👤 J Du

The plant cell wall is a dynamic structure that plays an essential role in development, but the mechanism regulating cell wall formation remains poorly understood. We demonstrate that two transcription factors, SlERF.H5 and SlERF.H7, control cell wall formation and tomato fruit firmness in an additive manner. Knockout of SlERF.H5, SlERF.H7, or both genes decreased cell wall thickness, firmness, and cellulose contents in fruits during early development, especially in double-knockout lines. Overexpressing either gene resulted in thicker cell walls and greater fruit firmness with elevated cellulose levels in fruits but severely dwarf plants with lower gibberellin contents. We further identified that SlERF.H5 and SlERF.H7 activate the cellulose biosynthesis gene SlCESA3 but repress the gibberellin biosynthesis gene GA20ox1. Moreover, we identified a conserved LPL motif in these ERFs responsible for their activities as transcriptional activators and repressors, providing insight into how bifunctional transcription factors modulate distinct developmental processes. Show less

As the drawbacks of antibiotics in treating bacterial infections emerged, physical methods such as near-infrared-activated (NIR-activated) bacterial killing, have attracted great interests for their advantages of no resistance, short action time and few side effects. In this manuscript, NIR-activated bacteria-killing performance of chiral copper sulphide nanoparticles (L-/d-CuS NPs) was investigated using linearly polarized light (LPL) and circularly polarized light (CPL) as illumination sources, respectively. Chiral CuS NPs showed enhanced NIR-activated bacteria-killing effect compared with achiral CuS NPs under the same conditions. Moreover, these chiral CuS NPs showed obvious chirality-related antibacterial effect: the bacterial killing was more efficient under CPL activation, and L- and d-CuS NPs had higher antibacterial efficiency under left circularly polarized light (LCPL) and right circularly polarized light (RCPL), respectively. The possible mechanism of bacteria-killing performance for chiral CuS NPs was discussed in detailed. Photothermal bacteria-killing tests of chiral CuS NPs "sealed" in polydimethylsiloxane (PDMS) demonstrated the individual influence of photothermal effect. These observations in this paper could provide ideas for the potential applications of chiral nanostructures with enhanced photothermal effect in efficient bacterial killing. Show less

Fish physiological health is often negatively impacted by high-temperature environments and there are few studies on how dietary lipids affect fish growth and physiology when exposed to heat stress. The main objective of this research was to examine the impact of dietary lipid levels on growth and physiological status of juvenile turbot (Scophthalmus maximus L.) and determine if dietary lipid concentration could alleviate the possible adverse effects of heat stress. Five diets containing 6.81%, 9.35%, 12.03%, 14.74%, and 17.08% lipid, respectively, were formulated and fed to turbot (initial weight 5.13 ± 0.02 g) under high-temperature conditions (24.0-25.0 °C). Meanwhile, the diet with 12.03% lipid (considered by prior work to be an optimal dietary lipid level) was fed to turbot of the same size at normal temperature. Results suggested that, among the different dietary lipid levels under high-temperature conditions, fish fed the optimal lipid (12.03%) exhibited better growth compared to non-optimal lipid groups, as evidenced by higher weight gain and specific growth rate. Simultaneously, the optimal lipid diet may better maintain lipid homeostasis, as attested by lower liver and serum lipid, along with higher liver mRNA levels of lipolysis-related genes (pgc1α, lipin1, pparα, lpl and hl) and lower levels of synthesis-related genes (lxr, fas, scd1, pparγ, dgat1 and dgat2). Also, the optimal lipid diet might mitigate oxidative damage by improving antioxidant enzyme activity, decreasing malondialdehyde levels, and up-regulating oxidation-related genes (sod1, sod2, cat, gpx and ho-1). Furthermore, the optimal lipid may enhance fish immunity, as suggested by the decrease in serum glutamic-oxalacetic/pyruvic transaminase activities, down-regulation of pro-inflammatory genes and up-regulation of anti-inflammation genes. Correspondingly, the optimal lipid level suppressed MAPK signaling pathway via decreased phosphorylation levels of p38, JNK and ERK proteins in liver. In summary, the optimal dietary lipid level facilitated better growth and physiological status in turbot under thermal stress. Show less

