Gene Expression In Tissues Research Articles

Microarray analysis of gene expression in lung tissues of indium-exposed rats: possible roles of S100 proteins in lung diseases

Microarray analysis of gene expression in lung tissues of indium-exposed rats: possible roles of S100 proteins in lung diseases

Identification of immune-associated genes for the diagnosis of ulcerative colitis-associated carcinogenesis via integrated bioinformatics analysis

BackgroundUC patients suffer more from colorectal cancer (CRC) than the general population, which increases with disease duration. Early colonoscopy is difficult because ulcerative colitis-associated colorectal cancer (UCAC) lesions are flat and multifocal. Our study aimed to identify promising UCAC biomarkers that are complementary endoscopy strategies in the early stages.MethodsThe datasets may be accessed from the Gene Expression Omnibus and The Cancer Genome Atlas databases. The co-expressed modules of UC and CRC were determined via weighted co-expression network analysis (WGCNA). The biological mechanisms of the shared genes were exported for analysis using the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. To identify protein interactions and hub genes, a protein-protein interaction network and CytoHubba analysis were conducted. To evaluate gene expression, external datasets and experimental validation of human colon tissues were utilized. The diagnostic value of core genes was examined through receiver operating characteristic (ROC) curves. Immune infiltration analysis was employed to investigate the associations between immune cell populations and hub genes.ResultsThree crucial modules were identified from the WGCNA of UC and CRC tissues, and 33 coexpressed genes that were predominantly enriched in the NF-κB pathway were identified. Two biomarkers (CXCL1 and BCL6) were identified via Cytoscape and validated in external datasets and human colon tissues. CRC patients expressed CXCL1 at the highest level, whereas UC and CRC patients showed higher levels than the controls. The UC cohort expressed BCL6 at the highest level, whereas the UC and CRC cohorts expressed it more highly than the controls. The hub genes exhibited significant diagnostic potential (ROC curve > 0.7). The immune infiltration results revealed a correlation among the hub genes and macrophages, neutrophils and B cells.ConclusionsThe findings of our research suggest that BCL6 and CXCL1 could serve as effective biomarkers for UCAC surveillance. Additionally, they demonstrated a robust correlation with immune cell populations within the CRC tumour microenvironment (TME). Our findings provide a valuable insight about diagnosis and therapy of UCAC.

Variability in non-tumor areas of colorectal cancer patients as revealed by endoscopic intestinal step biopsies

A comprehensive endoscopic small and large intestinal untargeted step biopsy procedure was conducted to compare gene expression between the normal intestinal mucosa of healthy individuals and that of patients with colorectal tumors. From 78 participants (healthy individuals [n = 17], patients with colorectal conventional adenomas [n = 6], patients with Tis–T1 colorectal cancer [n = 41], patients with T2–4 colorectal cancer [n = 14]), biopsies of normal mucosa of the terminal ileum, right-sided colon (cecum and ascending colon), and left-sided colorectum (descending colon, sigmoid colon, and rectum) were obtained using a lower gastrointestinal endoscope. RNA was extracted from all samples, and total transcriptome sequencing was performed. Transcriptome data from 388 samples was analyzed. DNA was also extracted from tumor biopsy tissues and analyzed for whole-exome sequencing. In healthy individuals, gene expression differed significantly among the terminal ileum, right-sided colon, and left-sided colorectum, presumably linked to embryological factors. There were differences in gene expression in the normal mucosa in colorectal cancer patients, compared to healthy controls. Patients with tumors, especially T2–4 colorectal cancer, showed considerable variation in gene expression in non-tumor tissues, even in the terminal ileum distant from the tumor site. Based on endoscopic biopsies, the results imply cancer-predisposing conditions in seemingly normal tissues. The present study points to the importance of small intestine and cancer-predisposing conditions in the colon of colorectal cancer patients, with possible implications for developing novel immunotherapy and other therapeutic modalities.

