Strong Cytotoxicity Research Articles

Vanadocene-functionalized mesoporous silica nanoparticles: platforms for the development of theranostic materials against breast cancer

Nanoscale materials have demonstrated a very high potential in anticancer therapy by properly adjusting their functionalization and physicochemical properties. Herein, we report the synthesis of some novel vanadocene-loaded silica-based nanomaterials incorporating four different S-containing amino acids (penicillamine, methionine, captopril, and cysteine) and different fluorophores (rhodamine B, coumarin 343 or Alexa Fluor™ 647), which have been characterized by diverse solid-state spectroscopic techniques viz; FTIR, diffuse reflectance spectroscopies, 13C and 51V solid-state NMR spectroscopy, thermogravimetry and TEM. The analysis of the biological activity of the novel vanadocene-based nanostructured silicas showed that the materials containing cysteine and captopril aminoacids demonstrated high cytotoxicity and selectivity against triple negative breast cancer cells, making them very promising antineoplastic drug candidates. According to the biological results it seems that vanadium activity is connected to its incorporation through the amino acid, resulting in synergy that increases the cytotoxic activity against cancer cells of the studied materials presumably by increasing cell internalization. The results presented herein hold significant potential for future developments in mesoporous silica-supported metallodrugs, which exhibit strong cytotoxicity while maintaining low metal loading. They also show potential for theranostic applications highlighted by the analysis of the optical properties of the studied systems after incorporating rhodamine B, coumarin 343 (possible) in vitro anticancer analysis, or Alexa Fluor™ 647 (in vivo studies of cancer models).

Hesperitin Synergistically Promotes the Senescence Induction of Pentagamavunone-1 in Luminal Breast Cancer Cells, T47D

Pentagamavunone-1 (PGV-1), a curcumin analog, is a promising anticancer candidate for several cancers that have been proven in vitro and in vivo. However, the efficacy of PGV-1 against breast cancer is subject to improvement to achieve a more suitable application. Here we propose hesperitin, a citrus flavonoid, to increase the anticancer potency of PGV-1 in luminal breast cancer cells. We use the T47D cell as the model to investigate the effect of co-administration of PGV-1 and hesperitin on cell cycle block, apoptosis modulation, and senescence phenomena. PGV-1 and hesperitin showed strong and weak cytotoxicity with an IC50 value of 2 µM and 100 µM, respectively. The co-treatment of PGV-1 and hesperitin resulted in strong synergistic effects with combination index (CI) value of ≤ 0.2. This combination caused apoptosis in correlation with cell cycle disruption in G2/M phase at 48 h. In particular, PGV-1 and hesperitin combination increased the incidence of cellular senescence significantly higher than the single treatment. Despite its senescence potentiation, hesperitin did not induce senescence in normal cells. Taken together, hesperitin may increase the anticancer potency of PGV-1 by modulating cell cycle arrest and apoptosis via the senescence mechanism.

Specific Targeting of Zinc Transporter LIV-1 with Immunocytokine Containing Anti-LIV-1 VHH and Human IL-2 and Evaluation of its In vitro Antitumor Activity.

Interleukin 2 (IL-2) is a vital cytokine in the induction of T and NK cell responses, the proliferation of CD8+ T cells, and the effective treatment of human cancers such as melanoma and renal cell carcinoma. However, widespread use of this cytokine is limited due to its short half-life, severe toxicity, lack of specific tumor targeting, and activation of Treg cells mediated by high-affinity interleukin-2 receptors. In this study, a tumor-targeting LIV-1 VHH-mutIL2 immunocytokine with reduced CD25 (α chain of the high-affinity IL-2 receptor) binding activity was developed to improve IL-2 half-life by decreasing its renal infiltration in comparison with wild and mutant IL-2 molecules. The recombinant immunocytokine was designed and expressed. The biological activity of the purified fusion protein was investigated in in vitro and in vivo experiments. The fusion protein represented specific binding to MCF7 (the breast cancer cell line) and more efficient cytotoxicity than wild-type IL-2 and mutant IL-2. The PK parameters of the recombinant immunocytokine were also improved in comparison to the IL-2 molecules. The observed results showed that LIV1-mIL2 immunocytokine could be considered as an effective agent in the LIV-1-targeted treatment of cancers due to its longer half-life and stronger cytotoxicity.

