Inhibited Cell Growth Research Articles

Base-Mediated Chemodivergent [4 + 1] and [2 + 1] Cycloadditions of N-Alkylpyridiniums and Enones.

Divergent synthesis of structurally different products from the same kinds of starting materials is highly synthetically useful but very challenging. Herein, we reported a base-mediated chemodivergent [4 + 1] and [2 + 1] cycloaddition of N-alkylpyridinium and enone under mild conditions, leading to furan-fused bicycles with high diastereoselectivity and spirobicycles, respectively, from moderate to high yields. N-Alkylpyridinium salts were modular nucleophilic transfer reagents and C1 synthons, which underwent tandem Michael addition to the α,β-unsaturated ketones and cyclization under the base conditions. Late-stage derivatization of 4-propyldicyclohexylanone from an important industrial raw of liquid crystal display (LCD) screens was realized. In vitro, compound 3f exhibited good activities against human colon cancer cells (HCT116) with IC50 values in 9.82 ± 0.27 μM. Further biological evaluations investigated the mechanism of the effective inhibition of cell growth, including apoptosis ratio detection, cell cycle analysis, and migration capacity of HCT116 cells. In apoptosis effect studies, complex 3f increased the percentage of apoptotic HCT116 cells to 26.8% (15 μM).

Cancer Therapy with Quinoxaline Derivatives: Dual Inhibition of Pi3k and Mtor Signaling Pathways

Quinoxaline is a heterocyclic compound with a benzene ring fused to a pyrazine ring. It learned much about his ability to cure many diseases, including cancer. Phosphoinositide 3kinase (PI3K) and the mTOR (mammalian target of rapamycin) are the 3 essential pathways which regulate the growth, survival, and development of cells. Dysregulation of such pathways is often seen in cancer, making them attractive targets for cancer therapy. In particular, several quinoxaline derivatives show promise as two inhibitors of the mTOR/PI3K signalling pathway, which is often dysregulated in cancer along with many other diseases. One such example is PX866, which has shown activity against several cancers in previous studies. In previous studies, another quinoxaline derivative, PKI587, also showed strong inhibitory activity against mTOR and PI3K. PKI587 was researched in several clinical trials for treating many cancer types, which include non-small cell lung as well as breast cancer. Dual inhibitors of mTOR and PI3K, including quinoxaline derivatives, inhibit cell growth and cancer by blocking the signalling of these two important factors. In recent years, quinoxaline derivatives have emerged as potent dual inhibitors of PI3K and mTOR, and in this review, we explore the latest developments in this area.

Assessment of plant- and microbial-derived protein hydrolysates as sustainable for fetal bovine serum in seafood cell culture media

This study seeks to explore alternatives by substituting or reducing the conventional 10% serum concentration in zebrafish embryonic stem cell (ESC) growth media with protein hydrolysates sourced from peas, mushrooms, yeast, and algae. Notably, algae exhibited the highest protein content, optimal amino acid balance, and favorable functional properties. When applied at concentrations ranging from 1 to 10 mg/mL, all protein hydrolysates demonstrated pro-apoptotic effects and inhibited cell growth, particularly when used in conjunction with 10% serum. However, concentrations ranging from 0.001 to 0.1 mg/mL displayed anti-apoptotic properties and promoted cell proliferation. The study found that media containing 1% or 2.5% serum, along with 0.01 mg/mL of protein hydrolysates, supported cell growth effectively. Lactate Dehydrogenase (LDH) Activity served as an indicator of cell health and integrity under the specified conditions of protein hydrolysate supplementation. Cells cultured in serum-free media exhibited significantly decreased cell membrane integrity (P < 0.05) compared to those in regular media or media containing low serum (1% and 2.5%) along with low concentrations (0.01 mg/mL) of protein hydrolysates. Furthermore, analysis of Greenhouse Gas emissions (GHG) suggested that media formulations containing 1% serum combined with low concentrations of protein hydrolysates present a sustainable approach for cell-based seafood production.

