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[Display omitted] Fusobacterium nucleatum (F. nucleatum), an oral anaerobe, is prevalent in colorectal cancer and is closely related to increased cancer cell growth, metastasis, and poor treatment outcomes. Bacterial vaccines capable of selectively eliminating bacteria present a promising approach to targeting intratumor F. nucleatum , thereby enhancing cancer treatment. Although adjuvants have been employed to enhance the immune response, the vaccine's effectiveness is constrained by inadequate T-cell activation necessary for eradicating intracellular pathogens. In this study, we developed a minimalistic, biomimetic nanovaccine by integrating highly immunostimulatory adjuvant cholesterol-modified CpG oligonucleotides into the autologously derived F. nucleatum membranes. Compared to the traditional vaccines consisting of inactivated bacteria and Alum adjuvant, the nanovaccine coupled with bacterial membranes and adjuvants could remarkably improve multiple antigens and adjuvant co-delivery to dendritic cells, maximizing their ability to achieve effective antigen presentation and strong downstream immune progress. Notably, the nanovaccine exhibits outstanding selective prophylactic and therapeutic effects, eliminating F. nucleatum without affecting intratumoral and gut microbiota. It significantly enhances chemotherapy efficacy and reduces cancer metastasis in F. nucleatum -infected colorectal cancer. Overall, this work represents the rational application of bacterial nanovaccine and provides a blueprint for future development in enhancing the antitumor effect against bacterial-infected cancer. [ABSTRACT FROM AUTHOR]

Exosomes are mediators of intercellular communication. Cancer cell-secreted exosomes allow exosome donor cells to promote cancer growth, as well as metastasis. Here, exosomes were isolated from the serum of non-small cell lung cancer (NSCLC) patients and characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and western blot analysis. NSCLC cell proliferation and migration were assessed using CCK-8, 5-ethynyl-2′-deoxyuridine (EdU) and Transwell assays. H1299 tumor formation and pulmonary metastasis were examined in a xenograft model in nude mice. We found that exosomes derived from NSCLC (NSCLC-Exos) promoted NSCLC cell migration and proliferation, and that NSCLC-Exo-mediated malignant progression of NSCLC was mediated by miR-199b-5p. Inhibition of miR-199b-5p decreased the effects of NSCLC-Exos on NSCLC malignant progression. HIF1AN was identified as a downstream target of miR-199b-5p. Furthermore, overexpression of HIF1AN reversed the effects of miR-199b-5p on NSCLC malignant progression. In summary, our findings demonstrated that exosomal-specific miR-199b-5p promoted proliferation in distant or neighboring cells via the miR-199b-5p/HIF1AN axis, resulting in enhanced tumor growth. • Exosomal-specific miR-199b-5p promoted tumor growth. • Cancer cell-derived exosomes may affect the tumor microenvironment. • miR-199b-5p/HIF1AN axis can affect the tumor microenvironment. [ABSTRACT FROM AUTHOR]

This work specifically examines the eco-friendly production of iron oxide nanoparticles from the red seaweed Hypnea valentiae (Hv-Fe 3 O 4 -NPs), with an emphasis on their potential applications in cancer treatment. The synthesised Hv-Fe 3 O 4 -NPs were characterised and confirmed through various analytical techniques such as UV–visible spectroscopy, Fourier Transform Infrared Spectroscopy (FTIR), Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), Energy-Dispersive X-ray Spectroscopy (EDS), X-Ray Diffraction analysis (XRD), Dynamic Light Scattering (DLS) and Vibrating Sample Magnetometry (VSM). Hv-Fe 3 O 4 -NPs exhibit notable DPPH and hydrogen peroxide scavenging abilities, suggesting their potential as antioxidants. Moreover, these nanoparticles exhibit effective anticancer efficacy against human MDA-MB-231 (breast cancer) cells (IC50 = 33.89 µg/mL) compared to lung cancer (A549 cells) (IC50 = 66.79 µg/mL). The Hv-Fe 3 O 4 -NPs effectively generates the reactive oxygen species (ROS) level to induce apoptotic activity in breast cancer cells. The RT-PCR gene expression analysis showed that Hv-Fe 3 O 4 -NPs could downregulate the expression of AKT and PI3K and upregulate the expression of PTEN at 34 µg/mL, showing strong anti-cancer activity. Moreover, the molecular docking examination of compounds from H. valentiae , which targeted the AKT/PI3K pathway proteins in breast carcinoma with aberrant mutations, resulted in advantageous binding scores. This research presents a sustainable and environmentally friendly approach with considerable potential for exhibiting antioxidant and anticancer properties, particularly against breast cancer. [Display omitted] • The red seaweed Hypnea valentiae is utilised to biologically synthesise Fe 3 O 4 -NPs. • The study emphasizes characterization and biological applications of Fe 3 O 4 -NPs. • Fe 3 O 4 -NPs demonstrated potent antioxidant activity by inhibiting free radicals. • The Fe 3 O 4 -NPs showed antitumor activity against human lung and breast cancer cells. • AKT/PI3K pathway regulates cell signalling, impacting cancer cell growth and survival. [ABSTRACT FROM AUTHOR]

• We propose and parameterize a mathematical model of healthy blood cell formation and acute myeloid leukemia. • The model accounts for symmetric and asymmetric stem cell divisions and various impacts of nonlinear feedback regulation. • We studied different clinically relevant scenarios including bone marrow transplantation and expansion of malignant cells. • Slight change in the cell fate probabilities is sufficient to observe onset of leukemia within the human lifespan. • Feedback regulation of symmetric and asymmetric division probabilities impacts on healthy cell recovery and cancer growth. Acute myeloid leukemia (AML) is a paradigmatic example of a stem cell-driven cancer. AML belongs to the most aggressive malignancies and has a poor prognosis. A hallmark of AML is the expansion of malignant cells in the bone marrow and the out-competition of healthy blood-forming (hematopoietic) cells. In the present study, we develop a nonlinear ordinary differential equation model to study the impact of feedback configurations and kinetic cell properties such as symmetric self-renewal probability, symmetric differentiation probability, asymmetric division probability, proliferation rate, or death rate on leukemic cell population dynamics. The model accounts for two healthy cell types (mature and immature) and for two leukemic cell types (cells that can divide and cells that have lost the ability to divide). The model considered here is a generalization of previous models and contains them as a special case. We consider multiple feedback configurations that differ in their impact on symmetric self-renewal, symmetric differentiation, and asymmetric division probabilities. Linearized stability analysis is performed to derive necessary and sufficient conditions for the expansion or extinction of leukemic cells. In our analysis, we distinguish three types of steady states, namely purely leukemic steady states (presence of leukemic and absence of healthy cells), healthy steady states (presence of healthy cells and absence of leukemic cells), and composite steady states where healthy and leukemic cells coexist. Steady-state analysis reveals that under biologically plausible assumptions the healthy and the purely leukemic steady states are unique. If composite steady states exist, they are non-unique and form a one-dimensional manifold. The purely leukemic steady state is locally asymptotically stable if and only if the steady state of healthy cells is unstable. The analytical results are illustrated by numerical simulations. Our models suggest that a slight increase of the symmetric self-renewal probability or a slight decrease of the symmetric differentiation probability in leukemic compared to healthy cells results in a destabilization of the homeostatic equilibrium and expansion of malignant cells. This finding is in line with the differentiation arrest observed in leukemic cells. Changes of these parameters in the opposite direction can re-establish the healthy population. Our model furthermore suggests that the configuration of the feedback loops impacts on healthy cell regeneration, the growth rate of malignant cells, the malignant cell burden in late stage leukemias and the decline of healthy cells in leukemic patients. [ABSTRACT FROM AUTHOR]

Liposomes are widely used as drug delivery nanoplatforms because of their versatility and biocompatibility; however, their ability to load certain drugs may be suboptimal. In this study, we generated liposomes using a combination of DSPE and DSPE-PEG-2 k lipids and loaded them with doxorubicin (DOX) and paclitaxel (PTX), to investigate the effects of light emitting diode (LED) irradiation on liposome structure and drug loading efficiency. Scanning and transmission electron microscopy revealed that the surface of liposomes irradiated with blue or near-infrared LEDs (LsLipo) was rougher and more irregular than that of non-LED-irradiated liposomes (NsLipo). Nuclear magnetic resonance analysis showed that the hydrogen peak originating from the lipid head groups was lower in LsLipo than in NsLipo preparations, indicating that LED irradiation changed the chemical and physical properties of the liposome. Structural changes, such as reduced rigidity, induced by LED irradiation, increased the loading efficiency of DOX and PTX. In vitro and in vivo experiments showed that LsLipo were more effective at inhibiting the growth of cancer cells than NsLipo. Our findings suggest that LED irradiation enhances the drug delivery efficacy of liposomes and offer new possibilities for improving drug delivery systems. [Display omitted] [ABSTRACT FROM AUTHOR]

Androgen receptor (AR) is one of the key targets for the treatment of castration-resistant prostate cancer (CRPC). Current endocrine therapy can greatly improve patients with CRPC. However, with the change of pathogenic mechanism, acquired resistance often leads to the failure of treatment. Studies have shown that tanshinone IIA (TS-IIA) and its derivatives have significant antitumor activity, and have certain AR-targeting effects, but the mechanism is unknown. In this study, the TS-IIA analog TB3 was found to significantly inhibit the growth of CRPC in vitro and in vivo. Molecular docking, cellular thermal shift assay, and cycloheximide experiments confirmed that AR was the target of TB3 and promoted the degradation of AR. Furthermore, TB3 can significantly inhibit glycolysis metabolism by targeting the AR/PKM2 axis. The addition of pyruvic acid could significantly alleviate the inhibitory effect of TB3 on CRPC cells. Besides, the knockdown of AR or PKM2 also could reverse the effect of TB3 on CRPC cells. Taken together, our study suggests that TS-IIA derivative TB3 inhibits glycolysis to prevent the CRPC process by targeting the AR/PKM2 axis. [ABSTRACT FROM AUTHOR]

