Search Results (19,593)

Chestnut honey has various benefits, such as antioxidative, anti-inflammatory, immunomodulatory, antibacterial, and antiviral effects. However, the effects of chestnut honey or the ethyl acetate fraction of chestnut honey (EACH) on neurodegenerative diseases and their related cognitive impairment and neurotoxicity have not yet been established. Therefore, in this study, we investigated the mitigating effect of the EACH on scopolamine (SCO)-injected cognitive decline in mice and glutamate-exposed neurotoxicity in HT22 cells. EACH administration significantly reversed SCO-induced cognitive decline in mice, as demonstrated through the Morris water maze and passive avoidance tests. The EACH treatment showed a significant alleviation effect by recovering more than 80% of the cell viability decrease induced by glutamate exposure in the HT22 neuronal cell model. Furthermore, the EACH significantly reduced reactive oxygen species accumulation, lactate dehydrogenase release, mitochondrial depolarization, and neuronal apoptosis. The EACH regulated the level of apoptosis-related proteins, induced the nuclear translocation of nuclear factor-E2-related factor 2 (Nrf-2) and the expression of related antioxidant proteins, and induced the phosphorylation of tropomyosin-related kinase receptor B (TrkB)/cAMP-calcium response element-binding protein (CREB) and the expression of brain-derived neurotrophic factor. These data indicate that the EACH can prevent neurons from oxidative damage and improve cognitive dysfunction by activating Nrf-2 and TrkB/CREB signaling pathways. Therefore, the EACH demonstrates potential therapeutic value in mitigating oxidative stress-induced neurotoxicity, cognitive decline, and related neurodegenerative diseases. Full article

Objective: To investigate the effects of licorice functional ingredient intake on blood pressure, explore its potential mechanisms of action, and provide safety information for personalized nutritional interventions in special populations and for the application of licorice-derived functional foods. Methods: PubMed, Cochrane Library, Medline, Embase, EBSCO, ScienceDirect, and Web of Science databases were searched from inception to 31 August 2024. Randomized controlled trials (RCTs) investigating the intake of licorice or its functional components were included. The range of continuous variables was assessed using the weighted mean difference (WMD) with 95% confidence intervals. Genes associated with hypertension were screened using an online database. Machine learning, receiver operating characteristic(ROC) curve analysis, molecular docking, and gene set enrichment analysis (GSEA) were employed to explore the potential mechanisms underlying licorice-induced blood pressure fluctuations. Results: Eight RCTs (541 participants) were included in the meta-analysis, which indicated interventions containing glycyrrhizic acid (GA) as the main component increased systolic blood pressure (SBP) and diastolic blood pressure (DBP) (SBP: WMD [95% CI] = 3.48 [2.74, 4.21], p < 0.001; DBP: WMD [95% CI] = 1.27 [0.76, 1.78], p < 0.001). However, interventions dominated by licorice flavonoids(LF) had no significant effect on SBP or DBP (SBP: WMD [95% CI] = 0.58 [−1.15, 2.31], p = 0.511; DBP: WMD [95% CI] = 0.17 [−1.53, 1.88], p = 0.843). Three machine learning algorithms identified five biomarkers associated with hypertension: calmodulin 3 (CALM3), cluster of differentiation 9 (CD9), growth factor independence 1B transcriptional repressor (GFI1B), myosin light chain kinase (MYLK), and Ras suppressor-1 (RSU1). After removing biomarkers with lower validity and reliability, GFI1B, MYLK, and RSU1 were selected for subsequent analysis. The network toxicology results suggested that GA and its metabolite glycyrrhetinic acid may act on GFI1B, MYLK, and RSU1, influencing blood pressure fluctuations by modulating nitrogen metabolism signaling pathways. Conclusions: There were distinct differences in the effects of licorice functional components on blood pressure. Functional constituents dominated by GA were shown to increase both SBP and DBP, whereas those dominated by LF did not exhibit significant effects on blood pressure. The hypertensive mechanism of GA may involve the modulation of GFI1B, MYLK, and RSU1 to regulate nitrogen metabolic pathways. Full article

