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Potential Protective Role of GNAS in White Matter Lesions in a Chronic Cerebral Hypoperfusion Rat Model
No full textBackground: Chronic cerebral hypoperfusion (CCH) is recognized as a significant contributor to dementia disease due to the pathological development of white matter lesions (WMLs). This study aimed to investigate cerebral perfusion changes and identify significant differentially expressed genes in the white matter (WM) of a CCH rat model. Methods: CCH was induced in rats through bilateral common carotid artery occlusion (BCCAO) in the BCCAO group while the Sham group underwent blood vessel isolation without ligation. The study involved three cohorts. Cohort 1 (6 rats per group) was longitudinally tracked to assess cerebral perfusion using magnetic resonance imaging arterial spin labeling sequence. Cohort 2 (10 rats per group) underwent cognition assessment via the Morris water maze test and evaluation of myelin damage using Luxol Fast Blue. Cohort 3 rats (6 per group) underwent high-throughput sequencing to identify differentially expressed genes, with expression verified at the gene and protein levels. Furthermore, WM apoptosis was determined via Caspase-3 (CASP3) expression using western blot and double-label immunofluorescence. Results: The CCH group exhibited significantly decreased WM perfusion, cognitive impairment, and myelin disorganization and loss (p < 0.05). High-throughput sequencing identified decreased expression of guanine nucleotide-binding protein, alpha-stimulating activity polypeptide (GNAS) gene which was subsequently validated by real-time polymerase chain reaction (qRT-PCR) and western blot (p < 0.01). Double-label immunofluorescence further corroborated decreased GNAS and increased CASP3 expression in the WM of the BCCAO group compared to the Sham group (p < 0.01). Conclusion: These findings suggest that GNAS may be a protective factor in the WM during CCH. By targeting the GNAS pathway, researchers may be able to develop more effective treatments to delay or inhibit disease progression
Identification of m7G-related Subtypes, Validation of Prognostic Models, and Tumor Immune Microenvironment in Gastric Cancer
Full text linkBackground: Gastric cancer (GC) ranks as the fourth most prevalent cancer globally, with heterogeneous prognosis and high mortality rates. Numerous studies have highlighted the close association between the occurrence and progression of gastric cancer and the N7-methylguanosine (m7G) mechanism. This study aims to determine the clinical significance of m7G-related genes (m7Gs) in gastric cancer prognosis and investigate their potential connection with the tumor immune microenvironment (TIME). Methods: Gastric cancer data was obtained from the Cancer Genome Atlas (TCGA) library to generate the m7G pattern prognosis-related genes (m7G-PRGs) matrix. Two distinct m7G typings were initially identified, followed by unsupervised clustering based on m7G-related cluster C1 and C2 (m7G-C1/2) integrated differentially expressed genes (DEGs) to acquire a scoring system. The m7G-related prognostic model (m7G-RPM) was then constructed, with key prognostic genes experimentally validated through Western blot analysis. Subsequently, gastric cancer patients were stratified into high/low-scoring subgroups using the calculated median m7G_score, facilitating the investigation of prognosis-related mechanisms. Furthermore, biological signaling pathways were systematically enriched, a nomogram was developed, and TIME in gastric cancer was assessed. Results: Alterations in m7Gs are associated with a poor prognosis, with the primary outcome being hypermethylation in cancer, which regulates immune signaling and promotes cellular infiltration. Two distinct m7G clusters were identified, revealing m7Gs bidirectional regulatory role in clinicopathological features and the TIME. A nomogram containing seven variable genes improved the clinical applicability of m7G-RPM, with increased solute carrier family 39 member 4 (SLC39A4) and matrix metallopeptidase 7 (MMP7) expression observed in gastric cancer cells. The m7G_score was significantly associated with microsatellite instability (MSI), tumor mutation burden (TMB), chemotherapeutic drug sensitivity, and cancer stem cell (CSC) index. Conclusion: A comprehensive analysis of m7G s in gastric cancer confirmed their potential role in genetic alterations, TIME, clinical traits, and prognosis, especially in tumor-infiltrating immune cells (TIICs). We constructed a novel prognostic model based on m7Gs and performed preliminary validation of the screened genes. These findings present innovative perspectives for assessing the prognosis of gastric cancer and guiding individualized immunotherapy strategies for patients
