fast and convenient method of precipitation with cold ethanol was used to isolate EPS from the culture medium. The chemical characteristics of the isolated EPS were examined by colorimetric and spectrophotometric analyses, HPSEC-RID and HPLC-UV chromatography, and FT-IR spectroscopy. The results showed that the isolated EPS sample consists of three carbohydrate fractions with different molecular weights (11.5 × 104 Da, 30.7 × 104 Da, and 72.4 × 104 Da, respectively) and contains 7.14 (w/w%) protein. HPLC-UV analysis revealed the presence of galactose and fucose. The total uronic acid content in the sample was 4.5 (w/w%). The IR-FT spectrum of EPS revealed the presence of various functional groups typical of a polysaccharide (or proteoglycan) composed primarily of neutral sugars. The anticancer potential of the obtained EPS was assessed using cell lines with cancerous and non-cancerous origins as in vitro experimental models. The results of the performed MTT assay showed that EPS reduced the viability of the cervical and mammary carcinoma cell lines HeLa and MCF-7, while the control non-cancer cell lines BALB/3T3 and HaCaT were less affected. The HeLa cell line showed the highest sensitivity to the effects of EPS and was therefore used for further studies of its anticancer potential. The ability of EPS to inhibit cancer cell migration was demonstrated by wound-healing (scratch) assay. The cell cycle FACS analysis indicated that the EPS treatment induced significant increases in the sub G1 cell population and decreases of the percentages of cells in the G1, S, and G2-M phases, compared to the control. The fluorescent microscopy studies performed using three different staining methods in combination with Annexin V-FITC flow cytometric analysis clearly demonstrate the ability of EPS to induce cancer cell death via the apoptosis pathway. Moreover, an altered pattern and intensity of the immunocytochemical staining for the apoptosis- and proliferation-related proteins p53, bcl2, and Ki67 was detected in EPS-treated HeLa cancer cells as compared to the untreated controls. The obtained results characterize the new local strain of green microalgae Coelastrella sp. BGV as a producer of EPS with selective antitumor activity and provide an opportunity for further studies of its pharmacological and biotechnological potential.

BACKGROUND: Xanthohumol is an isopentadienyl flavonoid in hops, which have several pharmacological effects. However, due to the poor bioavailability of xanthohumol, it cannot be widely used. RESULT: In this study, solvent extraction combined with preparative liquid chromatography was used to separate and purify xanthohumol in hop residue. And the purity, yield and recovery of xanthohumol was 983.0 ± 2.1 g kg−1, 921.61 ± 5.65 g kg−1, and 5.41 ± 0.07 g kg−1, respectively. Response surface methodology optimization revealed that 216.75 g kg−1 ethyl oleate, 574.1 g kg−1 polyoxyl‐35 castor oil (EL35) and 209.15 g kg−1 polyethylene glycol 200 (PEG200) produced the xanthohumol nanoemulsion with a loading capacity of 85.40 ± 0.33 g kg−1, mean droplet diameter of 42.35 ± 0.06 nm, and zeta potential of −21.78 ± 0.18 mV. CONCLUSION: Xanthohumol nanoemulsion has better relative stability. The relative oral bioavailability of xanthohumol nanoemulsion was increased by 1.76 times. These results provide a theoretical basis for the application of nanoemulsion containing xanthohumol in food and pharmaceutical industry. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Zhenyu Li,1 Jimin Liu,2 Haishan Cui,3 Wenlong Qi,4 Yangyang Tong,4 Tan Wang4 1College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, People’s Republic of China; 2Department of Respiratory, The Third Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, 130117, People’s Republic of China; 3Department of Traditional Chinese Medicine, The Third Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, 130117, People’s Republic of China; 4Department of Respiratory, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, 130021, People’s Republic of ChinaCorrespondence: Tan Wang, Department of Respiratory, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, 130021, People’s Republic of China, Email wangtan0215@163.comAbstract: The rising global morbidity and mortality rates of non-small cell lung cancer (NSCLC) underscore the urgent need for more effective treatments. Current therapeutic modalities—including surgery, radiotherapy, chemotherapy, and targeted therapy—face several limitations. Recently, Astragalus membranaceus, a traditional Chinese medicine (TCM), has captured significant attention due to its broad pharmacological properties, such as immune regulation, anti-inflammatory effects, and the modulation of reactive oxygen species (ROS) and enzyme activities. This review delivers a comprehensive summary of the most recent advancements and ongoing applications of Astragalus membranaceus in NSCLC treatment, underlining its potential for integration into existing treatment protocols. It also highlights essential areas for future research, including the elucidation of its molecular mechanisms, optimization of dosage and administration, and evaluation of its efficacy and safety alongside standard therapies, all of which could potentially improve therapeutic outcomes for NSCLC patients.Keywords: non-small cell lung cancer, Astragalus membranaceus, antitumor activity, immunoregulation, cisplatin

Potentilla kleiniana belongs to the family Rosaceae, which distributes in Central Asia, East Asia and Southeast Asia. In China, this plant is mainly found in east, south and southwest provinces. P. kleiniana has been prescribed for the treatment of various diseases in the field of traditional Chinese medicine, such as cough, fever, tuberculosis, mastitis, rheumatoid arthritis. Our previous study found that P. kleiniana had a certain cytotoxicity on tumor cells. The purpose of this paper was to investigate the chemical constituents of P. kleiniana and their cytotoxicity on tumor cells. The 60% ethanol extract of P. kleiniana were isolated by D-101 macroporous adsorptive resins, silica gel, Sephadex LH-20, Toyopearl HW-40F, semi-preparative high performance liquid chromatography and other methods, and their chemical structures were elucidated on the basis of physicochemical properties, NMR and HR-ESI-MS analysis. Meanwhile, all these compounds were evaluated for cytotoxicity against human cervical cancer cell line Hela. The results were as follows: (1) Thirteen lignans were isolated and identified as (+)-pionresinol (1), (+)-8-hydroxypinoresinol (2), (+)-syringaresinol (3), (+)-medioresinol (4), (+)-pionresinol-4-O-β-D-glucopyranoside (5), (+)-8′-hydroxypinoresinol-4-O-β-D-glucopyranoside (6), (+)-8′-hydroxypinoresinol-4′-O-β-D-glucopyranoside (7), (+)-pinoresinol-8′-O-β-D-glucopyranoside (8), schilignan F (9), (+)-pionresinol-4, 4′-O-bisglucopyranoside (10), (+)-lariciresinol-4′-O-β-D-glucopyranoside (11), neoolivil-4-O-β-D-glucopyranoside (12), 3,3′-bis［3,4-dihydro-4-hydroxy-6-methoxy-2H-1-benzopyran］(13). Among them, compounds 1-4, 7, 8, 10, 12, 13 were isolated from genus Potentilla for the first time, and compounds 5, 6, 9, 11 were isolated from P. kleiniana for the first time. (2) Cytotoxicity studies showed that compounds 1, 3 and 4 display certain inhibitory activities against Hela cells with IC50 values of (69.94 ± 1.89), (66.25 ± 2.11), (59.81 ± 1.73) μmol·L-1, respectively. Therefore, the study enriches the chemical constituents of P. kleiniana, and provides a material basis for the development of anti-cervical cancer drugs.

