Melanocortin 4 receptor (MC4R) mutations are the most common cause of human monogenic obesity and are associated with hyperphagia and increased linear growth. While MC4R is known to activate GsΞ±/cAMP Show more
Melanocortin 4 receptor (MC4R) mutations are the most common cause of human monogenic obesity and are associated with hyperphagia and increased linear growth. While MC4R is known to activate GsΞ±/cAMP signaling, a substantial proportion of obesity-associated MC4R mutations do not affect MC4R/GsΞ± signaling. To further explore the role of specific MC4R signaling pathways in the regulation of energy balance, we examined the signaling properties of one such mutant, MC4R (F51L), as well as the metabolic consequences of MC4RF51L mutation in mice. The MC4RF51L mutation produced a specific defect in MC4R/Gq/11Ξ± signaling and led to obesity, hyperphagia, and increased linear growth in mice. The ability of a melanocortin agonist to acutely inhibit food intake when delivered to the paraventricular nucleus (PVN) was lost in MC4RF51L mice, as well as in WT mice in which a specific Gq/11Ξ± inhibitor was delivered to the PVN; this provided evidence that a GsΞ±-independent signaling pathway, namely Gq/11Ξ±, significantly contributes to the actions of MC4R on food intake and linear growth. These results suggest that a biased MC4R agonist that primarily activates Gq/11Ξ± may be a potential agent to treat obesity with limited untoward cardiovascular and other side effects. Show less
Chronic itch is a common and complex symptom often associated with skin diseases such as atopic dermatitis (AD). Although IL-27 is linked to AD, its role and clinical significance in itch remain undef Show more
Chronic itch is a common and complex symptom often associated with skin diseases such as atopic dermatitis (AD). Although IL-27 is linked to AD, its role and clinical significance in itch remain undefined. We sought to investigate IL-27 function in itch using tissue-specific transgenic mice, various itch models, behavior scoring, RNA sequencing, and cytokine/kinase array. Our findings show that IL-27 receptors were overexpressed in human AD skin. Intradermal IL-27 injection failed to directly induce itch in mice but upregulated skin protease-activated receptor 2 (PAR2) transcripts, a key factor in itch and AD. IL-27 activated human keratinocytes, increasing PAR2 transcription and activity. Coinjection of SLIGRL (PAR2 agonist) and IL-27 in mice heightened PAR2-mediated itch. In addition, IL-27 boosted BST2 transcription in sensory neurons and keratinocytes. BST2 was upregulated in AD skin, and its injection in mice induced itch-like response. BST2 colocalized with sensory nerve branches in AD skin from both human and murine models. Sensory neurons released BST2, and mice with sensory neuron-specific BST2 knockout displayed reduced itch responses. Overall, this study provides evidence that skin IL-27/PAR2 and neuronal IL-27/BST2 axes are implicated in cutaneous inflammation and pruritus. The discovery of neuronal BST2 in pruritus shed light on BST2 in the itch cascade. Show less
Germline variants in the FOXE1 transcription factor have been associated with thyroid ectopy, cleft palate (CP) and thyroid cancer (TC). Here, we aimed to clarify the role of
The survival and suppressive function of regulatory T (Treg) cells rely on various intracellular metabolic and physiological processes. Our study demonstrates that Vps34 plays a critical role in maint Show more
The survival and suppressive function of regulatory T (Treg) cells rely on various intracellular metabolic and physiological processes. Our study demonstrates that Vps34 plays a critical role in maintaining Treg cell homeostasis and function by regulating cellular metabolic activities. Disruption of Vps34 in Treg cells leads to spontaneous fatal systemic autoimmune disorder and multi-tissue inflammatory damage, accompanied by a reduction in the number of Treg cells, particularly eTreg cells with highly immunosuppressive activity. Mechanistically, the poor survival of Vps34-deficient Treg cells is attributed to impaired endocytosis, intracellular vesicular trafficking and autophagosome formation, which further results in enhanced mitochondrial respiration and excessive ROS production. Removal of excessive ROS can effectively rescue the death of Vps34-deficient Treg cells. Functionally, acute deletion of Vps34 within established Treg cells enhances anti-tumor immunity in a malignant melanoma model by boosting T-cell-mediated anti-tumor activity. Overall, our results underscore the pivotal role played by Vps34 in orchestrating Treg cell homeostasis and function towards establishing immune homeostasis and tolerance. Show less