Do the same chlorinated organophosphorus flame retardants that cause cytotoxicity and DNA damage share the same pathway?

Organophosphorus flame retardants (OPFRs) have been frequently detected with relatively high concentrations in various environmental media and are considered emerging environmental pollutants. However, their biological effect and underlying mechanism is still unclear, and whether chlorinated OPFRs (Cl-OPFRs) cause adverse outcomes with the same molecular initial events or share the same key events (KEs) remains unknown. In this study, in vitro bioassays were conducted to analyze the cytotoxicity, mitochondrial impairment, DNA damage and molecular mechanisms of two Cl-OPFRs. The results showed that these two Cl-OPFRs, which have similar structures, induced severe cellular and molecular damages via different underlying mechanisms. Both tris(2-chloroethyl) phosphate (TCEP) and tris(1-chloro-2-propyl) (TCPP) induced oxidative stress-mediated mitochondrial impairment and DNA damage, as shown by the overproduction of intracellular reactive oxygen species (ROS) and mitochondrial superoxide. Furthermore, the DNA damage caused by TCPP resulted in p53/p21-mediated cell cycle arrest, as evidenced by flow cytometry and real-time PCR. At the cellular and molecular levels, TCPP increased the sub-G1 apoptotic peak and upregulated the p53/Bax apoptosis pathway, possibly resulted in apoptosis associated with its stronger cytotoxicity. Although structurally similar to TCPP, TCEP did not induce mitochondrial impairment and DNA damage by the same KEs. These results provide insight into the toxicity of Cl-OPFRs with similar structures but different mechanisms, which is of great significance for constructing adverse outcome pathways or determining intermediate KEs.

Dioclea violacea lectin inhibits tumorigenesis and tumor angiogenesis in vivo

Dioclea violacea seed mannose-binding lectin (DvL) has attracted considerable attention because of its interesting biological activities, including antitumor, antioxidant, and anti-inflammatory activities. This study evaluated the cytotoxic effect of DvL on tumor and normal cells using the mitochondrial activity reduction (MTT) assay, the carcinogenic and anti-carcinogenic activity by the epithelial tumor test (ETT) in Drosophila melanogaster, and the anti-angiogenic effect by the chick embryo chorioallantoic membrane (CAM) assay. Data demonstrated that DvL promoted strong selective cytotoxicity against tumor cell lines, especially A549 and S180 cells, whereas normal cell lines were weakly affected. Furthermore, DvL did not promote carcinogenesis in D. melanogaster at any concentration tested, but modulated DXR-induced carcinogenesis at the highest concentrations tested. In the CAM and immunohistochemical assays, DvL inhibited sarcoma 180-induced angiogenesis and promoted the reduction of VEGF and TGF-β levels at all concentrations tested. Therefore, our results demonstrated that DvL is a potent anticancer, anti-angiogenic, and selective cytotoxic agent for tumor cells, suggesting its potential application as a prototype molecule for the development of new drugs with chemoprotective and/or antitumor effects.

Green synthesis and anti-tumor activity of curcumin @ ZnO/CuO nanoparticles

Both zinc oxide and copper oxide nanoparticles are promising biologically active materials. Green synthesis approach was used to prepare mixed ZnO/CuO nanoparticles loaded with curcumin extract. The isolated mixed oxides loaded with curcumin (curcumin @ ZnO/CuO) was characterized by UV–visible spectra, FTIR spectra, X-ray powder diffractions (XRD),Transmittance electron microscope (TEM), Energy dispersive x-ray (EDX) and x-ray photoelectron spectroscopy (XPS) spectra. X-ray powder diffractions indicated that ZnO has wurtzite structure and CuO crystallizes in a monoclinic system. XPS confirmed the existence of both CuO and ZnO nanoparticles. TEM results indicated the formation of quantum dots of curcumin @ ZnO/CuO with size in the range 6–10 nm. The optical band gaps of curcumin @ ZnO/CuO were determined and found to be 3.4 and 4.05 eV, which are higher than the bulk. The effects of curcumin @ ZnO/CuO on hepatocellular (HEPG-2) and colorectal (HCT-116) carcinoma were estimated by cell viability, cell cycle and anti-apoptotic factors (caspase-3/7, topoisomerase 2beta and annexin). Strong cytotoxicity activity and apoptosis of tumor cells were observed for curcumin @ ZnO/CuO. The cytotoxicity of the current compounds showed higher activity in comparison with other compounds that were previously studied.

