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Nature Communications Jul 2024Cyclin-dependent kinases 4 and 6 (CDK4/6) play a pivotal role in cell cycle and cancer development. Targeting CDK4/6 has demonstrated promising effects against breast...
Cyclin-dependent kinases 4 and 6 (CDK4/6) play a pivotal role in cell cycle and cancer development. Targeting CDK4/6 has demonstrated promising effects against breast cancer. However, resistance to CDK4/6 inhibitors (CDK4/6i), such as palbociclib, remains a substantial challenge in clinical settings. Using high-throughput combinatorial drug screening and genomic sequencing, we find that the microphthalmia-associated transcription factor (MITF) is activated via O-GlcNAcylation by O-GlcNAc transferase (OGT) in palbociclib-resistant breast cancer cells and tumors. Mechanistically, O-GlcNAcylation of MITF at Serine 49 enhances its interaction with importin α/β, thus promoting its translocation to nuclei, where it suppresses palbociclib-induced senescence. Inhibition of MITF or its O-GlcNAcylation re-sensitizes resistant cells to palbociclib. Moreover, clinical studies confirm the activation of MITF in tumors from patients who are palbociclib-resistant or undergoing palbociclib treatment. Collectively, our studies shed light on the mechanism regulating palbociclib resistance and present clinical evidence for developing therapeutic approaches to treat CDK4/6i-resistant breast cancer patients.
Topics: Humans; Cyclin-Dependent Kinase 4; Breast Neoplasms; Cyclin-Dependent Kinase 6; Microphthalmia-Associated Transcription Factor; Female; Drug Resistance, Neoplasm; Piperazines; Pyridines; Cell Line, Tumor; N-Acetylglucosaminyltransferases; Animals; Mice; Protein Kinase Inhibitors; Xenograft Model Antitumor Assays
PubMed: 38961064
DOI: 10.1038/s41467-024-49875-w -
Cell Biochemistry and Biophysics Jul 2024Epithelial Ovarian Cancer (EOC) presents a global health concern, necessitating the development of innovative therapeutic strategies to combat its impact. This study was...
Epithelial Ovarian Cancer (EOC) presents a global health concern, necessitating the development of innovative therapeutic strategies to combat its impact. This study was employed to investigate the unexplored therapeutic efficacy of Cynodon dactylon phytochemicals against EOC using a multifaceted computational approach. A total of 19 out of 89 rigorously curated phytochemicals were assessed as potential drug targets via ADMET profiling, while protein-protein interaction analysis scrutinized the top 20 hub genes among 264 disease targets, revealing their involvement in cancer-related pathways and underscoring their significance in EOC pathogenesis. In molecular docking, Stigmasterol acetate showed the highest binding affinity (-10.9 kcal/mol) with Poly [ADP-ribose] polymerase-1 (PDB: 1UK1), while Arundoin and Beta-Sitosterol exhibited strong affinities (-10.4 kcal/mol and -10.1 kcal/mol, respectively); additionally, Beta-Sitosterol interacting with Mitogen-activated protein kinase 3 (PDB: 4QTB) showed a binding affinity of -10.1 kcal/mol, forming 2 hydrogen bonds and a total of 10 bonds with 10 residues. Molecular dynamics simulations exhibited the significant structural stability of the Beta-Sitosterol-4QTB complex with superior binding free energy (-36.61 kcal/mol) among the three complexes. This study identified C. dactylon phytosterols, particularly Beta-Sitosterol, as effective in targeting MAPK3 and PARP1 to combat EOC, laying the groundwork for further experimental validation and drug development efforts.
PubMed: 38961033
DOI: 10.1007/s12013-024-01375-w -
Child's Nervous System : ChNS :... Jul 2024Glioneuronal tumors (GNTs) are an expanding group of primary CNS neoplasms, commonly affecting children, adolescents and young adults. Most GNTs are relatively indolent,...
Glioneuronal tumors (GNTs) are an expanding group of primary CNS neoplasms, commonly affecting children, adolescents and young adults. Most GNTs are relatively indolent, low-grade, WHO grade I lesions. In the pediatric age group, GNTs have their epicenter in the cerebral cortex and present with seizures. Alterations in the mitogen-activated protein kinase (MAPK) pathway, which regulates cell growth, are implicated in tumorigenesis. Imaging not only plays a key role in the characterization and pre-surgical evaluation of GNTs but is also crucial role in follow-up, especially with the increasing use of targeted inhibitors and immunotherapies. In this chapter, we review the clinical and imaging perspectives of common pediatric GNTs.