Mechanism of PK/PD-based Combination of Biapenem and Other Antibiotics on Antibacterial Activity of Pseudomonas aeruginosa in Vitro
No full textBackground: The aim of this study was to utilize a pharmacokinetic/pharmacodynamic (PK/PD) model for evaluating the in vitro antibacterial effectiveness of biapenem when used in combination with amikacin, fosfomycin, and sulbactam against Pseudomonas aeruginosa (PAE). The single drug (combined) inhibitory concentrations of these four antibiotics against eight common bacteria were detected, and PK/PD model was established for evaluation. Methods: Twenty-one strains of PAE were isolated from sputum samples of the patients and the cultures were maintained on Mueller-Hinton (M-H) agar and M-H broth media. The sensitivity of bacteria to these antibacterial drugs was tested using K-B susceptibility disk method both as a single drug sensitivity test or combination therapy sensitivity test. Furthermore, minimum inhibitory concentration (MIC) was determined for each drug as well in combination. Moreover, the PK/PD model was developed by using probability of target attainment (PTA) and cumulative fraction of response (CFR) values. Results: Single drug sensitivity test showed that, out of the total PAE strains, 7 strains (33.33%) were resistant to biapenem, 5 strains (23.81%) were resistant to amikacin, 3 strains (14.29%) were resistant to fosfomycin, and 9 strains (42.86%) were resistant to sulbactam. Furthermore, the combined drug sensitivity test revealed that 3 PAE strains exhibited synergistic effect when biapenem was combined with amikacin, with a synergistic rate of 19.04%, 12 strains showed synergistic effect when biapenem was combined with fosfomycin, with a synergistic rate of 57.14%, and 11 strains showed synergistic effect when biapenem was combined with sulbactam, with a synergistic rate of 52.38%. Moreover, it was found that, except Acinetobacter baumannii, the MIC50, t > MIC50 of all strains exceeded 50%, However, the MIC90, t > MIC90 for PAE, Acinetobacter baumannii, and Serratia was equal to 0%. Conclusions: In summary, the combination of biapenem and sulbactam was recommended for the treatment of multidrug-resistant-induced infections to effectively control infections and improve therapeutic outcomes
Pharmacogenomics: The Promising Future of Clinical Therapeutics
No full textPharmacogenomics (PGx), a rapidly evolving field at the intersection of pharmacology and genomics, has the potential to revolutionize medical practice by investigating how an individuals genetic makeup influences their response to drugs. By optimizing drug selection, dosage, and treatment strategies based on an individuals genetic profile, pharmacogenomics aims to improve therapeutic outcomes, minimize adverse reactions, and enhance healthcare efficiency. Recent advancements in high-throughput genotyping technologies and the availability of genomic data have paved the way for personalized and targeted therapies. This review highlights pharmacogenomicss fundamental principles, applications, and challenges, emphasizing its potential to transform clinical practice and patient care. The field has made significant progress in understanding the impact of genetic variants on drug response, ranging from monogenic to complex polygenic variants. However, the implementation of pharmacogenomics in public health institutions remains limited. With continuous advancements and increasing integration of genomics into medicine, pharmacogenomics is poised to play a crucial role in precision medicine, improving drug efficacy, minimizing toxicity, and driving advancements in drug discovery and development
DPP-4 Inhibitor Improved Social Behavior in Acute Kidney Injury in a Murine Model: Possible Role in Mitochondrial Functions