FOXO1 is a transcription factor and potential tumor suppressor that is negatively regulated downstream of PI3K-PKB/ AKT signaling. Paradoxically, FOXO also promotes tumor growth, but the detailed mechanisms behind this role of FOXO are not fully understood. In this study, we revealed a molecular cascade by which the Thr24 residue of FOXO1 is phosphorylated by AKT and is dephosphorylated by calcineurin, which is a Ca2+-dependent protein phosphatase. Curiously, single nucleotide somatic mutations of FOXO1 in cancer occur frequently at and near Thr24. Using a calcineurin inhibitor and shRNA directed against calcineurin, we revealed that calcineurin-mediated dephosphorylation of Thr24 regulates FOXO1 protein stability. We also found that FOXO1 binds to the promoter region of MDM2 and activates transcription, which in turn promotes MDM2-mediated ubiquitination and degradation of p53. FOXO3a and FOXO4 are shown to control p53 activity; however, the significance of FOXO1 in p53 regulation remains largely unknown. Supporting this notion, FOXO1 depletion increased p53 and p21 protein levels in association with the inhibition of cell proliferation. Taken together, these results indicate that FOXO1 is stabilized by calcineurin-mediated dephosphorylation and that FOXO1 supports cancer cell proliferation by promoting MDM2 transcription and subsequent p53 degradation. [ABSTRACT FROM AUTHOR]

A major challenge facing photodynamic therapy (PDT) is that the activity of the immune-induced infiltrating CD8+ T cells is subject to the regulatory T lymphocytes (Tregs), leaving the tumor at risk of recurrence and metastasis after the initial ablation. To augment the antitumor response and reprogram the immunosuppressive tumor microenvironment (TME), a supramolecular photodynamic nanoparticle (DACss) is constructed by the host-guest interaction between demethylcantharidin-conjugated β -cyclodextrin (DMC-CD) and amantadine-terminated disulfide-conjugated FFVLGGGC peptide with chlorin e6 decoration (Ad-ss-pep-Ce6) to achieve intelligent delivery of photosensitizer and immunomodulator for breast cancer treatment. The acid-labile β -carboxamide bond of DMC-CD is hydrolyzed in response to the acidic TME, resulting in the localized release of DMC and subsequent inhibition of Tregs. The guest molecule Ad-ss-pep-Ce6 can be cleaved by a high level of intracellular GSH, reducing photosensitizer toxicity and increasing photosensitizer retention in the tumor. With a significant increase in the CTL/Treg ratio, the combination of Ce6-based PDT and DMC-mediated immunomodulation adequately achieved spatiotemporal regulation and remodeling of the TME, as well as improved primary tumor and in situ lung metastasis suppression with the aid of PD-1 antibody. Dual-responsive cyclodextrin-based supramolecular self-assembly system co-delivers photosensitizer and immunomodulator to induce tumor cell apoptosis and reverse the immunosuppressive microenvironment with PD-1 antibody for effective treatment of metastatic breast cancer. [Display omitted] [ABSTRACT FROM AUTHOR]

.Çó A highly-comprehensive and accurate proteomic workflow was employed to investigate the combination of gemcitabine and trabectedin in pancreatic cancer cells, which interact synergistically, and it revealed an exceptionally broad and detailed picture of cancer cell drug responses..Çó A systems pharmacodynamic (SPD) model was developed to characterize single- and combined drug responses in seven highly-impacted pathways covering the major targets of the drugs, alone and combined..Çó Part I of this two-part work describes the proteomic workflow and drug effects on the upstream portion of the SPD model developed, particularly pathways related to cell growth and migration, including the RTK-, integrin-, GPCR-, and calcium-signaling pathways..Çó Part II of these studies describes drug effects on pathways associated with the downstream portion of the SPD model, including the cell cycle, DNA damage response (DDR), and apoptosis. Pancreatic ductal adenocarcinoma (PDAC) is often chemotherapy-resistant, and novel drug combinations would fill an unmet clinical need. Previously we reported synergistic cytotoxic effects of gemcitabine and trabectedin on pancreatic cancer cells, but underlying protein-level interaction mechanisms remained unclear. We employed a reliable, sensitive, comprehensive, quantitative, high-throughput IonStar proteomic workflow to investigate the time course of gemcitabine and trabectedin effects, alone and combined, upon pancreatic cancer cells. MiaPaCa-2 cells were incubated with vehicle (controls), gemcitabine, trabectedin, and their combinations over 72 hours. Samples were collected at intervals and analyzed using the label-free IonStar liquid chromatography-mass spectrometry (LC-MS/MS) workflow to provide temporal quantification of protein expression for 4,829 proteins in four experimental groups. To characterize diverse signal transduction pathways, a comprehensive systems pharmacodynamic (SPD) model was developed. The analysis is presented in two parts. Here, Part I describes drug responses in cancer cell growth and migration pathways included in the full model: receptor tyrosine kinase- (RTK), integrin-, G-protein coupled receptor- (GPCR), and calcium-signaling pathways. The developed model revealed multiple underlying mechanisms of drug actions, provides insight into the basis of drug interaction synergism, and offers a scientific rationale for potential drug combination strategies. [Display omitted] [ABSTRACT FROM AUTHOR]

An increased risk of breast cancer is associated with high serum concentrations of oestradiol and testosterone in postmenopausal women, but little is known about how these hormones affect response to endocrine therapy for breast cancer prevention or treatment. We aimed to assess the effects of serum oestradiol and testosterone concentrations on the efficacy of the aromatase inhibitor anastrozole for the prevention of breast cancer in postmenopausal women at high risk. In this case-control study we used data from the IBIS-II prevention trial, a randomised, controlled, double-blind trial in postmenopausal women aged 40–70 years at high risk of breast cancer, conducted in 153 breast cancer treatment centres across 18 countries. In the trial, women were randomly assigned (1:1) to receive anastrozole (1 mg/day, orally) or placebo daily for 5 years. In this pre-planned case-control study, the primary analysis was the effect of the baseline oestradiol to sex hormone binding globulin (SHBG) ratio (oestradiol–SHBG ratio) on the development of all breast cancers, including ductal carcinoma in situ (the primary endpoint in the trial). Cases were participants in whom breast cancer was reported after trial entry and until the cutoff on Oct 22, 2019, and who had valid blood samples and no use of hormone replacement therapy within 3 months of trial entry or during the trial. For each case, two controls without breast cancer were selected at random, matched on treatment group, age (within 2 years), and follow-up time (at least that of the matching case). For each treatment group, we applied a multinominal logistic regression likelihood-ratio trend test to assess what change in the proportion of cases was associated with a one-quartile change in hormone ratio. Controls were used only to determine quartile cutoffs. Profile likelihood 95% CIs were used to indicate the precision of estimates. A secondary analysis also investigated the effect of the baseline testosterone–SHBG ratio on breast cancer development. We also assessed relative benefit of anastrozole versus placebo (calculated as 1 – the ratio of breast cancer cases in the anastrozole group to cases in the placebo group). The trial was registered with ISRCTN (number ISRCTN31488319) and completed recruitment on Jan 31, 2012, but long-term follow-up is ongoing. 3864 women were recruited into the trial between Feb 2, 2003, and Jan 31, 2012, and randomly assigned to receive anastrozole (n=1920) or placebo (n=1944). Median follow-up time was 131 months (IQR 106–156), during which 85 (4·4%) cases of breast cancer in the anastrozole group and 165 (8·5%) in the placebo group were identified. No data on gender, race, or ethnicity were collected. After exclusions, the case-control study included 212 participants from the anastrozole group (72 cases, 140 controls) and 416 from the placebo group (142 cases, 274 controls). A trend of increasing breast cancer risk with increasing oestradiol–SHBG ratio was found in the placebo group (trend per quartile 1·25 [95% CI 1·08 to 1·45], p=0·0033), but not in the anastrozole group (1·06 [0·86 to 1·30], p=0·60). A weaker effect was seen for the testosterone–SHBG ratio in the placebo group (trend 1·21 [1·05 to 1·41], p=0·011), but again not in the anastrozole group (trend 1·18 [0·96 to 1·46], p=0·11). A relative benefit of anastrozole was seen in quartile 2 (0·55 [95% CI 0·13 to 0·78]), quartile 3 (0·54 [0·22 to 0·74], and quartile 4 (0·56 [0·23 to 0·76]) of oestradiol–SHBG ratio, but not in quartile 1 (0·18 [–0·60 to 0·59]). These results suggest that serum hormones should be measured more routinely and integrated into risk management decisions. Measuring serum hormone concentrations is inexpensive and might help clinicians differentiate which women will benefit most from an aromatase inhibitor. Cancer Research UK, National Health and Medical Research Council (Australia), Breast Cancer Research Foundation, and DaCosta Fund. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is an aggressive cancer influenced by a complex interplay of genetic and environmental factors. Amongst these risk factors, the impact of Interleukin6 (IL6) gene polymorphisms in PCa risk has received a lot of attention. IL-6 is a cytokine that has been implicated in the pathogenesis of several malignancies, including PCa. Two IL-6 gene polymorphisms, − 174 G/C (rs1800795) and − 572 C/G (rs1800796), have received intellectual attention due to their potential role as modulators of prostate cancer risk. The main objective of this research was to comprehensively explore the potential associations between IL-6 rs1800795 and rs1800796 polymorphisms, and their impact on the occurrence of PCa. A case-control study was carried out with a well-defined cohort comprising 110 PCa cases and 110 controls (total n = 220). The genotyping of rs1800795 and rs1800796 was carefully performed using the highly sensitive and accurate Polymerase Chain Reaction-High Resolution Melting Curve (PCR-HRM) technique. The assessment of genetic associations was evaluated using various R packages, such as Haplo-Stats, SNP stat, pheatmap, and LD heatmap. The present study applied odds ratio (OR) analysis to reveal significant evidence of strong associations between the genotypes of rs1800795 and rs1800796 and the susceptibility to PCa. The findings of this study underscore the noteworthy impact of genetic variations in the IL-6 gene on the development of prostate cancer. Specifically, the C/G and G/G genotypes of rs1800795 demonstrated increased PCa risk, with odds ratios (OR) of 1.650 (95% CI = 1.068–2.549, p = 0.032) and 2.475 (95% CI = 1.215–5.043, p < 0.001), respectively. Similarly, the G/C genotype of rs1800796 exhibited an OR of 2.374 (95% CI = 1.363–4.130, p = 0.012) for elevated prostate cancer risk, while the C/C genotype had an OR of 1.81 (95% CI = 1.02–3.22, p = 0.7). Furthermore, our haplotype analysis have revealed an association between haplotype 4 (C-G) and increased risk of PCa (OR = 1.69, 95% CI = 1.05–2.73, p = 0.032). In conclusion, this case-control analysis presents compelling evidence for a significant association between IL-6 variants (rs1800795 and rs1800796) and increased susceptibility to prostate cancer. • Prostate cancer is a major global health concern, with approximately 1.4 million new cases diagnosed in 2020, making it the most prevalent non-skin malignancy and the leading cause of cancer-related mortality in men worldwide. • Prostate cancer's pathogenesis involves intricate interactions of genetic and epigenetic modifications, as well as inflammatory factors, which remain largely unexplored despite advances in cancer research. • Interleukin 6 (IL-6) emerges as a pivotal player in prostate cancer, with elevated levels observed during carcinogenesis and progression, and its interactions with androgen receptors promoting cancer cell growth. • Polymorphisms at positions − 174 and − 572 in the IL-6 gene have been identified as potential regulators of IL-6 expression and function, making them promising candidates for understanding prostate cancer susceptibility. [ABSTRACT FROM AUTHOR]

