Growth Inhibition Research Articles

Cinnamaldehyde-Based ROS-Responsive Polymeric Gene Vectors for Efficient Gene Delivery and Tumor Cell Growth Inhibition.

Reactive oxygen species (ROS)-sensitive polymers are extensively used in cancer therapies. However, the ROS levels in the tumor microenvironment are often insufficient to trigger an adequate therapeutic response. Herein, we report a cinnamaldehyde (CA)-based ROS-responsive cationic polymer (PCA) and demonstrate its high efficiency in gene delivery and tumor cell growth inhibition. CA could be released from the polymer via a ROS-sensitive thioacetal bond by endogenous ROS. The released CA successively induced more ROS accumulation through GSH depletion, and the positive feedback helped PCA to achieve self-accelerating degradation. Results proved that PCA/p53 complexes were efficient in depleting GSH, upregulating ROS levels, and gene transfection. Besides, PCA was also shown to be effective in delivering the therapeutic gene p53. More importantly, PCA/p53 complexes could significantly induce tumor cell growth suppression by a synergistic effect of PCA and p53, providing valuable insights into the design of self-amplifying ROS-responsive polymeric gene vectors.

PARP inhibition-associated heterochromatin confers increased DNA replication stress and vulnerability to ATR inhibition in SMARCA4-deficient cells

DNA replication stress (RS), a prevalent feature of various malignancies, arises from both genetic mutations and genotoxic exposure. Elevated RS levels increase the vulnerability of cancer cells to ataxia telangiectasia and Rad3-related kinase inhibitors (ATRis). Here, we screened for DNA damage response inhibitors that enhance ATRi-induced cytotoxicity using SWI/SNF complex-deficient cells and identified a potent synergy between ATRi and poly(ADP-ribose) polymerase inhibitor (PARPi), particularly in SMARCA4-deficient cells. PARP inhibition triggers chromatin changes, namely elevated histone H3 at lysine 9 di-methylation (H3K9me2), a hallmark of facultative heterochromatin, increasing dependence on ATR activity for replication fork progression and cell survival. Interestingly, SMARCA4 deficient cells, intrinsically vulnerable to replication stress, exhibited exacerbated DNA damage upon combined ATRi and PARPi treatment in a Mre11- and Mus81-mediated manner. In vivo, combined treatment with intermittent ATRi and continuous PARPi showed greater inhibition of tumor growth than ATRi alone in SMARCA4-deficient lung adenocarcinoma xenograft models. These findings demonstrate that PARPi-induced heterochromatin amplifies RS and ATRi susceptibility, providing a potential rationale for therapeutic strategies targeting SMARCA4-deficient tumors.

Antioxidant, antidiabetic, and antimicrobial efficacy of germinated Ocimum gratissimum and Ocimum basilicum seed.

