Search Results (34,861)

Ubiquitin-conjugating enzyme E2 T (UBE2T) is a crucial E2 enzyme in the ubiquitin-proteasome system (UPS), playing a significant role in the ubiquitination of proteins and influencing a wide range of cellular processes, including proliferation, differentiation, apoptosis, invasion, and metabolism. Its overexpression has been implicated in various malignancies, such as lung adenocarcinoma, gastric cancer, pancreatic cancer, liver cancer, and ovarian cancer, where it correlates strongly with disease progression. UBE2T facilitates tumorigenesis and malignant behaviors by mediating essential functions such as DNA repair, apoptosis, cell cycle regulation, and the activation of oncogenic signaling pathways. High levels of UBE2T expression are associated with poor survival outcomes, highlighting its potential as a molecular biomarker for cancer prognosis. Increasing evidence suggests that UBE2T acts as an oncogene and could serve as a promising therapeutic target in cancer treatment. This review aims to provide a detailed overview of UBE2T’s structure, functions, and molecular mechanisms involved in cancer progression as well as recent developments in UBE2T-targeted inhibitors. Such insights may pave the way for novel strategies in cancer diagnosis and treatment, enhancing our understanding of UBE2T’s role in cancer biology and supporting the development of innovative therapeutic approaches. Full article

Spinal cord injury (SCI) initiates a cascade of secondary damage driven by oxidative stress, characterized by the excessive production of reactive oxygen species and other reactive molecules, which exacerbate cellular and tissue damage through the activation of deleterious signaling pathways. This review provides a comprehensive and critical evaluation of recent advancements in antioxidant-based therapeutic strategies for SCI, including natural compounds, RNA-based therapies, stem cell interventions, and biomaterial applications. It emphasizes the limitations of single-regimen approaches, particularly their limited efficacy and suboptimal delivery to injured spinal cord tissue, while highlighting the synergistic potential of combination therapies that integrate multiple modalities to address the multifaceted pathophysiology of SCI. By analyzing emerging trends and current limitations, this review identifies key challenges and proposes future directions, including the refinement of antioxidant delivery systems, the development of multi-targeted approaches, and strategies to overcome the structural complexities of the spinal cord. This work underscores the pressing need for innovative and integrative therapeutic approaches to advance the clinical translation of antioxidant-based interventions and improve outcomes for SCI patients. Full article

Lung cancer remains a major global health problem because of its high cancer-related mortality rate despite advances in therapeutic approaches. Non-small cell lung cancer (NSCLC), a major subtype of lung cancer, is more amenable to surgical intervention in its early stages. However, the prognosis for advanced NSCLC remains poor, owing to limited treatment options. This underscores the growing need for novel therapeutic strategies to complement existing treatments and improve patient outcomes. In recent years, pentacyclic triterpenoids, a group of natural compounds, have emerged as promising candidates for cancer therapy due to their anticancer properties. Pentacyclic triterpenoids, such as lupeol, betulinic acid, betulin, oleanolic acid, ursolic acid, glycyrrhetinic acid, glycyrrhizin, and asiatic acid, have demonstrated the ability to inhibit cell proliferation and angiogenesis, induce apoptosis, suppress metastasis, and modulate inflammatory and immune pathways in NSCLC cell line models. These compounds exert their effects by modulating important signaling pathways such as NF-κB, PI3K/Akt, and MAPK. Furthermore, advances in drug delivery technologies such as nanocarriers and targeted delivery systems have improved the bioavailability and therapeutic efficacy of triterpenoids. However, despite promising preclinical data, rigorous clinical trials are needed to verify their safety and efficacy. This review explores the role of triterpenoids in NSCLC and therapeutic potential in preclinical models, focusing on their molecular mechanisms of action. Full article

