Search Results (94)

Rheumatoid arthritis (RA) is a progressive and systemic autoimmune disease, characterized by a chronic inflammatory process, affecting the lining of the synovial joints, many body organs/systems, and blood vessels. Its pathological hallmarks are hyperplasic synovium, bone erosion, and progressive joint destruction. Rheumatoid arthritis affects over 20 million people, with a worldwide prevalence of 0.5–1.0%, exhibiting gender, ethnic, and geographical differences. The progressive disability severely impairs physical motion and quality of life and is finally leading to a shortened life span. The pathogenesis of RA is a complex and still poorly understood process in which genetic and environmental factors are principally associated. Current treatment mostly relies on conventional/non-biological disease-modifying anti-rheumatic drugs (cDMARDs), analgesics, non-steroidal anti-inflammatory drugs, glucocorticoids, steroids, immunosuppresants, and biologic DMARDs, which only control inflammation and pain. Along with side effects (drug toxicity and intolerance), these anti-rheumatic drugs possess limited efficacy. Therefore, the discovery of novel multi-target therapeutics with an improved safety profile that function as inhibitors of RA-linked signaling systems are in high demand, and this is in the interest of both patients and clinicians. Plant-derived extracts, nutritional supplements, dietary medicine, and molecules with anti-inflammatory activity represent promising adjuvant agents or alternatives for RA therapeutics. This review not only aims to discuss the basic features of RA pathogenesis, risk factors, and signaling pathways but also highlights the research progress in pre-clinical RA in in vitro and in vivo models, revealing new avenues in the management of the disease in terms of comprehensive multidisciplinary strategies originating from medicinal plants and plant-derived molecules. Full article

Heterotopic ossification (HO) refers to an abnormal process characterized by the aberrant development of bone within soft tissues, leading to significant impairments in patients’ mobility and overall quality of life. Macrophages, as a crucial element of the immune system, are instrumental in the different stages of heterotopic ossification through their dynamic polarization state (pro-inflammatory M1 and anti-inflammatory M2 phenotypes) and secretion of different cytokines. This review explores novel mechanisms of M1 and M2 macrophage-mediated heterotopic ossification, emphasizing the involvement of the inflammatory microenvironment, osteogenic factors, and osteogenic signaling pathways. In addition, we explore promising therapeutic strategies targeting macrophage polarization and function, including agents that modulate the inflammatory microenvironment, such as IL-1 inhibitors, parovastatin, and metformin, as well as agents that affect macrophage osteogenic signaling, such as TGF-βRII-Fc, Galunisertib, and Ruxolitinib. A more comprehensive understanding of these mechanisms may open up new avenues for developing novel approaches to reducing HO in high-risk patients. Full article

Background: Neuroblastoma (NB) is one of the most common solid tumors in children, still showing a high mortality rate despite recent advances in therapy. A recent breakthrough was the introduction of Dinutuximab beta, yielding further improvements in survival. Dinutuximab beta is an anti-GD2 monoclonal antibody that targets GD2 expressed on the cell surface of neuroblastoma cells. Evidence suggests that Dinutuximab beta combined with Nivolumab may offer an effective synergistic treatment approach. Methods: In our center, immunotherapy was introduced in 2021 as part of maintenance treatment. The aim of this retrospective study was to analyze our data with a focus on the response, side effect profile and tolerability of Dinutuximab beta in HR and relapsed or refractory (r/r) NB. Results: Between 2021 and 2024, we treated 15 patients with neuroblastoma. Twelve patients had high-risk disease, of whom five received Dinutuximab beta as part of maintenance treatment according to protocol HR-NBL 1.8/SIOPEN. Two patients achieved complete remission after immunotherapy. One achieved long-lasting remission, while another relapsed. Three patients with inoperable tumors developed a partial response, but they relapsed and were diagnosed with metastases later. These patients subsequently initiated treatment with Temozolomide + Irinotecan in combination with Dinutuximab beta and also with Nivolumab as a relapse protocol. Therapeutic responses were assessed by the imaging, pathology and flow cytometry analysis of bone marrow. Apart from one complication (hypotension as part of capillary leak syndrome) subsiding spontaneously, no other severe adverse events were observed. Conclusions: Our experiences confirm that immunotherapy, including Dinutuximab beta and Nivolumab, is safe and well tolerated. The standardization of the application of Dinutuximab beta and in combination with novel therapeutic agents in maintenance and refractory/relapsed cases may contribute to improved treatment outcome results. Full article