Casticin: A Short Review on its Pharmacological Activity as an Anticancer Drug

Abstract: Casticin is a flavonoid that is derived from the Vitex species. Multiple studies have investigated the anticancer properties of casticin against many types of cancer, such as bladder cancer, breast cancer, oral cancer, lung cancer, and leukemia. Research has shown the ability of casticin to inhibit cell growth and induce programmed cell death. The chemical exhibits efficacy against numerous cancer cell lines through various molecular mechanisms. The substance hinders the processes of invasion, migration, and proliferation and triggers programmed cell death by multiple mechanisms, including the generation of reactive oxygen species and the dependence on mitochondria. Additionally, it inhibits the cell cycle at different stages. These effects are achieved by modulating several signaling cascades, specifically NF-κB, PI3K/Akt, FOXO3a/FoxM1, and STAT3. This review provides a concise overview of the chemotherapeutic efficacy of casticin as an anticancer drug.

An efficient green synthesis and in vitro evaluation of novel adamantane-containing 4-thiazolidinone derivatives as anticancer agents

The novel 4-thiazolidinone derivatives incorporating an adamantane moiety were synthesized in high yields through the reaction of N-adamantyl-substituted thioureas and dimethyl acetylenedicarboxylate (DMAD) using an environmentally benign method. These catalyst-free reactions were performed in an ethanol-water mixture at room temperature, with short reaction times of 3–8 minutes. The in vitro anticancer activity of the target compounds was evaluated against the A-549 human non-small cell lung cancer (NSCLC) cell line. Among the target compounds, 2b, 2c, and 2a exhibited promising cytotoxic effects, with IC50 values of 19.07, 32.92, and 63.38 µM, respectively. Additionally, the mechanisms for inhibition of cell growth and induction of apoptotic cell death were assessed using DAPI and Annexin V-FITC staining. The results indicated that the 4-thiazolidinone derivatives incorporating an adamantane moiety have significant potential for the development of anticancer therapeutics.

ITCH inhibits alkaliptosis in human pancreatic cancer cells through YAP1-dependent SLC16A1 activation

Alkaliptosis is a type of pH-dependent cell death and plays an emerging role in tumor suppression. However, the key modulation mechanism of alkaliptosis remains largely unknown. In particular, the nucleus, as the centre of genetic and metabolic regulation, is crucial for the regulation of cellular life. It is not known whether nuclear proteins are involved in the regulation of alkaliptosis. Here, we isolated nuclear proteins to perform a proteomics that identified itchy E3 ubiquitin protein ligase (ITCH) as a natural inhibitor of alkaliptosis in human pancreatic ductal adenocarcinoma (PDAC) cells. The downregulation of ITCH protein is associated with the induction of alkaliptosis in three human PDAC cell lines (SW1990, MiaPaCa2, and PANC1). Functionally, increasing ITCH expression reduces JTC801-induced growth inhibition and cell death. In contrast, knocking down ITCH using specific shRNA increases JTC801-induced cell growth inhibition in the short or long term, resulting in increased cell death. Mechanistically, JTC801-induced ITCH inhibition blocks large tumor suppressor kinase 1 (LATS1) ubiquitination, which in turn suppresses Yes1 associated transcriptional regulator (YAP1)-dependent the transcriptional activation of solute carrier family 16 member 1 (SLC16A1), a proton-linked monocarboxylate transporter that inhibits JTC801-induced alkaliptosis. Additionally, decreased expression of ITCH is associated with longer survival times in patients with PDAC. Collectively, our results establish an ITCH-dependent pathway that regulates alkaliptotic sensitivity in PDAC cells and deepen the understanding of alkaliptosis in targeted therapy.

Cell Cycle Modulation through Physical Confinement in Micrometer-Thick Hydrogel Sheaths.

