Long-term exposure to lead (Pb) can result in chronic damage to the body through accumulation in the central nervous system (CNS) leading to neurodegenerative diseases, such as Alzheimer's disease (AD Show more
Long-term exposure to lead (Pb) can result in chronic damage to the body through accumulation in the central nervous system (CNS) leading to neurodegenerative diseases, such as Alzheimer's disease (AD). This study delves into the intricate role of miR-671/CDR1as regulation in the etiology of AD-like lesions triggered by chronic Pb exposure in adult mice. To emulate the chronic effects of Pb, we established a rodent model spanning 10 months of controlled Pb administration, dividing 52 C57BL/6J mice into groups receiving varying concentrations of Pb (1, 2, or 4 g/L) alongside an unexposed control. Blood Pb levels were monitored using serum samples to ensure accurate dosing and to correlate with observed toxicological outcomes. Utilizing the Morris water maze, a robust behavioral assay for assessing cognitive functions, we documented a dose-dependent decline in learning and memory capabilities among the Pb-exposed mice. Histopathological examination of the hippocampal tissue revealed tell-tale signs of AD-like neurodegeneration, characterized by the accumulation of amyloid plaques and neurofibrillary tangles. At the molecular level, a significant upregulation of AD-associated genes, namely amyloid precursor protein (APP), β-secretase 1 (BACE1), and tau, was observed in the hippocampal tissue of Pb-exposed mice. This was accompanied by a corresponding surge in the protein levels of APP, BACE1, amyloid-β (Aβ), and phosphorylated tau (p-tau), further implicating Pb in the dysregulation of these key AD markers. The expression of CDR1as, a long non-coding RNA implicated in AD pathogenesis, was found to be suppressed in Pb-exposed mice. This observation suggests a potential mechanistic link between Pb-induced neurotoxicity and the dysregulation of the CDR1as/miR-671 axis, which warrants further investigation. Moreover, our study identified a dose-dependent alteration in the intracellular and extracellular levels of the transcription factor nuclear factor-kappa B (NF-κB). This finding implicates Pb in the modulation of NF-κB signaling, a pathway that plays a pivotal role in neuroinflammation and neurodegeneration. In conclusion, our findings underscored the deleterious effects of Pb exposure on the CNS, leading to the development of AD-like pathology. The observed modulation of NF-κB signaling and miR-671/CDR1as regulation provides a plausible mechanistic framework for understanding the neurotoxic effects of Pb and its potential contribution to AD pathogenesis. Show less
Lymph node metastasis (LNM) is the primary mode of metastasis in gastric cancer (GC). However, the precise mechanisms underlying this process remain elusive. Tumor cells necessitate lipid metabolic re Show more
Lymph node metastasis (LNM) is the primary mode of metastasis in gastric cancer (GC). However, the precise mechanisms underlying this process remain elusive. Tumor cells necessitate lipid metabolic reprogramming to facilitate metastasis, yet the role of lipoprotein lipase (LPL), a pivotal enzyme involved in exogenous lipid uptake, remains uncertain in tumor metastasis. Therefore, the aim of this study was to investigate the presence of lipid metabolic reprogramming during LNM of GC as well as the role of LPL in this process. Intracellular lipid levels were quantified using oil red O staining, BODIPY 493/503 staining, and flow cytometry. Lipidomics analysis was employed to identify alterations in intracellular lipid composition following LPL knockdown. Protein expression levels were assessed through immunohistochemistry, Western blotting, and enzyme-linked immunosorbent assays. The mouse popliteal LNM model was utilized to investigate differences in LNM. Immunoprecipitation and mass spectrometry were employed to examine protein associations. In vitro phosphorylation assays and Phos-tag sodium dodecyl-sulfate polyacrylamide gel electrophoresis assays were conducted to detect angiopoietin-like protein 4 (ANGPTL4) phosphorylation. We identified that an elevated intracellular lipid level represents a crucial characteristic of node-positive (N+) GC and further demonstrated that a high-fat diet can expedite LNM. LPL was found to be significantly overexpressed in N+ GC tissues and shown to facilitate LNM by mediating dietary lipid uptake within GC cells. Leptin, an obesity-related hormone, intercepted the effect exerted by ANGPTL4/Furin on LPL cleavage. Circulating leptin binding to the leptin receptor could induce the activation of inositol-requiring enzyme-1 (IRE1) kinase, leading to the phosphorylation of ANGPTL4 at the serine 30 residue and subsequently reducing its binding affinity with LPL. Moreover, our research revealed that LPL disrupted lipid homeostasis by elevating intracellular levels of arachidonic acid, which then triggered the cyclooxygenase-2/prostaglandin E2 (PGE2) pathway, thereby promoting tumor lymphangiogenesis. Leptin-induced phosphorylation of ANGPTL4 facilitates LPL-mediated lipid uptake and consequently stimulates the production of PGE2, ultimately facilitating LNM in GC. Show less
Major depressive disorder (MDD) is a common disease affecting 300 million people worldwide. The existing drugs are ineffective for approximately 30% of patients, so it is urgent to develop new antidep Show more
