Search Results (13,360)

Oral cancer is a leading cause of cancer-related deaths and significantly affects the quality of life of patients. However, many of its mechanisms remain unclear, and its treatment needs improvement. The G-protein-coupled receptor taste receptor type 2 member 14 (T2R14 or TAS2R14) is expressed in various cancer types. However, few studies have investigated its roles in oral cancer, and its effects on oral cancer cell proliferation and growth are unknown. This study aimed to examine T2R14’s impact on proliferation and cell population growth (CPG) of oral cancer cells. TAS2R14 gene knockout was performed, and cell numbers, cell viability, and colony formation were measured. This study showed that TAS2R14 knockout in oral cancer cells significantly decreased calcium mobilization, increased cell numbers, colony formation, the proliferation marker proliferating cell nuclear antigen, and the phosphorylation of mechanistic target of rapamycin, but did not affect cell viability. These observations are consistent with the clinical data that higher TAS2R14 mRNA expression is associated with better survival of patients with oral cancer. Therefore, T2R14 downregulation increased oral cancer CPG, suggesting a tumor-suppressor-like role. The study’s findings could improve our understanding of T2R14 mechanisms and help develop strategies to advance oral cancer treatment by targeting T2R14. Full article

The blood–brain barrier (BBB) is a major obstacle to the development of brain-targeted drug delivery systems, restricting greater than 98% of small molecules (<500 Da) and virtually all large-molecule drugs from entering the brain tissues from the bloodstream, resulting in suboptimal drug doses and therapeutic failure in the treatment of Alzheimer’s disease (AD). However, the advent of nanotechnology has provided significant solutions to the BBB challenges, enabling particle size reduction, enhanced drug solubility, reduced premature drug degradation, extended and sustained drug release, enhanced drug transport across the BBB, increased drug target specificity and enhanced therapeutic efficacy. In corollary, a library of brain-targeted surface-functionalized nanotherapeutics has been widely reported in the current literature. These promising in vitro, in vivo and pre-clinical results from the existing literature provide quantitative evidence for the relative clinical utility of each of the techniques, indicating remarkable capacity for brain-targeted carrier systems; many of them are still being tested in human clinical trials. However, despite the recorded research successes in drug transport across the BBB, there are currently no clinically proven medications that can slow or reverse the progression of AD because most of the novel therapeutics have not been successful during the clinical trials. Therefore, the main option for the treatment of AD is symptomatic treatment using cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists. Although these therapies help to alleviate symptoms of AD and improve patients’ quality of life, they neither slow the progression of disease nor cure it. Thus, an effective disease-modifying therapy for the treatment of AD is an unmet clinical need. It is apparent that a deeper understanding of the structural complexity and controlling dynamic functions of the BBB in tandem with a comprehensive elucidation of AD pathogenesis are crucial to the development of novel nanocarriers for the effective treatment of AD. Therefore, this narrative review describes the contextual analysis of several promising strategies that enhance brain-targeted drug delivery across the BBB in AD treatment and recent research efforts on two major AD biomarkers that have revolutionized AD diagnosis, amyloid-beta plaques and phosphorylated tau protein tangle, as potential targets in AD drug development. This has led to the Food and Drug Administration (FDA)’s approval of two intravenous (IV) anti-amyloid monoclonal antibodies, Lecanemab (Leqembi^®) and Donanemab (Kisunla^®), which were developed based on the Aβ cascade hypothesis for the treatment of early AD. This review also discusses the recent shift in the Aβ cascade hypothesis to Aβ oligomer (conformer), a soluble intermediate of Aβ, which is the most toxic mediator of AD and could be the most potent drug target in the future for a more accurate and effective drug development model for the treatment of AD. Furthermore, various promising nanoparticle-based drug carriers (therapeutic nanoparticles) that were developed from intensive research are discussed, including their clinical utility, challenges and prospects in the treatment of AD. Overall, it suffices to state that the advent of nanotechnology provided several innovative techniques for overcoming the BBB and improving drug delivery to the brain; however, their long-term biosafety is a relevant concern. Full article

