👤 Wei Yuan

Previous studies have demonstrated that naringenin possesses lipid-lowering effects; however, the underlying mechanisms, particularly its specific molecular targets, remain uncertain. Using bioinformatics, three traditional Chinese medicine databases and one human disease database were integrated to establish two naringenin-target-hyperlipidemia modules: naringenin-oxidative stress (OS) and naringenin-lipid metabolism (LM). Data on 1,850 proteins from 1,871 genetic instruments were sourced from seven previous studies. Using Mendelian randomization based on data from the Integrative Epidemiology Unit genome-wide association study (case, n = 5,153; control, n = 344,069), we identified potential drug targets that were subsequently validated in the UK Biobank (396,565 individuals) and FinnGen (412,181 individuals) cohorts. Using molecular docking and molecular dynamics simulation to verify the binding ability of naringenin and causal protein. In plasma, every standard deviation increase in apolipoprotein B (APOB) was associated with an increased risk of hyperlipidemia (odds ratio [OR] = 9.37, 95% confidence interval [CI], 5.12-17.12; This Mendelian randomization-based combined analysis offers a robust framework for elucidating the pharmacological effects of naringenin and identifying candidate proteins for further investigation in the context of hyperlipidemia treatment. Show less

Lipoprotein(a) (Lp(a)) is a circulating apolipoprotein B (ApoB) containing particle that has been observationally linked to atherosclerotic cardiovascular disease and is the target of emerging therapeutics. Recent work has highlighted the role of circulating lipoproteins in abdominal aortic aneurysm (AAA). We sought to triangulate human observational and genetic evidence to evaluate the role of Lp(a) in AAA. We tested the association between circulating levels of Lp(a) and clinically diagnosed abdominal aortic aneurysms while controlling for traditional AAA risk factors and levels of ApoB using logistic regression among 795 individuals with and 374,772 individuals without AAA in the UK Biobank (UKB). Multivariable Mendelian randomization (MVMR) was used to test for putatively causal associations between Lp(a) and AAA controlling for ApoB. Genetic instruments for Lp(a) and ApoB were created from genome-wide association studies (GWAS) of Lp(a) and ApoB comprising 335,796 and 418,505 UKB participants, respectively. The instruments were tested for association with AAA using data from a GWAS of 39,221 individuals with and 1,086,107 without AAA. Elevated Lp(a) levels were observationally associated with an increased risk of AAA (OR 1.04 per 10 nmol/L Lp(a); 95%CI 1.02-1.05; P<0.01). Clinically elevated Lp(a) levels (>150nmol/L) were likewise associated with an increased risk of AAA (OR 1.47; 95% CI 1.15-1.88; P < 0.01) when compared to individuals with Lp(a) levels <150nmol/L. MVMR confirmed a significant, ApoB-independent association between increased Lp(a) and increased risk of AAA (OR 1.13 per SD increase in Lp(a); 95%CI 1.02-1.24; P<0.02). Both observational and genetic analyses support an association between increased Lp(a) and AAA risk that is independent of ApoB. These findings suggest that Lp(a) may be a therapeutic target for AAA and drive the inclusion of AAA as an outcome in clinical trials of Lp(a) antagonists. Show less

Liver oncogenesis is accompanied by discernible protein changes in the bloodstream. By employing plasma proteomic profiling, we can delve into the molecular mechanisms of liver cancer and pinpoint potential biomarkers. In this nested case-control study, we applied liquid chromatography-tandem mass spectrometry for proteome profiling in baseline plasma samples. Differential protein expression was determined and was subjected to functional enrichment, network, and Mendelian randomization (MR) analyses. We identified 193 proteins with notable differential levels between the groups. Of these proteins, MR analysis offered a compelling negative association between apolipoprotein B (APOB) and liver cancer. This association was further corroborated in the UK Biobank cohort: genetically predicted APOB levels were associated with a 31% (95% CI 19-42%) decreased risk of liver cancer; and phenotypic analysis indicated an 11% (95% CI 8-14%) decreased liver cancer risk for every 0.1 g/L increase of circulating APOB levels. Multivariable MR analysis suggested that the hepatic fat content might fully mediate the APOB-liver cancer connection. In summary, we identified some plasma proteins, particularly APOB, as potential biomarkers of liver cancer. Our findings underscore the intricate link between lipid metabolism and liver cancer, offering hints for targeted prophylactic strategies and early detection. Show less