The effect of diet-induced weight-loss on subcutaneous adipose tissue expression of genes associated with thyroid hormone action

Background & AimsWe have recently demonstrated that subcutaneous adipose tissue (SAT) expression of genes associated with thyroid hormone (TH) action is altered in obesity and insulin resistance. The aim of the present study was to examine the effect of diet-induced weight-loss on SAT expression of genes associated with TH action. MethodsThe study group comprised 38 individuals with overweight/obesity, which completed 12-week dietary intervention program. Hyperinsulinemic-euglycemic clamp and SAT biopsy were performed before and after the program. Fifteen normal-weight individuals were examined at baseline only. ResultsOverweight/obese individuals had lower free thyroxine (fT4) and higher free triiodothyronine (fT3)/fT4 ratio, lower SAT TH receptor isoforms (TRα and TRβ, encoded by THRA and THRB, respectively) and peroxisome proliferator-activated receptor γ coactivator 1α (PPARGC1A) mRNA expression and higher SAT type II and type III iodothyronine deiodinase (encoded by DIO2 and DIO3, respectively) and nuclear receptor corepressor (NCOR1) mRNA expression in comparison with normal-weight individuals. Diet-induced weight loss resulted in a decrease in fT3 and fT3/fT4 ratio and an increase in SAT THRA, THRB and PPARGC1A. SAT NCOR1 and forkhead box protein O1 (FOXO1) decreased only in individuals, who lost at least 10 kg (n=20). Higher increase in insulin sensitivity after weight loss was associated with a lower decrease in fT3/fT4 ratio. ConclusionsDiet-induced weight loss partly reverses alterations in SAT expression of genes associated with TH action. Responses of circulating TH and SAT expression of genes associated with TH action to diet-induced weight loss are related to body weight and insulin sensitivity.

Evaluation of Fluctuations of BRAF Gene Expression and its Polymorphism at rs1267623 in Colorectal Cancer.

Molecular markers in Colorectal Cancer (CRC) are needed for more ac-curate classification and personalized treatment. In this way, we investigated the effects of the BRAF gene on clinical outcomes of its expression fluctuations and its polymorphism at rs1267623 in CRC. In this study, 36.36 percent of patients with CRC were women, and 63.63 percent were men. After the pathology department confirmed the tumor of the samples, the stage and grade of the tumor were determined according to the TNM system. Real-time PCR was used to check the expression of the BRAF gene in tumor and non-tumor tissues, and its polymorphism in rs1267623 was also checked using the Tetra-ARMs PCR technique. The expression of BRAF in tumor tissues was significantly higher than in non-tumoral tissues (P = 0.001), indicating an upregulation of BRAF gene expression in tumoral tissues. The user's text is empty. Furthermore, there was a significant correlation between BRAF expression and tumor stage (P = 0.001), as well as tumor grade (P = 0.003). However, no significant link was found between lymph node metastasis and distant metastasis of BRAF gene expression (P = 0.3). Additionally, no mutation was detected in the investigation of rs1267623 polymorphism. The BRAF gene was upregulated in tumoral tissues. Remarkably, no mutation was found in the rs1267623 polymorphism. As a result, this gene can be used as a biomarker in the diagnosis and treatment of CRC.

