Search Results (861)

Obesity-related kidney pathology (ORKP) is a major global issue that contributes to diabetic nephropathy and kidney cancer and leads to chronic/end-stage kidney disease. Current treatments for ORKP are limited because of the incomplete understanding of the disease pathogenesis. Here, we identified a novel role for hyaluronan (HA) and its membrane receptors, CD44 and RHAMM, in this condition. Obesity-induced increases in HA deposition and CD44 and RHAMM expression are detrimental to the kidney via activation of the TGF-β1/Smad2/3, P38/JNK MAPK, and ROCK/ERK pathways, leading to glomerulopathy, tubular injury, inflammation, albuminuria, and elevated serum creatinine concentrations. Either pharmacological or genetic ablation of HA, CD44, or RHAMM reverses these obesity-driven pathologies in vivo. We further established a mechanistic link between renal insulin resistance and ECM remodelling using human kidney cells in vitro, providing insight into the cell type-specific role of HA, CD44, and RHAMM in the pathogenesis of ORKP. Finally, analysis of glomerular and tubular fractions of human kidney biopsy samples revealed increased expression of CD44 and RHAMM in chronic kidney disease and diabetic nephropathy, and their expression correlated with markers of kidney dysfunction. Our findings provide evidence for HA-CD44/RHAMM as a potential therapeutic target in ORKP and subsequent prevention of chronic kidney disease. While previous studies have implicated CD44 and RHAMM in renal disease and fibrosis, our work for the first time provides an integrated analysis of both receptors in the context of ORKP. Full article

Dehydroandrographolide (DA), a bioactive diterpenoid from Andrographis paniculata with diverse biological activity, was investigated for its antioxidant and anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and dextran sulfate sodium (DSS)-induced murine colitis. In vitro, DA inhibited the inflammatory response by modulating extracellular Signal-Regulated Kinase (Erk), c-Jun N-terminal Kinase (Jnk), p38 Mitogen-Activated Protein Kinase (P38), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 activation, and downregulated interleukin-6 (il-6) and interleukin-1β (il-1β) mRNA. It also had antioxidant effects by upregulating Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2), NAD(P)H quinone dehydrogenase 1 (Nqo-1) and heme oxygenase-1 (Ho-1), promoting protein kinase B (Akt) and 5′-adenosine monophosphate-activated protein kinase-α1 (Ampk-α1) phosphorylation. DA decreased cyclooxygenase-2 (Cox-2) and inducible nitric oxide synthase (iNos) levels and alleviated intracellular reactive oxygen species (ROS) accumulation. In vivo, DA alleviated DSS-induced colitis in wild type (WT) mice by improving weight loss, disease activity index, colonic inflammation, and oxidative stress. The beneficial effects were linked to inhibiting Erk, Jnk, and P38 activation and enhancing Nrf2 signaling pathway. DA inhibited NOD-like receptor family pyrin domain-containing 3 (Nlrp3) inflammasome-mediated pryoptosis. However, DA’s protective effects were abolished in DSS-induced nrf2^−/− mice, suggesting its efficacy depends on Nrf2 signaling. Overall, DA alleviates oxidative stress, inflammatory responses, and pyroptosis in experimental colitis mice mainly by activating Nrf2 signaling pathway, highlighting its potential as a promising therapeutic option for inflammatory bowel disease. Full article

Roughly 25% of abalone viscera generated during processing is currently discarded, resulting in substantial protein wastage and environmental contamination. In the present study, abalone viscera served as the raw material; four commercial proteases—papain, bromelain, neutral protease and trypsin—were comparatively evaluated. Among them, the neutral-protease hydrolysate of abalone viscera (AVZH) exhibited the strongest suppression of nitric oxide (NO) release from lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis ultimately led to the identification of 18 novel peptides. Integrating bioinformatic prediction with solid-phase synthesis, two sequences—GYSFTTTAER and IKKPPQDEWGTGL—were further screened and confirmed to possess excellent cytocompatibility and pronounced anti-inflammatory potency. Mechanistic investigations revealed that both peptides dose-dependently attenuated the secretion and mRNA expression of IL-1β, IL-6 and TNF-α and concurrently blocked mitogen-activated protein kinase (MAPK) signaling by down-regulating the phosphorylation of ERK, JNK and p38. These findings demonstrate that abalone viscera represent an abundant reservoir of anti-inflammatory peptides, offering both a theoretical framework and a technological roadmap for the valorisation of marine waste proteins and the development of next-generation natural anti-inflammatory agents. Full article

