Search Results (217)

Background: Alzheimer’s disease is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss. Gamma (γ) oscillations are closely linked to learning and memory, and recent interest has grown around Gamma ENtrainment Using Sensory stimulation (GENUS) as a non-invasive neuromodulation strategy. However, the therapeutic impact of vibrotactile gamma stimulation under varying physical parameters such as acceleration remains underexplored. Methods: Differentiated SH-SY5Y cells were treated with amyloid-β (Aβ) and exposed to vibrotactile stimulation at 2.2 or 4.0 m/s². In vivo, male C57BL/6N mice (7 weeks old, 35 g) were administered scopolamine to induce neurotoxicity and randomly assigned to sham, scopolamine, donepezil, or vibrotactile stimulation groups (n = 10 each). Behavioral tests, biochemical assays, Western blotting, and immunohistochemistry were performed to evaluate cognitive function, oxidative stress, cholinergic activity, synaptic plasticity, and neuroinflammation. Results: In vitro, SH-SY5Y cells exposed to amyloid-beta (Aβ) were treated with vibrotactile stimulation, resulting in enhanced neuronal marker expression at 2.2 m/s². In vivo, mice receiving stimulation at 2.2 m/s² showed improved cognitive performance, reduced oxidative stress, restored cholinergic function, suppressed neuroinflammation, and enhanced synaptic plasticity. Mechanistically, these effects were associated with activation of the AKT/GSK3β/β-catenin pathway. Conclusions: Our findings demonstrate that vibrotactile gamma stimulation at 2.2 m/s² exerts greater therapeutic efficacy than higher acceleration, highlighting the importance of optimizing stimulation parameters. This work supports the potential of acceleration-tuned, non-invasive GENUS-based therapies as effective strategies for cognitive recovery in neurodegenerative conditions. Full article

Background/Objectives: Hair loss, driven by disrupted hair cycles, age-related hormonal imbalances, and oxidative stress, poses significant psychological challenges, necessitating the development of safe and effective therapies. This research investigates the trichogenic potential and underlying mechanisms of a standardized Ageratum conyzoides extract (ACE) using human follicle dermal papilla cells (HFDPCs) and C57BL/6 mice as models. Methods: HFDPCs were treated with ACE to assess its effects on 5α-reductase activity, estrogen receptor (ERα/ERβ) signaling, and activation of Wnt/β-catenin and MAPK pathways. Reactive oxygen species (ROS) levels and antioxidant enzyme expression were also evaluated. In vivo, C57BL/6 mice were administered ACE orally, and hair regrowth, follicle number and depth, and histological changes were measured. Results: In HFDPCs, ACE inhibited 5α-reductase activity, modulated ERα and ERβ signaling, and activated Wnt/β-catenin and MAPK pathways. ACE treatment at 100 μg/mL significantly increased β-catenin, p-GSK3β, and vascular endothelial growth factor (VEGF) expression (p < 0.01) and decreased Dickkopf-related protein-1 (DKK-)1 expression (p < 0.05). It also upregulated VEGF and other hair-growth-related factors and exhibited substantial antioxidant properties by reducing reactive oxygen species (ROS) and elevating the expression of antioxidant enzymes, notably SOD2 at 100 μg/mL. In C57BL/6 mice, oral administration of ACE significantly increased hair regrowth, with the 50 mg/kg group showing the most prominent effects, including increased hair follicle number and depth compared to the negative control group (p < 0.05). These effects were observed to be dose-dependent and comparable to those of minoxidil. Histological analysis confirmed enhanced anagen-phase follicle development. Conclusions: These findings highlight ACE’s multifaceted biological activity in promoting hair growth through hormonal modulation, pathway activation, and antioxidant protection, positioning it as a promising natural supplement for hair growth and health, although further clinical studies are required to confirm its efficacy in humans. Full article