Abstract Acute promyelocytic leukemia (APL) is characterized by rearrangements of the retinoic acid receptor, RARα, which makes all-trans retinoic acid (ATRA) highly effective in the treatment of this disease, inducing promyelocytes differentiation. Current therapy, based on ATRA in combination with arsenic trioxide, with or without chemotherapy, provides high rates of event-free survival and overall survival. However, a decline in the drug activity, due to increased ATRA metabolism and RARα mutations, is often observed over long-term treatments. Furthermore, dedifferentiation can occur providing relapse of the disease. In this study we evaluated fenretinide, a semisynthetic ATRA derivative, encapsulated in nanomicelles (nano-fenretinide) as an alternative treatment to ATRA in APL. Nano-fenretinide was prepared by fenretinide encapsulation in a self-assembling phospholipid mixture. Physico-chemical characterization was carried out by dinamic light scattering and spectrophotometry. The biological activity was evaluated by MTT assay, flow cytometry and confocal laser-scanning fluorescence microscopy. Nano-fenretinide induced apoptosis in acute promyelocytic leukemia cells (HL60) by an early increase of reactive oxygen species and a mitochondrial potential decrease. The fenretinide concentration that induced 90–100% decrease in cell viability was about 2.0 µM at 24 h, a concentration easily achievable in vivo when nano-fenretinide is administered by oral or intravenous route, as demonstrated in previous studies. Nano-fenretinide was effective, albeit at slightly higher concentrations, also in doxorubicin-resistant HL60 cells, while a comparison with TK6 lymphoblasts indicated a lack of toxicity on normal cells. The results indicate that nano-fenretinide can be considered an alternative therapy to ATRA in acute promyelocytic leukemia when decreased efficacy, resistance or recurrence of disease emerge after protracted treatments with ATRA.

Abstract Sugar esters display surface-active properties, wetting, emulsifying, and other physicochemical phenomena following their amphipathic nature and recognize distinct biological activity. The development of nutritional pharmaceuticals and other applications remains of great interest. Herein, three novel homologous series of several N-mono-fatty acyl amino acid glucosyl esters were synthesized, and their physicochemical properties and biological activities were evaluated. The design and preparation of these esters were chemically performed via the reaction of glucose with different fatty acyl amino acids as renewable starting materials, with the suggestion that they would acquire functional characteristics superior and competitive to certain conventional surfactants. The synthesized products are characterized using FTIR, 1H-NMR, and 13C-NMR spectroscopy. Further, their physicochemical properties, such as HLB, CMC, Γmax, γCMC, and Amin, were determined. Additionally, their antimicrobial and anticancer efficiency were assessed. The results indicate that the esters' molecular structure, including the acyl chain length and the type of amino acid, significantly influences their properties. The measured HLB ranged from 8.84 to 12.27, suggesting their use as oil/water emulsifiers, wetting, and cleansing agents. All esters demonstrate promising surface-active characteristics, with moderate to high foam production with good stability. Notably, compounds 6-O-(N-dodecanoyl, tetradecanoyl cysteine)-glucopyranose (34, 35), respectively and 6-O-(N-12-hydroxy-9-octadecenoyl cysteine)-glucopyranose (38) display superior foamability. Wetting efficiency increased with decreasing the chain length of the acyl group. The storage results reveal that increasing the fatty acyl hydrophobe length enhances the derived emulsion's stability for up to 63 days. Particularly, including cysteine in these glucosyl esters improves wetting, foaming, and emulsifying potentialities. Furthermore, the esters exhibit antibacterial activity against several tested Gram-positive and Gram-negative bacteria and fungi. On the other hand, they show significant antiproliferative effects on some liver tumor cell lines. For instance, compounds 6-O-(N-12-hydroxy-9-octadecenoylglycine)-glucopyranose (28), 6-O-(N-dodecanoyl, hexadecanoyl, 9-octadecenoyl and 12-hydroxy-9-octadecenoylvaline)- glucopyranose (29, 31, 32 and 33), respectively in addition to the dodecanoyl, hexadecanoyl, 9-octadecenoyl and 12-hydroxy-9-octadecenoyl cysteine glucopyranose (34, 36, 37 and 38), respectively significantly inhibit the examined cancer cells.

Background: Poly (ADP-ribose) polymerase 1 and 2 (PARP1/2) inhibitors (PARPi) are targeted therapies approved for homologous recombination repair (HRR)-deficient breast, ovarian, pancreatic, and prostate cancers. Since inhibition of PARP1 is sufficient to cause synthetic lethality in tumors with homologous recombination deficiency (HRD), PARP1 selective inhibitors such as saruparib (AZD5305) are being developed. It is expected that selective PARP1 inhibition leads to a safer profile that facilitates its combination with other DNA damage repair inhibitors. Here, we aimed to characterize the antitumor activity of AZD5305 in patient-derived preclinical models compared to the first-generation PARP1/2 inhibitor olaparib and to identify mechanisms of resistance. Methods: Thirteen previously characterized patient-derived tumor xenograft (PDX) models from breast, ovarian, and pancreatic cancer patients harboring germline pathogenic alterations in BRCA1, BRCA2, or PALB2 were used to evaluate the efficacy of AZD5305 alone or in combination with carboplatin or an ataxia telangiectasia and Rad3 related (ATR) inhibitor (ceralasertib) and compared it to the first-generation PARPi olaparib. We performed DNA and RNA sequencing as well as protein-based assays to identify mechanisms of acquired resistance to either PARPi. Results: AZD5305 showed superior antitumor activity than the first-generation PARPi in terms of preclinical complete response rate (75% vs. 37%). The median preclinical progression-free survival was significantly longer in the AZD5305-treated group compared to the olaparib-treated group (> 386 days vs. 90 days). Mechanistically, AZD5305 induced more replication stress and genomic instability than the PARP1/2 inhibitor olaparib in PARPi-sensitive tumors. All tumors at progression with either PARPi (39/39) showed increase of HRR functionality by RAD51 foci formation. The most prevalent resistance mechanisms identified were the acquisition of reversion mutations in BRCA1/BRCA2 and the accumulation of hypomorphic BRCA1. AZD5305 did not sensitize PDXs with acquired resistance to olaparib but elicited profound and durable responses when combined with carboplatin or ceralasertib in 3/6 and 5/5 models, respectively. Conclusions: Collectively, these results show that the novel PARP1 selective inhibitor AZD5305 yields a potent antitumor response in PDX models with HRD and delays PARPi resistance alone or in combination with carboplatin or ceralasertib, which supports its use in the clinic as a new therapeutic option. [ABSTRACT FROM AUTHOR]