Full text linkBackground: Kidney disease is usually complicated by multiple organ dysfunctions, such as cognitive impairment and neuropathy. Dipeptidyl peptidase-4 (DPP-4) inhibitors decrease the degradation of glucagon-like peptide-1 (GLP-1), improving glycemic control. This study investigated the effect of acute kidney injury (AKI) on social interaction and investigated the underlying role of inflammation, altered energetics, and the possible mode of action of a DPP-4 inhibitor on the brain in AKI. Methods: Forty rats constituted the animal model and were distributed into four groups (control, untreated, and treated AKI groups). We evaluated sociability; social novelty preferences in a three-chamber social apparatus; platelet counts; hippocampal mitochondrial enzyme complex (I–V) content by calorimetric methods; serum urea, blood urea nitrogen (BUN), and creatine phosphokinase levels by enzyme-linked immunoassay (ELISA); hippocampal adenosine triphosphate (ATP) content measured by ELISA; hippocampal glial fibrillary acidic protein (GFAP) expression; activity-regulated cytoskeleton-associated protein (Arc); Toll-like receptor 4 (TLR4) expression; and nuclear factor kappa B (NF-κB) expression by real-time polymerase chain reaction (RT‒PCR). Results: The sociability and social novelty indices, all hippocampal mitochondrial complexes (I to V), and platelet, ATP content, were significantly (p value ≤ 0.05) lower in the AKI group than in the control group. Serum creatinine, BUN, and creatine phosphokinase (CPK) levels, the relative expression of hippocampal GFAP, Arc, TLR4, and NF-κB were significantly (p value ≤ 0.05) increased in the AKI control group compared to those in the control group. Sections from the hippocampal cornu ammonis (CA) 1 (CA1) and 3 (CA3) regions and CA3 regions showed degeneration of pyramidal cells with microglial cell in filtration and the appearance of congested blood capillaries. Vildagliptin exerted a protective effect on uremic encephalopathy induced by AKI, as revealed by social behavior and biochemical measurements in the serum and hippocampus and confirmed by histological examination of the CA1 and CA3 hippocampal areas. The statistical significance was stated in parallel with intergroup variability. Conclusions: The present study showed the protective effect of vildagliptin on uremic encephalopathy induced by AKI, as revealed by social behavior and biochemical measurements in the serum and hippocampus and confirmed by histological examination of the CA1 and CA3 hippocampal areas. This improvement was attributed to improved mitochondrial function, which positively affects the energetics of the brain, attenuates the inflammatory response and alters the expression of synaptic proteins
The PTTG1-TRIM59 Protein Complex Promotes Proliferation and Metastasis of Pediatric Neuroblastoma by Stabilizing STAT3 Phosphorylation Status
No full textBackground: Neuroblastoma, originating from neural crest, presents a challenging pediatric malignancy. The pituitary tumor-transforming gene 1 (PTTG1) is a recently discovered oncogene implicated in various cancers. This study aimed to elucidate the impact of the PTTG1-tripartite motif 59 (TRIM59) protein complex on the proliferation and metastasis of pediatric neuroblastoma by modulating the phosphorylation status of signal transducer and activator of transcription 3 (STAT3). Methods: Utilizing SK-N-AS and SK-N-BE cell lines, we conducted in vitro experiments with gene expression regulation via cell transfection. Migration and invasion capabilities were assessed through matrix gel invasion, wound healing assays, cell activity detection via Cell Counting Kit-8 (CCK-8), and Kaplan-Meier survival analysis. PTTG1 expression in cancer tissue was determined via immunohistochemical techniques. Western blot and co-immunoprecipitation (co-IP) assays were employed to identify PTTG1/STAT3/phosphorylated (p)-STAT3/Bcl-2-associated X (Bax)/B-cell lymphoma-2 (Bcl-2)/TRIM59 expression and interaction. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was used to detect the expression levels of PTTG1/Bax/Bcl-2/E-Cadherin/Vimentin/Twist1/Twist2/Snai1/Slug/Zinc finger E-box binding homeobox 1 (ZEB1)/ZEB2. Results: PTTG1 knockdown inhibited neuroblastoma cell proliferation, migration, and invasion while promoting apoptosis. It also suppressed STAT3 phosphorylation and epithelial-mesenchymal transition (EMT). Patients exhibiting low PTTG1 expression (p < 0.05) had a significantly better prognosis. qRT-PCR analysis revealed increased expression (p < 0.05) of proapoptotic factors (Bax/E-cadherin) and STAT3-related transcription factors (Bax/Bcl-2/E-cadherin/Vimentin) upon PPTG1 knockdown. Notably, our findings demonstrate the role of the PTTG1-TRIM59 complex in facilitating neuroblastoma progression through the STAT3 pathway. Conclusion: The PTTG1-TRIM59 complex and STAT3 represent potential therapeutic targets for pediatric neuroblastoma. Our findings underscore the pivotal role of the PTTG1-TRIM59 complex in stabilizing STAT3 phosphorylation and promoting neuroblastoma growth and metastasis