Melanin overproduction contributes to hyperpigmentation disorders such as melasma and solar lentigines, leading to increasing demand for safe and effective skin-lightening agents. D-cycloserine (DCS), a known antimicrobial agent, has not been previously evaluated for dermatological applications. This study aimed to explore the potential of DCS as a novel anti-melanogenic compound and to elucidate its underlying molecular mechanisms in melanogenesis inhibition. The cytotoxicity and anti-melanogenic effects of DCS were assessed in B16F10 melanoma cells stimulated with α-MSH. Cell viability was determined via MTT assays, while melanin content, tyrosinase activity, and the expression levels of MITF, TYR, TRP-1, TRP-2, and major signaling proteins (e.g., CREB, MAPKs, GSK-3β/β-catenin) were evaluated using colorimetric assays and Western blotting. A 3D human skin model was also used to confirm in vitro findings, and a primary skin irritation test was conducted to assess dermal safety. DCS significantly reduced α-MSH-induced melanin content and tyrosinase activity without cytotoxicity at concentrations ≤100 µM. It downregulated MITF and melanogenic enzyme expression and modulated signaling pathways by enhancing ERK activation while inhibiting CREB, JNK, and p38 phosphorylation. Additionally, DCS suppressed β-catenin stabilization via GSK-3β activation. These effects were confirmed in a 3D human skin model, and a clinical skin irritation study revealed no adverse reactions in human volunteers. DCS exerts its anti-melanogenic effect by targeting multiple pathways, including CREB/MITF, MAPK, and GSK-3β/β-catenin signaling. Its efficacy and safety profiles support its potential as a novel cosmeceutical agent for the treatment of hyperpigmentation. Further clinical studies are warranted to confirm its therapeutic utility in human skin pigmentation disorders. Full article

Glycogen synthase kinase-3 (GSK-3)—particularly the GSK-3β isoform—plays a pivotal role in regulating dendritic cell (DC) functions, including maturation, cytokine production, and antigen presentation. In immature DCs, GSK-3β is continuously active, and its inhibition has been shown to enhance DC maturation and function. As a key upstream kinase of β-catenin, GSK-3 inhibition activates β-catenin in both human and murine DCs—a pathway traditionally linked to its immunomodulatory effects. However, our recent findings challenge this paradigm by uncovering β-catenin-independent, dual roles of GSK-3β in DCs. Our study reveals that while GSK-3β enhances DC-mediated cross-priming of CD8 T cells, it concurrently impairs the generation of memory CD8 T cells. These findings have significant implications for vaccine development and cancer immunotherapy, where both effective T-cell priming and durable memory responses are critical. This mini-review provides an in-depth analysis of mechanistic insights into GSK-3β’s paradoxical functions and discusses potential strategies to fine-tune GSK-3 activity for optimized immunotherapeutic outcomes. Full article

Hair loss is often associated with oxidative stress and mitochondrial dysfunction in human follicle dermal papilla cells (HFDPCs), resulting in impaired cellular function and follicle degeneration. Thus, many studies have been conducted on natural plants aimed at inhibiting hair loss. This study investigated the therapeutic potential of exosomes derived from the rhizomes of Iris germanica L. (Iris-exosomes) in HFDPCs damaged by dihydrotestosterone (DHT). Iris-exosomes significantly reduced reactive oxygen species (ROS) levels, restoring mitochondrial membrane potential and ATP production, thereby mitigating oxidative stress and improving mitochondrial function. These effects occurred alongside enhanced cellular processes critical for hair follicle regeneration, including increased cell migration, alkaline phosphatase (ALP) activity, and three-dimensional (3D) spheroid formation, which replicates the follicle-like microenvironment and promotes inductive potential. Furthermore, Iris-exosomes stimulated the Wnt/β-catenin signaling pathway by enhancing glycogen synthase kinase-3β (GSK-3β), AKT, and extracellular signal-regulated kinase (ERK), leading to β-catenin stabilization and nuclear translocation, thereby supporting the expression of genes essential for hair growth. Taken together, these findings suggest that Iris-exosomes can be promising ingredients for alleviating hair loss. Full article