The Japanese plum tree (Prunus salicina Lindl.) is mainly cultivated in temperate areas of China and some European countries. Certain amounts of wood (from pruning works) are generated every year from this crop of worldwide commercial significance. The main objective of this work was to value this agricultural woody residue, for which the chemical composition of pruning wood extracts from six Japanese plum cultivars was investigated, and the antiproliferative activity of extracts and pure phenolics present in those extracts was measured. For the chemical characterization, total phenolic content and DPPH radical-scavenging assays and HPLC‒DAD/ESI‒MS analyses were performed, with the procyanidin (−)-ent-epicatechin-(2α→O→7,4α→8)-epicatechin (5) and the propelargonidin (+)-epiafzelechin-(2β→O→7,4β→8)-epicatechin (7) being the major components of the wood extracts. Some quantitative differences were found among plum cultivars, and the content of proanthocyanidins ranged from 1.50 (cv. 'Fortune') to 4.44 (cv. 'Showtime') mg/g of dry wood. Regarding the antitumoral activity, eight wood extracts and four phenolic compounds were evaluated in MCF-7 cells after 48 h of induction, showing the wood extract from cv. 'Songold' and (‒)-annphenone (3), the best antiproliferative activity (IC50: 424 μg/mL and 405 μg/mL, respectively). [ABSTRACT FROM AUTHOR]

Silybin is a natural flavonolignan with potential anticancer, antioxidant, and hepatoprotective properties. In the present study, various loadings of silybin (1, 3, and 5 wt%) were encapsulated in poly-ε-caprolactone (PCL) fibers by electrospinning, in order to produce new pharmaceutical composites with improved bioactive and drug delivery properties. The morphological characteristics of the composite fibrous structures were evaluated by scanning electron microscopy (SEM), and the encapsulation efficiency and the release rate of silybin were quantified using a UV-Vis spectrophotometer. The analysis of the membranes' thermal behavior by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) revealed the existence of interaction between PCL and silybin. An investigation of the cytocompatibility of the composite membranes revealed that normal cells displayed an unimpeded proliferation in the respective silybin concentrations; however, tumor cell growth demonstrated a dose-dependent inhibition. Furthermore, an effective antioxidant activity against hydrogen peroxide-induced oxidative stress in HEK-293 cells was observed for the prepared electrospun fibrous mats. [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of cancer death worldwide and curcumin is a natural polyphenol product with a diversity of antitumor activities. However, its clinical utility is limited due to its relatively low instability and poor bioavailability. This study evaluates the antitumor activity and the underlying mechanism of eight new curcumin analogs in A549 cells. Cell proliferation, migration and apoptosis were examined, respectively, through MTT assay, clone formation, wound healing, transwell, JC-1 staining, Bcl-2 activity, and caspase 3 activity. Protein levels of TGF-βR, MEK, and ERK were determined via western blotting. The binding mode of the ligand and the receptor was simulated by molecular docking studies. Compound A7 was found as the most potent analog (IC50 = 25.78 μM) compared to curcumin (IC50 = 42.30 μM). A7 exposure suppressed A549 cell migration and induced apoptosis with significant differences. Western blot and molecular docking studies demonstrated that the potential mechanism may relate to regulating the TGF-βR/MEK/ERK signaling pathway. Therefore, inhibiting this signaling pathway may provide a potential therapeutic strategy for lung cancer. [ABSTRACT FROM AUTHOR]

Using triterpenoid betulin as an example, a convenient method for the synthesis of 5,6-dihydropyran derivatives containing a nor-triterpenoid fragment at position 4 was proposed. The method involves the reaction of lupane triterpenoids with paraformaldehyde in dioxane in the presence of sulfuric acid. Approaches to the synthesis of triterpene derivatives of 5,6-dihydropyran-2-one and penta-2,4-dienoic acid were developed based on the obtained 4-(3,28-diacetoxy-20,29,30-tri-nor-lupan-19-yl)-5,6-dihydropyran. Triterpene-substituted penta-2,4-dienoic acid heated with triphenylphosphonium triflate formed a quaternary phosphonium salt, which showed cytotoxicity against human cancer cells MCF-7 (breast cancer) and HCT116 (colon cancer) with IC50 4–19 µmol L−1, with its activity against these cell lines being superior to the activity of the comparison drug camptothecin. [ABSTRACT FROM AUTHOR]

