Incorporation of PD-1 blockade into induction chemotherapy improved tumor response in patients with locoregionally advanced nasopharyngeal carcinoma in a retrospective patient cohort.

OBJECTIVE: To investigate the short-term efficacy and safety of induction chemotherapy (IC) combined with anti-PD-1 immunotherapy in locoregionally advanced nasopharyngeal carcinoma (LA-NPC). METHODS: A total of 217 patients diagnosed with LA-NPC at the First Affiliated Hospital of Nanchang University, including 67 who received IC combined with anti-PD-1 and 150 who received IC, were retrospectively enrolled. Efficacy was evaluated at the end of the IC cycles and one month after radiotherapy based on RECIST v1.1 criteria. Acute toxicities were graded based on the CTCAE v5.0 criteria. Quantitative variables were compared by unpaired t-tests, and categorical variables were evaluated by Fisher Freeman-Halton test or Pearson Chi-square test. RESULTS: At the end of all induction therapy cycles, the objective response rate (ORR) of the IC + anti-PD-1 group was 88.1 % (59/67) as opposed to 70.0 % (105/150) in the IC group. Subgroup analysis showed that patients in both stage Ⅲ and ⅣA achieved a significant improvement in ORR with the inclusion of anti-PD-1 therapy. Patients with T3-4 or N2-3 category appeared to benefit more from anti-PD-1 compared to patients with T1-2 or N0-1 category. However, neither ORR nor the complete response (CR) rate was significantly different between the two treatment groups one month after the end of radiotherapy. In addition, the frequency of Grade 3-4 adverse events were also similar in both groups. CONCLUSIONS: IC combined with anti-PD-1 immunotherapy significantly improved the ORR of LA-NPC patients after induction therapy compared to IC alone.

Salvianolate ameliorates inflammation and oxidative stress in high-glucose induced HK-2 cells by blocking TGF-ß/Smad signal pathway.

The objective of this research is to assess how salvianolate impacts inflammation and oxidative stress in a laboratory setting, as well as to investigate the underlying mechanisms. HK-2 cells were subjected to different treatments, including normal glucose, mannitol, high glucose and high glucose plus salvianolate. Cell proliferation, death, MDA levels, IL-1ß, IL-6, TNF-α, MCP-1 concentrations, ROS levels, MMP, MPTP and ATP levels were assessed using various kits. The protein expressions of NOX4, TGF-ß1, P-Smad2, P-Smad3, Smad4 and Smad7 were ascertained through western blot analysis. Our results indicated salvianolate could reduce the release of IL-1ß, IL-6, TNF-α, as well as MCP-1, alleviate the levels of oxidative stress markers NOX4 and MDA, and improve mitochondrial function by increasing MMP and ATP levels while reducing ROS and MPTP opening. Furthermore, salvianolate inhibited the TGF-ß1/Smad2, Smad3 signaling pathway, suppressed Smad4 expression and increased Smad7 expression. Salvianolate seems to mitigate inflammation and oxidative stress through a variety of mechanisms. These discoveries offer valuable understanding into the possible mechanisms by which salvianolate may be employed in the treatment of diabetic nephropathy.

Metabolic control of adaptive ß-cell proliferation by the protein deacetylase SIRT2.

Selective and controlled expansion of endogenous ß-cells has been pursued as a potential therapy for diabetes. Ideally, such therapies would preserve feedback control of ß-cell proliferation to avoid excessive ß-cell expansion and an increased risk of hypoglycemia. Here, we identified a regulator of ß-cell proliferation whose inactivation results in controlled ß-cell expansion: the protein deacetylase Sirtuin 2 (SIRT2). Sirt2 deletion in ß-cells of mice increased ß-cell proliferation during hyperglycemia with little effect in homeostatic conditions, indicating preservation of feedback control of ß-cell mass. SIRT2 restrains proliferation of human islet ß-cells cultured in glucose concentrations above the glycemic set point, demonstrating conserved SIRT2 function. Analysis of acetylated proteins in islets treated with a SIRT2 inhibitor revealed that SIRT2 deacetylates enzymes involved in oxidative phosphorylation, dampening the adaptive increase in oxygen consumption during hyperglycemia. At the transcriptomic level, Sirt2 inactivation has context-dependent effects on ß-cells, with Sirt2 controlling how ß-cells interpret hyperglycemia as a stress. Finally, we provide proof-of-principle that systemic administration of a GLP1-coupled Sirt2-targeting antisense oligonucleotide achieves ß-cell selective Sirt2 inactivation and stimulates ß-cell proliferation under hyperglycemic conditions. Overall, these studies identify a therapeutic strategy for increasing ß-cell mass in diabetes without circumventing feedback control of ß-cell proliferation.