Melanogenesis is regulated by melanogenic enzymes such as tyrosinase (TYR), TRP-1, and TRP-2, whose expression is controlled by the microphthalmia-associated transcription factor (MITF). Various signaling pathways, including cAMP/PKA, MAPK/ERK, Wnt/β-catenin, and PI3K/Akt, are involved in this process and have been a focal point of research for treating pigmentation disorders. However, developing effective therapies for conditions like vitiligo remains a significant challenge. In this study, the effects of umckalin on melanogenesis and its molecular mechanisms were investigated using B16F10 cells, a mouse melanoma cell line widely used as a model for melanin production studies. B16F10 cells produce melanin via melanosomes and express key melanogenic enzymes such as TYR, TRP-1, and TRP-2, making them a reliable model system. Our findings demonstrate that umckalin promotes melanogenesis in a concentration-dependent manner by upregulating TRP-1 expression and activating the MITF signaling pathway. Additionally, umckalin modulated key signaling pathways, including GSK3β/β-catenin and MAPK, to enhance melanogenesis. In conclusion, umckalin enhances melanogenic enzyme activity by activating critical signaling pathways, thereby promoting melanin synthesis. These findings suggest that umckalin could be a promising candidate for developing therapeutic agents for pigmentation disorders such as vitiligo. Further studies are required to explore its mechanisms and clinical applications in greater detail. Full article

Background and Objective: Mammea siamensis (MS) is a Thai herb used in traditional medicine. Previous studies have reported the antiproliferative effects of its constituents in various cancer cell lines. However, the effects of MS extract on cytotoxicity and molecular mechanisms of apoptosis induction in HCT116 colon cancer cells have not been fully explored. Methods and Results: The cytotoxic effect of MS extract on HCT116 cells was assessed using the MTT assay. MS extract increased cytotoxicity in a concentration-dependent manner. It also induced nuclear morphological changes and disrupted the mitochondrial membrane potential (ΔΨm), as assessed by Hoechst 33342 and JC-1 staining, respectively. These findings indicated that MS extract induced apoptosis, which was further confirmed by flow cytometry showing an increase in the sub-G1 phase. To investigate the expression of signaling proteins, Western blot analysis was conducted. The results showed that MS extract activated caspase activity (caspase-8, -9, and -7) and inhibited PARP activity. Additionally, MS extract upregulated pro-apoptotic proteins (tBid, Bak, and cytochrome c) while downregulating anti-apoptotic proteins (Bcl-2 and Bcl-xL). Mechanistic studies revealed that MS extract activated MAPK pathways while inactivating the PI3K/Akt/NF-κB and GSK-3β/β-catenin pathways. Notably, MS extract also inhibited V-ATPases, as evaluated by acridine orange staining and Western blot analysis. Conclusions: Our findings suggest that MS extract induces apoptosis via the activation of both intrinsic and extrinsic pathways associated with the key signaling pathways. Therefore, MS extract shows potential as a therapeutic agent for colon cancer. Full article