PubMed: 38960918
DOI: 10.1007/s00381-024-06502-9 -
Journal of Microbiology and... Jun 2024Inflammation is a biodefense mechanism that provides protection against painful conditions such as inflammatory bowel disease, other gastrointestinal problems, and...
Inflammation is a biodefense mechanism that provides protection against painful conditions such as inflammatory bowel disease, other gastrointestinal problems, and irritable bowel syndrome. Paraprobiotics have probiotic characteristics of intestinal modulation along with merits of safety and stability. In this study, heat-killed KU15122 (KU15122) was investigated for its anti-inflammatory properties. KU15122 was subjected to heat-killed treatment for enhancement of its safety, and its concentration was set at 8 log CFU/mL for conducting different experiments. Nitric oxide production was most remarkably reduced in the KU15122 group, whereas it was increased in the LPS-treated group. In RAW 264.7 cells, KU15122 inhibited the expression of inducible nitric oxide synthase, cyclooxygenase-2, interleukin (IL)-1β, IL-6, and tumor necrosis factor-α. ELISA revealed that among the tested strains, KU15122 exhibited the most significant reduction in PGE2, IL-1β, and IL-6. Moreover, KU15122 inhibited various factors involved in the nuclear factor-kappa B, activator protein-1, and mitogen-activated protein kinase pathways. In addition, KU15122 reduced the generation of reactive oxygen species. The anti-inflammatory effect of KU15122 was likely attributable to the bacterial exopolysaccharides. Conclusively, KU15122 exhibits anti-inflammatory potential against inflammatory diseases.
PubMed: 38960876
DOI: 10.4014/jmb.2404.04052 -
Experimental Animals Jul 2024Acute lung injury (ALI) is a common complication after hemorrhagic shock (HS), which is associated with HS-induced inflammatory response, oxidative stress, and cell...
Acute lung injury (ALI) is a common complication after hemorrhagic shock (HS), which is associated with HS-induced inflammatory response, oxidative stress, and cell apoptosis. This study aimed to investigate the therapeutic efficacy of 8-Gingerol, a constituent extracted from ginger, on ALI after HS in rats. We established a fixed press hemorrhage model in SD rats, in which the HS rats were administered 15 or 30 mg/kg of 8-Gingerol by intraperitoneal injection before fluid resuscitation. H&E staining and TUNEL staining were performed to evaluate histopathological changes and cell apoptosis in lung tissues, respectively. Quantitative reverse transcription PCR and Western blot were used to measure gene and protein expression. Pro-inflammatory cytokines were detected by ELISA kits. Immunofluorescence of myeloperoxidase was used to evaluate neutrophil infiltration. 8-Gingerol reduced pulmonary edema, alveolar wall thickness, and cell apoptosis in lung tissues of HS rats. Regarding inflammatory responses, 8-Gingerol attenuated neutrophil infiltration in lung tissues, reduced pro-inflammatory cytokines in lung tissues and bronchoalveolar lavage fluid, and decreased the levels of NLRP3, ASC, and cleaved caspase 1 in lung tissues. Additionally, 8-Gingerol ameliorated oxidative stress in lung tissues as evidenced by increased antioxidant indicators (SOD and GSH) and decreased production of MDA and ROS. The therapeutic effects of 8-Gingerol were associated with the regulation of MAPK and Nrf2/HO-1 pathways. These results support 8-Gingerol as a promising drug for the treatment of HS-induced ALI.
PubMed: 38960678
DOI: 10.1538/expanim.23-0178 -
Life Science Alliance Sep 2024A pleiotropic immunoregulatory cytokine, TGF-β, signals via the receptor-regulated SMADs: SMAD2 and SMAD3, which are constitutively expressed in normal cells. Here, we...