The edible seeds of Ocimum gratissimum and Ocimum basilicum were found to be a potent source of phytochemicals with noteworthy antioxidant, antidiabetic, and antimicrobial properties. This study aimed to investigate the impact of germination and extraction solvents (ethanol (EtOH), distilled water) on the therapeutic properties exhibited and the ability of seed extracts to act as natural food preservatives. The EtOH extracts of germinated O. gratissimum and O. basilicum seeds exhibited more phytoconstituents content with significantly higher phenols (21.03 ± 0.01 mg gallic acid equivalent (GAE)/g and 21.46 ± 0.01 mg GAE/g respectively) and flavonoids (11.92 ± 0.03 mg quercetin equivalent (QE)/g and 14.45 ± 0.04 mg QE/g respectively) than other extracts did. Thus, they exhibited superior antioxidant potential with substantially lower half-maximal inhibitory concentration (IC50) values for scavenging 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) cation radical (0.013 ± 0.00 mg mL-1 and 0.007 ± 0.00 mg mL-1 respectively) and superoxide anion radical (4.33 ± 0.01 mg mL-1 and 4.14 ± 0.00 mg mL-1 respectively) and for inhibiting lipid oxidation (2.57 ± 0.00 mg mL-1 and 2.33 ± 0.00 mg mL-1 respectively) compared with other extracts. Further, they exhibited better antidiabetic potential with substantially lower IC50 values for inhibiting α-amylase activity (0.93 ± 0.01 mg mL-1 and 1.01 ± 0.01 mg mL-1 respectively) and α-glucosidase activity (0.60 ± 0.01 mg mL-1 and 0.51 ± 0.01 mg mL-1 respectively). Also, they showed superior antimicrobial potential with higher inhibition zones for Bacillus subtilis (13.98 ± 0.18 mm, 17.02 ± 0.18 mm respectively), Vibrio parahaemolyticus (19.00 ± 0.20 mm, 22.58 ± 0.45 mm respectively), Salmonella enterica (24.98 ± 0.18 mm, 22.17 ± 0.15 mm respectively), and Escherichia coli (23.50 ± 0.50 mm, 27.00 ± 0.20 mm respectively) and better inhibition of Aspergillus flavus growth (93.28% and 81.77% respectively) compared with other extracts. Both the O. gratissimum and O. basilicum seed extracts can be utilized efficiently as therapeutic agents to manage inflammation-driven diseases and diabetes, or as natural preservatives in foods and in edible films or coatings. © 2025 Society of Chemical Industry.

APD-L1-facilitated theranostic and tumor microenvironment remodeling of pancreatic cancer via docetaxel-loaded phase-transformation nanoparticles triggered by low-intensity pulsed ultrasound

Early diagnosis of pancreatic ductal adenocarcinoma (PDAC) is challenging because of its depth, which often leads to misdiagnosis during ultrasound examinations. The unique PDAC tumor microenvironment (TME) is characterized by significant fibrous tissue growth, and high interstitial pressure hinders drug penetration into tumors. Additionally, hypoxia and immune suppression within the tumor contribute to poor responses to radiotherapy and chemotherapy, ultimately leading to an unfavorable prognosis. In this study, aPD-L1-modified docetaxel and perfluoropentane-loaded liquid‒vapor phase-transformation lipid nanoparticles (aPDL1-DTX/PFP@Lipid) were synthesized and had an average diameter of 61.63 nm with 84.3% antibody modification. We demonstrated that the nanoparticles (NPs) exhibited excellent PDAC-targeting capabilities both in vitro and in vivo. Upon exposure to low-intensity pulsed ultrasound (LIPUS) stimulation, the NPs underwent a phase transformation to form microbubbles with substantial molecular ultrasound diagnostic effects, and combined treatment resulted in a tumor growth inhibition rate of 88.91%. This treatment strategy also led to the infiltration of CD8+ T cells, the downregulation of Treg cells, the promotion of M1 macrophage polarization, the inhibition of fibrosis to reduce tumor stromal pressure, and the facilitation of perfluoropentane (PFP) gasification to release O2 and improve tumor hypoxia. In conclusion, aPD-L1-modified liquid‒vapor phase-transformation nanoparticles loaded with docetaxel (DTX) and PFP were successfully combined with ultrasound for the molecular diagnosis and targeted treatment of PDAC. aPDL1-DTX/PFP@Lipid could reshape the PDAC TME, offering a new approach for ultrasound-mediated diagnosis and treatment with promising clinical applications.Graphical

Photodegradation of methylene blue from waste water under visible light and bacterial growth inhibition by GO and rGO blended CdO: Mn nanoparticles– a comparative study

Photodegradation of methylene blue from waste water under visible light and bacterial growth inhibition by GO and rGO blended CdO: Mn nanoparticles– a comparative study

Semi-mechanistic efficacy model for PARP + ATR inhibitors-application to rucaparib and talazoparib in combination with gartisertib in breast cancer PDXs.