Our study aimed to investigate the role of lipids in melanoma risk and the effect of lipid-lowering drug targets on melanoma. Using Mendelian Randomization analysis, we examined the genetic agents of nine lipid-lowering drugs and their association with melanoma risk. We found that genetically proxied inhibition of HMGCR, ABCG5/ABCG8, and ANGPTL3 was associated with a reduced risk of melanoma. On the other hand, inhibition of LPL and Apo-B100 was significantly associated with an increased risk of melanoma. Sensitivity analyses did not reveal any statistical evidence of bias from pleiotropy or genetic confounding. We did not find a robust association between lipid traits NPC1L1, PCSK9, APOC3 inhibition, and melanoma risk. These findings were validated using two independent lipid datasets. Our analysis also revealed that HMGCR, ANGPTL3, and ABCG5/ABCG8 inhibitors reduced melanoma risk independent of their effects on lipids. This suggests that these targets may have potential for melanoma prevention or treatment. In conclusion, our study provides evidence for a causal role of lipids in melanoma risk and highlights specific lipid-lowering drug targets that may be effective in reducing the risk of melanoma. These findings contribute to the understanding of the underlying mechanisms of melanoma development and provide potential avenues for further research and therapeutic interventions. 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 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

Hertwig's epithelial root sheath (HERS) interacts with dental apical mesenchyme and guides development of the tooth root, which is integral to the function of the whole tooth. However, the key genes in HERS essential for root development are understudied. Here, we show that Axin1, a scaffold protein that negatively regulates canonical Wnt signaling, is strongly expressed in the HERS. Axin1 ablation in the HERS of mice leads to defective root development, but in a manner independent of canonical Wnt signaling. Further studies reveal that Axin1 in the HERS negatively regulates the AKT1-mTORC1 pathway through binding to AKT1, leading to inhibition of ribosomal biogenesis and mRNA translation. Sonic hedgehog (Shh) protein, a morphogen essential for root development, is over-synthesized by upregulated mTORC1 activity upon Axin1 inactivation. Importantly, either haploinsufficiency of the mTORC1 subunit Rptor or pharmacological inhibition of Shh signaling can rescue the root defects in Axin1 mutant mice. Collectively, our data suggest that, independently of canonical Wnt signaling, Axin1 controls ribosomal biogenesis and selective mRNA translation programs via AKT1-mTORC1 signaling during tooth root development. Show less

This was a study of 12 cerebellar cortical dysplasias (CCDs) fetuses, these cases were characterized by a disorder of cerebellar fissures. Historically, CCD diagnosis was primarily performed using postnatal imaging. Unique to this study was the case series of CCD for prenatal diagnosis using prenatal ultrasound, as well as we found that AXIN1 and FOXC1 mutations may be related to CCD. Show less

According to recent research, metabolic-associated fatty liver disease (MAFLD) has emerged as an important underlying etiology of hepatocellular carcinoma (HCC). However, the molecular mechanism of MAFLD-HCC is still unclear. Tumor necrosis factor receptor-associated factor 2 (TRAF2) is the key molecule to mediate the signal of inflammatory NF-κB pathway. This study aims to investigate the potential dysregulation of TRAF2 and its biological function in MAFLD-HCC. Huh7 TRAF2 Show less

Previous studies have confirmed that choline exerts anti-fibrotic effect in the heart by activating the M Proliferation of cardiac fibroblasts was induced by transforming growth factor (TGF)-β1 The expression of miR-29b decreased when treated with TGF-β1 (P=0.0389) and increased after choline stimulated (P=0.0001). Overexpression of miR-29b could reverse the high expression of collagen I (P<0.0001), α-SMA (P=0.0007), and CTGF (P=0.0038) induced by TGF-β1, whereas inhibition of miR-29b had a tendency to even further increase the expression of fibrosis markers. Meanwhile, inhibition of miR-29b could reverse the anti-fibrotic effect of choline, increasing the expression of collagen I (P=0.0040), α-SMA (P=0.0001), and CTGF (P=0.0185), and promoting the fibroblast proliferation and migration. Moreover, BACE1 protein level, increased after TGF-β1 treatment (P=0.0037) and reversed by overexpression of miR-29b (P=0.0493). Choline could reduce the increase of BACE1 induced by TGF-β1 (P=0.0264), and 4-diphenylacetoxy-N-methyl-piperidine methiodide (4-DAMP) increased the expression of BACE1 (P=0.0060). Furthermore, overexpression of BACE1 could reverse the protective effect of miR-29b in cardiac fibrosis, increasing the protein level of collagen I (P=0.0404). The results suggested that M Show less

