Sensitivity Of Cells Research Articles

Diminished light sensitivities of ON alpha retinal ganglion cells observed in a mouse model of hyperglycemia

This study aimed to investigate potential functional changes in retinal ganglion cells (RGCs) in a mouse model of hyperglycemia and explore possible therapeutic approaches. Hyperglycemia resembling type 1 diabetes mellitus (DM) was induced in C57BL/6 mice through intraperitoneal injection of streptozotocin (STZ). Blood glucose levels were confirmed to be elevated after 1 week and 4 weeks of injection. Mice with blood glucose levels above 350 mg/mL after 4 weeks of one-dose STZ injection were considered hyperglycemic. The light sensitivity of ON alpha (α) retinal ganglion cells (RGCs), not OFF αRGCs, was reduced in the hyperglycemic mouse model. The number of apoptotic cells, RGCs, and amacrine cells (ACs) remained unaffected at this stage. Similarly, the eletroretinogram (ERG) and optokinetic test results showed no significant differences. The application of picrotoxin (PTX) to block GABA receptors could increase the light sensitivity of ON αRGCs by 1 log unit in hyperglycemic mice. The results show that ON αRGCs may be more susceptible to microenvironmental changes caused by hyperglycemia than OFF αRGCs. This decline in light sensitivity may occur before cell apoptosis during the early stages of the hyperglycemic mouse model but has the potential to be reversed.

LncRNA-Mediated TPI1 and PKM2 Promote Self-Renewal and Chemoresistance in GBM.

Temozolomide (TMZ) resistance is one of the major reasons for poor prognosis in patients with glioblastoma (GBM). Long noncoding RNAs (lncRNAs) are involved in multiple biological processes, including TMZ resistance. Linc00942 is a potential regulator of TMZ sensitivity in GBM cells is shown previously. However, the underlying mechanism of TMZ resistance induced by Linc00942 is unknown. In this study, the sequence of Linc00942 by rapid amplification of cDNA ends assay in TMZ-resistant GBM cells is identified and confirmed that Linc00942 contributes to self-renewal and TMZ resistance in GBM cells. Chromatin isolation by RNA purification followed by mass spectrometry (ChIRP-MS) and followed by Western blotting (ChIRP-WB) assays shows that Linc00492 interacted with TPI1 and PKM2, subsequently promoting their phosphorylation, dimerization, and nuclear translocation. The interaction of Linc00942 with TPI1 and PKM2 leads to increased acetylation of H3K4 and activation of the STAT3/P300 axis, resulting in the marked transcriptional activation of SOX9. Moreover, the knockdown of SOX9 reversed TMZ resistance induced by Linc00492 both in vitro and in vivo. In summary, Linc00942 strongly promotes SOX9 expression by interacting with TPI1 and PKM2 is found, thereby driving self-renewal and TMZ resistance in GBM cells. These findings suggest potential combined therapeutic strategies to overcome TMZ resistance in patients with GBM.

Augmented the sensitivity of photothermal-ferroptosis therapy in triple-negative breast cancer through mitochondria-targeted nanoreactor

Ferroptosis primarily relies on reactive oxygen (ROS) production and lipid peroxide (LPO) accumulation, which opens up new opportunities for tumor therapy. However, a standalone ferroptosis process is insufficient in inhibiting tumor progression. Unlike previously reported Fe-based nanomaterials, we have engineered a novel nanoreactor named IR780/Ce@EGCG/APT, which uses metal-polyphenols network (Ce@EGCG) based on rare-earth cerium and epigallocatechin gallate (EGCG) to encapsulate IR780 and modified with the aptamer (AS1411). The intricately designed nanoreactor is specifically taken up by tumor cells, releasing Ce3+, EGCG, and IR780. On the one hand, Ce3+ triggers ROS production via a Fenton-like reaction, inducing ferroptosis in tumor cells. On the other hand, IR780 accumulates in mitochondria and disrupts mitochondrial function upon laser irradiation, leading to tumor cell apoptosis. EGCG serves as a sensitizer, simultaneously enhancing the sensitivity of tumor cells to ferroptosis and photothermal therapy. After a single dose and three times of 808 nm laser irradiation for treatment, it has been observed that the nanoreactor induces dendritic cells (DCs) maturation, facilitates cytotoxic T lymphocyte infiltration, improves immunosuppressive microenvironment, activates the systemic immune system, and generates long-term immune memory.

