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Neuropharmacological Insights into Type 3 Diabetes: Molecular Mechanisms, Therapeutic Advances, and Future Directions
No full textDiabetes mellitus is a multifaceted metabolic disease with consequences for global health. It is characterized by insulin resistance and irregularities in insulin secretion. The global prevalence of diabetes necessitates a nuanced understanding beyond traditional classifications, emphasizing the dynamic nature of this health threat. Recent strides in genetics have led to the development of personalized treatments, while the emergence of type 3 diabetes underscores the need for refined classifications, standardized definitions, and improved screening methods. The fusion of neuropharmacology with diabetes care signals a transformative shift, with a focus on cognitive function and neuronal survival alongside glycaemic control. Repurposing antidiabetic medications for neurodegenerative diseases introduces a promising frontier at the intersection of diabetes and neurological research. Investigating the molecular and metabolic pathways that underlie diabetic problems reveals complex processes, including the generation of diacylglycerol, modified redox states, the polyol pathway, and advanced glycation end-product synthesis. Strategies targeting these pathways unveil novel therapeutic strategies to mitigate vascular dysfunction and oxidative stress. Antidiabetic drugs, including metformin, thiazolidinediones, and glucagon-like peptide-1 receptor-targeting compounds, show promise for neuroprotection, extending beyond glycaemic control to enhance insulin signaling and protect against degeneration. Molecular targets such as peroxisome proliferator-activated receptors (PPARs), protein tyrosine phosphatase 1B (PTP-1B), and glycogen synthase kinase-3 (GSK-3) offer potential avenues for reshaping diabetes management, presenting both challenges and opportunities in the pursuit of precision medicine. In envisioning the future, the concept of type 3 diabetes will become a focal point, leading to dedicated exploration for accurate diagnostics and targeted treatments. This paper serves as a catalyst for sustained exploration, interdisciplinary collaboration, and an unwavering commitment to pioneering the future of diabetes care, aiming to illuminate the present while shaping a future met with precision, empathy, and innovative solutions
Identification of Molecular Subtypes and a Novel Prognostic Model of Thyroid Cancer Based on a Pyroptosis and Mitophagy Related Gene Signature
No full textBackground: The global incidence of thyroid carcinoma (THCA) is gradually increasing. Our investigation aims to establish a signature relevant to pyroptosis and mitophagy, which could provide new insights into prognostic biomarkers and therapeutic targets associated with THCA. Methods: Gene sequencing data and clinical information were obtained from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database. A six-gene prognosis signature of pyroptosis- and mitophagy-related differentially expressed genes (PMRDEGs) was constructed using least absolute shrinkage and selection operator (LASSO) regression analysis. The prognostic efficacy of the risk score model in the TCGA-THCA cohort was evaluated using Kaplan-Meier (KM) survival plots and receiver operating characteristic (ROC) curve analysis. Functional enrichment analysis identified the potential for differential expression of biological pathways across various subgroups of risk scores. The features of the tumor microenvironment associated with the risk score were investigated using the CIBERSORT algorithm for immune infiltration analysis. The pyroptosis and mitophagy score was calculated to predict the response to immune-checkpoint inhibitor (ICI) treatment in thyroid cancer. Additionally, real-time quantitative PCR (qPCR) and Western Blot (WB) were utilized to investigate the expression levels of hub genes. Results: A prognostic signature consisting of six pyroptosis- and mitophagy-related genes (Apolipoprotein E (APOE), Ephrin type-A receptor 2 (EPHA2), DEAD-box helicase 3 (DDX3X), Centrosome protein 55 (CEP55), Kinesin family member 23 (KIF23), H2B clustered histone 9 (H2BC9)) was established, and participants were stratified into high- and low-risk groups based on their risk levels. When comparing the progression-free interval (PFI) of the high-risk group with that