Search Results (385)

Regulatory B cells (Bregs) are integral to the tumor microenvironment (TME) and influence immune responses through the secretion of immunosuppressive cytokines such as IL-10, IL-35, and TGF-β. This review highlights recent findings on the phenotype and mechanisms of Bregs, emphasizing their dual role in regulating immune responses within the TME. Importantly, we further explored the latest advances in Breg regulatory mechanisms from the novel perspectives of epigenetics and metabolic remodeling, including the effects of DNA methylation, histone acetylation, glycolysis, and oxidative phosphorylation on Bregs. We also investigate the therapeutic targeting of Bregs, with a focus on STAT3 inhibitors such as lipoxin A4, cucurbitacins, and resveratrol, which show promising potential in mitigating the suppressive function of Bregs. Furthermore, this review provides a detailed analysis of the impact of Bregs on tumorigenesis and metastasis, emphasizing the importance of inhibiting specific immune pathways to prevent tumor escape. Finally, this review offers a prospective outlook on immunotherapy strategies based on Bregs, foreseeing a more nuanced understanding of their TME function and the evolution of targeted treatments with enhanced therapeutic efficacy. Full article

The arachidonic acid pathway plays a pivotal role in the biosynthesis of important inflammatory and signal transducing agents such as prostaglandins, leukotrienes and thromboxanes. When this pathway is deregulated, it leads to pathological conditions such as cardiovascular diseases, metabolic diseases, and cancer. Two key enzymes of the pathway are cyclooxygenases (COXs) and lipoxygenases (LOXs), which are responsible for the production of prostaglandins and leukotrienes, respectively. Consequently, these enzymes have long been recognized as key therapeutic targets for the treatment and management of inflammatory disorders and other pathological conditions associated with inflammation. In this review, we describe the new evidence over the last 4 years regarding the arachidonic acid pathway. Moreover, we will pay attention to the structure and function of the COX-2 and 5-LOX enzymes and their role in inflammation, as well as define their active sites. Later, we will discuss the most potent, dual inhibitors of COX-2 and 5-LOX enzymes, based on in vitro and in vivo experiments, from 2020–2024. Structure–activity relationship (SAR) analysis of these compounds revealed four key structural features required for potent dual inhibition of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX). We refer to these criteria as “The Rule of Four for Inflammation”. Full article

Background: Cancer-associated fibroblasts (CAFs) are key mediators of metastatic progression in non-small cell lung cancer (NSCLC). Fibroblast activation protein (FAP) serves as the hallmark of CAF activation. However, the upstream regulation of FAP remains elusive, limiting stroma-targeted therapy development. Methods: ⁶⁸Ga-FAP inhibitor (FAPI)-04 PET/CT imaging was performed on 61 NSCLC patients to evaluate the clinical significance of FAP. CAFs and normal fibroblasts (NFs) were isolated from patient tissues. Bioinformatic analysis and qRT-PCR were employed to screen and validate miRNAs. Functional assays (CCK-8, collagen contraction, wound healing, transwell co-culture) were utilized to investigate the role of miR-624-5p in regulating fibroblast activation and the effects on the metastatic potential of NSCLC cells. The targeting relationship between miR-624-5p and FAP was validated using FISH, dual-luciferase assay, and Western blotting. Results: ⁶⁸Ga-FAPI-04 uptake was higher in advanced NSCLC (p < 0.001) and correlated with tumor size, lymph node metastases, and distant metastases (p < 0.05). Isolated primary CAFs significantly enhanced the migration and invasion of A549 and PC9 cells compared to NFs (p < 0.001). We identified miR-624-5p as a significantly downregulated miRNA in CAFs (p < 0.001). Functionally, miR-624-5p overexpression inhibited CAF proliferation and collagen contraction (p < 0.01) and reduced the proliferation, migration, and invasion capabilities of A549 and PC9 cells (p < 0.001). Mechanistically, miR-624-5p bound to FAP mRNA and negatively regulated FAP expression (p < 0.001), thus suppressing CAF activation and tumor metastasis. Conclusions: Our findings establish miR-624-5p as a novel upstream regulator that suppresses FAP expression, consequently inhibiting CAF activation and its pro-metastatic function. Targeting the miR-624-5p/FAP axis represents a promising therapeutic strategy for NSCLC metastasis. Full article