A new novel tetradentate ligand, [(1E,1′E)‐N,N′‐(1,2‐phenylene)bis(1‐(5‐(2‐fluorophenyl)furan‐2‐yl)methanimine) (PFPFMI), and its nano‐sized [Zn(PFPFMI)Cl2].3H2O complex were synthesized. The geometry of PFPFMI and its Zn(II) complex was described through CHN analyses, Fourier‐transform infrared spectroscopy (FTIR), UV–visible, X‐ray diffraction (XRD), thermal gravimetric analysis (TGA), and mass spectral data tests. The spectral data of the nano‐sized [Zn(PFPFMI)Cl2].3H2O complex indicates that the PFPFMI ligand functions as a tetradentate (N2O2) coordination through two azomethine nitrogen groups (N) and two furan ring oxygen (O) atoms. Density functional theory (DFT) calculations were performed using the molecular studio software to investigate the optimal geometry of PFPFMI and its [Zn(PFPFMI)Cl2].3H2O complex. The SEM, TEM, XRD, AFM, and energy dispersive X‐ray analysis (EDX) analyses of the studied complex unveil distinct and strong diffraction peaks, indicating its crystalline nature and providing evidence of its nano‐sized particle sizes. Additionally, the inhibition zone diameter was used to assess the in vitro antimicrobial action of PFPFMI and the particular complex against Gram‐positive bacteria Streptococcus pneumonia and Bacillus subtilis, Gram‐negative bacteria Pseudomonas aeruginosa, Salmonella typhi, and Escherichia coli, as well as fungi Aspergillus fumigatus, Geotricum candidum, Syncephalastrum racemosum, and Candida tropicalis. The [Zn(PFPFMI)Cl2].3H2O complex exhibits higher activity than the ligand PFPFMI. In vitro cytotoxicity of the synthesized [Zn(PFPFMI)Cl2].3H2O complex was explored using MCF7 (breast cancer), HCT116 (colon cancer), A549 (lung cancer), HePG‐2 (liver cancer), A375 (melanoma cancer), and normal lung fibroblast (WI38) cell lines. Based on IC50 and selective index (SI) values, it was shown that the complex exhibited higher potency against MCF7 cell lines. Moreover, the Zn(II) complex exhibited the ability to induce DNA damage in MCF7 cells, resulting in dose‐dependent cell apoptosis. Subsequent investigations revealed that complex 2 also induced cell cycle arrest in the G2 and S phases. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC), one of the malignancies with a wide expression of stress ligands recognized by Vδ1γδ T cells, has received much attention in adoptive immunotherapy of γδ T cells. In this study, we aimed to identify the potential anti-tumor Vδ1γδ T subpopulations in HCC. Healthy donors (HDs) and HCC patients were recruited from the Affiliated Cancer Hospital of Zhengzhou University. Blood and tumor tissue samples were obtained respectively. Bioinformatics methods were used to analyze total γδ T cells and subsets infiltration, overall survival of HCC patients with high and low infiltration level of Vδ1γδ T cells, and IFNG , granzyme A, granzyme B and perforin expression in TRDV1 high/low CD69 high/low groups. CD69 expression and Vδ1γδT cells infiltration in HCC were detected by immunofluorescence. Phenotypic analysis of Vδ1γδ T cells in blood and tumor tissue samples were performed by flow cytometry. Vδ1γδ T cells infiltrating in HCC were associated with better clinical outcome. Study in tumor micro-environment (TME) of HCC demonstrated that not total Vδ1γδ T but CD69+ Vδ1γδ subset infiltration was associated with smaller tumor volume. Moreover, HCC patients simultaneously with high TRDV1 and CD69 expression produced more effector molecules and had longer survival time. Since Vδ1γδ T cells in the tumor microenvironment were often difficult to access, we demonstrated that CD69+ Vδ1γδ T cells also existed in peripheral blood mononuclear cells (PBMC) of HCC and displayed enhanced cytotoxic potentials than HDs. Finally, we investigated the functions and found that CD69+ Vδ1γδ T cells exhibited stronger tumor reactivities when challenged by tumor cells. CD69+ Vδ1γδ T cells are functional Vδ1γδ T cell subsets in patients with HCC. Circulating CD69+ Vδ1γδ T cell is a promising candidate in immunotherapy of HCC. [Display omitted] • Vδ1γδ T associated with better clinical outcome of HCC. Higher CD69+ Vδ1γδ subset indicated smaller tumor. • CD69+ Vδ1γδ Tfrom PBMCs displayed enhanced cytotoxicity. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and poses a severe threat to human health. Ginkgo biloba leaf polysaccharide (GBLP) is a bioactive component, and its sulphated derivative (sulfated GBLP, SGBLP) may exhibit high antitumor activity in certain types of cancers. However, the precise mechanisms of the SGBLP antitumor activity, particularly in HCC, remain unclear. Here, we assessed the effect of SGBLP on HepG2 hepatocellular carcinoma cells. SGBLP was shown to inhibit cellular proliferation and promote apoptosis through the regulation of pro- as well as anti-apoptosis markers, and to induce autophagy by supressing the PI3K/AKT/mTOR pathway. In addition, the autophagy inhibitor 3-melyladenine (3-MA) enhanced the antiproliferative and proapoptotic effects of SGBLP in HepG2 cells. Thus, SGBLP exhibits antitumor activity, and its combination with an autophagy inhibitor may represent a promising anticancer strategy in the treatment of HCC. [ABSTRACT FROM AUTHOR]

Sporisorium reilianum is an important biotrophic pathogen that causes head smut disease. Polysaccharides extracted from diseased sorghum heads by Sporisorium reilianum exhibit significant medicinal and edible value. However, the structure and biological activities of these novel polysaccharides have not been explored. In this study, a novel polysaccharide (WM-NP'-60) was isolated and purified from the fruit bodies of S. reilianum and aimed to explore the structural characteristics and substantial antioxidant and antitumor properties of WM-NP'-60. Monosaccharide composition determination, periodate oxidation-Smith degradation, 1D/2D-NMR analysis, and methylation analysis revealed that WM-NP'-60 consisted mainly of β-1,6-D-Glcp, β-1,3-D-Glcp, and β-1,3,6-D-Glcp linkages. The antioxidant assays demonstrated that WM-NP'-60 exhibited great activities, including scavenging free radicals, chelating ferrous ions, and eliminating reactive oxygen species (ROS) within cells. The HepG2, SGC7901, and HCT116 cells examined by transmission electron microscopy (TEM) revealed typical apoptotic bodies. Therefore, a novel fungal polysaccharide (WM-NP'-60) was discovered, extracted, and purified in this experiment, with the aim of providing a reference for the development of a new generation of food and nutraceutical products suitable for human consumption. [ABSTRACT FROM AUTHOR]

In the present research, we have successfully synthesized and characterized two novel Bis-chalcones, namely 3-(4-(dimethylamino)benzylidene)pentane-2,4-dione (DBPD) and 3-(3-(4-dimethylamino)phenyl)allylidene)pentane-2,4-dione (DPAPD). Their photophysical properties were studied in a series of solvents. UV–Vis absorption spectra are insensitive to solvent polarity whereas the fluorescence spectra in the same solvent set show an important solvatochromic effect leading to large Stokes shifts. Linear solvation energy relations were employed to correlate the position of fluorescence spectra maxima with microscopic empirical solvent parameters. This study indicates that important intramolecular charge transfer, ICT, takes place during the excitation process. Furthermore, we extended our investigations to encompass absorption and fluorescence behaviors in mixed water-EtOH environments, allowing us to gauge microenvironmental polarity. DFT method with B3LYP/6-311++G(d,p) basis set has been used to analyze DBPD and DPAPD computationally, and to determine the most stable structure and the nature of the molecular orbitals, which are essential to understand the binding feature of the compounds. The experimental data from NMR, UV–Vis and FTIR were compared with the theoretical calculations of electronic and conformational properties. Moreover, the QTAIM (RDG) topological analysis was applied to both compounds using Multiwfn software. Also, we delved into the determination of binding constants and the assessment of micellar properties, including polarity and critical micelle concentration. The dynamic interactions between the investigated dyes and CT-DNA were investigated using electronic absorption and emission techniques. In the closing phases of our research, we delved into the exploration of the potential antitumor activity exhibited by the synthesized compounds. Moreover, the docking binding affinity of investigated compounds toward CT-DNA and tumors protein were estimated by the Schrödinger suite software. [ABSTRACT FROM AUTHOR]