of the low-risk group, Kaplan-Meier (KM) analysis revealed a statistically significant reduction in PFI for the high-risk group (p < 0.05). Gene Set Variation Analysis (GSVA) illustrated differential expression of 20 pathways between the high- and low-risk groups, including activation of Neurotrophic receptor tyrosine kinase 2 (NTRK2) signals through the Phosphoinositide 3-kinase (PI3K) pathway (p < 0.001). Immune infiltration analysis demonstrated significant variations in immune cell distribution between the two investigated groups (p < 0.05). According to quantitative real-time PCR (qRT-PCR) findings, mRNA expression levels of APOE, EPHA2, CEP55, and KIF23 were significantly higher in tumor cells (p < 0.01). Additionally, expression levels of the pyroptosis-associated proteins NOD-like receptor thermal protein domain associated protein 3 (NLRP3), Gasdermin-D, and Caspase-1 were significantly downregulated in the si-KIF23 group (p < 0.05). Conclusions: Our study developed a prognostic risk model for thyroid cancer, comprising six pyroptosis- and mitophagy-related genes. This model serves as a valuable marker for prognosis, diagnosis, and predicting the response to immunotherapy in individuals with THCA
Matrine Attenuates Mitochondrial Fragmentation in Ovalbumin-Induced Asthmatic Mice by Activating the AMPK/Nrf2 Pathway
No full textBackground: Asthma, a prevalent respiratory condition, is characterized by hyperresponsiveness and airway inflammation, and mitochondrial dysfunction and inflammation can exacerbate these symptoms. Therefore, this study aims to investigate whether matrine, known for its anti-inflammatory properties, attenuates mitochondrial fragmentation in asthmatic mice by activating the adenosine 5′-monophosphate-activated protein kinase (AMPK)/Nuclear Factor Erythroid 2-related Factor 2 (Nrf2) pathway. Methods: An asthma model was induced in BALB/c mice through sensitization with ovalbumin (OVA). The mice were given matrine (50 mg/kg, 100 mg/kg) and dexamethasone (2 mg/kg) through gavage feeding. Serum, lung tissue, and bronchoalveolar lavage fluid (BALF) were collected. Hematoxylin-eosin (H&E), Periodic Acid-Schiff (PAS) and immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), flow cytometry, and western blot analyses were used to assess changes in inflammation and oxidative stress levels in the airways and lung tissues. Furthermore, the expression levels of AMPK-dynamin-related protein 1 (DRP1)-NOD-like receptor family, pyrin-domain-containing-3 (NLRP3) pathway proteins were evaluated in the lung tissues. Results: Matrine treatment significantly reduced airway inflammation and mucus secretion in OVA-induced asthmatic mice (p < 0.05). Notably, inflammatory cell infiltration around the airway and mucus secretion in the airway, as evidenced by H&E and PAS staining, was substantially decreased in matrine-treated mice compared to the OVA group. Additionally, matrine significantly reduced T-helper cell type 2 (Th2) cytokine levels in mediastinal lymph nodes and BALF, as well as serum immunoglobulin (Ig)E levels (p < 0.05). Moreover, matrine exhibited antioxidant effects by enhancing superoxide dismutase (SOD) and catalase (CAT) activity while reducing malondialdehyde (MDA) expression and reactive oxygen species (ROS) accumulation in lung tissues (p < 0.05). Furthermore, the suppression of Caspase-1, NLRP3, and interleukin (IL)-1β by matrine indicated its anti-inflammatory properties (p < 0.05). Mechanistically, matrine increased AMPK phosphorylation, inhibited DRP1-mediated mitochondrial fission, and promoted mitochondrial fusion, suggesting its potential to alleviate airway inflammation (p < 0.05). Conclusions: Matrine alleviates allergic airway inflammation in OVA-induced asthmatic mice by regulating the AMPK-DRP1-NLRP3 pathway
UBE2H Inhibits Pyroptosis in Microglia Cells following Ischemic Stroke by Mediating the Ubiquitination of p53/CASP1