P-glycoprotein (P-gp), a transmembrane efflux pump encoded by the ABCB1/MDR1 gene, is a major contributor to multidrug resistance in hematological malignancies. These malignancies, arising from hematopoietic precursors at various differentiation stages, can manifest in the bone marrow, circulate in the bloodstream, or infiltrate tissues. P-gp overexpression in malignant cells reduces the efficacy of chemotherapeutic agents by actively expelling them, decreasing intracellular drug concentrations, and promoting multidrug resistance, a significant obstacle to successful treatment. This review examines recent advances in combating P-gp-mediated resistance, including the development of novel P-gp inhibitors, innovative drug delivery systems (e.g., nanoparticle-based delivery), and strategies to modulate P-gp expression or activity. These modulation strategies encompass targeting relevant signaling pathways (e.g., NF-κB, PI3K/Akt) and exploring drug repurposing. While progress has been made, overcoming P-gp-mediated resistance remains crucial for improving patient outcomes. Future research directions should prioritize the development of potent, selective, and safe P-gp inhibitors with minimal off-target effects, alongside exploring synergistic combination therapies with existing chemotherapeutics or novel agents to effectively circumvent multidrug resistance in hematological malignancies. Full article

Phosphorus is one of the most abundant minerals in the body and plays a critical role in numerous cellular and metabolic processes. Most of the phosphate is deposited in bones, 14% is present in soft tissues as various organic phosphates, and only 1% is found in extracellular space, mainly as inorganic phosphate. The plasma inorganic phosphate concentration is closely maintained between 2.5 and 4.5 mg/dL by intertwined interactions between fibroblast growth factor 23 (FGF-23), parathyroid hormone (PTH), and vitamin D, which tightly regulate the phosphate trafficking across the gastrointestinal tract, kidneys, and bones. Disruption of the strict hemostatic control of phosphate balance can lead to altered cellular and organ functions that are associated with high morbidity and mortality. In the past three decades, there has been a steady increase in the prevalence of kidney failure (KF) among populations. Individuals with KF have unacceptably high mortality, and well over half of deaths are related to cardiovascular disease. Abnormal phosphate metabolism is one of the major factors that is independently associated with vascular calcification and cardiovascular mortality in KF. In early stages of CKD, adaptive processes involving FGF-23, PTH, and vitamin D occur in response to dietary phosphate load to maintain plasma phosphate level in the normal range. However, as the CKD progresses, these adaptive events are unable to overcome phosphate retention from continued dietary phosphate intake and overt hyperphosphatemia ensues. As these hormonal imbalances and the associated adverse consequences are driven by the underlying hyperphosphatemic state in KF, it appears logical to strictly control serum phosphate. Conventional dialysis is inadequate in removing phosphate and most patients require dietary restrictions and pharmacologic interventions to manage hyperphosphatemia. However, diet control comes with many challenges with adherence and may place patients at risk for inadequate protein intake and malnutrition. Phosphate binders help to reduce phosphate levels but come with a sizable pill burden and high financial costs and are associated with poor adherence and psychosocial issues. Additionally, long-term use of binders may increase the risk of calcium, lanthanum, or iron overload or promote gastrointestinal side effects that exacerbate malnutrition and affect quality of life. Given the aforesaid challenges with phosphorus binders, novel therapies targeting small intestinal phosphate absorption pathways have been investigated. Recently, tenapanor, an agent that blocks paracellular absorption of phosphate via inhibition of enteric sodium–hydrogen exchanger-3 (NHE3) was approved for the treatment of hyperphosphatemia in KF. While various clinical tools are now available to manage hyperphosphatemia, there is a lack of convincing clinical data to demonstrate improvement in outcomes in KF with the lowering of phosphorus level. Conceivably, deleterious effects associated with hyperphosphatemia could be attributable to disruptions in phosphorus-sensing mechanisms and hormonal imbalance thereof. Further exploration of mechanisms that precisely control phosphorus sensing and regulation may facilitate development of strategies to diminish the deleterious effects of phosphorus load and improve overall outcomes in KF. Full article

