Diabetes, a global epidemic, is the leading cause of mortality globally. The aim of this study is to get better understanding of pathophysiology of diabetes. Palmitic acid (PA)-treated β-cells, db/db Show more
Diabetes, a global epidemic, is the leading cause of mortality globally. The aim of this study is to get better understanding of pathophysiology of diabetes. Palmitic acid (PA)-treated β-cells, db/db mice and high fat diet (HFD)-fed mouse model of type 2 diabetes were established. H&E was used to assess the histological changes of pancreas. IHC, FISH, western blot or qRT-PCR was employed to detect the expression of key molecules in primary islets or lipotoxic β-cells. Cell behaviors were detected by MTT, EdU incorporation assay, TUNEL assay and glucose-induced insulin secretion (GSIS). The associations among circMlxipl, Mbnl1 and Rbbp6 were validated by RIP and RNA pull-down assays, and the direct binding between Hdac3 and Mbnl1 promoter was examined by ChIP and luciferase assays. Co-IP was employed to assess the interaction between ChREBP and Rbbp6, as well as the ubiquitination of ChREBP. Hdac3 and ChREBP were upregulated, but Mbnl1 and circMlxipl were downregulated in islets from diabetic mice and lipotoxic β-cells. Mbnl1 overexpression protected against PA-induced impairments in lipotoxic β-cells through modulating back-splicing of circMlxipl and suppressing ChREBP. Hdac3 served as a transcriptional repressor of Mbnl1, and it was implicated in circMlxipl-mediated protection via regulating ChREBP expression in lipotoxic β-cells. Lack of circMlxipl inhibited Rbbp6-mediated ubiquitin-proteasomal degradation of ChREBP in lipotoxic β-cells. In vivo studies revealed that Hdac3 knockdown or Mbnl1 overexpression alleviated diabetes symptoms through circMlxipl-regulated ChREBP in diabetic mice. Mbnl1-mediated alternative splicing of circMlxipl regulates Rbbp6-involved ChREBP turnover to inhibit lipotoxicity-induced β-cell damage. Show less
Although polarized light can assist many animals in performing special visual tasks, current polarized light pollution (PLP) caused by urban construction has been shown to induce maladaptive behaviors Show more
Although polarized light can assist many animals in performing special visual tasks, current polarized light pollution (PLP) caused by urban construction has been shown to induce maladaptive behaviors of PL-sensitive animals and change ecological interactions. However, the underlying mechanisms remain unclear. Our previous work hypothesized that linearly polarized light (LPL) is an ecological trap for Oratosquilla oratoria, a common Stomatopoda species in the China Sea. Here we explored the underlying negative effects of artificially LPL on O. oratoria based on comparative transcriptomics. We identified 3616 differentially expressed genes (DEGs) in O. oratoria compound eyes continuous exposed to natural light (NL) and LPL scenarios. In comparison with the NL scenario, a total of 1972 up- and 1644 down- regulated genes were obtained from the O. oratoria compound eyes under LPL scenario, respectively. Furthermore, we performed functional annotation of those DEGs described above and identified 65 DEGs related to phototransduction, reproduction, immunity, and synapse. Based on the functional information, we suspected that continuous LPL exposure could block the light transmission, disrupt the reproductive process, and lead to the progressive failure of the immune response of O. oratoria. In conclusion, this study is the first to systematically describe the negative effects of artificial LPL exposure on O. oratoria at the genetic level, and it can improve the biological conservation theory behind PLP. Show less
Large-for-gestational-age (LGA) neonates have increased risk of adverse pregnancy outcomes and adult metabolic diseases. We aimed to investigate the relationship between plasma angiopoietin-like prote Show more
Large-for-gestational-age (LGA) neonates have increased risk of adverse pregnancy outcomes and adult metabolic diseases. We aimed to investigate the relationship between plasma angiopoietin-like protein 4 (ANGPTL4), a protein involved in lipid and glucose metabolism during pregnancy, placental function, growth factors, and the risk of LGA. We conducted a prospective cohort study and recruited women with singleton pregnancies at the National Taiwan University Hospital between 2013 and 2018. First trimester maternal plasma ANGPTL4 concentrations were measured. Among 353 pregnant women recruited, the LGA group had higher first trimester plasma ANGPTL4 concentrations than the appropriate-for-gestational-age group. Plasma ANGPTL4 was associated with hemoglobin A1c, post-load plasma glucose, plasma triglyceride, plasma free fatty acid concentrations, plasma growth hormone variant (GH-V), and birth weight, but was not associated with cord blood growth factors. After adjusting for age, body mass index, hemoglobin A1c, and plasma triglyceride concentrations, plasma ANGPTL4 concentrations were significantly associated with LGA risk, and its predictive performance, as measured by the area under the receiver operating characteristic curve, outperformed traditional risk factors for LGA. Plasma ANGPTL4 is associated with glucose and lipid metabolism during pregnancy, plasma GH-V, and birth weight, and is an early biomarker for predicting the risk of LGA. Show less