CD39 serves as a crucial biomarker for neoantigen-specific CD8+ T cells and is associated with antitumor activity and exhaustion. However, the relationship between CD39 expression levels and the function of chimeric antigen receptor T (CAR-T) cells remains controversial. This study aimed to investigate the role of CD39 in the functional performance of CAR-T cells against hepatocellular carcinoma (HCC) and explore the therapeutic potential of CD39 modulators, such as mitochondrial division inhibitor-1 (mdivi-1), or knockdown CD39 through short hairpin RNA. Our findings demonstrated that glypican-3-CAR-T cells with moderate CD39 expression exhibited a strong antitumor activity, while high and low levels of CD39 led to an impaired cellular function. Methods modulating the proportion of CD39 intermediate (CD39int)-phenotype CAR-T cells such as mdivi-1 and CD39 knockdown enhanced and impaired T cell function, respectively. The combination of mdivi-1 and CD39 knockdown in CAR-T cells yielded the highest proportion of infiltrated CD39int CAR-T cells and demonstrated a robust antitumor activity in vivo. In conclusion, this study revealed the crucial role of CD39 in CAR-T cell function, demonstrated the potential therapeutic efficacy of combining mdivi-1 with CD39 knockdown in HCC, and provided a novel treatment strategy for HCC patients in the field of cellular immunotherapy. [ABSTRACT FROM AUTHOR]

Objective: TQB3602 is a novel orally bioavailable proteasome inhibitor. This study is the first‐in‐human phase I clinical trial to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of TQB3602 in relapsed/refractory multiple myeloma (RRMM). Methods: This is a multicenter phase I clinical trial consisting of the 3+3 dose‐escalation phase and dose expansion phase. Patients with MM who have received ≥2 prior antimyeloma therapies were enrolled. TQB3602 is administered at a dose of 0.5~7mg on days 1, 8, 15 in 28‐day cycle. Results: Twenty‐five RRMM patients who relapsed or failed ≥2 lines of therapies were enrolled in the dose escalation phase. Two patients in the 7.0 mg dose group developed dose‐limiting toxicity events (one with grade 2 peripheral neuropathy [PN] complicated by pain and one with diarrhea and abdominal pain), leading to a maximum tolerated dose of 6.0 mg. Any‐grade adverse events (AEs) occurred in 24 (96.0%) patients, while grade ≥3 AEs occurred in 13 (52.0%). The most common grade ≥3 AEs was anemia (6, 24.0%). The incidence rate of PN was 16% with no grade ≥3 PN occurred. TQB3602 was rapidly absorbed, resulting in a time‐to‐plasma peak concentration of 0.8–1.5 h. The mean half‐life was approximately 82 h. The AUClast and Cmax were approximately 1.9 times higher on day 15 than on day 1. Among 22 response‐evaluable patients, 63.7% achieved stable disease or better. Conclusions: TQB3602 is well tolerated, with a favorable neurotoxicity profile, and has shown preliminary efficacy in patients with RRMM. The anticipated therapeutic dose was 6 mg and was adopted for an ongoing dose‐expansion phase. [ABSTRACT FROM AUTHOR]

Selenium, zinc, copper, and manganese are essential components of antioxidant enzymes involved in the elimination of reactive oxygen species (ROS). Given that cancer cells produce high levels of ROS and the accumulation of ROS can lead to cell death, cancer cells may be susceptible to strategies that reduce ROS elimination. In this work, we prepared several artificial diets that contained normal carbohydrate, protein, and lipid levels but lacked selenium, zinc, copper, or manganese. The anticancer activity of these diets was examined in a metastatic ovarian cancer model, established by injecting ID8 Trp53−/− murine ovarian cancer cells into the peritoneal cavity of C57BL/6JRj mice. Treatments started 15 days later and consisted of replacing a normal diet with one of the artificial diets for several weeks. A significant improvement in mice survival was observed when the normal diet was replaced with the selenium-free diet. Diets lacking zinc, copper, or manganese showed no significant impact on mice survival. All diets were very well tolerated. The anticancer efficacy of a diet lacking selenium was confirmed in mice with metastatic colon cancer and in mice with metastatic triple-negative breast cancer. These results suggest that diets lacking selenium hold potential for the treatment of metastatic cancers. [ABSTRACT FROM AUTHOR]

Alpha-terpineol is a monoterpene alcohol found in essential oils from medicinal plants with some well-known pharmacological activities and widely used in cosmetics. However, the toxicological effects and additional pharmacological activities need to be clarified. Thus, the study evaluated the toxic, cytotoxic, genotoxic, hemolytic, and oxidative potential of alpha-terpineol in non-clinical bioassays. Different concentrations of alpha-terpineol were used in bioassays, including MTT (50, 100, 200, and 400 μg/mL), Artemia salina (6.25–400 μg/mL), Allium cepa (10, 50, and 100 μg/mL), comet assay (100, 200, and 500 μg/mL), cytokinesis-block micronucleus (100, 250, and 500 μg/mL), confocal microscopy for apoptosis quantification (100 and 500 μg/mL), hemolysis and Saccharomyces cerevisiae central disk test (10, 35, and 75 μg/mL). For the MTT test, alpha-terpineol was more cytotoxic on melanoma murine B16–F10 cells rather than macrophages. For A. salina test, alpha-terpineol showed LC50 of 68.29 and 76.36 μg/mL for 24 h and 48 h of exposure time, respectively. Meanwhile, alpha-terpineol was also cytotoxic to meristematic cells, which revealed inhibition of cellular division and mutagenic action by formation of bridges and delayed anaphases. The compound increased damage index and frequency of damage corroborated by the presence of micronuclei, bridges and nuclear buds at 500 μg/mL, but it caused neither hemolysis, oxidative damage on the S. cerevisiae nor cell death in normal fibroblasts. The findings indicate alpha-terpineol has cytotoxic potential by cytogenetic and molecular mechanisms associated with apoptosis and probable target effects against melanoma cells. [ABSTRACT FROM AUTHOR]

In this work, we show the in vitro anticancer potential of surgical wires, obtained from zinc (ZnMg0.004) or magnesium (MgCa0.7) alloys by spatial technology comprising casting, extrusion, and final drawing processes. We also present the selective anticancer effects of applied soluble multilayer nanocoatings of zinc and magnesium onto titanium surfaces using the pulse laser deposition method. In the latter, the titanium samples were produced via 3D printing using the selective laser melting method and coated with various combinations of zinc and magnesium layers. For cytotoxicity studies, human dental pulp-derived stem cells (hDPSCs) and human osteosarcoma SaOS-2 cell line were used as representatives of healthy and cancer cells. Cells were examined against the 0.3–3.0 cm2/mL material extract ratios obtained from experimental and steel surgical wires, the latter being the current clinical industry standard. The MgCa0.7 alloy wires were approx. 1.5 times more toxic to cancer cells at all examined extract ratios vs. the extracts from steel surgical wires that exhibited comparable toxicity towards healthy and cancer cells. The ZnMg0.004 alloy wires displayed increased toxicity towards cancer cells with decreasing extract ratios. This was also reflected in the increased anticancer effectiveness, calculated based on the viability ratio of healthy cells to cancer cells, from 1.1 to 4.0 times. Healthy cell viability remained at 80–100%, whereas cancer cell survival fluctuated at 20–75%, depending on the extract ratio. Furthermore, the culture of normal or cancer cells on the surface of Zn/Mg-coated titanium allowed us to select combinations of specific coating layers that yielded a comparable anticancer effectiveness to that observed with the experimental wires that ranged between 2 and 3. Overall, this work not only demonstrates the substantial anticancer properties of the studied wires but also indicates that similar anticancer effects can be replicated with appropriate nanocoatings on titanium samples. We believe that this work lays the groundwork for the future potential development of the category of new implants endowed with anticancer properties. [ABSTRACT FROM AUTHOR]