The Different Responsiveness of C3- and C5-deficient Murine BM Cells to Oxidative Stress Explains Why C3 Deficiency, in Contrast to C5 Deficiency, Correlates with Better Pharmacological Mobilization and Engraftment of Hematopoietic Cells.

The liver-derived circulating in peripheral blood and intrinsic cell-expressed complement known as complosome orchestrate the trafficking of hematopoietic stem/progenitor cells (HSPCs) both during pharmacological mobilization and homing/engraftment after transplantation. Our previous research demonstrated that C3 deficient mice are easy mobilizers, and their HSPCs engraft properly in normal mice. In contrast, C5 deficiency correlates with poor mobilization and defects in HSPCs' homing and engraftment. The trafficking of HSPCs during mobilization and homing/engraftment follows the sterile inflammation cues in the BM microenvironment caused by stress induced by pro-mobilizing drugs or myeloablative conditioning for transplantation. Therefore, to explain deficiencies in HSPC trafficking between C3-KO and C5-KO mice, we evaluated the responsiveness of C3 and C5 deficient cells to low oxidative stress. As reported, oxidative stress in BM is mediated by the activation of purinergic signaling, which is triggered by the elevated level of extracellular adenosine triphosphate (eATP) and by the activation of the complement cascade (ComC). In the current work, we noticed that BM lineage negative cells (lin-) isolated from C3-KO mice display several mitochondrial defects reflected by an impaired ability to adapt to oxidative stress. In contrast, C5-KO-derived BM cells show a high level of adaptation to this challenge. To support this data, C3-KO BM lin- cells were highly responsive to eATP stimulation, which correlates with enhanced levels of reactive oxygen species (ROS) generation and more efficient activation of intracellular Nlrp3 inflammasome. We conclude that the enhanced sensitivity of C3-KO mice cells to oxidative stress and better activation of the Nox2-ROS-Nlrp3 inflammasome signaling axis explains the molecular level differences in trafficking between C3- and C5-deficient HSPCs.

DKK1 as a chemoresistant protein modulates oxaliplatin responses in colorectal cancer

Oxaliplatin is effective against colorectal cancer (CRC), but resistance hampers treatment. We found upregulated Dickkopf-1 (DKK1, a secreted protein) in oxaliplatin-resistant (OR) CRC cell lines and DKK1 levels increased by more than 2-fold in approximately 50% of oxaliplatin-resistant CRC tumors. DKK1 activates AKT via cytoskeleton-associated protein 4 (CKAP4, a DKK1 receptor), modulating oxaliplatin responses in vitro and in vivo. The leucine zipper (LZ) domain of CKAP4 and cysteine-rich domain 1 (CRD1) of secreted DKK1 are crucial for their interaction and AKT signaling. By utilizing the LZ protein, we disrupted DKK1 signaling, enhancing oxaliplatin sensitivity in OR CRC cells and xenograft tumors. This suggests that DKK1 as a chemoresistant factor in CRC via AKT activation. Targeting DKK1 with the LZ protein offers a promising therapeutic strategy for oxaliplatin-resistant CRC with high DKK1 levels. This study sheds light on oxaliplatin resistance mechanisms and proposes an innovative intervention for managing this challenge.