Alzheimer's disease (AD) is a significant global health concern, and it is crucial that we find effective methods to prevent or slow down AD progression. Recent studies have highlighted the essential role of blood vessels in clearing Aβ, a protein that contributes to AD. Scientists are exploring blood biomarkers as a potential tool for future AD diagnosis. One promising method that may help prevent AD is remote ischemic conditioning (RIC). RIC involves using sub-lethal ischemic-reperfusion cycles on limbs. However, a comprehensive understanding of how RIC can prevent AD and its long-term effectiveness is still lacking. Further research is essential to fully comprehend the potential benefits of RIC in preventing AD. Female wild-type (WT) and APP/PS1 transgenic rats, aged 12 months, underwent ovariectomy and were subsequently assigned to WT, APP/PS1, and APP/PS1 + RIC groups. RIC was conducted five times a week for 4 weeks. The rats' depressive and cognitive behaviors were evaluated using force swimming, open-field tests, novel objective recognition, elevated plus maze, and Barnes maze tests. Evaluation of the neurovascular unit (NVU), synapses, vasculature, astrocytes, and microglia was conducted using immunofluorescence staining (IF), Western blot (WB), and transmission electron microscopy (TEM). Additionally, the cerebro-vasculature was examined using micro-CT, and cerebral blood flow (CBF) was measured using Speckle Doppler. Blood-brain barrier (BBB) permeability was determined by measuring the Evans blue leakage. Finally, Aβ levels in the rat frontal cortex were measured using WB, ELISA, or IF staining. RIC enhanced memory-related protein expression and rescued depressive-like behavior and cognitive decline in APP/PS1 transgenic rats. Additionally, the intervention protected NVU in the rat frontal cortex, as evidenced by (1) increased expression of TJ (tight junction) proteins, pericyte marker PDGFRβ, and glucose transporter 1 (GLUT1), as well as decreased VCAM1; (2) mitigation of ultrastructure impairment in neuron, cerebral vascular, and astrocyte; (3) upregulation of A2 astrocyte phenotype markers and downregulation of A1 phenotype markers, indicating a shift toward a healthier phenotype. Correspondingly, RIC intervention alleviated neuroinflammation, as evidenced by the decreased Iba1 level, a microglia marker. Meanwhile, RIC intervention elevated CBF in frontal cortex of the rats. Notably, RIC intervention effectively suppressed Aβ toxicity, as demonstrated by the enhancement of α-secretase and attenuation of β-secretase (BACE1) and γ- secretase and Aβ1-42 and Aβ1-40 levels as well. Chronic RIC intervention exerts vascular and neuroprotective roles, suggesting that RIC could be a promising therapeutic strategy targeting the BBB and NVU during AD development. Show less

Altered branched chain amino acids (BCAAs), including leucine, isoleucine, and valine, are frequently observed in patients with advanced cancer. We evaluated the efficacy of chimeric antigen receptor (CAR) T cell-mediated cancer cell lysis potential in the immune microenvironment of BCAA supplementation and deletion. BCAA supplementation increased cancer cell killing percentage, while accelerating BCAA catabolism and decreasing BCAA transporter decreased cancer cell lysis efficacy. We thus designed BCKDK engineering CAR T cells for the reprogramming of BCAA metabolism in the tumor microenvironment based on the genotype and phenotype modification. BCKDK overexpression (OE) in CAR-T cells significantly improved cancer cell lysis, while BCKDK knockout (KO) resulted in inferior lysis potential. In an in vivo experiment, BCKDK-OE CAR-T cell treatment significantly prolonged the survival of mice bearing NALM6-GL cancer cells, with the differentiation of central memory cells and an increasing proportion of CAR-T cells in the peripheral circulation. BCKDK-KO CAR-T cell treatment resulted in shorter survival and a decreasing percentage of CAR-T cells in the peripheral circulation. In conclusion, BCKDK-engineered CAR-T cells exert a distinct phenotype for superior anticancer efficiency. Show less