Colon cancer continues to be a prevalent gastrointestinal malignancy with a bleak prognosis. The induction of ferroptosis, a new form of regulated cell death, has emerged as a potentially effective strategy for the treatment of colon cancer. However, numerous colon cancer cells display resistance to ferroptosis induced by erastin, a well-established ferroptosis inducer. Finding drugs that can enhance the susceptibility of colon cancer cells to erastin is of utmost importance. This study aimed to examine the synergistic therapeutic impact of combining erastin with a bioactive flavonoid compound luteolin on the ferroptosis-mediated suppression of colon cancer. Human colon cancer HCT116 and SW480 cells were used for the in vitro studies and a xenograft of colon cancer model in BALB/c nude mice was established for the in vivo experiments. The results showed that combinative treatment of luteolin and erastin effectively inhibited the viability and proliferation of colon cancer cells. Luteolin and erastin cotreatment synergistically induced ferroptosis, concomitant with a reduction in glutathione and an elevation in lipid peroxides. In vivo , combinative treatment of luteolin and erastin exhibited a pronounced therapeutic effect on xenografts of colon cancer, characterized by a significant induction of ferroptosis. Mechanistically, luteolin in combination with erastin synergistically reduced the expression of glutathione peroxidase 4 (GPX4), an antioxidase overexpressed in colon cancer cells. Furthermore, luteolin and erastin cotreatment significantly upregulated the expression of hypermethylated in cancer 1 gene (HIC1), a transcriptional repressor also recognized as a tumor suppressor. HIC1 overexpression notably augmented the suppression of GPX4 expression and facilitated ferroptotic cell death. In contrast, HIC1 silencing attenuated the inhibition of GPX4 expression and eliminated the ferroptosis. Conclusively, these results clearly demonstrated that luteolin acts synergistically with erastin and renders colon cancer cells vulnerable to ferroptosis through the HIC1-mediated inhibition of GPX4 expression, which may act as a promising therapeutic strategy. [Display omitted] • Luteolin and erastin synergistically inhibited the growth of colon cancer cells. • Luteolin and erastin synergistically inhibited xenografts of colon cancer. • Luteolin and erastin synergistically induced ferroptosis in colon cancer cells. • Luteolin and erastin synergistically upregulated HIC1 to inhibit GPX4 expression. [ABSTRACT FROM AUTHOR]

Since sirtuins (SIRTs) are closely associated with reactive oxygen species (ROS) and antioxidant system, the development of their selective inhibitors is drawing attention for understanding of cellular redox homeostasis. Here, we describe the pharmacological properties of SPC-180002, which incorporates a methyl methacrylate group as a key pharmacophore, along with its comprehensive molecular mechanism as a novel dual inhibitor of SIRT1/3. The dual inhibition of SIRT1/3 by SPC-180002 disturbs redox homeostasis via ROS generation, which leads to an increase in both p21 protein stability and mitochondrial dysfunction. Increased p21 interacts with and inhibits CDK, thereby interfering with cell cycle progression. SPC-180002 leads to mitochondrial dysfunction by inhibiting mitophagy, which is accompanied by a reduction in oxygen consumption rate. Consequently, SPC-180002 strongly suppresses the proliferation of cancer cells and exerts anticancer effect in vivo. Taken together, the novel SIRT1/3 dual inhibitor, SPC-180002, impairs mitochondrial function and redox homeostasis, thereby strongly inhibiting cell cycle progression and cancer cell growth. [Display omitted] • SPC-180002 is a novel dual inhibitor for SIRT1/3. • SPC-180002 disrupts redox homeostasis via ROS accumulation. • SPC-180002 causes mitochondrial dysfunction, resulting in a decrease in OCR. • SPC-180002 exerts an in vivo anticancer effect by impeding cell cycle progression. [ABSTRACT FROM AUTHOR]

A therapeutic system with the ability to target more than one protein is an important aim of cancer therapy since tumor growth is accompanied by dysregulation of many biological pathways. G-quadruplexes (G4s) are non-canonical structures formed by guanine-rich DNA or RNA oligonucleotides, with the ability to bind to different targets. In this study, we constructed ten novel bispecific G-quadruplex conjugates based on AT11, TBA, T40214 and T40231 aptamer structures, with the ability to bind two different targets at once in cancer cells. We analyzed the physicochemical aspects and the anticancer properties of novel molecules relating them with the single G-quadruplex unit and attempted to comprehend the correlation between the structures of bispecific G-quadruplexes with their biological activity. Our studies uncovered conjugates with considerable antiproliferative potential in HeLa and MCF-7 cancer cell lines, however with relatively low thermal stability or low nuclease resistance. Three conjugates among all studied oligonucleotides possess improved antiproliferative activity in MCF-7 cell line in comparison to their single G-quadruplex units leading to up to 90% inhibition of cancer cells growth, but their inhibitory potential is rather comparable to the effect observed for mix of two separate G-quadruplex units. Importantly, the conjugation enhances oligonucleotides enzymatic stability leading to the improvement of their therapeutic profile. The comprehensive studies presented herein indicate new approach for possibly effective cancer therapy and for the design of G4-based drugs. • Novel bispecific G-quadruplex conjugates containing two domains are developed. • G-quadruplexes have the ability to bind to two different targets. • Bispecific G-quadruplexes were characterized physicochemically and biologically. • Novel molecules have considerable anticancer activity in HeLa and MCF-7 cell lines. • The conjugation enhances oligonucleotides enzymatic stability. [ABSTRACT FROM AUTHOR]

In order to adapt to a higher proliferative rate and an increased demand for energy sources, cancer cells rewire their metabolic pathways, a process currently recognized as a hallmark of cancer. Even though the metabolism of glucose is perhaps the most discussed metabolic shift in cancer, lipid metabolic alterations have been recently recognized as relevant players in the growth and proliferation of cancer cells. Importantly, some of these metabolic alterations are reported to induce a drug resistant phenotype in cancer cells. The acquisition of drug resistance traits severely hinders cancer treatment, being currently considered one of the major challenges of the oncological field. Evidence suggests that Extracellular Vesicles (EVs), which play a crucial role in intercellular communication, may act as facilitators of tumour progression, survival and drug resistance by modulating several aspects involved in the metabolism of cancer cells. This review aims to gather and discuss relevant data regarding metabolic reprograming in cancer, particularly involving the glycolytic and lipid alterations, focusing on its influence on drug resistance and highlighting the relevance of EVs as intercellular mediators of this process. [Display omitted] • Due to a high demand for energy sources and biosynthetic macromolecules, cancer cells rewire their metabolic pathways. • Metabolic alterations may induce a drug resistant phenotype in cancer cells, severely hindering cancer treatment. • Extracellular vesicles may transfer metabolic traits to recipient cells, contributing to the intercellular transfer of drug resistance. [ABSTRACT FROM AUTHOR]

Tumor recurrence and chronic bacterial infection constitute two major criteria in postsurgical intervention for malignant melanoma. One plausible strategy is the equipment of consolidation therapy after surgery, which relies on adjuvants to eliminate the residual tumor cells and inhibit bacterial growth. Until now, a number of proof-of-concept hybrid nanoadjuvants have been proposed to combat tumor recurrence and postsurgical bacterial infection, which may suffer from the potential bio-unsafety or involve complex design and synthesis. The batch-to-batch inconsistencies in drug composition further delay the clinical trials. To circumvent these issues, herein we develop a programmable strategy to generate lipopeptide nanotherapeutics with identical constitution for tandem intervention of postsurgical bacterial infection and cancer recurrence of melanoma. Increasing the number of hydrophobic linoleic acid within lipopeptides has been found to be a simple and practical strategy to improve the therapeutic outcomes for both tumor cells and bacteria. Self-assembled lipopeptide nanotherapeutics with two linoleic acid molecules possesses excellent antitumor activity and antimicrobial function toward both susceptible strains and drug-resistant bacteria. Arising from the incorporation of unsaturated linoleic acid, the unavoidable hemolysis of cationic peptide drugs was effectively alleviated. In vivo therapeutic abilities of postsurgical infection and tumor recurrence were investigated in BALB/c nude mice bearing a B16-F10 tumor model, with an incomplete surgical resection and in situ infection by methicillin-resistant Staphylococcus aureus (MRSA). Self-assembled lipopeptide nanotherapeutics could effectively inhibit cancer cell growth and bacterial infection, as well as promote wound healing. The easily scalable large-scale production, broad-spectrum antitumor and antibacterial bioactivities as well as fixed component endows lipopeptide nanotherapeutics as promising adjuvants for clinically postsurgical therapy of melanoma. Lipopeptide nanotherapeutics with easy preparation, fixed component and low hemolysis are proposed for post-surgical melanoma treatment, which could inhibit chronic bacterial infection and tumor recurrence. [Display omitted] • Multifunctional lipopeptide nanotherapeutics with fixed component and low hemolysis is easy fabricated. • P3 nanotherapeutics exhibits excellent antitumor and antibacterial activities in vitro. • P3 inhibits melanoma growth and promotes wound healing in mice with incomplete tumor resection and MRSA infection. [ABSTRACT FROM AUTHOR]