Major depressive disorder (MDD) is a common disease affecting 300 million people worldwide. The existing drugs are ineffective for approximately 30% of patients, so it is urgent to develop new antidepressant drugs with novel mechanisms. Here, we found that norisoboldine (NOR) showed an antidepressant efficacy in the chronic social defeat stress (CSDS) depression model in the tail suspension, forced swimming, and sucrose consumption tests. We then utilized the drug-treated CSDS mice paradigm to segregate and gain differential protein groups of CSDS versus CON (CSDS Show less
Neurexin-3 (Nrxn3) has been genetically associated with obesity, but the underlying neural mechanisms remain poorly understood. This study aimed to investigate the role of Nrxn3 in the paraventricular Show more
Neurexin-3 (Nrxn3) has been genetically associated with obesity, but the underlying neural mechanisms remain poorly understood. This study aimed to investigate the role of Nrxn3 in the paraventricular nucleus of the hypothalamus (PVN) in regulating energy balance and glucose homeostasis. We found that Nrxn3 expression in the PVN was upregulated in response to metabolic stressors, including cold exposure and fasting. Using Cre-loxP technology, we selectively ablated Nrxn3 in CaMKIIα-expressing neurons of the PVN in male mice. This genetic manipulation resulted in marked weight gain attributable to increased adiposity and impaired glucose tolerance, without affecting food intake. Our findings identify PVN CaMKIIα-expressing neurons as a critical locus where Nrxn3 modulates energy balance by regulating adipogenesis and glucose metabolism, independently of appetite. These results reveal a novel neural mechanism potentially linking Nrxn3 dysfunction to obesity pathogenesis, suggesting that targeting PVN Nrxn3-dependent neural pathways may inform new therapeutic approaches for obesity prevention and treatment. Show less
Epithelial-to-mesenchymal transitions (EMTs) and extracellular matrix (ECM) remodeling are distinct yet important processes during carcinoma invasion and metastasis. Transforming growth factor β (TGF- Show more
Epithelial-to-mesenchymal transitions (EMTs) and extracellular matrix (ECM) remodeling are distinct yet important processes during carcinoma invasion and metastasis. Transforming growth factor β (TGF-β) and RAS, signaling through SMAD and RAS-responsive element-binding protein 1 (RREB1), jointly trigger expression of EMT and fibrogenic factors as two discrete arms of a common transcriptional response in carcinoma cells. Here, we demonstrate that both arms come together to form a program for lung adenocarcinoma metastasis and identify chromatin determinants tying the expression of the constituent genes to TGF-β and RAS inputs. RREB1 localizes to H4K16acK20ac marks in histone H2A.Z-loaded nucleosomes at enhancers in the fibrogenic genes interleukin-11 (IL11), platelet-derived growth factor-B (PDGFB), and hyaluronan synthase 2 (HAS2), as well as the EMT transcription factor SNAI1, priming these enhancers for activation by a SMAD4-INO80 nucleosome remodeling complex in response to TGF-β. These regulatory properties segregate the fibrogenic EMT program from RAS-independent TGF-β gene responses and illuminate the operation and vulnerabilities of a bifunctional program that promotes metastatic outgrowth. Show less
Endometriosis (EMT) is a common gynecological disease with a strong genetic component, while its precise etiology remains elusive. This study aims to integrate transcriptome-wide association study (TW Show more
Endometriosis (EMT) is a common gynecological disease with a strong genetic component, while its precise etiology remains elusive. This study aims to integrate transcriptome-wide association study (TWAS), Mendelian randomization (MR), and bioinformatics analyses to reveal novel putatively causal genes and potential mechanisms. We obtained summary-level data of the Genotype-Tissue Expression Project (GTEx), v8 expression quantitative loci (eQTL) data, and the genome-wide association study (GWAS) data of EMT and its subtypes from the R11 release results of the FinnGen consortium for analysis. GWAS data of modifiable risk factors were collected from IEU Open GWAS. Cross-tissue TWAS analyses were performed using the unified test for molecular signature (UTMOST), while functional summary-based imputation (FUSION) was employed for single-tissue TWAS analyses. Furthermore, we also conducted multi-marker analysis of genomic annotation (MAGMA) analyses to validate the significant associations. Subsequent Mendelian randomization (MR) and colocalization analysis elucidated the causal associations between the identified genes across various tissues and EMT. To further delve into mechanisms, two-sample network MR analyses were conducted. At last, bioinformatics analyses were employed to enhance our understanding of the functional implications and expression patterns of these identified genes. For EMT, 22 significant gene signals were identified by UTMOST, 615 by FUSION, and 354 by MAGMA. Ultimately, six genes, including CISD2, EFRB, GREB1, IMMT, SULT1E1, and UBE2D3, were identified as candidate susceptibility genes for EMT. Through similar procedures, we identified GREB1, IL1A, and SULT1E1 for EMT of the ovary, and we identified GREB1 for EMT of the pelvic peritoneum, EMT of rectovaginal septum and vagina, and deep EMT. In MR analyses, the expression of IMMT in 21 tissues, EFR3B in the adrenal gland, CISD2 in 17 tissues, and UBE2D3 in 7 tissues demonstrated causal relationships with EMT risk. In addition, CISD2, IMMT, and UBE2D3, across different tissues, exhibited strong colocalization with EMT (PPH4 > 0.7). Two-sample network MR analyses revealed that CISD2, EFR3B, and UBE2D3 could potentially regulate the levels of blood lipids and hip circumference so as to influence the risk of EMT. Furthermore, bioinformatics analyses confirmed our findings and delved into the biological functions of the identified genes. Our study unveiled seven novel candidate genes whose predicted expression was associated with the risk of EMT, providing new insights into the underlying genetic framework of EMT. These findings will facilitate a deeper comprehension of the tissue-specific transcriptional regulatory mechanisms associated with EMT, paving the way for optimizing the management and treatment of EMT. Show less