To explore the patterns of differentially expressed genes (DEGs) associated with different growth rates in rock carp (Procypris rabaudi), transcriptome sequencing was performed on the muscle, liver, a Show more
To explore the patterns of differentially expressed genes (DEGs) associated with different growth rates in rock carp (Procypris rabaudi), transcriptome sequencing was performed on the muscle, liver, and brain tissues of rock carp. Subsequently, bioinformatics analysis was conducted, and 2129, 1380, and 415 DEGs were identified in the muscle, liver, and brain tissues, respectively. GO enrichment and KEGG pathway analysis revealed that genes related to appetite regulation, protein degradation and digestion, lipid transport and metabolisms, and glycolysis/gluconeogenesis were upregulated in individuals with slower growth rates. Differential expression analysis identified 21 genes associated with feeding and metabolism across three tissues, including mc4r, npy, and npry in brain tissue; fatp, fabp, pparα, and apo in liver tissue; and prss, ctrl, and cela in muscle tissue. All these genes were upregulated in the slow-growing fish. Furthermore, weighted gene co-expression network analyses, including three modules (yellow, turquoise, and brown), significantly associated with growth. A network map that included these three modules enabled the identification of a series of hub genes, including rp13a, ube2o, h6pd, etc. These genes may be key candidate genes regulating the growth of rock carp. This study contributes to a deeper understanding of the growth control mechanism in rock carp and offers a scientific basis for efficient breeding and species improvement. Show less
Neurexins, essential synaptic proteins, are linked to neurodevelopmental and neuropsychiatric disorders like autism spectrum disorder (ASD) and schizophrenia. Through this systematic review, we aimed Show more
Neurexins, essential synaptic proteins, are linked to neurodevelopmental and neuropsychiatric disorders like autism spectrum disorder (ASD) and schizophrenia. Through this systematic review, we aimed to shed light on the relationship between neurexin dysfunction and its implications in neurodevelopmental and neuropsychiatric manifestations. Both animal and human-induced pluripotent stem cell (hiPSC) models served as our primary investigative platforms. Utilizing the PRISMA 2020 guidelines, our search strategy involved scouring articles from the PubMed and Google Scholar databases covering a span of two decades (2003-2023). Of the initial collection, 27 rigorously evaluated studies formed the essence of our review. Our review suggested the significant ties between neurexin anomalies and neurodevelopmental and neuropsychiatric outcomes, most notably ASD. Rodent-based investigations delineated pronounced ASD-associated behaviors, and hiPSC models derived from ASD-diagnosed patients revealed the disruptions in calcium dynamics and synaptic activities. Additionally, our review underlined the integral role of specific neurexin variants, primarily NRXN1, in the pathology of schizophrenia. It was also evident from our observation that neurexin malfunctions were implicated in a broader array of these disorders, including ADHD, intellectual challenges, and seizure disorders. This review accentuates the cardinal role neurexins play in the pathological process of neurodevelopmental and neuropsychiatric disorders. The findings underscore a critical need for standardized methodologies in developing animal and hiPSC models for future studies, aiming to minimize heterogeneity. Moreover, we highlight the need to expand research into less studied neurexin variants (i.e., NRXN2 and NRXN3), broadening the scope of our understanding in this field. Our observation also projects hiPSC models as potent tools for bridging research gaps, promoting translational research, and fostering the development of patient-specific therapeutic interventions. Show less
S Uzuner, L P Li · 2024 · BMC musculoskeletal disorders · BioMed Central · added 2026-04-24
Anterior cruciate ligament (ACL) injuries are often caused by high impact loadings during competitive sports but may also happen during regular daily activities due to tissue degeneration or altered m Show more