Recently, surface engineering of the cell membrane with biomaterials has attracted great attention for various biomedical applications. In this study, we investigated the possibility of modulating cell cycle progression using alginate and gelatin-based hydrogel sheaths with a thickness of ∼1 μm. The hydrogel sheath was formed on cell surfaces through cross-linking catalyzed by horseradish peroxidase immobilized on the cell surface. The hydrogel sheath did not decrease the viability (>95% during 2 days of culture) of the human cervical carcinoma cell line (HeLa) expressing the fluorescent ubiquitination-based cell cycle indicator 2 (HeLa/Fucci2). Coating the HeLa/Fucci2 cells with the hydrogel sheath resulted in a cell cycle arrest in the G2/M phase, which can be caused by the reduced F-actin formation. As a result of this cell cycle arrest, an inhibition of cell growth was observed in the HeLa/Fucci2 cells. Taken together, our results demonstrate that the hydrogel sheath coating on the cell surface is a feasible approach to modulating cell cycle progression.

CMTM5 influences Hippo/YAP axis to promote ferroptosis in glioma through regulating WWP2-mediated LATS2 ubiquitination.

Glioma, a common malignancy, is characterized by high morbidity and mortality. Promoting ferroptosis can delay tumor progression. Here, we aimed to explore the underlying mechanism of ferroptosis in glioma. In vitro and in vivo experiments were conducted using glioma cells and nude mice. The expression of genes and proteins was evaluated by RT-qPCR, Western blot assay, and immunohistochemical staining. Malignant activities of glioma cells were evaluated using MTT, EdU, and Transwell assays. The levels of Fe2+, lipid reactive oxygen species, and malondialdehyde were determined using commercial kits. The interplays among CMTM5, WWP2, and LATS2 were validated using Co-immunoprecipitation assay. The UALCAN database predicted downregulation of CMTM5 expression in glioma, and low expression of CMTM5 was associated with poor survival outcomes. CMTM5 overexpression inhibited cell growth and invasion and promoted ferroptosis of glioma cells. Besides, CMTM5 protein interacted with WWP2 protein and decreased WWP2 expression. WWP2 silencing attenuated LATS2 ubiquitination to enhance LATS2 expression and phosphorylation of YAP1. CMTM5 exerted a suppressive effect on cell growth and invasion and promoted ferroptosis of glioma cells by regulating the WWP2/LATS2 pathway. In the in vivo experiments, CMTM5 overexpression suppressed tumor growth and enhanced ferroptosis. CMTM5 regulated Hippo/YAP signaling to inhibit cell growth and invasion and to promote ferroptosis in glioma by regulating WWP2-mediated LATS2 ubiquitination, thereby attenuating glioma progression.

Natural Product Auraptene Targets SLC7A11 for Degradation and Induces Hepatocellular Carcinoma Ferroptosis.

The natural product auraptene can influence tumor cell proliferation and invasion, but its effect on hepatocellular carcinoma (HCC) cells is unknown. Here, we report that auraptene can exert anti-tumor effects in HCC cells via inhibition of cell proliferation and ferroptosis induction. Auraptene treatment induces total ROS and lipid ROS production in HCC cells to initiate ferroptosis. The cell death or cell growth inhibition of HCC cells induced by auraptene can be eliminated by the ROS scavenger NAC or GSH and ferroptosis inhibitor ferrostatin-1 or Deferoxamine Mesylate (DFO). Mechanistically, the key ferroptosis defense protein SLC7A11 is targeted for ubiquitin-proteasomal degradation by auraptene, resulting in ferroptosis of HCC cells. Importantly, low doses of auraptene can sensitize HCC cells to ferroptosis induced by RSL3 and cystine deprivation. These findings demonstrate a critical mechanism by which auraptene exhibits anti-HCC effects via ferroptosis induction and provides a possible therapeutic strategy for HCC by using auraptene or in combination with other ferroptosis inducers.

Plant competition cues activate a singlet oxygen signaling pathway in Arabidopsis thaliana.