Androgen receptor (AR) pathway inhibition remains the cornerstone for prostate cancer therapies. However, castration-resistant prostate cancer (CRPC) tumors can resist AR signaling inhibitors through Show more
Androgen receptor (AR) pathway inhibition remains the cornerstone for prostate cancer therapies. However, castration-resistant prostate cancer (CRPC) tumors can resist AR signaling inhibitors through AR amplification and AR splice variants in AR-positive CRPC (ARPC), and conversion to AR-null phenotypes, such as double-negative prostate cancer (DNPC) and small cell or neuroendocrine prostate cancer (SCNPC). We have shown previously that DNPC can bypass AR-dependence through fibroblast growth factor receptor (FGFR) signaling. However, the role of the FGFR pathway in other CRPC phenotypes has not been elucidated. RNA-Seq analysis was conducted on patient metastases, LuCaP patient-derived xenograft (PDX) models, and CRPC cell lines. Cell lines (C4-2B, VCaP, and 22Rv1) and ex vivo LuCaP PDX tumor cells were treated with enzalutamide (ENZA) and FGFR inhibitors (FGFRi) alone or in combination and sensitivity was determined using cell viability assays. In vivo efficacy of FGFRi in ARPC, DNPC, and SCNPC were evaluated using PDX models. RNA-Seq analysis of FGFR signaling in metastatic specimens, LuCaP PDX models, and CRPC cell lines revealed significant FGF pathway activation in AR-low PC (ARLPC), DNPC, and SCNPC tumors. In vitro/ex vivo analysis of erdafitinib and CH5183284 demonstrated robust and moderate growth suppression of ARPC, respectively. In vivo studies using four ARPC PDX models showed that combination ENZA and CH5183284 significantly suppressed tumor growth. Additional in vivo studies using four ARPC PDX models revealed that erdafitinib monotherapy was as effective as ENZA in suppressing tumor growth, and there was limited combination benefit. Furthermore, two of three DNPC models and two of four SCNPC models responded to CH5183284 monotherapy, suggesting FGFRi responses were model dependent. RNA-Seq and gene set enrichment analysis of end-of-study ARPC tumors treated with FGFRi displayed decreased expression of E2F and MYC target genes and suppressed G2M checkpoint genes, whereas end-of-study SCNPC tumors had heterogeneous transcriptional responses. Although FGFRi treatments suppressed tumor growth across CRPC phenotypes, our analyses did not identify a single pathway or biomarker that would identify tumor response to FGFRi. This is very likely due to the array of FGFR1-4 expression and tumor phenotypes present in CRPC. Nevertheless, our data nominate the FGFR pathway as a clinically actionable target that promotes tumor growth in diverse phenotypes of treatment-refractory metastatic CRPC. Show less
This study aimed to investigate the effects of hepatic microRNA-122 (miR-122) on Sortilin-mediated apolipoprotein B100 (apoB-100) secretion, and on aortic lipid deposition and atherosclerosis (AS) les Show more
This study aimed to investigate the effects of hepatic microRNA-122 (miR-122) on Sortilin-mediated apolipoprotein B100 (apoB-100) secretion, and on aortic lipid deposition and atherosclerosis (AS) lesions and to clarify the antiatherosclerotic mechanism of 6-methylcoumarin (6-MC) via the modulation of miR-122. Bioinformatics analysis revealed that miR-122 was putatively overexpressed in a liver-specific manner and was downregulated in steatotic livers. miR-122 was shown to suppress the expression of Sortilin by complementarily pairing to the 3'-untranslated region (3'-UTR) of Sortilin mRNA via bioinformatics and dual-luciferase reporter assays, impeding Sortilin-mediated apoB-100 secretion from HepG2 cells. Administration of 6-MC significantly upregulated hepatocellular miR-122 levels, reducing Sortilin expression and apoB-100 secretion in HepG2 cells. The miR-122 mimic vigorously enhanced 6-MC-depressed Sortilin expression, while miR-122 inhibitor repealed the inhibitory effect of 6-MC on Sortilin expression to some extent in HepG2 cells. After internal intervention with the miR-122 precursor, and 6-MC supplementation alone or in combination with the miR-122 sponge led to the reduction in blood triglyceride (TG) levels, low-density lipoprotein-cholesterol (LDL-C) and apoB-100 and a reduction in aortic lipid deposition and AS lesions in apolipoprotein E-deficient (ApoE Show less
Peritoneal metastasis, the third most common metastasis in colorectal cancer (CRC), has a poor prognosis for the rapid progression and limited therapeutic strategy. However, the molecular characterist Show more
