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PeerJ 2024Ischemic stroke (IS) is a disease with a high mortality and disability rate worldwide, and its incidence is increasing per year. Angiogenesis after IS improves blood...
β-asarone induces viability and angiogenesis and suppresses apoptosis of human vascular endothelial cells after ischemic stroke by upregulating vascular endothelial growth factor A.
Ischemic stroke (IS) is a disease with a high mortality and disability rate worldwide, and its incidence is increasing per year. Angiogenesis after IS improves blood supply to ischemic areas, accelerating neurological recovery. β-asarone has been reported to exhibit a significant protective effect against hypoxia injury. The ability of β-asarone to improve IS injury by inducing angiogenesis has not been distinctly clarified. The experimental rats were induced with middle cerebral artery occlusion (MCAO), and oxygen-glucose deprivation (OGD) model cells were constructed using human microvascular endothelial cell line (HMEC-1) cells. Cerebral infarction and pathological damage were first determined triphenyl tetrazolium chloride (TTC) and hematoxylin and eosin (H&E) staining. Then, cell viability, apoptosis, and angiogenesis were assessed by utilizing cell counting kit-8 (CCK-8), flow cytometry, spheroid-based angiogenesis, and tube formation assays in OGD HMEC-1 cells. Besides, angiogenesis and other related proteins were identified with western blot. The study confirms that β-asarone, like nimodipine, can ameliorate cerebral infarction and pathological damage. β-asarone can also upregulate vascular endothelial growth factor A (VEGFA) and endothelial nitric oxide synthase (eNOS) and induce phosphorylation of p38. Besides, the study proves that β-asarone can protect against IS injury by increasing the expression of VEGFA. experiments affirmed that β-asarone can induce viability and suppress apoptosis in OGD-mediated HMEC-1 cells and promote angiogenesis of OGD HMEC-1 cells by upregulating VEGFA. This establishes the potential for β-asarone to be a latent drug for IS therapy.
PubMed: 38948219
DOI: 10.7717/peerj.17534 -
Britannin suppresses MCF-7 breast cancer cell growth by inducing apoptosis and inhibiting autophagy.Avicenna Journal of Phytomedicine 2024Breast cancer is the main reason for cancer-related death in women. Britannin is a sesquiterpene lactone compound derived from with anti-tumor properties. We aimed to...
OBJECTIVE
Breast cancer is the main reason for cancer-related death in women. Britannin is a sesquiterpene lactone compound derived from with anti-tumor properties. We aimed to explore the impacts of britannin on apoptosis and autophagy in MCF-7 breast cancer cell line.
MATERIALS AND METHODS
The cytotoxic influences of britannin on MCF-7 cells were estimated by the MTT method. The expression levels of apoptosis-associated genes such as , , , , and and transcripts of autophagy markers including , , , , , , and were quantified using quantitative real time-PCR (qRT-PCR). Western blotting method was used to evaluate the amount of caspase 3, phosphorylated JAK2, phosphorylated STAT3, ATG1, ATG4, ATG5, Beclin1, and LC-III.
RESULTS
Treatment of MCF-7 cells with various concentrations of britannin remarkably hindered the viability of these cells compared to the controls. This compound significantly elevated the expression of pro-apoptotic caspase-3 but did not influence the levels of anti-apoptotic and . Britannin decreased the levels of phosphorylated forms of JAK2 and STAT3 proteins causing the blockage of the JAK/STAT pathway. Four autophagy factors expressions, including ATG4, ATG5, Beclin1, and LCIII, were reduced due to the effect of britannin on MCF-7 cells.
CONCLUSION
Britannin triggered apoptosis in MCF-7 cells by a mechanism that led to the blockade of the JAK/STAT pathway. Moreover, britannin prohibited autophagy in these cancer cells. This may suggest britannin as an agent for the suppression of breast tumors or as an adjutant for the enhancement of anti-breast cancer drugs effect.
PubMed: 38948174
DOI: 10.22038/AJP.2023.22995 -
MLife Jun 2024Methicillin-resistant (MRSA) is a current global public health problem due to its increasing resistance to the most recent antibiotic therapies. One critical approach...