Macrocycles and macrocyclization in anticancer drug discovery: Important pieces of the puzzle.

Increasing disease-related proteins have been identified as novel therapeutic targets. Macrocycles are emerging as potential solutions, bridging the gap between conventional small molecules and biomacromolecules in drug discovery. Inspired by successful macrocyclic drugs of natural origins, macrocycles are attracting more attention for enhanced binding affinity and target selectivity. Due to the conformation constraint and structure preorganization, macrocycles can reach bioactive conformations more easily than parent acyclic compounds. Also, rational macrocyclization combined with sequent structural modification will help improve oral bioavailability and combat drug resistance. This review introduces various strategies to enhance membrane permeability in macrocyclization and subsequent modification, such as N-methylation, intramolecular hydrogen bonding modulation, isomerization, and reversible bicyclization. Several case studies highlight macrocyclic inhibitors targeting kinases, HDAC, and protein-protein interactions. Finally, some macrocyclic agents targeting tumor microenvironments are illustrated.

Influence of oceanic mesoscale eddies on the deep chlorophyll maxima.

The deployment of the biogeochemical Argo network significantly enhances our understanding of the ecological effects of mesoscale eddies at different ocean depths. In this study, satellite data and more than one hundred thousand biogeochemical Argo float profiles were used to analyze the responses of the deep chlorophyll maximum (DCM) to mesoscale eddies. The DCM profiles were categorized into two types: DAM (adaptation maximum) and DBM (biomass maximum), based on their adaptation to light and maximum biomass characteristics. The variabilities in the DCM profiles in terms of latitude, seasonality, and their response to mesoscale eddies were subsequently investigated on a global scale. Our analysis demonstrates that light and nutrient availability explain a significant portion of the variability in the phytoplankton distribution across different regions and seasons. Statistical analysis reveals that cyclonic (anticyclonic) eddies enhance (weaken) the intensity of the DCM. The magnitude of this enhancement or weakening exhibits regional differences. Specifically, high-latitude regions are more influenced by eddies in terms of light-adapted DCM intensity, while in mid-latitude regions, eddies exhibit a stronger effect on the maximum biomass-driven DCM intensity. Moreover, our findings suggest that eddies in the North Atlantic Subtropical Gyre contribute to a downward shift in the euphotic zone depth, leading to an increased DCM depth and strengthened DCM intensity. However, in the equatorial region, eddies impact the DCM depth by influencing the nitracline (a layer in a body of water in which the nitrate concentration changes rapidly with depth). Similar patterns are frequently observed in different regions at the same latitude, providing a foundation for further detailed investigations of the DCM in specific areas.

Effects of weaning on intestinal longitudinal muscle-myenteric plexus function in piglets.

Weaning piglets usually suffer from severe diarrhea (commonly known as postweaning diarrhea, PWD) along with intestinal motility disorder. Intestinal peristalsis is mainly regulated by the longitudinal muscle-myenteric plexus (LM-MP). To understand the relationship between intestinal LM-MP function and the development of PWD, we compared the intestinal electrical activity, and the transcriptional profile of the LM-MP between 21-day-old piglets (just weaned, n=7) and 24-day-old piglets (suffered the most severe weaning stress, n=7). The results showed that 24-day-old piglets exhibited different degrees of diarrhea. A significant increase in the slow-wave frequency in the ileum and colon was observed in 24-day-old piglets, while c-kit expression in the intestinal LM-MPs was significantly decreased, indicating that PWD caused by elevated slow-wave frequency may be associated with loss of c-kit. The real-time quantitative PCR (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA) showed that intestinal LM-MPs in 24-day-old piglets may undergo inflammation and oxidative stress. Significant increases in 8-hydroxy-2'-deoxyguanosine and decreases in thioredoxin suggest that weaning may lead to DNA damage in the LM-MP of 24-day-old piglets. In addition, activating transcription factor 3 was significantly upregulated, indicating nerve damage in the LM-MP of 24-day-old piglets. The transcriptomic results showed that most of the differentially expressed genes in the ileal LM-MP after weaning were downregulated and closely related to the cell cycle process. Subsequent RT-qPCR analysis showed that the relative expression of p21 was upregulated, while the expression of cyclin A2, cyclin B1, and proliferating cell nuclear antigen was downregulated in the ileal and colonic LM-MP of 24-day-old piglets, suggesting that weaning may inhibit cell proliferation and cause G1/S cell cycle arrest in ileal and colonic LM-MP. In conclusion, weaning may lead to cell cycle arrest by causing DNA damage in the LM-MP, impairing intestinal motility regulation, and ultimately leading to diarrhea in piglets.

