• bladder cancer
• disease model

• Animals
• PTEN Phosphohydrolase/genetics
• PTEN Phosphohydrolase/deficiency
• Mice
• Tumor Suppressor Protein p53/genetics
• Mutation, Missense
• Urinary Bladder Neoplasms/genetics
• Urinary Bladder Neoplasms/pathology
• Urinary Bladder Neoplasms/immunology
• Humans
• Urothelium/pathology
• Urothelium/metabolism
• Urothelium/immunology
• Organoids/pathology
• Organoids/immunology
• Organoids/metabolism
• Loss of Heterozygosity
• Disease Models, Animal
• Mice, Nude

• JP19H03790, JP22H03211, JP25713055 MEXT | Japan Society for the Promotion of Science (JSPS)
• Princess Takamatsu Cancer Research Fund
• Kobayashi Foundation for Cancer Research
• Naito Foundation
• Uehara Memorial Foundation

• Nuclear factor κ B
• Pro-inflammatory cytokines
• Reactive oxygen species
• Redox signaling
• Skeletal muscle

• Humans
• Muscle, Skeletal/metabolism
• Muscle, Skeletal/physiology
• Signal Transduction
• NF-kappa B/metabolism
• NF-kappa B/genetics
• Exercise/physiology
• Animals
• Oxidation-Reduction
• Oxidative Stress

• antimicrobial growth promoter
• bacteriophage
• functional fatty acids
• growth
• intestinal health
• intestinal microbiota
• organic acid
• phytobiotics
• postbiotics
• probiotics

• 660101 North Carolina Agricultural Foundation
• Hatch 02893 USDA-NIFA

• ATRT
• atypical teratoid/rhabdoid tumor
• gemcitabine
• neuro oncology
• p53
• patient-derived models
• pediatric oncology
• sirtuin 1
• therapy development

• Gemcitabine
• Humans
• Deoxycytidine/analogs & derivatives
• Deoxycytidine/pharmacology
• Deoxycytidine/therapeutic use
• Sirtuin 1/metabolism
• Sirtuin 1/genetics
• Animals
• Tumor Suppressor Protein p53/metabolism
• Tumor Suppressor Protein p53/genetics
• Rhabdoid Tumor/drug therapy
• Rhabdoid Tumor/genetics
• Rhabdoid Tumor/metabolism
• Rhabdoid Tumor/pathology
• Teratoma/pathology
• Teratoma/drug therapy
• Teratoma/metabolism
• Teratoma/genetics
• Mice
• Xenograft Model Antitumor Assays
• Cell Line, Tumor
• NF-kappa B/metabolism

• medical and clinical diagnostics
• drug delivery
• chemical tools

• SVV260637 Univerzita Karlova v Praze (Charles University)
• SVV260521 Univerzita Karlova v Praze (Charles University)
• UNCE 204064 Univerzita Karlova v Praze (Charles University)
• Progres LF1 Q38 Univerzita Karlova v Praze (Charles University)
• Progres LF1 Q27 Univerzita Karlova v Praze (Charles University)
• Cooperatio ONCO Univerzita Karlova v Praze (Charles University)
• LM2023053 Ministerstvo Školství, Mládeže a Tělovýchovy (Ministry of Education, Youth and Sports)
• TN02000109 Technologická Agentura České Republiky (Technological Agency of the Czech Republic)
• NU22-08-00160 Ministerstvo Zdravotnictví Ceské Republiky (Ministry of Health of the Czech Republic)
• NU21-08-00407 Ministerstvo Zdravotnictví Ceské Republiky (Ministry of Health of the Czech Republic)
• MUNI/A/1587/2023 Masarykova Univerzita (Masaryk University)

• 6-OHDA
• NF-κB
• Nitric Oxide
• inflammation
• mangiferin

• Gastrointestinal mucositis
• Intestinal disorder
• Radiotherapy
• mucositis

• Humans
• Mucositis/drug therapy
• Mucositis/etiology
• Radiation Injuries/drug therapy
• Animals
• Radiotherapy/adverse effects
• Gastrointestinal Diseases/drug therapy
• Gastrointestinal Diseases/etiology