A novel protein SPECC1-415aa encoded by N6-methyladenosine modified circSPECC1 regulates the sensitivity of glioblastoma to TMZ

BackgroundCircular RNAs (circRNAs) can influence a variety of biological functions and act as a significant role in the progression and recurrence of glioblastoma (GBM). However, few coding circRNAs have been discovered in cancer, and their role in GBM is still unknown. The aim of this study was to identify coding circRNAs and explore their potential roles in the progression and recurrence of GBM.MethodsCircSPECC1 was screened via circRNAs microarray of primary and recurrent GBM samples. To ascertain the characteristics and coding ability of circSPECC1, we conducted a number of experiments. Afterward, through in vivo and in vitro experiments, we investigated the biological functions of circSPECC1 and its encoded novel protein (SPECC1-415aa) in GBM, as well as their effects on TMZ sensitivity.ResultsBy analyzing primary and recurrent GBM samples via circRNAs microarray, circSPECC1 was found to be a downregulated circRNA with coding potential in recurrent GBM compared with primary GBM. CircSPECC1 suppressed the proliferation, migration, invasion, and colony formation abilities of GBM cells by encoding a new protein known as SPECC1-415aa. CircSPECC1 restored TMZ sensitivity in TMZ-resistant GBM cells by encoding the new protein SPECC1-415aa. The m6A reader protein IGF2BP1 can bind to circSPECC1 to promote its expression and stability. Mechanistically, SPECC1-415aa can bind to ANXA2 and competitively inhibit the binding of ANXA2 to EGFR, thus resulting in the inhibition of the phosphorylation of EGFR (Tyr845) and its downstream pathway protein AKT (Ser473). In vivo experiments showed that the overexpression of circSPECC1 could combine with TMZ to treat TMZ-resistant GBM, thereby restoring the sensitivity of TMZ-resistant GBM to TMZ.ConclusionsCircSPECC1 was downregulated in recurrent GBM compared with primary GBM. The m6A reader protein IGF2BP1 could promote the expression and stability of circSPECC1. The sequence of SPECC1-415aa, which is encoded by circSPECC1, can inhibit the binding of ANXA2 to EGFR by competitively binding to ANXA2 and inhibiting the phosphorylation of EGFR and AKT, thereby restoring the sensitivity of TMZ-resistant GBM cells to TMZ.

Targeting MGST1 Makes Non-Small Cell Lung Cancer Cells Sensitive to Radiotherapy by Epigenetically Enhancing ALOX15-Mediated Ferroptosis.

Ferroptosis is closely related to radiotherapy resistance in multiple can-cers. Herein, the role of microsomal glutathione S-transferase 1 (MGST1) in regulating ferropto-sis and radiotherapy resistance in non-small cell lung cancer (NSCLC) was investigated. Radiation-resistant NSCLC cells (NCI-1299-IR and HCC827-IR cells) were estab-lished. After exposure to X-ray, cell proliferation and survival were assessed by colony formation assay and CCK-8 assay, and lipid ROS level was examined by the fluorophore BODIPY™ 581/591 C11. MDA, GSH, and Fe2+ levels were measured by ELISA kits. The molecular interac-tion was analyzed using ChIP and MSP assays. Our results showed that RSL3 treatment greatly enhanced the radiotherapy sensitivity of NCI-1299-IR and HCC827-IR cells. It was subsequently revealed that MGST1 was highly ex-pressed in NCI-1299-IR and HCC827-IR cells than its parent cells, and silencing of MGST1 re-duced radioresistance of NCI-1299-IR and HCC827-IR cells by facilitating ferroptosis. Mechanis-tically, MGST1 knockdown greatly reduced HO-1 and DNMT1/3A protein levels, leading to re-duced DNA methylation on the ALOX15 promoter region, thereby epigenetically upregulating ALOX15 expression. As expected, the promoting effects of MGST1 silencing on radiosensitivity and ferroptosis in radiation-resistant NSCLC cells were strikingly eliminated by ALOX15 knock-down. MGST1 knockdown epigenetically enhanced radiotherapy sensitivity of NCSLC cells by promoting ALOX15-mediated ferroptosis through regulating the HO-1/DNMT1 pathway.