Melanogenesis, the key biological process underlying skin hyperpigmentation, is tightly regulated by complex molecular signaling pathways. Consequently, targeting molecular regulators of this pathway is a crucial strategy for developing effective skin-whitening agents. Cannabinol (CBN), a minor cannabinoid, has been largely unexplored owing to its role in modulating skin pigmentation. This study aimed to elucidate the molecular mechanisms of CBN’s depigmenting effects using an α-MSH-induced B16F10 melanoma cell model. High-purity CBN was obtained via conversion of cannabidiol (CBD) and confirmed by HPLC. CBN significantly inhibited melanin synthesis and tyrosinase activity in a concentration-dependent manner, without any cytotoxicity. Furthermore, we investigated CBN’s impact on the melanogenesis signaling cascade. Our analysis revealed that CBN significantly downregulated the mRNA and protein levels of key melanogenic master regulators, including MITF, TYR, TYRP1, and TYRP2. Importantly, we also observed that CBN treatment selectively suppressed the protein phosphorylation of upstream signaling molecules such as p38 and JNK MAP kinases and NF-κB, while ERK phosphorylation remained unaffected. This finding indicates that its mechanism of action involves the selective modulation of pro-melanogenic signaling components. Collectively, these findings demonstrate that CBN effectively modulates the melanogenesis signaling pathway by targeting both upstream kinases and downstream melanogenic genes. These findings suggest that CBN holds great promise as a bioactive agent for skin-whitening applications and warrants further research to confirm its clinical efficacy and safety. Full article

Background/Objectives: Chamaecyparis pisifera (C. pisifera; family Cupressaceae) is known to have insecticidal and antibacterial activities, but its effects on skin depigmentation-related activities have not been elucidated. Thus, in the present study, we aimed to investigate the anti-hyperpigmentation potential of C. pisifera var. filifera leaf essential oil (CPEO), specially focusing on responses related to melanogenesis and melanin transport, using B16BL6 cells. Methods: CPEO was extracted by steam distillation, and its composition was determined by GC/MS spectrometry. The biological activities of CPEO on B16BL6 melanoma cells were analyzed using the water soluble tetrazolium salt, BrdU incorporation, ELISA, and immunoblotting assays. Results: Twenty-eight components were identified in CPEO. CPEO was noncytotoxic to B16BL6 cells at 1–100 μg/mL and reduced serum-induced proliferation in B16BL6 cells. CPEO significantly inhibited α-MSH-stimulated increases in melanin synthesis and tyrosinase activity in the cells (e.g., at 100 μg/mL CPEO, melanin synthesis: 117.89 ± 0.00% vs. 571.94 ± 0.81% with α-MSH; tyrosinase activity: 73.62 ± 0.00% vs. 322.60 ± 3.10% with α-MSH). CPEO also downregulated the expression levels of melanogenesis-related proteins (MITF, tyrosinase, TRP-1 and -2) and melanosome transport-related proteins (Rab27a, melanophilin, myosin Va) in cells exposed to α-MSH. Moreover, the essential oil increased the phosphorylations of MAPKs (p38, ERK1/2, and JNK) in α-MSH-treated B16BL6 cells. In addition, CPEO reduced the ultraviolet A (UVA) induced increases in α-MSH levels in HaCaT cells. In addition, conditioned medium from HaCaT cells irradiated with UVA (CM-UVA) in the presence of CPEO reduced melanin synthesis and tyrosinase activity in B16BL6 cells (e.g., at CM-UVA with 100 μg/mL CPEO, melanin synthesis: 100.92 ± 0.99% vs. 134.44 ± 0.97% with CM-UVA; tyrosinase activity: 101.02 ± 1.81% vs. 133.77 ± 1.88% with CM-UVA). Conclusions: These findings suggest that CPEO inhibits melanin production (probably through the regulation of MAPKs) and transport-related activities in B16BL6 cells, and that CPEO may serve as a potential natural anti-hyperpigmentation or skin whitening. Full article