A pleiotropic immunoregulatory cytokine, TGF-β, signals via the receptor-regulated SMADs: SMAD2 and SMAD3, which are constitutively expressed in normal cells. Here, we show that selective repression of SMAD3 induces cDC differentiation from the CD115 common DC progenitor (CDP). SMAD3 was expressed in haematopoietic cells including the macrophage DC progenitor. However, SMAD3 was specifically down-regulated in CD115 CDPs, SiglecH pre-DCs, and cDCs, whereas SMAD2 remained constitutive. SMAD3-deficient mice showed a significant increase in cDCs, SiglecH pre-DCs, and CD115 CDPs compared with the littermate control. SMAD3 repressed the mRNA expression of FLT3 and the cDC-related genes: IRF4 and ID2. We found that one of the SMAD transcriptional corepressors, c-SKI, cooperated with phosphorylated STAT3 at Y705 and S727 to repress the transcription of SMAD3 to induce cDC differentiation. These data indicate that STAT3 and c-Ski induce cDC differentiation by repressing SMAD3: the repressor of the cDC-related genes during the developmental stage between the macrophage DC progenitor and CD115 CDP.
Topics: Animals; Cell Differentiation; Dendritic Cells; Smad3 Protein; STAT3 Transcription Factor; Mice; Interferon Regulatory Factors; Inhibitor of Differentiation Protein 2; Mice, Knockout; Mice, Inbred C57BL; fms-Like Tyrosine Kinase 3; Proto-Oncogene Proteins; Smad2 Protein; Phosphorylation; Signal Transduction
PubMed: 38960622
DOI: 10.26508/lsa.201900581 -
BMJ Open Ophthalmology Jul 2024To investigate if there are improvements in trabeculectomy outcomes supporting filtration bleb formation caused by Rho-associated protein kinase (ROCK) inhibitors. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
To investigate if there are improvements in trabeculectomy outcomes supporting filtration bleb formation caused by Rho-associated protein kinase (ROCK) inhibitors.
METHODS
This prospective, multicentre, randomised, open-label clinical study examined open-angle glaucoma patients who underwent trabeculectomy or trabeculectomy combined with cataract surgery followed by 3-month postoperative ripasudil treatments. After randomly allocating patients to ripasudil-ROCK inhibitor (ripasudil) or without ripasudil (non-ripasudil) groups. Mean intraocular pressure (IOP) changes, success rate, and number of eyedrops were compared for both groups.
RESULTS
A total of 17 and 15 subjects dropped out in the ripasudil group and non-ripasudil group, respectively. At baseline, the mean IOP was 16.8±5.0 mm Hg in the ripasudil group (38 patients) and 16.2±4.4 in the non-ripasudil group (52 patients). The IOP decreased to 11.4±3.2 mm Hg, 10.9±3.9 mm Hg and 10.6±3.5 mm Hg at 12, 24 and 36 months in the ripasudil group, while it decreased to 11.2±4.1 mm Hg, 10.5±3.1 mm Hg and 10.9±3.2 mm Hg at 12, 24 and 36 months in the non-ripasudil group, respectively. There was a significant decrease in the number of IOP-lowering medications after trabeculectomy in the ripasudil group versus the non-ripasudil group at 24 (p=0.010) and 36 months (p=0.016). There was no statistically significant difference between the groups for the 3-year cumulative probability of success.
CONCLUSION
Although ripasudil application did not increase the primary trabeculectomy success rate, it did reduce IOP-lowering medications after trabeculectomy with mitomycin C.
Topics: Humans; Trabeculectomy; Male; Intraocular Pressure; Prospective Studies; Female; Glaucoma, Open-Angle; Isoquinolines; Aged; Sulfonamides; Mitomycin; Middle Aged; rho-Associated Kinases; Treatment Outcome; Alkylating Agents
PubMed: 38960415
DOI: 10.1136/bmjophth-2023-001449 -
Environmental Research Jul 2024Tetracycline (TC) and ciprofloxacin (CF) induce a synergistic effect that alters the biochemical composition, leading to a decrease in the growth and photosynthetic...