Prenatal exposure to low doses of benzophenone-3 elicits disruption of cortical vasculature in fetuses through perturbations in Wnt/β-catenin signaling correlating with depression-like behavior in offspring mice

Benzophenone-3 (BP-3), commonly used in personal care products, is routinely detected in environmental and human matrices. Evidence delineates a correlation between gestational BP-3 exposure and emotional and social disorders in children and adolescents. However, sensitive target cells and the mode of action underlying the early responses to environmentally relevant level of BP-3 exposure remain unclear. In this study, 0.3 and 3 mg/kg of BP-3 were administered to pregnant mice. Compared with the control group, the cortical blood vessel development process manifested the highest susceptibility to BP-3 exposure using transcriptomic sequencing at embryonic day 14 (E14). Notably, the diminution in vascular density and tight junction proteins presence was observed in the fetal cortex at E14, concomitant with the suppressed transcriptional activity of genes essential to angiogenesis and barrier formation. Strikingly, the investigation revealed that BP-3 exposure impeded vascular sprouting in aortic ring explants and neuroendothelial migration, implicating the Wnt/β-catenin signaling pathway. Moreover, BP-3 exposure compromised perivascular neural stem cell differentiation. Cortical vascular injury correlated with the exhibition of depression-like behavior in four-week postnatal progeny. These insights underscore the cerebrovasculature as an early sensitive target for low doses of BP-3 exposure, fostering the development of biomarkers and the establishment of the adverse outcome pathway framework for BP-3 hazard evaluation.

The cytotoxic activities of the major diterpene extracted from Salvia multicaulis (Bardakosh) are mediated by the regulation of heat-shock response and fatty acid metabolism pathways in human leukemia cells

BackgroundLeukemia is one of the most lethal cancers worldwide and represents the sixth-leading cause of cancer deaths. The results of leukemia treatment have not been as positive as desired, and recurrence is common. PurposeThus, there is an urgent requirement for the development of new therapeutic drugs. Salvia multicaulis (Bardakosh) is a widespread species that contains multiple phytochemical components with anti-cancer activities. MethodsWe isolated and characterized the major diterpene candesalvone B methyl ester from S. multicaulis and investigated its action as a cytotoxic agent towards sensitive and drug-resistant leukemia cells by the resazurin reduction assay. Additionally, the targeted genes and the affected molecular mechanisms attributed to the potent cytotoxic activities were discovered by transcriptome-wide mRNA expression profiling. The targets predicted to be regulated by candesalvone B methyl ester in each cell line were confirmed by qRT-PCR, molecular docking, microscale thermophoresis, and western blotting. Moreover, cell cycle distribution and apoptosis were analyzed by flow cytometry. ResultsCandesalvone B methyl ester was cytotoxic with IC50 values of 20.95 ± 0.15 µM against CCRF-CEM cells and 4.13 ± 0.10 µM against multidrug-resistant CEM/ADR5000 leukemia cells. The pathway enrichment analysis disclosed that candesalvone B methyl ester could regulate the heat-shock response signaling pathway via targeting heat shock factor 1 (HSF1) in CCRF-CEM cells and ELOVL fatty acid elongase 5 (ELOVL5) controls the fatty acid metabolism pathway in CEM/ADR5000 cells. Microscale thermophoresis showed the binding of candesalvone B methyl ester with HSF1 and ELOVL5, confirming the results of molecular docking analysis. Down-regulation of both HSF1 and ELOVL5 by candesalvone B methyl ester as detected by both western blotting and RT-qPCR was related to the reversal of drug resistance in the leukemia cells. Furthermore, candesalvone B methyl ester increased the arrest in the sub-G1 phase of the cell cycle in a dose-dependent manner from 1.3 % to 32.3 % with concomitant induction of apoptosis up to 29.0 % in CCRF-CEM leukemic cells upon inhibition of HSF1. ConclusionCandesalvone B methyl ester isolated from S. multicaulis exerted cytotoxicity by affecting apoptosis, cell division, and modulation of expression levels of genes contributing to the heat stress signaling and fatty acid metabolism pathways that could relieve drug resistance of leukemia cells.