Prenatal Chromosomal Microarray Analysis and Whole-Exome Sequencing in Fetuses with Thickened Nuchal Translucency
Full text linkBackground: Fetal chromosomal abnormalities predispose the fetus to developmental malformations, which can reduce the quality of newborn births. This study aimed to investigate the clinical utility of chromosomal microarray analysis (CMA) and whole-exome sequencing (WES) in fetuses with thickened nuchal translucency (NT). Methods: A total of 62 singleton pregnant women were enrolled in this study. Ultrasonography showed increased fetal NT (≥3.0 mm) with or without structural malformations. The subjects were divided into four groups based on the NT value: 3.0–3.4 mm (33 cases), 3.5–4.4 mm (21 cases), 4.5–5.4 mm (3 cases), and 5.5 mm (5 cases). Chromosomal abnormalities were initially analyzed using CMA, followed by trio familial whole-exome sequencing (Trio-WES) in 15 subjects with CMA-negative results. All the subjects were monitored for pregnancy outcomes. Results: Out of 62 cases, CMA identified 12 cases of aneuploidy, 1 case of pathogenic copy number variation (CNV-P), and 5 cases of unknown copy number variation (CNV-VOUS). The detection rate of fetal chromosomal abnormality was 21.0% (13/62). Fifteen CMA-negative fetuses without structural deformities were analyzed by Trio-WES, which produced six VOUS results with two loci each in SOS Ras/Rac guanine nucleotide exchange factor 1 (SOS1) and collagen type II alpha 1 chain (COL2A1) and one locus each in leucine-zipper-like transcription regulator 1 (LZTR1) and B-Raf proto-oncogene, serine/threonine kinase (BRAF). Conclusions: This study supports the application of CMA in prenatal diagnosis. It suggests that the positive detection rate of WES may be low in CMA-negative cases with increased NT without structural malformation. Therefore, appropriate genetic counseling should be provided to optimize the use of CMA and WES in prenatal diagnosis
Increased Expression of TRAIL and Its Death Receptors TRAIL-R1/2 Correlates with Progression of Radioactive Skin Injury
No full textBackground: The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) serves as a key mediator of apoptosis and inflammation. However, the role of TRAIL and its receptors in ionizing radiation (IR)-induced skin injury remains unclear. Soluble death receptor 5-Fc (sDR5-Fc), a synthetic TRAIL blocking agent, is comprised of the small, unstable, and short half-life endogenous human soluble death receptor 5 (sDR5) molecule along with the Fc portion of human immunoglobulin 1 (IgG 1). This compound has demonstrated efficacy in treating various diseases induced by TRAIL. The primary objective of this study was to investigate whether the TRAIL signaling pathway is implicated in the development of radiation-induced skin injury and to assess whether sDR5-Fc could alleviate such damage. Methods: The expression of TRAIL and its receptors in IR-induced human cells and C57 mouse skin was investigated through the application of immunohistochemistry (IHC) and flow cytometry (FCM). FCM and the Cell Counting Kit-8 (CCK-8) assay were employed to assess the apoptotic and proliferative effects of TRAIL on human keratinocyte (HaCat) cells. The potential alleviation of IR-induced skin damage in HaCat and human foreskin fibroblast-1 (HFF-1) cells, as well as in C57 mice, by sDR5-Fc, was examined using Western Blot (WB), flow cytometry (FCM), terminal deoxynucleotidyl transferase-mediated dUTP Nick-End Labeling (TUNEL) assay, and hematoxylin-eosin (H&E) staining. Results: The expression of TRAIL and TRAIL-R2 in the skin tissues of mice was upregulated after exposure to 30 gamma rays (Gy). Following IR, the expression of secreted TRAIL (sTRAIL), as well as TRAIL-R1 and TRAIL-R2 on the surface of HaCat cells, significantly increased. The addition of TRAIL induced apoptosis and dose-dependently inhibited the proliferation of HaCat cells. IR induced apoptosis in HaCat cells in a manner dependent on both time and dose, directly and through the bypass effect. This inhibited cell proliferation and stimulated interleukin-6 (IL-6) secretion from HaCat cells, which could be partially prevented by sDR5-Fc treatment. Furthermore, sDR5-Fc alleviated radiation-induced skin injury in mice, resulting in a significantly lower skin injury score, a thinner epidermis, more hair follicles, and fewer collagen fibers. Conclusions: We have demonstrated that TRAIL signaling plays a role in the pathogenesis of radiation-induced skin injury. This injury is alleviated both in vivo and in vitro through the use of sDR5-Fc, a TRAIL blocker