Chemical constituents from Microstachys chamaelea (Euphorbiaceae) with cytotoxic and antioxidant properties

Phytochemical investigation of Microstachys chamaelea led to the isolation and identification of fourteen known compounds after analysis of spectroscopic data. They consist of eight flavonoids (1–8), two benzoic acid derivatives (9–10), one brevifolin carboxylic acid derivative (11), one geraniinic acid derivative (12), shikimic acid (13), and β-daucosterol (14). Remarkably, it is the second isolation of compound 12 from a natural source. Several isolates were evaluated against ten cancer cell lines and on a set of targets involved in oxidative stress, as no such assays were undertaken in previous works. Compound 7 showed moderate to strong cytotoxicity against eight cell lines (IC50 values of 6.0–39.0 µM), while compounds 2, 8, and 11 showed weak to moderate cytotoxicity. Compounds 1–3, 5, and 11–12 showed moderate to strong DPPH and XXO inhibitory activities (IC50 values of 13.1–16.5 and 6.0–69.0 µM, respectively).

Morphological Changes and Strong Cytotoxicity in Yarrowia lipolytica by Overexpressing Delta-12-Desaturase.

In this study, delta-12 desaturase was overexpressed in Yarrowia lipolytica using the single-copy integrative vector pINA1312 and multicopy integrative vector pINA1292, resulting in the engineered yeast strains 1312-12 and 1292-12, respectively. The content of intracellular linoleic acid (LA) in the 1292-12 strain was much higher than in the 1312-12 strain and the control group. One interesting finding was that the 1292-12 strain showed obvious changes in surface morphology. The 1292-12 colonies were much smaller and smoother, whereas their single cells became much larger compared to the control strain. In addition, the dry cell weight (DCW) of the 1292-12 strain was obviously increased from 8.5 to 12.7 g/L, but the viable cell number sharply decreased from 107 to 105/mL. These results indicated that increased LA content in Yarrowia lipolytica could induce morphological changes or even oxidative stress-dependent cell death. The reactive oxygen species (ROS) and malondialdehyde (MDA) were accumulated in the 1292-12 strain, while the antioxidant activities of intracellular catalase (CAT) and superoxide dismutase (SOD) were significantly decreased by 27.6 and 32.0%, respectively. Furthermore, it was also revealed that these issues could be ameliorated by the exogenous supplementation of vitamin C, fish and colza oil.

Diffractaic acid exerts anti-cancer effects on hepatocellular carcinoma HepG2 cells by inducing apoptosis and suppressing migration through targeting thioredoxin reductase 1

Hepatocellular carcinoma (HCC) represents one of the most common malignant tumors worldwide. Due to the limited number of available drugs and their side effects, the development of new chemotherapeutic strategies for HCC treatment has become increasingly important. This study is aimed at investigating whether diffractaic acid (DA), one of the secondary metabolites of lichen, exhibits a potential anticancer effect on HepG2 cells and whether its anticancer effect is mediated by inhibition of thioredoxin reductase 1 (TRXR1), which is a target of chemotherapeutic strategies due to overexpression in tumor cells including HCC. XTT assay results showed that DA exhibited strong cytotoxicity on HepG2 cells with an IC50 value of 78.07 µg/mL at 48 h. Flow cytometric analysis results revealed that DA displayed late apoptotic and necrotic effects on HepG2 cells. Consistent with these findings, real-time PCR results showed that DA did not alter the BAX/BCL2 ratio in HepG2 cells but upregulated the P53 gene. Moreover, the wound healing assay results revealed a strong anti-migratory effect of DA in HepG2 cells. Real-time PCR and Western blot analyses demonstrated that DA increased TRXR1 gene and protein expression levels, whereas enzyme activity studies disclosed that DA inhibited TRXR1. These findings suggest that DA has an anticancer effect on HepG2 cells by targeting the enzymatic inhibition of TRXR1. In conclusion, DA as a TRXR1 inhibitor can be considered an effective chemotherapeutic agent which may be a useful lead compound for the treatment of HCC.