Inflammation is critical in the development of acute liver failure (ALF). Peroxisome proliferator-activated receptor delta (PPARδ) regulates anti-inflammatory responses and is protective in several diseases such as obesity and cancer. However, the beneficial effects and underlying mechanisms of PPARδ agonist GW501516 in ALF remain unclear. This study investigated the molecular mechanisms underlying the anti-inflammatory effects of GW501516 in macrophages and assessed its protective potential against lipopolysaccharide (LPS)/galactosamine (GalN)-induced ALF. In vivo administration of GW501516 significantly reduced LPS/GalN-induced hepatotoxicity, as evidenced by lower mortality, decreased liver damage, and attenuated secretion of IL-1β, IL-6, and TNF-α. GW501516 treatment also decreased LPS-induced nitric oxide synthase 2 (NOS2) expression and nitric oxide (NO) production in RAW264.7 cells, an effect reversed by PPARδ siRNA. Additionally, GW501516 inhibited LPS-induced phosphorylation of p38 and c-Jun N-terminal kinase (JNK), suggesting that inactivation of these MAPKs contributes to its effects. The secretion of IL-6, TNF-α, and NF-κB DNA-binding activity were also suppressed by GW501516, while the nuclear translocation of the NF-κB p65 subunit was unaffected. In conclusion, our findings suggest that GW501516 exerts protective effects in ALF by inhibiting the production of inflammatory mediators. Therefore, GW501516 may act as a potential agent for developing anti-inflammatory therapies for ALF. Full article

African swine fever (ASF), a highly infectious and devastating disease affecting both domestic pigs and wild boars, is caused by the African swine fever virus (ASFV). ASF has resulted in rapid global spread of the disease, leading to significant economic losses within the swine industry. A significant obstacle to the creation of safe and effective ASF vaccines is the existing knowledge gap regarding the pathogenesis of ASFV and its mechanisms of immune evasion. The cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway is a major pathway mediating type I interferon (IFN) antiviral immune response against infections by diverse classes of pathogens that contain DNA or generate DNA in their life cycles. To evade the host’s innate immune response, ASFV encodes many proteins that inhibit the production of type I IFN by antagonizing the cGAS-STING signaling pathway. Multiple proteins of ASFV are involved in promoting viral replication by protein–protein interaction during ASFV infection. The protein QP383R could impair the function of cGAS. The proteins EP364R, C129R and B175L could disturb the function of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). The proteins E248R, L83L, MGF505-11R, MGF505-7R, H240R, CD2v, E184L, B175L and p17 could interfere with the function of STING. The proteins MGF360-11L, MGF505-7R, I215L, DP96R, A151R and S273R could affect the function of TANK Binding Kinase 1 (TBK1) and IκB kinase ε (IKKε). The proteins MGF360-14L, M1249L, E120R, S273R, D129L, E301R, DP96R, MGF505-7R and I226R could inhibit the function of Interferon Regulatory Factor 3 (IRF3). The proteins MGF360-12L, MGF505-7R/A528R, UBCv1 and A238L could inhibit the function of nuclear factor kappa B (NF-Κb). Full article

The MET receptor, commonly known as HGF (hepatocyte growth factor) receptor, is a focus of extensive scientific research. MET has been linked to embryonic development, tissue regeneration following injury, tumorigenesis, and cancer metastasis. These functions underscore its involvement in numerous cellular processes, including stemness, proliferation, motility, cell dissociation, and survival. However, the enigmatic nature of MET becomes apparent in the context of cancer. When MET remains persistently activated, since its gene undergoes genetic alterations, it initiates a complex signaling cascade setting in motion an aggressive and metastatic program that is characteristic of malignant cells and is known as “invasive growth”. The expanding knowledge of MET signaling has opened up numerous opportunities for therapeutic interventions, particularly in the realm of oncology. Targeting MET presents a promising strategy for developing novel anti-cancer treatments. In this review, we provide an updated overview of drugs designed to modulate MET signaling, highlighting MET kinase inhibitors, degraders, anti-MET/HGF monoclonal antibodies, and MET-targeted antibody–drug conjugates. Through this review, we aim to contribute to the ongoing advancement of therapeutic strategies targeting MET signaling. Full article

Background: Chronic myeloid leukemia (CML) is one of the most commonly found types of myeloproliferative neoplasms, characterized by increased proliferation of granulocytic cells without losing their differentiation ability. Imatinib, a tyrosine kinase inhibitor (TKI), can be effectively used as therapy for CML. However, Imatinib can affect bone turnover thus having clinical implications on the bones of CML patients undergoing long-term Imatinib therapy. However, parameters that can accurately describe the bone condition in CML patients receiving Imatinib still need further study. A combination of imaging techniques such as bone mineral density (BMD) and bone turnover activity markers such as C-terminal telopeptide of type I collagen (CTX-1) and osteocalcin has the potential to be used as monitoring parameters for bone density abnormalities in CML patients receiving Imatinib. Objectives: This article explains the rationale for using BMD, CTX-1, and osteocalcin as monitoring parameters of bone remodeling in CML patients receiving Imatinib. Results: First, the physiological process of bone turnover will be explained. Then, we describe the role of tyrosine kinase in bone metabolism. Next, the impact of Imatinib on BMD, CTX-1, and osteocalcin will be explained. Conclusion: The assessment of bone health of CML patients on Imatinib should include both BMD tests and bone turnover marker assays such as CTX-1 and osteocalcin. Full article

