Baisheng Sun, Lina Bai, Qinglin Li+5 more · 2024 · Toxicology in vitro : an international journal published in association with BIBRA · Elsevier · added 2026-04-24
Sepsis-induced acute lung injury (ALI) is a life-threatening disease. Macrophage pyroptosis has been reported to exert function in ALI. We aimed to investigate the mechanisms of ANGPTL4-mediated cell Show more
Sepsis-induced acute lung injury (ALI) is a life-threatening disease. Macrophage pyroptosis has been reported to exert function in ALI. We aimed to investigate the mechanisms of ANGPTL4-mediated cell pyroptosis in sepsis-induced ALI, thus providing new insights into the pathogenesis and prevention and treatment measures of sepsis-induced ALI. In vivo animal models and in vitro cell models were established by cecal ligation and puncture (CLP) method and lipopolysaccharide-induced macrophages RAW264.7. ANGPTL4 was silenced in CLP mice or macrophages, followed by the determination of ANGPTL4 expression in bronchoalveolar lavage fluid (BALF) or macrophages. Lung histopathology was observed by H&E staining, with pathological injury scores evaluated and lung wet and dry weight ratio recorded. M1/M2 macrophage marker levels (iNOS/CD86/Arg1), inflammatory factor (TNF-α/IL-6/IL-1β/iNOS) expression in BALF, cell death and pyroptosis, NLRP3 inflammasome, cell pyroptosis-related protein (NLRP3/Cleaved-caspase-1/caspase-1/GSDMD-N) levels, NF-κB pathway activation were assessed by RT-qPCR/ELISA/flow cytometry/Western blot, respectively. ANGPTL4 was highly expressed in mice with sepsis-induced ALI, and ANGPTL4 silencing ameliorated sepsis-induced ALI in mice. In vivo, ANGPTL4 silencing repressed M1 macrophage polarization and macrophage pyroptosis in mice with sepsis-induced ALI. In vitro, ANGPTL4 knockout impeded LPS-induced activation and pyroptosis of M1 macrophages and hindered LPS-induced activation of the NF-κB pathway in macrophages. Knockdown of ANGPTL4 blocks the NF-κB pathway activation, hinders macrophage M1 polarization and pyroptosis, thereby suppressing sepsis-induced ALI. Show less
To investigate the association of polymorphisms in SEC16B rs633715, DNAJC27 rs713586, FTO rs11642015 and MC4R rs6567160 with overweight and obesity in Han Chinese preschool children. A total of 749 Ha Show more
To investigate the association of polymorphisms in SEC16B rs633715, DNAJC27 rs713586, FTO rs11642015 and MC4R rs6567160 with overweight and obesity in Han Chinese preschool children. A total of 749 Han Chinese preschool children from Henan and Guizhou Province of Long-term Health Effects Assessment Project of Infants and Toddlers Nutritional Pack were selected for the study and divided into an overweight and obese group and a normal control group in 2022. rs633715, rs713586, rs11642015 and rs6567160 were genotyped using Kompetitive allele-specific PCR(KASP) technology. The distribution of genotypic polymorphisms was compared using the χ~2 test. The association between the four loci and overweight and obesity in preschool children was analyzed using a multifactorial logistic regression model. The statistical analysis revealed a significant disparity(P<0.05) in the distribution of genotypic polymorphisms of rs633715 and rs6567160 among preschoolers in Henan and Guizhou Province. CC heterozygous mutant and recessive models at rs633715 locus were associated with susceptibility to overweight and obesity in preschool children [OR and 95% CI 2.915(1.163-7.305), and 2.997(1.226-7.323), respectively, both P<0.05]. TC heterozygous mutant and dominant models at rs713586 locus were also associated susceptibility to overweight and obesity in preschool children(OR and 95% CI were 2.362(1.054-5.289)and 2.362(1.054-5.289), respectively, both P<0.05). rs11642015 and rs6567160 loci were not associated with susceptibility to overweight and obesity in preschool children(P>0.05). The result of the analysis of the cumulative effect of rs633715 and rs713586 showed that the number of genotypes carrying the risk genotype was positively associated with the risk of overweight and obesity in preschool children(P₍trend)<0.01). Among Han Chinese preschool children, SEC16B rs633715 and DNAJC27 rs713586 were associated with susceptibility to overweight and obesity in preschool children. Moreover, rs633715 and rs713586 had a cumulative effect on susceptibility to overweight and obesity in preschool children, the number of risk genotypes carried was positively associated with childhood overweight and obesity risk. Show less
no PDFDOI: 10.19813/j.cnki.weishengyanjiu.2024.02.009
The neuronal ceroid lipofuscinoses (NCLs) comprise a group of inherited neurodegenerative disorders with thirteen NCL-disease causing genes ceroid lipofuscinosis neuronal ( We recruited 14 patients fr Show more
The neuronal ceroid lipofuscinoses (NCLs) comprise a group of inherited neurodegenerative disorders with thirteen NCL-disease causing genes ceroid lipofuscinosis neuronal ( We recruited 14 patients from 13 unrelated families who carried biallelic variants in the We detected 21 variants in three Patients with variants in the three Show less
A Necchi, D Pouessel, R Leibowitz+12 more · 2024 · Annals of oncology : official journal of the European Society for Medical Oncology · Elsevier · added 2026-04-24