Breast cancer is the most prevalent cancer in women worldwide and presents a major therapeutic challenge, particularly triple-negative breast cancer (TNBC), a subtype characterized by an aggressive clinical course but heightened sensitivity to chemotherapy. Natural products, such as triterpene glycosides derived from sea cucumbers, have emerged as promising candidates with high anticancer potential against TNBC. This study investigated the pathways of anticancer action of cucumarioside A₀-1 (Cuc A₀-1) and djakonovioside A (Dj A), isolated from the sea cucumber Cucumaria djakonovi, triggered and regulated in MDA-MB-231 cells (triple-negative breast cancer cell line). We employed functional assays (cAMP level, Ca²⁺ influx, control of cell proliferation and colony formation), Western blotting for mitogen-activated protein kinase MAPK) signaling, and in silico molecular docking. A_2B adenosine receptor (A_2BAR) was identified as a novel target for both glycosides. As antagonists, they reduced cAMP production and inhibited NECA (5-(N-ethylcarboxamido)adenosine)-induced Ca²⁺ influx. This A_2BAR blockade suppressed the MAPK pathway, profoundly inhibiting phospho-ERK1/2, p38, and JNK1/2, which led to the activation of the intrinsic apoptotic pathway and strong inhibition of cell proliferation and colony formation. Surprisingly, co-treatment with the NECA agonist enhanced the antiproliferative effects of the glycosides. It was supposed that the interaction of glycosides with the NECA-preactivated receptor may bias signaling toward the Gi and Gq/PLC/ERK1/2 pathways, underscoring the central role of the MAPK pathway in controlling cell growth. Molecular docking confirmed binding to the A_2BAR orthosteric site, revealing that Cuc A₀-1 and Dj A employ distinct interaction modes. To our knowledge, this is the first report to define A_2BAR as a target for sea cucumber glycosides. Their potent antitumor effects, mediated through the antagonism of A_2BAR and subsequent MAPK pathway inhibition, position them as promising lead compounds for cancer types with high expression A_2BAR. Full article

Fibroblasts determine repair quality during skin-wound healing. Our previous study found that Activin B promotes keratinocyte proliferation and migration, facilitating re-epithelialization. However, specific mechanisms governing fibroblast function during wound healing remain unclear. Here, we aimed to elucidate the mechanism by which Activin B regulates fibroblast activity during skin-wound healing. Using a murine skin-wound model, we performed hematoxylin-eosin, immunohistochemical, and Masson’s trichrome staining to evaluate Activin B’s effects on granulation tissue formation, angiogenesis, and collagen fiber synthesis. We assessed Activin B’s effects on fibroblast proliferation, migration, and collagen protein synthesis and investigated signaling pathway mechanisms in vitro. Animal experiments showed that Activin B accelerated wound healing by promoting granulation tissue regeneration and angiogenesis without affecting collagen fibers and Type I collagen synthesis. In vitro experiments demonstrated that Activin B modulates fibroblast proliferation and migration by activating JNK and ERK signaling pathways. Activin B may enhance angiogenesis by stimulating fibroblasts to secrete vascular endothelial growth factor, which induces dermal microvascular endothelial cell proliferation, promoting angiogenesis. Thus, we elucidated the dual regulatory paradigm of Activin B in fibroblasts; Activin B drives proliferation and migration via JNK/ERK signaling but does not directly regulate collagen synthesis. Full article

