Search Results (116)

The popularity of bioactive compounds extracted from sea cucumbers is growing due to their wide application in the pharmaceutical industry, particularly in the development of drugs for neurological disorders. Different types of compounds, such as saponins, phenolic compounds, cerebrosides, and glucocerebrosides, are being studied intensively for their efficacy in assessing the treatment of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and brain tumors, among others. Positive results have been observed in the upregulation in the content of p-CREB, p-PL3K, BDNF, SOD, and MDA. Furthermore, the neuroprotective mechanism of the compounds against Alzheimer’s disease revealed that suppressing the phosphorylation of tau protein by the PI3K/Akt/GSK3β pathway leads to improved synaptic plasticity and reduced nerve fiber tangles. This comprehensive review explores recent findings on the therapeutic potential of sea cucumber bioactives in the treatment of brain-related disorders. Full article

Acute heart failure (AHF) is a clinical syndrome characterized by the sudden onset or rapid worsening of heart failure signs and symptoms, frequently triggered by myocardial ischemia, pressure overload, or cardiotoxic injury. A central component of its pathophysiology is the activation of intracellular signal transduction cascades that translate extracellular stress into cellular responses. Among these, the mitogen-activated protein kinase (MAPK) pathways have received considerable attention due to their roles in mediating inflammation, apoptosis, hypertrophy, and adverse cardiac remodeling. The canonical MAPK cascades—including extracellular signal-regulated kinases (ERK1/2), p38 MAPK, and c-Jun N-terminal kinases (JNK)—are activated by upstream stimuli such as angiotensin II (Ang II), aldosterone, endothelin-1 (ET-1), and sustained catecholamine release. Additionally, emerging evidence highlights the role of receptor-mediated signaling, cellular stress, and myeloid cell-driven coagulation events in linking MAPK activation to fibrotic remodeling following myocardial infarction. The phosphatidylinositol 3-kinase (PI3K)/Akt signaling cascade plays a central role in regulating cardiomyocyte survival, hypertrophy, energy metabolism, and inflammation. Activation of the PI3K/Akt pathway has been shown to confer cardioprotective effects by enhancing anti-apoptotic and pro-survival signaling; however, aberrant or sustained activation may contribute to maladaptive remodeling and progressive cardiac dysfunction. In the context of AHF, understanding the dual role of this pathway is crucial, as it functions both as a marker of compensatory adaptation and as a potential therapeutic target. Recent reviews and preclinical studies have linked PI3K/Akt activation with reduced myocardial apoptosis and attenuation of pro-inflammatory cascades that exacerbate heart failure. Among the multiple signaling pathways involved, glycogen synthase kinase-3β (GSK-3β) has emerged as a key regulator of apoptosis, inflammation, metabolic homeostasis, and cardiac remodeling. Recent studies underscore its dual function as both a negative regulator of pathological hypertrophy and a modulator of cell survival, making it a compelling therapeutic candidate in acute cardiac settings. While earlier investigations focused primarily on chronic heart failure and long-term remodeling, growing evidence now supports a critical role for GSK-3β dysregulation in acute myocardial stress and injury. This comprehensive review discusses recent advances in our understanding of the MAPK signaling pathway, the PI3K/Akt cascade, and GSK-3β activity in AHF, with a particular emphasis on mechanistic insights, preclinical models, and emerging therapeutic targets. Full article