Fibroblast growth factor receptor 3 (FGFR3) alterations are oncogenic drivers of urothelial carcinoma (UC). Pemigatinib is a selective, oral inhibitor of FGFR1-3 with antitumor activity. We report the Show more
Fibroblast growth factor receptor 3 (FGFR3) alterations are oncogenic drivers of urothelial carcinoma (UC). Pemigatinib is a selective, oral inhibitor of FGFR1-3 with antitumor activity. We report the efficacy and safety of pemigatinib in the open-label, single-arm, phase II study of previously treated, unresectable or metastatic UC with FGFR3 alterations (FIGHT-201; NCT02872714). Patients ≥18 years old with FGFR3 mutations or fusions/rearrangements (cohort A) and other FGF/FGFR alterations (cohort B) were included. Patients received pemigatinib 13.5 mg once daily continuously (CD) or intermittently (ID) until disease progression or unacceptable toxicity. The primary endpoint was centrally confirmed objective response rate (ORR) as per RECIST v1.1 in cohort A-CD. Secondary endpoints included ORR in cohorts A-ID and B, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Overall, 260 patients were enrolled and treated (A-CD, n = 101; A-ID, n = 103; B, n = 44; unconfirmed FGF/FGFR status, n = 12). All discontinued treatment, most commonly due to progressive disease (68.5%). ORR [95% confidence interval (CI)] in cohorts A-CD and A-ID was 17.8% (10.9% to 26.7%) and 23.3% (15.5% to 32.7%), respectively. Among patients with the most common FGFR3 mutation (S249C; n = 107), ORR was similar between cohorts (A-CD, 23.9%; A-ID, 24.6%). In cohorts A-CD/A-ID, median (95% CI) DOR was 6.2 (4.1-8.3)/6.2 (4.6-8.0) months, PFS was 4.0 (3.5-4.2)/4.3 (3.9-6.1) months, and OS was 6.8 (5.3-9.1)/8.9 (7.5-15.2) months. Pemigatinib had limited clinical activity among patients in cohort B. Of 36 patients with samples available at progression, 6 patients had 8 acquired FGFR3 secondary resistance mutations (V555M/L, n = 3; V553M, n = 1; N540K/S, n = 2; M528I, n = 2). The most common treatment-emergent adverse events overall were diarrhea (44.6%) and alopecia, stomatitis, and hyperphosphatemia (42.7% each). Pemigatinib was generally well tolerated and demonstrated clinical activity in previously treated, unresectable or metastatic UC with FGFR3 mutations or fusions/rearrangements. Show less
Triple-negative breast cancer (TNBC) is a highly lethal malignancy with limited therapy options. Aberrant metabolism, a key hallmark of human cancers, plays a crucial role in tumor progression, therap Show more
Triple-negative breast cancer (TNBC) is a highly lethal malignancy with limited therapy options. Aberrant metabolism, a key hallmark of human cancers, plays a crucial role in tumor progression, therapeutic responses and TNBC-related death. However, the underlying mechanisms are not fully understood. In this study, we delineate a previously unrecognized role of aberrant glucose metabolism in regulating the turnover of Snail1, which is a key transcriptional factor of epithelial-mesenchymal transition (EMT) and critically contributes to the acquisition of stemness, metastasis and chemo-resistance. Mechanistically, we demonstrate that AMP-activated protein kinase (AMPK), when activated in response to glucose deprivation, directly phosphorylates Snail1 at Ser11. Such a phosphorylation modification of Snail1 facilitates its recruitment of the E3 ligase FBXO11 and promotes its degradation, thereby suppressing stemness, metastasis and increasing cellular sensitivity to chemotherapies in vitro and in vivo. Clinically, histological analyses reveal a negative correlation between p-AMPKα and Snail1 in TNBC specimens. Taken together, our findings establish a novel mechanism and functional significance of AMPK in linking glucose status to Snail1-dependent malignancies and underscore the potential of AMPK agonists as a promising therapeutic strategy in the management of TNBC. Show less
Dyslipidemia plays a very important role in the occurrence and development of cardiovascular disease (CVD). Genetic factors, including single nucleotide polymorphisms (SNPs), are one of the main risks Show more
Dyslipidemia plays a very important role in the occurrence and development of cardiovascular disease (CVD). Genetic factors, including single nucleotide polymorphisms (SNPs), are one of the main risks of dyslipidemia. 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) is not only the rate-limiting enzyme step of endogenous cholesterol production, but also the therapeutic target of statins. We investigated 405 Han Chinese and 373 Uyghur people who took statins for a period of time, recorded their blood lipid levels and baseline data before and after oral statin administration, and extracted DNA from each subject for SNP typing of In this study, for rs17671591, the CC We found that Show less
Benzo[a]pyrene (B[a]P) is a well-known polycyclic aromatic hydrocarbon (PAH) pollutant with high carcinogenicity, widespread environmental presence, and significant threat to public health. Epidemiolo Show more