Food-derived bioactive peptides are known to possess immunomodulatory properties, although their molecular mechanisms remain incompletely characterized. In this study, we investigated the immunoregulatory effects and underlying mechanisms of YPFPGPIH, a peptide derived from bovine β-casein, using the RAW264.7 macrophage model. Our results demonstrate that YPFPGPIH enhanced macrophage proliferation and phagocytosis in a dose-dependent manner and promoted chemotactic migration through the upregulation of monocyte chemoattractant proteins MCP-1 and MCP-3. Under lipopolysaccharide (LPS)-induced inflammatory conditions, YPFPGPIH significantly reduced the levels of pro-inflammatory mediators, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and nitric oxide (NO), while increasing the production of the anti-inflammatory cytokine interleukin-10 (IL-10), thereby reestablishing cytokine balance. Mechanistic studies revealed that YPFPGPIH inhibited LPS-induced activation of the NF-κB and MAPK pathways, as indicated by reduced nuclear translocation of p65 and decreased phosphorylation of ERK, JNK, and p38. Molecular docking analysis indicated strong binding affinities between YPFPGPIH and Toll-like receptors TLR2 and TLR4, suggesting the involvement of TLR-mediated signaling. Notably, YPFPGPIH downregulated inducible nitric oxide synthase (iNOS) expression and upregulated chemokine mRNA levels, reflecting its dual role in modulating inflammatory and migratory responses. These findings highlight YPFPGPIH as a multifunctional immunomodulatory peptide that fine-tunes macrophage activity through crosstalk between TLR, NF-κB, and MAPK signaling pathways. This study provides new insights for developing peptide-based therapeutics and functional foods aimed at managing inflammatory diseases. Full article

Orthodontic tooth movement (OTM) arises from force-induced mechanotransduction within the periodontal ligament (PDL), which coordinates osteoblast and osteoclast activity with immune responses to remodel the PDL and alveolar bone. This review integrates contemporary biological insights on OTM and assesses photobiomodulation (PBM) as an adjunctive therapy. We propose that mechanical and photonic inputs may interact and potentiate signaling through the Ca²⁺-NFAT, MAPK (ERK, p38, JNK), PI3K–Akt–mTOR, NF-kB, TGF-β/Smad, and Wnt/β-catenin pathways. Such interaction could influence processes such as cell proliferation, differentiation, specific cellular functions, apoptosis, autophagy, and communication between stromal and immune cells. This convergence establishes a solid foundation for understanding the context-dependent effects of PBM in OTM. In principle, PBM appears most effective as a phase-tuned adjunct, promoting early inflammatory recruitment of osteoclasts and subsequently facilitating late-phase remodeling through immunomodulatory and reparative mechanisms. However, inconsistent irradiation parameters, small sample sizes, trial heterogeneity, and the absence of mechanistic endpoints undermine current conclusions. Furthermore, the lack of integrated PBM–OTM models limits mechanistic understanding, as much of the available evidence is derived from non-OTM contexts. Overall, PBM remains a promising adjunct in orthodontics, with the potential to integrate mechanical and photonic signals in a phase-dependent manner, though its application is not yet standardized. Full article

Osteoarthritis (OA) is primarily a degenerative disease triggered by joint inflammation and oxidative stress. While Aster glehni is an edible and traditionally medicinal herb, the beneficial effect of A. glehni on OA progression remains unknown. This study aimed to investigate the effect of A. glehni extract (AGE) and its primary biological compound—3,5-dicaffeoylquinic acid (3,5-DCQA)—on inflammation and oxidative stress in chondrocytes. AGE effectively inhibited the expression of interleukin (IL)-6, cyclooxygenase (COX)-2, matrix metalloproteinase (MMP)-1, and MMP-13 in chondrocytes stimulated by IL-1β for 24 h. In contrast, 3,5-DCQA did not inhibit IL-6, COX-2, and MMP expressions under the same conditions. However, when chondrocytes were stimulated by IL-1β for a short duration (6 h), 3,5-DCQA suppressed IL-6, COX-2, and MMP expressions. The inhibition of IL-6, COX-2, and MMP expressions by AGE was associated with the p38 kinase and nuclear factor-κB signaling pathways, but not ERK and JNK signaling pathways. Furthermore, AGE prevented cell apoptosis and reduced intracellular reactive oxygen species levels in chondrocytes induced by hydrogen peroxide (H₂O₂). AGE restored the decreased superoxide dismutase 1 and catalase mRNA expressions caused by H₂O₂. Collectively, AGE may protect against cartilage deterioration by inhibiting inflammation and oxidative stress, making it a promising therapeutic agent for alleviating OA. Full article