Purpose: The molecular mechanisms involved in bone metabolism abnormalities in individuals with type 2 diabetes mellitus (T2DM) are a prominent area of investigation within the life sciences field. Myostatin (MSTN), a member of the TGF-β superfamily, serves as a critical negative regulator of skeletal muscle growth and bone metabolism. Current research on the exercise-mediated regulation of MSTN expression predominantly focuses on its role in skeletal muscle. However, due to the intricate and multifaceted mechanical and biochemical interactions between muscle and bone, the precise mechanisms by which exercise modulates MSTN to enhance bone metabolic disorders in T2DM necessitate additional exploration. The objective of this review is to systematically synthesize and evaluate the role of MSTN in the development of bone metabolism disorders associated with T2DM and elucidate the underlying mechanisms influenced by exercise interventions, aiming to offer novel insights and theoretical recommendations for enhancing bone health through physical activity. Methods: Relevant articles in Chinese and English up to July 2024 were selected using specific search terms and databases (PubMed, CNKI, Web of Science); 147 studies were finally included after evaluation, and the reference lists were checked for other relevant research. Results: Myostatin’s heightened expression in the bone and skeletal muscle of individuals with T2DM can impede various pathways, such as PI3K/AKT/mTOR and Wnt/β-catenin, hindering osteoblast differentiation and bone mineralization. Additionally, it can stimulate osteoclast differentiation and bone resorption capacity by facilitating Smad2-dependent NFATc1 nuclear translocation and PI3K/AKT/AP-1-mediated pro-inflammatory factor expression pathways, thereby contributing to bone metabolism disorders. Physical exercise plays a crucial role in ameliorating bone metabolism abnormalities in individuals with T2DM. Exercise can activate pathways like Wnt/GSK-3β/β-catenin, thereby suppressing myostatin and downstream Smads, CCL20/CCR6, and Nox4 target gene expression, fostering bone formation, inhibiting bone resorption, and enhancing bone metabolism in T2DM. Conclusion: In the context of T2DM, MSTN has been shown to exacerbate bone metabolic disorders by inhibiting the differentiation of osteoblasts and the process of bone mineralization while simultaneously promoting the differentiation and activity of osteoclasts. Exercise interventions have demonstrated efficacy in downregulating MSTN expression, disrupting its downstream signaling pathways, and enhancing bone metabolism. Full article

Neurological disorders are defined by a deterioration or disruption of the nervous system’s structure and function. These diseases, which include multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and schizophrenia, are caused by intricate pathological processes that include excitotoxicity, neuroinflammation, oxidative stress, genetic mutations, and compromised neurotrophic signaling. Although current pharmaceutical treatments relieve symptoms, their long-term efficacy is limited due to adverse side effects and weak neuroprotective properties. However, when combined with other neuroprotective drugs or adjunct therapy, they may offer additional benefits and improve treatment outcomes. Phytochemicals have emerged as attractive therapeutic agents due to their ability to regulate essential neurotrophic pathways, especially the brain-derived neurotrophic factor (BDNF) signaling cascade. BDNF is an important target for neurodegenerative disease (ND) treatment since it regulates neuronal survival, synaptic plasticity, neurogenesis, and neuroprotection. This review emphasizes the molecular pathways through which various phytochemicals—such as flavonoids, terpenoids, alkaloids, and phenolic compounds—stimulate BDNF expression and modulate its downstream signaling pathways, including GSK-3β, MAPK/ERK, PI3K/Akt/mTOR, CREB, and Wnt/β-catenin. This paper also highlights how phytochemical combinations may interact to enhance BDNF activity, offering new therapeutic options for ND treatment. Despite their potential for neuroprotection, phytochemicals face challenges related to pharmacokinetics, blood–brain barrier (BBB) permeability, and absorption, highlighting the need for further research into combination therapies and improved formulations. Clinical assessment and mechanistic understanding of BDNF-targeted phytotherapy should be the main goals of future studies. The therapeutic efficacy of natural compounds in regulating neurotrophic signaling is highlighted in this review, providing a viable approach to the prevention and treatment of NDs. Full article

Objective: Non-small cell lung cancer (NSCLC) remains one of the most significant contributors to cancer-related mortality. This investigation explores the influence and underlying mechanisms of the USP1 inhibitor SJB2-043 on A549 cells, with the aim of advancing the development of anti-NSCLC therapeutics. Methods: Publicly available databases were utilized to assess USP1 expression and its association with the progression of NSCLC. Gene expression variations were ascertained through RNA sequencing, followed by the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology pathway enrichment evaluations. Various doses of SJB2-043 were administered to A549 cells to evaluate its impact on cell multiplication, motility, apoptosis, and the cell cycle using CCK-8 assays, colony formation, wound healing, flow cytometry, and Western blotting (WB). Results: USP1 was found to be overexpressed in NSCLC specimens and linked to adverse prognosis. Treatment with SJB2-043 markedly inhibited A549 cell proliferation and migration, diminished clonogenic potential, and triggered apoptosis in a dose-dependent manner. Modifications in the cell cycle were observed, showing an elevated percentage of cells in the G2 phase while exhibiting a parallel decline in the G₁ phase. WB examination demonstrated diminished protein levels of N-cadherin, CyclinB₁, CDK1, C-myc, Bcl-2, p-ERK/ERK, p-p38/p38, p-JNK/JNK, p-AKT/AKT, and p-mTOR/mTOR, alongside an upregulation of E-cadherin, ZO-1, occludin, p53, Bax, p-β-catenin/β-catenin, and GSK3β. Conclusions: SJB2-043 exerts a suppressive effect on A549 cell proliferation, migration, and epithelial–mesenchymal transition while enhancing apoptosis. These cellular effects appear to be mediated through the inhibition of the MAPK, Wnt/β-catenin, and PI3K/AKT/mTOR signaling cascades, in addition to modulation of the cell cycle. Full article