Benzo[a]pyrene (B[a]P) is a well-known polycyclic aromatic hydrocarbon (PAH) pollutant with high carcinogenicity, widespread environmental presence, and significant threat to public health. Epidemiological studies have linked exposure to B[a]P and its metabolite 7,8-dihydroxy-9,10-epoxybenzo[a]pyrene (BPDE) to the development and progression of various cancers, including bladder cancer. However, its underlying mechanism remains unclear. Our study revealed that B[a]P and BPDE induced epithelial-mesenchymal transition (EMT), a critical early event in cell malignant transformation, involving a decrease in E-Cadherin and upregulation of N-Cadherin protein levels, leading to increased cell motility and migration in bladder epithelial cells. Further studies have indicated that LOXL1 DNA undergoes methylation and modification influenced by methyltransferase 3a (DNMT3a) and DNMT3b, resulting in decreased LOXL1 protein levels. The decreased LOXL1 promotes the zinc finger transcription factor SLUG, which then inhibits E-Cadherin protein levels and initiates the EMT process. Moreover, DNMT3a/3b expression appears to be influenced by intracellular oxidative stress levels. These findings suggest that exposure to B[a]P/BPDE promotes the EMT process through the pivotal factor LOXL1, thereby contributing to bladder carcinogenesis. Our study provides a theoretical basis for considering LOXL1 as a potential biomarker for early diagnosis and a novel target for the precise diagnosis and treatment of bladder cancer. Show less
Acute lung injury is a critical life-threatening complication of pulmonary and cardiac surgery with a high rate of morbidity and mortality. Fibroblast growth factor 21 (FGF21) has been reported to pla Show more
Acute lung injury is a critical life-threatening complication of pulmonary and cardiac surgery with a high rate of morbidity and mortality. Fibroblast growth factor 21 (FGF21) has been reported to play an important role in protecting vital organs from damage. This study aims to investigate the potential protective role and mechanism of FGF21 in pulmonary ischemia/reperfusion (I/R)-induced acute lung injury. A pulmonary epithelial cell line was treated with hypoxia/regeneration (H/R) in vitro and a mouse model of acute lung injury was induced with pulmonary I/R in vivo. Lung injury after pulmonary I/R was compared between FGF21-konckout (KO) mice and wild-type (WT) mice. Recombinant FGF21 was administrated in vivo and in vitro to determine its therapeutic effect. Circulating levels of FGF21 in mice with pulmonary I/R injury were significantly higher than in those without pulmonary I/R injury. Lung injury was aggravated in FGF21-KO mice compared with WT mice and the administration of FGF21 alleviated lung injury in mouse treated with I/R and pulmonary epithelial cell injury treated with H/R. FGF21 treatment decreased endoplasmic reticulum (ER) stress, Fe Our study reveals that FGF21 protects against pulmonary I/R injury via inhibiting ER stress-induced ferroptosis though FGFR1/PPARδ signaling pathway. Boosting endogenous FGF21 or the administration of recombinant FGF21 could be promising therapeutic strategies for pulmonary IRI. Show less
Parkinson's disease (PD) is a progressive neurodegenerative disease whose etiology is attributed to development of Lewy bodies and degeneration of dopaminergic neurons in the substantia nigra (SN). Cu Show more
Parkinson's disease (PD) is a progressive neurodegenerative disease whose etiology is attributed to development of Lewy bodies and degeneration of dopaminergic neurons in the substantia nigra (SN). Currently, there are no definitive diagnostic indicators for PD. In this study, we aimed to identify potential diagnostic biomarkers for PD and analyzed the impact of immune cell infiltrations on disease pathogenesis. The PD expression profile data for human SN tissue, GSE7621, GSE20141, GSE20159, GSE20163 and GSE20164 were downloaded from the Gene Expression Omnibus (GEO) database for use in the training model. After normalization and merging, we identified differentially expressed genes (DEGs) using the Robust rank aggregation (RRA) analysis. Simultaneously, DEGs after batch correction were identified. Gene interactions were determined through venn Diagram analysis. Functional analyses and protein-protein interaction (PPI) networks were used to the identify hub genes, which were visualized through Cytoscape. A Lasso Cox regression model was employed to identify the potential diagnostic genes. The GSE20292 dataset was used for validation. The proportion of infiltrating immune cells in the samples were determined via the CIBERSORT method. Sixty-two DEGs were screened in this study. They were found to be enriched in nerve conduction, dopamine (DA) metabolism, and DA biosynthesis Gene Ontology (GO) terms. The PPI network and Lasso Cox regression analysis revealed seven potential diagnostic genes, namely SLC18A2, TAC1, PCDH8, KIAA0319, PDE6H, AXIN1, and AGTR1, were subsequently validated in peripheral blood samples obtained from healthy control (HC) and PD patients, as well as in the GSE20292 dataset. The results revealed the exceptional sensitivity and specificity of these genes in PD diagnosis and monitoring. Moreover, PD patients exhibited a higher number of plasma cells, compared to HC individuals. The SLC18A2, TAC1, PCDH8, KIAA0319, PDE6H, AXIN1, and AGTR1 are potential diagnostic biomarkers for PD. Our findings also reveal the essential roles of immune cell infiltration in both disease onset and trajectory. Show less
In recent years, metal-organic framework (MOF) materials with long persistent luminescence (LPL) have inspired extensive attention and presented various applications in security systems, information a Show more