RNA-binding proteins (RBPs) contribute to the pathogenesis of proliferative diabetic retinopathy (PDR) by regulating gene expression through alternative splicing events (ASEs). However, the RBPs differentially expressed in PDR and the underlying mechanisms remain unclear. Thus, this study aimed to identify the differentially expressed genes in the neovascular membranes (NVM) and retinas of patients with PDR. The public transcriptome dataset GSE102485 was downloaded from the Gene Expression Omnibus database, and samples of PDR and normal retinas were analyzed. A mouse model of oxygen-induced retinopathy was used to confirm the results. The top 20 RBPs were screened for co-expression with alternative splicing genes (ASGs). A total of 403 RBPs were abnormally expressed in the NVM and retina samples. Functional analysis demonstrated that the ASGs were enriched in cell cycle pathways. Cell cycle-associated ASEs and an RBP-AS regulatory network, including 15 RBPs and their regulated ASGs, were extracted. Splicing factor proline/glutamine rich (SFPQ), microtubule-associated protein 1 B (MAP1B), heat-shock protein 90-alpha (HSP90AA1), microtubule-actin crosslinking factor 1 (MACF1), and CyclinH (CCNH) expression remarkably differed in the mouse model. This study provides novel insights into the RBP-AS interaction network in PDR and for developing screening and treatment options to prevent diabetic retinopathy-related blindness. Show less

DNA methylation is influenced by various exogenous factors such as nutrition, temperature, toxicants, and stress. Bulls from the Pacific Northwest region of the United States and other northern areas are exposed to extreme cold temperatures during winter. However, the effects of cold exposure on the methylation patterns of bovine sperm remain unclear. To address, DNA methylation profiles of sperm collected during late spring and winter from the same bulls were analyzed using whole genome bisulfite sequencing (WGBS). Bismark (0.22.3) were used for mapping the WGBS reads and R Bioconductor package DSS was used for differential methylation analysis. Cold exposure induced 3,163 differentially methylated cytosines (DMCs) with methylation difference ≥10% and a Show less

Primary ovarian insufficiency (POI) is a disorder characterized by the premature decline in ovarian function, leading to significant fertility and health impacts on women under 40. The unclear etiology of POI hinders the development of effective treatments, highlighting the need for novel therapeutic targets. This study employed genome-wide association analysis (GWAS) integrated with expression quantitative trait loci (eQTL) data from the GTEx and eQTLGen databases. Mendelian randomization (MR) and colocalization analyses were conducted to investigate causal relationships between genetic variants and POI and to identify potential therapeutic targets. We identified 431 genes with available index cis-eQTL signals, of which four (HM13, FANCE, RAB2A, and MLLT10) were significantly associated with POI. Colocalization analysis revealed strong evidence for FANCE and RAB2A, indicating their potential as therapeutic targets. Subsequent druggability assessments identified FANCE and RAB2A as promising candidates for POI treatment, supported by their involvement in DNA repair and autophagy regulation, respectively. Our study establishes a causal link between specific genes and POI, highlighting FANCE and RAB2A as potential drug targets. These findings provide a foundation for future research and therapeutic development, aiming to improve outcomes for women with POI. Validation in further trials is necessary to confirm these potential targets. Show less

To examine whether and how carbohydrate response element-binding protein (ChREBP) plays a role in diabetic retinopathy. Western blotting was used to detect ChREBP expression and location following high glucose stimulation of Human Retinal Microvascular Endothelial Cells (HRMECs). Flow cytometry, TUNEL staining, and western blotting were used to evaluate apoptosis following ChREBP siRNA silencing. Cell scratch, transwell migration, and tube formation assays were used to determine cell migration and angiogenesis. Diabetic models for wild-type (WT) and ChREBP knockout (ChKO) mice were developed. Retinas of WT and ChKO animals were cultivated in vitro with vascular endothelial growth factor + high glucose to assess neovascular development. ChREBP gene knockdown inhibited thioredoxin-interacting protein and NOD-like receptor family pyrin domain containing protein 3 expression in HRMECs, which was caused by high glucose stimulation, reduced apoptosis, hindered migration, and tube formation, and repressed AKT/mTOR signaling pathway activation. Compared with WT mice, ChKO mice showed suppressed high glucose-induced alterations in retinal structure, alleviated retinal vascular leakage, and reduced retinal neovascularization. ChREBP deficiency decreased high glucose-induced apoptosis, migration, and tube formation in HRMECs as well as structural and angiogenic responses in the mouse retina; thus, it is a potential therapeutic target for diabetic retinopathy. Show less