For a long time, glycolysis and mitochondrial oxidative phosphorylation were opposed to each other. Glycolysis works when there is a lack of oxygen; the mitochondria supply ATP in an oxygen environment. In recent decades, it has been discovered that glycolysis in vivo always works and the final product is lactate. Lactate can accumulate and is the transport form for pyruvate. In this review, we look at how obligate lactate formation during glycolysis affects the tricarboxylic acid (TCA) cycle and mitochondrial respiration. We conclude that fatty acid β-oxidation is a prerequisite for obligate lactate formation during glycolysis, which in turn promotes and enhances the anaplerotic functions of the TCA cycle. In this way, a supply of two types of substrates for mitochondria is formed: fatty acids as the basic energy substrates, and lactate as an emergency substrate for the heart, skeletal muscles, and brain. High steady-state levels of lactate and ATP, supported by β-oxidation, stimulate gluconeogenesis and thus support the lactate cycle. It is concluded that mitochondrial fatty acids β-oxidation and glycolysis constitute a single interdependent system of energy metabolism of the human body. Full article

Background/Objectives: Chronic stress leads to sustained elevations in cortisol levels, which promote neuronal damage and impair memory. Prolonged stress also enhances proinflammatory signaling. Adaptogens are plant-derived compounds associated with the ability to increase the body’s resistance to stress, thereby improving mental and physical performance. To identify potential interventions capable of attenuating stress-related memory alterations, this study investigated a formulation combining the adaptogen Bacopa monnieri L. with phosphatidylserine and choline (BPC). Methods: An in vitro model of stress-related neuroinflammation was established by exposing BV2 microglial cells to corticotropin-releasing hormone (CRH, 100 nM). SH-SY5Y cells exposed to conditioned medium from CRH-stimulated BV2 cells or to iron(II) sulfate and L-ascorbic acid (Fe/Asc) were used as models of neurotoxicity. Results: BPC attenuated CRH-induced proinflammatory microglial morphology, as well as the reduction in cell viability and cell number. BPC treatment restored the levels of stress-related markers, including SIRT-1, Nrf-2, and phosphorylated JNK (p-JNK). Furthermore, BPC protected against neurotoxicity induced by CRH and Fe/Asc and promoted cholinergic activation by restoring basal acetylcholinesterase (AChE) levels. The combined BPC formulation showed superior efficacy compared with its individual components across all experimental assays. Conclusions: Collectively, these findings indicate that the BPC formulation developed in this study effectively attenuates stress-related neuroinflammation and neurotoxicity. BPC may represent a promising strategy to help limit the progression of early cognitive dysfunction under conditions of prolonged stress. Full article

Background: Hyperpigmentation disorders lack effective therapies due to efficacy and safety limitations. Spirulina-derived peptides (SPs) show promises as anti-melanogenic agents, but their mechanisms remain unclear. Methods: SPs (<1 kDa, 3–6 amino acids) were isolated and assessed for tyrosinase inhibition, antioxidant, and anti-glycation activities. In vitro effects were tested in B16F10 cells; transcriptomic profiling used RNA sequencing. In vivo efficacy was evaluated in UVB-induced hyperpigmentation mouse models. Results: SPs exhibited mixed-type kinetic inhibition of tyrosinase along with strong antioxidant and anti-glycation activities. In vitro, SP suppressed melanin synthesis by directly inhibiting tyrosinase, downregulating the cAMP/PKA/CREB cascade, and activating the PI3K/Akt/GSK-3β pathway, resulting in reduced MITF and tyrosinase expression. Transcriptomic analysis revealed broad regulation of melanogenesis and inflammatory pathways. In vivo, topical SP treatment significantly reduced UVB-induced hyperpigmentation and skin inflammation, correlating with decreased CREB phosphorylation and tyrosinase expression. Conclusions: SP acts as a dual anti-melanogenic/anti-inflammatory agent through enzyme inhibition and signaling modulation, offering a novel therapeutic strategy for inflammation-associated hyperpigmentation. Full article

