Search Results (964)

Gastric cancer (GC) remains a major cause of cancer-related mortality, with limited options for early detection and precision therapy. Collagen family members are increasingly recognized as key structural and regulatory components of the tumor microenvironment. Collagen type X alpha 1 chain (COL10A1) appears among the top overexpressed genes in GC and has been linked with tumorigenesis, but its functional role in GC has not been completely elucidated. The oncogenic potential of COL10A1 was assessed in vitro in GC cell lines using adenoviral-mediated overexpression. Functional assays were further performed to evaluate proliferation, apoptosis, migration, invasion, and epithelial–mesenchymal transition (EMT) markers. Intracellular signaling alterations were analyzed by phosphokinase protein profiling and protein–protein interaction network analysis. COL10A1 overexpression significantly increased proliferation and migration, while reducing GC cell apoptosis. It promotes EMT by up-regulating mesenchymal markers (N-cadherin, Vimentin, Snail/Slug) and suppressing epithelial markers such as E-cadherin and β-catenin. Additionally, COL10A1 overexpression activated oncogenic signaling pathways, including the JNK and MAPK cascades, increasing proliferation and tumorigenic potential. Our results showed that COL10A1 functions as a driver for tumor progression by promoting proliferation, migration, and invasion along with EMT through activation of important oncogenic pathways. These findings highlight its biological role in tumor progression and contribute to a better understanding of GC pathogenesis. 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

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

Polystyrene microplastics (PS-MPs) are microplastic particles produced during plastic manufacturing and environmental degradation, accumulating over time and entering ecosystems through various pathways, ultimately affecting organisms and inducing toxic effects. Current research on the impact of PS-MPs on mammalian oocyte quality, along with potential preventive mechanisms and strategies to mitigate toxicity, remains limited. This study investigates the effects of antioxidant melatonin on oocyte quality in the presence of PS-MPs, focusing on their influence on oocyte meiotic maturation and embryonic developmental potential. PS-MPs at a concentration of 30 μg/mL significantly impaired first polar body extrusion and reduced the success rate of parthenogenetic activation of mature oocytes in vitro. Furthermore, exposure to PS-MPs exacerbated oxidative stress, mitochondrial dysfunction, apoptosis, and autophagy impairment. Additionally, PS-MPs exposure led to a reduction in antioxidant gene expression and an increase in apoptosis-related gene expression in porcine oocytes. Immunofluorescence assays revealed that PS-MPs may induce oxidative stress, mitochondrial damage, and inflammation through the NF-KB/Nrf2/JNK MAPK signaling pathway crosstalk. Further investigation demonstrated that melatonin supplementation alleviated the toxic effects of PS-MPs exposure, offering potential as a therapeutic approach for mitigating PS-MP-induced reproductive toxicity and preserving oocyte quality. Full article

Background: G2/M cell cycle arrest of proximal tubular epithelial cells following acute kidney injury results in maladaptive repair and promotes chronic kidney disease. We investigated whether erythropoiesis-stimulating agents (ESA) regulate G2/M arrest and mitigate kidney fibrosis. Methods: Human kidney 2 (HK-2) cells were stimulated with TGF-β or paclitaxel, treated with darbepoetin alfa (DARB) at 0.5 ug/mL or 5 ug/mL, and cell cycles were analyzed using flow cytometry. In vivo experiments involved intraperitoneal administration of DARB (0.5 or 5 ug/kg) to the unilateral ureteral obstruction (UUO) mouse model on post-operative days three and seven. Kidney fibrosis and cell cycle regulatory proteins were analyzed using immunohistochemistry, RT-PCR, and immunoblotting. The effect of DARB on kidney fibrosis was compared with that of a p53 inhibitor. Results: In HK-2 cells treated with TGF-β or paclitaxel, G2/M cell cycle regulatory proteins were upregulated; however, this effect was reversed by DARB treatment. Immunostaining for p53 and Ki-67 indicated that the proliferative and fibrotic activities observed in TGF-β-treated HK-2 cells were mitigated by DARB treatment. Histological analysis of UUO mice using F4/80 staining and TUNEL assay showed that DARB treatment reduced inflammatory cell infiltration and apoptotic cell accumulation. Additionally, fibrotic changes assessed by Masson’s trichrome, Sirius red, and PAS staining confirmed the antifibrotic effects of DARB treatment in UUO mice, independent of changes in hemoglobin levels, suggesting a mechanism distinct from its hematopoietic effects. DARB reduced fibrosis-related markers by suppressing G2/M cell cycle regulatory markers and inhibited the JNK and p38-MAPK signaling pathways, which play key roles in kidney fibrosis in TGF-β-treated HK-2 cells and UUO mice. Finally, DARB treatment demonstrated an anti-fibrotic effect in HK-2 cells stimulated with TGF-β or paclitaxel, comparable to that of a p53 inhibitor. Conclusions: DARB treatment decreased G2/M cell phase arrest and attenuated kidney fibrosis, suggesting a new renoprotective mechanism for ESA. 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