GPCR-G protein signaling from endosomes plays a crucial role in various physiological and pathological processes. However, the mechanism by which endosomal G protein signaling is terminated remains largely unknown. In this study, we aimed to investigate the regulatory mechanisms involved in terminating the signaling of Gα subunits from endosomes. Through structural analysis and cell-based assays, we have discovered that SNX25, a protein that targets endosomes via its PXA or PXC domain, interacts with regulator of G protein signaling (RGS) proteins (including RGS2, RGS4, RGS8, and RGS17) in a redox-regulated manner. The interaction between SNX25 and these RGS proteins enhances their GTPase-accelerating activity towards Gα Show less

Hypertrophic scar (HS) is a skin fibroproliferative disorder occurring after burns, surgeries or traumatic injuries, and it has caused a tremendous economic and medical burden. Its molecular mechanism is associated with the abnormal proliferation and transition of fibroblasts and excessive deposition of extracellular matrix. Cartilage intermediate layer protein 2 (CILP2), highly homologous to cartilage intermediate layer protein 1 (CILP1), is mainly secreted predominantly from chondrocytes in the middle/deeper layers of articular cartilage. Recent reports indicate that CILP2 is involved in the development of fibrotic diseases. We investigated the role of CILP2 in the progression of HS. It was found in this study that CILP2 expression was significantly higher in HS than in normal skin, especially in myofibroblasts. In a clinical cohort, we discovered that CILP2 was more abundant in the serum of patients with HS, especially in the early stage of HS. In vitro studies indicated that knockdown of CILP2 suppressed proliferation, migration, myofibroblast activation and collagen synthesis of hypertrophic scar fibroblasts (HSFs). Further, we revealed that CILP2 interacts with ATP citrate lyase (ACLY), in which CILP2 stabilizes the expression of ACLY by reducing the ubiquitination of ACLY, therefore prompting Snail acetylation and avoiding reduced expression of Snail. In vivo studies indicated that knockdown of CILP2 or ACLY inhibitor, SB-204990, significantly alleviated HS formation. CILP2 exerts a vital role in hypertrophic scar formation and might be a detectable biomarker reflecting the progression of hypertrophic scar and a therapeutic target for hypertrophic scar. Show less

Previous studies have shown that hepatocyte-like cells can be generated from fibroblasts using either lineage-specific transcription factors or chemical induction methods. However, these methods have their own deficiencies that restrict the therapeutic applications of such induced hepatocytes. In this study, we present a transgene-free, highly efficient chemical-induced direct reprogramming approach to generate hepatocyte-like cells from mouse embryonic fibroblasts (MEFs). Using a small molecule cocktail (SMC) as an inducer, MEFs can be directly reprogrammed into hepatocyte-like cells, bypassing the intermediate stages of pluripotent and immature hepatoblasts. These chemical-induced hepatocyte-like cells (ciHeps) closely resemble mature primary hepatocytes in terms of morphology, biological behavior, gene expression patterns, marker expression levels, and hepatic functions. Furthermore, transplanted ciHeps can integrate into the liver, promote liver regeneration, and improve survival rates in mice with acute liver damage. ciHeps can also ameliorate liver fibrosis caused by chronic injuries and enhance liver function. Notably, ciHeps exhibit no tumorigenic potential either in vitro or in vivo. Mechanistically, SMC-induced mesenchymal-to-epithelial transition and suppression of SNAI1 contribute to the fate conversion of fibroblasts into ciHeps. These results indicate that this transgene-free, chemical-induced direct reprogramming technique has the potential to serve as a valuable means of producing alternative hepatocytes for both research and therapeutic purposes. Additionally, this method also sheds light on the direct reprogramming of other cell types under chemical induction. Show less

The locus coeruleus (LC), enriched in vesicular glutamate transporter 2 (VGlut2) neurons, is a potential homeostasis-regulating hub. However, the identity of melanocortin-4 receptor (MC4R) neurons in the paraventricular nucleus (PVN) of the hypothalamus, PVN Show less