Promising cancer treatments, such as DDR inhibitors, are often challenged by the heterogeneity of responses in clinical trials. The present work aimed to build a computational framework to address those challenges. A semi-mechanistic pharmacokinetic-pharmacodynamic model of tumour growth inhibition was developed to investigate the efficacy of PARP and ATR inhibitors as monotherapies, and in combination. Key features of the DNA damage response were incorporated into the model to allow the emergence of synthetic lethality, including redundant DNA repair pathways that may be impaired due to genetic mutations, and due to PARP and ATR inhibition. Model parameters were calibrated using preclinical in vivo data for PARP inhibitors rucaparib and talazoparib and the ATR inhibitor gartisertib. The model successfully captured the monotherapy efficacies of rucaparib and talazoparib, as well as the combination efficacy with gartisertib. The model was evaluated against multiple tumour xenografts with diverse genetic backgrounds and was able to capture the observed heterogeneity of response profiles. By enabling simulation of in vivo tumour growth inhibition with PARP and ATR inhibitors for specific tumour types, the model provides a rational approach to support the optimisation of dosing regimens to stratified populations.

Anchoring Ru single-atoms on MXene achieves dual-enzyme activities for mild photothermal augmented nanocatalytic therapy.

Single-atom catalysts with abnormally high catalytic activity have garnered extensive attention and interest for their application in tumor therapy. Despite the advancements made with current nanotherapeutic agents, developing efficient systems for cancer treatment remains challenging due to low activity, uncontrollable behavior, and nonselective interactions. Herein, we have constructed Ru single-atom-anchored MXene nanozymes (Ru-Ti3C2Tx-PEG) with a mild photothermal effect and multi-enzyme catalytic activity for synergistic tumor therapy. Ru single atoms anchored on the surface of MXene nanosheets not only facilitate multi-enzyme catalytic activity but also amplify the photothermal performance owing to the localized surface plasmon resonance effect. The Ru single atoms could decompose H2O2 into toxic hydroxyl radicals (•OH) in response to the tumor microenvironment (TME) for enzyme catalytic therapy, and the heat produced by the nanozyme under near-infrared laser excitation enhanced the •OH generation yield. Moreover, the nanozyme exhibited oxygen formation and glutathione depletion capability in cancer cells, thereby regulating the TME and accelerating the •OH levels. The in vitro and in vivo studies in this work confirm that the two-dimensional Ru single-atom-anchored MXene nanozyme has an extraordinary tumor growth inhibition effect, thus presenting a rational therapeutic strategy for tumor ablation through the synergistic effect of photothermal activity and heat-promoted enzymatic catalysis.

Vitamin B2 Operates by Dual Thermodynamic and Kinetic Mechanisms to Selectively Tailor Urate Crystallization.

Here we demonstrate how a biologically relevant molecule, riboflavin (vitamin B2), operates by a dual mode of action to effectively control crystallization of ammonium urate (NH4HU), which is associated with cetacean kidney stones. In situ microfluidics and atomic force microscopy experiments confirm a strong interaction between riboflavin and NH4HU crystal surfaces that substantially inhibits layer nucleation and spreading by kinetic mechanisms of step pinning and kink blocking. Riboflavin does not alter the distribution of tautomeric urate isomers, but its adsorption on NH4HU crystal surfaces does interfere with the effects of minor urate tautomer by limiting its ability to induce NH4HU crystal defects while also suppressing NH4HU nucleation and inhibiting crystal growth by 80% at an uncharacteristically low modifier concentration. Time-resolved spectroscopy measurements, ab initio calculations, and molecular dynamics simulations confirm that each riboflavin molecule forms a complex with six or more urate molecules to lower supersaturation, thereby reducing the rate of NH4HU crystallization by a thermodynamically driven mechanism. The degree of complexation observed for riboflavin far exceeds that of common chelating agents, and results in crystal dissolution when the free urate concentration falls below NH4HU solubility. The synergism that is created by riboflavin's dual kinetic and thermodynamic mechanisms is rarely achieved by more conventional crystal growth inhibitors. These insights offer new approaches that could be influential for the design of molecular modifiers in crystal engineering applications, the development of therapeutics for pathological conditions, and establishing broader understanding of the roles played by foreign agents in natural and biological crystallization.