Branched-chain amino acid transferase 1 (BCAT1) is highly expressed in multiple cancers and is associated with poor prognosis, particularly in glioblastoma (GBM). However, the post-translational modification (PTM) mechanism of BCAT1 is unknown. Here, we investigated the cross-talk mechanisms between phosphorylation and ubiquitination modifications in regulating BCAT1 activity and stability. We found that BCAT1 is phosphorylated by branched chain ketoacid dehydrogenase kinase (BCKDK) at S5, S9, and T312, which increases its catalytic and antioxidant activity and stability. STUB1 (STIP1 homology U-box-containing protein 1), the first we found and reported E3 ubiquitin ligase of BCAT1, can also be phosphorylated by BCKDK at the S19 site, which disrupts the interaction with BCAT1 and inhibits its degradation. In addition, we demonstrate through in vivo and in vitro experiments that BCAT1 phosphorylation inhibiting its ubiquitination at multiple sites is associated with GBM proliferation and that inhibition of the BCKDK-BCAT1 axis enhances the sensitivity to temozolomide (TMZ). Overall, we identified novel mechanisms for the regulation of BCAT1 modification and elucidated the importance of the BCKDK-STUB1-BCAT1 axis in GBM progression. Show less

Lipid metabolism disorders appear to play an important role in the ageing process, thus understanding the cellular and molecular mechanisms underlying the association of ageing with elevated vulnerability to lipid metabolism related diseases is crucial towards promoting quality of life in old age. MicroRNAs (miRNAs) have emerged as crucial regulators of lipid metabolism, and some miRNAs have key roles in ageing. In this study, we investigated changes in liver lipid metabolism of ageing mice and the mechanisms of the altered expression of miRNAs in the ageing liver which contributes to the age-dependent increase in lipid synthesis. Here we found that miR-743b-3p was higher expressed in the liver tissues of ageing mice through the small RNA sequencing and bioinformatics analysis, and its target PPM1K was predicted and confirmed the target relationship of miR-743b-3p with PPM1K in the aged mouse liver tissues and the cultured senescent hepatocytes in vitro. Moreover, using the transfected miR-743b-3p mimics/inhibitors into the senescent hepatocyte AML12. We found that miR-743b-3p inhibition reversed the hepatocyte senescence, and finally decreased the expression of genes involved in lipid synthesis(Chrebp, Fabp4, Acly and Pparγ) through increasing the target gene expression of PPM1K which regulated the expression of branched-chain amino acids (BCAA) metabolism-related genes (Bckdhα, Bckdk, Bcat2, Dbt). These results identify that age-induced expression of miR-743b-3p inhibits its target PPM1K which induces BCAA metabolic disorder and regulates hepatocyte lipid accumulation during ageing. Show less

Cell phase engineering can significantly impact protein synthesis and cell size, potentially enhancing the production of lipophilic products. This study investigated the impact of G1 phase extension on resource allocation, metabolic functions, and the unfolded protein response (UPR) in yeast, along with the potential for enhancing the production of lipophilic compounds. In brief, the regulation of the G1 phase was achieved by deleting Show less

Multivalent pneumococcal vaccines have been developed successfully to combat invasive pneumococcal diseases (IPD) and reduce the associated healthcare burden. These vaccines employ pneumococcal capsular polysaccharides (PnPs), either conjugated or unconjugated, as antigens to provide serotype-specific protection. Pneumococcal capsular polysaccharides used for vaccine often contain residual levels of cell wall polysaccharides (C-Ps), which can generate a non-serotype specific immune response and complicate the desired serotype-specific immunity. Therefore, the C-P level in a pneumococcal vaccine needs to be controlled in the vaccine process and the anti C-P responses need to be dialed out in clinical assays. Currently, two types of cell-wall polysaccharide structures have been identified: a mono-phosphocholine substituted cell-wall polysaccharide C-Ps1 and a di-phosphocholine substituted C-Ps2 structure. In our effort to develop a next-generation novel pneumococcal conjugate vaccine (PCV), we have generated a monoclonal antibody (mAb) specific to cell-wall polysaccharide C-Ps2 structure. An antibody-enhanced HPLC assay (AE-HPLC) has been established for serotype-specific quantification of pneumococcal polysaccharides in our lab. With the new anti C-Ps2 mAb, we herein extend the AE-HPLC assay to the quantification and identification of C-Ps2 species in pneumococcal polysaccharides used for vaccines. Show less