Tetracycline (TC) and ciprofloxacin (CF) induce a synergistic effect that alters the biochemical composition, leading to a decrease in the growth and photosynthetic efficiency of microalgae. But the current study provides a novel insight into stress-inducing techniques that trigger a change in macromolecules, leading to an increase in the bioenergy potential and pathogen resistance of Chlorella variabilis biofilm. The study revealed that in a closed system, a light intensity of 167 μmol/m/s causes 93.5% degradation of TC and 16% degradation of CF after 7 days of exposure, hence availing the products for utilization by C. variabilis biofilm. The resistance to pathogens invasion was linked to 85% and 40% increase in the expression level of photosystem II oxygen-evolving enhancer protein 3 (PsbQ), and mitogen activated kinase (MAK) respectively. The results also indicate that a surge in light intensity triggers 49% increase in the expression level of lysophosphatidylcholine (LPC) (18:2), which is an important lipidomics that can easily undergo transesterification into bioenergy. The thermogravimetric result indicates that the biomass sample of C. variabilis biofilm cultivated under light intensity of 167 μmol/m2/s produces a higher residual mass of 45.5% and 57.5 under air and inert conditions, respectively. The Fourier transform infrared (FTIR) indicates a slight shift in the major functional groups, while the energy-dispersive X-ray spectroscopy (SEM-EDS) and X-ray fluorescence (XRF) indicate clear differences in the morphology and elemental composition of the biofilm biomass in support of the increase bioenergy potential of C. variabilis biofilm. The current study provides a vital understanding of a innovative method of cultivation of C. variabilis biofilm, which is resistant to pathogens and controls the balance between fatty acid and TAG synthesis leading to surge in bioenergy potential and environmental sustainability.
PubMed: 38960350
DOI: 10.1016/j.envres.2024.119521 -
International Journal of Biological... Jul 2024This study aimed to determine the immunostimulatory activities of ulvan type polysaccharides isolated from Ulva pertusa. First, U. pertusa polysaccharide (UPP) mainly...
This study aimed to determine the immunostimulatory activities of ulvan type polysaccharides isolated from Ulva pertusa. First, U. pertusa polysaccharide (UPP) mainly consists of rhamnose, glucuronic acid, iduronic acid, and xylose, which are typical ulvan type monosaccharides. UPP induced phosphorylation of the mitogen-activated protein kinase and nuclear factor-kappa B pathways in macrophages, subsequently triggering cytokine release and phagocytosis. The effects were closely associated with pattern recognition receptors such as dectin-1, mannose receptor, CD11b, CD14, and Toll-like receptors 2 and 4. Moreover, prophylactic administration of UPP was found to protect against body weight loss and lymphatic organ damage in cyclophosphamide-induced immunosuppressed mice. In addition, UPP demonstrated significant stimulatory effects on various immunocytes, such as T cells, B cells, macrophages, and natural killer cells derived from the spleen. These effects were closely related to the mitogen-activated protein kinase and nuclear factor-kappa B pathways, and significant secretion of immunostimulatory cytokines such as IL-6, -12, and TNF-α was noted in both blood and spleen samples. Impairment of the short-chain fatty acid balance in the cecum was prevented by UPP administration in a dose-dependent manner. Consequently, these results suggest that the UPP isolated from U. pertusa contributes to immune system activation.
PubMed: 38960236
DOI: 10.1016/j.ijbiomac.2024.133518 -
Biochimica Et Biophysica Acta.... Jul 2024Malignant cell plasticity is an important hallmark of tumor biology and crucial for metastasis and resistance. Cell plasticity lets cancer cells adapt to and escape the...
Malignant cell plasticity is an important hallmark of tumor biology and crucial for metastasis and resistance. Cell plasticity lets cancer cells adapt to and escape the therapeutic strategies, which is the leading cause of cancer patient mortality. Epithelial cells acquire mobility via epithelial-mesenchymal transition (EMT), whereas mesenchymal cells enhance their migratory ability and clonogenic potential by acquiring amoeboid characteristics through mesenchymal-amoeboid transition (MAT). Tumor formation, progression, and metastasis depend on the tumor microenvironment (TME), a complex ecosystem within and around a tumor. Through increased migration and metastasis of cancer cells, the TME also contributes to malignancy. This review underscores the distinction between invasion pattern morphological manifestations and the diverse structures found within the TME. Furthermore, the mechanisms by which amoeboid-associated characteristics promote resistance and metastasis and how these mechanisms may represent therapeutic opportunities are discussed.
PubMed: 38960056
DOI: 10.1016/j.bbadis.2024.167332