Mixed fungal strains challenge host resistance: insights into Magnaporthiopsis maydis pathogenicity in maize

Maize late wilt disease, caused by the fungus Magnaporthiopsis maydis, poses a significant threat to susceptible crops. Despite efforts to control it through resistant maize varieties, virulent fungal strains might overcome immunity. This study assessed Israeli M. maydis strains with weak, moderate, and highly pathogenic degrees in two open-air pot trials. Even weak pathogenic strains harmed susceptible cultivars (17% growth suppression and 33% death). In contrast, resistant cultivars were minimally affected, except when exposed to a highly aggressive isolate, resulting in a 5% growth suppression and 11% mortality at harvest. Unexpectedly, in a susceptible cultivar during sprouting, a mixed inoculum with the two more virulent isolates resulted in reduced disease (15%) compared to the highly aggressive strain alone (33%). At harvest (day 84), this pattern was reversed, and adding a weak virulent strain to this combination led to more severe growth (33%) and health (71%) disruption, accompanied by a higher level of M. maydis infection (371% compared to the aggressive strain alone). Similar interactions were found in other strain groups tested. Additionally, some subspecies groups specialize in growth suppression, while others in wilting, suggesting biotrophic/necrotrophic variations. The study revealed complex interactions in mixed populations, emphasizing the destructive potential of the pathogen to resistant cultivars. Understanding the role of maize age-related immunity in disease generation uncovers risks associated with this pathogen.

Growth inhibition by ppc deletion is rescued by isocitrate dehydrogenase mutations in Escherichia coli.

Phosphoenolpyruvate carboxylase encoded by ppc catalyzes the anaplerotic reaction of oxaloacetate in the TCA cycle in Escherichia coli. Deletion of ppc does not prevent the cells from replenishing oxaloacetate via the glyoxylate shunt, but the ppc-deletion strain almost did not grow on glucose. In the present study, we obtained evolved strains by deleting both ppc and mutS to increase the mutation rate and investigated the mechanisms for improving growth by analyzing the mutated genes. Genome resequencing revealed that the evolved strains have non-synonymous mutations in icd encoding isocitrate dehydrogenase (ICDH). The introduction of icd mutations rescued the growth defects caused by ppc deletion. ICDH activity was strongly reduced by the amino acid substitutions G205D or N232S. The evolved strains appeared to suppress the competitive pathway for increasing the glyoxylate shunt flux. In metabolic engineering, the deletion of iclR, which encodes a repressor of the aceBAK operon, has been used to activate the glyoxylate shunt. The growth rate of the ΔppcΔiclR strain slightly increased, but it was still much lower than that of the Δppc+icdG205D strains. This finding suggests that iclR deletion is not sufficient to enhance glyoxylate shunt flux and that inactivation of the competitive pathway by icd mutations is more effective.

Screening potential antileukemia ingredients from sweet potato: integration of metabolomics analysis, network pharmacology, and experimental validation

BackgroundActive dietary flavonoids are a promising resource for novel drug discovery. Sweet potato, a widely cultivated functional crop, is abundant in flavonoids. However, the active ingredients associated with acute myeloid leukemia (AML) treatment and their underlying mechanisms have not been reported to date.ObjectiveThis study aims to identify novel drugs against AML from sweet potato by integrating metabolomics analysis, network pharmacology, and experimental validation.MethodsFirstly, ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was employed to analyze the major constituents in sweet potato. Then, nine active ingredients were selected for validation of their anti-leukemia effects. Subsequently, three of them underwent network pharmacology analyses and in vitro experimental verification. Finally, the anti-leukemia effect of cynaroside was further confirmed through in vivo experimental validation.ResultsFirstly, the flavonoid content of stem, leaves, flesh, and peel from 13 sweet potato cultivars was examined. The leaves of Nanshu 017 exhibited the highest flavonoid content of 2.27% dry weight (DW). Then, an extract derived from these leaves was employed for in vitro experiments, demonstrating significant inhibition of AML cell growth. Subsequently, based on the results of metabolomics analysis and network pharmacology, cynaroside, nepitrin, and yuanhuanin were identified as potential antileukemia agents present in sweet potato for the first time; while CASP3, KDR, EGFR, and SRC were recognized as pivotal targets of these three monomers against AML. Finally, the antileukemia effects of cynaroside, nepitrin, and yuanhuanin were confirmed through in vitro and in vivo experimental validation.ConclusionIn summary, sweet potato leaves extract possesses an antileukemic effect while cynaroside, nepitrin, and yuanhuanin demonstrate potential as treatments for AML.