• catestatin
• chromogranin A
• preeclampsia
• pregnancy

• ethanol
• fish oil
• gastric ulcer

• Apoptosis
• DNA damage
• cancer
• extrinsic pathway
• genetic therapy.
• p38 signaling

• Humans
• Neoplasms/genetics
• Neoplasms/therapy
• DNA Damage/genetics
• Apoptosis/genetics
• Cell Death
• Signal Transduction

• cell signalling
• oncogenesis
• dna damage and repair

• the Key Research and Development Program of Shaanxi Province

• apoptosis
• mirnas

• Animals
• Horses
• Carcinogens/toxicity
• Carcinogens/metabolism
• 9,10-Dimethyl-1,2-benzanthracene/toxicity
• 9,10-Dimethyl-1,2-benzanthracene/metabolism
• NF-kappa B/metabolism
• Epithelial Cells/metabolism
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Apoptosis
• Anthracenes/metabolism
• Anthracenes/pharmacology
• Mammals
• Neoplasms/metabolism

• Albert C. Bostwick Foundation

• Caspese-3/AIF
• NF-κB/DNA-PK
• PARP inhibitor
• ionizing radiation
• p53/ROS

• Apoptosis
• Atherosclerosis
• CD68
• Inflammation
• Macrophage
• ROS

• Polyethyleneglycol-betulinic acid
• antioxidation
• apoptosis
• conjugation
• reactive oxygen species

• 105942 Wellcome Trust

• Apelin-13
• NF-κB
• cyclophosphamide
• lungs
• p53.
• sirt1

• Rats
• Male
• Animals
• NF-kappa B/metabolism
• Rats, Wistar
• Antioxidants/pharmacology
• Tumor Necrosis Factor-alpha/metabolism
• Sirtuin 1/metabolism
• Sirtuin 1/pharmacology
• Caspase 3/metabolism
• Tumor Suppressor Protein p53/metabolism
• Pulmonary Surfactant-Associated Protein D/metabolism
• Pulmonary Surfactant-Associated Protein D/pharmacology
• Oxidative Stress
• Cyclophosphamide/adverse effects
• Inflammation/drug therapy
• Inflammation/metabolism
• Lung
• Apoptosis
• Apelin/adverse effects
• Apelin/metabolism

• 21.GENEL.005 Afyonkarahisar Health Sciences University Scientific Research Projects Commission

• AKI
• BRAP
• SIRT2
• apoptosis
• necroptosis
• ubiquitination

NF‐κB signaling is widely linked to the pathogenesis and treatment resistance in cancers. Increasing attention has been paid to its anti‐oncogenic roles, due to its key functions in cellular senescence and the senescence‐associated secretory phenotype (SASP). Therefore, thoroughly understanding the function and regulation of NF‐κB in cancers is necessary prior to the application of NF‐κB inhibitors.

We established glioblastoma (GBM) cell lines expressing ectopic TCF4N, an isoform of the β‐catenin interacting transcription factor TCF7L2, and evaluated its functions in GBM tumorigenesis and chemotherapy in vitro and in vivo. In p65 knock‐out or phosphorylation mimic (S536D) cell lines, the dual role and correlation of TCF4N and NF‐κB signaling in promoting tumorigenesis and chemosensitivity was investigated by in vitro and in vivo functional experiments. RNA‐seq and computational analysis, immunoprecipitation and ubiquitination assay, minigene splicing assay and luciferase reporter assay were performed to identify the underlying mechanism of positive feedback regulation loop between TCF4N and the p65 subunit of NF‐κB. A eukaryotic cell‐penetrating peptide targeting TCF4N, 4N, was used to confirm the therapeutic significance.