Parasitic plants represent a significant challenge in global agriculture, with Broomrape (Orobanche/Phelipanche spp.) being a notable example of a holoparasitic species that targets the roots of host plants. This study employed comparative transcriptomics to investigate the mechanisms underlying the parasitism of P. aegyptiaca on melon, focusing on both resistant and susceptible interactions. The findings indicate that the critical phase of P. aegyptiaca parasitism occurs during the post-attachment stage. It is suggested that peptidases may play a role in the development of invasive cells, while cell wall-degrading enzymes (CWDEs) are likely involved in cell wall modification and degradation, and transferases, elicitors, and effectors may play a role in immune regulation. In this study, 25 tobacco rattle virus (TRV) recombinant vectors were successfully constructed and functionally validated using a host-induced gene silencing assay to explore the functions of candidate-secreted effector proteins. The results revealed that silencing Cluster-107894.0, Cluster-11592.0, and Cluster-12482.0 significantly decreased the parasitism rate of P. aegyptiaca on Nicotiana benthamiana. Notably, Cluster-107849.0 encodes a cellulase with hydrolase activity, Cluster-11592.0 encodes a periodic-dependent kinase inhibitor with phosphoprotein activity, and Cluster-12482.0 encodes a glucan 1,3-β-glucosidase with hydrolase activity. These findings potentially offer a novel theoretical framework and justification for understanding host–parasite plant interactions, and suggest new avenues for developing crop varieties resistant to parasitic infestation. Full article

Transcranial magnetic stimulation (TMS) methods have become exciting techniques for altering brain activity and improving synaptic plasticity, earning recognition as valuable non-medicine treatments for a wide range of neurological disorders. Among these methods, repetitive TMS (rTMS) and theta-burst stimulation (TBS) show significant promise in improving outcomes for adults with complex neurological and neurodegenerative conditions, such as Alzheimer’s disease, stroke, Parkinson’s disease, etc. However, optimizing their effects remains a challenge due to variability in how patients respond and a limited understanding of how these techniques interact with crucial neurotransmitter systems. This narrative review explores the mechanisms of rTMS and TBS, which enhance neuroplasticity and functional improvement. We specifically focus on their effects on GABAergic and glutamatergic pathways and how they interact with key receptors like N-Methyl-D-Aspartate (NMDA) and AMPA receptors, which play essential roles in processes like long-term potentiation (LTP) and long-term depression (LTD). Additionally, we investigate how rTMS and TBS impact neuroplasticity and functional connectivity, particularly concerning brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase receptor type B (TrkB). Here, we highlight the significant potential of this research to expand our understanding of neuroplasticity and better treatment outcomes for patients. Through clarifying the neurobiology mechanisms behind rTMS and TBS with neuroimaging findings, we aim to develop more effective, personalized treatment plans that effectively address the challenges posed by neurological disorders and ultimately enhance the quality of neurorehabilitation services and provide future directions for patients’ care. Full article

Receptor-interacting serine/threonine protein kinase 2 (RIPK2) is a kinase that is essential in modulating innate and adaptive immune responses. As a downstream signaling molecule for nucleotide-binding oligomerization domain 1 (NOD1), NOD2, and Toll-like receptors (TLRs), it is implicated in the signaling triggered by recognition of microbe-associated molecular patterns by NOD1/2 and TLRs. Upon activation of these innate immune receptors, RIPK2 mediates the release of pro-inflammatory factors by activating mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB). However, whether RIPK2 is essential for downstream inflammatory signaling following the activation of NOD1/2, TLRs, or both remains controversial. In this study, we examined the role of RIPK2 in NOD2- and TLR4-dependent signaling cascades following stimulation of microglial cells with bacterial muramyl dipeptide (MDP), a NOD2 agonist, or lipopolysaccharide (LPS), a TLR4 agonist. We utilized a highly specific proteolysis targeting chimera (PROTAC) molecule, GSK3728857A, and found dramatic degradation of RIPK2 in a concentration- and time-dependent manner. Importantly, the PROTAC completely abolished MDP-induced increases in iNOS and COX-2 protein levels and pro-inflammatory gene transcription of Nos2, Ptgs2, Il-1β, Tnfα, Il6, Ccl2, and Mmp9. However, increases in iNOS and COX-2 proteins and pro-inflammatory gene transcription induced by the TLR4 agonist, LPS, were only slightly attenuated with the GSK3728857A pretreatment. Further findings revealed that the RIPK2 PROTAC completely blocked the phosphorylation and activation of p65 NF-κB and p38 MAPK induced by MDP, but it had no effects on the phosphorylation of these two mediators triggered by LPS. Collectively, our findings strongly suggest that RIPK2 plays an essential role in the inflammatory responses of microglia to bacterial MDP but not to LPS. Full article