Chronic inflammation driven by Cyclooxygenase-2 (COX-2) overexpression plays a key role in lung cancer (LC) progression, making it a critical therapeutic target. This study explores thymoquinone (TQ), a potent bioactive phytochemical derived from Nigella sativa, known for its anti-inflammatory and anti-cancer effects, focusing on its ability to suppress lipopolysaccharide (LPS)-induced COX-2 expression via microRNA hsa-miR-199a-3p modulation in LC cells. Using A549 and SHP-77 LC cells, we tested the effect of TQ under LPS stimulation and miRNA inhibition. Advanced techniques like TaqMan qPCR, luciferase reporter gene constructs, and anti-miRNA transfection confirmed that miR-199a-3p directly silences COX-2. Western blot and ELISA assays revealed that TQ dramatically reduces COX-2 protein and PGE2 levels by boosting miRNA-199a-3p. Importantly, TQ also blocked MAPK (p38, JNK, ERK) and NF-κB activation, even when miR-199a-3p was suppressed, proving its multi-targeted action beyond miRNA regulation. These findings reveal a novel anti-inflammatory mechanism, where TQ curbs COX-2-driven inflammation by enhancing miR-199a-3p, simultaneously shutting down pro-cancer MAPK/NF-κB signaling pathways. Given the strong link between chronic inflammation and LC aggressiveness, this study positions TQ as a promising therapeutic candidate, especially for inflammation-mediated lung cancer progression. Its dual ability to modulate miRNA and key signaling cascades makes it a compelling option for future LC treatment strategies. Full article

Background: Temporal lobe epilepsy (TLE), a prevalent refractory focal epilepsy frequently complicated by comorbid anxiety and depression, poses significant therapeutic challenges due to the inadequate efficacy of current antiepileptic drugs in seizure control. Carbon dots (CDs) demonstrate notable biological activities and represent a promising class of nanomedicines for TLE intervention. Methods: This study established an eco-friendly calcination protocol to synthesize a novel suspension of Crinis Carbonisatus-derived carbon dots (CC-CDs) as a candidate therapeutic for TLE. Results: In a TLE mouse model, the CC-CDs suspension significantly inhibited phosphorylation of the MAPK pathway (p-JNK, p-ERK, p-p38; p < 0.01, p < 0.05), leading to reduced levels of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α; p < 0.01, p < 0.05), upregulation of TGF-β1 (p < 0.01, p < 0.05), and restoration of antioxidant enzyme activities (SOD, GSH, CAT; p < 0.01, p < 0.05). These modifications subsequently regulated the Glu/GABA balance, alleviating excitotoxicity (p < 0.05), attenuating neuronal damage and Nissl body loss in hippocampal CA1/CA3 regions, and improving cognitive function alongside reducing anxiety-like behaviors (p < 0.01, p < 0.05). In vitro, the CC-CDs suspension suppressed LPS-induced apoptosis in BV2 cells. Conclusions: The CC-CDs suspension ameliorates TLE by inhibiting MAPK signaling, thereby reducing neuroinflammation and oxidative stress, rectifying Glu/GABA imbalance, attenuating excitotoxicity, and ultimately improving behavioral deficits. These findings underscore the therapeutic potential of CC-CDs suspension for TLE treatment. Full article

