Biomolecules & Therapeutics最新文献

Diabetes mellitus (DM) is a disorder characterized by hyperglycemia, inflammation, and impaired metabolic activities. This study investigated the effects of sialyllactose (SL), a subgroup of human milk oligosaccharides, on streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM) in vivo. Male ICR mice were preadministered SL followed by a single intraperitoneal injection of STZ to establish the T1DM model. The evaluation was conducted through biochemical analyses, glucose and insulin tolerance tests, histological assessments, qRT-PCR, and western blotting. We found that SL pretreatment improved body weight, glucose tolerance, and fasting blood glucose levels in mice. SL mitigated STZ-induced organ injury, as evidenced by histological analysis and serum markers of liver, pancreas, kidney, and skeletal muscle damage. SL also improved electrolyte and lipid profiles, indicating its role in metabolism. Notably, SL exhibited strong anti-inflammatory properties by inhibiting hepatic TNF-α and MCP-1 mRNA expression and reducing inducible nitric oxide synthase protein expression. Taken together, our findings suggest that SL is a promising candidate for DM management based on its beneficial effects on inflammation and metabolic modulation.

Microglia have emerged as key regulators in Alzheimer's disease (AD), yet the molecular factors driving their dysfunction remain unclear. Through integrative transcriptomic and proteomic analyses, we identified PLXDC2, a transmembrane receptor, as a protein consistently upregulated in the AD brain and cerebrospinal fluid. Single-nucleus RNA-seq confirmed its microglia-specific enrichment, particularly in lipid-processing, phagocytic, and inflammatory subclusters. Functional assays revealed that PLXDC2 overexpression in BV2 microglial cells impaired Aβ uptake and suppressed pro-inflammatory cytokines Il-6 and Il-1β, without altering lipid droplet formation. These findings indicate that PLXDC2 plays a regulatory role in critical microglial functions and may drive AD pathogenesis by disrupting phagocytic activity and immune responses.

Human chimeric antigen receptor T (hCAR-T) cells are highly potent cellular therapeutics, but their clinical utility depends on stable long-term preservation due to high production costs and lengthy manufacturing processes. Cryopreservation is essential for ensuring the quality and logistics of these therapies. However, current commercial cryoprotectants such as CellBanker^® are limited by high cost, undisclosed composition, and lack of flexibility for optimization. This study aimed to evaluate defined sugar-based cryoprotectants-trehalose, sucrose, and glucose-as potential alternatives for hCAR-T cell preservation. hCAR-T cells were cryopreserved using various concentrations of the three sugars in combination with DMSO. Post-thaw evaluations included viability, recovery, apoptosis, proliferative capacity, and immunophenotypic analysis. At 18 h after thawing, glucose 50 mM significantly improved recovery (1.03 ± 0.29 vs. 1.59 ± 0.20×10⁶ cells) and reduced apoptosis (52.58 ± 7.31% vs. 39.50 ± 2.16%) compared with DMSO alone. These results were comparable to, and in some cases exceeded, those obtained with the commercial product CellBanker^®. Moreover, glucose at 50 mM exhibited approximately 1.9-fold higher cell proliferation after three days of culture compared to CellBanker^®, while preserving a stable CD4⁺/CD8⁺ ratio and central memory T cell (T_CM) profile. These findings indicate that sugar-based cryoprotectants, particularly glucose at 50 mM, can support post-thaw survival and function of hCAR-T cells. Given their defined composition, lower cost, and comparable efficacy, sugar-based formulations represent promising alternatives to commercial cryopreservation agents for advanced cell therapies.

Chitinase-3-like protein 1 (CHI3L1) is a secreted glycoprotein involved in macrophage polarization, apoptosis, and inflammation, and carcinogenesis. The expression of CHI3L1 is significantly increased in various inflammatory and immunological diseases, such as rheumatoid arthritis, Alzheimer's disease, and atopic dermatitis. Several studies suggest that CHI3L1 may be a viable therapeutic target for these diseases, given its ability to release various pro-inflammatory cytokines, including interleukin (IL)-1β, IL-4, IL-6, IL-13, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ). Therefore, CHI3L1 likely plays a role in the development of a broad spectrum of inflammatory diseases. However, the precise pathophysiological and pharmacological mechanisms by which CHI3L1 contributes to these diseases remain to be fully elucidated. This review synthesizes recent findings on the functional roles of CHI3L1 across diverse inflammatory conditions, highlighting its involvement in critical signaling pathways. Moreover, preclinical research underscores the therapeutic potential of CHI3L1 inhibition. Thus, targeted CHI3L1 interventions represent a compelling therapeutic strategy warranting further clinical exploration and validation.

Seborrheic dermatitis (SD) is a chronic inflammatory skin disorder that primarily affects areas with increased sebaceous gland activity, and is characterized by erythematous scaly lesions. Malassezia utilizes sebum lipids to produce free fatty acids that may disrupt the epidermal barrier and trigger inflammation in eczematous lesions. However, the pathogenesis and mechanisms underlying the exaggerated inflammatory response and sebogenesis regulation in SD remain unknown. Activation of pattern recognition receptors, including Toll-like receptors (TLRs), is crucial for initiating innate immunity. In the present study, we evaluated the efficacy of a novel antimicrobial cosmetic ingredient, AMPamide, and elucidated its molecular mechanisms underlying the suppression of inflammation and sebogenesis in SD. Specifically, we investigated the inhibitory effect of AMPamide on TLR activation and its impact on downstream signaling pathways in LPS-stimulated HaCaT cells. The effects of AMPamide on lipid production and the expression of related regulatory factors in IGF-1-stimulated SZ95 sebaceous gland cells were also examined. These analyses were performed using RT-qPCR, western blotting, immunofluorescence staining, and Nile Red staining. AMPamide exhibited anti-inflammatory and skin barrier-strengthening effects by inhibiting TLR4/6 expression and multiple signaling pathways. Additionally, AMPamide attenuated lipid overproduction and the expression of related regulatory factors in IGF-1-stimulated SZ95 sebaceous gland cells. Therefore, the observed effects of AMPamide on LPS-stimulated human keratinocytes were mediated via blockade of the TLR-MyD88-MAPK and NF-κB signaling pathway. These results revealed that AMPamide may be a potential therapeutic agent for SD that inhibits TLR4/6 activation.