The occurrence and progression of lung cancer are correlated with telomeres and telomerase. Telomere length is reduced in the majority of tumors, including lung cancers. Telomere length variations have been associated with lung cancer risk and may serve as therapeutic targets as well as predictive biomarkers for lung cancer. Nevertheless, the effects of telomere-associated genes on lung cancer prognosis have not been thoroughly studied. We aim to investigate the relationship between telomere-associated genes and lung cancer prognosis. The Cancer Genome Atlas and Genotype-Tissue Expression databases were used as training sets to build a predictive model. Three integrated Gene Expression Omnibus datasets served as validation sets. Using cluster consistency analysis and regression with the least absolute shrinkage and selection operator, we developed a telomere-related gene risk signature (TMGsig) based on 11 overall survival-related genes ( The results indicated a negative outcome for the high-risk score group. Immunological microenvironment and somatic mutations differed between the high- and low-risk groups. A statistically significant difference existed between the low-risk and high-risk groups in terms of the expression levels of B cells and CD4 cells, and the risk score was essentially inversely linked with immune cell expression. TMGsig can predict outcomes in patients with lung adenocarcinoma. Show less

The crosstalk between intervertebral disc degeneration (IVDD) and type 2 diabetes mellitus (T2DM) has been investigated. However, the common mechanism underlying this phenomenon has not been clearly elucidated. This study aimed to explore the shared gene signatures of IVDD and T2DM. The expression profiles of IVDD (GSE27494) and T2DM (GSE20966) were acquired from the Gene Expression Omnibus database. Five hub genes including ANGPTL4, CCL2, CCN3, THBS2, and INHBA were preliminarily screened. GO (Gene Ontology) enrichment analysis, functional correlation analysis, immune filtration, Transcription factors (TFs)-mRNA-miRNA coregulatory network, and potential drugs prediction were performed following the identification of hub genes. RNA sequencing, in vivo and in vitro experiments on rats were further performed to validate the expression and function of the target gene. Five hub genes (ANGPTL4, CCL2, CCN3, THBS2, and INHBA) were identified. GO analysis demonstrated the regulation of the immune system, extracellular matrix (ECM), and SMAD protein signal transduction. There was a strong correlation between hub genes and different functions, including lipid metabolism, mitochondrial function, and ECM degradation. The immune filtration pattern grouped by disease and the expression of hub genes showed significant changes in the immune cell composition. TFs-mRNA-miRNA co-expression networks were constructed. In addition, pepstatin showed great drug-targeting relevance based on potential drugs prediction of hub genes. ANGPTL4, a gene that mediates the inhibition of lipoprotein lipase activity, was eventually determined after hub gene screening, validation by different datasets, RNA sequencing, and experiments. This study screened five hub genes and ANGPTL4 was eventually determined as a potential target for the regulation of the crosstalk in patients with IVDD and T2DM. Show less

Angiopoietin-like 4 (ANGPTL4) is a potent regulator of TAG metabolism, but knowledge of the mechanisms underlying ANGPTL4 transcription in response to fatty acids is still limited in teleost. In the current study, we explored the molecular characterisation of ANGPTL4 and regulatory mechanisms of ANGPTL4 in response to fatty acids in large yellow croaker ( Show less

Systemic lupus erythematosus (SLE) is an autoimmune disease affecting thousands of people. There are still no effective biomarkers for SLE diagnosis and disease activity assessment. We performed proteomics and metabolomics analyses of serum from 121 SLE patients and 106 healthy individuals, and identified 90 proteins and 76 metabolites significantly changed. Several apolipoproteins and the metabolite arachidonic acid were significantly associated with disease activity. Apolipoprotein A-IV (APOA4), LysoPC(16:0), punicic acid and stearidonic acid were correlated with renal function. Random forest model using the significantly changed molecules identified 3 proteins including ATRN, THBS1 and SERPINC1, and 5 metabolites including cholesterol, palmitoleoylethanolamide, octadecanamide, palmitamide and linoleoylethanolamide, as potential biomarkers for SLE diagnosis. Those biomarkers were further validated in an independent cohort with high accuracy (AUC = 0.862 and 0.898 for protein and metabolite biomarkers respectively). This unbiased screening has led to the discovery of novel molecules for SLE disease activity assessment and SLE classification. Show less

Currently, the prevalence of allergic rhinitis (AR) remains high and there is a great need to develop better and safer ways to alleviate AR symptoms. The Adults aged from 18 to 60 years old and previously suffered from AR were recruited and received GUANKE probiotics treatment for 4 weeks. The questionnaires of Total nasal symptom scores (TNSS), total non-nasal symptom score (TNNSS), and rhinitis control assessment test (RCAT) were used to assess the effectiveness before and after treatment. The serum allergen-specific IgE and cytokines were also determined at baseline and after 4 weeks of probiotics administration. The results showed that TNSS and TNNSS were significantly reduced and the RCAT score was significantly increased compared to baseline. The sub-symptom score of rhinorrhea, itching, sneezing, and tearing in each questionnaire also showed significant changes, and the serum IgE level was markedly decreased. We further measured inflammatory-related proteins in serum and found that a total of 20 proteins (6 upregulated and 14 downregulated) were significantly changed compared to baseline, including IL-4, IL-7, IL-20, IL-33, CXCL1, CXCL5, CXCL6, CXCL11, CCL4, CCL23, TGF-alpha, LAP-TGF-beta-1, MMP-1, MMP-10, AXIN1, NT-3, OSM, SCF, CD6, and NRTN. Enrichment analysis showed that these significantly altered proteins were mainly enriched in cytokine and chemokine-related signaling pathways. Taken together, this study demonstrated the Show less