Verticillin A-Loaded Surgical Buttresses Prevent Local Pancreatic Cancer Recurrence in a Murine Model.

The fungal metabolite verticillin A is a potent and selective histone methyltransferase inhibitor. It regulates apoptosis, the cell cycle, and stress response, and displays potent activity in the suppression of tumor cell growth in several different in vivo models. Verticillin A sensitizes pancreatic cancer cells to anti-PD-1 immunotherapy by regulating PD-L1 expression. However, as with many natural products, delivery and systemic toxicity are challenges that must be overcome to advance their use as a chemotherapeutic. To both reduce systemic toxicity and improve delivery, we report a verticillin A-loaded surgical buttress, which is well-tolerated at a dose as high as 40 mg/kg. In contrast, free verticillin A administered systemically results in toxicity at a dose of 3 mg/kg. The verticillin A-loaded buttress suppresses tumor recurrence in vivo in a safe and dose-dependent manner against a highly aggressive and metastatic model of pancreatic cancer.

Advanced Platelet-Rich Fibrin (A-PRF) as Antibiotics Delivery System: In-Vitro Proof-of-Concept Study

Autologous blood centrifugation produces various forms of platelet concentrates widely used in tissue regenerative therapies due to their high concentrations of growth factors and abundance of autologous cells. Advanced Platelet-Rich Fibrin (A-PRF), introduced as a low-speed centrifugation product, contains an even higher concentration of growth factors, a greater number of cells, and a looser fibrin clot structure compared to previous Leukocyte and Platelet-Rich Fibrin (L-PRF). This study aims to assess the potential of A-PRF as a local delivery system for antibiotics. Different concentrations (0.5 mg/mL, 0.25 mg/mL, and 0.125 mg/mL) of injectable amoxicillin (AMX) and metronidazole (MTZ) were preliminarily tested for their impact on A-PRF clot formation, with 0.5 mg/mL selected for subsequent experiments. Blood samples from healthy volunteers were supplemented with antibiotics and centrifuged to form clots. Antibiotic-enriched A-PRF clots were immersed in phosphate-buffered saline (1x PBS) and analyzed at 24 h, 72 h, 7 days, and 14 days. AMX showed a consistent release (mean: 19.9 ± 4.8 ng/mL at 24 h) over 14 days, while MTZ demonstrated greater variability (mean: 12.8 ± 4.5 ng/mL at 24 h). AMX release remained constant over the 14-day period, with no significant variations among patients. In contrast, MTZ displayed a progressively lower release over time. Microbiological analysis revealed bacterial growth inhibition zones for Fusobacterium nucleatum (AMX: 23 mm, MTZ: 28 mm) and Prevotella intermedia (AMX: 34 mm, MTZ: 30 mm) at 24 h. These findings suggest that A-PRF can act as an effective local antibiotic delivery system, maintaining sustained antimicrobial activity and potentially reducing the need for systemic antibiotics.

CircPRKD3-loaded exosomes concomitantly elicit tumor growth inhibition and glioblastoma microenvironment remodeling via inhibiting STAT3 signaling.