Selective inhibition of CYP17A1 17,20-lyase is critical for treating hyperandrogenic disorders without the cortisol-depleting side effects of non-selective drugs like abiraterone. We evaluated tanshinones from Salvia miltiorrhiza as potential selective inhibitors using biochemical assays and computational modeling. Dihydrotanshinone (DT) emerged as the superior candidate; at 10 µM, it inhibited 17,20-lyase activity by 56.6% while preserving >93% of 17α-hydroxylase activity. This yields a selectivity index of 8.67, drastically outperforming abiraterone (0.73). Furthermore, DT displayed minimal off-target inhibition of CYP21A2 (14.9%) compared to abiraterone (29.8%). Molecular modeling suggests DT’s efficacy arises from a unique, functionally disruptive binding pose rather than superior thermodynamic affinity. Consequently, DT is validated as a potent natural product lead. Its dual selectivity over 17α-hydroxylase and CYP21A2 establishes the tanshinone scaffold as a promising candidate for developing safer therapies that suppress androgens while sparing cortisol biosynthesis. Full article

Alpha-1 antitrypsin (AAT) is a serine protease inhibitor with potent anti-inflammatory and immunomodulatory properties, but its role in cancer is context-dependent across tumor types. We integrated transcriptomic analyses of human melanoma cohorts, in vivo studies using AAT-transgenic (hAAT-TG) mice, and in vitro assays in murine and human melanoma cells to define the biological functions of AAT in melanoma. SERPINA1 expression increased progressively from normal skin to nevi and metastatic melanoma, yet higher intratumoral levels correlated with improved overall survival in metastatic disease. In hAAT-TG mice, melanoma growth was markedly inhibited compared with wild-type controls, and the inhibitory effect required CD8⁺ T cells and was enhanced by CD4⁺ T-cell depletion, demonstrating that AAT promotes cytotoxic T-cell activity while attenuating regulatory T-cell suppression. Histologic analysis showed heavily pigmented tumors in hAAT-TG mice. In vitro, hAAT upregulated melanocytic differentiation markers (MITF, TYR, PMEL, MART-1) and increased melanin production in murine and human melanoma lines, suggesting enhanced tumor immunogenicity. In conclusion, hAAT exerts antitumor effects in melanoma indirectly by reprogramming the tumor microenvironment toward differentiation and immune activation. These findings highlight a previously unrecognized role for AAT as a dual immunoregulatory and differentiation-promoting factor and support AAT as a potential immunoregulatory adjuvant in melanoma. Full article

The COVID-19 pandemic has profoundly affected societies around the world. Although the emergency phase of coronavirus disease 2019 (COVID-19) has ended, the threat it poses remains persistent. This review aims to clarify the mechanisms of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection to support effective management of the disease. A central focus is the host cellular response to the viral infection, with particular emphasis on the role of cytokines. Cytokines play a dual role in antiviral defense: they contribute to the inhibition of viral replication and facilitate the clearance of pathogens, yet dysregulated cytokine responses can result in severe immunopathology. Interferons (type I, type II, and type III) and other cytokines are pivotal in activating intracellular antiviral mechanisms and in orchestrating the recruitment of immune cells through extracellular signaling. Effective immune responses to viral infections are governed not only by primary immune cells—such as dendritic cells, T lymphocytes, and B lymphocytes—but also by the local cytokine milieu shaped by infected and neighboring cells. Given the presence of endogenous inhibitors and autoantibodies in vivo, it is essential to evaluate the functional activity of cytokines in clinical samples. We propose a novel approach to quantify biologically active cytokine levels. Full article

Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD) are characterized by complex pathologies with progressive neurodegeneration, protein misfolding, oxidative stress, and persistent inflammation. Recent findings indicate the pivotal involvement of epigenetic disruption, particularly aberrant histone deacetylase (HDAC) activity, in disease initiation and progression. In the current review, we systematically discuss the mechanistic function of HDACs across all classes (I, IIa, IIb, III, and IV) in neurodegenerative disease mechanisms, such as their involvement in the modulation of gene expression, mitochondrial function, proteostasis, and neuronal survival. We discuss the therapeutic potential, as well as limitations, of HDAC inhibitors (HDACis), such as pan-inhibitors and isoenzyme-selective inhibitors, and new multi-target-directed ligands with HDAC inhibition combined with acetylcholinesterase modulation, PDE modulation, MAO-B inhibition, or NMDAR modulation. Particular emphasis is placed on the development of HDAC6-selective inhibitors with enhanced brain permeability and reduced toxicity, which have shown promising preclinical efficacy in ameliorating hallmark pathologies of AD, PD, and HD. In addition, s-triazine-based scaffolds have recently emerged as promising chemotypes in HDAC inhibitor design, offering favorable pharmacokinetic profiles, metabolic stability, and the potential for dual-target modulation relevant to neurodegeneration. The review also explores the future of HDAC-targeted therapies, including PROTAC degraders, dual-inhibitor scaffolds, and sustainable, BBB-penetrant molecules. Collectively, this review underscores the importance of HDAC modulation as a multifaceted strategy in the treatment of neurodegenerative diseases and highlights the need for continued innovation in epigenetic drug design. Full article

Bacterial carbonic anhydrases (CAs) are essential for intracellular pH regulation, bicarbonate homeostasis, and energy metabolism, making them attractive antimicrobial targets. Here, building on evidence that acetazolamide (AZA) delivered via hyaluronic acid–palmitate (HA-PA) nanocarriers impairs Escherichia coli growth and its glucose uptake, we investigated the physiological roles of β- and γ-class CAs using sulphonamide inhibitors with distinct selectivity encapsulated in HA-PA nanomicelles to ensure intracellular delivery. AZA, a potent dual β/γ-CA inhibitor, ethoxzolamide (EZA), a selective β-CA inhibitor, and hydrochlorothiazide (HCT), a weaker inhibitor of both classes, were tested for effects on bacterial physiology. The nanoparticles reduced growth in a dose- and class-dependent manner, with AZA exerting the strongest activity, EZA intermediate inhibition, and HCT only modest effects at higher concentrations. Early metabolic responses assessed via intracellular ATP after three hours of exposure revealed an unexpected and reproducible ATP increase for all inhibitors relative to untreated cells, suggesting reduced ATP consumption in bicarbonate-dependent pathways. These findings provide indirect yet compelling evidence that β- and γ-class CAs influence bacterial energy homeostasis and support the rationale for CA inhibition as an antimicrobial strategy, while highlighting HA-PA carriers as effective systems for delivering CA inhibitors intracellularly and enhancing their functional activity in bacterial cells. Full article

The microglia, first identified by Pío del Río-Hortega, are resident macrophages in the CNS that aid in immune monitoring, synaptic remodeling, and tissue repair. Microglial biology’s dual functions in maintaining homeostasis and contributing to neurodegeneration are examined in this review, with a focus on neurodegenerative disease treatment targets. Methods: We reviewed microglial research using single-cell transcriptomics, molecular genetics, and neuroimmunology to analyze heterogeneity and activation states beyond the M1/M2 paradigm. Results: Microglia maintains homeostasis through phagocytosis, trophic factor production, and synaptic pruning. They acquire activated morphologies in pathological conditions, releasing proinflammatory cytokines and reactive oxygen species via NF-κB, MAPK, and NLRP3 signaling. Single-cell investigations show TREM2 and APOE-expressing disease-associated microglia (DAM) in neurodegenerative lesions. Microglial senescence, mitochondrial failure, and chronic inflammation result from Nrf2/Keap1 redox pathway malfunction in ageing. Microglial interactions with astrocytes via IL-1α, TNF-α, and C1q result in neurotoxic or neuroprotective A2 astrocytes, demonstrating linked glial responses. Microglial inflammatory or reparative responses are influenced by epigenetic and metabolic reprogramming, such as regulation of PGC-1α, SIRT1, and glycolytic flux. Microglia are essential to neuroprotection and neurodegeneration. TREM2 agonists, NLRP3 inhibitors, and epigenetic modulators can treat chronic neuroinflammation and restore CNS homeostasis in neurodegenerative illnesses by targeting microglial signaling pathways. Full article