Oxidative stress responses of Arabidopsis to reflected low red to far-red signals (R:FR ≈ 0.3) generated by neighboring weeds or an artificial source of FR light were compared with a weed-free control (R:FR ≈1.6). In the low R:FR treatments, induction of the shade avoidance responses (SAR) coincided with increased leaf production of singlet oxygen (1O2). This 1O2 increase was not due to protochlorophyllide accumulation and did not cause cell death. Chemical treatments, however, with 5-aminolevulinic acid (the precursor of tetrapyrrole biosynthesis) and glutathione (a quinone A reductant) enhanced cell death and growth inhibition. RNA sequencing revealed that transcriptome responses to the reflected low R:FR light treatments minimally resembled previously known Arabidopsis 1O2 generating systems that rapidly generate 1O2 following a dark to light transfer. The upregulation of only a few early 1O2 responsive genes (6 out of 1931) in the reflected low R:FR treatments suggested specificity of the 1O2 signaling. Moreover, increased expression of two enzyme genes, the SULFOTRANSFERASE ST2A (ST2a) and the early 1O2-responsive IAA-LEUCINE RESISTANCE (ILR)-LIKE6 (ILL6), which negatively regulate jasmonate level, suggested that repression of bioactive JAs may promote the shade avoidance (versus defense) and 1O2 acclimation (versus cell death) responses to neighboring weeds.

Linear polyubiquitylation of Gli protein regulates its protein stability and facilitates tumor growth in colorectal cancer

The linear ubiquitin chain assembly complex (LUBAC) mediates the linear ubiquitination of various proteins and is involved in NF-κB signaling and immune regulation. However, the function and mechanism of linear ubiquitination in regulating oncogenic signaling and tumor growth have remained poorly understood. Herein, we identified Gli proteins, key transcription factors in the Hedgehog (Hh) signaling pathway, as novel substrates of LUBAC. Linear ubiquitination stabilizes Gli proteins, leading to the noncanonical activation of Hh signaling in CRC cells. Furthermore, LUBAC facilitates tumor growth in CRC cells. Additionally, elevated expression of LUBAC components in CRC tissues was observed, and higher expression levels of these components correlated with poor prognosis in CRC patients. Interestingly, inhibition of LUBAC using either a small molecule agonist or RNA silencing specifically suppressed cell growth in CRC cells but had no effect on normal intestinal cells. Taken together, aberrant expression of LUBAC components activates Hh signaling noncanonically by mediating linear ubiquitination, promoting tumor growth in CRC, demonstrating the novel function of linear ubiquitination in regulating the protein stability of its substrates and highlighting the potential of targeting LUBAC as a therapeutic strategy in CRC.

Controlled Release of Curcumin and Hypocrellin A from Electrospun Poly(l-Lactic Acid)/Silk Fibroin Nanofibers for Enhanced Cancer Cell Inhibition.

Nanofibers have emerged as a highly effective method for drug delivery, attributed to their remarkable porosity and ability to regulate drug release rates while minimizing toxicity and side effects. In this study, we successfully loaded the natural anticancer drugs curcumin (CUR) and hypocrellin A (HA) into pure poly(l-lactic acid) (PLLA) and PLLA-silk protein (PS) composite nanofibers through electrospinning technology. This result was confirmed through comprehensive analysis involving SEM, FTIR, XRD, DSC, TG, zeta potential, and pH stability analysis. The encapsulation efficiency of all samples exceeded 85%, demonstrating the effectiveness of the loading process. Additionally, the drug release doses were significantly higher in the composites compared to pure PLLA, owing to the enhanced crystallinity and stability of the silk proteins. Importantly, the composite nanofibers exhibited excellent pH stability in physiological and acidic environments. Furthermore, the drug-loaded composite nanofibers displayed strong inhibitory effects on cancer cells, with approximately 28% (HA) and 37% (CUR) inhibition of cell growth and differentiation within 72 h, while showing minimal impact on normal cells. This research highlights the potential for controlling drug release through the manipulation of fiber diameter and crystallinity, paving the way for wider applications of electrospun green nanomaterials in the field of medicine.

Ultrasonic Cigarettes: Chemicals and Cytotoxicity are Similar to Heated-Coil Pod-Style Electronic Cigarettes.

