Search Results (166)

Glycogen synthase kinase 3 (GSK3/Shaggy-like) belongs to evolutionarily conserved serine/threonine protein kinases that regulate plant morphological development, multi-hormone crosstalk and adaptation to abiotic stresses. However, systematic genome-wide characterization of CmGSK3 is still absent in melon (Cucumis melo L.). This study identified six CmGSK3 members on a whole-genome level, unevenly distributed among four chromosomes. Combined phylogenetic and synteny profiling separated these six genes into four conserved subclades; orthologous links were discovered between melon, Arabidopsis, and rice, revealing evolutionary conservation between monocot and dicot crops. Prediction of promoter cis-regulatory motifs combined with transcriptome datasets suggested that CmGSK3 genes participate in hormone transduction and environmental stress adaptation. Quantitative real-time PCR further verified that exogenous brassinosteroid (BR) application dramatically induced transcriptional accumulation of CmSK21 and CmSK22. Heterologous overexpression of these two genes in wild-type Arabidopsis significantly lowered plant sensitivity to BR, confirming they may function as negative modulators of the BR signaling cascade. Collectively, CmGSK3 members coordinate multiple metabolic routes, dominated by BR-related signal transduction, to manipulate melon growth and stress adaptability. This study establishes the first systematic research on the melon GSK3 family and supplies elite candidate genes for molecular breeding targeting fruit quality and stress resistance improvement in melon. Full article

Background/Objectives: Colorectal cancer (CRC) remains one of the leading causes of cancer-related morbidity and mortality worldwide. Despite advances in treatment, outcomes for advanced CRC remain unsatisfactory due to uncontrolled proliferation, metastasis, and recurrence. This study investigated the anti-cancer effects of KMU-11342, an indolin-2-one-based multi-protein kinase inhibitor with previously reported anti-inflammatory properties, in human colorectal cancer models. Methods: The anti-cancer effects of KMU-11342 were evaluated in colorectal cancer cells and further investigated in three-dimensional (3D) spheroid and patient-derived organoid models. Cell proliferation, migration, apoptosis, and cell cycle progression were assessed. Kinase activity profiling and molecular docking analyses were performed to identify potential targets and characterize the underlying signaling pathways. Results: KMU-11342 significantly inhibited the proliferation and migration of CRC cells. It reduced CRC cell density by 58.9% and 83.3% at 0.5 and 1 μM, respectively. These effects were accompanied by G2/M cell cycle arrest and apoptotic cell death. In 3D models, spheroid formation was markedly reduced and stemness-related characteristics were diminished. Patient-derived CRC organoids also showed decreased viability, exhibiting 38.6% and 77.4% reductions at 1 and 2 μM, respectively. These effects were observed in a dose-dependent manner in both two-dimensional (2D) and 3D colorectal cancer models. Kinase activity profiling and molecular docking analyses identified glycogen synthase kinase 3 beta (GSK3β) and cyclin-dependent kinase 1 (CDK1) as potential mediators of the anti-cancer effects of KMU-11342 through the p53/nuclear factor kappa B (NF-κB) and FoxO1 signaling axes, respectively. Conclusions: KMU-11342 exhibits potent anti-tumor activity against CRC through suppressing proliferation, migration, and stemness in both 2D and 3D models, including patient-derived organoids. Its effects may be mediated, at least in part, through modulation of GSK3β and CDK1 via the p53/NF-κB and FoxO1 signaling pathways. Full article