Scaling and thermal loss on the surfaces of industrial equipment and pipelines usually lead to increased energy consumption and reduced operational efficiency. To solve these severe problems, developing advanced coatings with the dual functions of scale resistance and thermal insulation is an effective approach. Inspired by the antifouling agents released from corals and the thermal insulation of goose down, we herein have developed a bioinspired hollow silica microsphere-based (BHSM) coating, exhibiting the synergistic effect of anti-scaling and thermal insulation properties. The BHSM coating is composed of aluminum phosphate (AP) as an inorganic adhesive and scale inhibitor, and hollow silica microspheres (HSMs) as a thermal insulator. In brief, the effective anti-scaling capability comes from released phosphate ions of AP adhesive for chelating with mineral ions, while the high thermal insulation results from the internal air of the HSMs. Compared to the stainless steel (SS 304), the BHSM coating exhibited ~86% scale reduction. Furthermore, the extremely low thermal conductivity of the HSMs endows the BHSM coating with excellent thermal insulation, resulting in a 20% reduction in heat loss relative to the SS 304 surface. Thus, this work presents a promising strategy for anti-scaling and thermal insulation in industrial equipment and pipelines. Full article

P-glycoprotein (P-gp) is an ATP-driven transporter that effluxes a wide range of xenobiotics from cells, and its overexpression is a primary cause of multidrug resistance (MDR) in cancer. It is well-established that P-gp functions through conformational changes, yet its large-scale structural dynamics at work have been unexplored. Here, we directly visualized single P-gp molecules reconstituted in nanodiscs using high-speed atomic force microscopy (HS-AFM). The HS-AFM movies revealed that P-gp is intrinsically dynamic in its apo state, with its nucleotide-binding domains (NBDs) undergoing large, spontaneous opening and closing motions. However, addition of ATP stabilized a conformation characterized by NBD proximity with a strong tendency toward closure. We then leveraged this dynamic viewpoint to elucidate the relationship between Elacridar’s function and the resulting structural dynamics of P-gp. Elacridar is designed to overcome multidrug resistance (MDR) in cancer and acts as a potent dual inhibitor of both P-gp and the Breast Cancer Resistance Protein (BCRP), effectively blocking the drug efflux function of these transporters. This inhibitor has suggested concentration-dependent function: it is effluxed as a substrate at low concentrations and acts as an inhibitor at high concentrations. Our direct observations revealed that low concentrations induced active dynamics in P-gp, whereas high concentrations severely restricted its motion, leading to a rigid, non-productive state. Our study provides critical insights into how observing molecular motion itself can unravel complex biological mechanisms. Full article

The petroleum industry faces intensifying challenges related to the depletion of easily accessible reservoirs and the growing energy demand, necessitating the adoption of advanced chemical agents that can operate under extreme conditions. Cationic gemini surfactants, characterized by their unique dimeric architecture consisting of two hydrophilic head groups and two hydrophobic tails, have emerged as superior alternatives to conventional monomeric surfactants due to their enhanced interfacial activity and physicochemical resilience. This review provides a comprehensive analysis of the literature concerning the molecular structure, synthesis, and functional applications of cationic gemini surfactants across the entire oil value chain, from extraction to refining. The analysis reveals that gemini surfactants exhibit critical micelle concentrations significantly lower than their monomeric analogs and maintain stability in high-temperature and high-salinity environments. They demonstrate exceptional efficacy in enhanced oil recovery through ultra-low interfacial tension reduction and wettability alteration, while simultaneously serving as effective drag reducers, wax inhibitors, and dual-action biocidal corrosion inhibitors in transportation pipelines. Cationic gemini surfactants represent a transformative class of multifunctional materials for the oil industry. Full article