Background/Objectives: Endophytes can produce bioactive metabolites similar to their host plants. CM-YJ44 (Pseudomonas protegens CHA0, 99.24% similarity), an endophyte from Dendrobium officinale, has not yet validated hypoglycemic potential. This study aimed to evaluate its anti-insulin resistance (IR) activity and metabolite profile. Methods: The fermentation broth of CM-YJ44 was separated into three fractions (CM-YJ44-1, -2, and -3) using semi-preparative high-performance liquid chromatography (pre-HPLC). An IR HepG2 cell model was constructed to evaluate their glucose uptake capacity. CM-YJ44-3 was further tested for oxidative stress, inflammatory, and insulin signaling pathway activation. Metabolites in CM-YJ44-3 were preliminarily identified using the Q Exactive Focus LC-MS system (QE), and the dendrobine content was quantified by ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS). Molecular docking was performed to predict the binding affinities between dendrobine and target proteins. Results: Among the three fractions, CM-YJ44-3 significantly reduced nitric oxide (NO) and reactive oxygen species (ROS) levels in IR cells, enhanced glycogen synthesis, upregulated the activities of pyruvate kinase (PK) and hexokinase (HK), and suppressed the expression of inflammatory factors. Its mechanism of action was mainly through activation of the IRS1/PI3K/Akt/GSK3β/GLUT4 signaling pathway. QE analysis preliminarily identified 24 metabolites in CM-YJ44-3. Quantitative analysis by UPLC-MS/MS showed that the dendrobine content was 78.73 ± 4.29 ng/mL. Molecular docking results indicated that dendrobine exhibited binding energies below −5 kcal/mol with multiple target proteins involved in this signaling pathway, suggesting it may be a key bioactive component responsible for the anti-IR effect. Conclusions: This study provides the first evidence of hypoglycemic bioactive metabolite production by strain CM-YJ44, indicating its potential as a novel microbial candidate for alleviating IR. Full article

The Alzheimer’s disease (AD)-affected brain is known to be deficient in the utilization of glucose, its main energy substrate, and systemic diabetes is a significant risk factor for AD. In the course of biochemical and molecular investigations into this puzzling relationship, it has been shown that resistance to insulin action is a prominent feature of early stages of AD in the brain, thereby contributing to an energy failure state and a decline in synaptic function. In one AD-like cellular model, we found that β-amyloid (Aβ) accumulation inhibited insulin signaling and cell viability through an alteration of the PI3K/PDK-1/Akt signal pathway, an effect overcome by mTORC2 stimulation. A PDK-1 allosteric agonist, PS48, as well as newly synthesized analogs, were also found to reverse the metabolic defects caused by intracellular Aβ42 accumulation. In vivo, we previously showed that oral dosing of PS48 significantly improves learning and memory in APP/PS1 transgenic mice. Herein, we present evidence using unbiased immunohistological quantification and Western blot analyses demonstrating that ingested PS48 crosses into brain tissue where it targeted Akt and GSK3-β activities. Beneficial effects on neuronal number and Tau phosphorylation were found. Not unexpectedly, Aβ levels remained unchanged. These results support a path toward a future therapeutic trial of this untested strategy and agent in humans. 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/Objectives: This study aims to investigate the effects of 5,7-dihydroxy-4-methylcoumarin (5,7D-4MC) on melanogenesis in B16F10 murine melanoma cells and to evaluate its safety as a potential ingredient for functional cosmetics and therapeutic agents targeting pigmentation-related disorders. Method: The cytotoxicity of 5,7D-4MC was assessed using an MTT assay, and melanin content and tyrosinase activity were measured at different concentrations (25, 50, 100 µM). Western blot analyses were conducted to evaluate the expression of key melanogenesis-related proteins (TYR, TRP-1, TRP-2, and MITF) and to investigate the regulation of major signaling pathways, including PKA/cAMP, GSK3β, and PI3K/AKT. Additionally, a human primary skin irritation test was performed on 32 participants to assess the dermatological safety of 5,7D-4MC. Results: 5,7D-4MC did not affect cell viability at concentrations below 100 µM and significantly promoted melanin production in a dose-dependent manner. Tyrosinase activity and the expression levels of melanogenic proteins increased significantly following 5,7D-4MC treatment. PKA and GSK3β pathways were activated, while the PI3K/AKT pathway was downregulated. The skin irritation test showed that 5,7D-4MC exhibited low irritation potential at concentrations of 50 µM and 100 µM. Conclusions: 5,7D-4MC enhances melanogenesis and demonstrates low skin irritation, making it a promising candidate for therapeutic applications in treating hypopigmentation disorders, such as vitiligo, as well as a functional cosmetic ingredient. However, further studies involving human melanocytes and clinical trials are required to validate their efficacy. Full article