The fruits of Alpinia oxyphylla (Alpiniae Oxyphyllae Fructus, AOF) are one of the "Four Famous South Medicines" in China. In this study, beta-site amyloid protein precursor cleaving enzyme 1 (BACE1) w Show more
The fruits of Alpinia oxyphylla (Alpiniae Oxyphyllae Fructus, AOF) are one of the "Four Famous South Medicines" in China. In this study, beta-site amyloid protein precursor cleaving enzyme 1 (BACE1) was applied to explore the active components in AOF responsible for type 2 diabetes mellitus (T2DM)-related cognitive disorder. As a result, 24 compounds including three unreported ones (1, 3, 4) were isolated from AOF. Compound 1 is an unusual carbonβcarbon linked diarylheptanoid dimer, and compound 4 is the first case of 3,4-seco-eudesmane sesquiterpenoid with a 5/6-bicyclic skeleton. Four diarylheptanoids (3, 5-7), one flavonoid (9) and two sesquiterpenoids (14 and 20) showed BACE1 inhibitory activity, of which the most active 6 was revealed to be a non-competitive and anti-competitive mixed inhibitor. Docking simulation suggested that OH-4' of 6 played important roles in maintaining activity by forming hydrogen bonds with Ser36 and Ile126 residues. Compounds 3, 5, 9 and 20 displayed neuroprotective effects against amyloidΒ Ξ²Β (AΞ²)-induced damage in BV2 cells. Mechanism study revealed that compounds 5 and 20 downregulated the expression of BACE1 and upregulated the expression of Lamp2 to exert effects. Thus, the characteristic diarylheptanoids and sesquiterpenoids in AOF had the efficacy to alleviate T2DM-related cognitive disorder by inhibiting BACE1 activity and reversing AΞ²-induced neuronal damage. Show less
Anodized titania nanotubes have been considered as an effective coating for bone implants due to their ability to induce osteogenesis, whereas the osteogenic mechanism is not fully understood. Our pre Show more
Anodized titania nanotubes have been considered as an effective coating for bone implants due to their ability to induce osteogenesis, whereas the osteogenic mechanism is not fully understood. Our previous study has revealed the potential role of autophagy in osteogenic regulation of nanotubular surface, whereas how the autophagy is activated remains unknown. In this study, we focused on the cell membrane curvature-sensing protein Bif-1 and its effect on the regulation of autophagy. Both autophagosomes formation and autophagic flux were enhanced on the nanotubular surface, as indicated by LC3-II accumulation and p62 degradation. In the meanwhile, the Bif-1 was significantly upregulated, which contributed to autophagy activation and osteogenic differentiation through Beclin-1/PIK3C3 signaling pathway. In conclusion, these findings have bridged the gap between extracellular physical nanotopography and intracellular autophagy activation, which may provide a deeper insight into the signaling transition from mechanical to biological across the cell membrane. Show less
Fibroblast growth factor receptor (FGFR) alterations drive oncogenesis in multiple tumor types. Here we studied pemigatinib, a selective, potent, oral FGFR1-FGFR3 inhibitor, in the phase 2 FIGHT-207 b Show more
Fibroblast growth factor receptor (FGFR) alterations drive oncogenesis in multiple tumor types. Here we studied pemigatinib, a selective, potent, oral FGFR1-FGFR3 inhibitor, in the phase 2 FIGHT-207 basket study of FGFR-altered advanced solid tumors. Primary end points were objective response rate (ORR) in cohorts A (fusions/rearrangements, n = 49) and B (activating non-kinase domain mutations, n = 32). Secondary end points were progression-free survival, duration of response and overall survival in cohorts A and B, and safety. Exploratory end points included ORR of cohort C (kinase domain mutations, potentially pathogenic variants of unknown significance, n = 26) and analysis of co-alterations associated with resistance and response. ORRs for cohorts A, B and C were 26.5% (13/49), 9.4% (3/32) and 3.8% (1/26), respectively. Tumors with no approved FGFR inhibitors or those with alterations not previously confirmed to be sensitive to FGFR inhibition had objective responses. In cohorts A and B, the median progression-free survival was 4.5 and 3.7 months, median duration of response was 7.8 and 6.9 months and median overall survival was 17.5 and 11.4 months, respectively. Safety was consistent with previous reports. The most common any-grade treatment-emergent adverse events were hyperphosphatemia (84%) and stomatitis (53%). TP53 co-mutations were associated with lack of response and BAP1 alterations with higher response rates. FGFR1-FGFR3 gatekeeper and molecular brake mutations led to acquired resistance. New therapeutic areas for FGFR inhibition and drug failure mechanisms were identified across tumor types. ClinicalTrials.gov identifier: NCT03822117 . Show less