The Influencing Factors of Type 2 Diabetes Mellitus (T2DM) Combined with Cardiac Autonomic Neuropathy and Their Predictive Value Based on Ewing Test
No full textBackground: Type 2 diabetes mellitus (T2DM) is a widespread metabolic disorder characterized with various multifaceted complications, among which cardiac autonomic neuropathy (CAN) stands out as a significant concern. The CAN affects the autonomic nerves that regulate heart function, thereby exposing individuals with T2DM to considerable risks. The study aims to investigate the influencing factors of T2DM combined with CAN and their predictive value based on Ewing test. Methods: This study was conducted between March and November 2021. The clinical data of 119 T2DM patients were analyzed retrospectively. These patients were categorized into the diabetes cardiac autonomic neuropathy positive (DCAN+) and negative (DCAN-) groups based on Ewing test results. The results from venous blood test of the two groups were compared respectively. Various biochemical parameters, including fasting plasma glucose, insulin levels, and lipid profiles were determined. Logistic regression was employed to identify factors influencing T2DM combined with CAN, and the predictive performance of the model was subsequently evaluated. Results: Patients in the DCAN+ group exhibited higher age, body mass index, diabetic duration, prevalence of coronary heart disease, and peripheral neuritis compared to the DCAN- group (p < 0.05). Additionally, DCAN+ individuals had elevated levels of serum uric acid (SUA), fasting insulin (FINS), and homeostasis model assessment-β (HOMA-β) (p < 0.05). Multivariate logistic regression highlighted age, diabetic duration, peripheral neuritis, SUA, FINS, and HOMA-β as significant risk factors for DCAN. The predictive model demonstrated good diagnostic accuracy, with HOMA-β exhibiting particularly high clinical value (p < 0.01). Conclusions: Age, diabetic duration, peripheral neuritis, SUA, FINS, and HOMA-β emerged as influential risk factors for DCAN and demonstrated high diagnostic value with particular emphasis on the contribution of the HOMA-β. Establishing a model based on risk factors effectively predicts the risk of DCAN. Targeted measures should be taken to reduce the incidence of DCAN and improve the prognosis and quality of life of T2DM patients
Evaluating the Underlying Mechanisms of Bmal1/AKT/P53 Signaling Pathway-mediated Cardiomyocyte Ferroptosis and Oxidative Stress in Acute Myocardial Infarction
No full textBackground: Acute myocardial infarction (AMI) is a cardiovascular disease induced by acute or persistent hypoxia in cardiomyocytes, resulting in irreversible damage to the heart. Therefore, we aimed to elucidate the role and mechanism of the Brain and muscle Arnt-like protein-1 (Bmal1)/AKT/P53 signaling pathway in mediating cardiomyocyte ferroptosis, oxidative stress, and inflammatory response in AMI. Methods: This study utilized H9C2 cardiomyocytes for hypoxia culture to establish an in vitro AMI model. Quantitative polymerase chain reaction (qPCR), Western blot analysis, and Enzyme-Linked Immunosorbent Assay (ELISA) assays were used to assess the expression levels of Bmal1/AKT/P53 signaling pathway-related molecules, Bmal1, p-AKT, and P53, along with other expression levels of associated factors within cardiomyocytes. Results: We observed that cardiomyocyte hypoxia promoted cardiomyocyte reactive oxygen species (ROS) production through the Bmal1/AKT/P53 signaling pathway. Furthermore, the expression levels of acyl-CoA synthetase long-chain family member 4 (ACSL4) were significantly increased (p < 0.01), whereas glutathione peroxidase 4 (GPX4) and solute carrier family 7a member 11 (SLC7A11) were significantly decreased. Additionally, the inflammatory response-related factors, including interleukin-1α (IL-1α), IL-1β, IL-2, IL-6, Transforming growth factor β (TGF-β), and TGF-α were significantly increased (p < 0.01). Conclusion: This study explored that overexpression of Bmal1 activates AKT phosphorylation and inhibits oxidative stress, ferroptosis, and inflammation caused by cardiomyocyte hypoxia, thereby alleviating acute myocardial infarction