Obesity is a global health crisis and is one of the major reasons for the rising prevalence of metabolic disorders such as type 2 diabetes, cardiovascular diseases, and certain cancers. There has been growing interest in the search for natural molecules with potential anti-obesity effects; among the phytochemicals of interest are anthocyanins, which are flavonoid pigments present in many fruits and vegetables. Anthocyanins influence obesity via several signaling pathways. The PI3K/Akt signaling pathway plays a major role with a focus on downstream targets such as GLUT4, FOXO, GSK3β, and mTOR, which play a central role in the regulation of glucose metabolism, lipid storage, and adipogenesis. The influence of critical factors such as oxidative stress and inflammation also affect the pathophysiology of obesity. However, the studies reviewed have certain limitations, including variations in experimental models, bioavailability challenges, and a lack of extensive clinical validation. While anthocyanin shows tremendous potential, challenges such as poor bioavailability, stability, and regulatory matters must be overcome for successful functional food inclusion of anthocyanins. The future of anthocyanin-derived functional foods lies in their ability to overcome hurdles. Therefore, this review highlights the molecular mechanisms of obesity through the PI3K/Akt signaling pathways and explores how anthocyanins can modulate these signaling pathways to address obesity and related metabolic disorders. It also addresses some ways to solve the challenges, like bioavailability and stability, while emphasizing future possibilities for anthocyanin-based functional foods in obesity management. Full article

Gastrodia elata, Polygonatum sibiricum, and Poria cocos are traditional Chinese herbs commonly used as both medicinal and food ingredients, traditionally believed to improve liver and kidney functions, replenish vital energy (qi) and blood, and mitigate stress-induced damage. These herbs are combined in the Compound Gastrodia elata Formula (CGEF), a functional food formulation. Amidst growing interest in functional foods, this study explores the cognitive-enhancing effects of CGEF, focusing on cognitive function improvement. Cognitive impairment was induced in ICR mice via chronic sleep restriction. Behavioral assessments including the Y-maze test, object recognition test, Morris water maze test, and Passive avoidance test, were conducted to evaluate CGEF’s effects. Serum levels of inflammatory markers and oxidative stress were quantified while in rat hippocampus tissue expressions of inflammatory, apoptotic, and neuroprotective-related protein markers were analyzed by Western blotting. Neurotransmitter concentrations in both the hippocampus and prefrontal cortex were determined by LC-MS/MS. CGEF significantly alleviated cognitive impairments across all behavioral tests. The underlying mechanisms likely involve a reduction in oxidative stress and peripheral inflammatory factors, and suppression of the TLR2/MyD88/NF-κB signaling cascade in the hippocampus, thereby mitigating neuroinflammation and neuronal apoptosis. Furthermore, CGEF modulated the PI3K/AKT/GSK3β signaling pathway, potentially contributing to neuronal integrity and synaptic plasticity maintenance. CGEF also restored neurotransmitter balance and regulated tryptophan metabolism, further alleviating cognitive deficits associated with sleep disruption. These findings suggest CGEF’s potential as a functional food for reversing cognitive impairments caused by chronic sleep restriction, primarily through its anti-inflammatory and neuroprotective effects. 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

Chronic kidney disease (CKD) involves inflammation, oxidative stress, and fibrosis, leading to renal dysfunction. Dapagliflozin, an SGLT2 inhibitor, shows renoprotective effects beyond glucose control, but its precise molecular mechanisms remain unclear. This study utilizes network pharmacology and molecular docking to elucidate its multi-target effects in CKD. Dapagliflozin’s SMILES structure was analyzed for ADMET properties. Potential targets were identified via SwissTargetPrediction, GeneCards, and SEA, and common CKD-related targets were determined. A protein–protein interaction (PPI) network was constructed, and key pathways were identified using GO and KEGG enrichment analyses. Molecular docking was conducted to validate dapagliflozin’s binding affinities with hub proteins. A total of 208 common targets were identified, including EGFR, GSK3β, and IL-6. GO and KEGG analyses highlighted key pathways, such as PI3K-Akt, MAPK, and AGE-RAGE, involved in inflammation, oxidative stress, and metabolic regulation. Molecular docking confirmed strong binding affinities with EGFR (−8.42 kcal/mol), GSK3β (−7.70 kcal/mol), and IL-6 (−6.83 kcal/mol). Dapagliflozin exhibits multi-target therapeutic potential in CKD by modulating inflammation, oxidative stress, and metabolic pathways. This integrative approach enhances the understanding of its mechanisms, supporting future experimental validation and clinical application in CKD management. Full article