Micropropagation of Selenicereus hybrids is a key tool for breeding and conservation; however, further refining the balance between high multiplication rates and morphological quality remains a complex challenge within conventional protocols. This study explores targeted signaling modulation using nine bioactive small molecules—including three mammalian glycogen synthase kinase 3 (GSK3) inhibitors (TDZD-9, VP3.15 and VP0.7), three leucine rich repeat kinase 2 (LRRK2) inhibitors (JZ1.24, JZ1.3 and IGS4.75), and three phosphodiesterase (PDE) inhibitors—to complement traditional micropropagation. Explants were evaluated in two distinct contexts: a hormone-free basal medium (BM) and a plant growth regulator-supplemented medium (PIT2) and the response rates, yield, and quality were measured and integrated using a Global Efficiency Index (GEI). Results demonstrate that inhibitor efficacy is strictly context-dependent; while most molecules repressed budding in BM, they acted as response modulators by determining the specific type of morphogenic pathway in PIT2. Notably, the GSK3 inhibitor TDZD-9 reached the highest GEI (0.85) by maximizing productivity, whereas LRRK2 inhibitors effectively preserved architectural integrity. Flow cytometry confirmed cytogenetic stability across all treatments, with a 98.5% plantlet survival rate during acclimatization. In conclusion, the strategic integration of targeted signaling modulators and multi-parametric indices offers a refined and objective framework to enhance the efficiency of mass propagation protocols in pitahaya and other recalcitrant species. Furthermore, our findings provide new evidence of the strong potential of these small molecules as novel tools to improve plant micropropagation beyond traditional plant growth regulators. Full article

Objectives: To investigate the potential mechanisms of maternal pregestational diabetes-induced neural tube defects (NTDs) by integrating proteomic data and histone H4 lysine 5 acetylation (H4K5ac) ChIP-seq data from the mouse model. Methods: The diabetic mouse model was established by intraperitoneal injection of streptozotocin (STZ) into female friend leukemia virus B strain (FVB) mice, with subsequent blood glucose monitoring. Diabetic females were then mated with healthy males, and embryonic tissues were collected on embryonic day 9.5. Among the embryos obtained from diabetic pregnancies, six NTDs embryos and six control embryos were selected for protein expression profiling using tandem mass tag (TMT)-labeled liquid chromatography-tandem mass spectrometry (LC-MS/MS), as well as for assessment of H4K5ac modification by ChIP-seq. Multi-omics integration was performed to identify common differentially expressed genes, followed by functional enrichment analysis. Key genes were validated using RT-qPCR. Results: Proteomic analysis revealed that differentially expressed proteins were significantly enriched in focal adhesion pathway. Protein–protein interaction (PPI) network analysis indicated that these proteins (e.g., Integrin alpha 3 (Itga3), glycogen synthase kinase 3 beta (Gsk3b), mitogen-activated protein kinase 9 (Mapk9)) were associated with focal adhesion and cytoskeletal functions. Integrated multi-omics analysis identified 923 common differentially expressed genes, which were also significantly enriched in focal adhesion pathway. Within this pathway, the protein expression levels of Itga3, Gsk3b, and Mapk9 exhibited a consistent co-variation trend with H4K5ac enrichment. RT-qPCR results confirmed that Itga3 was significantly up-regulated, while Gsk3b was down-regulated in the NTDs group (p < 0.05). Conclusions: Maternal pregestational diabetes may contribute to NTDs by disrupting cytoskeletal reorganization, cell adhesion, and migration processes. This disruption is likely mediated through H4K5ac-regulated expression of key focal adhesion pathway genes such as Itga3 and Gsk3b. Full article

Neurological disorders, particularly Parkinson’s disease (PD), represent a pressing global health challenge with limited disease-modifying therapies. While Achyranthes bidentata exhibits neuroprotective potential, its bioactive constituents against PD remain poorly characterized. This study integrated phytochemical isolation and in silico target prediction to identify eight compounds from A. bidentata, followed by neuroprotective evaluation in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-challenged SH-SY5Y cells. Among these, 25R-inokosterone significantly downregulated Monoamine oxidase B (MAOB) and Glycogen synthase kinase-3β (GSK-3β) expression and showed superior neuroprotection compared to β-ecdysterone. It markedly restored mitochondrial membrane potential, suppressed Bcl-2-associated X protein (Bax)/Cysteinyl aspartate specific proteinase 3 (caspase-3) apoptotic signaling, and alleviated oxidative stress. Mechanistically, Nuclear factor erythroid 2-related factor 2 (Nrf2)/Heme oxygenase 1 (HO-1) activation was the dominant and indispensable mechanism for neuroprotection, while MAOB/GSK-3β expression downregulation served as an upstream synergistic regulatory event, as evidenced by the abolition of neuroprotection following Nrf2 knockdown in SH-SY5Y cells. These findings identify 25R-inokosterone as a promising multi-target natural lead for PD, which exerts antioxidant and anti-apoptotic effects predominantly by activating Nrf2, accompanied by the upstream modulation of MAOB/GSK-3β expression. Full article