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is highly conserved and essential for numerous biological functions triggered by extracellular signals, including cell proliferation, metabolism, immune response, and inflammation. Defects in STATs, either loss-of-function or gain-of-function defects, lead to a broad spectrum of clinical phenotypes in humans, including a wide range of infectious complications. The susceptibility to pathogens can stem from defects in immune cells within the hematopoietic compartment, impaired barrier functions of non-hematopoietic compartment, or a combination of both, depending on the specific STAT defect as well as the pathogen exposure history. Effective management involves antimicrobial prophylaxis tailored to the patient’s infection risk and improving disease control with targeted therapies and/or hematopoietic cell transplantation. Full article

Anabasis aretioïdes contain numerous bioactive compounds that provide several advantages, including antioxidant, antibacterial, anticancer, neuroprotective, anti-inflammatory, and antidiabetic characteristics. This study aimed to make a hydroethanolic extract from the aerial part of the plant, analyze its biochemical compounds, and test its biological activities. From HPLC-DAD analysis, cinnamic acid, sinapic acid, and vanillin bioactives were found to be the main compounds in the extract. The spectrometric tests revealed that the extract was rich in flavonoids (8.52 ± 0.32 mg RE/100 g DW), polyphenols (159.32 ± 0.63 mg GAE/100 g DW), and condensed tannins (8.73 ± 0.23 mg CE/100 g DW). The extract showed significant antioxidant activity. There were strong correlations between the amount of flavonoid or polyphenol and the antioxidant assays, including ABTS, DPPH, β-carotene, and TAC. The extract also showed highly effective results against Gram-positive bacteria Staphylococcus aureus and Enterococcus faecalis as well as against Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa, and showed promising cytotoxicity against breast cancer cell lines MCF-7 and MDA-MB-231. The in silico modeling of the bioactive compounds contained in the extract illustrated their interaction mode with the active sites of particular target proteins, and it showed that rutin had the strongest effect on stopping NADPH oxidase enzyme, with a glide score of −6.889 Kcal/mol. Sinapic acid inhibited E. coli beta-ketoacyl-[acyl carrier protein] synthase (−7.517 kcal/mol), and apigenin showed high binding affinity to S. aureus nucleoside di-phosphate kinase, with −8.656 kcal/mol. Succinic acid has the strongest anticancer effect for caspase-3, with a glide score of −8.102 kcal/mol. These bioactive components may be beneficial as antioxidant and antibacterial applications in medicine, foods, natural cosmetics, and breast cancer prevention in the future. As a result, the use of this indigenous plant must be considered to maximize its value and preservation. Full article

The present study aims to evaluate the effect of a dietary supplementation with 10% grape pomace (GP) on the whole blood transcriptome of lactating ewes. By applying a log₂FC higher than 0.5 or lower than −0.5 and a false discovery rate (FDR) <0.05, the down-regulation of genes coding for plexin C1, ethanolamine kinase 1, tax1-binding protein 1, transmembrane 9 superfamily member 2, and Beclin-1 was observed in animals that received the dietary supplementation. This aspect was also accompanied by a reduction in the blood activity of matrix metalloproteinase 9 (MMP-9; p < 0.05), a gelatinase commonly involved in both acute and chronic pathological events. The ELISA test on other factors involved in inflammatory processes, interleukin 1 (IL-1) and tumor necrosis factor α (TNF-α), as well as in the antioxidant response, glutathione peroxidase (GPx), and catalase (CAT), did not reveal any significant changes (p > 0.05). Overall, the introduction of GP in the diet of ewes gave indications of greater efficacy in preserving animal welfare, with interesting cues regarding the valorization of a by-product with a high biological value. Full article