Background/Objectives: Leukemia is a common cancer that arises in both children and adults when bone marrow’s hematopoietic stem cells proliferate unrestrained because of anomalies in normal cell regulatory systems. The present study focused on biological evaluation of oxazole-based oxadiazole scaffolds to evaluate the anti-proliferative effect on leukemic cancer cell lines. Methods: All novel oxazole-based oxadiazole scaffolds were synthesized and structurally characterized via ¹³C NMR, ¹H NMR, and HREI-MS. In order to identify an efficient anti-leukemia agent, the biological profiles of each compound were evaluated in comparison to the reference drug, Etoposide (IC₅₀ = 10.50 and 15.20 μM). Results: Analog 6 substituted with p-CF₃ at phenyl ring was identified with excellent inhibition against the HL-60 and PLB-985 cancer cell lines, with IC₅₀ of 8.50 and 12.50 μM. Through hydrogen bond formation, the trifluoromethyl moiety of analog 6 interacts with target tyrosine kinase enzyme (PDB-ID:4CSV). The interactive character of active ligands with target enzyme was demonstrated by molecular docking. The rate of inhibition in contrast with the drug concentration was also tested to check the inhibition percentage and inhibitor type via enzyme kinetics. Furthermore, the enzyme–ligand complex was also investigated via MD simulation along with pharmacophore modeling. DFT calculations were used to estimate the lead compounds’ relative stability and reactivity. According to ADMET investigation, there is safe toxicological profile for these compounds. Conclusions: The current study suggests that the potent compounds have significant anti-proliferative potential, and with further in vivo validation, hold promise for future optimization as potential leukemia treatments. Full article

T-cell acute lymphoblastic leukaemia (T-ALL) is an aggressive neoplastic malignancy characterised by the accumulation of multiple oncogenic and epigenetic alterations in haematopoietic T-cell precursors leading to their uncontrolled proliferation and accumulation in the bone marrow. For many years it has been established that the occurrence of activating mutations, alterations in transcription factors expression, impairment in cell cycle regulators, and hyperactivation of NOTCH1 signalling play prominent roles in the pathogenesis of this disease. Recently, the introduction of high-resolution screening and next-generation sequencing platforms revealed that T-cell progenitors accumulate additional mutations, affecting protein kinase signalling, protein translation, and epigenetic control mechanisms, providing novel attractive targets for therapy. While the contributions of direct genomic events are well understood as causative agents of hyperactive kinase signalling pathways, the epigenetic rewiring of kinase signalling cascades via DNA methylation, histone post-translational modifications, and non-coding miRNAs remains less well explored. In this review, we provide novel perspectives on epigenetic regulatory aspects of kinase signalling heterogeneity in T-ALL pathogenesis and therapeutic outcomes. Full article

Osteosarcoma is recognized as the most prevalent primary bone malignancy, primarily affecting children and adolescents. It is characterized by its aggressive behavior and high metastatic potential, which often leads to poor patient outcomes. Despite advancements in surgical techniques and chemotherapy regimens, the prognosis for patients with osteosarcoma remains unsatisfactory, with survival rates plateauing over the past few decades. A significant barrier to effective treatment is the development of chemotherapy resistance, which complicates the management of the disease and contributes to high rates of recurrence. This review article aims to provide a comprehensive overview of recent advancements in osteosarcoma therapy, particularly in overcoming chemotherapy resistance. We begin by discussing the current standard treatment modalities, including surgical resection and conventional chemotherapy agents such as methotrexate, doxorubicin, and cisplatin. While these approaches have been foundational in managing osteosarcoma, they are often limited by adverse effects and variability in efficacy among patients. To address these challenges, we explore novel pharmacological strategies that aim to enhance treatment outcomes. This includes targeted therapies focusing on specific molecular alterations in osteosarcoma cells and immunotherapeutic approaches designed to harness the body’s immune system against tumors. Additionally, we review innovative drug delivery systems that aim to improve the bioavailability and efficacy of existing treatments while minimizing toxicity. The review also assesses the mechanisms underlying chemotherapy resistance, such as drug efflux mechanisms, altered metabolism, and enhanced DNA repair pathways. By synthesizing current research findings, we aim to highlight the potential of new therapeutic agents and strategies for overcoming these resistance mechanisms. Ultimately, this article seeks to inform future research directions and clinical practices, underscoring the need for continued innovation in treating osteosarcoma to improve patient outcomes and survival rates. Full article