No full textBackground: Ischemic stroke is the leading cause of permanent disability, affecting approximately 14 million people annually. Therefore, this study aimed to elucidate the role and underlying mechanism of p53/cysteinyl aspartate specific proteinase 1 (CASP1) in ischemic stroke. Methods: The raw data regarding ischemic stroke were acquired from the GSE97537 data set of Gene Expression Omnibus (GEO). Moreover, a mouse model of cerebral ischemia was established. Neurons and microglia cells were used for in vitro experiments. Quantitative polymerase chain reaction (qPCR) and western blot analysis were used to assess the expression levels of target genes. Results: We observed that ubiquitinconjugating enzyme E2H (UBE2H) expression was downregulated following ischemic stroke. The expression of UBE2H was found to promote pyroptosis of microglia cells. Furthermore, a negative correlation was observed between CASP1 and UBE2H. The inhibition of CASP1 significantly reduced pyroptosis, while the inhibition of UBE2H increased CASP1 activity in microglia. Additionally, we observed a close association between elevated CASP1 expression and poorer survival in ischemic stroke. Conclusions: In summary, this study indicates that UBE2H inhibits microglial apoptosis following ischemic stroke by mediating the ubiquitination of p53/CASP1
ISYNA1 is a New Diagnostic and Prognostic Marker of Colorectal Cancer that Promotes Proliferation and Migration of Malignant Cells
No full textBackground: Colorectal cancer (CRC), a malignant tumor, shows the highest incidence and mortality rates in China and worldwide. Inositol-3-phosphate synthase 1 (ISYNA1) is the core enzyme involved in inositol biosynthesis. However, the effect of ISYNA1 on human cancer development, particularly CRC, has been poorly studied. Our study aimed to explore the precise molecular targets related to the diagnosis and treatment of CRC. Methods: We evaluated ISYNA1 expression and gene control networks in CRC applying sequencing data. We measured ISYNA1 mRNA and protein degrees in CRC cell lines applying quantitative real-time polymerase chain response and immunofluorescence imaging. While knocking down ISYNA1 expression in HCT116 and SW480 cell lines by small interfering RNA (siRNA) transfection, we verified this by cell viability, colony formation, and migration assays. Results: Evaluation on the cancer genome atlas (TCGA) database demonstrated the overexpression of ISYNA1 in CRC, and survival discussion demonstrated that patients with great ISYNA1 expression had a lower prognosis (p < 0.05). According to univariate and multivariate Cox regression models, ISYNA1 is an independent prognostic element for CRC. ISYNA1 affects tumor progression via multiple cancer-related signaling pathways. Real-time quantitative polymerase chain reaction (RT-qPCR) results demonstrated that HCT116 and SW480 cells displayed greatly higher ISYNA1 expression than DLD1 and HT29 cells (p < 0.05). ISYNA1 expression in HCT116 and SW480 cell lines was knocked down. Compared to the control group, ISYNA1-down-regulated CRC cell lines demonstrated significantly reduced proliferation, colony formation, and migration (p < 0.05). Conclusions: In conclusion, ISYNA1 may be a novel prognostic biomarker for CRC, laying the basis for further studies the effect of ISYNA1 on CRC occurrence and development
Synthesis and Characterization of Mesoporous SBA-15 as Carriers to Improve the Rutin Dissolution Rate
Full text linkBackground: Due to its low water solubility, Rutin, a crystalline medication used to treat a variety of conditions, has a limited rate of dissolution when given in gastrointestinal fluids. The present study planned to formulate and characterize Rutin using mesoporous silica material (SBA-15) as well as to determine the in-vitro dissolution properties. Methods: Rutin was formulated using mesoporous silica material such as SBA-15. Particle size distribution analysis, fourier transform-infrared (FT-IR) spectroscopy, scanning electron microscopy, and X-ray diffraction were used to characterize the compound in the complex. Rutins solubility and in-vitro release characteristics were assessed. Furthermore, the dissolution data (DD) Solver Excel add-in software was used to evaluate several mathematical models to interpret the Rutin dissolution kinetics from the mesoporous materials. Results: Differential scanning calorimetry was used to confirm Rutins amorphous state, which resulted in a significantly higher rate of dissolution than pure crystalline Rutin. The release of the drug from the Rutin/SBA-15 complex was well-simulated by the Weibull model. Notably, the SBA-15 carrier-mediated complex of Rutin exhibited the highest drug loading and dissolution rate, showing promising potential for enhancing Rutin bioavailability. Conclusion: The findings suggested that Rutin/SBA-15 could be easily incorporated into conventional oral pharmaceutical dosage forms such as capsules and therefore can be utilized for treating ailments such as allergies, inflammation, tumors, infections, protozoal diseases, and spasms. To assess the Rutin/SBA-15 complexs in-vivo pharmacokinetic performance and appropriateness for a range of pharmacological actions, more investigation is required