Background/Objectives: Cholangiocarcinoma (CCA) is a very aggressive biliary carcinoma characterised by significant molecular heterogeneity and restricted treatment alternatives. Despite genomic and proteomic investigations revealing recurrent changes, the signalling dynamics influencing tumour behaviour remain inadequately comprehended. Methods: We conducted high-resolution Liquid Chromatography–Tandem Mass Spectrometry (LC–MS/MS)-based phosphoproteomics on paired tumour and surrounding tissues from 13 CCA patients in Northeast Thailand, meticulously sampling four geographically unique tumour areas for each patient. Our analysis concentrated on phosphoproteins consistently identified across all regions, delineating strong tumour-specific and cohort-wide phosphorylation signatures. Results: Notwithstanding considerable inter-patient variability, two conserved signalling modules were identified: an adhesion/Wnt axis regulated by hyperphosphorylated CTNNB1 protein (β-catenin) and a metal-handling module facilitated by metallothionein-1G (MT1G) protein and metallothionein-2A (MT2A) protein. Pathway enrichment identified focal adhesion, ECM-receptor interaction, cytoskeletal modulation, and mineral absorption as critical activities. Conclusions: This study elucidates conserved oncogenic pathways by analysing phosphoproteomic signatures across regional and patient-level variability, emphasising phosphoproteomics as a robust framework for biomarker and therapeutic development in CCA. Full article

Phosphate-induced vascular calcification in chronic kidney disease is linked to cardiovascular mortality. This calcification process involves vascular smooth muscle cells (VSMCs), which can promote a pro-calcific environment in the vascular wall. However, the mechanisms underlying a putative phosphate sensing of VSMCs to modulate pro-calcific signaling are insufficiently clarified. In mammals, three isoforms of the inositol hexakisphosphate kinase (IP6K) exist, which have been implicated in cellular phosphate homeostasis. Therefore, each IP6K isoform was silenced in calcifying primary human aortic VSMCs. IP6K1 and IP6K2 mRNA expression were increased in calcifying VSMCs. Silencing of either IP6K1 or IP6K2 ameliorated phosphate-induced pro-calcific markers expression and VSMC calcification. IP6K3 mRNA expression was not modified during calcifying conditions, but IP6K3 silencing still resulted in some anti-calcific effects. Mechanistically, the IP6K product 5-IP7 may act as a potent inhibitor of AKT kinase signaling. Accordingly, pro-calcific conditions induced only transient AKT phosphorylation, and IP6K2 silencing increased AKT phosphorylation in calcifying VSMCs. In turn, AKT inhibition blunted the protective effects of IP6K2 knockdown, while serum- and glucocorticoid-inducible kinase 1 (SGK1) inhibition restored these effects. These observations indicate a role for IP6Ks during phosphate-induced VSMC calcification, which could be mediated by an altered balance between AKT and SGK1 signaling. Full article

Prolonged exposure to ultraviolet (UV) radiation in sunlight is a major extrinsic factor that impairs skin function and accelerates photoaging. In this study, a murine model of ultraviolet B (UVB)-induced photoaging exhibited characteristic symptoms, including skin roughness, erythema, hyperpigmentation, and increased wrinkle formation. Epicatechin gallate (ECG), a natural flavonoid, has demonstrated potential skin-protective properties. However, its specific effects and mechanisms against UVB-induced photoaging are not fully understood. Here, we investigated the protective role and underlying mechanism of ECG against UVB-induced damage in human epidermal keratinocytes (HaCaT cells). Using network pharmacology, p38 mitogen-activated protein kinase (p38 MAPK), specifically the p38α isoform, was identified as a key potential target of ECG. Our experimental results confirmed that ECG significantly attenuated UVB-induced photoaging. Mechanistically, ECG treatment effectively suppressed UVB-triggered phosphorylation of p38α, promoted autophagic flux (as evidenced by increased LC3B conversion and decreased p62 levels), and substantially reduced intracellular reactive oxygen species (ROS) accumulation. Consequently, ECG mitigated mitochondrial dysfunction, restored normal cell cycle progression, and decreased the expression of senescence-associated markers (p53, p16, p21) and inflammatory cytokines (IL6, TNF-α). In summary, our findings demonstrate that ECG protects against UVB-induced photoaging primarily by inhibiting p38α activation, thereby enhancing autophagy and alleviating oxidative stress. This study positions ECG as a promising therapeutic candidate for preventing and treating skin photoaging. Full article

