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Frontiers in Pharmacology 2024
PubMed: 38957389
DOI: 10.3389/fphar.2024.1440937 -
Frontiers in Pharmacology 2024[This corrects the article DOI: 10.3389/fphar.2023.1291900.].
[This corrects the article DOI: 10.3389/fphar.2023.1291900.].
PubMed: 38957385
DOI: 10.3389/fphar.2024.1438588 -
Frontiers in Oncology 2024There is no clear information in the literature about the relationship between the efficacy of CDK 4/6i combined with ET and HR positivity. However, we know that the...
Is the percentage of hormone receptor positivity in HR+ HER2-metastatic breast cancer patients receiving CDK 4/6 inhibitor with endocrine therapy predictive and prognostic?
PURPOSE
There is no clear information in the literature about the relationship between the efficacy of CDK 4/6i combined with ET and HR positivity. However, we know that the longest overall survival was in the ER-strong positive/PR intermediate or strong positive groups. Therefore, we aimed to investigate CDK4/6i treatments that create positivity in HR.
METHODS
Patients with the diagnosis of HR+/HER2- MBC who were treated with CDK 4/6i and HR >10% were retrospectively evaluated. To analyze the role of HR positivity, ER was moderately positive (10-49%) and ER was strongly positive (50-100%); PR was grouped as moderately positive (10-49%) and PR strongly positive (50-100%).
RESULTS
Median follow-up of 150 patients included in the study was 15.2 months (95% CI, 2.1-40.9 months). The highest response in the whole group was obtained in the ER-strong positive/PR moderate or strong positive group, and the ER moderate positive/PR moderate or strong group. This was followed by the ER strong positive/PR negative group, and then the ER moderate positive/PR negative group. Although these advantages were not statistically significant, they were numerically higher (ORR: 83.8% vs. 83.3% vs. 77.4% vs. 62.5%, p=0.488, respectively). The highest survival in the whole group was achieved in the ER strong positive/PR moderate or strongly positive group, followed by the ER moderately positive/PR moderate or strongly positive group, the ER strongly positive/PR negative group followed by the ER moderate positive/PR negative group, respectively(p=0.410). However, these advantages were not statistically significant.
CONCLUSION
As a result, HR+/HER2- MBC patients receiving CDK 4/6i combined with ET suggest that the percentage of HR positivity may have a predictive and prognostic role.
PubMed: 38957324
DOI: 10.3389/fonc.2024.1378563 -
APL Bioengineering Sep 2024Cell migration is the major driver of invasion and metastasis during cancer progression. For cells to migrate, they utilize the actin-myosin cytoskeleton and adhesion...
Cell migration is the major driver of invasion and metastasis during cancer progression. For cells to migrate, they utilize the actin-myosin cytoskeleton and adhesion molecules, such as integrins and CD44, to generate traction forces in their environment. CD44 primarily binds to hyaluronic acid (HA) and integrins primarily bind to extracellular matrix (ECM) proteins such as collagen. However, the role of CD44 under integrin-mediated conditions and vice versa is not well known. Here, we performed traction force microscopy (TFM) on U251 cells seeded on collagen I-coated polyacrylamide gels to assess the functional mechanical relationship between integrins and CD44. Performing TFM on integrin-mediated adhesion conditions, i.e., collagen, we found that CD44KO U251 cells exerted more traction force than wild-type (WT) U251 cells. Furthermore, untreated WT and CD44-blocked WT exhibited comparable results. Conversely, in CD44-mediated adhesive conditions, integrin-blocked WT cells exerted a higher traction force than untreated WT cells. Our data suggest that CD44 and integrins have a mutually antagonistic relationship where one receptor represses the other's ability to generate traction force on its cognate substrate.
PubMed: 38957223
DOI: 10.1063/5.0203028 -
JOR Spine Sep 2024Pre-clinical animal experiment.
STUDY DESIGN
Pre-clinical animal experiment.