The Slit2/Robo signaling pathway acts as a tumor suppressor in various cancers. This study identified an 8-amino acid peptide, LT1-3, derived from the Slit2 LamG domain, and demonstrated its ability to inhibit lung cancer cell proliferation and invasion independently of Robo receptors. Notably, LT1-3 was non-toxic to normal cells (Beas-2B, MRC5, and HUVECs). Combination treatment of LT1-3 and cisplatin synergistically inhibited the proliferation of lung cancer cells (CL1-5, A549, H1355, H460, H23, H661), but had no inhibitory effect on H1299 and H1975. Furthermore, combination therapy prolonged the median survival of tumor-bearing immunodeficient nude mice from 27.5 days (control) to 37.5 days (LT1-3 or cisplatin) and further to 47.5 days (LT1-3/cisplatin combination). The tumor suppressor TP53 positively influences LT1-3-mediated proliferation inhibition, while MAPK8 (JNK1) and PRKACA (PKA) have been identified as negative regulators. With the exception of the p53R273 variants, most TP53 mutants retained their function in this context. The p53 reactivator APR-246 restores sensitivity of p53R273H-expressing cells to LT1-3. JNK inhibition sensitizes p53-deficient or p53R273H-expressing cells to LT1-3-mediated proliferation inhibition. LT1-3, alone or in combination with a JNK inhibitor, enhances cisplatin efficacy, even in the presence of p53 mutations. Therefore, LT1-3 possesses multifunctional antitumor properties, directly inhibiting tumor cells and enhancing the efficacy of cisplatin, without causing toxicity to normal cells. Combining LT1-3 with cisplatin holds promise as a first-line therapy for lung cancer, while LT1-3 alone may be suitable for maintenance therapy. 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

Dairy cows experiencing negative energy balance (NEB) are prone to metabolic and inflammatory disorders, including ketosis, fatty liver, mastitis, endometritis, and hypocalcemia, which impair productive and reproductive performance. NEB elevates non-esterified fatty acids (NEFA) and β-hydroxybutyrate (BHBA), leading to disrupted lipid metabolism characterized by increased fatty acid synthesis (via SREBP-1c, ACC, FASN), impaired lipid export (downregulated MTTP, ApoB100, ACAT2), and reduced oxidation (suppressed SIRT1–PPARα–CPT1A/2 pathway), resulting in triacylglycerol (TAG) accumulation and ketosis. Excess reactive oxygen species (ROS) trigger oxidative and endoplasmic reticulum (ER) stress and apoptosis through JNK, p53/Nrf2, and PERK–eIF2α signaling, while HIF-2α–mediated hypoxia aggravates hepatic damage. Elevated NEFA/BHBA impair polymorphonuclear neutrophil (PMN) chemotaxis and phagocytosis, promoting mastitis and endometritis, and hypocalcemia further weakens immune defense. Rumen-protected choline (RPC) improves lipid metabolism by enhancing VLDL assembly and TAG export (upregulating MTTP, ApoB100, ATG3; inhibiting SREBF1, DGAT2), stimulating fatty acid oxidation (activating AMPK–PPARα–CPT1α), and reducing oxidative stress (suppressing ROS–ERN1). Moreover, RPC decreases IL-6 and TNF-α levels and enhances antioxidant capacity and PMN function. Overall, RPC alleviates NEB-induced metabolic and inflammatory diseases, supporting its inclusion in periparturient management to mitigate NEB and associated disorders. 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