Alzheimer's disease (AD) is one of the acute degenerative diseases of the brain that occurs in the central nervous system. This disease is caused by the abnormal deposition of insoluble plaques and peptide amyloid beta (Aβ), the formation of nodules, and synaptic disorder. The formation of these nodes disrupts the functioning of neural circuits and changes in behavioral response due to the activation of neurotransmitter receptors. Research in recent years has shown that microRNAs play an effective role in Alzheimer's disease and neurotransmitter factors. Recently, miR-107 is effective in the pathology of Alzheimer's disease (AD) through the regulation of NF-κB signaling pathway. Experiments conducted using the dual luciferase method and western blot analysis also showed that miR-107 in primary neurons affects neurotransmitter factors in Alzheimer's disease through the regulation of the NF-κB signaling pathway. The results showed that the reduction of miR-107 expression through the regulation of the NF-κB signaling pathway leads to the suppression of cell apoptosis in Alzheimer's patients. On the other hand, increasing the expression of miR-107 leads to increasing the breaking process of Amyloid precursor protein (APP). This factor increases the production of amyloid beta (Aβ) peptide plaques and increases the expression of the BACE1 gene, which ultimately leads to the induction of apoptosis and induction of Alzheimer's disease. Show less

Scutellarein hybrids were designed, synthesized and evaluated as multifunctional therapeutic agents for the treatment of Alzheimer's disease (AD). Compounds 11a-i, containing a 2-hydroxymethyl-3,5,6-trimethylpyrazine fragment at the 7-position of scutellarein, were found to have balanced and effective multi-target potencies against AD. Among them, compound 11e exhibited the most potent inhibition of electric eel and human acetylcholinesterase enzymes with IC Show less

Alzheimer's disease (AD) is a neurodegenerative disease with challenging early diagnosis and effective treatments due to its complex pathogenesis. AD patients are often diagnosed after the appearance of the typical symptoms, thereby delaying the best opportunity for effective measures. Biomarkers could be the key to resolving the challenge. This review aims to provide an overview of application and potential value of AD biomarkers in fluids, including cerebrospinal fluid, blood, and saliva, in diagnosis and treatment. A comprehensive search of the relevant literature was conducted to summarize potential biomarkers for AD in fluids. The paper further explored the biomarkers' utility in disease diagnosis and drug target development. Research on biomarkers mainly focused on amyloid-β (Aβ) plaques, Tau protein abnormal phosphorylation, axon damage, synaptic dysfunction, inflammation, and related hypotheses associated with AD mechanisms. Aβ Fluid biomarkers hold considerable potential in the diagnosis and drug development of AD. However, improvements in sensitivity and specificity, and approaches for managing sample impurities, need to be addressed for better diagnosis. Show less

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid-β peptide (Aβ) deposition. Aβ accumulation induces oxidative stress, leading to mitochondrial dysfunction, apoptosis, and so forth. Octadecaneuropeptide (ODN), a diazepam-binding inhibitor (DBI)-derived peptide, has been reported to have antioxidant properties. However, it is unclear whether ODN has neuroprotective effects in AD. To profile the potential effects of ODN on AD. We established a mouse model of AD via microinjection of Aβ in the lateral ventricle. Utilizing a combination of western blotting assays, electrophysiological recordings, and behavioral tests, we investigated the neuroprotective effects of ODN on AD. DBI expression was decreased in AD model mice and cells. Meanwhile, ODN decreased Aβ generation by downregulating amyloidogenic AβPP processing in HEK-293 cells stably expressing human Swedish mutant APP695 and BACE1 (2EB2). Moreover, ODN could inhibit Aβ-induced oxidative stress in primary cultured cells and mice, as reflected by a dramatic increase in antioxidants and a decrease in pro-oxidants. We also found that ODN could reduce oxidative stress-induced apoptosis by restoring mitochondrial membrane potential, intracellular Ca2+ and cleaved caspase-3 levels in Aβ-treated primary cultured cells and mice. More importantly, intracerebroventricular injection of ODN attenuated cognitive impairments as well as long-term potentiation in Aβ-treated mice. These results suggest that ODN may exert a potent neuroprotective effect against Aβ-induced neurotoxicity and memory decline via its antioxidant effects, indicating that ODN may be a potential therapeutic agent for AD. Show less