Our purpose was to test the hypothesis that ultrasonic cigarettes (u-cigarettes), which operate at relatively low temperatures, produce aerosols that are less harmful than heated-coil pod-style electronic cigarettes (e-cigarettes). The major chemicals in SURGE u-cigarette fluids and aerosols were quantified, their cytotoxicity and cellular effects were assessed, and a Margin of Exposure risk assessment was performed on chemicals in SURGE fluids. Four SURGE u-cigarette flavor variants ("Blueberry Ice," "Watermelon Ice," "Green Mint," and "Polar Mint") were evaluated. Flavor chemicals were quantified in fluids and aerosols using gas chromatography/mass spectrometry. Cytotoxicity and cell dynamics were assessed using the MTT assay, live-cell imaging, and fluorescence microscopy. WS-23 (a coolant) and total flavor chemical concentrations in SURGE were similar to e-cigarettes, while SURGE nicotine concentrations (13-19 mg/mL) were lower than many fourth generation e-cigarettes. Transfer efficiencies of dominant chemicals to aerosols in SURGE ranged from 44-100%. SURGE fluids and aerosols had four dominant flavor chemicals (>1 mg/mL). Toxic aldehydes were usually higher in SURGE aerosols than in SURGE fluids. SURGE fluids and aerosols had aldehyde concentrations significantly higher than pod-style e-cigarettes. Chemical constituents, solvent ratios, and aldehydes varied among SURGE flavor variants. SURGE fluids and aerosols inhibited cell growth and mitochondrial reductases, produced attenuated and round cells, and depolymerized actin filaments, effects that depended on pod flavor, chemical constituents, and concentration. The MOEs for nicotine, WS-23, and propylene glycol were <100 based on consumption of 1-2 SURGE u-cigarettes/day. Replacing the heating coil with a sonicator did not eliminate chemicals, including aldehydes, in aerosols or diminish toxicity in comparisons between SURGE and other e-cigarette pod products. The high concentrations of nicotine, WS-23, flavor chemicals, and aldehydes and the cytotoxicity of SURGE aerosols do not support the hypothesis that aerosols from u-cigarettes are less harmful than those from e-cigarettes.

Semisynthesis of novel chalcone hybrid compounds linked by 1,2,3-triazole and evaluation of their cytotoxic effects

A series of novel 1,2,3-triazole-chalcone hybrid compounds were designed and synthesized from thymol. The structural identity of the synthesized products 5a-h was unequivocally confirmed by spectroscopic techniques, including 1H and 13C NMR spectroscopy, and high-resolution mass spectrometry (HRMS), and SC-XRD for 5b. The in vitro anticancer activity of the synthesized compounds was evaluated against a panel of four human cancer cell lines: fibrosarcoma (HT-1080), lung adenocarcinoma (A-549), and breast adenocarcinoma (MCF-7 and MDA-MB-231). Notably, most of the 1,2,3-triazole-chalcone hybrids (5a-h) displayed promising cell growth inhibition with IC50 values ranging from 4.61 to 50 μM. Furthermore, compounds 5a and 5b, bearing a 1-phenyl-1,2,3-triazole moiety and a 1-cyano-1,2,3-triazole moiety, respectively, exhibited particularly significant antiproliferative activity against HT-1080 cells. These compounds displayed impressive IC50 values of approximately 4.61 μM and 9.08 μM, respectively.

Mir-744-5p inhibits cell growth and angiogenesis in osteosarcoma by targeting NFIX

