Search Results (346)

Current treatments against leukemia present several limitations, prompting the search for new therapeutic agents, particularly those derived from natural products. In this context, structural modifications were performed on the triterpene 3α,24-dihydroxylup-20(29)-en-28-oic acid (T1), isolated from Phoradendron wattii. Among the five derivatives obtained, 3α,24-dihydroxy-30-oxolup-20(29)-en-28-oic acid (T1c) exhibited the highest activity, with an IC₅₀ value of 12.90 ± 0.1 µM against THP-1 cells. T1c significantly reduced cell viability in both acute lymphoblastic leukemia (CCRF-CEM, REH, JURKAT, and MOLT-4) and acute myeloid leukemia (THP-1) cell lines, inducing apoptosis after 48 h of treatment, while showing minimal cytotoxicity toward normal mononuclear cells (MNCs). In silico molecular docking studies were conducted against three key protein targets: BCL-2 (B-cell lymphoma 2), EGFR (epidermal growth factor receptor, tyrosine kinase domain), and FLT3 (FMS-like tyrosine kinase 3). The lowest binding energies (kcal/mol) observed were as follows: T1–BCL-2: −10.12, EGFR: −12.75, FLT3: −14.05; T1c–BCL-2: −10.23, EGFR: −14.50, FLT3: −14.07; T2–BCL-2: −11.59, EGFR: −15.00, FLT3: −14.03. These findings highlight T1c as a promising candidate in the search for anti-leukemic drugs which deserves further study. Full article

Neutrophils play a key role in autoimmune diseases like rheumatoid arthritis, contributing to tissue damage through rapid recruitment and activation. In this study, we investigated the regulatory properties of two receptor-like tyrosine phosphatases (RPTPs), CD45 and CD148, in inflammatory arthritis. Using an in vivo mouse model of K/BxN serum transfer-induced arthritis, we found that CD45 and CD148 feature distinct regulatory properties during inflammatory arthritis. CD45 is required for neutrophil infiltration, cytokine release, and reactive oxygen species production, whereas CD148 deficiency leads to a delayed onset of arthritis but unaltered overall neutrophil infiltration and reduced ROS production. Furthermore, we could demonstrate that activation of Src family kinases in neutrophils is differentially regulated by CD45 and CD148 in a stimulus-dependent manner. Summarizing, our results suggest that CD45 is positively involved, while CD148 is positively and negatively involved in neutrophil recruitment and function during inflammatory arthritis. Full article

Neurotrophins and inflammatory mediators are known to influence endometrial function, but their interplay in luminal epithelial cells remains poorly characterized. In this study, sheep endometrial luminal epithelial cells (SELECs) were treated with nerve growth factor (NGF), lipopolysaccharide (LPS), or both, and the effects on gene expression and prostaglandin secretion were evaluated. NGF stimulation alone induced a clear transcriptional activation of NGF, neurotrophic receptor tyrosine kinase 1 (NTRK1), p75 neurotrophin receptor (p75NTR), cyclooxygenase 2 (COX2), and steroidogenic acute regulatory protein (STAR). LPS treatment selectively increased Toll-like receptor 4 (TLR4), COX2, and insulin-like growth factor binding protein 6 (IGFBP6). Combined NGF and LPS treatment did not enhance the transcriptional response beyond that induced by NGF alone, except for STAR. However, co-treatment resulted in a modest increase in prostaglandin production, particularly prostaglandin F2α (PGF2α), but not prostaglandin E2 (PGE2), compared to single treatments, suggesting a possible post-transcriptional modulation rather than a transcriptional synergy. These findings indicate that NGF acts as the primary transcriptional driver in SELECs, while LPS contributes selectively and may enhance prostaglandin output. The observed increase in prostaglandin production may involve post-transcriptional mechanisms, although this remains to be confirmed. Full article