Fibroblast growth factor-12 (FGF12) has been reported to play important role in regulating heart diseases. We aimed to explore the role of FGF12 in doxorubicin (DOX)-induced myocardial injury. DOX-ind Show more
Fibroblast growth factor-12 (FGF12) has been reported to play important role in regulating heart diseases. We aimed to explore the role of FGF12 in doxorubicin (DOX)-induced myocardial injury. DOX-induced mice and DOX-induced HL-1 cells were used as the myocardial injury in vivo and in vitro. Then, FGF12, Anp, Bnp, and Myh7 expression was detected. The pathological injury in myocardium tissue was observed by H&E staining. The levels of markers related to myocardial damage and oxidative stress were assessed. Then, immunohistochemistry and immunofluorescence staining were used to detect FGF12 and 4-HNE expression. Ferroptosis were detected by Prussian blue staining and western blot. The FGFR1/AMPK/NRF2 signaling was measured by western blot. FGF12 expression was downregulated in DOX-induced mice myocardium tissues. FGF12 overexpression alleviated DOX-induced myocardial tissue pathological injury and reduced Anp, Bnp, and Myh7 expression. Additionally, the levels of CK-MB, LDH and cTnT in serum were decreased after FGF12 upregulation in DOX-induced mice. Moreover, FGF12 overexpression reduced the levels of ROS, MDA, and 4-HNE but increased SOD and GSH-Px activities. Meanwhile, FGF12 led to less deposition of iron ion, decreased ACSL4, PTGS2 and increased GPX4, FTH1 expression. Additionally, FGF12 activated the expressions of FGFR1, p-AMPK, and NRF2. Moreover, FGFR1 silencing reversed the protective effects of FGF12 overexpression on cell viability, oxidative stress, ferroptosis, and FGFR1/AMPK/NRF2 pathway. To sum up, FGF12 inhibited mitochondria-dependent ferroptosis in cardiomyocytes induced by DOX through activation of FGFR1/AMPK/NRF2 signaling. These findings clarify a new mechanism of DOX-induced cardiac injury and provide a promising target to limit the disease development. Show less
Gene fusions and MET alterations are rare and difficult to detect in plasma samples. The clinical detection efficacy of molecular residual disease (MRD) based on circulating tumor DNA (ctDNA) in patie Show more
Gene fusions and MET alterations are rare and difficult to detect in plasma samples. The clinical detection efficacy of molecular residual disease (MRD) based on circulating tumor DNA (ctDNA) in patients with non-small cell lung cancer (NSCLC) with these mutations remains unknown. This prospective, non-intervention study recruited 49 patients with operable NSCLC with actionable gene fusions (ALK, ROS1, RET, and FGFR1), MET exon 14 skipping or de novo MET amplification. We analyzed 43 tumor tissues and 111 serial perioperative plasma samples using 1021- and 338-gene panels, respectively. Detectable MRD correlated with a significantly higher recurrence rate (P < 0.001), yielding positive predictive values of 100% and 90.9%, and negative predictive values of 82.4% and 86.4% at landmark and longitudinal time points, respectively. Patients with detectable MRD showed reduced disease-free survival (DFS) compared to those with undetectable MRD (P < 0.001). Patients who harbored tissue-derived fusion/MET alterations in their MRD had reduced DFS compared to those who did not (P = 0.05). To our knowledge, this is the first comprehensive study on ctDNA-MRD clinical detection efficacy in operable NSCLC patients with gene fusions and MET alterations. Patients with detectable tissue-derived fusion/MET alterations in postoperative MRD had worse clinical outcomes. Show less
Alzheimer's disease (AD) is a neurodegenerative disorder associated with age. A wealth of evidence indicates that the amyloid Ξ² (AΞ²) aggregates result from dyshomeostasis between AΞ² production and cle Show more
Alzheimer's disease (AD) is a neurodegenerative disorder associated with age. A wealth of evidence indicates that the amyloid Ξ² (AΞ²) aggregates result from dyshomeostasis between AΞ² production and clearance, which plays a pivotal role in the pathogenesis of AD. Consequently, therapies targeting AΞ² reduction represent a promising strategy for AD intervention. Tetramethylpyrazine nitrone (TBN) is a novel tetramethylpyrazine derivative with potential for the treatment of AD. Previously, we demonstrated that TBN markedly enhanced cognitive functions and decreased the levels of AΞ², APP, BACE 1, and hyperphosphorylated tau in 3ΓTg-AD mice. However, the mechanism by which TBN inhibits AΞ² deposition is still unclear. In this study, we employed APP/PS1 mice treated with TBN (60 mg/kg, ig, bid) for