Glioblastoma stem cells (GSCs) and their exosomes (exos) are involved in shaping the immune microenvironment, which is important for tumor invasion and recurrence. However, studies involving GSC-derived exosomal circular RNAs (GDE-circRNAs) in regulating tumor microenvironment (TME) remain unknown. Here, we comprehensively evaluated the significance of a novel immune-related GDE-circRNA in glioma microenvironment. GDE-circPRKD3 was screened out through high-throughput sequencing and verified by RT-PCR, sanger sequencing and RNase R assays. A series of in vitro and in vivo experiments were performed to investigate the function of GDE-circPRKD3. RNA-seq, RNA immunoprecipitation, multicolor flow cytometry and western blotting were used to explore the regulation of GDE-circPRKD3 on STAT3 signaling-mediated TME remodeling. We have characterized a circRNA PRKD3 in GSC exosomes, and lower circPRKD3 expression predicts a worse prognosis for glioblastoma patients. Overexpression of GDE-circPRKD3 significantly impairs the biological competence of glioma and prolongs the survival of xenograft mice. GDE-circPRKD3 binds to HNRNPC in an m6A-dependent manner, accelerates mRNA decay of IL6ST and inhibits downstream target STAT3. Notably, GDE-circPRKD3 promotes CXCL10 secretion by reprogramming tumor-associated macrophages, which in turn recruits CD8+ tumor infiltrating lymphocytes against GBM. Moreover, brain-targeted lipid nanoparticle delivery of circPRKD3 combined with immune checkpoint blockade therapy achieves significant combinatorial benefits. This study provides a novel mechanism by which GDE-circPRKD3 relies on STAT3 signaling to remodel immunosuppressive TME and offers a potential RNA immunotherapy strategy for GBM treatment.

EFFECT OF Cr AS A GRAIN GROWTH INHIBITOR ON CRYSTALLIZATION KINETICS FOR Fe73.5-xCrxCu1Nb3Si13.5B9 (x = 1, 5, 10, 12.5, 17.5)

Nanocrystalline Finemet© alloys of composition Fe73.5-xCrxCu1Nb3Si13.5B9 with x = 1, 5, 10, 12.5, 17.5 were synthesized using the melt spinning technique to study the impact of chromium (Cr) as a grain growth inhibitor on the crystallization kinetics. The alloys were studied under several heat treatments starting from the as-cast to 600℃ and the amorphousity of the ribbons is reduced as well as the nucleation of crystallizations starts. Differential Scanning Calorimetry (DSC) analysis shows that increasing Cr content shifts the crystallization temperatures to higher values, enhancing thermal stability. Moreover, the X-ray diffraction (XRD) and Field Emission Scanning Electron Microscopy (FESEM) confirmed the development of an ultra-fine α-Fe(Si) nanocrystalline phase, with the grain size decreasing as Cr content increased. The evolution of microstructure and thermal properties highlight the role of Cr content in delaying crystallization and reducing grain growth, thus improving the nanocrystalline state of the material. These findings provide insights into optimizing Fe-Si-B-based nanocrystalline alloys for advanced applications by balancing thermal treatments and Cr concentration. Bangladesh Journal of Physics, 28(1), 59-68, June 2021

Abstract B011: Adenosine signaling and immune modulation in the tumor microenvironment: insights from lung cancer murine model of radiation therapy