Methicillin-resistant (MRSA) is a current global public health problem due to its increasing resistance to the most recent antibiotic therapies. One critical approach is to develop ways to revitalize existing antibiotics. Here, we show that the phytogenic compound cinnamaldehyde (CIN) and β-lactam antibiotic combinations can functionally synergize and resensitize clinical MRSA isolates to β-lactam therapy and inhibit MRSA biofilm formation. Mechanistic studies indicated that the CIN potentiation effect on β-lactams was primarily the result of inhibition of the expression by targeting the staphylococcal accessory regulator . CIN alone or in combination with β-lactams decreased gene expression and increased SarA protein phosphorylation that impaired SarA binding to the promoter element and downregulated virulence genes such as those encoding biofilm, α-hemolysin, and adhesin. Perturbation of SarA- binding thus interfered with PBP2a biosynthesis and this decreased MRSA resistance to β-lactams. Furthermore, CIN fully restored the anti-MRSA activities of β-lactam antibiotics in vivo in murine models of bacteremia and biofilm infections. Together, our results indicated that CIN acts as a β-lactam adjuvant and can be applied as an alternative therapy to combat multidrug-resistant MRSA infections.
PubMed: 38948140
DOI: 10.1002/mlf2.12121 -
Theranostics 2024: Recent evidence highlights the pivotal role of mitochondrial dysfunction in mood disorders, but the mechanism involved remains unclear. We studied whether the...
: Recent evidence highlights the pivotal role of mitochondrial dysfunction in mood disorders, but the mechanism involved remains unclear. We studied whether the Hippo/YAP/14-3-3η signaling pathway mediates mitochondrial abnormalities that result in the onset of major depressive disorder (MDD) in a mouse model. : The ROC algorithm was used to identify a subpopulation of mice that were exposed to chronic unpredictable mild stress (CUMS) and exhibited the most prominent depressive phenotype (Dep). Electron microscopy, biochemical assays, quantitative PCR, and immunoblotting were used to evaluate synaptic and mitochondrial changes in the basolateral amygdala (BLA). RNA sequencing was used to explore changes in the Hippo pathway and downstream target genes. pharmacological inhibition and immunoprecipitation was used to confirm YAP/14-3-3η interaction and its role in neuronal mitochondrial dysfunction. We used virus-mediated gene overexpression and knockout in YAP transgenic mice to verify the regulatory effect of the Hippo/YAP/14-3-3η pathway on depressive-like behavior. : Transcriptomic data identified a large number of genes and signaling pathways that were specifically altered from the BLA of Dep mice. Dep mice showed notable synaptic impairment in BLA neurons, as well as mitochondrial damage characterized by abnormal mitochondrial morphology, compromised function, impaired biogenesis, and alterations in mitochondrial marker proteins. The Hippo signaling pathway was activated in Dep mice during CUMS, and the transcriptional regulatory activity of YAP was suppressed by phosphorylation of its Ser127 site. 14-3-3η was identified as an important co-regulatory factor of the Hippo/YAP pathway, as it can respond to chronic stress and regulate cytoplasmic retention of YAP. Importantly, the integrated Hippo/YAP/14-3-3η pathway mediated neuronal mitochondrial dysfunction and depressive behavior in Dep mice. : The integrated Hippo/YAP/14-3-3η pathway in the BLA neuron is critical in mediating depressive-like behaviors in mice, suggesting a causal role for this pathway in susceptibility to chronic stress-induced depression. This pathway therefore may present a therapeutic target against mitochondrial dysfunction and synaptic impairment in MDD.
PubMed: 38948066
DOI: 10.7150/thno.92676 -
Frontiers in Oncology 2024Hepatoblastoma (HB) is the most common pediatric hepatic malignancy. Despite the progress in HB treatment, investigating HB pathomechanisms to optimize stratification...
BACKGROUND
Hepatoblastoma (HB) is the most common pediatric hepatic malignancy. Despite the progress in HB treatment, investigating HB pathomechanisms to optimize stratification and therapies remains a focal point to improve the outcome for high-risk patients.
METHODS
Here, we pointed to explore the impact of these mechanisms in HB. An observational study was performed on liver samples from a cohort of 17 patients with a diagnosis of HB and two normal liver samples. The experiments were executed on the Huh6 human HB cell line treated with the FAK inhibitor TAE226.