In recent years, metal-organic framework (MOF) materials with long persistent luminescence (LPL) have inspired extensive attention and presented various applications in security systems, information anticounterfeiting, and biological imaging fields. However, obtaining LPL materials with ultralong lifetime remains challenging. Halogen atoms, as nonmetallic elements existing in the frameworks, can not only induce the heavy-atom effect, effectively enhancing spin-orbit coupling and promoting intersystem crossing (ISC) processes, but also suppress non-radiative transition of the triplet states through the intra- and intermolecular interactions. Specifically, fluorine atoms with the strongest electronegativity may form intermolecular aggregate interlockings through halogen-bonding interactions that restrict molecular motions and vibrations, thereby improving phosphorescent lifetime. With the aforementioned considerations, two distinct types of MOFs with/without fluorine atoms (namely, Ca-MOF and 5FCa-MOF) were synthesized. Notably, by introducing fluorine atoms into MOFs, fluorine-induced intermolecular aggregate interlockings effectively enhanced the phosphorescent lifetime of 5FCa-MOF exceeding 264 ms compared to that of Ca-MOF (103.94 ms). Remarkably, both MOFs displayed bright LPL to the naked eye after removal of the irradiation source, especially 5FCa-MOF which can last for about 2 s. By introducing fluorine atoms, 5FCa-MOF exhibits greatly enhanced ISC with a rate constant up to 4.1 × 10 Show less
Carcass traits are crucial indicators of meat production efficiency. However, the molecular regulatory mechanisms associated with these traits remain unclear. In this study, we conducted comprehensive Show more
Carcass traits are crucial indicators of meat production efficiency. However, the molecular regulatory mechanisms associated with these traits remain unclear. In this study, we conducted comprehensive transcriptomic and genomic analyses on 399 Tiannong partridge chickens to identify key genes and variants associated with carcass traits and to elucidate the underlying regulatory mechanisms. Based on association analyses with the elastic net (EN) model, we identified 12 candidate genes (AMY1A, AP3B2, CEBPG, EEF2, EIF4EBP1, FGFR1, FOXD3, GOLM1, LOC107052698, PABPC1, SERPINB6 and TBC1D16) for 4 carcass-related traits, namely live weight, dressed weight, eviscerated weight, and breast muscle weight. SERPINB6 was identified as the only overlapping gene by 3 analyses, EN model analysis, weighted gene co-expression network analysis and differential expression analysis. Cell-level experiments confirmed that SERPINB6 promotes the proliferation of chicken DF1 cells and primary myoblasts. Further expression genome-wide association study and association analysis indicated that rs317934171 is the critical site that enhances SERPINB6 expression. Furthermore, a dual-luciferase reporter assay proved that gga-miR-1615 targets the 3'UTR of SERPINB6. Collectively, our findings reveal that SERPINB6 serves as a novel gene for chicken carcass traits by promoting fibroblast and myoblast proliferation. Additionally, the downstream variant rs317934171 regulates SERPINB6 expression. These results identify a new target gene and molecular marker for the molecular mechanisms of chicken carcass traits. Show less
Migraine is a common primary headache that has a significant impact on patients' quality of life. The co-occurrence of migraine and depression is frequent, resulting in more complex symptoms and a poo Show more
Migraine is a common primary headache that has a significant impact on patients' quality of life. The co-occurrence of migraine and depression is frequent, resulting in more complex symptoms and a poorer prognosis. The evidence suggests that depression and migraine comorbidity share a polygenic genetic background. The aim of this study is to identify related genetic variants that contribute to genetic susceptibility to migraine with and without depression in a Chinese cohort. In this case-control study, 263 individuals with migraines and 223 race-matched controls were included. Eight genetic polymorphism loci selected from the GWAS were genotyped using Sequenom's MALDI-TOF iPLEX platform. In univariate analysis, The study indicates that there is an association between Show less
Bladder cancer (BLCA) is a tumor that affects men more than women. The biological function and prognostic value of androgen-responsive genes (ARGs) in BLCA are currently unknown. To address this, we e Show more
Bladder cancer (BLCA) is a tumor that affects men more than women. The biological function and prognostic value of androgen-responsive genes (ARGs) in BLCA are currently unknown. To address this, we established an androgen signature to determine the prognosis of BLCA. Sequencing data for BLCA from the TCGA and GEO datasets were used for research. The tumor microenvironment (TME) was measured using Cibersort and ssGSEA. Prognosis-related genes were identified and a risk score model was constructed using univariate Cox regression, LASSO regression, and multivariate Cox regression. Drug sensitivity analysis was performed using Genomics of drug sensitivity in cancer (GDSC). Real-time quantitative PCR was performed to assess the expression of representative genes in clinical samples. ARGs (especially the CDK6, FADS1, PGM3, SCD, PTK2B, and TPD52) might regulate the progression of BLCA. The different expression patterns of ARGs may lead to different immune cell infiltration. The risk model indicates that patients with higher risk scores have a poorer prognosis, more stromal infiltration, and an enrichment of biological functions. Single-cell RNA analysis, bulk RNA data, and PCR analysis support the reliability of this risk model, and a nomogram was also established for clinical use. Drug prediction analysis showed that high-risk patients had a better response to fludarabine, AZD8186, and carmustine. ARGs played an important role in the progression, immune infiltration, and prognosis of BLCA. The ARGs model has high accuracy in predicting the prognosis of BLCA patients and provides more effective medication guidelines. Show less