Private benefit of β-lactamase dictates selection dynamics of combination antibiotic treatment

β-lactam antibiotics have been prescribed for most bacterial infections since their discovery. However, resistance to β-lactams, mediated by β-lactamase (Bla) enzymes such as extended spectrum β-lactamases (ESBLs), has become widespread. Bla inhibitors can restore the efficacy of β-lactams against resistant bacteria, an approach which preserves existing antibiotics despite declining industry investment. However, the effects of combination treatment on selection for β-lactam resistance are not well understood. Bla production confers both private benefits for resistant cells and public benefits which faster-growing sensitive cells can also exploit. These benefits may be differentially impacted by Bla inhibitors, leading to non-intuitive selection dynamics. In this study, we demonstrate strain-to-strain variation in effective combination doses, with complex growth dynamics in mixed populations. Using modeling, we derive a criterion for the selection outcome of combination treatment, dependent on the burden and effective private benefit of Bla production. We then use engineered strains and natural isolates to show that strong private benefits of Bla are associated with increased selection for resistance. Finally, we demonstrate that this parameter can be coarsely estimated using high-throughput phenotyping of clonal populations. Our analysis shows that quantifying the phenotypic responses of bacteria to combination treatment can facilitate resistance-minimizing optimization of treatment.

Caveolin-1 modulates cisplatin sensitivity in oral squamous cell carcinoma through ferroptosis.

Cisplatin-based chemotherapy is widely used for the treatment of oral squamous cell carcinoma (OSCC), but drug resistance and decreased sensitivity often occur during the treatment, greatly weakening its therapeutic effect. Caveolin-1 (CAV1), a protein related to ferroptosis, is involved in regulating the resistance and sensitivity of various tumor chemotherapies. This study aims to investigate whether CAV1 can regulate the sensitivity of OSCC to cisplatin through ferroptosis. Through bioinformatics analysis, we analyzed the expression of CAV1 in OSCC and its impact on prognosis analyzed the relationship between CAV1 and tumor immune infiltration, and verified the expression of CAV1 in OSCC through immunohistochemistry experiments. We silenced the expression of CAV1 in OSCC cells through lentiviral transfection and evaluated the cell migration and invasion abilities through wound healing and Transwell assays, respectively. CCK8 assay was used to assess the sensitivity of cells to cisplatin, and ferroptosis-related biochemical marker changes were measured. Western blot was performed to detect the expression of ferroptosis-related proteins. The results revealed a high expression of CAV1 in OSCC, and its high expression predicted poor prognosis in OSCC. CAV1 is associated with drug metabolism pathways in OSCC, and its expression affects the infiltration levels of various immune cells in tumors. Further experiments indicated that CAV1 can inhibit ferroptosis and cisplatin sensitivity in cancer cells, promoting their migration and invasion. CAV1 promotes the progression of OSCC and can affect the sensitivity of cisplatin by regulating cellular ferroptosis.

Facile Synthesis of Fe-Based Metal-Quinone Networks for Mutually Enhanced Mild Photothermal Therapy and Ferroptosis.

Mild photothermal therapy (MPTT) has emerged as a promising therapeutic modality for attenuating thermal damage to the normal tissues surrounding tumors, while the heat-induced upregulation of heat shock proteins (HSPs) greatly compromises the curative efficacy of MPTT by increasing cellular thermo-tolerance. Ferroptosis has been identified to suppress the overexpression of HSPs by the accumulation of lipid peroxides and reactive oxygen species (ROS), but is greatly restricted by overexpressed glutathione (GSH) in tumor microenvironment and undesirable ROS generation efficiency. Herein, a synergistic strategy based on the mutual enhancement of MPTT and ferroptosis is proposed for cleaving HSPs to recover tumor cell sensitivity. A facile method for fabricating a series of Fe-based metal-quinone networks (MQNs) by coordinated assembly is proposed and the representative FTP MQNs possess high photothermal conversion efficiency (69.3%). Upon 808 nm laser irradiation, FTP MQNs not only trigger effective MPTT to induce apoptosis but more significantly, potentiate Fenton reaction and marked GSH consumption to boost ferroptosis, and the reinforced ferroptosis effect in turn can alleviate the thermal resistance by declining the HSP70 defense and reducing ATP levels. This study provides a valuable rationale for constructing a large library of MQNs for achieving mutual enhancement of MPTT and ferroptosis.