Lymphatic vessels are a kind of heterogeneous and versatile component of the lymphatic system, with a unique ability to respond to environmental changes in different organs. The heterogeneity and plasticity of lymphatic endothelial cells (LECs) and defective lymphatic architecture are critical for organ-specific lymphatic function. Moreover, lymphatic vessels have a dual effect on tumor microenvironment (TME), and lymphangiogenesis, an active and dynamic player, is a hallmark of cancer progression and treatment resistance. Dysregulation of lymphatic vessels and uncontrolled lymphangiogenesis contribute to the pathogenesis of many diseases, including cancer. Increasing evidence has indicated that lymphangiogenesis provides a critical target for inhibiting lymphatic metastasis, in which immune checkpoint inhibitors, either alone or combined with chemotherapy, may have a therapeutic value. This article reviews the current status of tumor-associated lymphangiogenesis and lymphatic remodeling, as well as the crosstalk among LECs, immune cells and cancer cells, which will help to further understand the role of lymphangiogenesis in cancer progression, metastasis, and therapy. Full article

Plasminogen activator inhibitor-1 (PAI-1) is a central regulator of the fibrinolytic system and is increasingly recognized for its pivotal roles in a broad spectrum of physiological and pathological processes. In addition to its classical function in fibrinolysis, accumulating evidence highlights the involvement of PAI-1 in cellular senescence, differentiation, fibrosis, thrombosis, and tumorigenesis. This review systematically summarizes recent advances in understanding the multifaceted biological functions of PAI-1, with a particular emphasis on its dual regulatory roles in cellular differentiation and senescence. Through manual curation and analysis of the literature, we constructed a PAI-1-centered signaling network associated with differentiation and further integrated this framework with known senescence-related pathways. This integrative approach aims to elucidate the crosstalk between differentiation and senescence mediated by PAI-1. By providing an in-depth overview of PAI-1 functions across various experimental models, this review offers a theoretical foundation for exploring its potential as a therapeutic target and presents novel perspectives for the development of intervention strategies for complex chronic diseases. Full article

Mild steel readily corrodes in acidic environments, and most industrial corrosion inhibitors are synthetic, often toxic, and environmentally harmful. In this study, electrocatalytically active Cd–Cs mixed oxide nanocomposites were synthesized via a green route using an aqueous extract of Trachyspermum ammi (ajwain) seeds as a natural reducing, stabilizing, and capping agent. This eco-friendly method eliminates harsh chemicals while producing nanomaterials with active surfaces capable of facilitating electron transfer and scavenging free radicals. Incorporation of cesium introduces basic, electron-rich sites on the Cd–Cs oxide surface, serving as inhibition promoters that enhance charge transfer at the metal/electrolyte interface and assist in the formation of an adsorbed protective film on steel. The nanocomposites were optimized by adjusting precursor ratios, pH, temperature, and reaction time, and were characterized by UV–Vis, FTIR, XRD, SEM–EDS, HR-TEM EDS, BET, DLS, XPS, and zeta potential analyses. Strong antioxidant activity in ABTS and DPPH assays confirmed efficient catalytic quenching of reactive radicals. Corrosion inhibition potential, evaluated by using potentiodynamic polarization, electrochemical impedance spectroscopy, and gravimetric analysis in 0.5 M HCl, shows an inhibition efficiency of 90–91%. This performance is associated with an electrocatalytically active, adsorbed barrier layer that suppresses both anodic dissolution and cathodic hydrogen evolution, which depicts mixed-type inhibition. Overall, the biosynthesized Cd–Cs mixed oxide nanocomposites function as promising green synthesized nanomaterial with dual antioxidant and corrosion-inhibiting functions, underscoring their potential for advanced surface engineering and corrosion protection. Full article