Peritoneal metastasis, the third most common metastasis in colorectal cancer (CRC), has a poor prognosis for the rapid progression and limited therapeutic strategy. However, the molecular characteristics and pathogenesis of CRC peritoneal metastasis are poorly understood. Here, we aimed to elucidate the action and mechanism of adipose-derived stem cells (ADSCs), a prominent component of the peritoneal microenvironment, in CRC peritoneal metastasis formation. Database analysis indicated that ADSCs infiltration was increased in CRC peritoneal metastases, and high expression levels of ADSCs marker genes predicted a poor prognosis. Then we investigated the effect of ADSCs on CRC cells in vitro and in vivo. The results revealed that CRC cells co-cultured with ADSCs exhibited stronger metastatic property and anoikis resistance, and ADSCs boosted the intraperitoneal seeding of CRC cells. Furthermore, RNA sequencing was carried out to identify the key target gene, angiopoietin like 4 (ANGPTL4), which was upregulated in CRC specimens, especially in peritoneal metastases. Mechanistically, TGF-β1 secreted by ADSCs activated SMAD3 in CRC cells, and chromatin immunoprecipitation assay showed that SMAD3 facilitated ANGPTL4 transcription by directly binding to ANGPTL4 promoter. The ANGPTL4 upregulation was essential for ADSCs to promote glycolysis and anoikis resistance in CRC. Importantly, simultaneously targeting TGF-β signaling and ANGPTL4 efficiently reduced intraperitoneal seeding in vivo. In conclusion, this study indicates that tumor-infiltrating ADSCs promote glycolysis and anoikis resistance in CRC cells and ultimately facilitate peritoneal metastasis via the TGF-β1/SMAD3/ANGPTL4 axis. The dual-targeting of TGF-β signaling and ANGPTL4 may be a feasible therapeutic strategy for CRC peritoneal metastasis. Show less
Fasting and refeeding systems can cause significant short-term fluctuations in nutrient and energy levels, triggering adaptive physiological responses in animals. This study examines the effects of fa Show more
Fasting and refeeding systems can cause significant short-term fluctuations in nutrient and energy levels, triggering adaptive physiological responses in animals. This study examines the effects of fasting and refeeding on blood biochemical indicators and transcriptional profiles in the hypothalamus and subcutaneous adipose tissue of geese. Biochemical assays reveal that fasting significantly increases levels of free fatty acids and glucagon, while reducing concentrations of triglycerides, leptin, and insulin. Transcriptomic analyses identify a complex transcriptional response in both the hypothalamus and subcutaneous adipose tissue, affecting several metabolic pathways and key genes associated with feed intake and energy metabolism. In subcutaneous adipose tissue, fasting downregulates genes involved in fatty acid synthesis ( Show less
Long-persistent luminescence (LPL) materials have attracted intensive attention due to their fascinating emission after excitation. However, current LPL materials typically depend on external doping t Show more
Long-persistent luminescence (LPL) materials have attracted intensive attention due to their fascinating emission after excitation. However, current LPL materials typically depend on external doping to introduce traps or emitting centers, resulting in a complex synthesis and controllability. For the first time, we develop another category of undoped LPL materials based on antimonate CaSb Show less
Long-persistent luminescent (LPL) materials have attracted considerable research interest due to their extensive applications and outstanding afterglow performance. However, the performance of red LPL Show more
Long-persistent luminescent (LPL) materials have attracted considerable research interest due to their extensive applications and outstanding afterglow performance. However, the performance of red LPL materials lags behind that of green and blue materials. Therefore, it is crucial to explore novel red LPL materials. This study introduces a straightforward and viable strategy for organic-inorganic hybrids, wherein the organic ligand 1,3,6,8-Tetrakis(4-carboxyphenyl)pyrene (TCPP) is coordinated to the surface of a red persistent phosphor Sr Show less
The global burden of renal diseases is increasingly severe, underscoring the need for in-depth exploration of the molecular mechanisms underlying renal disease progression and the development of poten Show more
The global burden of renal diseases is increasingly severe, underscoring the need for in-depth exploration of the molecular mechanisms underlying renal disease progression and the development of potential novel biomarkers or therapeutic targets. Angiopoietin-like protein 4 (ANGPTL4) is a multifunctional cytokine involved in the regulation of key biological processes, such as glucose and lipid metabolism, inflammation, vascular permeability, and angiogenesis, all of which play crucial roles in the pathogenesis of kidney diseases. Over the past 2 decades, ANGPTL4 has been regarded as playing a pivotal role in the progression of various kidney diseases, prompting significant interest from the scientific community regarding its potential clinical utility in renal disorders. This review synthesizes the available literature, provides a concise overview of the molecular biological effects of ANGPTL4, and highlights its relationship with multiple renal diseases and recent research advancements. These findings underscore the important gaps that warrant further investigation to develop novel targets for the prediction or treatment of various renal diseases. Show less
Purinergic signaling plays a causal role in the modulation of immune inflammatory response in the course of psoriasis, but its regulatory mechanism remains unclear. As a member of purinoceptors, P2Y
On-chip polarization-sensitive photodetectors are highly desired for ultra-compact optoelectronic systems. It has been demonstrated that polarization-sensitive photodetection can be realized using int Show more