Investigation of CST7 and hsa-miR-4793-5p gene expression in breast cancer

Breast cancer (BC) presents as a worldwide challenge, known as the most frequently diagnosed cancer in women. In 2022, BC was diagnosed in 2.3 million women with 670,000 deaths globally. In this research, our objective was to examine the CST7 and has-miR-4793-5p gene expression in BC tumor tissues and adjacent normal tissues.Using GSE57897 gene expression data from 422 BC samples and 31 breast samples from healthy controls which was based on the Platform GPL18722 (spotted oligonucleotide Homo sapiens microRNA (miRNA) array) in the Gene Expression Omnibus (GEO) and compare with miRNAs with a conserved target location on CST7 mRNA were found using databases. The study population included 60 fresh BC tissue samples and adjacent normal tissues as control. The Quantitative Real-Time PCR was used to evaluate the expression levels of CST7 and has-miR-4793-5p in the breast tissues.The present study, found that CST7 and hsa-miR-4793-5p were significantly increased in tumoral tissues in compare to normal tissues. Further analysis revealed a remarkable association between CST7 and hsa-miR-4793-5p gene expression alteration. ROC curve analysis demonstrated high accuracy for CST7 expression in BC tumors. Comparison of gene expression between different stages and patient family history showed significant findings. Due to the high sensitivity and specificity of the expression changes of these two genes, they are suitable candidates for further investigations to be considered as part of a diagnosis and prognosis panel.

The heterogeneity of breast cancer metastasis: a bioinformatics analysis utilizing single-cell RNA sequencing data.

Breast cancer is a common malignancy in women, and its metastasis is a leading cause of cancer-related deaths. Single-cell RNA sequencing (scRNA-seq) can distinguish the molecular characteristics of metastasis and identify predictor genes for patient prognosis. This article explores gene expression in primary breast cancer tumor tissue against metastatic cells in the lymph node and liver using scRNA-seq. Breast cancer scRNA-seq data from the Gene Expression Omnibus were used. The data were processed using R and the Seurat package. The cells were clustered and identified using Metascape. InferCNV is used to analyze the variation in copy number. Differential expression analysis was conducted for the cancer cells using Seurat and was enriched using Metascape. We identified 18 distinct cell clusters, 6 of which were epithelial. CNV analysis identified significant alterations with duplication of chromosomes 1, 8, and 19. Differential gene analysis resulted in 17 upregulated and 171 downregulated genes for the primary tumor in the primary tumor vs. liver metastasis comparison and 43 upregulated and 4 downregulated genes in the primary tumor in the primary tumor vs lymph node metastasis comparison. Several enriched terms include Ribosome biogenesis, NTP synthesis, Epithelial dedifferentiation, Autophagy, and genes associated with epithelial-to-mesenchymal transitions. No single gene or pathway can clearly explain the mechanisms behind tumor metastasis. Several mechanisms contribute to lymph node and liver metastasis, such as the loss of differentiation, epithelial-to-mesenchymal transition, and autophagy. These findings necessitate further study of metastatic tissue for effective drug development.

A Thorough Navigation of miRNA's Blueprint in Crafting Cardiovascular Fate.

Cardiovascular diseases contribute significantly to global morbidity and mortality. MicroRNAs are crucial in the development and progression of these diseases by regulating gene expression in various cells and tissues. Their roles in conditions like atherosclerosis, heart failure, myocardial infarction, and arrhythmias have been widely researched. The present study provides an overview of existing evidence regarding miRNAs' role in cardiovascular disease pathogenesis. Furthermore, the study examines current state-of-the-art technologies used in the study of miRNAs in cardiovascular disease. As a final point, we examine how miRNAs may serve as disease biomarkers, therapeutic targets, and prognostic indicators. In cardiology, microRNAs, small noncoding RNA molecules, are crucial to the posttranscriptional regulation of genes. Their role in regulating cardiac cell differentiation and maturation is critical during the development of the heart. They maintain the cardiac function of an adult heart by contributing to its electrical and contractile activity. By binding to messenger RNA molecules, they inhibit protein translation or degrade mRNA. Several cardiovascular diseases are associated with dysregulation of miRNAs, including arrhythmias, hypertension, atherosclerosis, and heart failure. miRNAs can be used as biomarkers to diagnose and predict diseases as well as therapeutic targets. A variety of state-of-the-art technologies have aided researchers in discovering, profiling, and analyzing miRNAs, including microarray analysis, next-generation sequencing, and others. Developing new diagnostics and therapeutic approaches is becoming more feasible as researchers refine their understanding of miRNA function. Ultimately, this will reduce the burden of cardiovascular disease around the world.