This study investigated the differences in efficacy between IHC(2+)/FISH-positive and IHC(3+) in HER2-positive breast cancer (BC) during neoadjuvant chemotherapy (NAC) combined with trastuzumab and pertuzumab. The research also aimed to provide insight into treatment strategies for clinical HER2(2+)/FISH-positive and HER2(3+) BC. A retrospective analysis was performed on the clinical and pathological data of patients with confirmed diagnoses of invasive BC treated via combined NAC and dual-target therapy who underwent surgery at the Breast Surgery Center of Sichuan Cancer Hospital between June 2019 and June 2022. The correlation between the clinicopathological characteristics and pathological complete response (pCR) was analyzed via the χ2 test, while logistic regression was performed using the SAS 9.4 statistical analysis software. This study examined 224 patients with an overall pCR rate of approximately 59.82%, which included 36 IHC(2+)/FISH-positive and 188 IHC(3+) cases with approximate pCR rates of 41.67% and 63.30%, respectively. Univariate and multifactorial analysis of the clinical and pathological data determined that age, menstrual status, family history, Ki67 expression, number of treatment cycles, and treatment regimen did not influence pCR. No statistical differences were evident between the univariate and multivariate models. However, the clinical stage, hormone receptor, and HER2 expression status significantly impacted pCR, with considerable consistent differences between the univariate and multifactor analyses. HER2 IHC(3+) BC displays a higher pCR rate than HER2 IHC(2+)/FISH-positive BC (p ≤ 0.05), with a positive correlation between the HER2 protein expression levels and the response to anti-HER2 therapy. • Different HER2 expression levels display different therapeutic responses. • The Ki67 expression level, menstrual status, age, and neoadjuvant therapy (EC-THP vs. TCbHP) are not independent pCR rate factors. • The clinical stage, HR, and HER2 expression status are significantly independent influencing factors for pCR. [ABSTRACT FROM AUTHOR]

ADP-ribosylation factor 6 (Arf6), a small G-protein of the Ras superfamily, plays pivotal roles in multiple cellular events, including exocytosis, endocytosis, actin remodeling, plasma membrane reorganization and vesicular transport. Arf6 regulates the progression of cancer through the activation of cell motility and invasion. Aberrant Arf6 activation is a potential therapeutic target. This review aims to understand the comprehensive function of Arf6 for future cancer therapy. The Arf6 GEFs, protein structure, and roles in cancer have been summarized. Comprehending the mechanism underlying Arf6-mediated cancer cell growth and survival is essential. The structural features of Arf6 and its efforts are discussed and may be contributed to the discovery of future novel protein-protein interaction inhibitors. In addition, Arf6 inhibitors and mechanism of action are listed in the table. This review further emphasizes the crucial roles in drug resistance and attempts to offer an outlook of Arf6 in cancer therapy. Arf6 is a potential target for cancer treatment. Its GEFs, protein structure, inhibitors, mechanisms and roles offer an outlook of Arf6 in cancer therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Programmed cell death plays a crucial role in maintaining the homeostasis and integrity of multicellular organisms, and its dysregulation contributes to the pathogenesis of many diseases. Programmed cell death is regulated by a range of macromolecules and low-molecular messengers, including ceramides. Endogenous ceramides have different functions, that are influenced by their localization and the presence of their target molecules. This article provides an overview of the current understanding of ceramides and their impact on various types of programmed cell death, including apoptosis, anoikis, macroautophagy and mitophagy, and necroptosis. Moreover, it highlights the emergence of dihydroceramides as a new class of bioactive sphingolipids and their downstream targets as well as their future roles in cancer cell growth, drug resistance and tumor metastasis. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the role of Translationally Controlled Tumor Protein (TCTP) in breast cancer (BC) and investigate the effects of sertraline, a serotonin selective reuptake inhibitor (SSRI), on BC cells. The objective was to assess the potential of sertraline as a therapeutic agent in BC treatment by examining its ability to inhibit TCTP expression and exert antitumor effects. We utilized five different BC cell lines representing the molecular heterogeneity and distinct subtypes of BC, including luminal, normal-like, HER2-positive, and triple-negative BC. These subtypes play a crucial role in determining clinical treatment strategies and prognosis. The highest levels of TCTP were observed in triple-negative BC cell lines, known for their aggressive behavior. Sertraline treatment reduced TCTP expression in BC cell lines, significantly impacting cell viability, clonogenicity, and migration. Additionally, sertraline sensitized triple-negative BC cell lines to cytotoxic chemotherapeutic drugs (doxorubicin and cisplatin) suggesting its potential as an adjunctive therapy to enhance the chemotherapeutic response. Bioinformatic analysis of TCTP mRNA levels in TCGA BC data revealed a negative correlation between TCTP levels and patient survival, as well as between TCTP/ tpt1 and Ki67. These findings contradict our data and previous studies indicating a correlation between TCTP protein levels and aggressiveness and poor prognosis in BC. Sertraline shows a promise as a potential therapeutic option for BC, particularly in triple-negative BC. Its ability to inhibit TCTP expression, enhance chemotherapeutic response, highlights its potential clinical utility in BC treatment, specifically in triple-negative BC subtype. [ABSTRACT FROM AUTHOR]

Long non-coding RNAs (lncRNAs) play an important role in cancer metastasis. Exploring metastasis-associated lncRNAs and developing effective strategy for targeted regulation of lncRNA function in vivo are of utmost importance for the treatment of metastatic cancer, which however remains a big challenge. Herein, we identified a new functional lncRNA (denoted lncBCMA), which could stabilize the expression of eukaryotic translation elongation factor 1A1 (eEF1A1) via antagonizing its ubiquitination to promote triple-negative breast cancer (TNBC) growth and metastasis. Based on this regulatory mechanism, an endosomal pH-responsive nanoparticle (NP) platform was engineered for systemic lncBCMA siRNA (siBCMA) delivery. This NPs-mediated siBCMA delivery could effectively silence lncBCMA expression and promote eEF1A1 ubiquitination, thereby leading to a significant inhibition of TNBC tumor growth and metastasis. These findings show that lncBCMA could be used as a potential biomarker to predict the prognosis of TNBC patients and NPs-mediated lncBCMA silencing could be an effective strategy for metastatic TNBC treatment. A new functional lncRNA (i.e. , lncBCMA) was identified as a key factor in promoting triple-negative breast cancer (TNBC) metastasis and NPs-mediated lncBCMA silencing could be an effective strategy for metastatic TNBC treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

Biomathematics has become one of the most significant areas of research as a result of interdisciplinary study. Chronic diseases sometimes referred to as non-communicable and communicable diseases, are conditions that develop over an extended period as a result of different factors like genetics, lifestyle, and environment. The most important common types of disease are cardiovascular, alcohol, cancer, and diabetes. More than three-quarters of the world's (31.4 million) deaths occur in low- and middle-income nations, which are disproportionately affected by different infections. Fractional Calculus is a prominent topic for research within the discipline of Applied Mathematics due to its usefulness in solving problems in many different branches of science, engineering, and medicine. Recent researchers have identified the importance of mathematical tools in various disease models as being very useful to study the dynamics with the help of fractional and integer calculus modeling. Due to the complexity of the underlying connections, both deterministic and stochastic epidemiological models are founded on an inadequate understanding of the infectious network. Over the past several years, the use of different fractional operators to model the problem has grown, and it is now a common way to study how epidemics spread. Recently, researchers have actively considered fractional calculus to study different diseases like COVID-19, cancer, TB, HIV, dengue fever, diabetes, cholera, pine welts, smoking and heart attacks, etc. With the help of fractional operator, we modified a mathematical model for the dynamical transmission, analysis, treatment, vaccination, and precaution leveling necessary to mitigate the negative impact of illness on society in the long run, overcoming the memory effect without defining or considering others parameters. In this review paper, we considered all the recent studies based on the fractional modeling of infectious and non-infectious diseases with different fractional operators such as Caputo, Caputo Fabrizio, ABC, and constant proportional with Caputo, etc. This review paper aims to bring all the information together by considering different fractional operators and their uses in the field of infectious disease modeling. The steps taken to accomplish the goal were developing a mathematical model, identifying the equilibrium point, figuring out the minimal reproductive number, and assessing the stability around the equilibrium point. For future direction, we consider the cancer model to study the growth cells of cancer and the impact of therapy to control infections. An equilibrium solution and an analysis of the behavior dynamics of the cell spread with treatment in the form of chemotherapy were obtained. The simulation shows that the population of cancer cells is influenced by the pace of cancer cell growth with the Caputo fractional derivative. The acquired results show how effective and precise the suggested approach is in helping to better understand how chemotherapy works. Chemotherapy medications have been found to increase immunity against particular cancer by reducing the number of tumor cells. Further, we suggested some future work directions with the help of the new hybrid fractional operator. Our innovative methodology might have significant effects on global stakeholders, policymakers, and national health systems. The current strategies for controlling outbreaks and the vaccination and prevention policies that have been implemented would benefit from a more accurate representation of the dynamics of contagious diseases, which necessitates the development of highly complex mathematical models. Microorganisms, interactions between individuals or groups, and environmental, social, economic, and demographic factors on a broader scale are all examples. [ABSTRACT FROM AUTHOR]