On-chip polarization-sensitive photodetectors are highly desired for ultra-compact optoelectronic systems. It has been demonstrated that polarization-sensitive photodetection can be realized using intrinsic chiral and anisotropy materials. However, these photodetectors can only realize the detection of either circularly polarized light (CPL) or linear polarized light (LPL) and are not applicable to multiple-polarization-sensitive photodetection. Herein, we experimentally demonstrate a metasurface-integrated semiconductor to realize multiple-polarization-sensitive photodetection at visible wavelengths. This device is composed of a MoSe Show less
To explore the causal relationship between inflammatory protein markers and the risk of colorectal cancer using a Mendelian randomization (MR) approach. We obtained data pertaining to colorectal cance Show more
To explore the causal relationship between inflammatory protein markers and the risk of colorectal cancer using a Mendelian randomization (MR) approach. We obtained data pertaining to colorectal cancer from Genome-Wide Association Study (GWAS) datasets and used 91 inflammatory protein markers as the exposure variables. A two-sample MR analysis model was used to assess the causal link between the inflammatory markers and colorectal cancer risk. The robustness of the results was evaluated through heterogeneity, pleiotropy, and sensitivity analyses using 5 MR models: Inverse Variance Weighted (IVW), Weighted Median, MR Egger, Simple Mode, and Weighted Mode. We examined the mRNA expressions of Using the IVW model, MR analysis revealed significant causal associations between a reduced risk of colorectal cancer and lowered expressions of AXIN1 (OR=0.866, 95% Lowered expressions of inflammatory protein markers AXIN1, β-NGF, and PD-L1 are causally correlated with a reduced risk of colorectal cancer and their expression levels are associated with TNM staging and tumor differentiation. These markers may thus serve as potential targets for colorectal cancer treatment and prevention. Show less
Centromere protein U (CENPU) is key for mitosis in the carcinogenesis of cancers. However, the roles of CENPU have not been inspected in nasopharyngeal carcinoma (NPC). Thus, we aimed to explore the f Show more
Centromere protein U (CENPU) is key for mitosis in the carcinogenesis of cancers. However, the roles of CENPU have not been inspected in nasopharyngeal carcinoma (NPC). Thus, we aimed to explore the functions and mechanisms of CENPU in NPC. Expression of CENPU was evaluated by real-time quantitative polymerase chain reaction, western blotting and immunohistochemistry. The biological functions of CENPU were evaluated CENPU was highly expressed in NPC. High expression of CENPU was associated with advanced tumor, node and metastasis (TNM) stage and poor overall survival. Cox regression analysis demonstrated that CENPU expression was an independent prognostic factor in NPC. Knockdown of CENPU inhibited proliferation and migration CENPU acts as an oncogene in NPC by interacting with DUSP6, and may represent a promising prognostic biomarker for patients with NPC. Show less
Precise wiring within sensory systems is critical for the accurate transmission of information. In the visual system, S-cone photoreceptors specialize in detecting short-wavelength light, crucial to c Show more
Precise wiring within sensory systems is critical for the accurate transmission of information. In the visual system, S-cone photoreceptors specialize in detecting short-wavelength light, crucial to color perception and environmental cue detection. S-cones form specific synapses with S-cone bipolar cells (SCBCs), a connection that is remarkably consistent across species. Yet, the molecular mechanisms guiding this specificity remain unexplored. To address this, we used the cone-dominant ground squirrel for deep-sequencing of cone subtype transcriptomes and identified Nrxn3 as an essential molecule for the S-cone to SCBC synapse. Using transgenic mouse models, we further examined the role of Nrxn3 in S-cones and discovered a significant reduction of SCBC connections in the absence of Nrxn3. This finding extends the known functions of neurexins, typically associated with synapse regulation, by highlighting their essential role in a specific synaptic connection for the first time. Moreover, the differentially expressed genes identified here pave the way for further investigations into the unique functions of cone subtypes. Show less
To evaluate the impact of differential emergency treatment measures on the prognosis of patients with ACS. 76 patients with ACS treated in the emergency department of our hospital from January 2017 to Show more
To evaluate the impact of differential emergency treatment measures on the prognosis of patients with ACS. 76 patients with ACS treated in the emergency department of our hospital from January 2017 to September 2021 were selected as the research objects. According to their main symptoms, general signs, and various examination results when arriving at the hospital, differential emergency treatment measures were implemented, so as to ensure the curative effect. After comprehensive emergency treatment, the venous blood test indicators of patients, including creatinine (CR), uric acid (UA), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), lipoprotein A (LPA), Apolipoprotein AI (ApoAI), Apolipoprotein B (ApoB), Potassium ion (K+), glucose (GLU), Cardiac troponin I (cTn) returned to normal. In addition, the proportion of patients without cardiogenic shock, ventricular fibrillation, respiratory and cardiac arrest, cerebral infarction, cerebral hemorrhage, arrhythmia, heart rupture, and other adverse reactions are as high as 92% (70/76). For patients with ACS, it is necessary to take correct emergency rescue and treatment measures immediately, especially to actively implement the percutaneous coronary intervention (PCI) method, so as to give full play to the safety and effectiveness of emergency treatment and curb the possibility of patient death as much as possible. Show less