BackgroundOsteosarcoma (OS) is a malignant bone tumor that commonly occurs in children and adolescents under the age of 20. Dysregulation of microRNAs (miRNAs) is an important factor in the occurrence and progression of OS. MicroRNA miR-744-5p is aberrantly expressed in various tumors. However, its roles and molecular targets in OS remain unclear.MethodsDifferentially expressed miRNAs in OS were analyzed using the Gene Expression Omnibus dataset GSE65071, and the potential hub miRNA was identified through weighted gene co-expression network analysis. Quantitative real-time PCR (qRT-PCR) was used to detect the expression of miR-744-5p in OS cell lines. In vitro experiments, including CCK-8 assays, colony formation assays, flow cytometry apoptosis assays, and tube formation assays, were performed to explore the effects of miR-744-5p on OS cell biological behaviors. The downstream target genes of miR-744-5p were predicted through bioinformatics, and the binding sites were validated by a dual-luciferase reporter assay.ResultsThe lowly expressed miRNA, miR-744-5p, was identified as a hub miRNA involved in OS progression through bioinformatic analysis. Nuclear factor I X (NFIX) was confirmed as a direct target for miR-744-5p in OS. In vitro studies revealed that overexpression of miR-744-5p could restrain the growth of OS cells, whereas miR-744-5p inhibition showed the opposite effect. It was also observed that treatment with the conditioned medium from miR-744-5p-overexpressed OS cells led to poorer proliferation and angiogenesis in human umbilical vein endothelial cells (HUVECs). Furthermore, NFIX overexpression restored the suppression effects of miR-744-5p overexpression on OS cell growth and HUVECs angiogenesis.ConclusionOur results indicated that miR-744-5p is a potential tumor-suppressive miRNA in OS progression by targeting NFIX to restrain the growth of OS cells and angiogenesis in HUVECs.

Bisdemethoxycurcumin Augments Docetaxel Efficacy for Treatment of Prostate Cancer.

Bisdemethoxycurcumin (BDMC) is one of major forms of curcuminoids found in the rhizomes of turmeric. Docetaxel (DTX) is the standard of care for men diagnosed with androgen-independent prostate cancers. Here we report for the first time that BDMC could reinforce the effect of DTX against prostate cancer in vitro and in vivo. In vitro study, PC3 and LNCaP cells were cultured and treated with BDMC and DTX alone or in combination. The effects on cell viability were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was assessed by annexin V/propidium iodide (PI) staining, while cell cycle was assessed by PI staining. Bax, Bcl-2, caspase, poly(ADP-ribose)polymerase (PARP), cyclin B1 and CDK1 expression were assayed by Western blot. We found that a combination treatment of BDMC (10 µM) with DTX (10 nM) was more effective in the inhibition of PC3 and LNCaP cell growth and induction of apoptosis as well as G2/M arrest, which is accompanied with the significant inhibition of Bcl-2, cyclin B1, CDK1 expression and significant increase of Bax, cleaved caspase-9, cleaved caspase-3 and cleaved PARP, than those by treatment of BDMC or DTX alone. Moreover, in vivo evaluation further demonstrated the superior anticancer efficacy of BDMC and DTX compared to DTX alone in a murine prostate cancer model. These results suggest that BDMC can be an attractive therapeutic candidate in enhancing the efficacy of DTX in prostate cancer treatment.

The composition of linoleic acid and conjugated linoleic acid has potent synergistic effects on the growth and death of RAW264.7 macrophages: The role in anti-inflammatory effects

Linoleic acid (LA) is an omega-6 polyunsaturated fatty acid. Conjugated linoleic acid (CLA) is a family of LA isomers that includes both a trans fatty acid and a cis fatty acid. Both fatty acids play a nutritional role in maintaining health. Inflammation is critical in the pathogenesis of many diseases, including cancer. This study found that the combination of LA and CLA (LA/CLA), each of which had no effect, had a strong anti-synergistic effect on inflammatory macrophage RAW264.7 cells in vitro. Cells were cultured in a DMEM containing fetal bovine serum with or without either LA, CLA, or a combination of LA/CLA. The composition of LA and CLA at a comparatively lower concentration synergistically suppressed cell growth, resulting in a reduction in cell number. The underlying mechanism of this effect was based on reduced levels of Ras, PI3K, Akt, MAPK, and mTOR and elevated levels of p21, p53, and Rb, which are associated with cell growth. In addition, the combination of LA and CLA at a lower concentration stimulated potential cell death associated with increased caspase-3 and cleaved caspase-3 levels. Notably, this composition synergistically suppressed the production of TNF-α, IL-6, and PGE2, which are a major mediator of inflammation, with lipopolysaccharide stimulation in RAW264.7 cells This effect was associated with decreased levels of COX-1, COX-2, and NF-κB p65. This study may provide a useful tool for treating inflammatory conditions with the composition of LA and CLA.

