Browsing by Author "Chang, Gary Ro-Lin"

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BLF Stimulates Neuronal Differentiation Via Activation of P35/Cdk5 Signaling and AMPK-Mediated Mitochondrial Regulation
(Pergamon-Elsevier Science Ltd, 2026) Cidem, Abdulkadir; Oner, Muhammet; Chang, Gary Ro-Lin; Yen, Chih-Ching; Chen, Ke-Rong; Yang, Shang-Hsun; Chen, Chuan-Mu
Lactoferrin (LF) is a multifunctional glycoprotein with established roles in non-neuronal cell growth and differentiation and has underexplored potential in neurodevelopment. Here, we investigated bovine lactoferrin (bLF) as a neurotrophic agent, systematically evaluating its effects on neuronal differentiation, morphology, and mitochondrial regulation in PC12 cells. We demonstrated that bLF (50 mu g/mL) induces neurite outgrowth comparable to nerve growth factor (NGF) while maintaining >90 % cell viability. Mechanistically, bLF activated TrkA by phosphorylation at Ser490, followed by ERK phosphorylation at Thr202/Tyr204 within 60 min, mirroring canonical NGF signaling. bLF also upregulates p35 (CDK5 activator) and phosphorylates Synapsin-I, driving presynaptic maturation. Structurally predicted to bind TrkA's ligand-binding interface, bLF synergizes with NGF to amplify differentiation outcomes. Furthermore, TMRE staining and AMPK phosphorylation assays revealed that bLF enhances axonal mitochondrial activity, surpassing NGF's effects. These results establish bLF as a multifunctional neurotrophic agent that coordinates TrkA-ERK-p35/CDK5 signaling, synaptic protein activation, and AMPK-driven mitochondrial regulation. Given its safety profile and synergy with endogenous neurotrophic pathways, bLF emerges as a promising candidate for neuroregenerative therapies targeting nerve injury or neurodegeneration.
Kefir Peptides Ameliorate Osteoporosis in Akr1a1 Knockout Mice with Vitamin C Deficiency by Promoting Osteoblastogenesis and Inhibiting Osteoclastogenesis
(Elsevier France-Éditions Scientifiques Médicales Elsevier, 2022) Chang, Gary Ro-Lin; Lin, Wei-Yu; Fan, Hueng-Chuen; Tu, Min-Yu; Liu, Yu-Hsien; Yen, Chih-Ching; Chen, Chuan-Mu
The AKR1A1 protein is a member of the aldo-keto reductase superfamily that catalyzes the transformation of D-glucuronate to L-gulonate in the synthesis of L-ascorbic acid (vitamin C, Vit C). We previously demonstrated that AKR1A1 knockout mice (AKR1A1eGFP/eGFP) with Vit C deficiency exhibited aberrant bone formation and oste-oporosis. In this study, we aimed to evaluate the osteoprotective effects of kefir peptides (KPs) in AKR1A1eGFP/ eGFP mice and uncover the underlying mechanism of KPs in the modulation of bone remodeling. Six male CD-1 mice and 24 male AKR1A1eGFP/eGFP mice were used in this study, in which the AKR1A1eGFP/eGFP mice were randomly divided into four groups (n = 6). KPs treatment for 12 weeks exerted several effects in AKR1A1eGFP/eGFP mice including the reduction of serum proinflammatory cytokines (IL-18, IL-6, TNF-alpha), bone resorption markers (CTX-1, RANKL), and the increase of serum bone formation markers (P1NP, OPG, OC). mu-CT analysis indicated that KPs prevented the bone loss in the femurs of AKR1A1eGFP/eGFP mice by significantly increasing the trabecular parameters of bone mineral density, bone volume and bone number. Nanoindentation analysis demonstrated that KPs enhanced the elasticity and hardness of femoral cortical bones in AKR1A1eGFP/eGFP mice. KPs promoted bone marrow mesenchymal stem cells (BMMSCs)-derived osteoblast differentiation and mineralization by upregu-lating positive regulators of osteoblastogenesis (Runx2, 8-catenin, BMP-2, NFATc1). Conversely, KPs inhibited bone marrow macrophages (BMMs)-derived osteoclast differentiation and bone resorption, which was demon-strated by the facts that KPs suppressed RANKL-induced p38, NF-Kappa B, Akt, PLC gamma 2 and CREB-1 phosphorylation, decreased the nuclear translocation of NFATc1 and c-Fos. Our findings demonstrate the efficacy of KPs in the prevention of osteoporosis in AKR1A1eGFP/eGFP mice and also unveil the dual effects of KPs in osteogenic promotion and osteoclastic inhibition. This study supports the use of KPs as nutritional supplements for the prevention of osteoporosis.