Identification of Genes Associated with Familial Focal Segmental Glomerulosclerosis Through Transcriptomics and In Silico Analysis, Including RPL27, TUBB6, and PFDN5

Focal segmental glomerulosclerosis (FSGS) is a major cause of nephrotic syndrome and often leads to progressive kidney failure. Its varying clinical presentation suggests potential genetic diversity, requiring further molecular investigation. This study aims to elucidate some of the genetic and molecular mechanisms underlying FSGS. The study focuses on the use of bioinformatic analysis of gene expression data to identify genes associated with familial FSGS. A comprehensive in silico analysis was performed using the GSE99340 data set from Gene Expression Omnibus (GEO) comparing gene expression in glomerular and tubulointerstitial tissues from FSGS patients (n = 10) and Minimal Change Disease (MCD) patients (n = 8). These findings were validated using transcriptomics data obtained using RNA sequencing from FSGS (n = 3) and control samples (n = 3) from the UAE. Further validation was conducted using qRT-PCR on an independent FFPE cohort (FSGS, n = 6; MCD, n = 7) and saliva samples (FSGS, n = 3; Control, n = 7) from the UAE. Three genes (TUBB6, RPL27, and PFDN5) showed significant differential expression (p < 0.01) when comparing FSGS and MCD with healthy controls. These genes are associated with cell junction organization and synaptic pathways of the neuron, supporting the link between FSGS and the neural system. These genes can potentially be useful as diagnostic biomarkers for FSGS and to develop new treatment options.

Sleep deprivation stimulates adaptive thermogenesis by activating AMPK pathway in mice.

Sleep deprivation (SD) can affect the adaptive thermogenesis in laboratory rodents, but the molecular mechanism and the crosstalk with other organs remain largely unknown. In order to investigate the effects and mechanisms of SD on thermoregulation and energy metabolism, here we measured the changes of body weight, body fat mass, body temperature, resting metabolic rate (RMR), and thermogenic gene expression in brown adipose tissue (BAT), white adipose tissue (WAT), skeleton muscle and liver in C57BL/6J mice during 7-day SD with rotating rod sleep deprivation device. Results showed that compared with the control group, the body weight and body fat mass of SD mice were decreased and RMR of SD mice increased. The gene expression of Ampk, Pgc1α and Ucp1 which related to thermogenesis in BAT and WAT were significantly increased, and the expression of Ampk, Serca1, Serca2 and Ucp3 which related to thermogenesis in skeletal muscle were significantly increased in SD mice. Taken together, these data demonstrated that 7-day SD enhanced the adaptive thermogenesis in mice by activating AMPK, including the upregulation of the AMPK - PGC1α - UCP1 pathway in BAT, and the AMPK - UCP3 and SLN - SERCA pathway in skeleton muscle. Our data provide the molecular evidence for SD-stimulated adaptive thermogenesis and energy metabolism in small mammals.

Weight Changes Are Linked to Adipose Tissue Genes in Overweight Women with Polycystic Ovary Syndrome

Women with polycystic ovary syndrome (PCOS) have varying difficulties in achieving weight loss by lifestyle intervention, which may depend on adipose tissue metabolism. The objective was to study baseline subcutaneous adipose tissue gene expression as a prediction of weight loss by lifestyle intervention in obese/overweight women with PCOS. This is a secondary analysis of a randomized controlled trial where women with PCOS, aged 18–40 and body mass index (BMI) ≥ 27 were initially randomized to either a 4-month behavioral modification program or minimal intervention according to standard care. Baseline subcutaneous adipose tissue gene expression was related to weight change after the lifestyle intervention. A total of 55 obese/overweight women provided subcutaneous adipose samples at study entry. Weight loss was significant after behavioral modification (−2.2%, p = 0.0014), while there was no significant weight loss in the control group (−1.1%, p = 0.12). In microarray analysis of adipose samples, expression of 40 genes differed significantly between subgroups of those with the greatest weight loss or weight gain. 10 genes were involved in metabolic pathways including glutathione metabolism, gluconeogenesis, and pyruvate metabolism. Results were confirmed by real-time polymerase chain reaction (RT-PCR) in all 55 subjects. Expressions of GSTM5, ANLN, and H3C2 correlated with weight change (R = −0.41, p = 0.002; R = −0.31, p = 0.023 and R = −0.32, p = 0.016, respectively). GSTM5, involved in glutathione metabolism, was the strongest predictor of weight loss, and together with baseline waist-hip ratio (WHR) explained 31% of the variation in body weight change. This study shows that baseline subcutaneous adipose tissue genes play a role for body weight outcome in response to lifestyle intervention in overweight/obese women with PCOS.