This study investigated the effect of dietary lipid levels on growth performance, lipid metabolism, antioxidant capacity, digestive enzyme activity, and metamorphosis rate of bullfrog (
Plant phenolics have been known for various biological activities. This study aims to extract and examine the presence of phenolics in Bao mango (Mangifera indica L. var.) peel ethanolic extract (MPE) Show more
Plant phenolics have been known for various biological activities. This study aims to extract and examine the presence of phenolics in Bao mango (Mangifera indica L. var.) peel ethanolic extract (MPE). Further, antioxidant, anti-diabetic (α-amylase, and α-glucosidase inhibitory activity), and anti- Alzheimer's disease (AD) (acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-secretase (BACE-1) inhibitory activity) efficacy of MPE were determined. The results indicated that mangiferin (8755.89 mg/ 100 g extract) was the major phenolic compound in MPE. An antioxidant mechanism revealed that MPE had a higher radical scavenging ability (4266.70 µmol TE/g extract) compared to reducing power (FRAP) or oxygen radical absorption capacity (ORAC). Further Show less
Vps34 is the unique member of the class III phosphoinositide 3-kinase family that performs both vesicular transport and autophagy. Its role in natural killer (NK) cells remains uncertain. In this stud Show more
Vps34 is the unique member of the class III phosphoinositide 3-kinase family that performs both vesicular transport and autophagy. Its role in natural killer (NK) cells remains uncertain. In this study, a model without Vps34 (Vps34 Show less
Organic afterglow with long-persistent luminescence (LPL) after photoexcitation is highly attractive, but the realization of narrowband afterglow with small full-width at half-maximum (FWHM) is a huge Show more
Organic afterglow with long-persistent luminescence (LPL) after photoexcitation is highly attractive, but the realization of narrowband afterglow with small full-width at half-maximum (FWHM) is a huge challenge since it is intrinsically contradictory to the triplet- and solid-state emission nature of organic afterglow. Here, narrow-band, long-lived, and full-color organic LPL is realized by isolating multi-resonant thermally activated delayed fluorescent (MR-TADF) fluorophores in a glassy steroid-type host through a facile melt-cooling treatment. Such prepared host becomes capable of exciton dissociation and recombination (EDR) upon photoirradiation for both long-lived fluorescence and phosphorescence; and, the efficient Förster resonance energy transfer (FRET) from the host to various MR-TADF emitters leads to high-performance LPL, exhibiting small FWHM of 33 nm, long persistent time over 10 s, and facile color-tuning in a wide range from deep-blue to orange (414-600 nm). Moreover, with the extraordinary narrowband LPL and easy processability of the material, centimeter-scale flexible optical waveguide fibers and integrated FWHM/color/lifetime-resolved multilevel encryption/decryption devices have been designed and fabricated. This novel EDR and singlet/triplet-to-singlet FRET strategy to achieve excellent LPL performances illustrates a promising way for constructing flexible organic afterglow with easy preparation methods, shedding valuable scientific insights into the design of narrow-band emission in organic afterglow. Show less
Axis inhibition protein 1 (AXIN1), a scaffold protein interacting with various critical molecules, plays a vital role in determining cell fate. However, its impact on the antiviral innate immune respo Show more
Axis inhibition protein 1 (AXIN1), a scaffold protein interacting with various critical molecules, plays a vital role in determining cell fate. However, its impact on the antiviral innate immune response remains largely unknown. Here, we identify that AXIN1 acts as an effective regulator of antiviral innate immunity against both DNA and RNA virus infections. In the resting state, AXIN1 maintains the stability of the transcription factor interferon regulatory factor 3 (IRF3) by preventing p62-mediated autophagic degradation of IRF3. This is achieved by recruiting ubiquitin-specific peptidase 35 (USP35), which removes lysine (K) 48-linked ubiquitination at IRF3 K366. Upon virus infection, AXIN1 undergoes a phase separation triggered by phosphorylated TANK-binding kinase 1 (TBK1). This leads to increased phosphorylation of IRF3 and a boost in IFN-I production. Moreover, KYA1797K, a small molecule that binds to the AXIN1 RGS domain, enhances the AXIN1-IRF3 interaction and promotes the elimination of various highly pathogenic viruses. Clinically, patients with HBV-associated hepatocellular carcinoma (HCC) who show reduced AXIN1 expression in pericarcinoma tissues have low overall and disease-free survival rates, as well as higher HBV levels in their blood. Overall, our findings reveal how AXIN1 regulates IRF3 signaling and phase separation-mediated antiviral immune responses, underscoring the potential of the AXIN1 agonist KYA1797K as an effective antiviral agent. Show less