Alzheimer's disease presents an abnormal cognitive behavior. TgCtwh6 is one of the predominant T. gondii strains prevalent in China. Although T. gondii type II strain infection can cause host cognitive behavioral abnormalities, we do not know whether TgCtwh6 could also cause host cognitive behavioral changes. So, in this study, we will focus on the effect of TgCtwh6 on mouse cognitive behavior and try in vivo and in vitro to explore the underlying mechanism by which TgCtwh6 give rise to mice cognitive behavior changes at the cellular and molecular level. C57BL/6 mice were infected orally with TgCtwh6 cysts. From day 90 post-infection on, all mice were conducted through the open field test and then Morris water maze test to evaluate cognitive behavior. The morphology and number of cells in hippocampus were examined with hematoxylin-eosin (H&E) and Nissl staining; moreover, Aβ protein in hippocampus was determined with immunohistochemistry and thioflavin S plaque staining. Synaptotagmin 1, apoptosis-related proteins, BACE1 and APP proteins and genes from hippocampus were assessed by western blotting or qRT-PCR. Hippocampal neuronal cell line or mouse microglial cell line was challenged with TgCtwh6 tachyzoites and then separately cultured in a well or co-cultured in a transwell device. The target proteins and genes were analyzed by immunofluorescence staining, western blotting and qRT-PCR. In addition, mouse microglial cell line polarization state and hippocampal neuronal cell line apoptosis were estimated using flow cytometry assay. The OFT and MWMT indicated that infected mice had cognitive behavioral impairments. The hippocampal tissue assay showed abnormal neuron morphology and a decreased number in infected mice. Moreover, pro-apoptotic proteins, as well as BACE1, APP and Aβ proteins, increased in the infected mouse hippocampus. The experiments in vitro showed that pro-apoptotic proteins and p-NF-κBp65, NF-κBp65, BACE1, APP and Aβ proteins or genes were significantly increased in the infected HT22. In addition, CD80, pro-inflammatory factors, notch, hes1 proteins and genes were enhanced in the infected BV2. Interestingly, not only the APP and pro-apoptotic proteins in HT22, but also the apoptosis rate of HT22 increased after the infected BV2 were co-cultured with the HT22 in a transwell device. Neuron apoptosis, Aβ deposition and neuroinflammatory response involved with microglia polarization are the molecular and cellular mechanisms by which TgCtwh6 causes mouse cognitive behavioral abnormalities. Show less

Acute myocardial infarction (MI) results in loss of cardiomyocytes and abnormal cardiac remodeling with severe inflammation and fibrosis. However, how cardiac repair can be achieved by timely resolution of inflammation and cardiac fibrosis remains incompletely understood. Our previous findings have shown that dual-specificity phosphatase 6 (DUSP6) is a regeneration repressor from zebrafish to rats. In this study, we found that intravenous administration of the DUSP6 inhibitor (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI) improved heart function and reduced cardiac fibrosis in MI rats. Mechanistic analysis revealed that BCI attenuated macrophage inflammation through NF-κB and p38 signaling, independent of DUSP6 inhibition, leading to the downregulation of various cytokines and chemokines. In addition, BCI suppressed differentiation-related signaling pathways and decreased bone-marrow cell differentiation into macrophages through inhibiting DUSP6. Furthermore, intramyocardial injection of poly (D, L-lactic-co-glycolic acid)-loaded BCI after MI had a notable effect on cardiac repair. In summary, BCI improves heart function and reduces abnormal cardiac remodeling by inhibiting macrophage formation and inflammation post-MI, thus providing a promising pro-drug candidate for the treatment of MI and related heart diseases. This article has an associated First Person interview with the first author of the paper. Show less