Kadsura coccinea is a traditional Chinese medicine whose roots have long been used to treat various ailments, but little is known about the efficacy of its leaves. In this study, the antidiabetic activity of K. coccinea leaf extract (KCLE) was determined, the main components of KCLE were identified using UPLC-TOF-MS, and network pharmacology and molecular docking were integrated to elucidate the antidiabetic mechanism of KCLE. The results showed that KCLE effectively increased the glucose consumption of IR-HepG2 cells through pyruvate kinase (PK) and hexokinase (HK), promoted glycogen synthesis, and inhibited α-glucosidase and α-amylase activities. KCLE also improves diabetes by regulating AKT1, TNF, EGFR, and GSK3β. These targets (especially AKT1 and TNF) have a high binding affinity with the main active ingredients of KCLE (rutin, luteolin, demethylwedelolactone, maritimetin, and polydatin). Pathway enrichment analysis showed that the antidiabetic effect of KCLE was closely related to the PI3K-Akt signaling pathway, MAPK signaling pathway, AGE-RAGE signaling pathway, and FoxO signaling pathway. These findings provide a theoretical basis for promoting the pharmacodynamic development of K. coccinea and its application in treating diabetes. Full article

Background: Ophioglossum vulgatum Linn. is a medical herb widely distributed in Southwest China. It has been used for the treatment of various diseases, including wounds or dermatitis, since ancient times, but little is known about its pharmacological and pharmaceutical chemistry. Methods: The ethyl acetate fraction of O. vulgatum (OpvE) was prepared with the reflex extraction and fractional extraction method. Its components were detected and identified with the UPLC-Q/TOF-MS system and the SCIEX OS database. The related biological activities and the underlying mechanisms were predicted by computational analysis. HaCaT cells were treated with gradient concentrations of OpvE, and a CCK-8 assay was performed to determine the cell viability. The OpvE-pretreated HaCaT cells were exposed to H₂O₂ or LPS for antioxidative and anti-inflammatory assessment. DPPH, GSH, SOD, and MDA kits were used to evaluate oxidative stress. A serially diluted microbiota assay and a disc diffusion assay were used to evaluate anti-Staphylococcus aureus activities. The transcription of genes was semi-quantitatively studied by reversed real-time PCR. Protein levels were determined with western blotting. Results: The extract ratio of OpvE was 2.00 ± 0.12% (g/g). A total of 21 ingredients were identified. The computational analysis found that the PI3K/Akt signaling pathway might be a crucial target of OpvE. OpvE (7.5~125 μg/mL) stimulated HaCaT cell proliferation and migration by stimulating the over-expressed collagen type I alpha 1 Chain (COL1A1) and fibronectin 1 (FN1) and upregulating PI3K/AKT/GSK3-β signaling pathway. In the antioxidative assay test, 250 μg/mL OpvE scavenged obvious 97.28% DPPH-released free radicals. Pretreatment of OpvE inhibited H₂O₂-induced oxidative stress and protected against LPS-induced inflammatory injury by respectively regulating the Nrf2/HO-1/COX2 and TLR4/MYD88 signaling pathways. OpvE also showed anti-S. aureus properties with a MIC of 1.2 mg/mL, and with this concentration, OpvE produced an 8.3 ± 0.16 mm inhibition zone on a bacterial plate. Conclusions: This work highlighted the phytochemical character and some bioactivities, as well as the underline mechanism, which would support the further studies and application of O. vulgatum Linn. 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