Anterior cruciate ligament (ACL) injuries are often caused by high impact loadings during competitive sports but may also happen during regular daily activities due to tissue degeneration or altered mechanics after a previous knee injury or surgery such as meniscectomy. Most existing research on ACL injury has focused on impact loading scenarios or the consequence of ACL injury on meniscus. The objective of the present study was to investigate the effects of varying degrees of medial meniscectomy on the mechanics of intact ACL by performing a poromechanical finite element analysis under moderate creep loadings. Four clinical scenarios with 25%, 50%, 75% and total medial meniscectomy were compared with the intact knee finite element model. Our results suggested that different medial meniscal resections may increase, at different extents, the knee laxity and peak tensile stress in the ACL, potentially leading to collagen fiber fatigue tearing and altered mechanobiology under normal joint loadings. Interestingly, the ACL stress actually increased during early knee creep (~ 3 min) before it reached an equilibrium. In addition, meniscectomy accelerated ACL stress reduction during knee creep, transferred more loading to tibial cartilage, increased contact pressure, and shifted the contact center posteriorly. This study may contribute to a better understanding of the interaction of meniscectomy and ACL integrity during daily loadings. Show less
Fibroblast growth factor receptor 2 (FGFR2) represents an appealing therapeutic target for multiple cancers, yet no selective FGFR2 inhibitors have been approved for clinical use to date. Here, we rep Show more
Fibroblast growth factor receptor 2 (FGFR2) represents an appealing therapeutic target for multiple cancers, yet no selective FGFR2 inhibitors have been approved for clinical use to date. Here, we report the discovery of a series of new selective, irreversible FGFR2 inhibitors. The representative compound LHQ490 potently inhibited FGFR2 kinase activity with an IC 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
As a transcription factor, Nuclear Receptor Subfamily 4 Group A Member 1 (NR4A1) binds to downstream target genes to participate in cell proliferation and cell differentiation. We found that the NR4A1 Show more
As a transcription factor, Nuclear Receptor Subfamily 4 Group A Member 1 (NR4A1) binds to downstream target genes to participate in cell proliferation and cell differentiation. We found that the NR4A1 reached the highest expression at 60 h after the differentiation of goat intramuscular preadipocytes. Overexpression of goat NR4A1 increased the number of intracellular lipid droplets and up-regulated the expression of adipocyte-differentiation-related marker genes including 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
Retinopathy is a common complication of diabetes mellitus and the leading cause of visual impairment. Danggui Buxue decoction (RRP) has been used as a traditional drug for the treatment of diabetic ne Show more
Retinopathy is a common complication of diabetes mellitus and the leading cause of visual impairment. Danggui Buxue decoction (RRP) has been used as a traditional drug for the treatment of diabetic nephropathy for many years. The aim of this study was to investigate the effects of RRP on hypoxia-induced retinal Müller cell injury. A model of retinal Müller cell damage was created using high glucose levels (25 mmol/L) and/or exposure to low oxygen conditions (1% O2). RRP was given to rats by continuous gavage for 7 days to obtain drug-containing serum. After sterilization, the serum was added to the culture medium at a ratio of 10%. Cell viability, apoptosis, and cell proliferation were assessed using the CCK-8 kit, Annexin V-FITC/propidium iodide apoptosis kit, and EdU kit. The mRNA levels of angiogenesis factors (ANGPTL4, VEGF) and inflammatory factors (IL-1B, ICAM-1) were detected by RT-qPCR. Western blot analysis was employed to assess the levels of proteins related to the ATF4/CHOP pathway. Following hypoxia for 48 h and 72 h, there was a significant decrease in cell viability and proliferation, as well as a notable increase in apoptosis compared to the control group (21% O2). However, high glucose stimulation had no significant effect, and high glucose combined with hypoxia had no further damage to cells. After 48 h of exposure to low oxygen levels, the mRNA expression levels of ANGPTL4, VEGF, IL-1B, and ICAM-1 in retinal Müller cells were significantly higher than in the control group (21% O2). RRP treatment significantly alleviated the increase of cell apoptosis and the upregulation of IL-1B and-1 in retinal Müller cells induced by hypoxia. RRP has the potential to reduce the suppression of the ATF4/CHOP pathway in hypoxia-induced retinal Müller cells, and it significantly alleviates cell apoptosis through regulating inflammatory factors and the ATF4/CHOP pathway. 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
The purpose of this study was to identify biomarkers associated with hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) and to develop a new combination with good diagnostic performance. Show more