Ipsilateral synchronous papillary renal neoplasm with reverse polarity and urothelial carcinoma in a renal transplant recipient: a rare case report with molecular analysis and literature review.

BACKGROUND: Renal transplant recipients (RTRs) have a 3- to 5-fold higher risk of developing malignant tumors than the general population, with new malignant tumors after transplantation considered to be the leading cause of death in RTRs. In pathological practice, it is rare for neoplasms with different histology to be located in the same organ. We report the first case of a synchronous papillary renal neoplasm with reverse polarity (PRNRP) and urothelial carcinoma (UC) in the ipsilateral kidney in an RTR. Molecular detection was conducted by next-generation sequencing. CASE PRESENTATION: A 68-year-old female suffered from uremia 19 years ago and underwent renal transplantation (RT) after receiving dialysis for 6 months. Hematuria occurred one month ago and an enhanced CT showed that there were two abnormal density foci in the middle and lower parts of the autologous left kidney. A laparoscopic left nephrectomy and ureterectomy were performed. Gross examination revealed a mass (I) in the left renal parenchyma, 2*1.8*1.5 cm in size, that protruded from the renal capsule, and a cauliflower-like mass (II), 5*2.5*2 cm in size, adjacent to the mass (I). Microscopic findings revealed these lesions were PRNRP and UC, respectively. PCR analysis revealed a KRAS gene mutation (G12D in exon 2) in the PRNRP, while NGS analysis revealed FGFR3 (S249C in exon 7) and KDM6A (Q271Ter in exon 10 and A782Lfs in exon 17) mutations in the UC. CONCLUSIONS: We report here for the first time an extraordinarily rare case of synchronous renal tumors of a PRNRP and UC in the ipsilateral kidney of an RTR. We identified simultaneous KRAS, FGFR3, and KDM6A mutations in two different renal masses in the ipsilateral kidney. Pathologic assessment with comparative molecular analysis of mutational profiles facilitates tumor studies after RT and may be of great value in clinical management strategies.

Effect of SGLT-2 inhibitor, dapagliflozin, on left ventricular remodeling in patients with type 2 diabetes and HFrEF.

The current study evaluated the effect of SGLT-2 inhibitor, dapagliflozin, on left ventricular remodeling in patients with type 2 diabetes and HFrEF. 60 patients were randomized (1:1) to receive dapagliflozin 10 mg once daily, or placebo double blind for 1 year. Patients underwent transthoracic echocardiography and doppler evaluation prior to dapagliflozin initiation and at 1 year. At 1year, adjusted mean difference versus placebo in change from baseline in LVEF was 2.5% (95% CI: 1.00-4.06, P = 0.002). Adjusted mean difference versus placebo in change from baseline in LVED volume was - 6.0ml (95% CI: -8.07 --3.87, P<0.001). Adjusted mean difference versus placebo in change from baseline in LVES volume was - 8.1ml (95% CI: -11.07 --5.14, P<0.001). Similarly, adjusted mean difference versus placebo in change from baseline in LVED diameter was - 1.6 mm (95% CI: -2.67 --0.62, P = 0.002). Adjusted mean difference versus placebo in change from baseline in VTI was 0.20 cm (95% CI: 0.01-0.38, P = 0.036). Dapagliflozin was well tolerated. Dapagliflozin was associated with significant and clinically meaningful improvement in echocardiographic parameters versus placebo in patients with type 2 diabetes and HFrEF.Registration number and date: ChiCTR2300072707, 21/06/2023.