The epsilon toxin from Clostridium perfringens stimulates calcium-activated chloride channels, generating extracellular vesicles in Xenopus oocytes.

The epsilon toxin (Etx) from Clostridium perfringens has been identified as a potential trigger of multiple sclerosis, functioning as a pore-forming toxin that selectively targets cells expressing the plasma membrane (PM) myelin and lymphocyte protein (MAL). Previously, we observed that Etx induces the release of intracellular ATP in sensitive cell lines. Here, we aimed to re-examine the mechanism of action of the toxin and investigate the connection between pore formation and ATP release. We examined the impact of Etx on Xenopus laevis oocytes expressing human MAL. Extracellular ATP was assessed using the luciferin-luciferase reaction. Activation of calcium-activated chloride channels (CaCCs) and a decrease in the PM surface were recorded using the two-electrode voltage-clamp technique. To evaluate intracellular Ca2+ levels and scramblase activity, fluorescent dyes were employed. Extracellular vesicles were imaged using light and electron microscopy, while toxin oligomers were identified through western blots. Etx triggered intracellular Ca2+ mobilization in the Xenopus oocytes expressing hMAL, leading to the activation of CaCCs, ATP release, and a reduction in PM capacitance. The toxin induced the activation of scramblase and, thus, translocated phospholipids from the inner to the outer leaflet of the PM, exposing phosphatidylserine outside in Xenopus oocytes and in an Etx-sensitive cell line. Moreover, Etx caused the formation of extracellular vesicles, not derived from apoptotic bodies, through PM fission. These vesicles carried toxin heptamers and doughnut-like structures in the nanometer size range. In conclusion, ATP release was not directly attributed to the formation of pores in the PM, but to scramblase activity and the formation of extracellular vesicles.

Exocyclic and Linker Editing of Lys63‐linked Ubiquitin Chains Modulators Specifically Inhibits Non‐homologous End‐joining Repair

AbstractDespite the great advances in discovering cyclic peptides against protein targets, their reduced aqueous solubility, cell permeability, and activity of the cyclic peptide restrict its utilization in advanced biological research and therapeutic applications. Here we report on a novel approach of structural alternation of the exocyclic and linker parts that led to a new derivative with significantly improved cell activity allowing us to dissect its mode of action in detail. We have identified an effective cyclic peptide (CP7) that induces approximately a 9‐fold increase in DNA damage accumulation and a remarkable increase in apoptotic cancer cell death compared to the reported molecule. Notably, treating cells with CP7 leads to a dramatic decrease in the efficiency of non‐homologous end joining (NHEJ) repair of DNA double‐strand breaks (DSBs), which is accompanied by an increase in homologous recombination (HR) repair. Interestingly, treating BRCA1‐deficient cells with CP7 restores HR integrity, which is accompanied by increased resistance to CP7. Additionally, CP7 treatment increases the sensitivity of cancer cells to ionizing radiation. Collectively, our findings demonstrate that CP7 is a selective inhibitor of NHEJ, offering a potential strategy to enhance the effectiveness of radiation therapy.