Miltirone suppresses ESCC cell viability and invasion by promoting E3 ligase mediated‐FZD2 ubiquitination and degradation

AbstractEsophageal squamous cell carcinoma (ESCC) is the most common subtype of esophageal cancer and lacks effective treatment. A growing number of studies have confirmed that Frizzled class receptor 2 (FZD2), a receptor for Wnts, regulates cancer metastasis in cancers. This study aims to reveal the anti‐metastatic activity of miltirone on ESCC cells and its mechanism on FZD2 in vitro. Cell‐counting‐kit‐8 (CCK‐8) was used to detect the effect of miltirone on cell growth in ESCC cells. The invasion of ESCC cells was detected by wound healing and transwell assay. Immunofluorescence staining was used to detect the expressions of epithelial‐mesenchymal transition (EMT) markers and the location of FZD2. Western blot and quantitative polymerase chain reaction (q‐PCR) were used to detect levels of target genes, and FZD2 ubiquitination was detected by the co‐immunoprecipitation method. The levels of roof plate‐specific spondins (RSPO1‐4) in cells were determined by ELISA, q‐PCR, and western blot assays. Miltirone exhibits its strongest cytotoxicity with IC50 values of 6.80 μM and 8.43 μM for K30 and K150 cells, respectively. Miltirone inhibited the cell viability and expression of EMT markers, affecting the invasion ability of ESCC, attenuated the Wnt2/FZD2 pathway, and down‐regulated the level of FZD2, which is regulated by the ubiquitination of E3 ubiquitin ligase. Furthermore, we found that miltirone could reduce the expression of RSPO1, and RSPO2, increasing E3 protein levels, and promoting FZD2 ubiquitination, leading to the ubiquitination and subsequent degradation of FZD2. Collectively, our results revealed that miltirone might be a promising drug for the treatment of ESCC, at least partly through regulation of the FZD2 ubiquitination.

The Effect of Salvia tomentosa Miller Extracts, Rich in Rosmarinic, Salvianolic and Lithospermic Acids, on Bacteria Causing Opportunistic Infections.

Methanolic-aqueous extracts of Salvia tomentosa Miller roots, aerial parts, and inflorescences were examined for their content of polyphenolic derivatives and the antimicrobial and cytotoxic effect. In the polyphenolic-rich profile, rosmarinic, salvianolic, and lithospermic acids along with various derivatives were predominant. A total of twenty phenolic compounds were identified using the UPLC/DAD/qTOF-MS technique. These were caffeic acid, rosmarinic acid derivatives, lithospermic acid derivatives, salvianolic acids B, F, and K derivatives, as well as sagerinic acid, although rosmarinic acid (426-525 mg/100 g of dry weight-D.W.) and salvianolic acid B (83-346.5 mg/100 g D.W.) were significantly predominant in the metabolic profile. Strong antibacterial activity of S. tomentosa extracts was observed against Staphylococcus epidermidis (MIC/MBC = 0.625 mg/mL) and Bacillus cereus (MIC = 0.312-1.25 mg/mL). The extracts showed low cytotoxicity towards the reference murine fibroblasts L929 and strong cytotoxicity to human AGS gastric adenocarcinoma epithelial cells in the MTT reduction assay. The observed cytotoxic effect in cancer cells was strongest for the roots of 2-year-old plant extracts.

Diisoprenyl Cyclohexene-Type Meroterpenoids with Cytotoxic Activity from a Mangrove Endophytic Fungus Aspergillus sp. GXNU-Y85.

Five new diisoprenyl cyclohexene-type meroterpenoids, aspergienynes J-N (1-5), along with three known analogues (6-8), were obtained from the mangrove endophytic fungal strain Aspergillus sp. GXNU-Y85. The chemical structures, including their absolute configurations, were established via spectroscopic data and comparison of experimental and calculated ECD spectra. Cytotoxicity assay results indicated that compound 8 had strong cytotoxicity against HeLa cancer cells, and its IC50 value was 11.8 μM. In addition, flow cytometry analysis revealed that the cytotoxicity of 8 was due to the induction of G1 cell cycle arrest and apoptosis in HeLa cells.