A macrophage plasma membrane-coated and DNA structured nanomedicine targets to alleviate rheumatoid arthritis via dual inhibition to TNF-α and NF-κB.

High heterogenicity of rheumatoid arthritis (RA) leads to poor response in many patients. Combined therapies that simultaneously inhibit multiple proinflammatory targets may improve anti-RA efficacy. However, which monotherapies to combine and how to achieve the combination are critical issues. Here, we design a macrophage plasma membrane-coated and DNA structured nanomedicine to achieve a dual inhibitory therapy to Tumor necrosis factor alpha (TNF-α) and NF-κB. An anti-NF-κB decoy oligodeoxynucleotides (dODN) is first conjugated to a DNA cage with precise numbers and locations (Cage-dODN). Meanwhile, an anti-TNF-α siRNA is anchored to extracted macrophage plasma membrane (siRNA@M). Subsequently, siRNA@M is used to encapsulate Cage-dODN to fabricate siRNA@M(Cage-dODN) (siMCO). The size and zeta potential of siMCO are 63.1 ± 15.7 nm and -20.7 ± 3.8 mV respectively. siMCO shows increased intracellular uptake by inflamed macrophages and enhanced accumulation in inflamed mouse paws. siMCO also reduces pro-inflammatory factors at genetic and protein levels, alleviates arthritic symptoms, and shows no influence to major blood components. These results show that siMCO is a potential targeted, efficient, and safe dual inhibitory therapy for the treatment of inflammatory arthritis. The macrophage plasma membrane can be utilized to improve the targeting, stability, and efficacy of DNA structured nanomedicines.

The Effects of Phytase and Non-Starch Polysaccharide-Hydrolyzing Enzymes on Trace Element Deposition, Intestinal Morphology, and Cecal Microbiota of Growing-Finishing Pigs.

This study investigated the effects of supplementing phytase and non-starch polysaccharide-degrading enzymes (NSPases) to corn-soybean meal-based diet on the growth performance, trace element deposition, and intestinal health of growing-finishing pigs. Fifty pigs were randomly assigned into the control (basal diet), phytase (basal diet + 100 g/t of phytase), ß-mannanase (basal diet + 40 g/t of ß-mannanase), ß-glucanase (basal diet + 100 g/t of ß-glucanase), and xylanase (basal diet + 100 g/t of xylanase) groups. The results show that the supplementation of phytase and NSPases had no impacts (p > 0.05) on the growth performance of pigs. Compared with the control group, pigs fed with xylanase had higher (p < 0.05) Zn concentrations in the ileum and muscle and those fed with phytase had higher (p < 0.05) Zn concentrations in the ileum. Phytase and xylanase supplementation decreased (p < 0.05) fecal Zn concentrations in pigs compared with the control group (p < 0.05). In addition, phytase, ß-mannanase, ß-glucanase, and xylanase supplementation up-regulated (p < 0.05) the FPN1 expression, whereas xylanase up-regulated (p < 0.05) the Znt1 expression in the duodenum of pigs compared with the control group. Moreover, phytase, ß-glucanase, and xylanase supplementation up-regulated (p < 0.05) the jejunal Znt1 expression compared with the control group. The intestinal morphology results show that the phytase, ß-mannanase, and xylanase groups had increased villus heights (VHs), an increased villus height-crypt depth ratio (VH:CD), and decreased crypt depths (CDs) in the duodenum, whereas phytase, ß-mannanase, ß-glucanase, and xylanase groups had decreased VH and VH:CD, and increased CD in the jejunum compared with the control group (p < 0.05). Pigs fed with exogenous enzymes had decreased bacterial diversity in the cecum. The dietary supplementation of NSPases increased the relative abundance of Firmicutes and decreased spirochaetes (p < 0.05). Compared with the control group, dietary NSPase treatment decreased (p < 0.05) the opportunistic pathogens, such as Treponema_2 and Eubacterium_ruminantium. Moreover, the relative abundances of Lachnospiraceae_XPB1014 and Lachnospiraceae were enriched in the ß-glucanase and ß-mannanase groups (p < 0.05), respectively. In conclusion, phytase and xylanase supplementation may promote zinc deposition in pigs. Additionally, the supplementation of NSPases may improve the gut health of pigs by modulating the intestinal morphology and microbiota.