Brain Cancer Treatment with Gene Editing

The first method is used gene editing to knock out the PD-L1 receptor located on the T cell surface so that PD-1 on the cancer cell surface cannot combine with the PD-L1, in that case, T cell can identify the abnormal cell and kill it. At the beginning, researchers use protein-guided editing technology, but it is not easy to control and not specific enough, so they choose to use CRISPR-Cas9 to edit the target gene. Comparing with the traditional protein-guided nucleases, CRISPR-Cas9 system is more easy-handle, highly specific, and it is an more efficient tool for engineering eukaryotic genomes; because CRISPR-Cas9 system aims to edit the targeting genes by tiny RNAs guiding the Cas9 nuclease to the target site by base pairing.The second treatment is mainly used “fighting cancer with cancer”.Because living tumor cells have the ability to home and target tumors, thus, if those living tumor cells can be engineered to secrete therapeutic agents, the tumor cells can be effectively cured. Shah’s team picked the agent interferon-β (IFN-β). However, this idea of treatment is limited by the premature cell death due to autocrine toxicity.The researchers solved this problem by first using CRISPR Cas9 to knock out the IFN-β–specific receptor (IFNAR1) in inherently IFN-β–sensitive syngeneic tumor cells, and subsequently engineered them to constitutively produce IFN-β for tumor cell targeting and simultaneous immunomodulation. These therapeutic cells are further designed to coexpress granulocyte-macrophage colony-stimulating factor (GM-CSF) that facilitates the differentiation, proliferation, and recruitment of dendritic cells (DCs). The last approach can stop cancer cell repairing their DNA when it gets damaged.

Glioblastoma Multiforme: Sensitivity to Antimicrobial Peptides LL-37 and PG-1, and Their Combination with Chemotherapy for Predicting the Overall Survival of Patients

Background/Objectives: Glioblastomas (GBMs) are the most malignant and intractable of all cancers, with an unfavorable clinical prognosis for affected patients. The objective was to analyze the sensitivity of GBM cells to the antimicrobial peptides (AMPs) cathelicidin (LL-37) and protegrin-1 (PG-1), both alone and in combination with chemotherapy, to predict overall survival (OS) in the patients. Methods: The study was conducted on 27 GBM patients treated in the neurosurgical department of the Almazov Medical Research Centre (Saint Petersburg, Russia) from 2021 to 2024. The cytotoxic effects of chemotherapy, AMPs, and their combinations on brain tumor cells were assessed by an MTT assay using a 50% inhibitory concentration (IC50). Results: In GBM cells from the patients, LL-37 and PG-1 exhibited strong anticancer effects, surpassing those of chemotherapy drugs. These LL-37 and PG-1 anticancer effects were associated with a statistically significant increase in life expectancy and OS in GBM patients. These findings were confirmed by experiments on rats with C6 glioma, where the intranasal administration of LL-37 (300 μM) and PG-1 (600 μM) increased the life expectancy of the animals to 69 and 55 days, respectively, compared to 24 days in the control group (HR = 4.139, p = 0.0005; HR = 2.542, p = 0.0759). Conclusions: Additionally, the combination of LL-37 and PG-1 with chemotherapy drugs showed that a high IC50 of LL-37 with cisplatin (cutoff > 800 μM) in GBM cells was associated with increased life expectancy (19 vs. 5 months, HR = 4.708, p = 0.0101) and OS in GBM patients. These combinations could be used in future GBM treatments.

Unveil the Molecular Interplay between Aminoglycosides and Pseudouridine in IRES Translation.

Loss of pseudouridine increases cell sensitivity to aminoglycosidesPseudouridine enhances ribosome thermostabilityHygromycin B competes with eEF2 for the non-rotated ribosomeHygromycin B deforms the codon-anticodon duplex.

A review on antitumor effect of pachymic acid.

Poria cocos, also known as Jade Ling and Songbai taro, is a dry fungus core for Wolfiporia cocos, which is parasitic on the roots of pine trees. The ancients called it "medicine of four seasons" because of its extensive effect and ability to be combined with many medicines. Pachymic acid (PA) is one of the main biological compounds of Poria cocos. Research has shown that PA has various pharmacological properties, including anti-inflammatory and antioxidant. PA has recently attracted much attention due to its anticancer properties. Researchers have found that PA showed anticancer activity by regulating apoptosis and the cell cycle in vitro and in vivo. Using PA with anticancer drugs, radiotherapy, and biomaterials could also improve the sensitivity of cancer cells and delay the progression of cancer. The purpose of this review was to summarize the anticancer mechanism of PA by referencing the published documents. A review of the collected data indicated that PA had the potential to be developed into an effective anticancer agent.