This review systematically examines the oral complications associated with conventional and novel anti-cancer therapies. It highlights that while molecularly targeted agents including monoclonal antibodies targeting the vascular endothelial growth factor and its receptor, the epidermal growth factor receptor, tyrosine kinase inhibitors, and immune checkpoint inhibitors tend to exhibit a lower overall toxicity profile compared to traditional cytotoxic chemotherapeutics, they are nonetheless linked to significant oral adverse events. These complications encompass inflammatory mucosal reactions known as mucositis, salivary gland dysfunction leading to a sensation of dryness in the mouth, taste alterations referred to as dysgeusia, and, critically, medication-related osteonecrosis of the jaw. In particular, bone-modifying agents such as bisphosphonates and denosumab disrupt bone remodeling and the formation of new blood vessels, thereby increasing the susceptibility to osteonecrosis of the jaw, especially following invasive dental procedures. The review delineates the multifactorial pathogenesis underlying these toxicities, which involves direct cell toxicity, impaired wound healing, and secondary infections. Furthermore, it emphasizes the importance of pre-treatment dental evaluation and preventive strategies including patient education, prophylactic dental care, and the integration of adjunctive therapies such as laser therapy and autologous platelet concentrates to mitigate these adverse effects. The analysis advocates for interdisciplinary collaboration between oncologists and dental professionals to optimize management protocols, enhance treatment adherence, and ultimately improve the quality of life for oncology patients undergoing anti-cancer therapy. Full article

CD8⁺ T cells are critical players in anti-tumor immunity against solid tumors, targeted by immunotherapies. Emerging evidence suggests that CD8⁺ T cells also play a crucial role in anti-tumor responses and determining treatment outcomes in hematologic malignancies like myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML). In this review, we focus on the implication of CD8⁺ T cells in the treatment response of patients with MDS and AML. First, we review reported studies of aberrant functionality and clonality of CD8⁺ T cells in MDS and AML, often driven by the immunosuppressive bone marrow microenvironment, which can hinder effective antitumor immunity. Additionally, we discuss the potential use of CD8⁺ T cell subpopulations, including memory and senescent-like subsets, as predictive biomarkers for treatment response to a variety of treatment regimens, such as hypomethylating agents, which is the standard of care for patients with higher-risk MDS, and chemotherapy which is the main treatment of patients with AML. Understanding the multifaceted role of CD8⁺ T cells and their interaction with malignant cells in MDS and AML will provide useful insights into their potential as prognostic/predictive biomarkers, but also uncover alternative approaches to novel treatment strategies that could reshape the therapeutic landscape, thus improving treatment efficacy, aiding in overcoming treatment resistance and improving patient survival in these challenging myeloid neoplasms. Full article

Epigenetics encompasses heritable and stable changes in gene expression caused by external chromosomal modifications, without altering the underlying DNA sequence. Epigenetic modifications, established during early development and maintained through successive cell divisions, play a critical role in regulating gene expression. Post-translational modifications (PTMs) are a key aspect of epigenetics and are essential for modulating protein functionality, as well as regulatory cellular processes, including proliferation, differentiation, metabolic pathways, and tumorigenic events. Among these, the small ubiquitin-related modifier (SUMOylation) system is a reversible PTM mechanism that alters target protein interaction surfaces through covalent binding to lysine residues, thereby influencing protein structure and function. Acute myeloid leukemia (AML) is a highly aggressive malignancy characterized by the clonal expansion of primitive hematopoietic stem cells of the myeloid lineage in the bone marrow. Despite recent advancements in therapeutic strategies and an improved understanding of leukemogenic pathways, patient outcomes remain poor, particularly in elderly populations. Consequently, efforts have focused on developing novel agents, including co-targeting specific mutations or integrating targeted therapies into combinatorial chemotherapeutic regimens. Emerging evidence suggests that SUMOylation plays a significant role in AML pathogenesis and treatment response, representing a promising therapeutic target for advanced disease cases. This review provides a brief analysis of the functional role of the SUMOylation system in AML and highlights its potential as a therapeutic target. We also discuss current knowledge gaps and propose directions for future research to advance precision medicine approaches for AML treatment. Full article