Cancer remains a leading cause of death worldwide, often resulting from uncontrolled growth in various organs. Protein kinase inhibitors represent an important class of targeted cancer therapies. Recently, the kinases BRAF and VEGFR-2 have shown synergistic effects on tumor progression. Seeking to develop dual BRAF/VEGFR-2 inhibitors, we synthesized 18 amino-benzothiazole derivatives with structural similarities to reported dual inhibitors. Four compounds—4a, 4f, 4l, and 4r—demonstrated remarkable cytotoxicity, with IC50 values ranging from 3.58 to 15.36 µM, against three cancer cell lines. Furthermore, these compounds showed IC50 values of 38.77–66.22 µM in the case of a normal cell line, which was significantly safer than the reference, sorafenib. Subsequent investigation revealed that compound 4f exhibited the capacity to inhibit the BRAF and VEGFR-2 enzymes, with IC50 values similar to sorafenib (0.071 and 0.194 µM, respectively). Moreover, compound 4f caused G2-M- and S-phase cycle arrest. Molecular modeling demonstrated binding patterns compatible with inhibition for both targets, where 4f exerted the critical interactions in the BRAF site and interacted in the VEGFR-2 site in a manner akin to sorafenib, demonstrating affinity similar to dabrafenib. [ABSTRACT FROM AUTHOR]

A short 19 bp dsRNA with 3′-trinucleotide overhangs acting as immunostimulating RNA (isRNA) demonstrated strong antiproliferative action against cancer cells, immunostimulatory activity through activation of cytokines and Type-I IFN secretion, as well as anti-tumor and anti-metastatic effects in vivo. The aim of this study was to determine the tolerance of chemical modifications (2′-F, 2′-OMe, PS, cholesterol, and amino acids) located at different positions within this isRNA to its ability to activate the innate immune system. The obtained duplexes were tested in vivo for their ability to activate the synthesis of interferon-α in mice, and in tumor cell cultures for their ability to inhibit their proliferation. The obtained data show that chemical modifications in the composition of isRNA have different effects on its individual functions, including interferon-inducing and antiproliferative effects. The effect of modifications depends not only on the type of modification but also on its location and the surrounding context of the modifications. This study made it possible to identify leader patterns of modifications that enhance the properties of isRNA: F2/F2 and F2_S/F2 for interferon-inducing activity, as well as F2_S5/F2_S5, F2-NH2/F2-NH2, and Ch-F2/Ch-F2 for antiproliferative action. These modifications can improve the pharmacokinetic and pharmacodynamic properties, as well as increase the specificity of isRNA action to obtain the desired effect. [ABSTRACT FROM AUTHOR]

Quinoxaline compounds are widely used in the fields of medicine and chemical industry, especially in the development of anticancer drugs, due to their significant biological activity. 6-fluoro-4-hydroxy-3-oxo-3,4-dihydroquinoline-1 (2H)-carboxylic acid tert-butyl ester was synthesized through a four-step reaction method in this paper, and its single crystal was obtained by solution crystallization method. Crystallographic analysis indicates that the compound belongs to monoclinic crystal system with space group C2/c, the unit cell dimensions are a =1.286 63(10) nm, b =2.252 49(17) nm, c =1.015 64(7) nm, Z =8, ρc =1. 359 g·cm-3, R =0. 053 8, Rw =0. 140 6. The optimal structure was calculated using density functional theory (DFT) in B3LYP/6-311 + G (2d, p) mode. The results are basically consistent with those obtained by X-ray single crystal diffraction. The antitumor activity study shows that the compound has good antitumor effect. In addition, the electrostatic potential and frontier molecular orbitals of the molecules were calculated by DFT to further understand their physical and chemical properties. [ABSTRACT FROM AUTHOR]

Two polyamine-diarylidenyl piperidone (DAP) derivatives, dimer polyamine-H-4073 and tetrameric polyamine-H-4073, were designed and synthesized as antitumor agents by coupling the bifluoro-substituted DAP STAT3 inhibitor H-4073 to two different polyamines through the binary fatty acid chains, respectively. MTT assay and a SW480 xenograft model identified dimer polyamine-H-4073 as good candidate antitumor agent with good efficacy, limited toxicity, and low resistance, in comparison with H-4073, cisplatin, and doxorubicin. Western blot analysis results indicated that dimer polyamine-H-4073 exhibited effectively inhibition on signal transducer and activator of transcription 3 (STAT3), indicating that it may be a STAT3 inhibitor. [ABSTRACT FROM AUTHOR]

In order to explore the effect of chemical modification on the inhibitory effect of intracellular polysaccharides of Phaeodactylum tricornutum (PTP) on the proliferation of cervical cancer Hela cells, in this study, the PTP was extracted by the ultrasound-assisted wall-breaking method combined with the hot water extraction method. Four types of chemical modification (sulfation modification, phosphorylation modification, acetylation modification and carboxymethylation modification ) were carried out on the PTP. The inhibitory effects of the initial PTP, sulfated polysaccharide (S-PTP), phosphorylated polysaccharide (P-PTP), acetylated polysaccharide (A-PTP) and carboxymethylated polysaccharide (C-PTP) on the proliferation of cervical cancer Hela cells were studied. The results showed that the degree of substitution of the S-PTP was 0.714, and the inhibitory effect of S-PTP on the proliferation rate of Hela cells could be up to 9.22% higher than that of PTP. The degree of substitution of P-PTP was 0.191, and the inhibitory effect of P-PTP on the proliferation rate of Hela cells could be up to 4.01% higher than that of PTP. The degree of substitution of acetylated polysaccharide A-PTP was 0.513, and the inhibitory effect of P-PTP on the proliferation rate of Hela cells could be up to 13.53% higher than that of PTP. The degree of substitution of C-PTP was 0.915, and the inhibitory effect of C-PTP on the proliferation rate of Hela cells could be up to 8.39% higher than that of PTP. The results showed that the inhibitory effects of four modified polysaccharides on the proliferation of Hela cells were all greater than that of PTP. Acetylation modification had the greatest inhibitory effect on the proliferation of Hela cells. Compared with PTP, the inhibitory effect of A-PTP against the proliferation rate of cervical cancer Hela cells was increased by 13.53%, reaching 46.05%. Through the experiments of chemical modification of PTP, it was proven that the introduction of a new chemical group into the molecular structure of PTP can lead to a great influence on the inhibition of cervical cancer cell proliferation. This result provides an important reference for further study on the biological activity of Phaeodactylum tricornutum and an experimental basis for subsequent drug research and development. [ABSTRACT FROM AUTHOR]