Combined serplulimab and chemotherapy demonstrated improved clinical survival outcomes in patients with advanced esophageal squamous cell carcinoma (ESCC) and PD-L1 combined positive scores (CPS) ≥ 1. The present study aimed to evaluate the economic viability of integrating serplulimab in combination with chemotherapy as a potential therapeutic approach for treating ESCC in China. A Markov model was constructed to evaluate the economic and health-related implications of combining serplulimab with chemotherapy. With the incremental cost-effectiveness ratio (ICER), costs and results in terms of health were estimated. For assessing parameter uncertainty, one-way and probabilistic sensitivity studies were carried out. The combination of serplulimab and chemotherapy yielded incremental costs and QALYs of $3,163 and 0.14, $2,418 and 0.10, and $3,849 and 0.15, respectively, for the overall population as well as patients with PD-L1 CPS1-10 and PD-L1 CPS ≥ 10. This corresponds to ICER values per QALY of $23,657, $23,982, and $25,134. At the prespecified WTP limit, the probabilities of serplulimab with chemotherapy being the preferred intervention option were 74.4%, 61.3%, and 78.1% for the entire patient population, those with PD-L1 1 ≤ CPS < 10, and those with PD-L1 CPS ≥ 10, respectively. The stability of the presented model was confirmed through sensitivity studies. In conclusion, the combination of Serplulimab and chemotherapy showed excellent cost-effectiveness compared to chemotherapy alone in treating PD-L1-positive patients with ESCC in China. Show less

The understanding of membranous nephropathy (MN) has undergone impressive advancements in the last 5 years, particularly due to identification of novel antigenic targets. M-type phospholipase A2 receptor (PLA2R) and thrombospondin type 1 domain-containing 7A (THSD7A) account for approximately 70% and 1-5% of the target antigens in primary MN, respectively. Recently, more novel/putative antigens have been identified in the remaining cases of MN that include exostosin 1/exostosin 2 (EXT1/EXT2), neural epidermal growth factor-like 1 protein (NELL-1), semaphorin 3B (SEMA3B) and protocadherin 7 (PCDH7). However, comparatively little is known about the PCDH7 among these novel antigens. As such, we herein described a unique case of positive glomerular PCDH7 deposits in PLA2R-associated MN, which may offer a deeper insight into the role of PCDH7 in MN and improve our understanding of glomerular diseases in the post-COVID era, particularly with the emerging variants. Show less

Beef flavor plays a crucial role in consumer preference, yet research on this trait has been limited by past technological constraints. Intramuscular fat (IMF) is a key determinant of beef quality, influencing taste, marbling, and overall flavor. Xinjiang brown cattle (XBC), an indigenous breed from northern Xinjiang, China, presents significant variation in meat quality, with IMF content ranging from 0.2 % to 4.3 % within the population. This variation suggests strong potential for breeding improvement. In this study, we selected 82 XBC for slaughter and meat quality analysis, categorizing them based on IMF content. Using two-dimensional gas chromatography-time-of-flight mass spectrometry (GC×GC-TOF MS), we analyzed volatile flavor compounds across different beef cuts (Longissimus dorsi, Semitendinosus, Supraspinatus). Our results showed that beef with higher IMF levels exhibited enhanced flavor profiles, characterized by sweet, green, fruity, and waxy notes, while castrated bulls displayed the weakest flavor intensity. Metabolomic analysis further revealed significant differences in flavor substances between high and low IMF content beef. RNA-Seq analysis identified key genes (AQP4, FZD2, FADS1, BPG1, CEBPD, FABP4) associated with flavor formation, offering valuable insights for breeding strategies aimed at improving XBC meat quality. This comprehensive study provides a robust theoretical foundation for advancing the genetic improvement of XBC. Show less

Infigratinib, an FGFR1-3 selective oral tyrosine kinase inhibitor, has shown clinical activity in cancers with FGFR alterations. The pharmacokinetics (PK) of infigratinib and its major metabolites have been characterized in global populations. This study examined the PK profile of infigratinib and its metabolites in Chinese patients. In this phase II, open-label, single-arm study in China, patients with advanced gastric cancer (GC) or gastroesophageal junction adenocarcinoma (GEJ) harboring FGFR2 gene amplification received 125 mg infigratinib orally once daily in a "3 weeks on, 1 week off" schedule for 28-day cycles. Plasma PK parameters were calculated with a non-compartmental model. Data were available from 21 patients (19 GC and two GEJ). After a single dose, peak infigratinib plasma concentration was reached at a median time of 3.1 h, with geometric mean C Show less