The purpose of this study was to identify biomarkers associated with hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) and to develop a new combination with good diagnostic performance. This study was divided into four phases: discovery, verification, validation, and modeling. A total of four candidate tumor-associated autoantibodies (TAAb; anti-ZIC2, anti-PCNA, anti-CDC37L1, and anti-DUSP6) were identified by human proteome microarray (52 samples) and bioinformatics analysis. Subsequently, these candidate TAAbs were further confirmed by indirect ELISA with two testing cohorts (120 samples for verification and 663 samples for validation). The AUC for these four TAAbs to identify patients with HBV-HCC from chronic hepatitis B (CHB) patients ranged from 0.693 to 0.739. Finally, a diagnostic panel with three TAAbs (anti-ZIC2, anti-CDC37L1, and anti-DUSP6) was developed. This panel showed superior diagnostic efficiency in identifying early HBV-HCC compared with alpha-fetoprotein (AFP), with an AUC of 0.834 [95% confidence interval (CI), 0.772-0.897] for this panel and 0.727 (95% CI, 0.642-0.812) for AFP (P = 0.0359). In addition, the AUC for this panel to identify AFP-negative patients with HBV-HCC was 0.796 (95% CI, 0.734-0.858), with a sensitivity of 52.4% and a specificity of 89.0%. Importantly, the panel in combination with AFP significantly increased the positive rate for early HBV-HCC to 84.1% (P = 0.005) and for late HBV-HCC to 96.3% (P < 0.001). Our findings suggest that AFP and the autoantibody panel may be independent but complementary serologic biomarkers for HBV-HCC detection. We developed a robust diagnostic panel for identifying patients with HBV-HCC from patients with CHB. This autoantibody panel provided superior diagnostic performance for HBV-HCC at an early stage and/or with negative AFP results. Our findings suggest that AFP and the autoantibody panel may be independent but complementary biomarkers for HBV-HCC detection. Show less
Is there a relationship between serum uric acid and fructose levels in polycystic ovary syndrome (PCOS)? Elevated serum uric acid levels in women with PCOS positively correlate with serum fructose lev Show more
Is there a relationship between serum uric acid and fructose levels in polycystic ovary syndrome (PCOS)? Elevated serum uric acid levels in women with PCOS positively correlate with serum fructose levels, and elevated serum fructose levels are an independent risk factor for hyperuricemia in women with PCOS. Our previous study suggested a link between elevated serum fructose levels and PCOS. Fructose is unique as it generates uric acid during metabolism, and high uric acid levels are associated with metabolic disorders and an increased risk of anovulation. However, the relationship between serum uric acid and fructose levels in women with PCOS remains unclear. In a case-control study of 774 women (482 controls and 292 patients with PCOS) between May and October 2020 at the Shengjing Hospital of China Medical University, the relationship between uric acid and fructose levels in women with PCOS was examined. Participants were divided into subgroups based on various factors, including BMI, insulin resistance, dyslipidemia, metabolic syndrome, and hyperuricemia. Serum uric acid concentrations were measured using enzymatic assays, and serum fructose levels were determined using a fluorescent enzyme immunoassay. Dietary fructose data were collected through a validated food-frequency questionnaire of 81 food items. We applied restricted cubic splines to a flexibly model and visualized the linear/nonlinear relationships between serum uric acid and fructose levels in PCOS. Multivariate logistic analysis was executed to assess the association between serum fructose levels and hyperuricemia in PCOS. Human granulosa cell and oocyte mRNA profile sequencing data were downloaded for mapping uric acid and fructose metabolism genes in PCOS. Further downstream analyses, including Gene Ontology, Kyoto Encyclopedia of Genes and Genomes analysis, and protein-protein interactions were then carried out on the differentially expressed genes (DEGs). The correlation between uric acid and fructose metabolism genes was calculated using the Pearson correlation coefficient. The GeneCards database was used to identify DEGs related to uric acid and fructose metabolism in PCOS, and then several DEGs were confirmed by quantitative real-time PCR. Both serum fructose and uric acid levels were significantly increased in women with PCOS compared with the control women (P < 0.001), and there was no statistically significant difference in dietary fructose intake between PCOS and controls, regardless of metabolic status. There was a positive linear correlation between serum uric acid and fructose levels in women with PCOS (Poverall < 0.001, Pnon-linear = 0.30). In contrast, no correlation was found in control women (Poverall = 0.712, Pnon-linear = 0.43). Additionally, a non-linear association was observed in the obese subgroup of patients with PCOS (Poverall < 0.001, Pnon-linear = 0.02). Serum uric acid levels were linearly and positively associated with serum fructose levels in patients with PCOS with insulin resistance, dyslipidemia, and metabolic syndrome. Furthermore, even after adjusting for confounding factors, elevated serum fructose levels were an independent risk factor for hyperuricemia in patients with PCOS (P = 0.001; OR, 