OBJECTIVE
In this study, we investigated therapeutic effects of silibinin in a spinal cord injury (SCI) model. In SCI, loss of cells due to secondary damage mechanisms exceeds that caused by primary damage. Ferroptosis, which is iron-dependent non-apoptotic cell death, is shown to be influential in the pathogenesis of SCI.
METHODS
The study was conducted as an in vivo experiment using a total of 78 adult male/female Sprague Dawley rats. Groups were as follows: Sham, SCI, deferoxamine (DFO) treatment, and silibinin treatment. There were subgroups with follow-up periods of 24 h, 72 h, and 6 weeks in all groups. Malondialdehyde (MDA), glutathione (GSH), and Fe levels were measured by spectrophotometry. Glutathione peroxidase-4 (GPX4), ferroportin (FPN), transferrin receptor (TfR1), and 4-hydroxynonenal (4-HNE)-modified protein levels were assessed by Western blotting. Functional recovery was assessed using Basso-Beattie-Bresnahan test.
RESULTS
Silibinin achieved significant suppression in MDA and 4-HNE levels compared to the SCI both in 72-h and 6 weeks group ( < 0.05). GSH, GPX4, and FNP levels were found to be significantly higher in the silibinin 24 h, 72 h, and 6 weeks group compared to corresponding SCI groups ( < 0.05). Significant reduction in iron levels was observed in silibinin treated rats in 72 h and 6 weeks group ( < 0.05). Silibinin substantially suppressed TfR1 levels in 24 h and 72 h groups ( < 0.05). Significant difference among recovery capacities was observed as follows: Silibinin > DFO > SCI ( < 0.05).
CONCLUSION
Impact of silibinin on iron metabolism and lipid peroxidation, both of which are features of ferroptosis, may contribute to therapeutic activity. Within this context, our findings posit silibinin as a potential therapeutic candidate possessing antiferroptotic properties in SCI model. Therapeutic agents capable of effectively and safely mitigating ferroptotic cell death hold the potential to be critical points of future clinical investigations.
PubMed: 38957164
DOI: 10.1002/jsp2.1344 -
Cancer Research Communications Jul 2024Various lines of investigation support a signaling interphase shared by receptor tyrosine kinases and the DNA damage response. However, the underlying network nodes and...
Various lines of investigation support a signaling interphase shared by receptor tyrosine kinases and the DNA damage response. However, the underlying network nodes and their contribution to the maintenance of DNA integrity remain unknown. We explored MET-related metabolic pathways whose interruption compromises proper resolution of DNA damage. Discovery metabolomics combined with transcriptomics identified changes in pathways relevant to DNA repair following MET inhibition (METi). METi by tepotinib was associated with formation of γH2AX foci and with significant alterations in major metabolic circuits such as glycolysis, gluconeogenesis, and purine, pyrimidine, amino acids, and lipids metabolism. 5'-Phosphoribosyl-N-formylglycinamide (FGAR), a de novo purine synthesis pathway metabolite, was consistently decreased in in vitro and in vivo MET-dependent models, and a METi-related depletion of dNTPs was observed. METi instigated the downregulation of critical purine synthesis enzymes including phosphoribosylglycinamide formyltransferase (GART) which catalyzes FGAR synthesis. Genes encoding these enzymes are regulated through E2F1, whose levels decrease upon METi in MET-driven cells and xenografts. Transient E2F1 overexpression prevented dNTPs depletion and the concomitant METi-associated DNA damage in MET-driven cells. We conclude that DNA damage following METi results from dNTPs reduction via downregulation of E2F1 and a consequent decline of de novo purine synthesis.
PubMed: 38957115
DOI: 10.1158/2767-9764.CRC-23-0370 -
Journal of Cellular and Molecular... Jul 2024Pruritus is often accompanied with bacterial infections, but the underlying mechanism is not fully understood. Although previous studies revealed that...