RESULTS
Our results highlight a significant up-regulation of mRNA and protein expression of FAK in livers from HB with respect to normal livers. The increased protein expression of total and Tyr397 phosphorylated FAK (pTyr397FAK) was significantly correlated with the expression of some epigenetic regulators of histone H3 methylation and acetylation. Of note, the expression of pTyr397FAK, N-methyltransferase enzyme (EZH2) and tri-methylation of the H3K27 residue correlated with tumor size and alpha-fetoprotein (AFP) levels. Finally, TAE226 caused a significant reduction of pTyr397FAK, epigenetic regulators, , , , and , in association with anti-proliferative and pro-apoptotic effects on HB cells.
CONCLUSION
Our results suggest a role of FAK in HB that requires further investigations mainly focused on the exploration of its effective diagnostic and therapeutic translatability.
PubMed: 38947885
DOI: 10.3389/fonc.2024.1397647 -
Cureus May 2024Advanced glycation end products (AGEs) accumulate in the brain, leading to neurodegenerative conditions such as Alzheimer's disease (AD). The pathophysiology of AD is... (Review)
Review
Advanced glycation end products (AGEs) accumulate in the brain, leading to neurodegenerative conditions such as Alzheimer's disease (AD). The pathophysiology of AD is influenced by receptors for AGEs and toll-like receptor 4 (TLR4). Protein glycation results in irreversible AGEs through a complicated series of reactions involving the formation of Schiff's base, the Amadori reaction, followed by the Maillard reaction, which causes abnormal brain glucose metabolism, oxidative stress, malfunctioning mitochondria, plaque deposition, and neuronal death. Amyloid plaque and other stimuli activate macrophages, which are crucial immune cells in AD development, triggering the production of inflammatory molecules and contributing to the disease's pathogenesis. The risk of AD is doubled by risk factors for atherosclerosis, dementia, advanced age, and type 2 diabetic mellitus (DM). As individuals age, the prevalence of neurological illnesses such as AD increases due to a decrease in glyoxalase levels and an increase in AGE accumulation. Insulin's role in proteostasis influences hallmarks of AD-like tau phosphorylation and amyloid β peptide clearance, affecting lipid metabolism, inflammation, vasoreactivity, and vascular function. The high-mobility group box 1 (HMGB1) protein, a key initiator and activator of a neuroinflammatory response, has been linked to the development of neurodegenerative diseases such as AD. The TLR4 inhibitor was found to improve memory and learning impairment and decrease Aβ build-up. Therapeutic research into anti-glycation agents, receptor for advanced glycation end products (RAGE) inhibitors, and AGE breakers offers hope for intervention strategies. Dietary and lifestyle modifications can also slow AD progression. Newer therapeutic approaches targeting AGE-related pathways are needed.
PubMed: 38947632
DOI: 10.7759/cureus.61373 -
IScience Jun 2024Glioblastoma multiforme (GBM) is one of the most lethal brain tumors, characterized by profound heterogeneity. While single-cell transcriptomic studies have revealed...
Glioblastoma multiforme (GBM) is one of the most lethal brain tumors, characterized by profound heterogeneity. While single-cell transcriptomic studies have revealed extensive intra-tumor heterogeneity, shed light on intra-tumor diversity, spatial intricacies remain largely unexplored. Leveraging clinical GBM specimens, this study employs spatial transcriptomics technology to delve into gene expression heterogeneity. Our investigation unveils a significant enrichment of tissue stem cell signature in regions bordering necrosis and the peritumoral area, positively correlated with the mesenchymal subtype signature. Moreover, upregulated genes in these regions are linked with extracellular matrix (ECM)-receptor interaction, proteoglycans, as well as vascular endothelial growth factor (VEGF) and angiopoietin-Tie (ANGPT) signaling pathways. In contrast, signatures related to glycogen metabolism and oxidative phosphorylation show no relevance to pathological zoning, whereas creatine metabolism signature is notably exclusive to vascular-enriched areas. These spatial profiles not only offer valuable references but also pave the way for future in-depth functional and mechanistic investigations into GBM progression.
PubMed: 38947514
DOI: 10.1016/j.isci.2024.110064 -
IScience Jun 2024High salt (HS) consumption is a risk factor for multiple autoimmune disorders via disturbing immune homeostasis. Nevertheless, the exact mechanisms by which HS...