This review study investigates conventional anticancer treatments derived from the world's different parts as a wonderful substitute for pharmaceuticals since they have fewer or no side effects and can fix the disease at its source. This study provides thorough information regarding physiologically active substances derived from various parts of the plant for cancer treatment such as Alkaloids (ervine, methylervine, ervolanine, and aervolanine), Terpenoids, Vitamins, Coumarins, Tannins, Carbohydrates, Flavonoids (kaempferol, quercetin, isorhamnetin, persinol, persinosides A and B), Fatty Acids, and Essential Oils). This technique is beneficial in clinical studies for breast, prostate, and colon cancer. The ongoing rise in cancer incidence, the inability of traditional chemotherapies to manage cancer, and the excessive toxicity of chemotherapies all call for a new strategy. The first trial to establish the effectiveness of chemoprevention was conducted in breast cancer patients using tamoxifen, which indicated a substantial reduction in invasive breast cancer. The effectiveness of utilizing chemopreventive drugs to protect high-risk people from cancer suggests that the technique is sound and promising. Dietary components such as capsaicin, cucurbitacin B, isoflavones, catechins, lycopene, benzyl isothiocyanate, phenethyl isothiocyanate, and piperlongumine have been shown to suppress cancer cell growth, indicating that they might be used as chemopreventive agents. [Display omitted] • Different plant families are discussed which contain antitumour activities. • Different type of cancer is discussed in brief. • Different plant parts stem, leaves, bark etc. discussed. • Phytochemical are discussed for particular cancer treatments. Author arcid ID [ABSTRACT FROM AUTHOR]

The CXCR4 chemokine is a key molecular regulator of many biological functions controlling leukocyte functions during inflammation and immunity, and during embryonic development. Overexpression of CXCR4 is also associated with many types of cancer where its activation promotes angiogenesis, tumor growth/survival, and metastasis. In addition, CXCR4 is involved in HIV replication, working as a co-receptor for viral entry, making CXCR4 a very attractive target for developing novel therapeutic agents. Here we report the pharmacokinetic profile in rats of a potent CXCR4 antagonist cyclotide, MCo-CVX-5c, previously developed in our group that displayed a remarkable in vivo resistance to biological degradation in serum. This bioactive cyclotide, however, was rapidly eliminated through renal clearance. Several lipidated versions of cyclotide MCo-CVX-5c showed a significant increase in the half-life when compared to the unlipidated form. The palmitoylated version of cyclotide MCo-CVX-5c displayed similar CXCR4 antagonistic activity as the unlipidated cyclotide, while the cyclotide modified with octadecanedioic (18-oxo-octadecanoic) acid exhibited a remarkable decrease in its ability to antagonize CXCR4. Similar results were also obtained when tested for its ability to inhibit growth in two cancer cell lines and HIV infection in cells. These results show that the half-life of cyclotides can be improved by lipidation although it can also affect their biological activity depending on the lipid employed. [Display omitted] • CXCR4 cyclotide antagonist MCo-CVX-5c displays a remarkable in vivo resistance to biological degradation, however, is rapidly eliminated through renal clearance. • Lipidated versions of cyclotide MCo-CVX-5c show a significant increase in the half-life when compared to the unlipidated form. • The palmitoylated version of cyclotide MCo-CVX-5c displays similar CXCR4 antagonistic activity as the unlipidated cyclotide, while the cyclotide modified with octadecanedioic (18-oxo-octadecanoic) acid exhibits a remarkable decrease in its ability to antagonize CXCR4. • Our results indicate that half-life of bioactive cyclotides can be improved by lipidation although it can also affect their biological activity depending on the lipid employed. [ABSTRACT FROM AUTHOR]

[Display omitted] The azido-Ugi reaction of methyl maleopimarate N -(2- aminoethyl) imide with isocyanides, paraformaldehyde and trimethylsilyl azide in one step leads to 1,5-disubstituted diterpene bis-tetrazoles. The compounds demonstrate selective cytotoxicity against NCI-60 cancer cell panel. [ABSTRACT FROM AUTHOR]

Cold atmospheric plasma-treated liquids (PTLs) exhibit selective toxicity toward tumor cells and are provoked by a cocktail of reactive oxygen and nitrogen species in such liquids. Compared to the gaseous phase, these reactive species are more persistent in the aqueous phase. This indirect plasma treatment method has gradually gathered interest in the discipline of plasma medicine to treat cancer. PTL's motivated effect on immunosuppressive proteins and immunogenic cell death (ICD) in solid cancer cells is still not explored. In this study, we aimed to induce immunomodulation by plasma-treated Ringer's lactate (PT-RL) and phosphate-buffered saline (PT-PBS) solutions for cancer treatment. PTLs induced minimum cytotoxicity in normal lung cells and inhibited cancer cell growth. ICD is confirmed by the enhanced expression of damage-associated molecular patterns (DAMPs). We evidenced that PTLs induce intracellular nitrogen oxide species accumulation and elevate immunogenicity in cancer cells owing to the production of pro-inflammatory cytokines, DAMPs, and reduced immunosuppressive protein CD47 expression. In addition, PTLs influenced A549 cells to elevate the organelles (mitochondria and lysosomes) in macrophages. Taken together, we have developed a therapeutic approach to potentially facilitate the selection of a suitable candidate for direct clinical applications. [Display omitted] • Plasma-treated liquid (PTL) treatment results in immunogenic cell death in cancer. • Plasma-treated liquids stimulate the immune system and enhance anti-cancer efficacy. • Release of damage-associated molecular patterns is evident in treated cancer cells. • Macrophage organelles elevate after co-culturing with treated cancer cells. • PTLs stimulate pro-inflammatory cytokines and alleviate immunosuppressive CD47. [ABSTRACT FROM AUTHOR]

Traditionally, γ-aminobutyric acid (GABA) is best known for its role as a primary inhibitory neurotransmitter reducing neuronal excitability in the mammalian central nervous system (CNS), thereby producing calming effects. However, an emerging body of data now supports a function for GABA beyond neurotransmission as a potent factor regulating cancer cell growth and metastasis, as well as the antitumor immune response, by shaping the tumor microenvironment (TME). Here, we review the current knowledge on GABA's effects on the function of tumor cells, tumor–immune interactions, and the underlying molecular mechanisms. Since altered GABAergic signaling is now recognized as a feature of certain types of solid tumors, we also discuss the potential of repurposing existing GABAergic agents as a new class of anticancer therapy. Aberrant γ-aminobutyric acid (GABA) signaling plays critical roles in solid tumor growth and progression. GABA accumulates in certain types of solid tumors, where it can drive cancer cell proliferation and metastasis. Brain tumors can catabolize GABA for energy production. GABAergic signaling in the tumor microenvironment contributes to immune evasion. Targeting GABAergic components using existing medications may provide new avenues for therapeutic intervention against cancer. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma remains an aggressive and deadly malignancy that is often diagnosed late. Intrinsic tumour characteristics and the growth pattern of cancer cells contribute to the challenges of diagnosis and chemoresistance. However, establishing an early and accurate diagnosis, and in some instances identifying targetable changes, has the potential to impact survival. Primary sclerosing cholangitis, a chronic cholangiopathy prodromal to the development of a minority of cholangiocarcinomas, poses a particular diagnostic challenge. We present our diagnostic and theranostic approach to the initial evaluation of cholangiocarcinomas, focusing on extrahepatic cholangiocarcinoma. This involves a multipronged strategy incorporating advanced imaging, endoscopic methods, multiple approaches to tissue sampling, and molecular markers. We also provide an algorithm for the sequential use of these tools. [ABSTRACT FROM AUTHOR]

Mitophagy is a cargo-specific autophagic process that recycles damaged mitochondria to promote mitochondrial turnover. PTEN-induced putative kinase 1 (PINK1) mediates the canonical mitophagic pathway. However, the role of PINK1 in diseases where mitophagy has been purported to play a role, such as colorectal cancer, is unclear. Our results here demonstrate that higher PINK1 expression is positively correlated with decreased colon cancer survival, and mitophagy is required for colon cancer growth. We show that doxycyclineinducible knockdown (KD) of PINK1 in a panel of colon cancer cell lines inhibited proliferation, whereas disruption of other mitophagy receptors did not impact cell growth. We observed that PINK KD led to a decrease in mitochondrial respiration, membrane hyperpolarization, accumulation of mitochondrial DNA, and depletion of antioxidant glutathione. In addition, mitochondria are important hubs for the utilization of iron and synthesizing iron-dependent cofactors such as heme and iron sulfur clusters. We observed an increase in the iron storage protein ferritin and a decreased labile iron pool in the PINK1 KD cells, but total cellular iron or markers of iron starvation/overload were not affected. Finally, cellular iron storage and the labile iron pool are maintained via autophagic degradation of ferritin (ferritinophagy). We found overexpressing nuclear receptor coactivator 4, a key adaptor for ferritinophagy, rescued cell growth and the labile iron pool in PINK1 KD cells. These results indicate that PINK1 integrates mitophagy and ferritinophagy to regulate intracellular iron availability and is essential for maintaining intracellular iron homeostasis to support survival and growth in colorectal cancer cells. [ABSTRACT FROM AUTHOR]

Drug resistance presents one of the major causes for the failure of cancer chemotherapy. Cancer stem-like cells (CSCs), a population of self-renewal cells with high tumorigenicity and innate chemoresistance, can survive conventional chemotherapy and generate increased resistance. Here, we develop a lipid-polymer hybrid nanoparticle for co-delivery and cell-distinct release of the differentiation-inducing agent, all- trans retinoic acid and the chemotherapeutic drug, doxorubicin to overcome the CSC-associated chemoresistance. The hybrid nanoparticles achieve differential release of the combined drugs in the CSCs and bulk tumor cells by responding to their specific intracellular signal variation. In the hypoxic CSCs, ATRA is released to induce differentiation of the CSCs, and in the differentiating CSCs with decreased chemoresistance, DOX is released upon elevation of reactive oxygen species to cause subsequent cell death. In the bulk tumor cells, the drugs are released synchronously upon the hypoxic and oxidative conditions to exert potent anticancer effect. This cell-distinct drug release enhances the synergistic therapeutic efficacy of ATRA and DOX with different anticancer mechanism. We show that treatment with the hybrid nanoparticle efficiently inhibit the tumor growth and metastasis of the CSC-enriched triple negative breast cancer in the mouse models. This study developed an easy-to-fabricate lipid-polymer hybrid nanoparticle for co-delivery and cell-distinct release of the differentiation-inducing agent ATRA, and the chemotherapeutic drug DOX, to overcome the CSC-associated chemoresistance. [Display omitted] [ABSTRACT FROM AUTHOR]