Lectins are non-covalent glycan-binding proteins found in all living organisms, binding specifically to carbohydrates through glycan-binding domains. Lectins have various biological functions, including cell signaling, molecular recognition, and innate immune responses, which play multiple roles in the physiological and developmental processes of organisms. Moreover, their diversity enables biotechnological exploration as biomarkers, biosensors, drug-delivery platforms, and lead molecules for anticancer, antidiabetic, and antimicrobial drugs. Lectins from Rhodophytes (red seaweed) have been extensively reported and characterized for their unique molecular structures, carbohydrate-binding specificities, and important biological activities. The increasing number of sequenced Rhodophyte genomes offers the opportunity to further study this rich source of lectins, potentially uncovering new ones with properties significantly different from their terrestrial plant counterparts, thus opening new biotechnological applications. We compiled literature data and conducted an in-depth analysis of the phycolectomes from all Rhodophyta genomes available in NCBI datasets. Using Hidden Markov Models capable of identifying lectin-type domains, we found at least six different types of lectin domains present in Rhodophytes, demonstrating their potential in identifying new lectins. This review integrates a computational analysis of the Rhodophyte phycolectome with existing information on red algae lectins and their biotechnological potential. Full article

Royal jelly (RJ), a natural bee product known for its abundance of bioactive compounds, is often referred to as a “superfood” and has been utilized in alternative medicine for centuries. Numerous studies have highlighted its therapeutic properties, including anticancer activity. A major challenge in standard cancer therapy is the migration of cancer cells, which leads to metastasis and the formation of secondary tumors with often fatal outcomes. Cancer cell migration is facilitated by the epithelial-to-mesenchymal transition (EMT) and the aberrant activation of the Wnt/β-catenin signaling pathway. A key component of this pathway, the transcription factor β-catenin, regulates the expression of various cellular components that play critical roles in cell motility. This study investigated the antimigratory potential of RJ on the colorectal cancer cell line SW-480 and its effects on β-catenin protein expression. RJ significantly suppressed the motility of SW-480 cells and markedly reduced β-catenin protein levels 24 h after treatment. These findings underscore the potential of RJ as a functional food to regulate colorectal cancer cell motility through modulation of β-catenin, thereby reducing disease aggressiveness. Full article

MicroRNAs (miRNAs) are short sequences of single-stranded non-coding RNAs that target messenger RNAs, leading to their repression or decay. Interestingly, miRNAs play a role in the cellular response to low oxygen levels, known as hypoxia, which is associated with reactive oxygen species and oxidative stress. However, the physiological implications of hypoxia-induced miRNAs (“hypoxamiRs”) remain largely unclear. Here, we investigate the role of miR-210 in brown adipocyte differentiation and thermogenesis. We treated the cells under sympathetic stimulation with hypoxia, CoCl₂, or IOX2. To manipulate miR-210, we performed reverse transfection with antagomiRs. Adipocyte markers expression, lipid accumulation, lipolysis, and oxygen consumption were measured. Hypoxia hindered BAT differentiation and suppressed sympathetic stimulation. Hypoxia-induced HIF-1α stabilization increased miR-210 in brown adipocytes. Interestingly, miR-210-5p enhanced differentiation under normoxic conditions but was insufficient to rescue the inhibition of brown adipocyte differentiation under hypoxic conditions. Although adrenergic stimulation activated HIF-1α signaling and upregulated miR-210 expression, inhibition of miR-210-5p did not significantly influence UCP1 expression or oxygen consumption. In summary, hypoxia and adrenergic stimulation upregulated miR-210, which impacted brown adipocyte differentiation and thermogenesis. These findings offer new insights for the physiological role of hypoxamiRs in brown adipose tissue, which could aid in understanding oxidative stress and treatment of metabolic disorders. Full article