As a typical halogenated hydrocarbon environmental pollutant, 1,2-dichloroethane (1,2-DCE) exhibits clinically confirmed hepatotoxicity with incompletely understood mechanisms. This study integrated network toxicology, molecular docking, and in vitro experiments to investigate necroptosis in 1,2-DCE-induced liver injury. Computational analysis predicted involvement of the aryl hydrocarbon receptor (AHR)/cytochrome P450 1A1 (CYP1A1) pathway, and molecular docking suggested potential binding between 1,2-DCE and AHR (−6.5 kcal/mol). CCK-8 assays showed that 1,2-DCE reduced THLE-2 hepatocyte viability in a concentration-dependent manner. Notably, 1,2-DCE triggered rapid AHR nuclear translocation within 1 h and transiently upregulated CYP1A1 at both the transcriptional and protein levels (3–6 h). Further studies revealed elevated intracellular reactive oxygen species (ROS) at 24 h. After 48 h exposure, CYP1A1 expression was significantly suppressed, accompanied by activation of necroptosis markers, including increased lactate dehydrogenase (LDH) release, enhanced propidium iodide (PI) staining, and elevated phosphorylation of receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL). These findings reveal a dual-phase mechanism: an early adaptive stress response via the AHR-CYP1A1 axis, followed by pathway dysfunction and transition to necroptosis, suggesting AHR as a potential target for intervening in 1,2-DCE-induced hepatotoxicity. Full article

Blossom-end rot (BER) in tomatoes is a physiological disorder primarily caused by the disruption of calcium absorption and transport. This study cultivated tomatoes using a trough-based vermiculite system. Two treatments were established: a calcium-deficient nutrient solution and a calcium-deficient nutrient solution supplemented with 0.1 mg/L BR (n = 40 plants per treatment). The activities of catalase (CAT), peroxidase (POD), and superoxide dismutase (SOD), as well as the contents of malondialdehyde (MDA) and hydrogen peroxide (H₂O₂), were measured in the leaves. Calcium ion content was also determined in various plant parts. Statistical analysis of differences was performed using Duncan’s multiple range test at a significance level of p < 0.01. Concurrently, transcriptome sequencing of root, stem, and leaf tissues was conducted via high-throughput sequencing technology. The results showed that foliar application of BR under calcium deficiency significantly reduced the incidence of BER (from 26.67% to 6.67%) and effectively increased calcium ion content in leaves, stems, and roots. At the physiological level, BR treatment markedly enhanced the activities of CAT, POD, and SOD in leaves (by 105.70%, 117.12%, and 82.77%, respectively), while reducing H₂O₂ and MDA contents (by 36.90% and 16.38%, respectively). This indicates that BR alleviates membrane lipid peroxidation damage by enhancing the antioxidant defense system. Gene Ontology (GO) enrichment analysis revealed that the differentially expressed genes (DEGs) were primarily involved in biological processes, such as secondary metabolic processes, response to oxygen-containing compounds, and cell wall organization. KEGG pathway analysis further indicated significant enrichment in pathways, including phenylpropanoid biosynthesis, plant hormone signal transduction, and plant–pathogen interaction. Additionally, key genes, such as the cytochrome c oxidase (COX) gene (Solyc03g013460.1), exhibited a gradient up-regulation pattern (root > stem > leaf) in the oxidative phosphorylation pathway. In conclusion, BR likely enhances tomato tolerance to calcium deficiency stress and effectively reduces BER incidence through multiple pathways: regulating calcium absorption and distribution, activating the antioxidant system, modulating hormone signaling pathways, and enhancing energy metabolism. These findings provide a theoretical basis for the application of BR in agricultural production. Full article