Out of at least 20,000 human proteins fewer than 700 are targeted by drugs. Arrestins regulate G protein-coupled receptors, the largest family of signaling proteins in animals, as well as many receptor-independent signaling pathways. Humans express four arrestin subtypes, two of which are ubiquitous and were already shown to serve as versatile hubs of cellular signaling. So far, arrestin proteins are not directly targeted by any drugs. Here we describe potential targets on arrestins and/or interacting proteins, possible approaches for the development of targeting compounds, expected biological outcomes, and possible research and therapeutic value of targeting the interactions of arrestins with receptors and other signaling and trafficking proteins.

Interstitial lung disease (ILD) represents a heterogeneous group of diseases in which inflammation and/or fibrosis in the pulmonary interstitium results in an impaired gas exchange, difficulties in breathing, and reduced quality of daily life, and contributes to elevated global morbidity and mortality rates. ILD is an umbrella term, with idiopathic pulmonary fibrosis (IPF) being a prime focus because of its progressive and severe form. Out of 300 underlying etiologies, ILD is one of the major reasons for global morbidity and mortality. This review offers a comprehensive overview of six main categories of ILD covering autoimmune, idiopathic interstitial pneumonia, hypersensitivity pneumonitis, drug-induced, infection-related, and unclassified ILD that underscore the complexity of diagnosis and treatment challenges. This review also provides an evidence-based overview of recent advancements in the diagnosis and management of ILD, with precision pharmacotherapy, multidisciplinary care, and emerging therapeutic strategies. From clinical trial data, it also recommends the disease-specific use of pharmacological agents-such as pirfenidone and nintedanib for IPF, and mycophenolate mofetil for connective tissue disease-associated ILD. The manuscript also emphasizes the evolving role of non-pharmacological interventions, including the 6-minute walk test and pulmonary rehabilitation, in enhancing functional capacity and quality of life. To address the current global health concerns, topics of post-COVID-19 ILD and immune checkpoint inhibitor-associated lung disease are integrated. Additionally, future directions are explored, including the role of lung transplantation and novel antifibrotic therapies like anti-Transforming Growth Factor (TGF)-β antibody cocktails. Together, these insights aim to refine diagnostic precision, personalize treatment, and improve clinical outcomes across the heterogeneous ILD spectrum.

Xylene is an aromatic hydrocarbon widely used as a solvent and emitted from numerous commercial products in industrial or indoor settings. Epidemiological studies of occupational exposure indicate that xylene primarily targets the central nervous system, producing neurobehavioral impairments and other neurological disorders. Both environmental and occupational exposure to volatile organic compounds, therefore, raise concerns about neurodevelopmental risk; however, the specific neurotoxicity of xylene in developing neurons remains poorly characterized. Here, we investigated the effects of xylene (2 or 5 mM) on developing mouse hippocampal neurons, with a focus on Ca²⁺ homeostasis, presynaptic function, and electrophysiological activity. We assessed Ca²⁺ homeostasis with selective inhibitors of voltage-gated Ca²⁺ channels and organelle-specific Ca²⁺ indicators. Presynaptic activity was evaluated in transgenic mouse pups expressing a genetically encoded pH sensor within the synaptic vesicle lumen. Xylene suppressed cytosolic Ca²⁺ transients by inhibiting P/Q-type Ca²⁺ channels, thereby reducing Ca²⁺ uptake into the endoplasmic reticulum. It also decreased Ca²⁺ influx at both presynaptic and postsynaptic sites, impairing synaptic vesicle exocytosis and endocytosis. Electrophysiological and morphological analyses further showed reduced spontaneous firing and hindered synaptic maturation. Collectively, these findings provide mechanistic insight into the neurotoxic actions of xylene and underscore its potential hazard to brain development and function.

Methylglyoxal (MGO), a reactive glycolytic byproduct, contributes to skeletal muscle atrophy by promoting oxidative stress, inflammation, and protein degradation. This study investigated the therapeutic potential of trans-resveratrol and hesperidin (tRES-HESP) supplementation, alone or in combination with aerobic exercise, in ameliorating MGO-induced muscle dysfunction in mice. ICR mice were divided into five groups and treated with MGO, tRES-HESP, treadmill exercise, or both interventions over eight weeks. Muscle mass, grip strength, endurance performance, histopathology, and molecular biomarkers were assessed. Combined treatment with tRES-HESP and exercise significantly improved muscle function and morphology, restored muscle mass, and suppressed fibrosis. In terms of signaling pathways, the protective effects were associated with activation of the AMPK/SIRT1/PGC-1α pathway for mitochondrial biogenesis, stimulation of the AKT/mTOR pathway for muscle protein synthesis, suppression of MuRF1-mediated protein degradation, and upregulation of MyoD and MyHC, key markers of muscle regeneration and structural integrity. Additionally, inflammatory balance was restored via suppression of pro-inflammatory IL-6 and elevation of anti-inflammatory IL-10 levels. These findings highlight the synergistic benefits of combining polyphenol supplementation with aerobic exercise as a promising strategy for mitigating muscle atrophy under metabolic stress conditions.