Background/Objectives: Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer, with limited responsiveness to immune checkpoint inhibitors (ICIs). Cancer vaccine therapy is a promising novel immunotherapeutic approach that stimulates tumor-specific T cells. Receptor tyrosine kinase-like orphan receptor 1 (ROR1), which is overexpressed in malignant tumors but minimally expressed in normal tissues, presents a promising target for immunotherapy. This study aimed to evaluate ROR1 as a target for helper T lymphocyte (HTL)-based peptide vaccine immunotherapy in HNSCC. Methods: ROR1 expression in HNSCC tissues was assessed by immunohistochemistry. A novel ROR1-derived epitope (ROR1_403–417) was identified and used to generate ROR1-reactive HTLs. Functional assays measuring IFN-γ and granzyme B secretion, as well as direct cytotoxicity, were performed. The effects of ICIs on HTL activity were also examined. The presence of ROR1-reactive T cells in the peripheral blood of patients with HNSCC was evaluated. Results: ROR1 positivity rates in HNSCC tissues were significantly higher (80.0%) than those in healthy controls (16.7%), and high ROR1 expression correlated with advanced clinical stages. HTL lines recognized the ROR1_403–417 peptide in a human leukocyte antigen (HLA)-DR-restricted manner, secreted effector cytokines, and exhibited direct cytotoxicity against ROR1+ tumor cells. Dual PD-L1/PD-L2 blockade further enhanced HTL responses. ROR1-reactive T cells were detected in the peripheral blood of patients with HNSCC. Conclusions: ROR1 represents a promising target for immunotherapy in HNSCC. The ROR1_403–417 peptide can elicit ROR1-reactive HTLs that exhibit antitumor responses against HNSCC cell lines, which can be enhanced by ICIs. These findings support the potential of ROR1-targeted peptide vaccine therapy for HNSCC. Full article

Background: Chronic postsurgical pain (CPSP) poses a major clinical challenge due to unresolved links between neurotrophic pathways and endoplasmic reticulum (ER) stress. While Neurotrophic Tyrosine Kinase Receptor Type 1 (NTRK1) modulates ER stress in neuropathic pain, its interaction with Insulin-Like Growth Factor II (IGF2) in CPSP remains uncharacterized, impeding targeted therapy. This study defined the spinal NTRK1-IGF2-ER stress axis in CPSP. Methods: Using a skin/muscle incision–retraction (SMIR) rat model, we integrated molecular analyses and intrathecal targeting of NTRK1 (GW441756) or IGF2 (siRNA). Results: SMIR surgery upregulated spinal NTRK1, IGF2, and ER stress mediators. NTRK1 inhibition reduced both NTRK1/IGF2 expression and ER stress, reversing mechanical allodynia. IGF2 silencing attenuated ER stress and pain but did not affect NTRK1, revealing a unidirectional signaling cascade where NTRK1 drives IGF2-dependent ER stress amplification. These findings expand understanding of stress-response networks in chronic pain. Conclusions: We show that spinal NTRK1 drives IGF2-mediated ER stress to sustain CPSP. The NTRK1-IGF2-ER stress axis represents a novel therapeutic target; NTRK1 inhibitors and IGF2 biologics offer non-opioid strategies for precision analgesia. This work advances CPSP management and demonstrates how decoding unidirectional signaling hierarchies can transform neurological disorder interventions. Full article