1.380; 95% CI, 1.207-1.577). There were 28 uric acid and 25 fructose metabolism genes which showed a significant correlation in PCOS. Seven upregulated genes (CAT, CRP, CCL2, TNF, MMP9, GCG, and APOB) related to uric acid and fructose metabolism in PCOS ovarian granulosa cells were ultimately successfully validated using quantitative real-time PCR. Due to limited conditions, more possible covariates (such as smoking and ethnicity) were not included, and the underlying molecular mechanism between fructose and uric acid levels in women with PCOS remains to be further investigated. The results of this study and our previous research indicate that the high uric acid status of PCOS may be mediated by fructose metabolism disorders, highlighting the importance of analyzing fructose metabolism, and especially its metabolic byproduct uric acid, during the clinical diagnosis of PCOS. These results suggest the adverse effects of high uric acid in PCOS, and the importance of taking early interventions regarding uric acid levels to reduce the occurrence and development of further clinical signs, such as metabolic disorders in women with PCOS. This work was supported by: the National Natural Science Foundation of China (No. 82371647, No. 82071607, and No. 32100691); LiaoNing Revitalization Talents Program (No. XLYC1907071); Fok Ying Tung Education Foundation (No. 151039); and Outstanding Scientific Fund of Shengjing Hospital (No. 202003). No competing interests were declared. N/A. Show less
Although tumor cells undergoing epithelial-mesenchymal transition (EMT) typically exhibit spindle morphology in experimental models, such histomorphological evidence of EMT has predominantly been obse Show more
Although tumor cells undergoing epithelial-mesenchymal transition (EMT) typically exhibit spindle morphology in experimental models, such histomorphological evidence of EMT has predominantly been observed in rare primary spindle carcinomas. The characteristics and transcriptional regulators of spontaneous EMT in genetically unperturbed non-spindled carcinomas remain underexplored. We used primary culture combined with RNA sequencing (RNA-seq), single-cell RNA-seq (scRNA-seq), and in situ RNA-seq to explore the characteristics and transcription factors (TFs) associated with potential spontaneous EMT in non-spindled breast carcinoma. Our primary culture revealed carcinoma cells expressing diverse epithelial-mesenchymal traits, consistent with epithelial-mesenchymal plasticity. Importantly, carcinoma cells undergoing spontaneous EMT did not necessarily exhibit spindle morphology, even when undergoing complete EMT. EMT was a favored process, whereas mesenchymal-epithelial transition appeared to be crucial for secondary tumor growth. Through scRNA-seq, we identified TFs that were sequentially and significantly upregulated as carcinoma cells progressed through the EMT process, which correlated with increasing VIM expression. Once upregulated, the TFs remained active throughout the EMT process. ZEB1 was a key initiator and sustainer of EMT, as indicated by its earliest significant upregulation in the EMT process, its exact correlation with VIM expression, and the reversal of EMT and downregulation of EMT-upregulated TFs upon ZEB1 knockdown. The correlation between ZEB1 and vimentin expression in triple-negative breast cancer and metaplastic breast carcinoma tumor cohorts further highlighted its role. The immediate upregulation of ZEB2 following that of ZEB1, along with the observation that the knockdown of ZEB1 or ZEB2 downregulates both ZEB1 and ZEB2 concomitant with the reversal of EMT, suggests their functional cooperation in EMT. This finding, together with that of a lack of correlation of SNAI1, SNAI2, and TWIST1 expression with the mesenchymal phenotype, indicated EMT-TFs have a context-dependent role in EMT. Upregulation of EMT-related gene signatures during EMT correlated with poor patient outcomes, highlighting the biological importance of the model. Elevated EMT gene signatures and increased ZEB1 and ZEB2 expression in vimentin-positive compared to vimentin-negative carcinoma cells within the corresponding primary tumor tissue confirmed ZEB1 and ZEB2 as intrinsic, instead of microenvironmentally-induced, EMT regulators, and vimentin as an in vivo indicator of EMT. Our findings provide insights into the characteristics and transcriptional regulators of spontaneous EMT in primary non-spindled carcinoma. Show less
Adenosine-to-inosine (A-to-I) editing is the most common type of RNA editing in humans and the role of A-to-I RNA editing remains unclear in Parkinson's disease (PD). We aimed to explore the potential Show more