Results of a phase 1b/2 study of ADG126 (a masked anti-CTLA-4 SAFEbody) in combo with pembrolizumab (Pembro) in patients (Pts) with metastatic microsatellite-stable (MSS) colorectal cancer (CRC).

127 Background: ADG126 is a fully human anti-CTLA-4 IgG1 SAFEbody that has a cleavable masking peptide that blocks the antigen binding site. ADG126 is preferentially activated in the tumor microenvironment to afford prolonged on-tumor drug exposure and limited off-tumor toxicity. Activated ADG126 binds to a unique CTLA-4 epitope to prime T cells via partial ligand blockade and deplete immunosuppressive Tregs through strong antibody-dependent cellular cytotoxicity (ADCC)/phagocytosis (ADPC). Preclinical studies showed that ADG126/Pembro combination effectively increases Teff/Treg ratio. In Phase 1b/2 studies, ADG126 demonstrated a favorable safety profile and clinical efficacy as monotherapy and in combination with anti-PD-1 therapy. Here we present results of the entire dose escalation and ongoing dose expansion cohorts including a cohort of patients with MSS CRC free of liver metastasis (NCT05405595). Methods: This is a Phase 1b/2, open-label, multicenter dose escalation and expansion study of ADG126/Pembro. Pts received ADG126 [6 or 10 mg/kg (mpk), Q3W or Q6W, IV] plus Pembro (200 mg, Q3W, IV). Primary endpoints are safety and tolerability. Secondary endpoints are PK, ADA, ORR, DCR, DOR and PFS per RECIST 1.1. Results: As of Aug 29, 2023, a total of 47 Pts have been treated in dose escalation (N=11) and expansion cohorts (N=36). The median age is 60.5 yrs (26-78); 31.9% Pts had at least 3 prior therapies, 12.8% Pts received prior IO therapies. A majority of Pts (74.5%) have what are considered immunologically “cold” tumors. ADG126 was dosed at 6 mpk Q6W (1 Pt) and Q3W (5 Pts), 10 mpk Q6W (17 Pts) and Q3W (24 Pts), and Pembro was dosed at 200 mg Q3W. No DLT or Grade 4/5 TRAE was observed at any dose level. TRAEs more than 10% are pruritis (N=9, 19.1%) and diarrhea (N=5, 10.6%). Grade 3 TRAEs were observed in 5 subjects: 1 G3 diarrhea (6 mpk, 16.7%), 1 G3 adrenal insufficiency (10 mpk Q6W, 5.9%), 1 each G3 pancreatitis, blurred vision and lipase increase (10 mpk Q3W, 12.5%); all TRAEs occurred after repeat dosing. For the MSS CRC expansion cohort, 7 SDs at ADG126 10 mpk Q6W dose level (N=11) were observed, and 2 PRs (including 1 initial PR) and 4 SDs at 10 mpk Q3W (N=13) were observed. Conclusions: ADG126/Pembro combination is well-tolerated up to the maximally administered dose of 10 mpk Q3W, with limited G3 TRAEs comparable to Pembro monotherapy. The 10 mpk ADG126 Q3W repeat dosing regimen maintains a favorable safety profile and demonstrates anti-tumor activity. The MSS CRC cohort of 10 mpk ADG126 Q3W surpassed the threshold set for part 1 of the Simon’s 2-stage design, and the second stage of the cohort is now enrolling. In conclusion, ADG126/Pembro has a significantly improved therapeutic index over the same class agents in combination with anti-PD-1 therapy, and encouraging early outcomes in patients of MSS CRC without liver metastasis. Clinical trial information: NCT05405595 .