Lung cancer, the leading cause of cancer-related incidence and mortality worldwide, is characterised by high invasiveness and poor prognosis. Novel therapeutic targets are required, especially for patients with inoperable metastatic disease requiring systemic therapies to improve patients' welfare. Recently, studies indicated that TMEM176B is a positive regulator in breast and gastric cancers, and it could be a potential target for treatment. In this study, we used single-cell sequencing, proteomics, Co-IP, and in vivo and in vitro experimental models to investigate the role of TMEM176B in lung adenocarcinoma development. Our study indicated that TMEM176B expression was enhanced in lung adenocarcinoma tissues, and it was associated with shorter overall survival (OS). TMEM176B promoted cellular functions, including cell proliferation, invasion, migration and adhesion in vitro and tumour growth in vivo. Moreover, the tube formation ability of endothelial cells was enhanced by treating with the tumour cell-conditioned medium. We have also demonstrated that TMEM176B regulated EMT via the FGFR1/JNK/Vimentin/Snail signalling cascade. Overall, our study suggests TMEM176B could be a potential therapeutic target in lung adenocarcinoma. Show less

Fibroblast growth factor (FGF) signaling encompasses a multitude of functions, including regulation of cell proliferation, differentiation, morphogenesis, and patterning. FGFs and their receptors (FGFR) are crucial for adult tissue repair processes. Aberrant FGF signal transduction is associated with various pathological conditions such as cartilage damage, bone loss, muscle reduction, and other core pathological changes observed in orthopedic degenerative diseases like osteoarthritis (OA), intervertebral disc degeneration (IVDD), osteoporosis (OP), and sarcopenia. In OA and IVDD pathologies specifically, FGF1, FGF2, FGF8, FGF9, FGF18, FGF21, and FGF23 regulate the synthesis, catabolism, and ossification of cartilage tissue. Additionally, the dysregulation of FGFR expression (FGFR1 and FGFR3) promotes the pathological process of cartilage degradation. In OP and sarcopenia, endocrine-derived FGFs (FGF19, FGF21, and FGF23) modulate bone mineral synthesis and decomposition as well as muscle tissues. FGF2 and other FGFs also exert regulatory roles. A growing body of research has focused on understanding the implications of FGF signaling in orthopedic degeneration. Moreover, an increasing number of potential targets within the FGF signaling have been identified, such as FGF9, FGF18, and FGF23. However, it should be noted that most of these discoveries are still in the experimental stage, and further studies are needed before clinical application can be considered. Presently, this review aims to document the association between the FGF signaling pathway and the development and progression of orthopedic diseases. Besides, current therapeutic strategies targeting the FGF signaling pathway to prevent and treat orthopedic degeneration will be evaluated. Show less

Abnormal hippocampal neurodevelopment, particularly in the dentate gyrus region, may be a key mechanism of attention-deficit/hyperactivity disorder (ADHD). In this study, we investigate the effect of the most commonly used Chinese herb for the treatment of ADHD, Rehmanniae Radix Preparata (RRP), on behavior and hippocampal neurodevelopment in spontaneously hypertensive rats (SHR). Behavior tests, including Morris water maze (MWM) test, open field test (OFT) and elevated plus maze (EPM) test were performed to assess the effect of RRP on hyperactive and impulsive behavior. Hippocampal neurodevelopment was characterized by transmission electron microscopy, immunofluorescence, Golgi staining and Nissl staining approaches. Regulatory proteins such as Trkb, CDK5, FGF2/FGFR1 were examined by Western blot analysis. The results showed that RRP could effectively control the impulsive and spontaneous behavior and improve the spatial learning and memory ability. RRP significantly reduced neuronal loss and increased the number of hippocampal stem cells, and promoted synaptic plasticity. In addition, FGF/FGFR signaling was upregulated after RRP treatment. RRP can effectively reduce impulsive and spontaneous behavior and ameliorate hippocampal neurodevelopmental abnormalities in ADHD rat model. Show less

The aberrant activation of FGFR acts as a potent driver of multiple types of human cancers. Despite the development of several conventional small-molecular FGFR inhibitors, their clinical efficacy is largely compromised because of low selectivity and side effects. In this study, we report the selective FGFR1/2-targeting proteolysis-targeting chimera BR-cpd7 that displays significant isoform specificity to FGFR1/2 with half maximal degradation concentration values around 10 nmol/L while sparing FGFR3. The following mechanistic investigation reveals the reduced FGFR signaling, through which BR-cpd7 induces cell-cycle arrest and consequently blocks the proliferation of multiple FGFR1/2-dependent tumor cells. Importantly, BR-cpd7 has almost no antiproliferative activity against cancer cells without FGFR aberrations, furtherly supporting its selectivity. In vivo, BR-cpd7 exhibits robust antitumor effects in FGFR1-dependent lung cancer at well-tolerated dose schedules, accompanied by complete FGFR1 depletion. Overall, we identify BR-cpd7 as a promising candidate for developing a selective FGFR1/2-targeted agent, thereby offering a new therapeutic strategy for human cancers in which FGFR1/2 plays a critical role. Show less