Adenosine-to-inosine (A-to-I) editing is the most common type of RNA editing in humans and the role of A-to-I RNA editing remains unclear in Parkinson's disease (PD). We aimed to explore the potential causal association between A-to-I editing and PD, and to assess whether changes in A-to-I editing were associated with cognitive progression in PD. The RNA-seq data from 380 PD patients and 178 healthy controls in the Parkinson's Progression Marker Initiative cohort was used to quantify A-to-I editing sites. We performed cis-RNA editing quantitative trait loci analysis and a two-sample Mendelian Randomization (MR) study by integrating genome-wide association studies to infer the potential causality between A-to-I editing and PD pathogenesis. The potential causal A-to-I editing sites were further confirmed by Summary-data-based MR analysis. Spearman's correlation analysis was performed to characterize the association between longitudinal A-to-I editing and cognitive progression in patients with PD. We identified 17 potential causal A-to-I editing sites for PD and indicated that genetic risk variants may contribute to the risk of PD through A-to-I editing. These A-to-I editing sites were located in genes NCOR1, KANSL1 and BST1. Moreover, we observed 57 sites whose longitudinal A-to-I editing levels correlated with cognitive progression in PD. We found potential causal A-to-I editing sites for PD onset and longitudinal changes of A-to-I editing were associated with cognitive progression in PD. We anticipate this study will provide new biological insights and drive the discovery of the epitranscriptomic role underlying Parkinson's disease. Show less
The purpose of this study was to screen the genes and pathways that are involved in spermatogonia stem cell (SSC) differentiation regulation during the transition from A The GO analysis showed that RN Show more
The purpose of this study was to screen the genes and pathways that are involved in spermatogonia stem cell (SSC) differentiation regulation during the transition from A The GO analysis showed that RNA transport, the MAPK pathway and the p53 pathway may play vital roles in early SSC differentiation, and Show less
Fuel substrate switching between carbohydrates and fat is essential for maintaining metabolic homeostasis. During aerobic exercise, the predominant energy source gradually shifts from carbohydrates to Show more
Fuel substrate switching between carbohydrates and fat is essential for maintaining metabolic homeostasis. During aerobic exercise, the predominant energy source gradually shifts from carbohydrates to fat. While it is well known that exercise mobilizes fat storage from adipose tissues, it remains largely obscure how circulating lipids are distributed tissue-specifically according to distinct energy requirements. Here, we demonstrate that aerobic exercise is linked to nutrient availability to regulate tissue-specific activities of lipoprotein lipase (LPL), the key enzyme catabolizing circulating triglyceride (TG) for tissue uptake, through the differential actions of angiopoietin-like (ANGPTL) proteins. Exercise reduced the tissue binding of ANGPTL3 protein, increasing LPL activity and TG uptake in the heart and skeletal muscle in the postprandial state specifically. Mechanistically, exercise suppressed insulin secretion, attenuating hepatic Angptl8 transcription through the PI3K/mTOR/CEBPα pathway, which is imperative for the tissue binding of its partner ANGPTL3. Constitutive expression of ANGPTL8 hampered lipid utilization and resulted in cardiac dysfunction in response to exercise. Conversely, exercise promoted the expression of ANGPTL4 in white adipose tissues, overriding the regulatory actions of ANGPTL8/ANGPTL3 in suppressing adipose LPL activity, thereby diverting circulating TG away from storage. Collectively, our findings show an overlooked bifurcated ANGPTL-LPL network that orchestrates fuel switching in response to aerobic exercise. Show less
Platycodon grandiflorum (PG) has been widely applied as a conductant drug by ancient and modern traditional Chinese medicine practitioners during long-term clinical practice. However, determining how Show more
Platycodon grandiflorum (PG) has been widely applied as a conductant drug by ancient and modern traditional Chinese medicine practitioners during long-term clinical practice. However, determining how to guide other medicines to the targeted lungs in traditional Chinese medicine (TCM) prescription remains unclear. An ethanol soluble fraction (Fr. B) was obtained by macroporous resin and 75 % ethanol precipitate. The components were unambiguously determined as fructooligosaccharides and small molecule weight (M Show less
Sisi Zheng, Sitong Feng, Nan Song+8 more · 2024 · The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry · Taylor & Francis · added 2026-04-24
Depersonalisation-derealization disorder (DPD) is a dissociative disorder that impairs cognitive function and occupational performance. Emerging evidence indicate the levels of tumour necrosis factor- Show more