Microcirculation in cutaneous tissue is essential to balance oxygen delivery and maintain the health of the skin. Senescence contributes to microcirculatory dysfunction through mechanisms involving chronic inflammation, structural remodeling of microvessels, and disturbances in hemodynamics. In this study we investigated the promoting effect of escin on blood flow through topical application. To elucidate the molecular mechanisms of escin, kinase phosphorylation changes in human umbilical vein endothelial cells (HUVECs) were examined. Escin stimulates the Wnt/β-Catenin and c-Jun N-terminal kinase (JNK) signaling pathway in cultured HUVECs. To clarify the target of escin in the Wnt/β-Catenin signaling pathway, gene expression in response to escin treatment was evaluated, and escin-mediated signaling activation was accompanied by glycogen synthase kinase-3 beta (Gsk3β), according to inhibitor studies performed with IWR1 (tankyrase inhibitor). In addition, the expression level of the Gsk3β were down-regulated by escin treatment in cultured HUEVCs. Escin also enhanced vascular remodeling, and, when applied topically, led to a sustained increase in cutaneous blood flow. Escin-mediated Wnt signaling activation could enhance blood vessel networks via Gsk3β down-regulation. In conclusion, our data demonstrate that escin promotes angiogenic behavior and enhances adenosine-induced perfusion in humans, thereby supporting its potential role in modulating cutaneous microcirculation. 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

Oxidative stress occurs within bovine when exposed to harmful stimuli, accompanied by substantial accumulation of reactive oxygen species. Without timely clearance, these reactive oxygen species attack vascular endothelial cells, concurrently inducing extensive production of lipid peroxides within the vascular endothelium, and thereby triggering ferroptosis. Aspirin eugenol ester (AEE) showed pharmacological activity against oxidative stress-induced vascular endothelial damage. However, whether it could alleviate vascular endothelial damage by inhibiting ferroptosis remains unclear. This study aimed to evaluate the effects of AEE on vascular endothelial ferroptosis and elucidate its underlying molecular mechanisms. This study established vascular endothelial damage models in vitro and in vivo to explore the ability of AEE to inhibit ferroptosis and oxidative stress by measuring ferroptosis- and oxidative stress-related biomarkers. Transcriptomic and network pharmacology analyses were performed to identify AEE-regulated pathways and key targets. Validation of the pathways were conducted using molecular docking, cellular thermal shift assay, and specific protein agonists/inhibitors. AEE inhibited oxidative stress and ferroptosis in bovine aortic endothelial cells induced by hydrogen peroxide (H₂O₂) or RSL3 via suppressing the upregulation of ferroptosis-related genes and enhancing the expression of antioxidant genes. Transcriptomic and network pharmacology analyses identified JNK as a core target of AEE in regulating ferroptosis. JNK agonists enhanced H₂O₂-induced ferritinophagy; on the contrary, JNK inhibitors alleviated it. AEE suppressed H₂O₂-induced phosphorylation of JNK/c-Jun and ferritinophagy. In a carrageenan-induced rat aortic vascular endothelial damage model, AEE alleviated vascular endothelial damage and ferroptosis-related gene changes, promoted antioxidant gene expression, and inhibited JNK/c-Jun phosphorylation and ferritinophagy. AEE inhibited vascular endothelial ferroptosis by enhancing antioxidant ability, blocking downstream ferritinophagy, and reducing ferrous ion release. Full article

Wnt signaling is an ancient developmental mechanism that drives the initial specification and patterning of the primary axis in many metazoan embryos. Yet, it is unclear how exactly the various Wnt components interact in most Wnt-mediated developmental processes as well as in the molecular mechanism regulating adult tissue homeostasis. Recent work in invertebrate deuterostome sea urchin embryos indicates that three different Wnt signaling pathways (Wnt/β-catenin, Wnt/JNK, and Wnt/PKC) form an interconnected Wnt signaling network that specifies and patterns the primary anterior–posterior (AP) axis. Here, we detail our current knowledge of this critical regulatory process in sea urchin embryos. We also illustrate examples from a diverse group of metazoans, from cnidarians to vertebrates, that suggest aspects of the sea urchin AP Wnt signaling network are deeply conserved. We explore how the sea urchin is an excellent model to elucidate a detailed molecular understanding of AP axis specification and patterning that can be used for identifying unifying developmental principles across animals. 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