Diabetes and its complications cause a heavy burden of disease worldwide. In recent years, Mendelian randomization (MR) has been widely used to discover the pathogenesis and epidemiology of diseases, as well as to discover new therapeutic targets. Therefore, based on systematic "druggable" genomics, we aim to identify new therapeutic targets for diabetes and analyze its pathophysiological mechanisms to promote its new therapeutic strategies. We used double sample MR to integrate the identified druggable genomics to evaluate the causal effect of quantitative trait loci (eQTLs) expressed by druggable genes in blood on type 1 and 2 diabetes (T1DM and T2DM). Repeat the study using different data sources on diabetes and its complications to verify the identified genes. Not only that, we also use Bayesian co-localization analysis to evaluate the posterior probabilities of different causal variations, shared causal variations, and co-localization probabilities to examine the possibility of genetic confounding. Finally, using diabetes markers with available genome-wide association studies data, we evaluated the causal relationship between established diabetes markers to explore possible mechanisms. Overall, a total of 4,477 unique druggable genes have been gathered. After filtering using methods such as Bonferroni significance (P<1.90e-05), the MR Steiger directionality test, Bayesian co-localization analysis, and validation with different datasets, Finally, 7 potential druggable genes that may affect the results of T1DM and 7 potential druggable genes that may affect the results of T2DM were identified. Reverse MR suggests that C4B may play a bidirectional role in the pathogenesis of T1DM, and none of the other 13 target genes have a reverse causal relationship. And the 7 target genes in T2DM may each affect the biomarkers of T2DM to mediate the pathogenesis of T2DM. This study provides genetic evidence supporting the potential therapeutic benefits of targeting seven druggable genes, namely MAP3K13, KCNJ11, REG4, KIF11, CCNE2, PEAK1, and NRBP1, for T2DM treatment. Similarly, targeting seven druggable genes, namely ERBB3, C4B, CD69, PTPN22, IL27, ATP2A1, and LT-β, has The potential therapeutic benefits of T1DM treatment. This will provide new ideas for the treatment of diabetes and also help to determine the priority of drug development for diabetes. Show less

Diabetic kidney disease (DKD) is one of the most common microvascular complications in patients with diabetes mellitus. In this condition, renal tubular epithelial mesenchymal transition (EMT) is an important factor accelerating the progression of DKD and a major cause of renal fibrosis and end-stage renal disease. However, the therapeutic effect is unsatisfactory because of the lack of effective drugs. Jia Wei Qingxin Lotus Seed Drink (QISD) is a traditional Chinese medicine compound formula that has shown to be effective in the clinical treatment of DKD. However, the potential of QISD in DKD-EMT treatment has yet to be fully explored. This study aimed to investigate the role of QISD in ameliorating DKD-EMT injury and its mechanism. The active ingredients of QISD were identified via ultra-performance liquid chromatography-mass spectrometry/mass spectrometry (UHPLC-MS/MS). A DKD mouse model was constructed by high-fat diet feeding and intraperitoneal injection of STZ (60 mg/kg), and QISD (14.46, 28.92, and 57.84 g/kg/day) was administered by gavage for 12 consecutive weeks. Dapagliflozin (1 mg/kg/d) was used as a positive control. Renal pathological damage was observed by HE, PAS, and Masson staining. The expression levels of EMT-related proteins and pathway proteins were detected via immunohistochemistry, RT-qPCR, and western blot. In in vitro experiments, EMT injury was induced in human kidney tubular epithelial cells (HK-2) by using lipopolysaccharide (LPS). A combination of CCK8 assay, wound healing assay, small-molecule inhibitor intervention, and overexpression lentiviral transfection was used to investigate the effects of QISD on cell migration ability, adhesion ability, fibrotic factor formation, and mesenchymal properties. Animal experiments showed that QISD improved blood glucose, body weight, symptoms of excessive drinking and eating, and renal pathological injury in mice, reduced extracellular matrix deposition, delayed renal EMT injury, and inhibited the activation of the histone demethylase JMJD1C. UHPLC-MS/MS and molecular docking indicated that baicalin, wogonoside, oroxylin A-7-O-β-D-glucuronide, and glulisine A found in QISD could bind to JMJD1C. The ameliorating effect of QISD on DKD-EMT injury might be related to JMJD1C. The improvement of DKD-EMT injury by QISD was accompanied by the reduction of SP1 and ZEB1 expression. The SP1 overexpression not only reversed the therapeutic effect of JIB-04, an inhibitor of JMJD1C, on DKD-EMT but also exacerbated the expression of ZEB1 and downstream EMT-related factors. Thus, QISD might affect the expression of the epithelial marker E-cadherin by inhibiting the JMJD1C/SP1/ZEB1 signaling pathway, consequently preventing the transformation of epithelial cells to mesenchymal cells and ameliorating DKD-EMT injury. This study was the first to demonstrate that QISD might ameliorate DKD-EMT injury by inhibiting the JMJD1C/SP1/ZEB1 signaling pathway. These findings provide strong pharmacologic evidence for the clinical use of QISD in the treatment of DKD. Show less