Polycystic Ovary Syndrome (PCOS) is a prevalent endocrine disorder in women of reproductive age, characterized by hyperandrogenism, insulin resistance, and ovarian dysfunction. Current therapies are often associated with adverse effects, highlighting the need for safer therapeutic alternatives. Peganum harmala (P. harmala), a medicinal plant rich in bioactive metabolites, was investigated through in silico approaches to identify compounds with predicted binding affinity for the androgen receptor (AR), steroid 17α-hydroxylase/17,20-lyase (CYP17A1), and glycogen synthase kinase-3 beta (GSK-3β). GC-MS analysis of P. harmala leaf essential oil collected in Riyadh, Saudi Arabia, identified 109 compounds, with terpenoids as the dominant class (21.89%). The major constituents were cis-chrysanthenyl acetate (3.48%), cis-β-damascenone (3.06%), farnesylacetone (1.44%), β-calacorene (1.36%), dihydroedulan II (1.04%), and trans-calamenene (0.46%). In silico ADMET evaluation indicated that most compounds complied with Lipinski’s rule of five and showed favorable predicted pharmacokinetic properties. Safety profiling suggested an overall acceptable toxicity profile, with minimal predicted CYP450 inhibition, except for L11, which showed broader inhibitory potential. Molecular docking showed that L15 (trans-calamenene), L14 (dihydroedulan II), L6 (β-calacorene), L3 (farnesylacetone), and L8 exhibited higher predicted binding affinity toward the androgen receptor; L3, L10 (cis-β-damascenone), and L16 (cis-chrysanthenyl acetate) interacted with CYP17A1, while L3, L9, and L6 exhibited higher affinity toward GSK-3β. Overall, these findings provide hypothesis-generating in silico predictions of ligand–target binding affinities and drug-likeness profiles. These computational findings highlight the importance of future experimental investigations to substantiate the biological activity, pharmacokinetic behavior, and safety profile of P. harmala constituents. Full article