Abstract Introduction: Radiation therapy (RT) induces adenosine signaling by releasing ATP in the tumor microenvironment (TME), promoting immune suppression and tumor progression. This study investigates how RT impacts adenosine signaling and immune cell infiltration in a preclinical model of non-small cell lung cancer (NSCLC). Using immunophenotyping of tumor-infiltrating immune cells in LLC1 murine model, we aim to explore the potential of targeting the adenosine pathway in combination with RT to enhance antitumor immunity and clinical outcomes. Methods: LLC1 tumor cells (5 x 105) were implanted subcutaneously in the flanks of C57BL/6 mice. After 12 days, mice received RT (4 Gy x 3 or 8 Gy x 3). Tumor volumes were measured thrice a week and harvested 5- and 10-days post-RT. We performed immunophenotyping of tumor tissue to assess changes in immune (CD45+) and CD45- compartments. The expression of adenosine signaling pathway members was quantified in distinct immune cell populations. Results: RT caused significant inhibition in tumor growth in a dose- and time-dependent manner. 5-days post-RT, CD73 (P< 0.01) and CD39 expressions (P< 0.01) were significantly upregulated in the immune compartment, while A2BR (P< 0.01) and A2AR (P< 0.05) were decreased in the non-immune compartment. RT decreased T cell populations, including CD4+ and CD8+ T cells. Further, CD4+ T cells downregulate adenosine signaling markers, particularly CD73 (P< 0.05) and ENPP1 (P< 0.05), while CD8+ T cells decreased in CD73 expression (P< 0.01). Myeloid subtype abundance was unchanged, but A2AR, A2BR, CD39, and CD73 expressions increased in the M2-like macrophage compartment (F4-80+MHCII-). 10 days post-RT, all adenosine signaling pathway markers significantly increased in the immune compartment and significantly decreased in the non-immune compartment. T cells (TCRb+) and macrophages (F4-80+) increased in abundance, including immuno-suppressive Arg+ macrophages (P< 0.05). Macrophage population that expressed the adenosine signaling markers increased by 10-15% (P< 0.05). While the proportion of CD4+ T cells and Tregs (CD4+FoxP3+) that expressed CD39 and CD73 also increased (P< 0.05). Conclusions: Our study revealed that RT promotes an immunosuppressive TME, in part through adenosine signaling. 5 days post-RT, we observed lymphocyte depletion and upregulation of the adenosine signaling pathway in M2-like macrophages. 10 days post-RT, adenosine signaling significantly increased across the immune compartment and decreased in the non-immune compartment, suggesting that the increase in adenosine signaling post-RT is immunologically mediated and largely driven by the myeloid compartment. These data lead to the hypothesis that inhibition of the adenosine signaling pathway may partially mitigate RT-induced immune suppression and improve RT efficacy. Ongoing work includes quantification of adenosine by LC-MS, extension to a preclinical SCC model of NSCLC, and evaluating adenosine pathway inhibition in combination with RT as a therapeutic strategy to improve antitumor immune responses. Citation Format: Krishan K. Saini, Samanta Sarti, Chelsea L. Rahiman, Brian E. Ragaishis, Patrick J. McCann, Shruti Bansal, Jason Cham, Julia An, Rosa Martin, Ariel Chen, Catherine S. Spina. Adenosine signaling and immune modulation in the tumor microenvironment: insights from lung cancer murine model of radiation therapy. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B011.

Engineering Covalent Aptamer Chimeras for Enhanced Autophagic Degradation of Membrane Proteins

AbstractTargeted degradation of membrane proteins represents an attractive strategy for eliminating pathogenesis‐related proteins. Aptamer‐based chimeras hold great promise as membrane protein degraders, however, their degradation efficacy is often hindered by the limited structural stability and the risk of off‐target effects due to the non‐covalent interaction with target proteins. We here report the first design of a covalent aptamer‐based autophagosome‐tethering chimera (CApTEC) for the enhanced autophagic degradation of cell‐surface proteins, including transferrin receptor 1 (TfR1) and nucleolin (NCL). This strategy relies on the site‐specific incorporation of sulfonyl fluoride groups onto aptamers to enable the cross‐linking with target proteins, coupled with the conjugation of an LC3 ligand to hijack the autophagy‐lysosomal pathway for targeted protein degradation. The chemically engineered CApTECs exhibit enhanced on‐target retention and improved structural stability. Our results also demonstrate that CApTECs achieve remarkably enhanced and prolonged degradation of membrane proteins compared to the non‐covalent designs. Furthermore, the CApTEC targeting TfR1 is combined with 5‐fluorouracil (5‐FU) for synergistic tumor therapy in a mouse model, leading to substantial suppression of tumor growth. Our strategy may provide deep insights into the LC3‐mdiated autophagic degradation, affording a modular and effective strategy for membrane protein degradation and precise therapeutic applications.