Koolen-De Vries syndrome (KdVS, OMIM: 612452), also known as 17q21.31 microdeletion syndrome, is an autosomal dominant genetic disease. In the study, we analyze of clinical phenotype and gene variation of a child with Koolen-De Vries syndrome, review the literature to improve the understanding of the disease. The patient is a male, aged 1 month and 3 days. The patient has poor airway development, difficulty weaning from respiratory support, seizures, and recurrent low granulocyte counts. High-throughput sequencing showed a heterozygous mutation NM₀₀₁₁₉₃₄₆₆.1: c.1574₁₅₇₈del (P.525HFS *24) in the KANSL1 gene of the proband, which was considered a new mutation since neither of his parents carried this mutation based on Sanger sequencing results. Combining clinical features and genetic results, the proband was diagnosed as KdVS. The patient was in good condition after receiving bronchoscopy and laser interventional therapy, meeting the criteria for discharge. Follow-up for 1 year and 6 months indicated that the patient's physical signs were normal and there was no recurrence. According to literature review, KdVS is a multi-organ disease characterized by feeding difficulties, seizures, characteristic facial features, dysplasia of the respiratory system and cardiac abnormalities. In this study, laryngeal malacia accounted for 23.2% of the clinical manifestations of KdVS patients, limb convulsions/seizures accounted for 62.5%, and cardiac development defects accounted for 23.5%. The disease was rare in China and had a variety of clinical manifestations. The summary of reported cases can enable doctors to have more understanding of the disease. The new mutations enrich the KANSL1 gene mutation spectrum. Show less

Balanced lipid metabolism can improve the growth performance and meat quality of livestock. The m6A methylation-related genes METTL3 and FTO play important roles in animal lipid metabolism; however, the mechanism through which they regulate lipid metabolism in sheep is unclear. We established lipid deposition models of hepatocytes and preadipocytes in Hu sheep. In the hepatocyte lipid deposition model, the genes expression levels of FABP4, Accα, ATGL and METTL3, METTL14, and FTO-were significantly up-regulated after lipid deposition (P < 0.05). Transcriptomic and metabolomic analyses showed that lipid deposition had a significant effect on MAPK, steroid biosynthesis, and glycerophospholipid metabolism pathway in hepatocytes. The m6A methylation level decreased but the difference was not significant after METTL3 interference, and the expression levels of FABP4 and ATGL increased significantly (P < 0.05); the m6A methylation level significantly increased following METTL3 overexpression, and LPL and ATGL expression levels significantly decreased (P < 0.05), indicating that overexpression of METTL3 inhibited the expression of lipid deposition-related genes in a m6A-dependent manner. The m6A methylation level was significantly increased, ATGL expression was significantly decreased (P < 0.05), and LPL, FABP4, and Accα expression was not significantly changed following FTO interference (P > 0.05); the m6A methylation level was significantly decreased after FTO overexpression, and LPL, FABP4, and ATGL expression was significantly increased (P < 0.05), indicating that FTO overexpression increased the expression of lipid deposition-related genes in a m6A-dependent manner. Transcriptomic and metabolomic analyses showed that m6A methylation modification mainly regulated lipid metabolism through triglyceride metabolism, adipocytokine signaling, MAPK signaling, and fat digestion and absorption in hepatocytes. In the lipid deposition model of preadipocytes, the regulation of gene expression is the same as that in hepatocytes. METTL3 significantly inhibited the expression of lipid deposition-related genes, whereas FTO overexpression promoted lipid deposition. Our study provides a theoretical basis and reference for accurately regulating animal lipid deposition by mastering METTL3 and FTO genes to promote high-quality animal husbandry. Show less