Nutrient regulation of the islet epigenome controls adaptive insulin secretion.

Adaptation of the islet ß cell insulin-secretory response to changing insulin demand is critical for blood glucose homeostasis, yet the mechanisms underlying this adaptation are unknown. Here, we have shown that nutrient-stimulated histone acetylation plays a key role in adapting insulin secretion through regulation of genes involved in ß cell nutrient sensing and metabolism. Nutrient regulation of the epigenome occurred at sites occupied by the chromatin-modifying enzyme lysine-specific demethylase 1 (Lsd1) in islets. ß Cell-specific deletion of Lsd1 led to insulin hypersecretion, aberrant expression of nutrient-response genes, and histone hyperacetylation. Islets from mice adapted to chronically increased insulin demand exhibited shared epigenetic and transcriptional changes. Moreover, we found that genetic variants associated with type 2 diabetes were enriched at LSD1-bound sites in human islets, suggesting that interpretation of nutrient signals is genetically determined and clinically relevant. Overall, these studies revealed that adaptive insulin secretion involves Lsd1-mediated coupling of nutrient state to regulation of the islet epigenome.

Effects of prebiotics, probiotics and synbiotics on serum creatinine in non-dialysis patients: a meta-analysis of randomized controlled trials.

OBJECTIVE: Serum creatinine level are influenced by many factors. Although accumulated data suggested that prebiotics, probiotics and synbiotics supplements could affect serum creatinine level, the results remained controversial. The aim of the present paper was to evaluate the effects of prebiotics, probiotics and synbiotics on serum creatinine in non-dialysis patients. METHODS: PubMed, EMBASE (Excerpta Medica Database) and the Cochrane Library databases were searched for eligible randomized, controlled trials (RCTs) which were limited to English language studies until 30 September 2022. A random-effects model was performed to analyze the impact of pooled trials. RESULT: Twelve randomized, controlled trial studies were included in the meta-analysis. Prebiotics, probiotics or synbiotics supplementation did not significantly decrease the serum creatinine levels in non-dialysis patients compared to placebo [standardized mean difference (SMD) = 0.05; 95% confidence interval (CI): (-0.21, 0.31); p = 0.72; I2 = 61%]. CONCLUSION: The present meta-analysis indicated that supplementation with prebiotics, probiotics and synbiotics could not act as promising adjuvant therapies to decrease the serum creatinine levels in non-dialysis patients.

Characterization of circular RNA expression profiles in the age-related thymic involution of Magang goose.

The thymus is a vital immune organ, but its function gradually declines with age. Circular RNAs (circRNAs) are related to the development of tissues and organs. In this study, bioinformatics analysis showed that 1329, 755, and 417 circRNAs were differentially expressed between the comparison groups of 6-month age (M6) and 20-embryo age (E20), 3-day post-hatch (P3), and 3-month age (M3) Magang geese, respectively. Among them, 167 circRNAs were differentially co-expressed between thymic development (E20, P3, and M3) and involution (M6). Functional analysis showed significant enrichment of phosphorylation and positive regulation of GTPase activity. Furthermore, pathway analysis has shown that glycerolipid metabolism and the Wnt signaling pathway are critical pathways in the thymic involution process. Finally, we constructed the competitive endogenous RNA (ceRNA) network. The results of this study suggest that circRNAs may be involved in the age-related thymic involution of the Magang goose.

Tea intake and risk of kidney stones: A mendelian randomization study.

OBJECTIVES: Observational studies indicate that tea intake is associated with a decreased risk of kidney stones. Here we performed a mendelian randomization (MR) analysis to evaluate whether this association is causal. METHODS: Forty-four independent genetic variants strongly associated with tea intake were identified from a large genome-wide association study, including 448 060 individuals of the UK Biobank. We additionally obtained genome-wide association study summary statistics for kidney stones from the FinnGen consortium (5985 cases and 253 943 controls) and UK Biobank (6536 cases and 388 508 controls). Random-effect inverse variance weighted regression was used to evaluate causal estimates. The random-effect inverse variance weighted estimates based on the FinnGen consortium and UK Biobank were meta-analyzed using fixed-effects meta-analysis. Other MR methods, including MR-Egger, weighted median, weighted mode, and MR-Pleiotropy RESidual Sum and Outlier, were also performed to test the robustness of our results. RESULTS: In a combined sample of 12 521 cases and 642 451 controls, the inverse variance weighted analysis indicated that genetically predicted tea intake was causally associated with a decreased risk of kidney stones (odds ratio = 0.47; 95% CI, 0.34-0.66; P < 0.001). This association was consistent in other MR methods. CONCLUSIONS: This study suggests that tea intake may be causally associated with a decreased risk of kidney stones.