Macrophages undergo polarization, resulting in distinct phenotypes. These transitions, including de-/repolarization, lead to hysteresis, where cells retain genetic and epigenetic signatures of previous states, influencing macrophage function. We previously identified a set of interferon-stimulated genes (ISGs) associated with high lipid levels in macrophages that exhibited hysteresis following M1 polarization, suggesting potential alterations in lipid metabolism. In this study, we applied weighted gene co-expression network analysis (WGCNA) and conducted comparative analyses on 162 RNA-seq samples from de-/repolarized and lipid-loaded macrophages, followed by functional exploration. Our results demonstrate that during M1 hysteresis, the sustained high expression of Marco (SR-A6) enhances lipid uptake, while the suppression of Abca1/2 reduces lipid efflux, collectively leading to elevated intracellular lipid levels. This accumulation may compensate for reduced cholesterol biosynthesis and provide energy for sustained inflammatory responses and interferon signaling. Our findings elucidate the relationship between M1 hysteresis and lipid metabolism, contributing to understanding the underlying mechanisms of macrophage hysteresis. Full article

The Hippo pathway, a kinase cascade, coordinates with many intracellular signals and mediates the regulation of the activities of various downstream transcription factors and their coactivators to maintain homeostasis. Therefore, the aberrant activation of the Hippo pathway and its associated molecules imposes significant stress on tissues and cells, leading to cancer, immune disorders, and a number of diseases. Cellular senescence, the mechanism by which cells counteract stress, prevents cells from unnecessary damage and leads to sustained cell cycle arrest. It acts as a powerful defense mechanism against normal organ development and aging-related diseases. On the other hand, the accumulation of senescent cells without their proper removal contributes to the development or worsening of cancer and age-related diseases. A correlation was recently reported between the Hippo pathway and cellular senescence, which preserves tissue homeostasis. This review is the first to describe the close relationship between aging and the Hippo pathway, and provides insights into the mechanisms of aging and the development of age-related diseases. In addition, it describes advanced findings that may lead to the development of tissue regeneration therapies and drugs targeting rejuvenation. Full article

The octapeptide angiotensin II (Ang II) is a circulating hormone as well as a locally formed agonist synthesized by the angiotensin-converting enzyme (ACE) of endothelial cells. It forms a powerful mechanism to control the amount and pressure of body fluids. All main effects are directed to save body salt and water and ensure blood pressure under basic conditions and in emergencies. All blood vessels respond to stimulation by Ang II; the immediate response is smooth muscle contraction, increasing vascular resistance, and elevating blood pressure. Such effects are conveyed by type 1 angiotensin receptors (AT₁Rs) located in the plasma membrane of both endothelial and vascular smooth muscle cells. AT₁Rs are heterotrimeric G protein-coupled receptors (GPCRs), but their signal pathways are much more complicated than other GPCRs. In addition to G_q/11, the G_12/13, JAK/STAT, Jnk, MAPK, and ERK 1/2, and arrestin-dependent and -independent pathways are activated because of the promiscuous attachment of different signal proteins to the intracellular G protein binding site and to the intracellular C terminal loop. Substantial changes in protein expression follow, including the intracellular inflammation signal protein NF-κB, endothelial contact proteins, cytokines, matrix metalloproteinases (MMPs), and type I protocollagen, eliciting the inflammatory transformation of endothelial and vascular smooth muscle cells and fibrosis. Ang II is an important contributor to vascular pathologies in hypertensive, atherosclerotic, and aneurysmal vascular wall remodeling. Such direct vascular effects are reviewed. In addition to reducing blood pressure, AT₁R antagonists and ACE inhibitors have a beneficial effect on the vascular wall by inhibiting pathological wall remodeling. Full article