There is huge potential in the phyto-chemical compounds obtained from the seaweeds naming brown (Phaeophyta), red (Rhodophyta) and green (Chlorophyta) macroalgae. These seaweeds are abundant in anti-cancer and anti-HIV agents. Chlorophyta are polydisperse heteropolysaccharides and Phaeophyta are fucoidans which are wither fucose containing sulfated polysaccharides. Brown seaweeds are rich in fucoidans, alginic acids and laminarans which possess anti-cancer activity by inhibiting growth, proliferation of cancer cells and target various molecular and signaling pathways to prevent the growth and proliferation of cancer cell lines. The phytochemicals like phlorotannins, lectins, sulfated polysaccharides and diterpenes possess activity against HIV infection. The most effective method of preventing HIV infection is to inhibit the virus attachment and virus penetration on the host cell by preventing the binding of receptors to cell membrane surface. The properties of macroalgae can be explored more prominently to combat cancer and HIV-infection medically and professionally. Most of them are only included for traditional or local medicinal therapy and these species are mostly included in the dietary food and supplements of society. To fully grasp their depth capability and promise for the future, more research into these marine macroalgae and their phytocompounds is required. • Anti-cancer bioactive compounds obtained from marine macroalgae. • Anti-HIV bioactive compounds obtained from marine macroalgae. • Bioactive compounds inhibitory effect on cancer growths and prompt of cancer cell death by stimulating apoptosis. • Affecting virus attachment and replication to prevent HIV infection. [ABSTRACT FROM AUTHOR]

This study evaluates protosappanin B's (PSB) role in inflammation, proliferation, and subsequent apoptosis of human melanoma A875 cells. The cell lines were treated with PSB (15 and 20 μM) for 24 h of incubation mediated cytotoxicity was assessed by MTT assay; ROS was studied by flow cytometry. PSB treatment mediated nuclear fragmentation and apoptotic morphological features were analyzed by AO, EtBr, PI, and DAPI stainings. The mRNA and protein expression of inflammatory, proliferation, cell survival and apoptosis were studied by RT-PCR and western blotting. PSB (15 and 20 μM) treatment with A875 produces cytotoxicity associated with nuclear fragmentation, and apoptotic changes were observed. PSB inhibits inflammatory proteins (TNF-α, NF-κB, COX-2, IL-6, iNOS, and VEGF) in A875 cells. Furthermore, PSB induces pro-apoptotic protein expressions i.e. Bax, caspase-3; inhibiting anti-apoptotic, cell proliferative proteins (cyclin-D1, Bcl-2, c-Myc, and survivin) in A875 cells. The p-PI3K, p-AKT, and p-GSK-3β contribute to oncogenic progression; hence, inhibition of these signaling events is considered a significant target for the treatment of melanoma. This study observed that PSB treatment magnificently inhibited the p-PI3K, p-AKT, and p-GSK-3β in A875 cells. Thus, PSB inhibits inflammation, proliferation, and survival; promotes apoptosis by suppressing PI3K, AKT, and GSK-3β in human melanoma cancer. [Display omitted] • Protosappanin-B concern as a natural drug that has numerous biological activity. • Protosappanin-B inhibits inflammation and proliferation in A875 cells. • Protosappanin-B inhibits melanoma cancer via suppression of PI3K/AKT expressions. [ABSTRACT FROM AUTHOR]

Prospective tumor pH-responsive and charge-convertible nanoparticles have been utilized to reduce side effects and improve the active tumor-targeting ability and nuclear/cytoplasmic localization of chemo- and gene therapeutics for the treatment of head and neck cancer (HNC). Oxaliplatin (Oxa) is a third-generation platinum compound that prevents DNA replication. miR-320 may regulate cancer cell apoptosis, resistance, and progression. Innovative nanoparticles incorporating miR-320 and Oxa were modified with a ligand, cell-penetrating peptide, and nucleus-targeted peptide. The nanoparticles were coated with a charge/size-tunable shield to prevent peptide degradation and decoated at acidic tumor sites to expose peptides for active targeting. Results indicated that the designed nanoparticles exhibited a uniform size and satisfactory drug encapsulation efficiency. The nanoparticles displayed the pH-responsive release and uptake of Oxa and miR-320 into human tongue squamous carcinoma SAS cells. The nanoparticles successfully delivered Oxa and miR-320 to the nucleus and cytoplasm, respectively. This work is the first to demonstrate the concurrent intracellular modulation of the NRP1/Rac1, PI3K/Akt/mTOR, GSK-3β/FOXM1/β-catenin, P-gp/MRPs, KRAS/Erk/Oct4/Yap1, and N-cadherin/Vimentin/Slug pathways to inhibit the growth, progression, and multidrug resistance of cancer cells. In SAS-bearing mice, co-treatment with Oxa- and miR-320-loaded nanoparticles exhibited superior antitumor efficacy and remarkably decreased Oxa-associated toxicities. The nucleus/cytoplasm-localized nanoparticles with a tumor pH-sensitive and size/charge-adjustable coating may be a useful combinatorial spatiotemporal nanoplatform for nucleic acids and chemotherapeutics to achieve maximum therapeutic safety and efficacy against HNC. Innovative nanoparticles incorporating miR-320 and oxaliplatin were modified with a ligand, cell-penetrating peptide, and nucleus-targeted peptide. The tumor pH-sensitive and charge/size-adjustable shield of polyglutamic acid–PEG protected against peptide degradation during systemic circulation. This work represents the first example of the concurrent intracellular modulation of the NRP1/Rac1, PI3K/Akt/mTOR, GSK-3β/FOXM1/β-catenin, P-gp/MRPs, KRAS/Erk/Oct4/Yap1, and N-cadherin/Vimentin/Slug pathways to inhibit cancer cell growth, cancer cell progression, and multidrug resistance simultaneously. The versatile nanoparticles with a tumor pH-functionalized coating could deliver chemotherapeutics and miRNA to the nucleus/cytoplasm. The nanoparticles successfully reduced chemotherapy-associated toxicities and maximized the antitumor efficacy of combinatorial therapy against head and neck cancer. [Display omitted] [ABSTRACT FROM AUTHOR]

The poor prognosis of triple negative breast cancer (TNBC) results from a lack of approved targeted therapies coupled with aggressive proliferation and metastasis, which is associated with high recurrence and short overall survival. Here we developed a strategy by employing tumor-targeted self-assembled nanoparticles to coordinately regulate BACH1 (BTB domain and CNC homology 1) and mitochondrial metabolism. The BACH1 inhibitor hemin and mitochondria function inhibitor berberine derivative (BD) were used to prepare nanoparticles (BH NPs) followed by the modification of chondroitin sulfate (CS) on the surface of BH NPs to achieve tumor targeting (CS/BH NPs). CS/BH NPs were found to be able to inhibit tumor migration and invasion by significantly decreasing the amounts of tumor cell metabolites, glycolysis and metastasis-associated proteins, which were related to the inhibition of BACH1 function. Meanwhile, decreased mitochondrial membrane potential, activated caspase 3/9 and increased ROS production demonstrated coordinated regulation of BACH1 and mitochondrial metabolism. In a xenograft mice model of breast cancer, CS/BH NPs significantly inhibited tumor growth and metastasis due to the synergetic effect of hemin and BD without showing obvious toxicities for major organs. In sum, the results of efficacy and safety experiments suggest potential clinical significance of the prepared self-assembled CS/BH nanoparticles for the treatment of TNBC. Chondroitin sulfate (CS)-coated self-assembled nanoparticles (CS/BH NPs) to co-deliver berberine derivative (BD) and hemin for combinational treatment of triple negative breast cancer (TNBC) was developed. [Display omitted] [ABSTRACT FROM AUTHOR]

Deregulation of E3 ubiquitin ligases drives the proliferation and metastasis of various cancers; however, the underlying mechanisms remain unknown. This study aimed to investigate the role of tripartite motif-containing 22 (TRIM22), a poorly investigated E3 ubiquitin ligase in the TRIM family, as a tumor suppressor in breast cancer. High expression of TRIM22 in breast cancer correlated with better prognosis. Functional experiments demonstrated that TRIM22 significantly inhibited the proliferation and invasion of breast cancer cells. Label-free proteomics and biochemical analyses revealed that the copper chaperone for superoxide dismutase (CCS), an oncoprotein that is upregulated in breast cancer and promotes the growth and invasion of breast cancer cells, was a target of TRIM22 for degradation via K27-linked ubiquitination. Notably, the ability of the coiled-coil domain-defective mutants of TRIM22 to induce CCS ubiquitination and degradation diminished, with lysine 76 of the CCS serving as the ubiquitination site. Moreover, the TRIM22-mediated inhibition of the proliferation and invasion of breast cancer cells was restored by ectopic CCS expression. RNA-sequencing experiments using Gene Set Enrichment Analysis demonstrated that TRIM22 is involved in the JAK-STAT signaling pathway. TRIM22 overexpression also improved reactive oxygen species levels in breast cancer cells and inhibited STAT3 phosphorylation, which was restored via CCS overexpression or N-acetyl- l -cysteine treatment. Chromatin immunoprecipitation-quantitative polymerase chain reaction results showed that TRIM22 overexpression decreased the enrichment of phosphorylated STAT3 in FN1, VIM and JARID2 promoters. Clinically, low TRIM22 expression correlated with high CCS expression and decreased survival rates in patients with breast cancer. Moreover, TRIM22 upregulation was associated with a better prognosis in patients with breast cancer who received classical therapy. TRIM22 expression was downregulated in many cancer types, including colon, kidney, lung, and prostate cancers. To the best of our knowledge, the E3 ubiquitin ligase TRIM22 was first reported as a tumor suppressor that inhibits the proliferation and invasion of breast cancer cells through CCS ubiquitination and degradation. TRIM22 is a potential prognostic biomarker in patients with breast cancer. • TRIM22 is first recognized as a tumor suppressor in breast cancer. • TRIM22 is the first reported E3 ligase for CCS degradation. • TRIM22 inhibits the proliferation and invasion of breast cancer through inhibiting STAT3 signaling. • TRIM22 may serve as a prognostic biomarker in breast cancer. [ABSTRACT FROM AUTHOR]