This experiment investigated the effects of dietary Artemisia ordosica Krasch. (AOK) supplementation on the n3-polyunsaturated fatty acid (n3-PUFA) profile of subcutaneous adipose tissue (SADT) in Arbas cashmere goats and explored the underlying transcriptional mechanisms. Forty healthy, weaned kids (120 ± 10 days of age; similar body weight) were randomly allocated to two groups (n = 20): a control group (CON, basal diet) and an AOK group (AOK, basal diet with 3% of the roughage replaced by AOK). The feeding trial spanned 104 days, consisting of a 14-day adaptation period and 90 days of data acquisition. Compared with the CON group, AOK significantly reduced the content of saturated fatty acids (SFAs) and n6-polyunsaturated fatty acids (n6-PUFAs)/n3-PUFAs (n6/n3). In contrast, the levels of n3-PUFAs in the SADT of cashmere goats increased markedly (p < 0.05). Compared with the CON group, AOK exhibited significantly higher activities of hormone-sensitive lipase (HSL) (p = 0.027), adenylyl cyclase 2 (ADCY2) (p = 0.010), adenylyl cyclase 5 (ADCY5) (p = 0.046), cluster of differentiation 36 (CD36) (p = 0.013), solute carrier family 27 member 4 (SLC27A4) (p = 0.021), and fatty acid binding protein 4 (FABP4) (p = 0.040), along with significantly lower activities of fatty acid synthase (FAS) (p = 0.002), lipoprotein lipase (LPL) (p = 0.048), and stearoyl-coa desaturase (SCD) (p = 0.026) in SADT. Compared with the CON group, the activities of superoxide dismutase (SOD) (p = 0.032), catalase (CAT) (p = 0.010), glutathione peroxidase (GSH-PX) (p = 0.029), and total antioxidant capacity (T-AOC) (p = 0.002) were significantly increased in the AOK group. Transcriptomic profiling revealed that AOK supplementation downregulated mRNA levels of ADCY2, ADCY5, LPL, FAS, SCD, stearoyl-CoA desaturase 1 (SCD1), stearoyl-CoA desaturase 2 (SCD2), glycogen synthase 1 (GYS1), acyl-CoA oxidase 1 (ACOX1), acetyl-CoA carboxylase (ACC), diacylglycerol acyltransferase 1 (DGAT1), fatty acid desaturase 1 (FADS1), solute carrier family 27 member 2 (SLC27A2), erythroblastic leukemia viral oncogene homolog 4 (ERBB4), and carnitine palmitoyltransferase 1B (CPT1B) (p < 0.05). It also markedly induced acyl-CoA synthetase long-chain family member 4 (ACSL4) (p < 0.01) in SADT. Genes significantly enriched in the adenosine-monophosphate-activated protein kinase (AMPK) signaling pathway included LPL, SCD1, CPT1B, and GYS1 (p = 0.010). Genes significantly enriched in the phosphatidylinositol 3-kinase-akt (PI3K-Akt) signaling pathway included GYS1 and ERBB4 (p = 0.015). CPT1B, ADCY2, and GYS1 were identified as the genes significantly enriched in the insulin resistance signaling pathway (p = 0.048). LPL was the only gene significantly enriched in the cholesterol metabolism pathway (p = 0.049). Genes showing a tendency toward significant enrichment in the peroxisome-proliferator-activated receptor (PPAR) signaling pathway included ACSL4, CPT1B, SCD1, and LPL (p = 0.051). These interconnected cascades improve insulin sensitivity, stimulate triglyceride (TG) hydrolysis, and modulate n3-PUFA levels. Supplementation with AOK enhances n3-PUFA content by accelerating TG breakdown while simultaneously restraining FA oxidation in SADT. Consequently, AOK supplementation can be effectively used to enhance the nutritional value of cashmere goat meat through improved n3-PUFA deposition in SADT. Full article

Type 2 diabetes (T2D) features insulin resistance that promotes cerebrovascular injury, yet the immune signals linking metabolic stress to vascular dysfunction remain unclear. We tested the hypothesis that insulin resistance and soluble vascular cell adhesion molecule-1 (sVCAM1) act through complementary pathways in mast cells (MCs) to raise circulating histamine levels and impair cerebral vascular function. In a high-fat diet (HFD) plus low-dose streptozotocin (STZ) model, plasma histamine rose sharply after the onset of insulin resistance and remained elevated. Plasma sVCAM1 levels also increased after insulin resistance. In vitro, recombinant sVCAM1 upregulated histidine decarboxylase (HDC) in native MCs in a dose-dependent manner, indicating a shift toward histamine synthesis, but did not enhance degranulation. In contrast, pharmacological inhibition of Akt with MK2206 activated Glycogen Synthase Kinase 3 beta (GSK3β) and increased MC degranulation without affecting HDC expression. Diabetic endothelial cell monolayers exhibited a ~twofold reduction in transendothelial electrical resistance consistent with impaired blood–brain barrier (BBB) integrity. Diabetic cerebral arteries showed receptor remodeling that favored constriction with histamine H1 receptor (H1R) expression increasing in vascular smooth muscle, while endothelial H1R and histamine H2 receptor (H2R) decreased. Functionally, insulin treatment lowered HOMA2-IR in T2D mice but did not restore cerebral artery myogenic tone or improve stroke outcomes after distal middle cerebral artery occlusion (dMCAO). Neutralizing VCAM1 with a monoclonal antibody reduced circulating sVCAM1 and histamine levels, and, together with the GSK3β inhibitor Tideglusib, stabilized MCs, normalized cerebral artery tone, and reduced post-MCAO infarct size and edema. These findings identify two distinct yet complementary mast cell pathways in T2D, highlight an immune-vascular interface that drives cerebrovascular dysfunction, and propose sVCAM1 blockade plus GSK3β inhibition as rational strategies to protect cerebral vascular function in the diabetic brain. Full article