The main goal of this study was to introduce a nanohybrid based on graphene oxide and zinc oxide with strong antitumor activity for the treatment of hepatitis B virus-associated hepatocarcinoma. In this regard, the nanohybrid was fabricated through the first attachment of locust bean gum chains on the graphene oxide surface and subsequently zinc oxide nanoparticles decorated on the surface of graphene oxide-locust bean gum nanosheets. Then, the prepared ternary nanohybrid was assessed in terms of physicochemical and microstructural characteristics, cytotoxicity, and antitumor activity. Our primary results indicated the successful fabrication of nanohybrids. The results of toxicity assays showed that the prepared nanohybrid represented higher cytotoxicity on the cancer cell line compared to the normal cells. Antitumor activity results demonstrated that the synthesized nanohybrid can superiorly decline viral and cellular oncogenes and induce cell apoptosis in liver cancer cells. In conclusion, the fabricated nanohybrid demonstrated strong antitumor activity against hepatocarcinoma cells, which can be considered a promising candidate for the treatment of hepatocarcinoma. [ABSTRACT FROM AUTHOR]

Acute promyelocytic leukemia (APL) is characterized by rearrangements of the retinoic acid receptor, RARα, which makes all-trans retinoic acid (ATRA) highly effective in the treatment of this disease, inducing promyelocytes differentiation. Current therapy, based on ATRA in combination with arsenic trioxide, with or without chemotherapy, provides high rates of event-free survival and overall survival. However, a decline in the drug activity, due to increased ATRA metabolism and RARα mutations, is often observed over long-term treatments. Furthermore, dedifferentiation can occur providing relapse of the disease. In this study we evaluated fenretinide, a semisynthetic ATRA derivative, encapsulated in nanomicelles (nano-fenretinide) as an alternative treatment to ATRA in APL. Nano-fenretinide was prepared by fenretinide encapsulation in a self-assembling phospholipid mixture. Physico-chemical characterization was carried out by dinamic light scattering and spectrophotometry. The biological activity was evaluated by MTT assay, flow cytometry and confocal laser-scanning fluorescence microscopy. Nano-fenretinide induced apoptosis in acute promyelocytic leukemia cells (HL60) by an early increase of reactive oxygen species and a mitochondrial potential decrease. The fenretinide concentration that induced 90–100% decrease in cell viability was about 2.0 µM at 24 h, a concentration easily achievable in vivo when nano-fenretinide is administered by oral or intravenous route, as demonstrated in previous studies. Nano-fenretinide was effective, albeit at slightly higher concentrations, also in doxorubicin-resistant HL60 cells, while a comparison with TK6 lymphoblasts indicated a lack of toxicity on normal cells. The results indicate that nano-fenretinide can be considered an alternative therapy to ATRA in acute promyelocytic leukemia when decreased efficacy, resistance or recurrence of disease emerge after protracted treatments with ATRA. [ABSTRACT FROM AUTHOR]

The crystal structures of two newly synthesized nitrilotriacetate oxidovanadium(IV) salts, namely [QH][VO(nta)(H2O)](H2O)2 (I) and [(acr)H][VO(nta)(H2O)](H2O)2 (II), were determined. Additionally, the cytotoxic effects of four N-heterocyclic nitrilotriacetate oxidovanadium(IV) salts—1,10-phenanthrolinium, [(phen)H][VO(nta)(H2O)](H2O)0.5 (III), 2,2′-bipyridinium [(bpy)H][VO(nta)(H2O)](H2O) (IV), and two newly synthesized compounds (I) and (II)—were evaluated against prostate cancer (PC3) and breast cancer (MCF-7) cells. All the compounds exhibited strong cytotoxic effects on cancer cells and normal cells (HaCaT human keratinocytes). The structure–activity relationship analysis revealed that the number and arrangement of conjugated aromatic rings in the counterion had an impact on the antitumor effect. The compound (III), the 1,10-phenanthrolinium analogue, exhibited the greatest activity, whereas the acridinium salt (II), with a different arrangement of three conjugated aromatic rings, showed the lowest toxicity. The increased concentrations of the compounds resulted in alterations to the cell cycle distribution with different effects in MCF-7 and PC3 cells. In MCF-7 cells, compounds I and II were observed to block the G2/M phase, while compounds III and IV were found to arrest the cell cycle in the G0/G1 phase. In PC3 cells, all compounds increased the rates of cells in the G0/G1 phase. [ABSTRACT FROM AUTHOR]

Sugar esters display surface-active properties, wetting, emulsifying, and other physicochemical phenomena following their amphipathic nature and recognize distinct biological activity. The development of nutritional pharmaceuticals and other applications remains of great interest. Herein, three novel homologous series of several N-mono-fatty acyl amino acid glucosyl esters were synthesized, and their physicochemical properties and biological activities were evaluated. The design and preparation of these esters were chemically performed via the reaction of glucose with different fatty acyl amino acids as renewable starting materials, with the suggestion that they would acquire functional characteristics superior and competitive to certain conventional surfactants. The synthesized products are characterized using FTIR, 1H-NMR, and 13C-NMR spectroscopy. Further, their physicochemical properties, such as HLB, CMC, Γmax, γCMC, and Amin, were determined. Additionally, their antimicrobial and anticancer efficiency were assessed. The results indicate that the esters' molecular structure, including the acyl chain length and the type of amino acid, significantly influences their properties. The measured HLB ranged from 8.84 to 12.27, suggesting their use as oil/water emulsifiers, wetting, and cleansing agents. All esters demonstrate promising surface-active characteristics, with moderate to high foam production with good stability. Notably, compounds 6-O-(N-dodecanoyl, tetradecanoyl cysteine)-glucopyranose (34, 35), respectively and 6-O-(N-12-hydroxy-9-octadecenoyl cysteine)-glucopyranose (38) display superior foamability. Wetting efficiency increased with decreasing the chain length of the acyl group. The storage results reveal that increasing the fatty acyl hydrophobe length enhances the derived emulsion's stability for up to 63 days. Particularly, including cysteine in these glucosyl esters improves wetting, foaming, and emulsifying potentialities. Furthermore, the esters exhibit antibacterial activity against several tested Gram-positive and Gram-negative bacteria and fungi. On the other hand, they show significant antiproliferative effects on some liver tumor cell lines. For instance, compounds 6-O-(N-12-hydroxy-9-octadecenoylglycine)-glucopyranose (28), 6-O-(N-dodecanoyl, hexadecanoyl, 9-octadecenoyl and 12-hydroxy-9-octadecenoylvaline)- glucopyranose (29, 31, 32 and 33), respectively in addition to the dodecanoyl, hexadecanoyl, 9-octadecenoyl and 12-hydroxy-9-octadecenoyl cysteine glucopyranose (34, 36, 37 and 38), respectively significantly inhibit the examined cancer cells. [ABSTRACT FROM AUTHOR]