Effects of Acorns on Meat Quality and Lipid Metabolism-Related Gene Expression in Muscle Tissues of Yuxi Black Pigs

Objectives: The aim of this study was to investigate the effects of acorn diets on the composition of fatty acid (FA) and the intramuscular fat (IMF) content in Yuxi black pigs. Methods: Ninety Yuxi black pigs with similar body weight (99.60 ± 2.32 kg) were randomly divided into five groups. The control group was fed a basal diet, and the AD20, AD30, AD40, and AD50 groups were fed experimental diets which contained 20%, 30%, 40%, and 50% acorns, respectively. The feeding experiment lasted for 120 days. Results: The results showed that compared with the control group, the content of SFA in longissimus dorsi and biceps femoris tissues in the AD30 group decreased by 8.57% and 20.10%, and the content of MUFA increased by 5.40% and 15.83%, respectively, while the PUFA content of biceps femoris increased by 5.40% (p < 0.05). Meanwhile, the IMF content of the AD30 group was significantly higher than that of the control group in the longissimus dorsi and biceps femoris. In addition, the mRNA expression levels of the ATGL, PPARγ, and FABP4 genes in longissimus dorsi (p < 0.05) were up-regulated, and HSL were down-regulated (p < 0.05) in the AD30 group. In the biceps femoris of the AD30 group, it was observed that the expression levels of the ACC and FAS genes were up-regulated (p < 0.05), while HSL and ATGL genes were down-regulated (p < 0.05). Conclusions: These results demonstrated that the addition of appropriate amounts of acorn to the diet (a 30% acorn diet) could improve the nutritional value of pork.

Investigation of the efficacy of different cryoprotectants in the freezing of testicular tissue and epididymal sperm: Spermatological parameters, tissue viability and PARP-1 gene expression

The presented study covers testicular tissue and epididymal spermatozoa cryopreservation processes in bulls and aims to investigate the effects of these applications on spermatological parameters, cell viability in testicular tissue, and the expression of the PARP-1 gene, a DNA repair enzyme. Testes of 20 bulls over 2 years old, slaughtered in a slaughterhouse, were used in the study. After spermatological evaluations, the semen obtained from the cauda epididymis was frozen in liquid nitrogen vapor according to the straw method and stored in liquid nitrogen (−196 °C). Testicular tissue pieces obtained from the testicles were frozen by the slow freezing method in cryotubes in diluents containing Dimethylsulfoxide (DMSO) and Ethylene Glycol (EG) cryoprotectants and stored in liquid nitrogen (−196 °C). The total motility (TM) (85.89 ± 12.83 %), progressive motility (PM) (54.02 ± 15.77 %), and kinematic parameter values of fresh sperm were significantly higher compared to the TM (57.62 ± 13.13 %), PM (29.60 ± 10.76 %), and kinematic parameter values after thawing (P < 0.05). Significant decreases in plasma membrane integrity (PMI) and viability and an increase in chromatin condensation and morphological disorders in the head, middle part, and tail regions were observed in post-thaw semen samples (P < 0.05). When the effects of DMSO and EG on cell viability after thaw in frozen testicular tissue were evaluated, it was observed that the cell viability values of testicular tissues frozen with EG (45.70 ± 10.00) were statistically significantly lower than those frozen with DMSO (51.20 ± 7.70) (P < 0.05). When the effects of both cryoprotectants on gene expression in tissue and semen samples were examined, it was determined that gene expression increased on average 0.19 ± 0.27 times in the tissue samples in the DMSO group compared to fresh tissue samples and 0.17 ± 0.19 times in the tissue samples in the EG group. It was determined that gene expression levels increased by an average of 1.20 ± 1.08 times in post-thaw epididymal spermatozoa samples compared to fresh semen samples. The results show that cryopreservation can activate cellular repair mechanisms by stimulating PARP-1 gene expression and affect gene expression by activating specific pathways in tissues and cells.