High salt (HS) consumption is a risk factor for multiple autoimmune disorders via disturbing immune homeostasis. Nevertheless, the exact mechanisms by which HS exacerbates rheumatoid arthritis (RA) pathogenesis remain poorly defined. Herein, we found that heightened phosphorylation of PDPK1 and SGK1 upon HS exposure attenuated FoxO1 expression to enhance the glycolytic capacity of CD4 T cells, resulting in strengthened Th17 but compromised Treg program. GSK2334470 (GSK), a dual PDPK1/SGK1 inhibitor, effectively mitigated the HS-induced enhancement in glycolytic capacity and the overproduction of IL-17A. Therefore, administration of GSK markedly alleviated HS-exacerbated RA progression in collagen-induced arthritis (CIA) model. Collectively, our data indicate that HS consumption subverts Th17/Treg homeostasis through the PDPK1-SGK1-FoxO1 signaling, while GSK could be a viable drug against RA progression in clinical settings.
PubMed: 38947509
DOI: 10.1016/j.isci.2024.109798 -
Journal of Cancer 2024Head and neck squamous cell carcinoma (HNSC) is a dangerous cancer that represents an important threat to human health. Niclosamide is an anti-helminthic drug that has...
Head and neck squamous cell carcinoma (HNSC) is a dangerous cancer that represents an important threat to human health. Niclosamide is an anti-helminthic drug that has received FDA approval. In drug repurposing screens, niclosamide was found to inhibit proliferative activity for a range of tumor types. Its functional effects in HNSC, however, have yet to be established. MTT and colony formation assays were used to explore the impact of niclosamide on the proliferation of HNSC cells, while wound healing and Transwell assays were employed to assess migration and invasivity. Flow cytometry and Western immunoblotting were respectively used to assess cellular apoptosis and protein expression patterns. An HNSC xenograft tumor model system was used to evaluate the antitumor activity of niclosamide, and immunofluorescent staining was employed to assess cleaved Caspase3 and Ki67 expression. The ability of niclosamide to prevent metastatic progression was assessed with a model of pulmonary metastasis. These analyses revealed the ability of niclosamide to suppress HNSC cell migration, proliferation, and invasivity while promoting apoptotic death. From a mechanistic perspective, this drug suppressed Stat3 phosphorylation and β-catenin expression, while increasing cleaved Caspase3 levels in HNSC cells and reducing Bcl-2 levels. Importantly, this drug was able to suppress tumor growth and pulmonary metastasis formation, with immunofluorescent staining confirming that it reduced Ki67 levels and increased cleaved Caspase3 content. In conclusion, these analyses highlight the ability of niclosamide to inhibit HNSC cell migration and proliferative activity while provoking apoptotic death mediated via p-Stat3 and β-catenin pathway inactivation. Niclosamide thus holds promise for repurposing as a candidate drug for the more effective clinical management of HNSC.
PubMed: 38947381
DOI: 10.7150/jca.95682 -
Journal of Cancer 2024Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has emerged as a significant obstacle in managing patients with EGFR-mutant...
Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has emerged as a significant obstacle in managing patients with EGFR-mutant non-small-cell lung cancer (NSCLC), necessitating the exploration of novel therapeutic approaches. Tanreqing injection (TRQ) is a kind of Chinese patent medicine known for its heat-clearing and detoxifying properties. Studies have shown a correlation between tumor drug resistance and enrichment of cancer stem cells (CSCs). We aim to investigate the feasibility of TRQ enhancing sensitivity to gefitinib by targeting CSCs and reactive oxygen species (ROS). In our study, TRQ significantly inhibited cell proliferation in gefitinib-resistant non-small-cell lung cancer (NSCLC) models including 2D cell lines, 3D cell spheres, tumor-bearing animal and organoids. Compared with the gefitinib group alone, addition of TRQ elevated ROS levels, attenuated upregulation of the protein levels of sex-determining region Y-box 2 (SOX2) and aldehyde dehydrogenase 1 family member A1 (ALDH1A1) induced by gefitinib treatment, and inhibited the phosphorylation of signal transducer and activator of transcription 3 (STAT3). Scavenging ROS could restore tumor stemness, attenuate the inhibitory effect on the phosphorylation of STAT3, and promote cell proliferation. These results suggested that TRQ could enhance sensitivity of NSCLC models to gefitinib, providing a new combined treatment strategy.
PubMed: 38947380
DOI: 10.7150/jca.94438