Strongly ROS-Correlated, Time-Dependent, and Selective Antiproliferative Effects of Synthesized Nano Vesicles on BRAF Mutant Melanoma Cells and Their Hyaluronic Acid-Based Hydrogel Formulation.

Cutaneous metastatic melanoma (CMM) is the most aggressive form of skin cancer with a poor prognosis. Drug-induced secondary tumorigenesis and the emergency of drug resistance worsen an already worrying scenario, thus rendering urgent the development of new treatments not dealing with mutable cellular processes. Triphenyl phosphonium salts (TPPSs), in addiction to acting as cytoplasmic membrane disruptors, are reported to be mitochondria-targeting compounds, exerting anticancer effects mainly by damaging their membranes and causing depolarization, impairing mitochondria functions and their DNA, triggering oxidative stress (OS), and priming primarily apoptotic cell death. TPP-based bola amphiphiles are capable of self-forming nanoparticles (NPs) with enhanced biological properties, as commonly observed for nanomaterials. Already employed in several other biomedical applications, the per se selective potent antibacterial effects of a TPP bola amphiphile have only recently been demonstrated on 50 multidrug resistant (MDR) clinical superbugs, as well as its exceptional and selective anticancer properties on sensitive and MDR neuroblastoma cells. Here, aiming at finding new molecules possibly developable as new treatments for counteracting CMM, the effects of this TPP-based bola amphiphile (BPPB) have been investigated against two BRAF mutants CMM cell lines (MeOV and MeTRAV) with excellent results (even IC50 = 49 nM on MeOV after 72 h treatment). With these findings and considering the low cytotoxicity of BPPB against different mammalian non-tumoral cell lines and red blood cells (RBCs, selectivity indexes up to 299 on MeOV after 72 h treatment), the possible future development of BPPB as topical treatment for CMM lesions was presumed. With this aim, a biodegradable hyaluronic acid (HA)-based hydrogel formulation (HA-BPPB-HG) was prepared without using any potentially toxic crosslinking agents simply by dispersing suitable amounts of the two ingredients in water and sonicating under gentle heating. HA-BPPB-HA was completely characterized, with promising outcomes such as high swelling capability, high porosity, and viscous elastic rheological behavior.

Knockdown of SLC16A3 decreases extracellular lactate concentration in hepatocellular carcinoma, alleviates hypoxia and induces ferroptosis

SLC16A3/monocarboxylate transporter 4 (MCT4) regulates intracellular lactate transport and is highly expressed in many tumors, indicating poor prognosis. It may be related to inducing hypoxia, apoptosis and other mechanisms, but the study of MCT4 in HCC is far from complete. In this study, we first analyzed the expression of SLC16A3 in HCC tumor and non-tumor tissue samples based on TCGA data and immunohistochemistry. Subsequently, the effects of SLC16A3 expression on cell proliferation and invasion were analyzed using hepatocellular carcinoma (HCC) lines, and Western blot (WB) analysis was performed to explore the changes in pathway proteins and ferroptosis proteins. Finally, the drug sensitivity was tested by CCK8 kit. We found that SLC16A3 was significantly upregulated in tumor tissues, and was significantly correlated with TNM stage, histological grade, and macrovascular invasion. TCGA data and WB analysis showed that the high expression of SLC16A3 induced hypoxia, and knockdown could reverse hypoxia and inhibit ERK phosphorylation, thus limiting the malignant behavior of HCC cells. Moreover, knockdown of SLC16A3 significantly increased the level of lipid peroxidation and reactive oxygen species (ROS), while the expressions of GPX4, DHODH and SLC7A11 were inhibited. The expression of SLC16A3 affected the sensitivity of HCC cells to chemotherapy and targeted drugs, and RNA sequencing data suggested that the expression level influenced tumor microenvironment and response to immunotherapy. So, we draw a conclude that SLC16A3 is associated with poor prognosis of HCC. Inhibition of SLC16A3 expression is a potential therapeutic target for HCC.