Cancer remains a major global health burden driven by complex biological mechanisms, and while targeted therapies like tyrosine kinase inhibitors (TKIs) have revolutionized treatment, their efficacy and safety are significantly influenced by drug–drug interactions (DDIs). Tyrosine-kinase receptors (RTKs) regulate critical cellular processes, and their dysregulation through mutations or overexpression drives oncogenesis, with TKIs designed to inhibit these aberrant signaling pathways by targeting RTK phosphorylation. Pharmacokinetic DDIs can critically impact the efficacy and safety of TKIs such as erlotinib, gefitinib, and pazopanib by affecting their absorption, distribution, and metabolism. The modification of pH can influence drug absorption; furthermore, the inhibition or induction of metabolizing enzymes may affect biotransformation, while distribution can be altered through the modulation of transmembrane transporters. Additionally, ensuring quality of life during TKI treatment requires vigilant monitoring and management of adverse events, which range from mild (e.g., rash, diarrhea, fatigue) to severe (e.g., hepatotoxicity, cardiotoxicity). Drug-specific toxicities, such as hyperlipidemia with lorlatinib or visual disturbances with crizotinib, must be assessed using specific criteria, with dose adjustments and supportive care tailored to individual patient responses. Thus, optimal TKI therapy relies on managing drug interactions through multidisciplinary care, monitoring, and patient education to ensure safety and treatment efficacy. Full article

The large yellow croaker, or Larimichthys crocea, is highly prized for its golden color and nutritional content. The purpose of this study was to investigate the differences in body composition, mucus biochemical indices and body color in five strains of large yellow croakers (body weight: 347.01 ± 5.86 g). To conduct genetic diversity analyses of the populations, a total of 50 tailfin samples were randomly chosen from the following populations of large yellow croakers: wild (LYC1), Dai-qu population (LYC2), Yongdai 1 (LYC3), Min-yuedong population (LYC4), and Fufa 1 (LYC5). The findings demonstrated that the LYC3 group’s pigment contents, crude protein, crude lipid, and chromatic values were comparable to those of the LYC1 group (p > 0.05). There was no significant difference between the LYC1 and LYC5 groups’ mucus superoxide dismutase (SOD) and catalase (CAT) activities (p > 0.05). The alkaline phosphatases (ALP), acid phosphatases (ACP), and lysozyme (LYS) activities of the mucus in the LYC1 group were not significantly different from the LYC3 group (p > 0.05). The back skin mRNA expressions of tyrosinase (tyr), tyrosinase-related protein 1 (tyrp1), dopachrome tautomerase (dct), microphtalmia-associated transcription factor (mitf), and melanocortin 1 receptor (mc1r) were significantly up-regulated in the LYC2 and LYC4 groups compared to the LYC1, LYC3, and LYC5 groups (p < 0.05). Forkhead box d3 (foxd3), paired box 3 (pax3), purine nucleoside phosphorylase 4a (pnp4a), aristaless-like homeobox 4a (alx4a), cAMP dependent protein kinase (pka), anaplastic lymphoma kinase (alk), leukocyte receptor tyrosine kinase (ltk), and colony stimulating factor (fms) were among the mRNA expressions of the abdominal skin in the LYC1, LYC3, and LYC5 groups significantly higher than those in the LYC2 and LYC4 groups (p < 0.05). In conclusion, the LYC3 group’s crude protein, crude lipid, carotenoid, and lutein contents were most similar to those of the large yellow croaker found in the wild. Furthermore, the molecular mechanism underlying the variations in body color among the various strains of large yellow croakers was supplied for additional research. Full article

Cancer therapy-induced hypertension (HTN) is an increasingly recognized complication associated with a wide range of anticancer agents, including vascular endothelial growth factor (VEGF) inhibitors, proteasome inhibitors, tyrosine kinase inhibitors, and alkylating agents. The pathogenesis of HTN in this setting is multifactorial, involving mechanisms such as endothelial dysfunction, nitric oxide (NO) suppression, sympathetic nervous system activation, and vascular remodeling. Additional factors, including paraneoplastic syndromes, poorly controlled pain, mood disturbances, and overlapping cardiovascular risk factors like obesity and diabetes, further contribute to the complexity of diagnosis and management. Despite its prevalence and clinical implications, cancer therapy-induced HTN is often addressed using general population guidelines, with limited oncology-specific protocols available. Accurate blood pressure measurement and individualized treatment plans are critical to optimize outcomes and avoid interruptions to cancer therapy. Antihypertensive agents such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), and calcium channel blockers have shown efficacy in both blood pressure control and, in some cases, oncologic outcomes. A multidisciplinary approach involving oncologists, cardiologists, and primary care providers is essential to navigate the interplay between cancer treatment and cardiovascular health. Ongoing research is needed to develop targeted guidelines and improve the long-term care of cancer patients affected by treatment-induced HTN. Full article