Glycogen synthase kinase 3 (GSK3/SHAGGY-like kinase) plays a pivotal role in regulating plant growth, development, and stress responses. To elucidate the characteristics of the GSK family in Glycine max, this study employed whole-genome data combined with bioinformatic and gene expression analyses to investigate the gene structure, chromosomal localization, collinearity, phylogenetic evolution, promoter cis-elements and differential gene expression analysis. Additionally, the expression patterns of GmGSK genes under manganese (Mn) stress and their associated phenotypic alterations were analyzed. A total of 22 GmGSK family members were identified, all harboring the characteristic GSK kinase domain. These members are distributed across 16 chromosomes, encoding proteins ranging from 380 to 802 amino acids (aa) in length. Phylogenetic analysis classified the GmGSK family into four evolutionary clades, consistent with patterns observed in Arabidopsis and Oryza sativa. Members within the same clade share identical exon-intron structures and conserved motifs. Collinearity analysis revealed that segmental duplication events have been crucial in the functional expansion of the GmGSK family through intraspecific collinearity. In recent years, alongside industrial development and fertilizer imbalance, the effective manganese concentration in agricultural soils has risen abnormally in some regions of China, leading to toxic effects on crops. Soybean, an oilseed crop relatively sensitive to manganese, has been adversely impacted. Clarifying the response mechanisms of soybean seedlings to manganese stress is therefore of significant importance for improving both yield and quality. Manganese stress treatment induced significant up-/down-regulation of specific GmGSK members in soybean, concomitant with pronounced inhibition of root elongation and leaf growth. This study provides a theoretical framework for deciphering the molecular regulatory mechanisms by which the GmGSK gene family mediates plant responses to Mn stress, offers insights into soybean Mn tolerance mechanisms, and establishes a foundation for genetic improvement of Mn-tolerant traits in crops. Full article

Glycogen synthase kinase 3 (GSK3/Shaggy-like) is a highly conserved serine/threonine kinase that orchestrates growth, hormone signaling, and abiotic stress responses in both animals and plants, yet its role in watermelon remains unexplored. In this study, we conducted a whole-genome identification, identifying a total of eight members of the GSK3 gene family (ClGSK3) distributed across seven chromosomes. Phylogenetic and synteny analyses resolved the eight ClGSK3s into four subfamilies that display one-to-one or one-to-many orthology with Arabidopsis and rice GSK3 genes, indicating conserved genomic micro-collinearity across dicots and monocots. Predictions of cis-acting elements and transcriptome data analysis indicate that ClGSK3s may be involved in hormone- and stress-responsive conditions. Protein–protein interaction networks predicted 53 candidate partners for five ClGSK3 proteins; yeast two-hybrid assays subsequently confirmed that ClSK21 associates with three of them—orthologs of the core brassinosteroid (BR)-signaling components BKI1 and BZR1. qRT-PCR revealed that ClSK21, ClSK31, and ClSK41 are rapidly and significantly reprogrammed by BR treatment. Collectively, our data suggest that ClGSK3s modulate fruit development and stress tolerance by integrating hormone-related pathways, especially BR signaling. Future studies are encouraged to integrate genetics and multi-omics approaches to systematically validate the roles of ClGSK3s in hormone signaling and abiotic stress responses. Full article