Pruritus is often accompanied with bacterial infections, but the underlying mechanism is not fully understood. Although previous studies revealed that lipopolysaccharides (LPS) could directly activate TRPV4 channel and TRPV4 is involved in the generation of both acute itch and chronic itch, whether and how LPS affects TRPV4-mediated itch sensation remains unclear. Here, we showed that LPS-mediated TRPV4 sensitization exacerbated GSK101-induced scratching behaviour in mice. Moreover, this effect was compromised in TLR4-knockout mice, suggesting LPS acted through a TLR4-dependent mechanism. Mechanistically, LPS enhanced GSK101-evoked calcium influx in mouse ear skin cells and HEK293T cells transfected with TRPV4. Further, LPS sensitized TRPV4 channel through the intracellular TLR4-PI3K-AKT signalling. In summary, our study found a modulatory role of LPS in TRPV4 function and highlighted the TLR4-TRPV4 interaction in itch signal amplification.
Topics: TRPV Cation Channels; Animals; Toll-Like Receptor 4; Pruritus; Lipopolysaccharides; Humans; Signal Transduction; Mice; HEK293 Cells; Phosphatidylinositol 3-Kinases; Mice, Knockout; Mice, Inbred C57BL; Male; Calcium; Proto-Oncogene Proteins c-akt
PubMed: 38957035
DOI: 10.1111/jcmm.18509 -
International Neurourology Journal Jun 2024To critically analyse the relationship of bladder pain syndrome (BPS/IC), as defined, to the posterior fornix syndrome, "PFS" predictably co-occurring bladder urgency,...
To critically analyse the relationship of bladder pain syndrome (BPS/IC), as defined, to the posterior fornix syndrome, "PFS" predictably co-occurring bladder urgency, frequency, nocturia, chronic pelvic pain, emptying symptoms/retention, caused by uterosacral ligament (USL) laxity and cured by USL repair. The starting and end points of this paper are the questions, "Are there arguments that BPS/IC can, in some cases, be linked to PFS?" And if so, "To what extent?" We used the criteria required by Ueda for proper diagnosis: "understanding symptoms, detecting abnormal findings and verifying them as a cause of the symptoms." Literature, diagnostic and surgical, indicate that chronic pelvic pain "of unknown origin" can be caused by unsupported visceral pelvic plexuses because of weak USLs; these cause fire of afferent impulses, which the brain mistakenly interprets as coming from the end-organ itself (i.e., genitourinary pain, lower urinary tract symptoms). The same lax USLs can also weaken the pelvic muscles which contract to stretch the vagina to support the urothelial stretch receptors from below: these may prematurely fire off afferent impulses to activate micturition at lower bladder volumes, interpreted as urgency. A speculum placed in the vagina can relieve pain and urgency by mechanically supporting the vaginal wall and USLs, thus predicting an eventual cure by USL repair. There is need to evaluate what percentage of women with known BPS/IC also pass the criteria for PFS. Identifying a significant percentage of BPS/IC women with the causative relation between PFS pathogenesis and BPS/ IC may open a new way of diagnosing and treating BPS/IC in some women.
PubMed: 38956769
DOI: 10.5213/inj.2346344.172 -
Parasites & Vectors Jul 2024Toxoplasma gondii infection affects a significant portion of the global population, leading to severe toxoplasmosis and, in immunocompromised patients, even death....
BACKGROUND
Toxoplasma gondii infection affects a significant portion of the global population, leading to severe toxoplasmosis and, in immunocompromised patients, even death. During T. gondii infection, disruption of gut microbiota further exacerbates the damage to intestinal and brain barriers. Therefore, identifying imbalanced probiotics during infection and restoring their equilibrium can regulate the balance of gut microbiota metabolites, thereby alleviating tissue damage.
METHODS
Vimentin gene knockout (vim-/-) mice were employed as an immunocompromised model to evaluate the influence of host immune responses on gut microbiota balance during T. gondii infection. Behavioral experiments were performed to assess changes in cognitive levels and depressive tendencies between chronically infected vim-/- and wild-type (WT) mice. Fecal samples were subjected to 16S ribosomal RNA (rRNA) sequencing, and serum metabolites were analyzed to identify potential gut probiotics and their metabolites for the treatment of T. gondii infection.