Sphingosine-1-Phosphate Metabolic Pathway in Cancer: Implications for Therapeutic Targets

Cancer biology revolves around understanding how cells undergo uncontrolled proliferation leading to the formation of malignant tumors. Key aspects include self-sufficiency in growth signals, the lack of response to signals of growth inhibition, the evasion of apoptosis, sustained angiogenesis, the evasion of immune response, the capacity to invade and metastasize, and alterations in cellular metabolism. A vast amount of research, which is exponentially growing, over the past few decades highlights the role of sphingolipids in cancer. They act not only as structural membrane components but also as bioactive molecules that regulate cell fate in different physio-pathological conditions. In cancer, sphingolipid metabolism is dysregulated, contributing to tumor progression, metastasis, and drug resistance. In this review, we outline the impact of sphingosine-1-phosphate (S1P) as a key bioactive sphingolipid in cancer. We give an overview of its metabolism summarizing the role of S1P as an intracellular and extracellular mediator through specific plasma membrane receptors in different cancers. We also describe previous findings on how the disruption in the balance between S1P and ceramide (Cer) is common in cancer cells and can contribute to tumorigenesis and resistance to chemotherapy. We finally consider the potential of targeting the metabolic pathways of S1P as well as its receptors and transporters as a promising therapeutic approach in cancer treatments.

Hydrogen Sulfide Mitigates Manganese-Induced Toxicity in Malus hupehensis Plants by Regulating Osmoregulation, Antioxidant Defense, Mineral Homeostasis, and Glutathione Ascorbate Cycle

Manganese (Mn) is a toxic metal element that adversely affects plant growth. Hydrogen sulfide (H2S) is considered an important signaling molecule with significant potential in alleviating various abiotic stresses. However, there is limited information available on the role of H2S in alleviating manganese stress in plants. In this study, the effects of exogenous H2S and its scavenger, homocysteine thiolactone (HT), on the physiological and biochemical parameters of Malus hupehensis var. pingyiensis seedlings were evaluated. Our results show that H2S treatment significantly alleviates growth inhibition and oxidative damage induced by manganese stress in Malus hupehensis seedlings, primarily by enhancing antioxidant enzyme activity and up-regulating the ascorbate-glutathione (ASA-GSH) cycle. H2S treatment increased photosynthetic pigment content and helped maintain osmotic balance in leaves, thereby enhancing key gas exchange parameters and mitigating manganese-induced suppression of photosynthesis. H2S treatment enhanced the absorption of Ca, Mg, Fe and Zn under manganese stress, significantly reduced manganese accumulation in Malus hupehensis seedlings, and modulated the transcriptional expression of MTPs, facilitating the transfer of manganese to the leaves. Thus, H2S reduces oxidative damage and promotes growth under Mn stress, highlighting its important role in plant stress tolerance.

Growth-Inhibitory Effect of Chicken Egg Yolk Polyclonal Antibodies (IgY) on Zoonotic Pathogens Campylobacter jejuni, Salmonella spp. and Escherichia coli, In Vitro

The overuse of antibiotics in animal husbandry has driven the search for alternative strategies to combat zoonotic pathogens. Foodborne zoonotic diseases caused by pathogenic bacteria pose a significant threat to human health, and therefore food safety should be a priority. This study investigates the in vitro inhibitory effects of chicken egg yolk immunoglobulin Y (IgY) on the growth and viability of three major foodborne pathogens: Campylobacter jejuni, Salmonella spp., and Escherichia coli. IgY was isolated from immunized hen egg yolks using a modified water dilution method, and its antigen-specificity confirmed through agglutination assays. Growth inhibition was evaluated across multiple doses and time points, revealing a dose-dependent bacteriostatic effect against all tested pathogens. A single dose of IgY (0.5 mg/mL) significantly reduced C. jejuni counts by up to 7 log, while repeated doses were required for Salmonella spp. and E. coli. These findings highlight egg yolk immunoglobulin’s potential as a source of sustainable, effective, ethical, readily available, and inexpensive antibiotic substitutes in livestock management. Future research will focus on validating these results in vivo and exploring large-scale production of IgY for practical application in animal healthcare.