Our results indicated that p65 subunit phosphorylation at Ser 536 (S536) and nuclear accumulation was a promising prognostic marker for GBM, and endowed the dual functions of NF‐κB in promoting tumorigenesis and chemosensitivity. p65 S536 phosphorylation and nuclear stability in GBM was regulated by TCF4N. TCF4N bound p65, induced p65 phosphorylation and nuclear translocation, inhibited its ubiquitination/degradation, and subsequently promoted NF‐κB activity. p65 S536 phosphorylation was essential for TCF4N‐led senescence‐independent SASP, GBM tumorigenesis, tumor stem‐like cell differentiation and chemosensitivity. Activation of p65 was closely connected to alterative splicing of TCF4N, a likely positive feedback regulation loop between TCF4N and p65 in GBM. 4N increased chemosensitivity, highlighting a novel anti‐cancer strategy.

Our study defined key roles of TCF4N as a novel regulator of NF‐κB through mutual regulation with p65 and provided a new avenue for GBM inhibition.

• TCF4N
• chemosensitivity
• nuclear translocation
• p65
• stability
• tumourigenesis
• ubiquitination

• immunology
• innate immunity

• Cancer
• EGFR
• Kigelia africana
• NF-κB
• Neuroblastoma
• Phytotherapeutics

• DNA damage
• crosstalk
• melanoma
• senescence
• theabrownin
• zebrafish

• DRAM family
• autophagy
• cell death
• nutrient deprivation

• Apoptosis/physiology
• Autophagy/physiology
• Cell Survival/genetics
• Humans
• Membrane Proteins/metabolism
• Nutrients
• Tumor Suppressor Protein p53/genetics

• 15816 Cancer Research UK
• A22903 Cancer Research UK
• A31287 Cancer Research UK
• C596/A17196 Cancer Research UK
• Cancer Research UK

• Apoptosis
• Chlorella vulgaris
• Morphometry
• Nicotine
• α7-nAchR

NF-κB is diffusely recognized as a transcriptional factor able to modulate the expression of various genes involved in a broad spectrum of cellular functions, including proliferation, survival and migration. NF-κB is, however, also acting outside the nucleus and beyond its ability to binds to DNA. NF-κB is indeed found to localize inside different cellular organelles, such as mitochondria, endoplasmic reticulum, Golgi and nucleoli, where it acts through different partners in mediating various biological functions. Here, we discuss the relationship linking NF-κB to the cellular organelles, and how this crosstalk between cellular organelles and NF-κB signalling may be evaluated for anticancer therapies.

• Golgi
• NF-κB—nuclear factor kappa B
• anticancer therapy
• endoplasmic reticulum (ER)
• lysosome
• mitochondria

Non-coding micro-RNA (miRNAs) regulate the protein expression responsible for cell growth and proliferation. miRNAs also play a role in a cancer cells’ response to drug treatment. Knowing that leukemia and lymphoma cells show different responses to active forms of vitamin D₃, we decided to investigate the role of selected miRNA molecules and regulated proteins, analyzing if there is a correlation between the selected miRNAs and regulated proteins in response to two active forms of vitamin D₃, calcitriol and tacalcitol. A total of nine human cell lines were analyzed: five leukemias: MV-4-1, Thp-1, HL-60, K562, and KG-1; and four lymphomas: Raji, Daudi, Jurkat, and U2932. We selected five miRNA molecules—miR-27b, miR-32, miR-125b, miR-181a, and miR-181b—and the proteins regulated by these molecules, namely, CYP24A1, Bak1, Bim, p21, p27, p53, and NF-kB. The results showed that the level of selected miRNAs correlates with the level of proteins, especially p27, Bak1, NFκB, and CYP24A1, and miR-27b and miR-125b could be responsible for the anticancer activity of active forms of vitamin D₃ in human leukemia and lymphoma.

• Cell Line/drug effects
• Cell Line/metabolism
• Cell Proliferation
• Cholecalciferol/pharmacology
• Humans
• Leukemia/genetics
• Leukemia/metabolism
• Lymphoma/genetics
• Lymphoma/metabolism
• MicroRNAs/drug effects
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Vitamin D3 24-Hydroxylase

Parkinson’s disease is a neurodegenerative disorder and is marked by inflammation and death of neurons in the striatum region of the midbrain. It has been reported that expression of NF-κB increases during Parkinson’s disease, which promotes oxidative stress, stimulates release of proinflammatory cytokines, and induces expression of nitric oxide. Therefore, in this study, we have used mangiferin a specific NF-κB inhibitor. Mangiferin is a polyphenolic compound traditionally used for its antioxidant and anti-inflammatory properties.