Background/Objectives: Bone regeneration using nanomaterial-based approaches shows promise for treating critical bone defects. However, developing sustainable and cost-effective therapeutic materials remains challenging. This study investigates the osteogenic potential of clove-derived carbon dots (C-CDs) for bone regeneration applications. Methods: C-CDs were synthesized using a green hydrothermal method. The osteogenic potential was evaluated in human bone marrow-derived mesenchymal stem cells (hBM-MSCs) and validated using ectopic bone formation and calvarial defect models. Results: C-CDs demonstrated uniform morphology (~10 nm) with efficient cellular uptake. In vitro studies showed successful osteogenic differentiation through the upregulation of RUNX2, ALP, COL1A1, and BMP-2 mediated by Wnt/β-catenin/GSK3β and BMP signaling pathways. In vivo models have also demonstrated that C-CDs are effective in promoting bone regeneration. Conclusions: These findings establish C-CDs as promising candidates for bone regeneration therapy, offering a sustainable alternative to current treatments. While optimization is needed, their demonstrated osteogenic properties warrant further development for regenerative medicine applications. Full article

L-Theanine, a natural amino acid found in green tea (Camellia sinensis) leaves, is known for its diverse psychotropic effects. This study aimed to evaluate the inhibitory effect of L-theanine on melanin production and uncover its regulatory mechanism. We evaluated the anti-melanogenic activities of L-theanine in vitro and in vivo. In B16F10 murine melanoma cells induced by α-melanocyte-stimulating hormone, melanin content and intracellular tyrosinase activity were determined, and melanogenesis-related protein expression and signaling pathways were analyzed by Western blotting. Melanin reduction was further assessed using the zebrafish (Danio rerio) test. L-Theanine reduced the intracellular tyrosinase activity and melanin content of B16F10 cells. It also attenuated the expression of melanogenesis-related proteins, such as microphthalmia- associated transcription factor, tyrosinase (TYR), TYR-related protein-1, and dopachrome tautomerase. L-Theanine modulated the protein kinase A (PKA), cAMP responder element binding protein (CREB), phosphorylation of/protein kinase B (Akt), glycogen synthase kinase-3β (GSK-3β), and β-catenin. The antimelanogenic activity of L-theanine (<2 mg/mL) was further confirmed using zebrafish larvae. L-Theanine inhibited melanogenesis by downregulating the PKA/CREB and Akt/GSK-3β/β-catenin signaling pathways. In summary, L-theanine shows potential as a skin-whitening compound, warranting further investigation for its possible applications in cosmetic and pharmaceutical products. Full article