Neuroinflammation is a complex and dynamic response of the central nervous system (CNS) to injury, infection, and disease. While acute neuroinflammation plays a protective role by facilitating pathogen clearance and tissue repair, chronic and dysregulated inflammation contributes significantly to the progression of neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and Multiple Sclerosis. This review explores the cellular and molecular mechanisms underlying neuroinflammation, focusing on the roles of microglia, astrocytes, and peripheral immune cells. Key signaling pathways, including NF-κB, JAK-STAT, and the NLRP3 inflammasome, are discussed alongside emerging regulators such as non-coding RNAs, epigenetic modifications, and the gut–brain axis. The therapeutic landscape is evolving, with traditional anti-inflammatory drugs like NSAIDs and corticosteroids offering limited efficacy in chronic conditions. Immunomodulators, gene and RNA-based therapeutics, and stem cell methods have all shown promise for more specific and effective interventions. Additionally, the modulation of metabolic states and gut microbiota has emerged as a novel strategy to regulate neuroinflammation. Despite significant progress, challenges remain in translating these findings into clinically viable therapies. Future studies should concentrate on integrated, interdisciplinary methods to reduce chronic neuroinflammation and slowing the progression of neurodegenerative disorders, providing opportunities for revolutionary advances in CNS therapies. Full article

Erythroleukemia, a complex myeloproliferative disorder presenting as acute or chronic, is characterized by aberrant proliferation and differentiation of erythroid cells. Although nootkatone, a sesquiterpene derived from grapefruit peel and Alaska yellow cedar, has shown anticancer activity predominantly in solid tumors, its effects in erythroleukemia remain unexplored. This study aimed to investigate the impact of nootkatone and its derivatives on erythroleukemia. Our results demonstrate that the nootkatone derivative nootkatone-(E)-2-iodobenzoyl hydrazone (N2) significantly inhibited erythroleukemia cell proliferation in a concentration- and time-dependent manner. More importantly, N2 induced megakaryocytic differentiation, as evidenced by significant morphological changes, and upregulation of megakaryocytic markers CD41 and CD61. In vivo, N2 treatment led to a marked increase in platelet counts and megakaryocytic cell counts. Mechanistically, N2 activated a crosstalk between the JAK2/STAT3 and PKCδ/MAPK signaling pathways, enhancing transcriptional regulation of key factors like GATA1 and FOS. Network pharmacology and experimental validation confirmed that N2 targeted JAK2, and knockdown of JAK2 abolished N2-induced megakaryocytic differentiation, underscoring JAK2’s critical role in erythroleukemia differentiation. In conclusion, N2 shows great promise as a differentiation therapy for erythroleukemia, offering a novel approach by targeting JAK2-mediated signaling pathways to induce megakaryocytic differentiation. Full article

Thoracic malignancies (lung cancers and malignant pleural mesothelioma) are prevalent worldwide and are associated with high morbidity and mortality. Effective treatments are needed for patients with advanced disease. Cell therapies are a promising approach to the treatment of advanced cancers that make use of immune effector cells that have the ability to mediate antitumor immune responses. In this review, we discuss the prospect of chimeric antigen receptor-T (CAR-T) cells, natural killer (NK) cells, T cell receptor-engineered (TCR-T) cells, and tumor-infiltrating lymphocytes (TILs) as treatments for thoracic malignancies. CAR-T cells and TILs have proven successful in several hematologic cancers and advanced melanoma, respectively, but outside of melanoma, results have thus far been unsuccessful in most other solid tumors. NK cells and TCR-T cells are additional cell therapy platforms with their own unique advantages and challenges. Obstacles that must be overcome to develop effective cell therapy for these malignancies include selecting an appropriate target antigen, combating immunosuppressive cells and signaling molecules present in the tumor microenvironment, persistence, and delivering a sufficient quantity of antitumor immune cells to the tumor. Induced pluripotent stem cells (iPSCs) offer great promise as a source for both NK and T cell-based therapies due to their unlimited expansion potential. Here, we review clinical trial data, as well as recent basic scientific advances that offer insight into how we may overcome these obstacles, and provide an overview of ongoing trials testing novel strategies to overcome these obstacles. Full article