Depersonalisation-derealization disorder (DPD) is a dissociative disorder that impairs cognitive function and occupational performance. Emerging evidence indicate the levels of tumour necrosis factor-α and interleukin associated with the dissociative symptoms. In this study, we aimed to explore the role of the immune system in the pathology of DPD. We screened the protein expression in serum samples of 30 DPD patients and 32 healthy controls. Using a mass spectrometry-based proteomic approach, we identified differential proteins that were verified in another group of 25 DPD patients and 30 healthy controls using immune assays. Finally, we performed a correlation analysis between the expression of differential proteins and clinical symptoms of patients with DPD. We identified several dysregulated proteins in patients with DPD compared to HCs, including decreased levels of C-reactive protein (CRP), complement C1q subcomponent subunit B, apolipoprotein A-IV, and increased levels of alpha-1-antichymotrypsin (SERPINA3). Moreover, the expression of CRP was positively correlated with visuospatial memory and the ability to inhibit cognitive interference of DPD. The expression of SERPINA3 was positively correlated with the ability to inhibit cognitive interference and negatively correlated with the perceptual alterations of DPD. The dysregulation of the immune system may be the underlying biological mechanism in DPD. And the expressions of CRP and SERPINA3 can be the potential predictors for the cognitive performance of DPD. 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
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
Widespread metastasis is the primary reason for the high mortality associated with ovarian cancer (OC), and effective targeted therapy for tumor aggressiveness is still insufficient in clinical practi Show more
Widespread metastasis is the primary reason for the high mortality associated with ovarian cancer (OC), and effective targeted therapy for tumor aggressiveness is still insufficient in clinical practice. Therefore, it is urgent to find new targets to improve prognosis of patients. PDE4A is a cyclic nucleotide phosphodiesterase that plays a crucial role in the occurrence and development in various malignancies. Our study firstly reported the function of PDE4A in OC. Expression of PDE4A was validated through bioinformatics analysis, RT-qPCR, Western blot, and immunohistochemistry. Additionally, its impact on cell growth and motility was assessed via in vitro and in vivo experiments. PDE4A was downregulated in OC tissues compared with normal tissues and low PDE4A expression was correlated with poor clinical outcomes in OC patients. The knockdown of PDE4A significantly promoted the proliferation, migration and invasion of OC cells while overexpression of PDE4A resulted in the opposite effect. Furthermore, smaller and fewer tumor metastatic foci were observed in mice bearing PDE4A-overexpressing OVCAR3 cells. Mechanistically, downregulation of PDE4A expression can induce epithelial-mesenchymal transition (EMT) and nuclear translocation of Snail, which suggests that PDE4A plays a pivotal role in suppressing OC progression. Notably, Rolipram, the PDE4 inhibitor, mirrored the effects observed with PDE4A deletion. In summary, the downregulation of PDE4A appears to facilitate OC progression by modulating the Snail/EMT pathway, underscoring the potential of PDE4A as a therapeutic target against ovarian cancer metastasis. 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
Magnesium phosphate bone cements (MPC) have been recognized as a viable alternative for bone defect repair due to their high mechanical strength and biodegradability. However, their poor porosity and Show more
Magnesium phosphate bone cements (MPC) have been recognized as a viable alternative for bone defect repair due to their high mechanical strength and biodegradability. However, their poor porosity and permeability limit osteogenic cell ingrowth and vascularization, which is critical for bone regeneration. In the current study, we constructed a novel hierarchically-porous magnesium phosphate bone cement by incorporating extracellular matrix (ECM)-mimicking electrospun silk fibroin (SF) nanofibers. The SF-embedded MPC (SM) exhibited a heterogeneous and hierarchical structure, which effectively facilitated the rapid infiltration of oxygen and nutrients as well as cell ingrowth. Besides, the SF fibers improved the mechanical properties of MPC and neutralized the highly alkaline environment caused by excess magnesium oxide. Bone marrow stem cells (BMSCs) adhered excellently on SM, as illustrated by formation of more pseudopodia. CCK8 assay showed that SM promoted early proliferation of BMSCs. Our study also verified that SM increased the expression of OPN, RUNX2 and BMP2, suggesting enhanced osteogenic differentiation of BMSCs. We screened for osteogenesis-related pathways, including FAK signaing, Wnt signaling and Notch signaling, and found that SM aided in the process of bone regeneration by suppressing the Notch signaling pathway, proved by the downregulation of NICD1, Hes1 and Hey2. In addition, using a bone defect model of rat calvaria, the study revealed that SM exhibited enhanced osteogenesis, bone ingrowth and vascularization compared with MPC alone. No adverse effect was found after implantation of SM Show less