Abstract C078: Inhibiting the autophagy-lysosomal pathway in pancreatic ductal adenocarcinoma using novel small molecules

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers with a 5-year survival rate of 11.5% due to poor early detection and a lack of effective therapies. To meet the energetic demands, PDAC relies on autophagy to sustain growth and proliferation. Autophagy inhibitors such as hydroxychloroquine (HCQ) only showed limited autophagy inhibition in vivo and failed to provide clinical benefit to patients. However, studies have shown that the combination of HCQ and the MEK/ERK inhibitors can render better therapeutic results with stronger cytotoxicity. Our lab has designed and developed a class of small molecules (GN compounds) that target the autophagy-lysosomal pathway (ALP). Our GN compounds show autophagy inhibition and induction of extrinsic apoptosis markers by Western blot. Furthermore, GN64 affects the function of endosomes and lysosomes by immunofluorescence (IF). The combination treatment of GN79 and Binimetinib, a MEKi, inhibits the ALP and confers enhanced cytotoxicity in a panel of human PDAC cell lines. Future directions are aimed at determining the protein target and mechanism of GN compounds that leads to ALP inhibition. Completion of this project will advance the therapeutic development of novel ALP inhibitors and advance our understanding of the ALP with the possibility to imrpove the current therapeutic regimen for PDAC patients. Citation Format: Yangjingyi Ruan, Daniel W. Worroll, Grady Nelson, Yue-Ming Li. Inhibiting the autophagy-lysosomal pathway in pancreatic ductal adenocarcinoma using novel small molecules [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C078.

Biogenic selenium nanoparticles and selenium/chitosan-Nanoconjugate biosynthesized by Streptomyces parvulus MAR4 with antimicrobial and anticancer potential

BackgroundAs antibiotics and chemotherapeutics are no longer as efficient as they once were, multidrug resistant (MDR) pathogens and cancer are presently considered as two of the most dangerous threats to human life. In this study, Selenium nanoparticles (SeNPs) biosynthesized by Streptomyces parvulus MAR4, nano-chitosan (NCh), and their nanoconjugate (Se/Ch-nanoconjugate) were suggested to be efficacious antimicrobial and anticancer agents.ResultsSeNPs biosynthesized by Streptomyces parvulus MAR4 and NCh were successfully achieved and conjugated. The biosynthesized SeNPs were spherical with a mean diameter of 94.2 nm and high stability. Yet, Se/Ch-nanoconjugate was semispherical with a 74.9 nm mean diameter and much higher stability. The SeNPs, NCh, and Se/Ch-nanoconjugate showed significant antimicrobial activity against various microbial pathogens with strong inhibitory effect on their tested metabolic key enzymes [phosphoglucose isomerase (PGI), pyruvate dehydrogenase (PDH), glucose-6-phosphate dehydrogenase (G6PDH) and nitrate reductase (NR)]; Se/Ch-nanoconjugate was the most powerful agent. Furthermore, SeNPs revealed strong cytotoxicity against HepG2 (IC50 = 13.04 μg/ml) and moderate toxicity against Caki-1 (HTB-46) tumor cell lines (IC50 = 21.35 μg/ml) but low cytotoxicity against WI-38 normal cell line (IC50 = 85.69 μg/ml). Nevertheless, Se/Ch-nanoconjugate displayed substantial cytotoxicity against HepG2 and Caki-1 (HTB-46) with IC50 values of 11.82 and 7.83 μg/ml, respectively. Consequently, Se/Ch-nanoconjugate may be more easily absorbed by both tumor cell lines. However, it exhibited very low cytotoxicity on WI-38 with IC50 of 153.3 μg/ml. Therefore, Se/Ch-nanoconjugate presented the most anticancer activity.ConclusionThe biosynthesized SeNPs and Se/Ch-nanoconjugate are convincingly recommended to be used in biomedical applications as versatile and potent antimicrobial and anticancer agents ensuring notable levels of biosafety, environmental compatibility, and efficacy.

Competition of Cd(II) and Pb(II) on the bacterial cells: a new insight from bioaccumulation based on NanoSIMS imaging.