Cardiovascular disease is one of the leading causes of death and serious illness in Europe and worldwide. Conventional treatment—replacing the damaged blood vessel with an autologous graft—is not always affordable for the patient, so alternative approaches are being sought. One such approach is patient-specific tissue bioprinting, which allows for precise distribution of cells, material, and biochemical signals. With further developmental support, a functional replacement tissue or vessel can be created. This review provides an overview of the current state of bioprinting for vascular graft manufacturing and summarizes the hydrogels used as bioinks, the material of carriers, and the current methods of fabrication used, especially for vessels smaller than 6 mm, which are the most challenging for cardiovascular replacements. The fabrication methods are divided into several sections—self-supporting grafts based on simple 3D bioprinting and bioprinting of bioinks on scaffolds made of decellularized or nanofibrous material. Full article

Background/Objectives: The avascular nature of the follicle creates a hypoxic microenvironment, establishing a niche where granulosa cells (GCs) rely on glycolysis to produce energy in the form of lactate (L-lactate). Autophagy, an evolutionarily conserved stress-response process, involves the formation of autophagosomes to encapsulate intracellular components, delivering them to lysosomes for degradation. This process plays a critical role in maintaining optimal follicular development. However, whether hypoxia regulates autophagy in GCs via lactate remains unclear. Methods: In this study, we investigated lactate-induced autophagy under hypoxia by utilizing glycolysis inhibitors or silencing related genes. Results: We observed a significant increase in autophagy in ovarian GCs under hypoxic conditions, indicated by elevated LC3II levels and reduced P62 levels. Suppressing lactate production through glycolytic inhibitors (2-DG and oxamate) or silencing lactate dehydrogenase (LDHA/LDHB) effectively reduced hypoxia-induced autophagy. Further investigation revealed that the HIF1-α/BNIP3/Beclin-1 axis is essential for lactate-induced autophagy under hypoxic conditions. Inhibiting HIF-1α activity using siRNAs or PX-478 downregulated BNIP3 expression and subsequently suppressed autophagy. Similarly, BNIP3 silencing with siRNAs repressed lactate-induced autophagy in hypoxic conditions. Mechanistically, immunoprecipitation experiments showed that BNIP3 disrupted pre-existing Bcl-2/Beclin-1 complexes by competing with Bcl-2 to form Bcl-2/BNIP3 complexes. This interaction released Beclin-1, which subsequently triggered lactate-induced autophagy under hypoxic conditions. Conclusions: These findings unveil a novel mechanism by which hypoxia regulates GC autophagy through lactate production, highlighting its potential role in sustaining follicular development under hypoxic conditions. Full article

It is known that probiotics have direct and indirect effects on many systems in the body, especially the gastrointestinal system. Interest in using probiotic strain-derived cell components and metabolites has also increased as a result of the significant benefits of probiotics. Although many terminologies and definitions are used for these components and metabolites, the International Scientific Association of Probiotics and Prebiotics (ISAPP) recommended the use of the term postbiotic in 2021, which is defined as “a preparation of inanimate microorganisms and/or their components that confers a health benefit on the host”. Postbiotics are bioactive metabolites such as organic acids, peptides/proteins, cell wall components, functional enzymes, short-chain fatty acids, vitamins, and phenols. These molecules mediate many positive effects such as immunomodulatory, antimicrobial, and antioxidant effects. These positive effects on maintaining health have enabled the identification of many new postbiotic proteins such as p40, p75, and HM0539. In this review, the postbiotic proteins p40, p75, and HM0539 derived from lactobacilli and their functional effects are systematically summarized. The p40 protein, in particular, has been shown to support gut barrier activity and reduce inflammation, potentially through mechanisms involving epidermal growth factor receptor-dependent signaling. Additionally, p40 and p75 proteins exhibit protective effects on intestinal epithelial tight junctions, suggesting their therapeutic potential in preventing intestinal damage and diseases such as colitis. HM0539 enhances intestinal barrier integrity, exhibits antiinflammatory properties, and protects against bacterial infection, suggesting its possible as a therapeutic for inflammatory bowel disease. This review may contribute to future studies on the therapeutic use of p40, p75, and HM0539 postbiotic proteins in inflammatory gastrointestinal system diseases. Full article