Despite significant progress made over the past two decades in the treatment of chronic myeloid leukemia (CML), there is still an unmet need for effective and safe agents to treat patients with resistance and intolerance to the drugs used in clinic. In this work, we designed 2-arylaminopyrimidine amides of isoxazole-3-carboxylic acid, assessed in silico their inhibitory potential against Bcr-Abl tyrosine kinase, and determined their antitumor activity in K562 (CML), HL-60 (acute promyelocytic leukemia), and HeLa (cervical cancer) cells. Based on the analysis of computational and experimental data, three compounds with the antitumor activity against K562 and HL-60 cells were identified. The lead compound efficiently suppressed the growth of these cells, as evidenced by the low IC50 values of 2.8 ± 0.8 μM (K562) and 3.5 ± 0.2 μM (HL-60). The obtained compounds represent promising basic structures for the design of novel, effective, and safe anticancer drugs able to inhibit the catalytic activity of Bcr-Abl kinase by blocking the ATP-binding site of the enzyme. [ABSTRACT FROM AUTHOR]

Objective: Dehydroepiandrosterone plays an important role in the human beings due to its ability to be converted into androgens and oestrogens. The aim of this paper is to synthesize a series of novel dehydroepiandrosteronyl 1,2,3-triazole derivatives and study the antitumor activity of the synthesized compounds. Methods: Novel dehydroepiandrosteronyl 1,2,3-triazole derivatives were synthesized across the Mitsunobu and click reaction, respectively. The cytotoxicities of the synthesized compounds against HeLa, HGC-27, and HEK-293T cells were determined by MTT assay. Results and Discussion: The results showed that compound (V) (3R,8R,9S,10R,13S,14S)3-(4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro17H-cyclopenta[a]phenanthren-17-one had better inhibitory activity against the tumor cell lines tested. The IC50 value of inhibitory activity on human cervical cancer cell (HeLa) and human gastric cancer cell (HGC-27) was 33.6 and 22.3 μmolL–1, respectively. Conclusions: This work provides useful strategies for the design and synthesis of new steroidal antitumor drugs. The synthesized compounds have certain inhibitory activity on tumor cell growth and proliferation, but have little damage on normal cells, which deserves further study. [ABSTRACT FROM AUTHOR]

Potentilla kleiniana belongs to the family Rosaceae, which distributes in Central Asia, East Asia and Southeast Asia. In China, this plant is mainly found in east, south and southwest provinces. P. kleiniana has been prescribed for the treatment of various diseases in the field of traditional Chinese medicine, such as cough, fever, tuberculosis, mastitis, rheumatoid arthritis. Our previous study found that P. kleiniana had a certain cytotoxicity on tumor cells. The purpose of this paper was to investigate the chemical constituents of P. kleiniana and their cytotoxicity on tumor cells. The 60% ethanol extract of P. kleiniana were isolated by D-101 macroporous adsorptive resins, silica gel, Sephadex LH-20, Toyopearl HW-40F, semi-preparative high performance liquid chromatography and other methods, and their chemical structures were elucidated on the basis of physicochemical properties, NMR and HR-ESI-MS analysis. Meanwhile, all these compounds were evaluated for cytotoxicity against human cervical cancer cell line Hela. The results were as follows:(1)Thirteen lignans were isolated and identified as(+)-pionresinol(1),(+)-8-hydroxypinoresinol(2),(+)-syringaresinol(3),(+)-medioresinol(4),(+)-pionresinol-4-O-β-D-glucopyranoside(5),(+)-8'-hydroxypinoresinol-4-O-β-D-glucopyranoside(6),(+)-8'-hydroxypinoresinol-4'-O-β-D-glucopyranoside(7),(+)-pinoresinol-8'-O-β-D-glucopyranoside(8), schilignan F(9),(+)-pionresinol-4, 4'-O-bisglucopyranoside(10),(+)-lariciresinol-4'-O-β-D-glucopyranoside(11), neoolivil-4-O-β-D-glucopyranoside(12), 3,3'-bis [3,4-dihydro-4-hydroxy-6-methoxy-2H-1-benzopyran](13). Among them, compounds 1-4, 7, 8, 10, 12, 13 were isolated from genus Potentilla for the first time, and compounds 5, 6, 9, 11 were isolated from P. kleiniana for the first time.(2)Cytotoxicity studies showed that compounds 1, 3 and 4 display certain inhibitory activities against Hela cells with IC50 values of(69.94 ± 1.89),(66.25 ± 2.11),(59.81 ± 1.73)μmol·L-1, respectively. Therefore, the study enriches the chemical constituents of P. kleiniana, and provides a material basis for the development of anti-cervical cancer drugs. [ABSTRACT FROM AUTHOR]

Interleukin 2, also known as T cell growth factor, brought a great revolution in the field of immunology. IL-2 is a pleiotropic cytokine and one of the cytokines that is approved by FDA for cancer immunotherapy particularly kidney and skin cancer. Interleukin-2 (IL-2) is a 4-helix-bundle type I cytokine possessing a cytokine receptor chain essential for the immune response. The current study presents a vector/host combination (pET28a(+)/IL-2) and optimization of expression in LB, TB and M9 media with varying concentrations of inducers (IPTG and lactose) and post induction time. Maximum expression of IL-2 was achieved in LB with 0.5 mM IPTG for 6 hours post induction time. A denaturing purification scheme (Immobilized metal affinity chromatography) was employed for the purification of IL-2. The refolding of the purified IL-2 was achieved by stepwise dialysis method using urea gradient (8M-0M). Human IL-2 was recovered from 1 litre culture to a purity level of ~95%. In vitro cytotoxic potential of IL-2 on HepG-2 and MCF-7 cell lines revealed that it possess sufficient cytotoxic potential and can inhibit the growth of these cell lines directly. Thus, refolded IL-2 had activity identical to that of authentic IL-2 and enhanced the anti-tumor activity of HepG-2 as compared to MCF-7 cells. These conclusions suggest the potential use of the refolded cytokine as immunotherapeutic agent for treatment of hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]