Advances in bacterial artificial chromosome (BAC) transgenic mice for gene analysis and disease research.

Transgenic mice, including those created using Bacterial Artificial Chromosomes (BACs), are artificial manipulations that have become critical tools for studying gene function. While conventional transgenic techniques face challenges in achieving precise expression of foreign genes in specific cells and tissues, BAC transgenic mice offer a solution by incorporating large DNA segments that can include entire expression units with tissue-specific enhancers. This review provides a thorough examination of BAC transgenic mouse technology, encompassing both traditional and humanized models. We explore the benefits and drawbacks of BAC transgenesis compared to other techniques such as knock-in and CRISPR/Cas9 technologies. The review emphasizes the applications of BAC transgenic mice in various disciplines, including neuroscience, immunology, drug metabolism, and disease modeling. Additionally, we address crucial aspects of generating and analyzing BAC transgenic mice, such as position effects, copy number variations, and strategies to mitigate these challenges. Despite certain limitations, humanized BAC transgenic mice have proven to be invaluable tools for studying the pathogenesis of human diseases, drug development, and understanding intricate gene regulatory mechanisms. This review discusses current topics on BAC transgenic mice and their evolving significance in biomedical research.

Astragaloside IV augments anti-PD-1 therapy to suppress tumor growth in lung cancer by remodeling the tumor microenvironment.

Programmed cell death protein-1 (PD-1) inhibitors are increasingly utilized in the treatment of lung cancer (LC). Combination therapy has recently gained popularity in treating LC. This study aimed to assess the efficacy of combining Astragaloside IV (AS-IV) and anti-PD-1 in LC. C57BL/6J mice were subcutaneously injected with Lewis lung carcinoma (LLC) cells. After 3 weeks, the animals were sacrificed, and the tumors were harvested for analysis. Ki-67 immuno-labeling and TUNEL assay were used for evaluating cell proliferation and apoptosis in tumor tissues. In addition, anti-cleaved caspase 3 was used for immunolabelling of apoptotic cells. Immune cell infiltration (macrophages and T cells) and gene expression in tumor tissues were also investigated by using immunofluorescence staining. Compared to treatment with anti-PD-1 or AS-IV, the combination of AS-IV and anti-PD-1 notably reduced tumor volume and weight of LLC-bearing mice. Additionally, the combination treatment strongly induced the apoptosis and suppressed the proliferation in tumor tissues through inactivating PI3K/Akt and ERK signaling pathways, compared to single treatment group. Moreover, the combination treatment elevated levels of the M1 macrophage marker mCD86, reduced levels of the M2 macrophage marker mCD206, as well as upregulated levels of the T cell activation marker mCD69 in tumor tissues. Collectively, the combination treatment effectively inhibited tumor growth in LLC mice through promoting M1 macrophage polarization and T cell activation. These findings showed that combining AS-IV with anti-PD-1 therapy could be a promising therapeutic approach for LC.

ECM1 attenuates hepatic fibrosis by interfering with mediators of latent TGF-β1 activation

ObjectiveExtracellular matrix protein 1 (ECM1) serves as a gatekeeper of hepatic fibrosis by maintaining transforming growth factor-β1 (TGF-β1) in its latent form. ECM1 knockout (KO) causes latent (L) TGF-β1 activation,...