Introduction: Incomplete polymerization of in vivo composite resins (CR) poses a significant problem, with monomer-to-polymer conversion rates ranging from around 60 to 75%. Furthermore, oxygen exposure hampers polymerization in the surface layers. This research aims to evaluate the autophagy-inducing potential of three types of CRS and to explore the role of the Akt/mTOR–autophagy–apoptosis crosstalk in composite resin-induced autophagy. The study uses human gingival fibroblasts and three composite materials (M1 and M2, which are 3D printed, and M3, which is milled). Materials and Methods: SEM analysis was performed on the dental materials, and cells kept in contact for 24 h were subjected to tests including the following: MTT, LDH, NO, immunological detection of proteins involved in autophagy and apoptosis, as well as immunofluorescence tests (Annexin V and nucleus; mitochondria and caspase 3/7; detection of autophagosomes). Results: The results showed statistically significant decreases in cell viability with M1 and M2, linked to increases in cytotoxicity and oxidative stress (LDH and NO). Using multiplex techniques, significant increases in glycogen synthase kinase 3 beta (GSK3b) protein were observed in both M1 and M2; a decrease in mTOR (mechanistic target of rapamycin) expression was noted in M1 and M3. Immunofluorescence tests revealed an increase in Annexin V across all materials studied, and an increase in autophagosomes in M1 and M2, whereas a decrease was observed in M3. Conclusions: The relationship between apoptosis and autophagy is highly complex, indicating they may occur sequentially, coexist, or be mutually exclusive. Understanding this complex interplay can help in designing new 3D-printing protocols and monomer compositions to prevent autophagy imbalance. Full article

WNT/β-catenin signaling is essential for intestinal stem cell development and self-renewal, while its dysregulation can drive tumorigenesis. GSK3, a key negative regulator of β-catenin, in intestinal homeostasis remains incompletely understood. In this study, we investigated the role of GSK3 in intestinal development, niche maintenance, and physiological function. Unlike Apc^Min/+ mice that developed intestinal polyps, neither GSK3α nor GSK3β deficiency disrupted intestinal homeostasis. However, complete GSK3 deletion (DKO) resulted in perinatal lethality, characterized by disturbed crypt–villus architecture, Paneth cell redistribution, and villus elongation. GSK3 deficiency disrupted the intestinal niche, leading to expanded and mislocalized stem cells and Paneth cells, along with reduced tuft and enteroendocrine cells. These alterations impaired nutrient absorption and gut motility. Mechanistically, β-catenin-positive cells were significantly increased following GSK3 deletion. Genetic ablation of β-catenin under GSK3-deficient conditions reduced stem and Paneth cell populations while restoring tuft and enteroendocrine cells, thereby ameliorating niche abnormalities and improving absorptive and peristaltic functions. This study indicates the essential role of GSK3/β-catenin signaling in maintaining intestinal niche integrity and digestive physiology, highlighting potential therapeutic targets for intestinal and digestive disorders. Full article

Neuroinflammation plays a central role in the pathogenesis of Alzheimer’s disease (AD), with amyloid-β (Aβ) deposition and neurofibrillary tangles driving both central and peripheral inflammatory responses. This study investigated the neuroprotective and anti-inflammatory effects of Vitex trifolia (VT), Plantago major (PM), Apocyni Veneti Folium (AVF), and Eucommiae folium (EF) using network pharmacology and a co-culture model of PC12 neuronal and Caco-2 intestinal epithelial cells. Bioactive compounds were identified via high-performance liquid chromatography (HPLC) and screened with network pharmacology analysis, yielding 27 for VT, 10 for PM, 6 for AVF, and 3 for EF. Molecular docking confirmed strong binding affinities between the key bioactive compounds and AD-related targets. A co-culture system of PC12 neuronal and Caco-2 intestinal epithelial cells was established to evaluate the effects of VT, PM, AVF, and EF extracts (at concentrations of 10 µg/mL, 20 µg/mL, and 50 µg/mL) and donepezil hydrochloride (positive-control) on Aβ_25–35-induced neurotoxicity and lipopolysaccharide (LPS)-induced intestinal inflammation, to assess cell viability, and effects on oxidative stress, mitochondrial function, and inflammatory markers. The VT, PM, AVF, and EF extracts activated phosphoinositide 3-kinase (PI3K)-Akt-glycogen synthase kinase-3β (GSK-3β) signaling, enhanced phosphorylation of AMP kinase, suggesting inhibition of Aβ accumulation and tau hyperphosphorylation (p < 0.05). However, donepezil hydrochloride only enhanced AMPK phosphorylation. The extracts reduced lipid peroxidation and acetylcholinesterase by about 5-fold. JC-1 staining confirmed preserved mitochondrial membrane potential, while hematoxylin and eosin staining indicated improved intestinal barrier integrity (p < 0.05). PM and AVF reduced the number of mast cells (p < 0.05). In conclusion, these findings highlight the multi-target potential of VT, PM, AVF, and EF in mitigating both neuronal and intestinal inflammation. Their dual regulatory effects on the gut–brain axis suggest promising therapeutic applications in AD through the modulation of central and peripheral immune responses. Full article