To investigate the mechanism underlying the regulation of blood-brain barrier permeability changes during cryptococcal meningitis by NLRP3 and Vimentin. Sprague-Dawley rats were treated with WT Crypto Show more
To investigate the mechanism underlying the regulation of blood-brain barrier permeability changes during cryptococcal meningitis by NLRP3 and Vimentin. Sprague-Dawley rats were treated with WT Cryptococcus neoformans (Cn) or CPS1-/- Cn. Neuronal apoptosis was assessed using TUNEL staining, and pathological changes were observed using electron microscopy and HE staining. The expressions of NLRP3, Vimentin, and NF-κB in the cerebral cortex and human brain microvascular endothelial cells (HBMECs) were examined through Western blot and qRT-PCR. siNLRP3 and siVimentin were separately transfected into HBMECs, the expressions of specific factors were assessed. NF-κB and Vimentin levels were detected through immunofluorescence, apoptosis was measured using flow cytometry, and changes in the optical density (OD) of HRP were determined using ELISA. The expressions of NLRP3, Vimentin, and NF-κB were upregulated following intervention with WT Cn Vimentin and the NLRP3 inflammasome are both implicated in the pathological process of cryptococcal meningitis. An interaction between Vimentin and the NLRP3 inflammasome is evident, likely mediated through the NF-κB signaling pathway. Show less
Osteoarthritis is recognized as a common geriatric condition characterized by irregular chronic pain. Its prevalence is steadily increasing, posing significant challenges to global public health, whil Show more
Osteoarthritis is recognized as a common geriatric condition characterized by irregular chronic pain. Its prevalence is steadily increasing, posing significant challenges to global public health, while some studies indicate a trend towards younger individuals being affected. This condition severely impacts patients' quality of life. Using the Gene Expression Omnibus (GEO) database, we downloaded datasets GSE114007, GSE169077, and GSE206848. We utilized R software to screen and confirm differentially expressed genes (DEGs) related to the development of osteoarthritis. A cross-analysis of the three datasets was conducted, with the least overlapping dataset, GSE206848, selected as the validation set. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed on the DEGs from GSE114007 and GSE169077. Weighted Gene Co-Expression Network Analysis (WGCNA) was employed to identify modules closely associated with osteoarthritis, and genes from these intersecting modules were entered into the STRING database to construct Protein-Protein Interaction Networks. The top ten genes by connectivity were identified and validated using GSE206848. Key genes were identified and preliminarily validated using Quantitative Real-Time PCR (QPCR). Subsequent validation of related genes was carried out through Western Blot (WB) analysis. Differentially expressed genes were identified from the GSE114007 and GSE169077 datasets and validated in the GSE206848 dataset, with ANGPTL4 selected as the key gene. QPCR results indicated a significant difference in ANGPTL4 expression levels between normal and osteoarthritic chondrocytes. Western Blot analysis confirmed a significant difference in ANGPTL4 protein expression between normal and osteoarthritic chondrocytes. Based on the experimental findings, ANGPTL4 appears to be a potential key gene in osteoarthritis. Show less
Cyclic dipeptides (CDPs), known for their diverse biological activities, have potential therapeutic applications in mental and behavioral disorders (MBDs), particularly schizophrenia. This study explo Show more
Cyclic dipeptides (CDPs), known for their diverse biological activities, have potential therapeutic applications in mental and behavioral disorders (MBDs), particularly schizophrenia. This study explores the CDPs' therapeutic potential using bibliometric analysis, network pharmacology, molecular docking, and experimental verification, focusing on the interactions with the SIGMA1 receptor. A literature review over three decades utilizing the Web of Science Core Collection (WOSCC) was conducted to identify the emerging trends in CDPs research. A compound library was constructed from the PubChem database, and target prediction using SwissTargetPrediction revealed 800 potential protein targets. A compound-target network highlighted the key interactions with kinases, G protein-coupled receptors, and chromatin-modifying enzymes. Enrichment analysis revealed significant associations with schizophrenia and other MBDs. Schizophrenia-related targets among the potential protein targets were identified using the GEO database. Molecular docking results showed interactions of MC4R, OPRK1, SIGMA1, and CDK5R1 with various CDPs compounds, with SIGMA1 being especially noteworthy. Most CDPs exhibited lower binding energies than the control compounds NE-100 and duloxetine. Experimental validation demonstrated that CDPs such as Cyclo(Ala-Gln), Cyclo(Ala-His), and Cyclo(Val-Gly) exhibited IC Show less