Psychological Resilience among Left-Behind Children in a Rural Area of Eastern China.

Childhood is an important period for individuals' psychological development. Due to long-term separation from the parents, left-behind children (LBC) more easily develop deviation in cognition and abnormal personality. In this study, we aimed to explore the status of psychological resilience among LBC in a rural area of eastern China. We carried out a cross-sectional survey including middle and high school students from Qingyuan County of Zhejiang Province. Psychological resilience was measured using a modified scale developed for Chinese children. Data from a total of 1086 participants were collected, and the mean ± standard deviation score of psychological resilience was 4.11 ± 0.42. Multivariable linear regression analyses revealed that being a class leader (p = 0.010) and having high self-evaluation of academic performance (p < 0.001) were related with psychological resilience. Moreover, high contact frequency between parents and children (p = 0.019) was associated with better psychological resilience among LBC. In conclusion, we found that being a class leader and having high self-evaluation of academic performance were associated with better psychological resilience among the children in this rural area and contact between parent and child was an essential factor associated with psychological resilience among LBC.

Stanniocalcin 2 Is Upregulated by Calcium-Sensing Receptor and Protects Human Vascular Smooth Muscle Cells from High-Phosphate-Induced Apoptosis.

INTRODUCTION: Apoptosis of vascular smooth muscle cells induced by hyperphosphatemia is a critical mechanism of chronic kidney disease-related vascular disorders. The present study investigated whether extracellular calcium-sensing receptor (CaSR) regulates stanniocalcin 2 (STC2) expression in HAoSMCs and subsequently protects HAoSMCs from high-phosphate-induced apoptosis. METHODS: HAoSMCs were cultured, and STC2 expression was determined by qPCR. A calcimimetic (NPS R-568) or calcilytic (NPS-2143) was applied to HAoSMCs. STC2 mRNA and protein levels were measured by qPCR and Western blot, respectively, and confocal microscopy was employed to investigate subcellular localization. STC2 overexpression and silencing were induced to assess the effects of STC2 on high-phosphate-induced apoptosis, which was determined by caspase-3 levels and TUNEL staining. The anti-apoptotic effect of CaSR-induced STC2 was confirmed by interfering with STC2 expression in the presence of NPS R-568. RESULTS: The constitutive expression of STC2 was confirmed. STC2 mRNA and protein levels were increased by NPS R-568 with or without high phosphate. NPS-2143 resulted in decreased STC2 mRNA levels, but decreased STC2 protein levels were only found under the high-phosphate condition. Confocal microscopy demonstrated the colocalization of STC2 and plasma membrane or endoplasmic reticulum markers. STC2 overexpression reduced HAoSMCs apoptosis, which were reversed with STC2 silencing. NPS R-568 treatment reduced HAoSMCs apoptosis, but STC2 silencing abolished the protective effect. CONCLUSION: This is the first evidence that STC2 is regulated by CaSR in HAoSMCs. CaSR activation-induced STC2 has putative anti-apoptotic effects against high phosphate. Calcimimetics are promising agents to treat uremic vascular injury.

Effects of PAMK on lncRNA, miRNA, and mRNA expression profiles of thymic epithelial cells.