The association between serum angiopoietin-like 4 (ANGPTL4) levels and the severity of diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus remains unclear. A total of 1,115 type 2 Show more
The association between serum angiopoietin-like 4 (ANGPTL4) levels and the severity of diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus remains unclear. A total of 1,115 type 2 diabetes mellitus patients were analyzed in this cross-sectional study. DKD index included DKD stages defined by estimated glomerular filtration rate, the albuminuria grades and DKD risk management grades. Serum levels of ANGPTL4 and other biomarkers were detected. Multivariable-adjusted linear and logistic analyses were used to study the association between ANGPTL4 and DKD. The protein levels of ANGPTL4 were assessed in the kidney. Renal tubular cells were stimulated with glucose to study ANGPTL4 expression. Compared with the participants in the third or fourth quantile of ANGPTL4, those in the first or second quantile of ANGPTL4 were younger, with lower glycated hemoglobin, triglycerides and urinary albumin creatinine ratio (all P < 0.05). There was a negative nonlinear relationship between ANGPTL4 and estimated glomerular filtration rate in type 2 diabetes mellitus patients. One standard deviation increased serum ANGPTL4 levels, the odds ratio of having DKD was 1.40 (95% confidence interval 1.08-1.80). The mediation analysis showed that triglycerides did not mediate the association between ANGPTL4 and DKD. Furthermore, ANGPTL4 could be the strongest among multiple panels of biomarkers in its association of DKD. Compared with mice at 8 weeks-of-age, db/db mice at 18 weeks-of-age had increased ANGPTL4 expression in glomeruli and tubular segments. In vitro, glucose could stimulate ANGPTL4 expression in tubular cells in a dose-dependent manner. ANGPTL4 could be a potential marker and therapeutic target for DKD treatment. Show less
The excessive accumulation of abdominal fat in chickens has resulted in a reduction in both the feed conversion efficiency and the slaughter yield. To elucidate the regulatory mechanisms and metabolic Show more
The excessive accumulation of abdominal fat in chickens has resulted in a reduction in both the feed conversion efficiency and the slaughter yield. To elucidate the regulatory mechanisms and metabolic pathways affecting abdominal fat deposition in the context of broiler breeding, a cohort of 400 Qingyuan partridge chickens with varying abdominal fat deposition was established. Whole transcriptome sequencing analyses were conducted on the duodenum of 20 representative chickens to ascertain the regulatory networks at this vital digestive and absorptive organ. Consequently, 116 differentially expressed genes were identified, exhibiting a trend of increasing or decreasing expression in correlation with the accumulation of abdominal fat. A total of 36 DEmRNAs, 170 DElncRNAs, 92 DEcircRNAs and 88 DEmiRNAs were identified as differentially expressed between chickens with extremely high and low abdominal fat deposition. The functional enrichment analyses demonstrated that the differentially expressed RNA in the duodenum were involved in the regulation of chicken abdominal fat deposition by mediating a series of metabolic pathways, including the Wnt signaling pathway, the PPAR signaling pathway, the Hippo signaling pathway, the FoxO signaling pathway, the MAPK signaling pathway and other signaling pathways that are involved in fatty acid metabolism and degradation. The construction of putative interaction pairs led to the suggestion of two lncRNA-miRNA-mRNA ceRNA networks comprising two mRNAs, two miRNAs, and 29 lncRNAs, as well as two circRNA-lncRNA-miRNA-mRNA ceRNA networks comprising 26 mRNAs, 12 miRNAs, 17 lncRNAs, and nine circRNAs, as core regulatory networks in the duodenum affecting chicken abdominal fat deposition. The aforementioned genes including TMEM150C, REXO1, PIK3C2G, ppp1cb, PARP12, SERPINE2, LRAT, CYP1A1, INSR and APOA4, were proposed as candidate genes, while the miRNAs, including miR-107-y, miR-22-y, miR-25-y, miR-2404-x and miR-16-x, as well as lncRNAs such as ENSGALT00000100291, TCONS₀₀₀₆₃₅₀₈, TCONS₀₀₀₆₁₂₀₁ and TCONS₀₀₀₇₉₄₀₂ were the candidate regulators associated with chicken abdominal fat deposition. The findings of this study provide a theoretical foundation for the molecular mechanisms of mRNAs and non-coding RNAs in duodenal tissues on abdominal fat deposition in chickens. Show less
(Pro)renin receptor (PRR) is highly expressed in renal tubules, which is involved in physiological and pathological processes. However, the role of PRR, expressed in renal tubular epithelial cells, in Show more