RESULTS
Compared to the immunocompetent WT sv129 mice, the immunocompromised mice exhibited lower levels of neuronal apoptosis and fewer neurobehavioral abnormalities during chronic infection. 16S rRNA sequencing revealed a significant decrease in the abundance of probiotics, including several species of Lactobacillus, in WT mice. Restoring this balance through the administration of Lactobacillus murinus and Lactobacillus gasseri significantly suppressed the T. gondii burden in the intestine, liver, and brain. Moreover, transplantation of these two Lactobacillus spp. significantly improved intestinal barrier damage and alleviated inflammation and neuronal apoptosis in the central nervous system. Metabolite detection studies revealed that the levels of various Lactobacillus-related metabolites, including indole-3-lactic acid (ILA) in serum, decreased significantly after T. gondii infection. We confirmed that L. gasseri secreted much more ILA than L. murinus. Notably, ILA can activate the aromatic hydrocarbon receptor signaling pathway in intestinal epithelial cells, promoting the activation of CD8 T cells and the secretion of interferon-gamma.
CONCLUSION
Our study revealed that host immune responses against T. gondii infection severely disrupted the balance of gut microbiota, resulting in intestinal and brain damage. Lactobacillus spp. play a crucial role in immune regulation, and the metabolite ILA is a promising therapeutic compound for efficient and safe treatment of T. gondii infection.
Topics: Animals; Gastrointestinal Microbiome; Mice; Toxoplasma; Mice, Knockout; Brain Injuries; Probiotics; Brain; Lactobacillus; Disease Models, Animal; Immunocompromised Host; Toxoplasmosis; RNA, Ribosomal, 16S; Male; Intestines
PubMed: 38956725
DOI: 10.1186/s13071-024-06349-8 -
Stem Cell Research & Therapy Jul 2024Repairation of bone defects remains a major clinical problem. Constructing bone tissue engineering containing growth factors, stem cells, and material scaffolds to...
BACKGROUND
Repairation of bone defects remains a major clinical problem. Constructing bone tissue engineering containing growth factors, stem cells, and material scaffolds to repair bone defects has recently become a hot research topic. Nerve growth factor (NGF) can promote osteogenesis of bone marrow mesenchymal stem cells (BMSCs), but the low survival rate of the BMSCs during transplantation remains an unresolved issue. In this study, we investigated the therapeutic effect of BMSCs overexpression of NGF on bone defect by inhibiting pyroptosis.
METHODS
The relationship between the low survival rate and pyroptosis of BMSCs overexpressing NGF in localized inflammation of fractures was explored by detecting pyroptosis protein levels. Then, the NGF/BMSCs-NSA-Sca bone tissue engineering was constructed by seeding BMSCs overexpressing NGF on the allograft bone scaffold and adding the pyroptosis inhibitor necrosulfonamide(NSA). The femoral condylar defect model in the Sprague-Dawley (SD) rat was studied by micro-CT, histological, WB and PCR analyses in vitro and in vivo to evaluate the regenerative effect of bone repair.
RESULTS
The pyroptosis that occurs in BMSCs overexpressing NGF is associated with the nerve growth factor receptor (P75NTR) during osteogenic differentiation. Furthermore, NSA can block pyroptosis in BMSCs overexpression NGF. Notably, the analyses using the critical-size femoral condylar defect model indicated that the NGF/BMSCs-NSA-Sca group inhibited pyroptosis significantly and had higher osteogenesis in defects.
CONCLUSION
NGF/BMSCs-NSA had strong osteogenic properties in repairing bone defects. Moreover, NGF/BMSCs-NSA-Sca mixture developed in this study opens new horizons for developing novel tissue engineering constructs.
Topics: Animals; Nerve Growth Factor; Mesenchymal Stem Cells; Rats; Tissue Scaffolds; Rats, Sprague-Dawley; Osteogenesis; Bone Regeneration; Allografts; Male; Tissue Engineering; Pyroptosis; Sulfonamides; Cell Differentiation; Mesenchymal Stem Cell Transplantation; Bone Transplantation
PubMed: 38956719
DOI: 10.1186/s13287-024-03807-z