This study aimed to investigate the clinical significance of exostosin 1 (EXT1) in confirmed and suspected lupus membranous nephropathy (LMN). EXT1 was detected in 67 renal tissues of M-type phospholipase A2 receptor (PLA2R)-negative and ANA-positive membranous nephropathy by immunohistochemistry, and cases were divided into confirmed LMN and suspected LMN. The clinicopathological data were compared among the above groups, as well as EXT1-positive group and EXT1-negative group. Twenty-two cases (73.3%) of confirmed LMN and six cases (16.2%) of suspected LMN exhibited EXT1 expression on the glomerular basement membrane and/or mesangium area, showing a significant difference (p<0.001). Concurrently, lupus nephritis (LN) of pure class V demonstrated a lower frequency of EXT1 positivity compared with mixed class V LN in the confirmed LMN group (31.8% vs 68.2%, p=0.007). EXT1-positive patients in the confirmed and suspected LMN group showed significant differences in some clinicopathological data comparing with EXT1-negative patients (p<0.05). Follow-up data revealed that a greater proportion of patients in the EXT1-positive group achieved complete remission post-treatment (p<0.05). Cox regression analysis showed that EXT1 positivity was significantly correlated with complete remission across the entire study cohort (HR 5.647; 95% CI, 1.323 to 12.048; p=0.019). Kaplan-Meier analysis indicated that the EXT1-positive group had a higher rate of accumulated nephrotic remission compared with the EXT1-negative group in the whole study cohort (p=0.028). The EXT1-positive group exhibited a higher active index and a more favourable renal outcome than the EXT1-negative group. It would be better to recognise suspected LMN with EXT1 positivity as a potential autoimmune disease and maintain close follow-up due to its similarities with confirmed LMN. Show less

Temporal oscillations in intestinal nutrient processing and absorption are coordinated by the local clock, which leads to the hypothesis that the intestinal clock has major impacts on shaping peripheral rhythms via diurnal nutritional signals. Here, we investigate the role of the intestinal clock in controlling liver rhythmicity and metabolism. Transcriptomic analysis, metabolomics, metabolic assays, histology, quantitative (q)PCR, and immunoblotting were performed with Bmal1-intestine-specific knockout (iKO), Rev-erba-iKO, and control mice. Bmal1 iKO caused large-scale reprogramming of the rhythmic transcriptome of mouse liver with a limited effect on its clock. In the absence of intestinal Bmal1, the liver clock was resistant to entrainment by inverted feeding and a high-fat diet. Importantly, Bmal1 iKO remodelled diurnal hepatic metabolism by shifting to gluconeogenesis from lipogenesis during the dark phase, leading to elevated glucose production (hyperglycaemia) and insulin insensitivity. Conversely, Rev-erba iKO caused a diversion to lipogenesis from gluconeogenesis during the light phase, resulting in enhanced lipogenesis and an increased susceptibility to alcohol-related liver injury. These temporal diversions were attributed to disruption of hepatic SREBP-1c rhythmicity, which was maintained via gut-derived polyunsaturated fatty acids produced by intestinal FADS1/2 under the control of a local clock. Our findings establish a pivotal role for the intestinal clock in dictating liver rhythmicity and diurnal metabolism, and suggest targeting intestinal rhythms as a new avenue for improving metabolic health. Our findings establish the centrality of the intestinal clock among peripheral tissue clocks, and associate liver-related pathologies with its malfunction. Clock modifiers in the intestine are shown to modulate liver metabolism with improved metabolic parameters. Such knowledge will help clinicians improve the diagnosis and treatment of metabolic diseases by incorporating intestinal circadian factors. Show less

Vascular endothelial growth factor receptors (VEGFRs) have emerged as the most promising anti-angiogenic therapeutic targets for the treatment of recurrent glioblastomas (GBM). However, anti-VEGF treatments led to the high proportion of non-responder patients or non lasting clinical response and the tumor progression to the greater malignant stage. To overcome these problems, there is an utmost need to develop innovative anti-angiogenic therapies. In this study, we report the development of a series of new FGFR1 inhibitors. Among them, compound 4i was able to potently inhibit FGFR1 kinase activities both in vitro and in vivo. This compound displayed strong anti-angiogenic activity in HUVECs and anti-tumor growth and anti-invasion effects in U-87MG cell line. These results emphasize the importance of FGFR1-mediated signaling pathways in GBM and reveal that pharmacological inhibition of FGFR1 can enhance the anti-tumoral, anti-angiogenic and anti-metastatic efficiency against GBM. These data support targeting of FGFR1 as a novel anti-angiogenic strategy and highlight the potential of compound 4i as a promising anti-angiogenic and anti-metastatic candidate for GBM therapy. Show less