Increasing evidence has indicated that long non-coding RNAs (lncRNAs) have been proven to regulate esophageal cancer progression. The lncRNA protein disulfide isomerase family A member 3 pseudogene 1 Show more
Increasing evidence has indicated that long non-coding RNAs (lncRNAs) have been proven to regulate esophageal cancer progression. The lncRNA protein disulfide isomerase family A member 3 pseudogene 1 (PDIA3P1) has been shown to promote cancer stem cell properties; however, its mechanism of action remains unclear. In this study, we investigated the regulation of esophageal cancer stem cell properties by the interaction of PDIA3P1 with proteins. The GEPIA2 and Gene Expression Omnibus databases were used to analyze gene expression. PDIA3P1 expression in human esophageal squamous cell carcinoma (ESCC) tissues and cell lines was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Loss-of-function experiments were performed to determine the effects of PDIA3P1 on ESCC cell proliferation, migration, and invasion. The sphere formation assay, number of side population cells, and CD271 + /CD44 + cells were detected by flow cytometry to identify the cancer stem cell properties. RNA immunoprecipitation (RIP), RNA pull-down, co-immunoprecipitation (co-IP), dual luciferase reporter, and cleavage under targets and tagmentation (CUT&Tag) assays were performed to elucidate the underlying molecular mechanisms. PDIA3P1 expression was upregulated in ESCC cell lines and tissues. Functionally, higher PDIA3P1 expression promoted cell proliferation, invasion, and metastasis and inhibited apoptosis in esophageal cancer. Importantly, PDIA3P1 promoted cancer stem cell properties in ESCC. Mechanistically, PDIA3P1 interacted with and stabilized octamer-binding transcription factor 4 (OCT4) by eliminating its ubiquitination by the ubiquitinating enzyme WW domain-containing protein 2 (WWP2). Moreover, as a transcription factor, OCT4 bound to the PDIA3P1 promoter and promoted its transcription. Our research revealed a novel mechanism by which a positive feedback loop exists between PDIA3P1 and OCT4. It also demonstrated that the PDIA3P1-WWP2-OCT4 loop is beneficial for promoting the cancer stem cell properties of ESCC. Owing to this regulatory relationship, the PDIA3P1-WWP2-OCT4-positive feedback loop might be used in the diagnosis and prognosis, as well as in the development of novel therapeutics for esophageal cancer. Show less
Human fibroblast growth factor 19 (FGF19, or FGF15 in rodents) plays a central role in controlling bile acid (BA) synthesis through a negative feedback mechanism. This process involves a postprandial Show more
Human fibroblast growth factor 19 (FGF19, or FGF15 in rodents) plays a central role in controlling bile acid (BA) synthesis through a negative feedback mechanism. This process involves a postprandial crosstalk between the BA-activated ileal farnesoid X receptor and the hepatic Klotho beta (KLB) coreceptor complexed with fibrobalst growth factor receptor 4 (FGFR4) kinase. Additionally, FGF19 regulates glucose, lipid, and energy metabolism by coordinating responses from functional KLB and FGFR1-3 receptor complexes on the periphery. Pharmacologically, native FGF19 or its analogs decrease elevated BA levels, fat content, and collateral tissue damage. This makes them effective in treating both cholestatic diseases such as primary biliary or sclerosing cholangitis (PBC or PSC) and metabolic abnormalities such as nonalcoholic steatohepatitis (NASH). However, chronic administration of FGF19 drives oncogenesis in mice by activating the FGFR4-dependent mitogenic or hepatic regenerative pathway, which could be a concern in humans. Agents that block FGF19 or FGFR4 signaling have shown great potency in preventing FGF19-responsive hepatocellular carcinoma (HCC) development in animal models. Recent phase 1/2 clinical trials have demonstrated promising results for several FGF19-based agents in selectively treating patients with PBC, PSC, NASH, or HCC. This review aims to provide an update on the clinical development of both analogs and antagonists targeting the FGF19-FGFR4 signaling pathway for patients with cholestatic, metabolic, and cancer diseases. We will also analyze potential safety and mechanistic concerns that should guide future research and advanced trials. Show less
Yanhua Zhou, Dayu Yan, Xiulan Zhang+3 more · 2024 · Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · added 2026-04-24
Pelvic organ prolapse (POP) is a common condition in postmenopausal women, with an increasing prevalence due to aging. Some women experience POP recurrence after surgical treatment, significantly affe Show more
Pelvic organ prolapse (POP) is a common condition in postmenopausal women, with an increasing prevalence due to aging. Some women experience POP recurrence after surgical treatment, significantly affecting their physical and mental health. The uterosacral ligament is a critical pelvic support structure. This study aims to investigate the molecular pathological changes in the uterosacral ligament of postmenopausal women with recurrent POP using transcriptomic analysis. Transcriptomic data of uterosacral ligament tissues were obtained from the public dataset GSE28660, which includes samples from 4 postmenopausal women with recurrent POP, 4 with primary POP, and 4 without POP. Differentially expressed genes (DEGs) were identified between recurrent POP and both primary and non-POP groups. Further analysis included intersection analysis of DEGs, gene ontology enrichment, protein-protein interaction (PPI) network construction, gene set enrichment analysis (GSEA), single-sample GSEA, and xCell immune cell infiltration analysis to explore molecular pathological changes in recurrent POP. Additionally, histological and molecular differences in the uterosacral ligament were compared between simulated vaginal delivery (SVD) rat models with and without ovariectomy. Compared with primary POP and non-POP groups, recurrent POP exhibited activation of adipogenesis and inflammation-related pathways, while pathways related to muscle proliferation and contraction were downregulated in the uterosacral ligament. Nine key DEGs ( Adipogenesis and inflammation in the uterosacral ligament may contribute to its reduced supportive function, potentially leading to recurrence POP in postmenopausal women. Show less