The study utilized male Wistar rats weighing 200–250 g (56 rats; n = 8/group). On day “0,” stereotaxic surgery of rats was done to induce 6-hydroxydopamine lesioning in rats. Coordinates for substantia nigra were anteroposterior-2 mm, mediolateral-5 mm and dorsoventral-8.2 mm. After 14 days, those rats which show at least 210 contralateral rotations after administration of apomorphine (0.5 mg/kg S.C.) were selected for the study and were given treatment for 28 days. On day 28 of treatment, rats were subjected to behavioral studies to evaluate the effect of mangiferin and their brains were taken out after euthanasia to perform biochemical, molecular and immunological studies.

Treatment with mangiferin significantly improves the key parameters of locomotor activity and oxidative stress and reduces the parameters of inflammatory stress. Also, the activity of caspases was reduced. Significant decrease in activity of both cyclooxygenase 1 and 2 was also observed. Maximum improvement in all parameters was observed in rats treated with grouping of mangiferin 45 µg/kg and levodopa 10 mg/kg. Treatment with levodopa alone has no significant effect on biochemical and molecular parameters though it significantly improves behavioral parameters.

Current treatment of Parkinson’s disease does not target progression of Parkinson’s disease. Results of this study suggest that mangiferin has protective effect in hemi-Parkinsonian rats. Therefore, the combination therapy of mangiferin and levodopa can be helpful in management of Parkinson’s disease.

• 6-OHDA
• Caspases
• Cox
• Inflammation
• Mangiferin
• NF-κB
• Parkinson’s disease

• Apoptosis
• Cell cycle arrest
• E-cadherin
• Nuclear factor-kappa B
• Oxidative stress
• Solid Ehrlich carcinoma

The transcription factor p53 is frequently lost during tumor development in solid tumors; however, most melanomas retain a wild type p53 protein. The presence of wild type p53 in melanoma has fueled speculation that p53 may play a neutral or pro-tumorigenic role in this disease. Here we show that p53 is functional in human melanoma cell lines, and that loss of p53 results in a general reduction in basal NF-kB regulated cytokine production. The reduced cytokine expression triggered by p53 loss is broad and includes key inflammatory chemokines, such as CXCL1, CXCL8, and the IL6 class cytokine LIF, resulting in a reduced ability to induce chemotactic-dependent migration of tumor cells and immune cells and increased sensitivity to BRAF inhibition. Taken together, this result indicates that wild type p53 regulates cytokine expression and induces cytokine-dependent phenotype on melanoma.

• BRAF inhibitor
• NF-kB
• cytokines
• melanoma
• wild type p53

• Bcl-2
• C-fos
• KIM-1
• NF-κB/p53
• chloroacetaldehyde
• ifosfamide
• kidney
• morin
• nephrotoxicity
• rats

• Cancer progression
• Cancer therapy
• Gain of function mutation
• Tumor suppressor gene
• p53 signaling