Mucin 3A Hypomethylation Facilitated Gastric Cancer Cell Growth and Progression via Regulating Programmed Cell Death-Ligand 1 and AKT Phosphorylation
No full textBackground: Methylation-induced alterations of mucin 3A (MUC3A) expression have been observed in various malignancies, yet few studies have investigated its role in gastric cancer (GC). Herein, we elucidate the role of MUC3A in GC progression and its associated mechanisms. Methods: GC cells were treated with 5-Aza-2′-Deoxycytidine (5-Aza) and the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway inhibitor LY294002, or transfected with short hairpin RNA targeting MUC3A (shRNA-MUC3A), MUC3A overexpression, and DNA methyltransferase 2 (DNMT2) overexpression constructs. Quantification of MUC3A was conducted using quantitative reverse transcription-PCR (qRT-PCR), while the methylation level of MUC3A was evaluated through methylation-specific PCR. Cell proliferation, migration, invasion, and apoptosis were assessed using 5-Ethynyl-2′-Deoxyuridine (EdU) incorporation assay, wound healing assay, Transwell assay, and flow cytometry, respectively. Additionally, protein expressions of programmed cell death-ligand 1 (PD-L1), phospho-AKT (p-AKT), and total AKT were determined through Western blot analysis. Results: Upregulation of MUC3A was observed in GC tissues (p < 0.001), while methylation of MUC3A was nearly absent in tumor tissues. Treatment with 5-Aza promoted proliferation, migration, invasion, and PD-L1 expression while inhibiting apoptosis in GC cells (p < 0.05). Conversely, shRNA-MUC3A demonstrated opposite effects (p < 0.05). Moreover, the effects induced by 5-Aza on GC cells could be reversed by MUC3A knockdown (p < 0.05). Additionally, overexpression of MUC3A enhanced the malignant behaviors of GC cells (p < 0.01), but this effect was reversed by pre-treatment with LY294002, a PI3K/AKT pathway inhibitor (p < 0.05). Furthermore, DNMT2 was found to bind to the MUC3A CpG island site, and overexpression of DNMT2 weakened the impact of MUC3A overexpression on accelerating the progression of GC (p < 0.05). Conclusion: Hypomethylation of MUC3A can promote the malignant behaviors of GC cells through the regulation of PD-L1 and the PI3K/AKT pathway, suggesting its potential as a biomarker in gastric carcinogenesis
The Influence of Thymic Stromal Lymphopoietin on Macrophage Polarization via the Nuclear Factor Kappa B Signaling Pathway in Fungal Keratitis
No full textBackground: Fungal keratitis (FK) is characterized by corneal inflammation induced by fungal infection. Thymic stromal lymphopoietin (TSLP) is crucial in FK pathogenesis. This study aimed to explore the impact of TSLP on FK and elucidate the mechanism of TSLP signaling on macrophage-mediated inflammation. Methods: Transformed human corneal epithelial cells (THCEs) were stimulated with heat-killed fragments of Aspergillus fumigatus hyphae. TSLP secretion was assessed using quantitative polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA), and western blotting (WB). THCEs stimulated with hyphae or recombinant thymic stromal lymphopoietin (rTSLP) were co-cultured with tohoku hospital pediatrics-1 (THP-1) cell-derived macrophages. The inflammatory activity of rTSLP was evaluated in THP-1 macrophages through real-time PCR, ELISA, WB, and flow cytometry. Additionally, high-throughput transcriptome sequencing was employed to elucidate the underlying mechanisms. Results: Secretion of TSLP by A. fumigatus-stimulated THCEs was correlated with increased inflammation in THP-1 macrophage. Treatment with rTSLP resulted in elevated expression of proinflammatory markers associated with macrophage type 1 (M1) phenotype, including tumor necrosis factor-alpha (TNF-α) (p < 0.01), interleukin-1 beta (IL-1β) (p < 0.01), inducible nitric oxide synthase (iNOS) (p < 0.001), and CD86 (p < 0.001) at 24 hours. Exposure of THP-1 macrophages to rTSLP induced activation of the nuclear factor kappa B (NF-κB) signaling pathway. The improved level of phosphorylated NF-κB and inflammatory factors (iNOS, IL-1β, TNF-α) were attenuated by a specific NF-κB inhibitor. Conclusions: In A. fumigatus keratitis, TSLP secreted by THCEs promoted TNF-α, IL-1β, and iNOS secretion in THP-1-derived macrophages by upregulating the NF-κB signaling pathway. This led to dysregulation of the pro-inflammatory (M1)/alternative (M2) macrophage ratio and polarization of THP-1 macrophages towards the pro-inflammatory phenotype