Myeloid/lymphoid neoplasms with tyrosine kinase gene fusions (MLN-TK) represent a distinct group of hematologic malignancies recognized in the latest WHO classification due to shared clinical, morphological, and molecular features, and their responsiveness to tyrosine kinase inhibitors (TKIs). Among these, fusions involving the SYK gene, such as ETV6::SYK and ITK::SYK, have emerged as rare but potentially targetable genetic events in both myeloid and lymphoid neoplasms. SYK, a non-receptor tyrosine kinase critical for hematopoietic signalling, can become constitutively activated through gene fusions, driving oncogenesis via the PI3K/AKT, MAPK, and JAK-STAT pathways. ETV6::SYK has been primarily associated with myeloid neoplasms, often presenting with eosinophilia, bone marrow dysplasia, and skin involvement. In vitro and in vivo models confirm its leukemogenic potential and identify SYK as a therapeutic target. Although SYK inhibitors like fostamatinib have shown transient efficacy, resistance mechanisms, possibly involving alternative pathway activation, remain a challenge. The ITK::SYK fusion, on the other hand, has been identified in peripheral T-cell lymphomas, particularly of the follicular helper T-cell subtype, with similar pathway activation and potential for targeted intervention. Additional rare SYK fusions, such as PML::SYK and CTLC::SYK, have been reported in myeloid neoplasms and juvenile xanthogranuloma, respectively, expanding the spectrum of SYK-driven diseases. Accumulating evidence supports the inclusion of SYK fusions in future classification systems and highlights the need for broader molecular screening and clinical evaluation of SYK-targeted therapies. Full article

Leucine-rich repeat receptor-like kinases (LRR-RLKs) have evolved to perceive environmental changes. Among LRR-RLKs, PEPR1 perceives the pep1 peptide and triggers defense signal transduction in Arabidopsis thaliana. In the present study, we focused on PEPR1 and PEPR2, which are the receptors of pep1, to understand the role of tyrosine phosphorylation. PEPR1-CD (cytoplasmic domain) recombinant protein exhibited strong tyrosine autophosphorylation, including threonine autophosphorylation. We subjected all tyrosine residues in PEPR1-CD to site-directed mutagenesis. The recombinant proteins were purified along with PEPR1-CD, and Western blotting was performed using a tyrosine-specific antibody. Among the 13 tyrosine residues in PEPR1-CD, the PEPR1(Y995F)-CD recombinant protein showed significantly reduced tyrosine autophosphorylation intensity compared to PEPR1-CD and other tyrosine mutants, despite little change in threonine autophosphorylation. To confirm the autophosphorylation site, we generated a phospho-specific peptide Ab, pY995. As a result, Tyr-995 of PEPR1-CD was a major tyrosine autophosphorylation site in vitro. To understand the function of tyrosine phosphorylation in vivo, we generated transgenic plants, expressing PEPR1-Flag, PEPR1(Y995F)-Flag, and PEPR1(Y995D)-Flag in a pepr1/2 double mutant background. Interestingly, the root growths of PEPR1(Y995F)-Flag and PEPR1(Y995D)-Flag were not inhibited by pep1 peptide treatment, compared to Col-0 and PEPR1-Flag (pepr1/2) transgenic plants. Also, we analyzed downstream components, which included PROPEP1, MPK3, WRKY33, and RBOHD gene expressions in four different genotypes (Col-0, PEPR1-Flag, PEPR1(Y995F)-Flag, and PEPR1(Y995D)-Flag) of plants in the presence of the pep1 peptide. Interestingly, the expressions of PROPEP1, MPK3, WRKY33, and RBOHD were not regulated by pep1 peptide treatment in PEPR1(Y995F)-Flag and PEPR1(Y995D)-Flag transgenic plants, in contrast to Col-0 and PEPR1-Flag. These results suggest that specific tyrosine residues play an important role in vivo in the plant receptor function. Full article