Lactoferrin Targeting INTL1 Receptor Inhibits Hepatocellular Carcinoma Progression Via Apoptosis and Cell Cycle Signaling Pathways
(Nature Portfolio, 2024) Cidem, Abdulkadir; Chang, Gary Ro-Lin; Yen, Chih-Ching; Chen, Ming-Shan; Yang, Shang-Hsun; Chen, Chuan-Mu
Hepatocellular carcinoma (HCC) constitutes 90% of liver cancer cases and ranks as the third leading cause of cancer-related mortality, necessitating urgent development of alternative therapies. Lactoferrin (LF), a natural iron-binding glycoprotein with reported anticancer effects, is investigated for its potential in liver cancer treatment, an area with limited existing studies. This study focuses on evaluating LF's anti-liver cancer effects on HCC cells and assessing the preventive efficacy of oral LF administration in a murine model. Data showed that LF exerted anti-proliferative effects on HepG2, Hep3B, and SK-Hep1 cells while having no cytotoxicity on healthy liver cells (FL83B). Mechanistically, LF induces mitochondrial-mediated apoptosis and G0/G1 cell cycle arrest in HepG2 cells, associated with increased phosphorylation of p38 MAPK and JNK for apoptosis, and ERK phosphorylation for cell cycle arrest. Intelectin-1 (INTL1) is identified as the receptor facilitating LF endocytosis in HepG2 cells, and downregulation of INTL1 inhibits LF-induced signaling pathways. Notably, oral LF administration prevents HCC development in nude mice with orthotopic HepG2 cell injection. This study unveils the mechanistic basis of LF action in HepG2 cells, showcasing its potential in HCC prevention. Importantly, we report the novel identification of INTL1 as the LF receptor in HepG2 cells, providing valuable insights for future exploration of LF and its derivatives in liver cancer therapy.
miRNA Signature in an in Vitro Keratinocyte Model of Diabetic Wound Healing
(MDPI, 2024) Tsai, Hsin-Chung; Chang, Gary Ro-Lin; Tung, Min-Che; Tu, Min-Yu; Chen, I-Chien; Liu, Yu-Hsien; Chen, Chuan-Mu
Treating diabetic wounds effectively remains a significant clinical challenge. Emerging studies suggest that microRNAs (miRNAs) play crucial roles in various physiological and pathological processes and hold promise as therapeutic tools. This study investigates the miRNA expression profile in keratinocytes using a cell model of diabetic wounds. Microarray analysis revealed that 43 miRNAs from wounded keratinocytes incubated under diabetic conditions (high glucose/hypoxia) exhibited a two-fold change in expression compared to those incubated under normal conditions (low glucose/normoxia). Quantitative RT-PCR confirmed significant differences in the expression of eight miRNAs, with miR-3138 and miR-3679-5p being further analyzed for their roles in keratinocyte migration. Transfection with a miR-3138 mimic and a miR-3679-5p inhibitor indicated that upregulation of miR-3138 and downregulation of miR-3679-5p enhance keratinocyte migration in both normal and diabetic wounds. Pathway and gene ontology (GO) analyses identified potential pathways and functional annotations associated with miR-3138 and miR-3679-5p in diabetic wound healing. Potential human gene targets of miR-3138 and miR-3679-5p were predicted using a three-way comparison of the TargetScan, miRDB, and DIANA databases. This study elucidates the miRNA expression signature of human keratinocytes in a diabetes-like environment, providing deeper insights into the pathogenesis of diabetic wounds.
Potential of Kefir-Derived Peptides, Probiotics, and Exopolysaccharides for Osteoporosis Management
(Springer, 2025) Lai, Jen-Chieh; Chang, Gary Ro-Lin; Tu, Min-Yu; Cidem, Abdulkadir; Chen, I-Chien; Chen, Chuan-Mu
Purpose of ReviewOsteoporosis is a prevalent skeletal disorder in postmenopausal women and older adults. Kefir has gained attention for its potent antioxidative, anti-inflammatory, and immunomodulatory properties. This review consolidates findings on kefir-derived peptides' interventions in osteoporosis models and evaluates the therapeutic potential of kefir components in preventing osteoporosis, thereby enhancing its application in clinical nutrition strategies for osteoporosis management.Recent FindingsKefir-derived peptides exhibit osteoprotective potential in various animal models of osteoporosis, in which several antioxidative and ACE-inhibitory peptides have been shown to promote osteoblast differentiation and mineralization. In addition, emerging evidence supports the role of kefir-derived probiotics and exopolysaccharides (kefiran) in mitigating bone loss.SummaryKefir holds significant promise in the management of osteoporosis due to its unique composition of bioactive components promoting bone health. While research is still in its early stages, evidence suggests kefir's potential as a natural approach to osteoporosis prevention and management.