• CRISPR screen
• HOIP
• IFN-gamma
• TNF
• immunotherapy

Preeclampsia is a pregnancy disorder associated with shallow placentation, forcing placental cells to live in hypoxic conditions. This activates the transcription factor kappa B (NFκB) in maternal and placental cells. Although the role of NFκB in preeclampsia is well documented, its mechanism of activation in trophoblastic cells has been never studied. This study investigates the mechanism of NFκB activation in a first trimester trophoblastic cell line (HTR8/SVneo) stimulated by a medium containing serum from preeclamptic (PE) or normotensive (C) women in hypoxic (2% O₂) or normoxic (8% O₂) conditions. The results indicate that in HTR8/SVneo cells, the most widely studied NFκB pathways, i.e., canonical, non-canonical and atypical, are downregulated in environment PE 2% O₂ in comparison to C 8% O₂. Therefore, other pathways may be responsible for NFκB activation. One such pathway depends on the activation of NFκB by the p53/RSK1 complex through its phosphorylation at Serine 536 (pNFκB Ser536). The data generated by our study show that inhibition of the p53/RSK1 pathway by p53-targeted siRNA results in a depletion of pNFκB Ser536 in the nucleus, but only in cells incubated with PE serum at 2% O₂. Thus, the p53/RSK1 complex might play a critical role in the activation of NFκB in trophoblastic cells and preeclamptic placentas.

• NFκB activation pathways
• p53/RSK1 complex
• preeclampsia
• trophoblastic cell line

• Phytochemicals
• cancer
• chemotherapy
• inflammation
• sensitization
• toxicity

• Apoptosis
• Autophagy
• Cancer
• Cell death
• Cytoprotection
• Tumor homeostasis

The advancement of nanotechnology in the last decade has developed an abundance of novel and intriguing TiO₂-based nanomaterials that are widely used in many sectors, including industry (as a food additive and colorant in cosmetics, paints, plastics, and toothpaste) and biomedicine (photoelectrochemical biosensing, implant coatings, drug delivery, and new emerging antimicrobial agents). Therefore, the increased use of engineered nanomaterials in the industry has raised serious concern about human exposure and their unexpected cytotoxic effects. Since inhalation is considered the most relevant way of absorbing nanomaterials, different cell death mechanisms induced in MRC-5 lung fibroblasts, following the exposure to functionalized TiO₂ NPs, were investigated. Long-term exposure to TiO₂ nanoparticles co-doped with 1% of iron and nitrogen led to the alteration of p53 protein activity and the gene expression controlled by this suppressor (NF-kB and mdm2), DNA damage, cell cycle disruptions at the G2/M and S phases, and lysosomal membrane permeabilization and the subsequent release of cathepsin B, triggering the intrinsic pathway of apoptosis in a Bax- and p53-independent manner. Our results are of major significance, contributing to the understanding of the mechanisms underlying the interaction of these nanoparticles with in vitro biological systems, and also providing useful information for the development of new photocatalytic nanoparticles that are active in the visible spectrum, but with increased biocompatibility.

• TiO2
• apoptosis
• autophagy
• cathepsin
• lung fibroblasts
• lysosome membrane permeabilization

• Apoptosis/drug effects
• Carbon Monoxide/chemistry
• Cell Cycle/drug effects
• Cell Death/drug effects
• Cell Line
• Cell Survival/drug effects
• Fibroblasts/drug effects
• Fibroblasts/metabolism
• Humans
• Iron/chemistry
• Lung/cytology
• Lung/metabolism
• Metal Nanoparticles/administration & dosage
• Metal Nanoparticles/chemistry
• Metal Nanoparticles/ultrastructure
• Microscopy, Electron, Transmission
• Nitrogen/chemistry
• Photoelectron Spectroscopy
• Reactive Oxygen Species/metabolism
• Titanium/chemistry
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism
• X-Ray Diffraction

p53 and NF-κBp65 are essential transcription factors (TFs) in the cellular response to stress. Two signaling systems can often be entwined together and generally produce opposing biological outcomes in a cell context-dependent manner. Inhibitor of apoptosis-stimulating protein of p53 (iASPP) has the potential to inhibit both p53 and NF-κBp65, yet how such activities of iASPP are integrated with cancer remains unknown. Here, we utilized different cell models with diverse p53/NF-κBp65 activities. An iASPP(295–828) mutant, which is exclusively located in the nucleus and has been shown to be essential for its inhibitory effects on p53/NF-κBp65, was used to investigate the functional interaction between iASPP and the two TFs. The results showed that iASPP inhibits apoptosis under conditions when p53 is activated, while it can also elicit a proapoptotic effect when NF-κBp65 alone is activated. Furthermore, we demonstrated that iASPP inhibited the transcriptional activity of p53/NF-κBp65, but with a preference toward p53, thereby producing an antiapoptotic outcome when both TFs were simultaneously activated. This may be due to stronger binding between p53 and iASPP than NF-κBp65 and iASPP. Overall, these findings provide important insights into how the activities of p53 and NF-κBp65 are modulated by iASPP. Despite being a well-known oncogene, iASPP may have a proapoptotic role, which will guide the development of iASPP-targeted therapies to reach optimal outcomes in the future.