Background/Objectives: SLC13A5 encodes a sodium–citrate cotransporter implicated in early-onset epileptic encephalopathy and metabolic brain dysfunction, yet its developmental regulation and molecular context in the human brain remain incompletely defined. Methods: Leveraging human developmental transcriptomes from the Evo-Devo resource, we delineated tissue trajectories and network context for SLC13A5 across the fetal–postnatal life. Results: In the cerebrum, SLC13A5 expression rises from late fetal stages to peak in the first postnatal year and then declines into adulthood, while cerebellar levels increase across the lifespan; liver shows a fetal decrease followed by sustained postnatal upregulation. A transcriptome-wide scan identified extensive positive and negative associations with SLC13A5, and a signed weighted gene co-expression network analysis (WGCNA) built on biweight midcorrelation placed SLC13A5 in a large module. The module eigengene tracked brain maturation (Spearman rho = 0.802, p = 8.62 × 10⁻⁶) and closely matched SLC13A5 abundance (rho = 0.884, p = 2.73 × 10⁻⁶), with a significant partial association after adjusting for developmental rank (rho = 0.672, p = 6.17 × 10⁻⁴). Functional enrichment converged on oxidative phosphorylation and mitochondria. A force-directed subnetwork of the top intramodular members (|bicor| > 0.6) positioned SLC13A5 adjacent to a densely connected nucleus including CYP46A1, ITM2B, NRGN, GABRD, FBXO2, CHCHD10, CYSTM1, and MFSD4A. Conclusions: Together, these results define a developmentally tuned, mitochondria-centered program that co-varies with SLC13A5 in the human brain across the lifespan. It may provide insights to interrogate age-dependent phenotypes and therapeutic avenues for disorders involving citrate metabolism. Full article

Background/Objectives: Doxorubicin (DOX) is an effective chemotherapeutic agent whose clinical utility is limited by cardiotoxicity. To investigate underlying mechanisms, we employed a multi-omics approach integrating transcriptomics and proteomics, leveraging established mouse models of chronic DOX-induced cardiotoxicity. Methods: Five-week-old male mice received weekly DOX (4 mg/kg) or saline injections for six weeks, with heart tissues harvested 4 days post-treatment. Differentially expressed genes (DEGs) and proteins (DEPs) were identified by bulk RNA-seq and proteomics, validated via qPCR and Western blot, respectively. Key DEPs were validated in plasma samples from DOX-treated breast cancer patients. Additionally, temporal comparison was conducted between DEPs in the mice hearts 4 days and 6 weeks post-DOX. Results: RNA-seq revealed upregulation of stress-responsive genes (Phlda3, Trp53inp1) and circadian regulators (Nr1d1), with downregulation of Apelin and Cd74. Proteomics identified upregulation of serpina3n, thrombospondin-1, and epoxide hydrolase 1. Plasma SERPINA3 concentrations were significantly elevated in breast cancer patients 24 h post-DOX. Gene set enrichment analysis (GSEA) revealed upregulated pathways, including p53 signaling, apoptosis, and unfolded protein response. Integrated omics analysis revealed 2089 gene–protein pairs. GSEA of concordant gene–protein pairs implicated p53 signaling, apoptosis, and epithelial–mesenchymal transition in upregulated pathways, while oxidative phosphorylation and metabolic pathways were downregulated. Temporal comparison with a delayed timepoint (6 weeks post-DOX) uncovered dynamic remodeling of cardiac signaling, with early response dominated by inflammatory and apoptotic responses, and delayed response marked by cell cycle and DNA repair pathway activation. Conclusions: This integrated omics study reveals key molecular pathways and temporal changes in DOX-induced cardiotoxicity, identifying potential biomarkers for future cardioprotective strategies. Full article