Prosapogenin A induces GSDME-dependent pyroptosis of anaplastic thyroid cancer through vacuolar ATPase activation-mediated lysosomal over-acidification

Anaplastic thyroid cancer (ATC) is among the most aggressive and metastatic malignancies, often resulting in fatal outcomes due to the lack of effective treatments. Prosapogenin A (PA), a bioactive compound prevalent in traditional Chinese herbs, has shown potential as an antineoplastic agent against various human tumors. However, its effects on ATC and the underlying mechanism remain unclear. Here, we demonstrate that PA exhibits significant anti-ATC activity both in vitro and in vivo by inducing GSDME-dependent pyroptosis in ATC cells. Mechanistically, PA promotes lysosomal membrane permeabilization (LMP), leading to the release of cathepsins that activate caspase 8/3 to cleave GSDME. Remarkably, PA significantly upregulates three key functional subunits of V-ATPase—ATP6V1A, ATP6V1B2, and ATP6V0C—resulting in lysosomal over-acidification. This over-acidification exacerbates LMP and subsequent lysosomal damage. Neutralization of lysosomal lumen acidification or inhibition/knockdown of these V-ATPase subunits attenuates PA-induced lysosomal damage, pyroptosis and growth inhibition of ATC cells, highlighting the critical role for lysosomal acidification and LMP in PA’s anticancer effects. In summary, our findings uncover a novel link between PA and lysosomal damage-dependent pyroptosis in cancer cells. PA may act as a V-ATPase agonist targeting lysosomal acidification, presenting a new potential therapeutic option for ATC treatment.

Targeting BCL2 with Venetoclax Enhances the Efficacy of the KRASG12D Inhibitor MRTX1133 in Pancreatic Cancer.

MRTX1133 is currently being evaluated in patients with pancreatic ductal adenocarcinoma (PDAC) tumors harboring a KRASG12D mutation. Combination strategies have the potential to enhance the efficacy of MRTX1133 to further promote cell death and tumor regression. In this study, we demonstrated that MRTX1133 increased the levels of the pro-apoptotic protein BIM in PDAC cells and conferred sensitivity to the FDA-approved BCL2 inhibitor venetoclax. Combined treatment with MRTX1133 and venetoclax resulted in cell death and growth suppression in 3D cultures. BIM was required for apoptosis induced by the combination treatment. Consistently, BIM was induced in tumors treated with MRTX1133, and venetoclax enhanced the efficacy of MRTX1133 in vivo. Venetoclax could also re-sensitize MRTX1133-resistant PDAC cells to MRTX1133 in 3D cultures, and tumors established from resistant cells responded to the combination of MRTX1133 and venetoclax. These results provide a rationale for the clinical testing of MRTX1133 and venetoclax in PDAC patients.

Inhibitory Effect of Combined Exposure to Copper Ions and Polystyrene Microplastics on the Growth of Skeletonema costatum

As two significant pollutants, the increased concentrations of copper ions and microplastics in coastal waters pose a substantial threat to the health of marine ecosystems. This study explored the individual and combined toxic effects of copper ions and microplastics on the marine diatom Skeletonema costatum. The results indicated that copper ions at a concentration of 0.05 mg/L exerted a negative impact on the growth of S. costatum; however, the influence of microplastics on algal cell growth was more complex: there was no significant inhibition of algal cell growth observed within the first 72 h of cultivation, but a pronounced negative effect on cell growth was noted between 72 and 96 h, with high concentrations (10.00 mg/L) of microplastics even causing a premature stagnation phase in algal cell growth. When both pollutants were present simultaneously, their impact on cell growth was similar to that of the microplastic pollution group, yet the growth condition was better than that of the copper ion pollution group. Through investigation of adsorption rates and toxicity mitigation rates, it was found that the adsorption of copper ions by microplastics was a significant reason for the improved growth condition of algal cells in the mixed pollution group compared to the copper ion pollution group. However, in the later stages of cultivation, the inhibitory effect of microspheres on algal cell growth counteracted their mitigating effect on copper ion toxicity. This study provides a reference for evaluating the impact of microplastics and heavy metals on coastal ecosystem health and for revealing the interactions between different pollutants.