Ephedra Sinica Extract Ameliorates Cognitive Function in Rats with Alzheimer’s Disease by Modulating Neuroinflammation through NLRP3
No full textBackground: Ephedra sinica extract (ESE) exhibits anti-inflammatory, antioxidant, and neuroprotective effects. Previous studies have reported the efficacy of ESE against Alzheimers disease (AD). Nevertheless, its mechanism is still a mystery. This research aimed to explore the effect of ESE on AD from the perspective of neuroinflammation and oxidative damage. Methods: An AD rat model was built by injecting 10 μg of amyloid-β peptide (Aβ1-42) into the bilateral hippocampus CA1 region. Subsequently, the AD rats received intragastric administration of 100, 200, or 300 mg/kg of ESE for 4 weeks. The effects of ESE on the cognitive performance of AD rats were studied through passive avoidance and Morris water maze tests. The concentrations of inflammatory factors (Interleukin-1 β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α)) and oxidative factors [glutathione (GSH), malondialdehyde (MDA) and nitric oxide (NO)] in rat hippocampal tissue were measured with corresponding biochemical kits, and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-associated protein expression levels in rat hippocampal tissue were measured by Western blot. Results: The behavioral tests confirmed that ESE ameliorated the cognitive dysfunction of AD rats (p < 0.05 and p < 0.01). ESE treatment significantly lowered the concentration of all inflammatory factors (IL-1β, IL-6, and TNF-α) and oxidative factors (MDA and NO) (p < 0.05 and p < 0.01), whereas it increased the levels of GSH in the hippocampus of the AD rats (p < 0.05). Additionally, inhibition of NLRP3 inflammasome-associated protein expression was observed after ESE administration (p < 0.05 and p < 0.01). Conclusion: ESE ameliorates AD rats cognitive dysfunction by reducing neuroinflammation and oxidative stress
Overexpression of DNMT1 Accelerates Migration and Invasion of Lung Squamous Cell Carcinoma Cells by Decreasing TCF21 Expression via the Akt/p65 Signaling Pathway
No full textBackground: Hypermethylation and downregulation of transcription factor 21 (TCF21) are frequently observed in non-small cell lung cancer (NSCLC). DNA methyltransferase 1 (DNMT1) is highly expressed in lung squamous cell carcinoma (LUSC). Accordingly, this study examines the biological roles of TCF21 and DNMT1 in LUSC cells. Methods: Analyses concerning TCF21 expression in LUSC and the correlation between DNMT1 and TCF21 were performed using bioinformatics. After transfection of DNMT1/TCF21 overexpression plasmids, or small interfering RNAs targeting TCF21 and DNMT1 (siTCF21 and siDNMT1) into LUSC cells, the regulatory effects of TCF21 and DNMT1 on the malignant behavior of LUSC cells were verified by cell counting kit-8 assay, flow cytometry, and transwell assay. Quantitative real-time reverse transcription polymerase chain reaction or western blot was used for quantification. Results: TCF21 expression was downregulated in LUSC tissues and cells (p < 0.05), and expressions of DNMT1 and TCF21 were negatively correlated (r = –0.09, p = 0.047). TCF21 silencing enhanced viability, migration, and invasion, reduced apoptosis, upregulated expressions of paired box 8 (PAX8), baculoviral IAP repeat containing 3 (BIRC3), B-cell lymphoma-2 (Bcl-2), X-linked inhibitor of apoptosis (XIAP), matrix metallopeptidase 9 (MMP9), N-cadherin, Vimentin, phosphorylated-protein kinase B (p-Akt) and phosphorylated-p65 (p-p65), downregulated expressions of BCL2 associated X protein (Bax) and E-cadherin, and elevated p-Akt/Akt and p-p65/p65 ratios in LUSC cells (p < 0.05). DNMT1 overexpression exerted the same effects in LUSC cells as TCF21 silencing, while DNMT1 silencing did the opposite effect. DNMT1 overexpression decreased, while DNMT1 silencing increased TCF21 expression. Additionally, DNMT1 overexpression reversed the effects of TCF21 overexpression in LUSC cells (p < 0.05). Conclusion: DNMT1 overexpression promotes LUSC cell migration and invasion by downregulating TCF21 through activation of the Akt/p65 pathway