Drug repurposing is a cost-effective and innovative strategy for identifying new therapeutic applications for existing drugs, thereby shortening development timelines and accelerating the availability of treatments. Applying this approach to the development of cosmeceutical ingredients enables the creation of functional compounds with proven safety and efficacy, adding significant value to the cosmetic industry. This study evaluated the potential of rifampicin, a drug widely used for the treatment of tuberculosis and leprosy, as a cosmeceutical agent. The anti-melanogenic effects of rifampicin were assessed in B16F10 melanoma cells, showing no cytotoxicity at concentrations up to 40 µM and a significant reduction in intracellular tyrosinase activity and melanin content. Mechanistically, rifampicin reduced the expression of melanogenic enzymes, including tyrosinase, tyrosinase-related protein (TRP)-1, and TRP-2, via a protein kinase A (PKA)-dependent pathway, leading to the suppression of microphthalmia-associated transcription factor (MITF), which is a key regulator of melanogenesis. Additionally, rifampicin inhibited the p38 signaling pathway but was independent of the PI3K/protein kinase B (Akt) pathway. Furthermore, it decreased Ser9 phosphorylation, enhancing glycogen synthase kinase-3β (GSK-3β) activity, promoted β-catenin phosphorylation, and facilitated β-catenin degradation, collectively contributing to the inhibition of melanin synthesis. To evaluate the topical applicability of rifampicin, primary human skin irritation tests were conducted, and no adverse effects were observed at concentrations of 20 µM and 40 µM. These findings demonstrate that rifampicin inhibits melanogenesis through multiple signaling pathways, including PKA, MAPKs, and GSK-3β/β-catenin. This study highlights the potential of rifampicin to be repurposed as a topical agent for managing hyperpigmentation disorders, offering valuable insights into novel therapeutic strategies for pigmentation-related conditions. Full article

The extract of Scenedesmus deserticola JD052 has been reported to exhibit anti-aging effects on the skin, with research indicating an increase in loliolide, a major active component, through heterotrophic cultivation. In this study, we evaluated the effects of extracts obtained from both photoautotrophic (PE) and heterotrophic (HE) cultures on hair-inductive properties in human dermal papilla (HDP) cells. Biochemical assays demonstrated that both extracts enhanced HDP cell viability and increased the size of three-dimensional dermal papilla (DP) spheres. Notably, the activation of β-catenin, a crucial marker associated with hair growth, was assessed using a luciferase reporter assay, revealing that HE exhibited a significantly higher efficacy than PE. Further analyses indicated that HE promoted the translocation of β-catenin into the nucleus through the phosphorylation and activation of AKT, which also elevated the expression levels of DP signature genes and hair-growth-related autocrine factors. Additionally, conditioned media from HE-treated HDP cells enhanced keratinocyte migration and increased the expression of growth factors, including VEGF and IGF-1. HPLC-MS analysis showed no significant difference in loliolide content; however, specific peaks in HE were identified as pheophorbide A and linolelaidic acid. Thus, HE may enhance hair growth inductivity via AKT/β-catenin signaling. Full article

The extract of Paspalum thunbergii, a native perennial herb in Korea belonging to the rice family, was investigated for its anti-inflammatory activity and the underlying mechanisms driving its effects. Fifteen chemical components of the P. thunbergii extract, including rosmarinic acid and isoquercitrin, were identified using LC-MS. The extract showed antioxidative activity through DPPH and ABTS cation radical scavenging activity. The P. thunbergii extract significantly inhibited lipopolysaccharide (LPS)-induced nitric oxide (NO) production in macrophage RAW 264.7 cells. The extract inhibited the expression of lipopolysaccharide-induced iNOS and COX-2, which are inflammation-related enzymes. To explore the underlying anti-inflammatory mechanism, the expression levels of signal proteins related to MAPK, NF-κB, JAK/STAT, and Wnt/β-catenin signaling were measured. As a result, the P. thunbergii extract inhibited the expression of p-p38, and p-JNK increased by LPS in RAW 264.7 cells. Additionally, it decreased the expression of LPS-induced p-IKKβ and p-NF-κB p65 and prevented the migration of p-NF-κB into the nucleus caused by LPS. Notably, p-JAK1, p-STAT3, Wnt 3α, β-catenin, and p-GSK-3β protein expressions were also inhibited. Therefore, the prominent anti-inflammatory activity of the P. thunbergii extract may be via the MAPK, NF-κB, JAK/STAT, Wnt/β-catenin signal pathway. Full article