Epidemiological studies suggested an association between omega-3 fatty acids and cognitive function. However, the causal role of the fatty acid desaturase (FADS) gene, which play a key role in regulat Show more
Epidemiological studies suggested an association between omega-3 fatty acids and cognitive function. However, the causal role of the fatty acid desaturase (FADS) gene, which play a key role in regulating omega-3 fatty acids biosynthesis, on cognitive function is unclear. Hence, we used two-sample Mendelian randomization (MR) to estimate the gene-specific causal effect of omega-3 fatty acids (N = 114,999) on cognitive function (N = 300,486). Tissue- and cell type-specific effects of FADS1/FADS2 expression on cognitive function were estimated using brain tissue cis-expression quantitative trait loci (cis-eQTL) datasets (GTEx, N ≤ 209; MetaBrain, N ≤ 8,613) and single cell cis-eQTL data (N = 373), respectively. These causal effects were further evaluated in whole blood cis-eQTL data (N ≤ 31,684). A series of sensitivity analyses were conducted to validate MR assumptions. Leave-one-out MR showed a FADS gene-specific effect of omega-3 fatty acids on cognitive function [β = -1.3 × 10 Show less
Poor proliferative capacity of adult cardiomyocytes is the primary cause of heart failure after myocardial infarction (MI), thus exploring the molecules and mechanisms that promote the proliferation o Show more
Poor proliferative capacity of adult cardiomyocytes is the primary cause of heart failure after myocardial infarction (MI), thus exploring the molecules and mechanisms that promote the proliferation of adult cardiomyocytes is crucially useful for cardiac repair after MI. Here, we found that miR-130b-5p was highly expressed in mouse embryonic and neonatal hearts and able to promote cardiomyocyte proliferation both in vitro and in vivo. Mechanistic studies revealed that miR-130b-5p mainly promoted the cardiomyocyte proliferation through the MAPK-ERK signaling pathway, and the dual-specific phosphatase 6 (Dusp6), a negative regulator of the MAPK-ERK signaling, was the direct target of miR-130b-5p. Moreover, we found that overexpression of miR-130b-5p could promote the proliferation of cardiomyocytes and improve cardiac function in mice after MI. These studies thus revealed the critical role of miR-130b-5p and its targeted MAPK-ERK signaling in the cardiomyocyte proliferation of adult hearts and proved that miR-130b-5p could be a potential target for cardiac repair after MI. Show less
Baozhu Guo, Junfen Liu, Xiaoli Han+5 more · 2024 · Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · added 2026-04-24
Adverse cardiovascular events are the leading cause of death in peritoneal dialysis patients. Identifying indicators that can predict adverse cardiovascular events in these patients is crucial for pro Show more
Adverse cardiovascular events are the leading cause of death in peritoneal dialysis patients. Identifying indicators that can predict adverse cardiovascular events in these patients is crucial for prognosis. This study aims to assess the value of dual-specificity phosphatase 6 (DUSP6) in peripheral blood mononuclear cells as a predictor of adverse cardiovascular events after peritoneal dialysis in diabetic nephropathy patients. A total of 124 diabetic nephropathy patients underwent peritoneal dialysis treatment at the Department of Nephrology of the First Affiliated Hospital of Hebei North University from June to September 2022 were selected as study subjects. The levels of DUSP6 in peripheral blood mononuclear cells were determined using Western blotting. Patients were categorized into high-level and low-level DUSP6 groups based on the median DUSP6 level. Differences in body mass index, serum albumin, high-sensitivity C-reactive protein, and dialysis duration were compared between the 2 groups. Pearson, Spearman, and multiple linear regression analyses were performed to examine factors related to DUSP6. Patients were followed up to monitor the occurrence of adverse cardiovascular events, and risk factors for adverse cardiovascular events after peritoneal dialysis were analyzed using Kaplan-Meier and Cox regression. By the end of the follow-up, 33 (26.61%) patients had experienced at least one adverse cardiovascular event. The high-level DUSP6 group had higher body mass index, longer dialysis duration, and higher high-sensitivity C-reactive protein, but lower serum albumin levels compared to the low-level DUSP6 group (all Dialysis duration and high-sensitivity C-reactive protein are independently associated with DUSP6 levels in peripheral blood mononuclear cells of diabetic nephropathy patients undergoing peritoneal dialysis. High DUSP6 levels indicate a higher risk of adverse cardiovascular events. Show less