Celery (Apium graveolens L.), one of the numerous members of the Apiaceae family, has been traditionally used as food and medicine due to its nutraceutical properties. Nevertheless, understanding the neuroprotective effects of this species requires evaluation through different mechanisms relevant to Alzheimer’s disease (AD) treatment. This study explored the neuroprotective potential of ethanolic extracts of celery leaves. Liquid chromatography and mass spectrometry-based metabolomics analysis of the extract revealed the existence of a diverse array of secondary metabolites, including phenolic acids, hydroxycinnamic acid, flavonoids, flavonoid O-glycosides, flavonol, glycosides, and isoflavones. Celery extract protects human neuroblastoma SH-SY5Y cells against 15 µM amyloid-beta (Aβ_1–42) toxicity, enhancing their vitality from 67% to 81.74% at 100 µg/mL. The extract inhibited the enzymes associated with AD, including acetylcholinesterase (AChE), butyrylcholinesterase (BChE), glycogen synthase kinase 3 beta (GSK3β), cyclooxygenase 1 (COX-1), and cyclooxygenase 2 (COX-2) with IC₅₀ values of 21.84, 61.27, 45.94, 34.1, and 52.2 µg/mL, respectively. In conclusion, celery leaf extract components may be potential therapeutic candidates for AD prevention and treatment. Full article

Metabolic syndrome (MetS) poses considerable toxicological risks due to its association with an increased likelihood of metabolic dysfunction-associated steatotic liver disease (MASLD), and is characterized by hypertension, hyperglycemia, dyslipidemia, and obesity. This study aimed to investigate the therapeutic potential of flavonoid-rich lotus seedpod extract (LSE) in alleviating MetS and MASLD-related hepatic disturbances. In vivo, mice subjected to a high-fat diet (HFD) and streptozotocin (STZ) injection were supplemented with LSE or simvastatin for 6 weeks. Obesity indicators included body weight and epididymal fat, while insulin resistance was measured by fasting serum glucose, serum insulin, homeostasis model assessment–insulin resistance index (HOMA-IR), and oral glucose tolerance (OGTT). Also, the levels of serum lipid profiles and blood pressure were evaluated. Adipokines, proinflammatory cytokines, liver fat droplets, and peri-portal fibrosis were analyzed to clarify the mechanism of MetS. LSE significantly reduced the HFD/STZ-induced MetS markers better than simvastatin, as demonstrated by hypoglycemic, hypolipidemic, antioxidant, and anti-inflammatory effects. In vitro, LSE improved oleic acid (OA)-triggered phenotypes of MASLD in hepatocyte HepG2 cells by reducing lipid accumulation and enhancing cell viability. This effect might be mediated through proteins involved in lipogenesis that are downregulated by adenosine monophosphate-activated protein kinase (AMPK). In addition, LSE reduced reactive oxygen species (ROS) generation and glycogen levels, as demonstrated by enhancing insulin signaling involving reducing insulin receptor substrate-1 (IRS-1) Ser307 phosphorylation and increasing glycogen synthase kinase 3 beta (GSK3β) and protein kinase B (PKB) expression. These benefits were dependent on AMPK activation, as confirmed by the AMPK inhibitor compound C. These results indicate that LSE exhibits protective effects against MetS-caused toxicological disturbances in hepatic carbohydrate and lipid metabolism, potentially contributing to its efficacy in preventing MASLD or MetS. Full article