Intermittent Exercise and Cigarette Smoke Extract-Induced Pulmonary Tensegrity Dysfunction; Monitoring Elastin, Matrix Metalloproteinase-12, Transforming Growth Factor-beta 1

Background: Cigarette smoke causes inflammation of the alveoli, leading to airflow restriction and potentially irreversible changes in lung architecture, including pulmonary emphysema. This study investigates the effects of a six-week aerobic interval training regimen on elastin activity in a rat model of cigarette smoke-induced COPD (CS-COPD). Objectives: Specifically, we observe the variables matrix metalloproteinase-12 (MMP12) and transforming growth factor-beta (TGF-β1). Methods: Twenty male Wistar rats, aged eight weeks, were divided into four groups (n = 5 per group): Control, aerobic interval training (Exe), cigarette smoke extract (CSE), and CSE + Exe. The aerobic interval training (Exe) was performed for 49 min/day, five days per week for six weeks in interval form. The CSE group received an intraperitoneal (IP) injection of 150 µL of cigarette smoke extract, one day per week for six weeks. Results: The CSE and CSE + Exe groups showed a significant decrease in elastin gene expression in lung tissue compared to the healthy control group (P = 0.0002 and P = 0.0057, respectively) and the Exe group (P = 0.0002 and P = 0.0042, respectively). Additionally, the CSE group exhibited a significant increase in lung MMP12 gene expression compared to the healthy control and Exe groups (P = 0.0008 and P = 0.0013, respectively). Notably, the CSE + Exe group showed a significant decrease in MMP12 gene expression in lung tissue compared to the CSE group (P = 0.0015). Furthermore, the CSE and CSE + Exe groups demonstrated a significant increase in TGFB1 gene expression in lung tissue compared to the healthy control group (P &lt; 0.0001 and P = 0.0022, respectively) and the Exe group (P &lt; 0.0001 for both). Conclusions: Our findings indicate that the group exposed to cigarette smoke experienced a significant decrease in elastin levels, accompanied by an increase in MMP12 and TGF-β1 expression. Although aerobic interval training provided some protection against the detrimental effects of cigarette smoke exposure, it was not sufficient to fully reverse the harmful impacts of the disease.

Poly (ADP-Ribose) Polymerase 1 Induces Cyclic GMP-AMP Synthase-stimulator of Interferon Genes Pathway Dysregulation to Promote Immune Escape of Colorectal Cancer Cells

Colorectal cancer (CRC) ranks third globally in cancer incidence and mortality, posing a significant human concern. Recent advancements in immunotherapy are noteworthy. This study explores immune modulation for CRC treatment. Initially targeting poly (ADP-ribose) polymerase 1 (PARP-1), a gene overexpressed in CRC tissues per The Cancer Genome Atlas, we examined its correlation with immune cell infiltration using the Tumor Immune Estimation Resource tool. Quantitative reverse transcription polymerase chain reaction assessed PARP-1 mRNA and inflammation-related gene expression in tumor tissues and cells. Assessing CD8+ T-cell proliferation and cytotoxicity towards HCT116 cells involved carboxyfluorescein diacetate succinimidyl ester and lactate dehydrogenase kits. Chemotaxis was gauged using a Transwell system in a CD8+ T-cell coculture setup, with immunofluorescence revealing cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) levels in HCT116 cells. Enzyme-linked immunosorbent assay kits measured CD8+ T-cell cytokine secretion. The findings suggested that PARP-1 was overexpressed in CRC tissues and cells and this overexpression was positively correlated with Treg cell infiltration. Overexpression of PARP-1 could significantly reduce the proportion of cGAS and STING-positive cells in HCT116 cells, dampen the proliferation, tumor-killing capacity, and chemotaxis of CD8+ T cells, and inhibit the secretion of related cytokines. The introduction of STING agonists could reverse the effects caused by overexpressed PARP-1. In vivo experiments affirmed the independent anti-tumor effects of PARP-1 inhibitors and STING agonists, synergistically inhibiting tumor growth. Silencing PARP-1 in HCT116 cells potentially boosts CD8+ T-cell activity against these cells through the cGAS-STING pathway.