Background: Abnormal activation of Angiotensin II (Ang II) serves as a primary trigger for myocardial hypertrophy and cardiac injury. Isoquercitrin (IQ) and Quercetin (Que) possess anti-inflammatory and anti-apoptotic properties, but their protective effects against Ang II-induced cardiac injury remain unclear. This study aimed to investigate the mechanisms and therapeutic efficacy of IQ and Que in heart failure. Methods: Cytotoxic effects of IQ and Que on Ang II-induced H9c2 rat cardiomyocyte apoptosis models were assessed in vitro using the CCK-8 assay. Reactive Oxygen Species (ROS) generation and apoptotic fluorescence levels were measured. WB analysis examined protein expression in inflammatory and apoptotic pathways. In vivo heart failure model was established in mice, with cardioprotective effects of IQ and Que evaluated via echocardiography. Molecular docking was employed to analyze ligand–target interactions. Results: IQ outperformed Que in promoting cell viability and decreasing ROS. IQ exhibited a more potent inhibitory effect on apoptosis through regulating Bax, Caspase-3, CytoC, and Bcl-2 and demonstrated superior suppression of cardiac inflammation by inhibiting phosphorylation of ERK, JNK, and P38. Compared with Que, IQ more effectively attenuated Ang II-induced cardiac injury by ameliorating reductions in EF% and FS%, suppressing ST-segment elevation, and significantly reducing serum levels of CK-MB, LDH, ANP, BNP, and FFA in a heart failure model. Molecular docking verified stronger binding affinity of IQ for key targets. Conclusions: IQ demonstrates superior cardioprotection over Que by regulating MAPK signaling and mitochondrial apoptosis pathways, supporting its potential as a therapeutic candidate for heart failure. Full article

Obesity is closely associated with the development of insulin resistance (IR) and type 2 diabetes mellitus (T2DM), primarily due to dysfunctional adipose tissue expansion and the secretion of pro-inflammatory cytokines such as interleukin-1β (IL-1β). 14-Deoxy-11,12-didehydroandrographolide (deAND), a major diterpenoid component of Andrographis paniculata, has demonstrated notable antioxidant and anti-inflammatory activities. This study aimed to investigate the protective effects and mechanisms of deAND against IL-1β-induced IR in 3T3-L1 adipocytes. Network pharmacology analysis indicated that deAND targets several IR-related signaling pathways, particularly the MAPK and IRS-1/AKT pathways. The experimental results show that IL-1β stimulated p67phox membrane translocation and reactive oxygen species (ROS) production, contributing to impaired insulin signaling by activating ERK and JNK and reducing IRS-1/AKT phosphorylation, which ultimately decreased insulin-stimulated glucose uptake. Pretreatment with deAND effectively inhibited NOX2-derived ROS generation, suppressed ERK/JNK activation, restored IRS-1/AKT phosphorylation, and reversed the reduction in glucose uptake caused by IL-1β. These findings suggest that deAND can alleviate IR by inhibiting NOX2-mediated oxidative stress, restoring insulin signaling and improving glucose uptake, highlighting its potential as a therapeutic agent for obesity-related IR. Full article

Skin health is significantly impacted by factors such as melanin production, UV-induced photodamage, and wound healing. Excessive melanin leads to hyperpigmentation, while UVA radiation accelerates skin aging and oxidative stress. This study investigated the multi-functional dermatological potential of S strain LS-derived cell-free supernatant (CFS-LS) to address these concerns. Our findings demonstrate that CFS-LS effectively inhibits melanogenesis in B16F10 cells. It significantly reduced α-MSH-induced melanin synthesis, comparable to arbutin, by downregulating key melanogenic enzymes (tyrosinase, TRP-1, and TRP-2) and regulatory proteins (p-CREB, MITF, SOX9, and SOX10). Mechanistically, CFS-LS suppressed the phosphorylation of MEK, ERK, p38, and JNK, indicating a dual inhibitory effect on both PKA/CREB and MAPK pathways. Furthermore, CFS-LS mitigated UVA-induced photodamage in HaCaT cells by significantly reducing intracellular reactive oxygen species and suppressing the downstream phosphorylation of p53 and α-MSH levels. It also restored UVA-suppressed Nrf-2 and HO-1 expression, enhancing cellular antioxidant defenses. Lastly, CFS-LS promoted skin wound healing by significantly enhancing HaCaT cell migration in a scratch assay, associated with increased p-MEK1/2 and p-ERK1/2 levels, and notably elevated collagen type I synthesis. Collectively, these results highlight CFS-LS as a potent multi-functional agent for skin protection and repair, with significant potential for cosmetic and therapeutic applications. The active components of CFS-LS warrant further investigation. Full article