Polymetallic exposure causes complex toxicity to microorganisms. In this study, we investigated the responses of Escherichia coli under co-existence of cadmium (Cd) and lead (Pb), primarily based on biochemical analysis and RNA sequencing. Cd completely inhibited bacterial growth at a concentration of 2.41 mmol/L, with its removal rate as low as <10%. In contrast, the Pb removal rate was >95% under equimolar sole Pb stress. In addition, the Raman analysis confirmed the loss of proteins for the bacterial cells. Under the co-existence of Cd and Pb, the Cd toxicity to E. coli was alleviated. Meanwhile, the biosorption of Pb cations was more intense during the competitive sorption with Cd. Transmission electron microscopy images showed that a few cells were elongated during incubation, i.e., the average cellular length increased from 1.535 ± 0.407 to 1.845 ± 0.620 µm. Moreover, NanoSIMS imaging showed that the intracellular distribution of Cd and Pb was coupled with sulfur. Genes regulating sulfate transporter were also upregulated to promote sulfate assimilation. Then, the subsequent production of biogenic sulfide and sulfur-containing amino acids was enhanced. Although this strategy based on S enrichment could resist the polymetallic stress, not all related genes were induced to upregulate under sole Cd stress. Therefore, the S metabolism might remodel the microbial resistance to variable occurrence of heavy metals. Furthermore, the competitive sorption (in contrast to sole Cd stress) could prevent microbial cells from strong Cd toxicity.IMPORTANCEMicrobial tolerance and resistance to heavy metals have been widely studied under stress of single metals. However, the polymetallic exposure seems to prevail in the environment. Though microbial resistance can alleviate the effects of exogenous stress, the taxonomic or functional response to polymetallic exposure is still not fully understood. We determined the strong cytotoxicity of cadmium (Cd) on growth, and cell elongation would be driven by Cd stress. The addition of appropriate lead (Pb) showed a stimulating effect on microbial bioactivity. Meanwhile, the biosorption of Pb was more intense during co-existence of Pb and Cd. Our work also revealed the spatial coupling of intracellular S and Cd/Pb. In particular, the S assimilation was promoted by Pb stress. This work elucidated the microbial responses to polymetallic exposure and may provide new insights into the antagonistic function during metal stresses.

Anticancer activity and mechanism studies of photoactivated iridium(III) complexes toward lung cancer A549 cells.

Cyclometalated iridium(III) compounds have been widely explored due to their outstanding photo-physical properties and multiple anticancer activities. In this paper, three cyclometalated iridium(III) compounds [Ir(ppy)2(DBDIP)]PF6 (5a), [Ir(bzq)2(DBDIP)]PF6 (5b), and [Ir(piq)2(DBDIP)]PF6 (5c) (ppy: 2-phenylpyridine; bzq: benzo[h]quinoline; piq: 1-phenylisoquinoline, and DBDIP: 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-imidazo[4,5-f][1,10]phenanthroline) were synthesized and the mechanism of antitumor activity was investigated. Compounds photoactivated by visible light show strong cytotoxicity against tumor cells, especially toward A549 cells. Biological experiments such as migration, cellular localization, mitochondrial membrane potential and permeability, reactive oxygen species (ROS) and calcium ion level detection were performed, and they demonstrated that the compounds induced the apoptosis of A549 cells through a mitochondrial pathway. At the same time, oxidative stress caused by ROS production increases the release of damage-related molecules and the expression of porogen gasdermin D (GSDMD), and the content of LDH released from damaged cell membranes also increased. Besides, the content of the lipid peroxidation product, malondialdehyde (MDA), increased and the expression of GPX4 decreased. These indicate that the compounds promote cell death by combining ferroptosis and pyroptosis. The results reveal that cyclometalated iridium(III) compounds 5a-5c may be a potential chemotherapeutic agent for photodynamic therapy of cancers.

Natural Coptidis Rhizoma Nanoparticles Improved the Oral Delivery of Docetaxel.