• A theranostic system Mn@medi-MOF-1 was constructed by medi-MOF-1 and Mn ions. • The system displayed T 1 -weighted magnetic resonance performance. • The system exhibited anticancer therapeutic effect via chemodynamic therapy and chemotherapy. A metal-organic framework (MOF) medi-MOF-1 containing curcumin with inhibitory effect on tumor growth was adopted for cancer therapy. And theranostic agents Mn ions were loaded to construct a theranostic system Mn@medi-MOF-1 (Mn 14.82 wt% and curcumin 31.62 wt%). In vitro, it displayed T 1 -weighted magnetic resonance performance, ideal ability of ROS production for chemodynamic therapy and stimuli-responsive drug release to inhibit cancer cell growth, indicating its potential applications for multimodal cancer theranostic. A MOF-based system containing 14.82 wt% Mn and 31.62 wt% curcumin was constructed. The system displayed good property of magnetic resonance imaging, chemodynamic therapy and chemotherapy. [Display omitted] [ABSTRACT FROM AUTHOR]

PIM-1 kinase belongs to the Ser/Thr kinases family, an attractive therapeutic target for prostate cancer. Here, we screened about 100 natural substances to find potential PIM-1 inhibitors. Two natural compounds, Naringenin and Quercetin, were finally selected based on their PIM-1 inhibitory potential and binding affinities. The docking score of Naringenin and Quercetin with PIM-1 is −8.4 and − 8.1 kcal/mol, respectively. Fluorescence binding studies revealed a strong affinity (K a values, 3.1 × 104 M−1 and 4.6 × 107 M−1 for Naringenin and Quercetin, respectively) with excellent IC 50 values for Naringenin and Quercetin (28.6 μM and 34.9 μM, respectively). Both compounds inhibited the growth of prostate cancer cells (LNCaP) in a dose-dependent manner, with the IC 50 value of Naringenin at 17.5 μM and Quercetin at 8.88 μM. To obtain deeper insights into the PIM-1 inhibitory effect of Naringenin and Quercetin, we performed extensive molecular dynamics simulation studies, which provided insights into the binding mechanisms of PIM-1 inhibitors. Finally, Naringenin and Quercetin were suggested to serve as potent PIM-1 inhibitors, offering targeted treatments of prostate cancer. In addition, our findings may help to design novel Naringenin and Quercetin derivatives that could be effective in therapeutic targeting of prostate cancer. • PIM-1 is an attractive drug target for prostate cancer therapy. • We have discovered Naringenin and Quercetin as potent PIM-1 kinase inhibitors. • Docking and MD simulation studies suggested a strong binding and the formation of stable protein-ligands complexes. • Naringenin and Quercetin significantly inhibit the activity of PIM-1 with excellent IC50 values. • Both compounds show cytotoxic effect on LNCaP cells with admirable IC 50 values. [ABSTRACT FROM AUTHOR]

Mini-chromosome maintenance protein 2 (MCM2) is a potential target for the development of cancer therapeutics. However, small molecule inhibitors targeting MCM2 need further investigation. Molecular dynamics simulation was performed to identify active pockets in the MCM2 protein structure (6EYC). The active pocket was used as a docking model to discover MCM2 inhibitors by using structure-based virtual screening and surface plasmon resonance (SPR) assay. Furthermore, the efficacy of pixantrone targeting MCM2 in ovarian cancer was evaluated in vitro and in vivo. Pixantrone was identified as a novel inhibitor of MCM2 by virtual screening. SPR binding affinity analysis confirmed the direct binding of pixantrone to MCM2 protein. Pixantrone significantly reduced the viability of ovarian cancer cells A2780 and SKOV3 in a dose- and time-dependent manner. In addition, pixantrone inhibited DNA replication, and induced cell cycle arrest and apoptosis in ovarian cancer cells via targeting MCM2. Knockdown of MCM2 could attenuate the inhibitory activity of pixantrone in ovarian cancer cells. Furthermore, pixantrone significantly suppressed ovarian cancer growth in the A2780 cell xenograft mouse model and showed favorable safety. These findings suggest that pixantrone may be a promising drug for ovarian cancer patients by targeting MCM2 in the clinic. [Display omitted] • Pixantrone identified as a novel MCM2 inhibitor through virtual screening. • Surface plasmon resonance confirms direct binding of pixantrone to MCM2 protein. • Pixantrone inhibits ovarian cancer cell proliferation and induces apoptosis. • Knockdown of MCM2 attenuates the inhibitory effect of pixantrone on cancer cells. • Pixantrone significantly suppresses ovarian cancer growth in a mouse model. [ABSTRACT FROM AUTHOR]

Sentrin/small ubiquitin-like modifier (SUMO)-specific proteases (SENPs) perform pivotal roles in SUMO maturation and recycling, which modulate the balance of SUMOylation/de-SUMOylation and spatiotemporal functions of SUMOylation targets. The malfunction of SENPs often results in cellular dysfunction and various diseases. However, studies rarely investigated the correlation between SENP2 and lung cancer. This study revealed that SENP2 is a required contributor to lung cancer-cell growth and targets nuclear Dbf2-related 2 (NDR2, also known as serine/threonine kinase 38L or STK38L) for de-SUMOylation, which improves NDR2 kinase activity. This condition leads to the instability of downstream target p21 in accelerating the G 1 /S cell cycle transition and suggests SENP2 as a promising therapeutic target for lung cancer in the future. Specifically, astragaloside IV, an active ingredient of Jinfukang Oral Liquid (JOL, a clinical combination antilung cancer drug approved by the National Food and Drug Administration (FDA) of China), can repress lung cancer-cell growth via the SENP2–NDR2–p21 axis, which provides new insights into the molecular mechanism of JOL for lung cancer treatment. [ABSTRACT FROM AUTHOR]

• SIRT6 down-regulated the expression level of Survivin to promote mitochondrial apoptosis. • SIRT6 directly binds to the promoter of Survivin to inactivate its transcription. • Survivin promoted colon cancer cell growth and eliminated NVP-235 induced apoptosis. • Survivin inhibition by YM155 suppressed colon cancer cell growth to induce apoptosis and autophagy. • Survivin inhibition showed positive feedback on Akt/FoxO3a/SIRT6 pathway. • Targeting Survivin by YM155 showed potent tumor regression in vivo. SIRT6, an evolutionarily conserved histone deacetylase, has been identified as a novel direct downstream target of Akt/FoxO3a and a tumor suppressor in colon cancer in our previous research. Nevertheless, the precise mechanisms through which SIRT6 hinders tumor development remain unclear. To ascertain whether SIRT6 directly impacts Survivin transcription, a ChIP assay was conducted using an anti-SIRT6 antibody to isolate DNA. YM155 was synthesized to explore Survivin's role in mitochondrial apoptosis, autophagy and tumor progression. Our investigation into the regulation of Survivin involved real-time fluorescence imaging in living cells, real-time PCR, immunohistochemistry, flow cytometry, and xenograft mouse assays. In this current study, we delved into the role of SIRT6 in colon cancer and established that activated SIRT6 triggers mitochondrial apoptosis by reducing Survivin expression. Subsequent examinations revealed that SIRT6 directly binds to the Survivin promoter, impeding its transcription. Notably, direct inhibition of Survivin significantly impeded colon cancer proliferation by inducing mitochondrial apoptosis and autophagy both in vitro and in vivo. More interestingly, Survivin inhibition reactivated the Akt/FoxO3a pathway and elevated SIRT6 levels, establishing a positive feedback loop. Our results identify Survivin as a novel downstream transcriptional target of SIRT6 that fosters tumor growth and holds promise as a prospective target for colon cancer therapy. [ABSTRACT FROM AUTHOR]

Colon cancer poses a major threat to human health and a heavy burden on the national economy. As a member of the SOX transcription factor family, SRY-box transcription factor 21 (SOX21) is associated with various cancers, but its mechanism of action in colon cancer remains unclear. This study focused on the molecular mechanisms of transcription factor SOX21 in proliferation and metastasis of colon cancer cells. We analyzed SOX21 expression level and its impact on survival in colon cancer patients by bioinformatics analysis. We used public databases for gene correlation, GSEA enrichment analysis. Cell function experiments (colony formation assay, wound healing assay, Transwell migration and invasion assay) were utilized to determine the impact of SOX21 silencing and over-expression on cell proliferation and metastasis. The luciferase reporter assay, CUT&RUN-qPCR assay and Methylation Specific PCR were used to explore SOX21 -POU class 4 homeobox 2 (POU4F2) molecular interactions. The molecular mechanisms were verified by Quantitative real-time PCR and Western blot analysis. SOX21 is highly expressed and affects the overall survival of colon cancer patients. SOX21 can attenuates POU4F2 methylation state by binding with it. In addition, this interaction facilitate its transcriptional activation of Hedgehog pathway, mediates epithelial-mesenchymal transition (EMT), consequently promoting the proliferation and metastasis of colon cancer cells. Our study reveals that SOX21 is an oncogenic molecule and suggests its regulatory role in colon carcinogenesis and progression, providing new insights into the treatment of this disease. [ABSTRACT FROM AUTHOR]