This study aimed to clarify the sequence characteristics and spatiotemporal expression patterns of the insulin-like growth factor 1 receptor (IGF1R) gene in Alopex lagopus (Arctic fox), thereby addressing the existing knowledge gap regarding IGF1R-mediated growth regulation in this species. The findings establish a crucial foundation for subsequent investigations into the correlation between this gene and Arctic fox growth traits. Specific primers were designed based on the cDNA sequence of the canine IGF1R gene (Accession No. XM_545828). The full-length coding sequence (CDS) of the Arctic fox IGF1R gene (1617 bp, encoding 538 amino acids) was successfully cloned via RT-PCR. Phylogenetic analysis using the Unweighted Pair Group Method with Arithmetic Mean (UPGMA) algorithm revealed a 99% sequence homology in the IGF1R gene between the Arctic fox and canine, confirmed their closest evolutionary relationship. Protein characterization showed that the IGF1R protein has a molecular weight of 60.62 kDa (theoretical isoelectric point pI = 5.15), containing one fibronectin type-III domain and one tyrosine kinase domain, classifying it as an acidic hydrophilic transmembrane protein. Phosphorylation site prediction identified 27 phosphorylation sites, with secondary structures dominated by α-helices (26.39%) and random coils (52.79%). The IGF1R gene displayed significant tissue-specific expression variations across 12 examined tissues in Arctic foxes: highest expression levels in testis, minimal expression in stomach, and no detectable expression in duodenum. Spatiotemporal expression analysis revealed that in 2-, 4-, and 6-month-old individuals, hepatic IGF1R exhibited a progressive increase, testicular expression reached peak levels at 6 months, and skeletal muscle demonstrated transient upregulation peaking at 4 months. These spatiotemporal expression patterns suggest that IGF1R may participate in metabolism and organ developmental processes during critical growth stages of Arctic foxes through tissue-specific regulation. Full article

Glioblastoma is a fatal and aggressive cancer with no cure. It is becoming increasingly clear that glioblastoma initiation is a result of adult neural stem cell (NSC) transformation—most likely those within the subventricular zone (SVZ). Indeed, transcriptomic analysis indicates that glioblastomas are reminiscent of a neurodevelopmental hierarchy, in which neural stem and progenitor markers are widely expressed by tumour stem-like cells. However, NSC fates and the cues that drive them are poorly understood. Studying the crosstalk within NSC niches may better inform our understanding of glioblastoma initiation and development. Insulin-like growth factor binding protein 2 (IGFBP-2) has a well-established prognostic role in glioblastoma, and cell-based mechanistic studies show the independent activation of downstream oncogenic pathways. However, IGFBP-2 is more commonly recognised as a modulator of insulin-like growth factors (IGFs) for receptor tyrosine kinase signal propagation or attenuation. In the adult human brain, both IGFBP-2 and IGF-II expression are retained in the choroid plexus (ChP) and secreted into the cerebral spinal fluid (CSF). Moreover, secretion by closely associated cells and NSCs themselves position IGFBP-2 and IGF-II as interesting factors within the NSC niche. In this review, we will highlight the experimental findings that show IGFBP-2 and IGF-II influence NSC behaviour. Moreover, we will link this to glioblastoma biology and demonstrate the requirement for further analysis of these factors in glioma stem cells (GSCs). Full article