Polysaccharides from Atractylodes macrocephala Koidz (PAMK) can promote the proliferation of thymocytes and improve the body's immunity. However, the effect of PAMK on thymic epithelial cells has not been reported. Studies have shown that miRNAs and lncRNAs are key factors in regulating cell proliferation. In this study, we found that PAMK could promote the proliferation of mouse medullary thymic epithelial cell line 1 (MTEC1) cells through CCK-8 and EdU experiments. To further explore its mechanism, we detected the effect of PAMK on the expression profiles of lncRNAs, miRNAs, and mRNAs in MTEC1 cells. The results showed that PAMK significantly affected the expression of 225 lncRNAs, 29 miRNAs, and 800 mRNAs. Functional analysis showed that these differentially expressed genes were significantly enriched in cell cycle, cell division, NF-kappaB signaling, apoptotic process, and MAPK signaling pathway. Finally, we used Cytoscape to visualize lncRNA-miRNA-mRNA(14 lncRNAs, 17 miRNAs, 171 mRNAs) networks based on ceRNA theory. These results suggest that lncRNAs and miRNAs may be involved in the effect of PAMK on the proliferation of MTEC1 cells, providing a new research direction for exploring the molecular mechanism of PAMK promoting the proliferation of thymic epithelial cells.

Integrative bioinformatics analysis of potential therapeutic targets and immune infiltration characteristics in dilated cardiomyopathy.

Background: Dilated cardiomyopathy (DCM) is currently the major cause of systolic heart failure. This study explored potential therapeutic targets and investigated the role of immune cell infiltration in DCM. Methods: Three DCM datasets (GSE3585, GSE9800, and GSE84796) from the Gene Expression Omnibus (GEO) database were merged into an integrated dataset, and batch effects were removed. Differentially expressed genes (DEGs) were screened and the associations between gene co-expression modules and clinical traits were assessed by weighted gene co-expression network analysis (WGCNA) in R software. Any DEGs from the integrated dataset overlapped with the significant module genes were defined as common genes (CGs). Enrichment analysis of the CGs was performed. The protein-protein interaction (PPI) network of the CGs was visualized and the hub gene was identified by using Cytoscape 3.8.2 software. The miRNA-transcription factor-mRNA (miRNA-TF-mRNA) network was constructed using Cytoscape to unveil the regulatory relationships in DCM. Finally, the CIBERSORT method (https://cibersort.stanford.edu/) was used to investigate immune cell infiltration in DCM. Results: A total of 53 DEGs were identified, and 5 gene co-expression modules were detected by WGCNA of the DCM and control group samples of cardiac tissue. Genes such as FRZB, ASPN, and PHLDA1 were significantly upregulated, whereas IDH2 and ENDOG were significantly downregulated. Functional enrichment analysis showed that CGs were mainly enriched in the extracellular matrix (ECM) signaling pathway. ASPN was the hub gene in the PPI network. The miRNA-TF-mRNA network revealed that FRZB and ASPN were targeted by paired related homeobox 2 (Prrx2). We also found that miR-129-5p could regulate ASPN, PHLDA1, and IDH2 simultaneously. The immune infiltration analysis revealed higher levels of M1 macrophages in DCM samples than in the control samples. Conclusions: In conclusion, we speculate that miR-129-5p might target ASPN in regulating DCM via the ECM signaling pathway. Macrophage infiltration may be involved in ECM remodeling and eventually lead to DCM.

miR-152-3p Represses the Proliferation of the Thymic Epithelial Cells by Targeting Smad2.

MicroRNAs (miRNAs) control the proliferation of thymic epithelial cells (TECs) for thymic involution. Previous studies have shown that expression levels of miR-152-3p were significantly increased in the thymus and TECs during the involution of the mouse thymus. However, the possible function and potential molecular mechanism of miR-152-3p remains unclear. This study identified that the overexpression of miR-152-3p can inhibit, while the inhibition of miR-152-3p can promote, the proliferation of murine medullary thymic epithelial cell line 1 (MTEC1) cells. Moreover, miR-152-3p expression was quantitatively analyzed to negatively regulate Smad2, and the Smad2 gene was found to be a direct target of miR-152-3p, using the luciferase reporter assay. Importantly, silencing Smad2 was found to block the G1 phase of cells and inhibit the cell cycle, which was consistent with the overexpression of miR-152-3p. Furthermore, co-transfection studies of siRNA-Smad2 (siSmad2) and the miR-152-3p mimic further established that miR-152-3p inhibited the proliferation of MTEC1 cells by targeting Smad2 and reducing the expression of Smad2. Taken together, this study proved miR-152-3p to be an important molecule that regulates the proliferation of TECs and therefore provides a new reference for delaying thymus involution and thymus regeneration.