Excessive fluoride exposure induces developmental neurotoxicity, but effective preventive strategies are currently scarce. Melatonin (Mel), a lipophilic hormone secreted by the pineal gland, exerts antioxidant, anti-inflammatory, and neuroprotective properties. This study aimed to explore Mel’s protective effect and mechanism against fluoride-induced developmental brain injury. We employed a network pharmacology approach to screen the common targets of Mel and fluoride-induced brain injury and performed enrichment analysis. A total of 189 common targets were identified, and these targets were mainly enriched in the HIF-1 signaling pathway and oxidative stress-related pathways. In vivo, Sprague Dawley rats were subjected to perinatal sodium fluoride (NaF) exposure with/without Mel; in vitro, HT22 cells were subjected to NaF and/or Mel. The results showed that Mel improved cognitive impairments and alleviated structural damage to hippocampal neurons and mitochondria. Furthermore, Mel upregulated SIRT3 and downregulated HIF-1α, thereby restoring mitochondrial oxidative phosphorylation and ATP content. This study demonstrates that Mel alleviates fluoride-induced developmental neurotoxicity by improving mitochondrial function through regulating the SIRT3/HIF-1α signaling pathway. This not only offers a novel perspective for elucidating the underlying molecular mechanisms of fluoride-induced developmental neurotoxicity but also provides a theoretical foundation for Mel as a potential protective candidate against fluoride exposure. Full article

Mitochondria play a crucial role in metabolism and energy production by generating adenosine triphosphate (ATP) through oxidative phosphorylation. They also help maintain intracellular calcium levels, facilitate communication between the nucleus and cytoplasm, detoxify reactive oxygen species (ROS), and regulate apoptosis. Reversible acetylation of mitochondrial proteins is a key post-translational modification influencing these processes, with the NAD⁺-dependent deacetylase SIRT3 being a major regulator. While SIRT3 has been described as a tumor suppressor in some contexts and as a tumor promoter in others, its role appears to be tissue- and metabolism-specific. Here, we compared the proteomic and acetylomic responses of lung adenocarcinoma (A549) and breast adenocarcinoma (MCF7) cell lines to SIRT3 inhibition by 3-TYP. The two lines were selected based on distinct metabolic phenotypes and reported differences in basal SIRT3 abundance. Total proteome and mitochondrial-enriched fractions were analyzed separately for each cell line to avoid cross-line normalization bias. We identified 6457 proteins and 4199 acetylated peptides, revealing distinct pathway enrichments and acetylation changes after SIRT3 inhibition. A549 cells showed increased oxidative metabolism, while MCF7 cells exhibited metabolic reprogramming. These results indicate that the proteomic impact of SIRT3 modulation is strongly influenced by cellular metabolic context. All raw mass spectrometry data are publicly available in PXD063181. Full article

Background/Objectives: Histamine H₁ receptors mediate multiple physiological and pathophysiological processes, including inflammation and allergy, by regulating downstream gene expression via transcription factors. cAMP response element-binding protein (CREB) is a major transcription factor whose phosphorylation is regulated by multiple signaling pathways. Although CREB is closely involved in multiple physiological and pathophysiological processes, the detailed intracellular signaling pathway of H₁ receptor-mediated CREB phosphorylation remains to be elucidated. We investigated the roles of G_q proteins and arrestins in H₁ receptor-mediated CREB phosphorylation. Methods: We constructed Chinese hamster ovary (CHO) expressing human wild-type (WT) H₁ receptors and two types of C-terminal mutants. One mutant was constructed by truncating the serine 487 residue only at the C-terminus (S487Trunc), and the other was constructed by substituting the serine 487 residue at the C-terminus with alanine (S487A). S487Trunc is a G_q protein-biased while S487A is an arrestin-biased receptor. The expressions of CREB and its phosphorylated form were assessed by immunoblotting. Results: Histamine promoted CREB phosphorylation in CHO cells expressing WT or S487Trunc receptors, but not in cells expressing S487A. Inhibitors of protein kinase C (PKC), extracellular signal-regulated kinase (ERK), or c-Jun N-terminal kinase (JNK), and Ca²⁺ chelator suppressed histamine-induced CREB phosphorylation in CHO cells expressing WT or S487Trunc receptors. Basal CREB phosphorylation levels increased following β-arrestin overexpression and decreased after their siRNA-mediated knockdown, thus modulating histamine-stimulated CREB phosphorylation in WT CHO cells. Conclusions: H₁ receptor-mediated CREB phosphorylation is induced through G_q protein/Ca²⁺/PKC-dependent ERK and JNK activation; arrestins can modulate this process by regulating basal CREB phosphorylation. Full article