(Pro)renin receptor (PRR) is highly expressed in renal tubules, which is involved in physiological and pathological processes. However, the role of PRR, expressed in renal tubular epithelial cells, in diabetic kidney disease (DKD) remain largely unknown. In this study, kidney biopsies, urine samples, and public RNA-seq data from DKD patients were used to assess PRR expression and cell pyroptosis in tubular epithelial cells. The regulation of tubular epithelial cell pyroptosis by PRR was investigated by in situ renal injection of adeno-associated virus9 (AAV9)-shRNA into db/db mice, and knockdown or overexpression of PRR in HK-2 cells. To reveal the underlined mechanism, the interaction of PRR with potential binding proteins was explored by using BioGrid database. Furthermore, the direct binding of PRR to dipeptidyl peptidase 4 (DPP4), a pleiotropic serine peptidase which increases blood glucose by degrading incretins under diabetic conditions, was confirmed by co-immunoprecipitation assay and immunostaining. Higher expression of PRR was found in renal tubules and positively correlated with kidney injuries of DKD patients, in parallel with tubular epithelial cells pyroptosis. Knockdown of PRR in kidneys significantly blunted db/db mice to kidney injury by alleviating renal tubular epithelial cells pyroptosis and the resultant interstitial inflammation. Moreover, silencing of PRR blocked high glucose-induced HK-2 pyroptosis, whereas overexpression of PRR enhanced pyroptotic cell death of HK-2 cells. Mechanistically, PRR selectively bound to cysteine-enrich region of C-terminal of DPP4 and augmented the protein abundance of DPP4, leading to the downstream activation of JNK signaling and suppression of SIRT3 signaling and FGFR1 signaling, and then subsequently mediated pyroptotic cell death. This study identified the significant role of PRR in the pathogenesis of DKD; specifically, PRR promoted tubular epithelial cell pyroptosis via DPP4 mediated signaling, highlighting that PRR could be a promising therapeutic target in DKD. Show less
Lung cancer, a common type of malignant neoplasm, has seen significant advancements in the treatment of lung adenocarcinoma (LUAD). However, the management of lung squamous cell carcinoma (LSCC) conti Show more
Lung cancer, a common type of malignant neoplasm, has seen significant advancements in the treatment of lung adenocarcinoma (LUAD). However, the management of lung squamous cell carcinoma (LSCC) continues to pose challenges. Traditional treatment methods for LSCC encompass surgical resection, chemotherapy, and radiotherapy. The introduction of targeted therapy and immunotherapy has greatly benefited LSCC patients, but issues such as limited immune response rates and adverse reactions persist. Therefore, gaining a deeper comprehension of the underlying mechanisms holds immense importance. This review provides an in-depth overview of classical signaling pathways and therapeutic targets, including the PI3K signaling pathway, CDK4/6 pathway, FGFR1 pathway and EGFR pathway. Additionally, we delve into alternative signaling pathways and potential targets that could offer new therapeutic avenues for LSCC. Lastly, we summarize the latest advancements in targeted therapy combined with immune checkpoint blockade (ICB) therapy for LSCC and discuss the prospects and challenges in this field. Show less
Obstructive sleep apnea (OSA) is considered to be an important contributor of dyslipidemia. However, there lacks observational studies focusing on the potential effect of lipid management on OSA risk. Show more
Obstructive sleep apnea (OSA) is considered to be an important contributor of dyslipidemia. However, there lacks observational studies focusing on the potential effect of lipid management on OSA risk. Thus, we aimed to investigate the genetic association of lipid-modifying therapy with risk of OSA. A drug-target mendelian randomization (MR) study using both cis-variants and cis-expression quantitative trait loci (eQTLs) of lipid-modifying drug targets was performed. The MR analyses used summary-level data of genome wide association studies (GWAS). Primary MR analysis was conducted using inverse-variance-weighted (IVW) method. Sensitivity analysis was performed using weighted median (WM) and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods. Genetically proxied low-density lipoprotein cholesterol (LDL-C)-lowering effect of cholesteryl ester transfer protein (CETP) was associated with reduced risk of OSA (odds ratio [OR] =0.75, 95% confidence interval [CI]: 0.60-0.94, false discovery rate [FDR] q value = 0.046). A significant MR association with risk of OSA was observed for CETP expression in subcutaneous adipose tissue (OR = 0.94, 95%CI: 0.89-1.00, FDR q value = 0.049), lung (OR = 0.94, 95%CI: 0.89-1.00, FDR q value = 0.049) and small intestine (OR = 0.96, 95%CI: 0.93-1.00, FDR q value = 0.049). No significant effects of high-density lipoprotein cholesterol (HDL-C)-raising effect of CETP inhibition, LDL-C-lowering and triglycerides-lowering effect of other drug targets on OSA risk were observed. The present study presented genetic evidence supporting the association of LDL-C-lowering therapy by CETP inhibition with reduced risk of OSA. These findings provided novel insights into the role of lipid management in patients with OSA and encouraged further clinical validations and mechanistic investigations. Show less
Extramammary Paget's disease (EMPD) is a rare cancer that occurs within the epithelium of the skin, arising predominantly in areas with high apocrine gland concentration such as the vulva, scrotum, pe Show more