Clinical studies have shown that epileptic seizures worsen Alzheimer's disease (AD) pathology and related cognitive deficits; however, the underlying mechanism is unclear. To assess the effects of sei Show more
Clinical studies have shown that epileptic seizures worsen Alzheimer's disease (AD) pathology and related cognitive deficits; however, the underlying mechanism is unclear. To assess the effects of seizures on the progression of AD, chronic temporal lobe epilepsy was induced in five familial AD mutation (5×FAD) mice by kindling with the chemoconvulsant pentylenetetrazole (PTZ) at 3-3.5 months of age. The amyloidogenic pathway, tauopathy, synaptic damage, neuronal death, neurological inflammatory response and associated kinase signaling pathway dysregulation were examined at 9 months of age. We found that APP, p-APP, BACE1, Aβ and kinase-associated p-tau levels were elevated after PTZ kindling in 5×FAD mice. In addition, PTZ kindling exacerbated hippocampal synaptic damage and neuronal cell death, as determined by scanning electron microscopy and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining, respectively. Finally, the levels of the neuroinflammation markers GFAP and Iba1, as well as the inflammatory cytokine IL-1β, were increased after PTZ insult. PTZ kindling profoundly exacerbated extracellular regulated kinase (ERK)-death-associated protein kinase (DAPK) signaling pathway overactivation, and acute ERK inhibitor treatment downregulated Aβ production and p-APP and p-tau levels in epileptic 5×FAD mice. In addition, long-term use of the antiseizure drug carbamazepine (CBZ) alleviated seizure-induced accelerated amyloid and tau pathology and ERK-DAPK overactivation in 5×FAD mice. Collectively, these results demonstrate that seizure-induced increases in AD-like neuropathology in 5×FAD mice are partially regulated by the ERK-DAPK pathway, suggesting that the ERK-DAPK axis could be a new therapeutic target for the treatment of AD patients with comorbid seizures. 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
High altitude pulmonary edema (HAPE) is an idiopathic, noncardiogenic form of pulmonary edema that occurs at high altitudes. It is characterized by a severe clinical course and carries a significant m Show more
High altitude pulmonary edema (HAPE) is an idiopathic, noncardiogenic form of pulmonary edema that occurs at high altitudes. It is characterized by a severe clinical course and carries a significant mortality risk. Despite its clinical relevance, the molecular mechanisms underlying HAPE are not well understood. We conducted whole-transcriptome RNA sequencing on blood samples from 6 pairs of HAPE patients and healthy controls to identify differentially expressed (DE) mRNAs, miRNAs, circRNAs, lncRNAs, along with alternative splicing (AS) events, gene fusions, and novel transcripts. To explore the regulatory dynamics, we constructed ceRNA networks and analyzed immune cell infiltration patterns, further annotating the biological functions of these transcripts. For empirical validation, we selected five circRNAs from the ceRNA network and conducted RT-qPCR on 50 paired samples. Additionally, we assessed the correlations between circRNA expression levels and clinical data to evaluate their diagnostic potential. We observed 2,023 differentially expressed mRNAs (DEmRNAs), 84 DEmiRNAs, 200 DEcircRNAs, and 3,573 DElncRNAs. A total of 139 'A3SS' events, 103 'A5SS' events, 545 'MXE' events, 14 'RI' events, and 1,482 'SE' events were identified in the AS events analysis between the two groups. Two ceRNA networks were constructed. T cells, follicular helper, and Macrophages M1 cells exhibited the strongest positive correlation (R=0.82), while naive B cells and memory B cells demonstrated the strongest negative correlation (R=-0.62). In total, the expression of three circRNAs was significantly different in a larger cohort. Hsa_circ₀₀₅₈₄₉₇, hsa_circ₀₀₈₁₀₀₆, and hsa_circ₀₀₈₃₂₂₀ demonstrated consistent with the RNA sequencing results. These three circRNAs strongly correlate with clinical indicators and exhibit potential as diagnostic biomarkers. Finally, we verified five genes (CXCR4, HSD17B2, ANGPTL4, TIMP3, N4BP3) that were differentially expressed in endothelial cells under normoxia and hypoxia through bioinformatics and RT-qPCR analyses. This study elucidates the differential expression of coding and non-coding RNAs (ncRNAs) in HAPE, identifies new transcripts and genes, and enhances our understanding of the transcriptional characteristics of HAPE. Moreover, it highlights the potential role of circRNAs in advancing the diagnosis and treatment of HAPE. Show less
Cholesterol is regarded as a signaling molecule in regulating the metabolism and function of fat cells, in which 7-Dehydrocholesterol reductase (DHCR7) is a key enzyme that catalyzes the conversion of Show more
Cholesterol is regarded as a signaling molecule in regulating the metabolism and function of fat cells, in which 7-Dehydrocholesterol reductase (DHCR7) is a key enzyme that catalyzes the conversion of 7-dehydrocholesterol to cholesterol, however, the exact function of Show less