Background/Objectives: Anti-CD20 monoclonal antibodies combined with alkylator-based chemotherapy enhance survival in chronic lymphocytic leukemia (CLL). However, the risks of infection and bone marrow suppression may mean that new, targeted therapies are more appropriate for some patients than fludarabine–cyclophosphamide–rituximab (FCR). In the Republic of Korea, where insurance limits coverage to novel agents, FCR therapy should be carefully considered for patients with CLL. Methods: Using clinical data from 144 FCR-treated patients with CLL, we retrospectively analyzed clinical characteristics impacting survival outcomes, the impact of cytopenia after FCR, and the durable remission status in terms of measurable residual disease (MRD). We compared the impact of bicytopenia with those of other hematologic conditions. Results: The 5-year overall survival (OS) and 5-year progression-free survival (PFS) for all patients were 84.4% and 68.3%, respectively. FCR-treated patients in the bicytopenia and TP53-positive groups exhibited poor OS and PFS; in particular, the bicytopenia group often experienced prolonged anemia and thrombocytopenia (6–12 months). The responder group achieved sustained remission for a median of 5 years for MRD negativity. Conclusions: In bicytopenia, FCR can induce prolonged cytopenia, making it difficult to switch to second-line therapy or complete cycles of chemoimmunotherapy, directly affecting poor survival outcomes. The cautious application of FCR therapy in CLL without bicytopenia or TP53 positivity can achieve long-term remission. Full article

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of neoplastic CD5⁺/CD19⁺ B lymphocytes in the blood. These cells migrate to and proliferate in the bone marrow and lymphoid tissues. Despite the development of new therapies for CLL, drug resistance and disease relapse still occur; novel treatment approaches are therefore still needed. Inhibition of the angiogenesis involved in the progression of CLL might be a relevant therapeutic strategy. The literature data indicate that vascular endothelial growth factor, angiopoietin-2, and matrix metalloproteinase-9 are pro-angiogenic factors in CLL. A number of other CLL factors might have pro-angiogenic activity: fibroblast growth factor-2, certain chemokines (such as CXCL-12 and CXCL-2), tumor necrosis factor-α, insulin-like growth factor-1, neutrophil gelatinase-associated lipocalin, and progranulin. All these molecules contribute to the survival, proliferation, and migration of CLL cells. Here, we review the literature on these factors’ respective expression profiles and roles in CLL. We also summarize the main results of preclinical and clinical trials of novel agents targeting most of these molecules in a CLL setting. Through the eradication of leukemic cells and the inhibition of angiogenesis, these therapeutic approaches might alter the course of CLL. Full article

Pulmonary arterial hypertension (PAH) is a progressive and rare condition characterised by the occlusion of pulmonary arterioles, with clinical manifestations resulting from the cross-sectional area reduction of the small pulmonary arteries. The disease is driven by a combination of factors including vasoconstriction, thrombosis, inflammation, proliferation, and the obstructive remodelling of the pulmonary artery walls. Heterozygous mutations in the type II bone morphogenetic protein receptor (BMPR2) underlie the majority of the inherited and familial forms of PAH. Current evidence indicates that in PAH, the BMPR2-mediated-signalling is diminished and the TGFβ signalling is heightened. Even when managed with current therapeutic approaches, the disease eventually results in increased pulmonary vascular resistance, right heart failure, and premature death. Natural products act as vascular disease treatment agents and have been used in clinical practice following compelling clinical trials. The rationale for the selection of natural compounds derives from their multi-targeted approach and synergistic effects. Although novel medicines licenced by the FDA (USA) between 1981 and 2010, constitute approximately 34% natural products or derivatives of natural products, their potentials for the treatment of PAH are not fully explored. The objective of this review is to emphasise the significance of natural products in the therapeutic resolution of PAH. Full article

Background: As a unique joint that facilitates the articulation of the upper and lower jaws, the temporomandibular joint (TMJ) is concerned with several critical functions, such as speech and mastication. Pain that can become incapacitating is a result of temporomandibular disorders (TMDs), which are complex disorders affecting the masticatory muscles and the TMJ. Several anomalies and TMDs have an interdisciplinary relationship. Complementary and concurrent disorders may be caused by occlusal anomalies, psychological disorders, and changes in spine posture. Methods: This article examines the clinical characteristics of TMDs, their classification, their etiological factors, and the impact of TMJ disorders on the human body with reference to their anatomies and histological structures. Results: The clinical picture of some TMJ pathologies may be unknown, so certain biomarkers, such as cytokines, may be useful for an accurate diagnosis as they are frequently seen in TMJ disorders. Furthermore, novel therapeutic approaches that target pro-inflammatory cytokines and treat TMDs by using tissue engineering and regenerative medicine while permitting TMJ cartilage and bone regeneration may offer numerous benefits that require clinical translation. Conclusions: Implementation of recent modalities such as microvesicles and platelet-rich plasma in growth factors may provide a promising approach to enhance bone formation. In addition, we target different biological markers that give insights into the introduction of new pharmaceutical agents for therapy. Full article