Background and objective: Cannabinoids are commonly used as adjuvant cancer drugs to overcome numerous adverse side effects for patients. The aim of this study was to identify the target genes that show a synergistic anti-tumor role in combination with the cannabinoid WIN55212-2 in vitro and in vivo. Methods: A human kinome RNAi library was used to screen the targeted gene that silencing plus WIN55212-2 treatment synergistically inhibited cancer cell growth in an INCELL Analyzer 2000. Cell viability, cell phase arrest and apoptosis were evaluated by MTT and flow cytometry assay. In vivo combined anti-tumor effects and regulatory mechanisms were detected in immunocompromised and immunocompetent mice. Results: Using RNAi screening, we identified the tyrosine receptor kinase AXL as a potential gene whose silencing plus WIN55212-2 treatment synergistically inhibited the proliferation of cancer cells in an INCELL Analyzer 2000. Subsequently, we demonstrated that inhibition of AXL by TP-0903 potentiated the inhibitory role of WIN55212-2 on cellular viability, colony formation and 3D tumor sphere in HCT-8 cells. Meanwhile, TP-0903 plus WIN55212-2 treatment promoted the apoptosis of HCT-8 cells. We then investigated the synergistic anti-tumor effect of TP-0903 and WIN55212-2 using colon cancer cell xenografts in immunocompromised and immunocompetent mice. The in vivo study demonstrated that combined administration of TP-0903 plus WIN55212-2 effectively reduced tumor volume and microvessel density and promoted apoptotic cells of tumor tissues in HCT-8 exogenous mice compared to either TP-0903 or WIN55212-2 treatment alone. Moreover, in addition to tumor suppression, the combination therapy of TP-0903 and WIN55212-2 induced the infiltration of cytotoxic CD8⁺ T cells and significantly reduced mTOR and STAT3 activation in tumor tissues of C57BL/6J mice bearing MC-38 cells. Conclusions: This study demonstrated that targeting AXL could sensitize cannabinoids to cancer therapy by interfering with tumor cells and tumor-infiltrating CD8⁺ T cells. Full article

RASopathies are a group of genetic syndromes caused by germline mutations in genes involved in the RAS/Mitogen-Activated Protein Kinase signaling pathway, which regulates cellular proliferation, differentiation, and angiogenesis. Despite their involvement at different levels of this pathway, RASopathies share overlapping clinical phenotypes. Noonan syndrome is the most prevalent RASopathy, with an estimated incidence of 1 in 2500 live births, and it is typically inherited in an autosomal dominant manner, with 50% of cases involving gain-of-function mutations in the PTPN11 gene. De novo mutations are common, accounting for 60% of cases. The phenotype of Noonan syndrome includes characteristic facial and physical features, congenital cardiac defects, lymphatic and cerebrovascular anomalies, renal malformations, hematological abnormalities, developmental issues, and an increased risk of cancer. Severe congenital cardiac defects and lymphatic abnormalities significantly impact prognosis, contributing to increased morbidity and mortality. Recent therapeutic advancements have introduced trametinib, an MEK1/2 inhibitor, for treating Noonan syndrome patients with severe cardiac and lymphatic complications. To assess its efficacy, here, we present a case of a newborn with Noonan syndrome who exhibited refractory chylothorax, ventricular hypertrophy, and pulmonary stenosis who was treated with trametinib. The patient demonstrated significant improvement in chylothorax and left ventricular hypertrophy, though pulmonary stenosis persisted. This case further confirms trametinib’s potential as a therapeutic option for severe Noonan syndrome complications, emphasizing the need for further clinical trials to optimize treatment protocols and evaluate long-term outcomes. Full article

Somatic embryogenesis is valuable for clonal propagation and genetic improvement, and it also serves as an ideal system for studying plant development mechanisms. In Larix kaempferi, microRNA171 and its target gene L. kaempferi SCARECROW-LIKE6 (LaSCL6), which has two alternative splicing variants, can regulate somatic embryogenesis; however, the underlying molecular mechanism is still unknown. In this study, we overexpressed these two LaSCL6 variants in Oryza sativa and Arabidopsis thaliana and then used the RNA-Seq method to screen genes from O. sativa and A. thaliana, whose expression patterns are related to those of LaSCL6 variants. The screened genes were then used to search L. kaempferi proteins to identify the candidate target genes of LaSCL6. After yeast one-hybrid and dual- luciferase transcriptional activity assays, cytochrome P450, family 89, subfamily A, polypeptide 5 (CYP89A5), and wall-associated receptor kinase-like 20 (WAKL20) were confirmed to be the target genes of LaSCL6-var1; in addition, WAKL20 and UDP-glycosyltransferase 85A3 (UGT85A3) were confirmed to be the target genes of LaSCL6-var2. Moreover, APETALA2-like protein 2, a transcription factor from the AP2/ERF family, was shown to interact with LaSCL6-var1 and LaSCL6-var2. Taken together, our results suggest a regulatory network of miR171-LaSCL6. The findings presented here not only provide novel insights into the regulation of the miR171-LaSCL6 module but also explain the mechanism underlying larch somatic embryogenesis and other biological processes. Full article