Extramammary Paget's disease (EMPD) is a rare cancer that occurs within the epithelium of the skin, arising predominantly in areas with high apocrine gland concentration such as the vulva, scrotum, penis and perianal regions. Here, we aim to integrate clinicopathological data with genomic analysis of aggressive, rapidly-progressing de novo metastatic EMPD responding to HER2-directed treatment in combination with other agents, to attain a more comprehensive understanding of the disease landscape. Immunohistochemical staining on the scrotal wall tumor and bone marrow metastasis demonstrated HER2 overexpression. Whole genome sequencing of the tumor and matched blood was performed. Notable copy number gains (log Whole genome sequencing revealed the underlying copy number variation landscape in HER2-positive metastatic EMPD. The presence of alternative signalling pathways and genetic variants suggests potential interactions with HER2 signalling, which possibly contributed to the HER2 overexpression and observed response to HER2-directed therapy combined with other agents in a comprehensive treatment regimen. Show less
The effectiveness of ketogenic diet (KD) in ameliorating fatty liver has been established, although its mechanism is under investigation. Fibroblast growth factor 21 (FGF21) positively regulates obesi Show more
The effectiveness of ketogenic diet (KD) in ameliorating fatty liver has been established, although its mechanism is under investigation. Fibroblast growth factor 21 (FGF21) positively regulates obesity-associated metabolic disorders and is elevated by KD. FGF21 conventionally initiates its intracellular signaling via receptor β-klotho (KLB). However, the mechanistic role of FGF21-KLB signaling for KD-ameliorated fatty liver remains unknown. This study aimed to delineate the critical role of FGF21 signaling in the ameliorative effects of KD on hepatic steatosis. Eight-week-old C57BL/6 J mice were fed a chow diet (CD), a high-fat diet (HFD), or a KD for 16 weeks. Adeno-associated virus-mediated liver-specific KLB knockdown mice and control mice were fed a KD for 16 weeks. Phenotypic assessments were conducted during and after the intervention. We investigated the mechanism underlying KD-alleviated hepatic steatosis using multi-omics and validated the expression of key genes. KD improved hepatic steatosis by upregulating fatty acid oxidation and downregulating lipogenesis. Transcriptional analysis revealed that KD dramatically activated FGF21 pathway, including KLB and fibroblast growth factor receptor 1 (FGFR1). Impairing liver FGF21 signaling via KLB knockdown diminished the beneficial effects of KD on ameliorating fatty liver, insulin resistance, and regulating lipid metabolism. KD demonstrates beneficial effects on diet-induced metabolic disorders, particularly on hepatic steatosis. Liver FGF21-KLB signaling plays a critical role in the KD-induced amelioration of hepatic steatosis. Show less
The transcription factor TFEB is a major regulator of lysosomal biogenesis and autophagy. There is growing evidence that posttranslational modifications play a crucial role in regulating TFEB activity Show more
The transcription factor TFEB is a major regulator of lysosomal biogenesis and autophagy. There is growing evidence that posttranslational modifications play a crucial role in regulating TFEB activity. Here, we show that lactate molecules can covalently modify TFEB, leading to its lactylation and stabilization. Mechanically, lactylation at K91 prevents TFEB from interacting with E3 ubiquitin ligase WWP2, thereby inhibiting TFEB ubiquitination and proteasome degradation, resulting in increased TFEB activity and autophagy flux. Using a specific antibody against lactylated K91, enhanced TFEB lactylation was observed in clinical human pancreatic cancer samples. Our results suggest that lactylation is a novel mode of TFEB regulation and that lactylation of TFEB may be associated with high levels of autophagy in rapidly proliferating cells, such as cancer cells. Show less
Evidence has revealed that oestrogen deprivation-induced osteolysis is microbiota-dependent and can be treated by probiotics. However, the underlying mechanism require further investigation. This stud Show more
Evidence has revealed that oestrogen deprivation-induced osteolysis is microbiota-dependent and can be treated by probiotics. However, the underlying mechanism require further investigation. This study aims to provide additional evidence supporting the use of probiotics as an adjuvant treatment and to explore the pathophysiology of oestrogen-deprived osteolysis. Forty-five SD rats were randomly divided into five groups (n = 9). Rats from four groups were ovariectomised and treated with NS, calcium, probiotics, or calcium + probiotics, while one group underwent a sham operation and was treated with NS. The osteometabolic effects were evaluated, and the mechanistic role of the probiotic supplement was explored. Intragastric administration of Bifidobacterium animalis subsp. lactis LPL-RH (LPL-RH) markedly suppressed osteoclastic activation and bone calcium loss by downregulating TRAP enzymatic activity, the OPG/RANKL ratio, and the downstream signalling pathway RANKL/TRAF6/NF-κB/NFATc1/TRAP in ovariectomised SD rats. LPL-RH also reduced CD4 Collectively, LPL-RH suppressed osteoclastogenesis and osteolysis by modulating type 17 immunity and gut microbiome. Show less