Poor outcomes have been widely reported for younger vs. older breast cancer patients, but whether this is due to age itself or the enrichment of aggressive clinical features remains controversial. We have evaluated the clinicopathologic characteristics and genomic profiles of real-world hormone receptor-positive (HR+)/HER2-negative (HER2-) metastatic breast cancer (MBC) patients to examine the determinants of outcome for younger vs. older patients in a single clinical subtype undergoing treatment in the same clinic. This study included patients presenting at the Peking University Cancer Hospital with primary stage IV or first-line metastatic HR+/HER2- breast cancer who consented to an additional blood draw for genomic profiling prior to treatment. Plasma samples were analyzed with a targeted 152-gene NGS panel to assess somatic circulating tumor DNA (ctDNA) alterations. Genomic DNA (gDNA) extracted from peripheral blood mononuclear cells was analyzed for germline variants using a targeted 600-gene NGS panel. Kaplan-Meier survival analysis was performed to analyze disease free survival (DFS), progression free survival (PFS) and overall survival (OS) in association with clinicopathologic and genomic variables. Sixty-three patients presenting with HR+/HER2- MBC were enrolled in this study. Fourteen patients were < 40 years, 19 were 40-50 years, and 30 were > 50 years at the time of primary cancer diagnosis. No significant associations were observed between age and DFS, PFS or OS. Shorter OS was associated with In this group of real-world HR+/HER2- MBC breast cancer patients younger age was not associated with poor outcomes. While current guidelines recommend treatment decisions based on tumor biology rather than age, young HR+ breast cancer patients are more likely to receive chemotherapy. Our findings support the development of biomarker-driven treatment strategies for these patients. Show less

Intravenous immunoglobulin (IVIG) is a first-line drug prepared from human plasma for the treatment of autoimmune diseases (AIDs), especially immune thrombocytopenia (ITP). Significant differences exist in protein types and expression levels between male and female plasma, and the prevalence of autoimmune diseases varies between sexes. The present study seeks to explore potential variations in IVIG sourced from distinct sex-specific plasma (DSP-IVIG), including IVIG sourced from female plasma (F-IVIG), IVIG sourced from male plasma (M-IVIG), and IVIG sourced from a blend of male and female plasma (Mix-IVIG). To address this question, we used an ITP mouse model and a monocyte-macrophage inflammation model treated with DSP IVIG. The analysis of proteomics in mice suggested that the pathogenesis and treatment of ITP may involve FcγRs mediated phagocytosis, apoptosis, Th17, cytokines, chemokines, and more. Key indicators, including the mouse spleen index, CD16 Show less

Sepsis engenders an imbalance in the body's inflammatory response, with cytokines assuming a pivotal role in its progression. A relatively recent addition to the interleukin-17 family, denominated interleukin-17D (IL-17D), is notably abundant within pulmonary confines. Nevertheless, its implication in sepsis remains somewhat enigmatic. The present study endeavors to scrutinize the participation of IL-17D in sepsis-induced acute lung injury (ALI). The levels of IL-17D in the serum and bronchoalveolar lavage fluid (BALF) of both healthy cohorts and septic patients were ascertained through an ELISA protocol. For the creation of a sepsis-induced ALI model, intraperitoneal lipopolysaccharide (LPS) injections were administered to male C57/BL6 mice. Subsequently, we examined the fluctuations and repercussions associated with IL-17D in sepsis-induced ALI, probing its interrelation with nuclear factor erythroid 2-related factor 2 (Nrf2), alveolar epithelial permeability, and heme oxygenase-1. IL-17D levels exhibited significant reduction both in the serum and BALF of septic patients (P<0.001). Similar observations manifested in mice subjected to LPS-induced acute lung injury (ALI) (P=0.002). Intraperitoneal administration of recombinant interleukin 17D protein (rIL-17D) prompted increased expression of claudin 18 and concomitant enhancement of alveolar epithelial permeability, thus, culminating in improved lung injury (P<0.001). Alveolar epithelial type II (ATII) cells were identified as the source of IL-17D, regulated by Nrf2. Furthermore, a deficiency in HO-1 yielded elevated IL-17D levels (P=0.004), albeit administration of rIL-17D ameliorated the exacerbated pulmonary damage resulting from HO-1 deficiency. Nrf2 fosters IL-17D production within AT II cells, thereby conferring a protective role in sepsis-induced ALI. Show less