The ineffectiveness of cisplatin therapy in treating colorectal cancer (CRC) is attributed to an increase of resistance. It's necessary to investigate adjunctive agents capable of enhancing drug efficacy. Previous studies have shown that ropivacaine inhibit the growth of various cancer cells, but its impact on cisplatin resistance in tumors is not well understood. This study was to illustrate the impact and mechanism of ropivacaine enhanced cisplatin-sensitivity of CRC. Cisplatin alone treatment resulted in the elevation of reactive oxygen species (ROS) and intracellular Fe2+ levels, as well as a reduction in mitochondrial membrane potential (MMP) in cisplatin-sensitive LOVO cells, while these effects were mitigated in the cisplatin-resistant LOVO/DDP cells. The co-administration of ropivacaine with cisplatin inhibited cell viability and cell migration, decreased MMP, and promoted ROS accumulation and apoptosis in both LOVO cells and LOVO/DDP cells. And they upregulated the levels of ferroptosis makers and downregulated the expression of anti-ferroptosis proteins. However, this effect was reversed by ferroptosis inhibitor ferrostatin-1 or liproxstatin-1. Furthermore, we o demonstrated that the co-administration of ropivacaine and cisplatin resulted in a decrease in SIRT1 expression, and SIRT1 knockdown in LOVO/DDP cells enhanced the ferroptosis and the anti-tumor properties of ropivacaine, while also inhibiting the activation of the Nrf2/Keap1 pathway. The above results suggested that ropivacaine increased the sensitivity of CRC cells to cisplatin by promoting ferroptosis through the inhibition of SIRT1 expression, which proposes a therapeutic approach for overcoming cisplatin resistance in CRC. The schematic diagram illustrating ropivacaine facilitate cisplatin-induced apoptosis and ferroptosis. [Display omitted] • Ropivacaine enhanced cisplatin sensitivity to the human colorectal cancer (CRC). • Co-administration of ropivacaine with cisplatin induced oxidative stress and mitochondrial dysfunction in CRC. • Co-administration of ropivacaine with cisplatin promoted apoptosis and ferroptosis in CRC. • Ropivacaine enhanced cisplatin sensitivity by binding to SIRT1 to promote SIRT1-mediated ferroptosis. [ABSTRACT FROM AUTHOR]

• We successfully constructed the LwaCas13a: crRNA dual plasmid system for the suppression of HPV 18 E6 mRNA in HeLa cells by utilizing the ability of the CRISPR/Cas13a system to target and cleave RNA. • CRISPR/Cas13a system could effectively and specifically knock down the level of HPV18 E6 mRNA and restore the expression of the tumor suppressor gene P53 protein, inhibiting the growth and increasing the apoptosis of cervical cancer cells. • CRISPR/Cas13a system enhanced the proliferation inhibition and apoptosis induction of cisplatin in cervical cancer HeLa cells. The E6 protein is a known oncogene in cervical cancer and plays a key role in the development and progression of cervical cancer by reducing the expression level of the tumor suppressor protein P53 and ultimately leading to enhanced cell proliferation and reduced apoptosis. Therefore, antiviral agents that inhibit the expression of E6 oncoprotein are expected to be potential therapies for human cervical cancer. Here we developed CRISPR/Cas13a: crRNA dual plasmid system and demonstrated that CRISPR/Cas13a could effectively and specifically knock down human papillomavirus 18 E6 mRNA, downregulate the expression level of E6 protein, and restore the expression of the tumor suppressor gene P53 protein, thereby inhibiting the growth of cervical cancer cells and increasing their apoptosis, the E6-2, E6-3, and E6-5 groups resulted in apoptosis rates of 25.4%, 22.4%, and 22.2% in HeLa cells. Moreover, CRISPR/Cas13a enhances the proliferation inhibition and apoptosis induction of cisplatin in cervical cancer HeLa cells. The CRISPR/Cas13a system targeting HPV E6 mRNA may be a promising therapeutic approach for the treatment of human papillomavirus-associated cervical cancer. [ABSTRACT FROM AUTHOR]

• Investigated the regulatory patterns of oxidative stress in LUAD based on oxidative stress-related genes systematically. • We constructed a 10-gene(CLEC3B, CYP4B1, SFTPB, TPX2, SLC34A2, CRTAC1, MS4A1, CPS1, JCHAIN, and S100P) risk profile by univariate Cox regression analysis and LASSO regression analysis, then validated the prognostic efficacy of the risk score in the validation set. We subsequently performed univariate and multivariate Cox analyses of the variables to determine whether the risk score was an independent prognostic factor for patients with LUAD, and the results showed that the risk score was an independent predictor of OS. Two genes with the most significant differential expression, SFTPB and S100P , were selected through qRT-PCR. Cell experiments including CCK-8, Edu, transwell assays confirmed their effects on lung cancer cells growth, consistent with the results of bioinformatics analysis. These findings suggested that this model held potential clinical value for evaluating the prognosis of lung adenocarcinoma. • We systematically investigated the regulatory patterns of oxidative stress in LUAD based on oxidative stress-related genes and systematically correlated these regulatory patterns with the cellular infiltration characteristics of the TIME. We found that oxidative stress was differentially regulated in the high- and low-risk score groups and that the TIMEs of the two groups were different. Lung adenocarcinoma (LUAD), the most common subtype of lung cancer globally, has seen improved prognosis with advancements in diagnostic, surgical, radiotherapy, and molecular therapy techniques, while its 5-year survival rate remains low. Molecular biomarkers provide prognostic value. Oxidative stress factors, such as reactive nitrogen species and ROS, are crucial in various stages of tumor progression, influencing cell transformation, proliferation, angiogenesis, and metastasis. ROS demonstrate dual roles, affecting tumor cells, hypoxia sensitivity, and the microenvironment. Comprehensive analysis of oxidative stress in LUAD has not been conducted to date. Therefore, we systematically investigated the regulatory patterns of oxidative stress in LUAD based on oxidative stress-related genes and correlated these patterns with cellular infiltration characteristics of the tumor immune microenvironment. The model utilizes single-factor Cox analysis to screen key differential genes with prognostic value and employs least absolute shrinkage and selection operator (LASSO) penalized Cox regression analysis to construct a prognostic-related prediction model. Ten candidate genes were selected based on this model. The risk score was constructed using the coefficients and expression levels of these ten genes. Furthermore, the impact of this risk score on overall survival (OS) was determined. Two genes with the most significant differential expression, SFTPB and S100P , were selected through qRT-PCR. Cell experiments including CCK-8, Edu, transwell assays confirmed their effects on lung cancer cells growth, consistent with the results of bioinformatics analysis. These findings suggested that this model held potential clinical value for evaluating the prognosis of lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

[Display omitted] • TRIM40 expression is positively correlated with esophagus cancer in human patients and OA-challenged in vitro. • TRIM40 maintains ER homeostasis by antagonizing OA-induced ROS produce. • TRIM40 directly binds to KEAP1 to facilitate its ubiquitination and degradation. • TRIM40 promotes NRF2 signaling activation by facilitating its nuclear translocation in response to OA challenge. • NRF2 is required for TRIM40-regualted esophagus cancer cell proliferation under OA treatment. • TRIM40 deficiency in esophagus cancer cells inhibits tumor growth in response to OA treatment. Oroxylin A (OA), a naturally active O -methylated flavone derived from Scutellaria baicalensis , is regarded as a potential drug with strong anticancer effects. Unfortunately, our understanding of the antineoplastic mechanism of oral exposure to such flavonoids is inadequate. Growing evidence has confirmed the important role of OA in the regulation of oxidative stress- and inflammatory-response-induced tissue injury. However, it remains unknown whether OA is capable of mitigating esophagus cancer (EC) progression and its potential molecular mechanism. Furthermore, the tripartite motif containing 40 (TRIM40) is a ubiquitin ligase that mediates the immune response. The potential molecular function of TRIM40 in regulating EC is largely unknown. We confirmed that OA-triggered oxidative stress markedly upregulates TRIM40. During the OA challenge, increased TRIM40 reduced oxidative stress and promoted the ER stress response. Inversely, deletion of TRIM40 facilitated oxidative stress and blocked cancer cell growth in vivo and in vitro. Mechanistically, in response to OA treatment, TRIM40 directly interacts with Keap1 and promotes ubiquitin–proteasome degradation, thus leading to the promotion of Nrf2 nuclear translocation and its downstream cascade activation, which increases antioxidant defense and cell survival. TRIM40 expression was positively correlated with Nrf2 expression and negatively associated with Keap1 expression in EC xenografts and human specimens. In addition, high TRIM40 expression correlates with poor patient survival in EC. The findings suggested that oral exposure to OA significantly mitigates EC development by targeting TRIM40 activity. These findings further elucidated the potential role of TRIM40 in EC progression by mediating Keap1 degradation, which could be considered a therapeutic target for the treatment of such a disease. [ABSTRACT FROM AUTHOR]

EGFR tyrosine kinase inhibitor (TKI) resistance is a major challenge for EGFR-mutant non-small cell lung cancer (NSCLC) treatment. Our previous work revealed that overexpression of AXL promoted EGFR-TKI resistance through epithelial-mesenchymal transition (EMT) in a subset of NSCLC patients. Compared with erlotinib resistant and sensitive cells, RP11-874 J12.4 was upregulated in erlotinib-resistant NSCLC cells (HCC827-ER3). Interestingly, the expression of RP11-874 J12.4 positively correlated with AXL. Besides, RP11-874 J12.4 promotes NSCLC cell proliferation and metastasis in vitro. Mechanistically, RP11-874 J12.4 promoted AXL expression through sponge with miR-34a-5p, which was reported to inhibit the translation of AXL mRNA. Meanwhile, the expression of RP11-874 J12.4 in lung cancer tumors were higher than the adjacent tissue, and those patients with high expression of RP11-874 J12.4 showed a poor prognosis in clinical. High expression of RP11-874 J12.4 might be a biomarker for NSCLC patients with erlotinib resistance. These findings reveal a novel insight into the mechanism of erlotinib resistance in NSCLC, and it might be a promising target for the diagnosis and treatment of NSCLC. • RP11-874 J12.4 is overexpressed in erlotinib resistant NSCLC cells. • RP11-874 J12.4 promotes lung cancer cells growth and metastasis. • RP11-874 J12.4 sponge with miR-34a-5p to increase the translation of AXL. • The high expression of RP11-874 J12.4 and AXL correlate with poor prognosis. [ABSTRACT FROM AUTHOR]