In the classic medicinal chemistry hit discovery procedure, large virtual libraries undergo different filtering and prediction steps until a small group of molecules is selected for their subsequent synthesis and biological testing. The starting molecular libraries can easily be composed of millions of molecules, hindering the selection of the most representative and promising compounds. Moreover, the resulting molecular systems tend to be overcomplex structures, hardly attainable, and often involve extrapolations of the prediction models used. We present a rational-based method to reduce the structural complexity of molecular candidates without compromising their biological activity, improving the attainability and efficiency of hit discovery. This approach has been successfully applied to identify potential tyrosine kinase dual inhibitors against Fibroblast Growth Factor Receptor 2 (FGFR2) and Insulin-Like Growth Factor 1 Receptor (IGF1R), a set of overexpressed proteins in different cancers, such as pancreatic ductal adenocarcinoma (PDAC). Full article

Bruton’s tyrosine kinase (BTK) is a key signaling molecule involved in both hematological malignancies and solid tumors. In B-cell malignancies such as chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), BTK mediates B-cell receptor signaling, promoting tumor survival and proliferation, leading to the development of BTK inhibitors like ibrutinib that improve patient outcomes. In solid tumors, BTK isoforms, particularly p65BTK, contribute to tumor growth and therapy resistance, with inhibition showing promise in cancers like colorectal, ovarian, and non-small cell lung cancer. BTK also influences the tumor microenvironment by modulating immune cells such as myeloid-derived suppressor cells and tumor-associated macrophages, aiding immune evasion. BTK inhibition can enhance anti-tumor immunity and reduce inflammation-driven tumor progression. Additionally, BTK contributes to tumor angiogenesis, with inhibitors like ibrutinib showing anti-angiogenic effects. Beyond cancer, BTK is linked to aging, where its modulation may reduce senescent cell accumulation and preserve cognitive function. This review explores BTK’s dual role, focusing on its oncogenic effects and potential impact on aging processes. We also discuss the use of BTK inhibitors in cancer treatment and their potential to address age-related concerns, providing a deeper understanding of BTK as a therapeutic target and mediator in the complex relationship between cancer and aging. Full article

Peri-implantitis (PI) is a chronic inflammatory disease that ultimately leads to the dysfunction and loss of implants with established osseointegration. Ferroptosis has been implicated in the progression of PI, but its precise mechanisms remain unclear. This study explores the molecular mechanisms of ferroptosis in the pathology of PI through bioinformatics, offering new insights into its diagnosis and treatment. The microarray datasets for PI (GSE33774 and GSE106090) were retrieved from the GEO database. The differentially expressed genes (DEGs) and ferroptosis-related genes (FRGs) were intersected to obtain PI-Ferr-DEGs. Using three machine learning algorithms, the Least Absolute Shrinkage and Selection Operator (LASSO), Support Vector Machine-Recursive Feature Elimination (SVM-RFE), and Boruta, we successfully identified the most crucial biomarkers. Additionally, these key biomarkers were validated using a verification dataset (GSE223924). Gene set enrichment analysis (GSEA) was also utilized to analyze the associated gene enrichment pathways. Moreover, immune cell infiltration analysis compared the differential immune cell profiles between PI and control samples. Also, we targeted biomarkers for drug prediction and conducted molecular docking analysis on drugs with potential development value. A total of 13 PI-Ferr-DEGs were recognized. Machine learning and validation confirmed toll-like receptor-4 (TLR4) and FMS-like tyrosine kinase 3 (FLT3) as ferroptosis biomarkers in PI. In addition, GSEA was significantly enriched by the biomarkers in the cytokine–cytokine receptor interaction and chemokine signaling pathway. Immune infiltration analysis revealed that the levels of B cells, M1 macrophages, and natural killer cells differed significantly in PI. Ibudilast and fedratinib were predicted as potential drugs for PI that target TLR4 and FLT3, respectively. Finally, the occurrence of ferroptosis and the expression of the identified key markers in gingival fibroblasts under inflammatory conditions were validated by RT-qPCR and immunofluorescence analysis. This study identified TLR4 and FLT3 as ferroptosis and immune cell infiltration signatures in PI, unraveling potential novel targets to treat PI. Full article