Docetaxel (DTX) is a valuable anti-tumor chemotherapy drug with limited oral bioavailability. This study aims to develop an effective oral delivery system for DTX using natural nanoparticles (Nnps) derived from Coptidis Rhizoma extract. DTX-loaded self-assembled nanoparticles (Nnps-DTX) were created using an optimized heat-induction strategy. Nnps-DTX's shape, size, Zeta potential, and in vitro stability were all carefully examined. Additionally, the study investigated the encapsulation efficiency, loading capacity, crystal form, and intermolecular interactions of DTX in Nnps-DTX. Subsequently, the solubility, release, cellular uptake, metabolic stability, and preclinical pharmacokinetics of DTX in Nnps-DTX were systematically evaluated. Finally, the cytotoxicity of Nnps-DTX was assessed in three tumor cell lines. Nnps-DTX was spherical in shape, 138.6 ± 8.2 nm in size, with a Zeta potential of -20.8 ± 0.6 mV, a DTX encapsulation efficiency of 77.6 ± 8.5%, and a DTX loading capacity of 6.8 ± 1.9%. Hydrogen bonds, hydrophobic interactions, and electrostatic interactions were involved in the formation of Nnps-DTX. DTX within Nnps-DTX was in an amorphous form, resulting in enhanced solubility (23.3 times) and release compared to free DTX. Following oral treatment, the mice in the Nnps-DTX group had DTX peak concentrations 8.8, 23.4, 44.6, and 5.7 times higher in their portal vein, systemic circulation, liver, and lungs than the mice in the DTX group. Experiments performed in Caco-2 cells demonstrated a significant increase in DTX uptake by Nnps-DTX compared to free DTX, which was significantly inhibited by indomethacin, an inhibitor of caveolae-mediated endocytosis. Furthermore, compared to DTX, DTX in Nnps-DTX demonstrated better metabolic stability in liver microsomes. Notably, Nnps-DTX significantly reduced the viability of MCF-7, HCT116, and HepG2 cells. The novel self-assembled nanoparticles considerably enhanced the cellular absorption, solubility, release, metabolic stability, and pharmacokinetics of oral DTX and demonstrated strong cytotoxicity against tumor cell lines.

Lipid Composition, Cytotoxic and Acetylcholinesterase Inhibition Effects of Two Brown Algae Species Lobophora tsengii and Lobophora australis.

In this paper, the lipid classes, compositions of the neutral lipids, phospholipids and fatty acids, acetylcholinesterase inhibition and cytotoxic activity of two brown algae Lobophora tsengii D. Tien & Z. Sun and Lobophora australis Z. Sun, F. C. Gurgel & H. Kawai have been investigated. The polar lipid class had the highest content in total lipid (TL) (43.47% in L. tsengii and 48.95% in L. australis). Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were the main components in the phospholipids of two studied brown algae with contents varied from 32.27% to 52.33%. Total lipids were rich in PUFA (42.54% of total fatty acids for L. australis and 32.98% for L. tsengii), with EPA (11.46%, 14.30%) and AA (8.0%, 11.96%). L. tsengii methanol extract inhibited acetylcholinesterase (AChE) in in vitro assay with an IC50 value of 25.45 µg/mL. Both Lobophora methanol extracts display cytotoxic effects against four human cancer cell lines (KB, MCF7, HepG2 and A549) with IC50 in the range of 21.11-83.61 µg/mL. Especially, L. australis extract showed a strong cytotoxicity against KB cell lines with IC50 value of 21.11±0.39 µg/mL.

The Potential Role of Phytochemicals of Juniperus procera in the Treatment of Ovarian Cancer and the Inhibition of Human Topoisomerase II Alpha Activity.

A variety of active chemicals found in medicinal plants can be used to develop new medications with few adverse effects. In vitro and in silico analyses were used to evaluate the anticancer properties of Juniperus procera fruit and leaf extracts. Here, we show that the methanolic extract from J procera fruit and leaf extracts inhibits 2 human ovarian cancer cell lines, A2780CP and SKOV-3. The leaf extract demonstrated strong cytotoxicity against A2780CP with an IC50 of 1.2 μg/mL, almost matching the IC50 of the anticancer medication doxorubicin (0.9 μg/mL). Higher antioxidant activity was observed in the fruit than leaf extract. The molecular docking results showed that the active component, podocarpusflavone A, was the best-docked chemical with the human topoisomerase II alpha enzyme. According to our knowledge, this is the first in vitro study to show the cytotoxicity of J procera extracts against the 2 previously described human ovarian cancer cell lines. The fact that the podocarpusflavone A molecule may have an inhibitory effect on the human topoisomerase II alpha enzyme was also revealed by this first in silico analysis. Our findings imply that the J procera fruit and leaf methanolic extract has anticancer characteristics that may guide future in vivo studies.