Oligoasthenozoospermia is alleviated in a mouse model by [Gly14]-humanin-mediated attenuation of oxidative stress and ferroptosis.

Oligoasthenozoospermia is a common cause of male infertility, for which effective treatments are urgently needed. Humanin (HN) is a peptide associated with this condition. To investigate the ameliorative effect of [Gly14]-Humanin (HNG) on oligoasthenozoospermia and the mechanisms. Mice were treated with cyclophosphamide (CP) to construct a mice model of oligoasthenozoospermia. The resulting model mice were treated with saline or HNG. Subsequently, the testis weights, organ indices, testicular structure, sperm counts and motilities, litter sizes, and serum testosterone concentrations of the mice were determined. Differential gene expression in testicular tissues was determined by RNA sequencing. TM3, TM4, GC1, and GC2 cells were exposed to erastin to induce ferroptosis, followed by treatment with HNG or HNG + ML385 (a nuclear factor erythroid 2-related factor 2 inhibitor). Levels of reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), and ferrous ions (Fe2+) were determined and their expression of ferroptosis-related proteins was determined by immunofluorescence and western blot. The HNG treatment improved testis and sperm parameters and increased litter size and serum testosterone concentrations in model mice. Kyoto Encyclopaedia of Genes and Genomes pathway enrichment analysis revealed significant differential expression of ferroptosis-related genes. The expression of ferroptosis-related proteins increased in testicular tissues after the HNG treatment. The concentrations of ROS, MDA, and Fe2+ decreased and the concentrations of GSH increased in testicular tissues and in TM3 and TM4 cells after HNG treatment. In vitro experiments confirmed that HNG activated the nuclear factor erythroid 2-related factor 2/glutathione peroxidase 4 (Nrf2/GPX4) pathway. However, these effects of HNG were blocked by ML385 treatment. HNG demonstrated a therapeutic effect on oligoasthenozoospermia in a mouse model by reducing oxidative stress and ferroptosis. In TM3 and TM4 cells, HNG attenuated cellular oxidative stress and inhibited ferroptosis via the Nrf2/GPX4 pathway.

Proteomic Signatures of Right Ventricular Outcomes in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a disease of progressive right ventricular (RV) failure with high morbidity and mortality. Our goal is to investigate proteomic features and pathways associated with RV-focused outcomes including mortality, RV dilation, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) in PAH. Participants in a single-institution cohort with 3 years of follow-up underwent proteomic profiling of their plasma using 7288 aptamers (targeting 6467 unique human proteins). Partial least squares discriminant analysis was performed to assess global protein variation associated with mortality, RV dilation, and NT-proBNP levels. Differentially abundant proteins and enriched pathways associated with outcomes were identified following baseline adjustments. RV vulnerability models estimated associations for individuals with similar afterload following adjustment for pulmonary vascular resistance. A total of 117 participants with PAH were included. Partial least squares discriminant analysis of the proteome showed clear separation between survivors and nonsurvivors, participants with dilated versus nondilated RVs, and across NT-proBNP levels. Proteins and pathways involving the ECM (extracellular matrix) were upregulated in participants who died during follow-up, those with severe RV dilation, and those with higher levels of NT-proBNP. Pulmonary vascular resistance adjustment reinforced the importance of ECM proteins in the association with RV vulnerability, independent of afterload. These findings were confirmed in independent PAH cohorts with available plasma proteomics and RV tissue gene and protein expression. Distinct plasma proteomic profiles are associated with mortality, RV dilation, and NT-proBNP in PAH. Proteins and pathways governing tissue remodeling are strongly associated with poor outcomes, may mediate RV vulnerability to right heart failure, and represent promising candidates as biomarkers and potential therapeutic targets.