Chemotherapy and ionizing radiation (IR) can induce autophagy in tumor cells. Here, we report that the level of autophagy in tumor cells was related to the background of p53 gene that NF-κB acts as a negative regulator of autophagy in mutant p53 (p53-R273H) cells, and that acetylation was involved in the IR-induced nuclear translocation of NF-κB. We found that autophagy-related proteins were highly expressed in wild-type p53 (wt-p53) cells and that IR increased their levels further. p53-R273H cells exhibited low levels of autophagy; there was no change following IR treatment. The nuclear translocation of p65 was upregulated in p53-R273H cells following IR; when p65 was competitively inhibited from entering the nucleus with SN50, the level of autophagy increased. The nuclear translocation of p65 was mediated by p300; this factor also regulates the nuclear behavior of NF-κB. The knockdown of p300 in p53-R273H cells led to an inhibition of p65 expression and an increase in autophagy. In addition, the inhibition of p300 or p65 not only activated autophagy, it also induced radiosensitivity in p53-R273H cells. The relationship between the p53 gene, NF-κB, and autophagy was further analyzed in a mouse model of xenograft tumors and in clinical tumor pathological specimens; the results were consistent with the in vitro experiments. Our findings indicate that autophagy may be regulated by NF-κB in p53-R273H cells. These findings may help to improve the therapeutic strategy adopted for tumors related to the mutant p53-R273H gene; such therapy would aim to target NF-κB to induce autophagy.

• Delta like canonical Notch ligand 3
• Immune infiltration
• Invasive breast cancer
• P53 signaling pathway
• Prognosis biomarker

• FBXO32/atrogin-1
• FoxO transcription factor
• aging
• cellular clearance system
• immune cells
• mild cognitive impairment
• neurodegeneration
• ubiquitin proteasome system (UPS)

• R01 AG031517 NIA NIH HHS
• R01 AG045058 NIA NIH HHS
• UL1 TR000101 NCATS NIH HHS
• UL1 TR001409 NCATS NIH HHS

• cancer metabolism
• drug development

• Animals
• Antineoplastic Combined Chemotherapy Protocols/pharmacology
• Apoptosis/drug effects
• Bortezomib/pharmacology
• Brain Neoplasms/drug therapy
• Brain Neoplasms/enzymology
• Brain Neoplasms/pathology
• Cell Line, Tumor
• Cell Movement/drug effects
• Cell Proliferation/drug effects
• Ciclopirox/pharmacology
• Drug Synergism
• Glioblastoma/drug therapy
• Glioblastoma/enzymology
• Glioblastoma/pathology
• Humans
• JNK Mitogen-Activated Protein Kinases/metabolism
• Male
• Mice, Inbred BALB C
• Mice, Nude
• NF-kappa B/metabolism
• Neoplasm Invasiveness
• Oxidative Phosphorylation/drug effects
• Reactive Oxygen Species/metabolism
• Signal Transduction
• Tumor Burden/drug effects
• Xenograft Model Antitumor Assays
• p38 Mitogen-Activated Protein Kinases/metabolism
• Mice

• National Natural Science Foundation of China (National Science Foundation of China)
• Key Discipline of Zhejiang Province in Medical Technology (First Class, Category A to B.L.)
• Key Research Project of Traditional Chinese Medicine of Zhejiang Province of China (2019ZZ015 to Z.S.)

• Amino Acids/chemistry
• Animals
• Bacteria/metabolism
• Dysbiosis
• Ecosystem
• Immunoglobulin A/metabolism
• Intestines
• Mammals/metabolism