six months, and N2a/APP695swe cells treated with TBN (300 ΞΌM) to explore the mechanism of TBN in AΞ² reduction. Our results indicate that TBN significantly alleviated cognitive impairment and reduced AΞ² deposition in APP/PS1 mice. Further investigation of the underlying mechanisms revealed that TBN decreased the expression of APP and BACE1, activated the AMPK/mTOR/ULK1 autophagy pathway, inhibited the PI3K/AKT/mTOR/ULK1 autophagy pathway, and decreased the phosphorylation levels of JNK and ERK in APP/PS1 mice. Moreover, TBN was found to significantly reduce the mRNA levels of APP and BACE1, as well as those of SP1, CTCF, TGF-Ξ², and NF-ΞΊB, transcription factors involved in regulating gene expression. Additionally, TBN was observed to decrease the level of Show less
Platycodin D (PD) has been reported to treat metabolic diseases, including non-alcoholic fatty liver disease. In addition, platycodin D has been reported to activate intestinal 5'AMP-activated protein Show more
Platycodin D (PD) has been reported to treat metabolic diseases, including non-alcoholic fatty liver disease. In addition, platycodin D has been reported to activate intestinal 5'AMP-activated protein kinase (AMPK) phosphorylation levels, thereby reducing lipid absorption. Therefore, the aim of this study is to explore whether PD activation of intestinal AMPK and reduced lipid absorption can improve non-alcoholic fatty liver disease. Clean-grade male C57/BL mice were fed a high-fat diet (HFD) (containing 60% calories) for 16 weeks, and oral PD (10Β mg/kg/day) was administered at the same time. The liver and intestines were the collected, and the intestines were tested. The expressions of lipid absorption genes (CD36, NPC1L1, and ApoB), the serum total triglyceride (TG) and total cholesterol (TC) levels in the intestines and livers, the fecal free fatty acid (FFA) levels, and the expression of AMPK phosphorylated proteins in the intestines were examined using Western blot analyses. The lipid distribution in the livers, intestines, and fat was detected using Oil Red O and hematoxylin and eosin (H&E) staining. A colon cancer cell line (Caco2) was used to confirm the effect of PD on the cellular lipid uptake PD had a very significant therapeutic or preventive effect on metabolic syndrome and fatty liver induced by a high-fat diet. PD improved body weight, insulin sensitivity, and glucose tolerance in mice fed a high-fat diet and also prevented non-alcoholic fatty liver disease, reduced blood lipid levels, and increased fecal lipid excretion. In addition, PD reduced lipid absorption by activating the intestinal AMPK protein, which may have involved the inhibition of the gene expression levels of intestinal lipid absorption genes (CD36, NPC1L1, and ApoB). The combined effect of these factors improved hepatic lipid accumulation and lipid accumulation in adipose tissue. It was further found that PD also improved the body weights and blood lipid levels of leptin-deficient mice (OB) mice. PD had a very strong therapeutic effect on mice under a high-fat diet. PD reduced high-fat diet-induced obesity and non-alcoholic fatty liver disease by inhibiting intestinal fat absorption. Show less
Glucose-dependent insulinotropic polypeptide (GIP) is a ligand of glucose-dependent insulinotropic polypeptide receptor (GIPR) that plays an important role in the digestive system. In recent years, GI Show more
Glucose-dependent insulinotropic polypeptide (GIP) is a ligand of glucose-dependent insulinotropic polypeptide receptor (GIPR) that plays an important role in the digestive system. In recent years, GIP has been regarded as a hormone-like peptide to regulate the local metabolic environment. In this study, we investigated the antioxidant role of GIP on the neuron and explored the possible mechanism. Cell counting Kit-8 (CCK-8) was used to measure cell survival. TdT-mediated dUTP Nick-End Labeling (TUNEL) was used to detect apoptosis inΒ vitro and inΒ vivo. Reactive oxygen species (ROS) levels were probed withΒ 2', 7'-Dichloro dihydrofluorescein diacetate (DCFH-DA), and glucose intake was detected with 2-NBDG. Immunofluorescence staining and western blot were used to evaluate the protein level in cells and tissues. Hematoxylin-eosin (HE) staining, immunofluorescence staining and tract-tracing were used to observe the morphology of the injured spinal cord. Basso-Beattie-Bresnahan (BBB) assay was used to evaluate functional recovery after spinal cord injury. GIP reduced the ROS level and protected cells from apoptosis in cultured neurons and injured spinal cord. GIP facilitated wound healing and functional recovery of the injured spinal cord. GIP significantly improved the glucose uptake of cultured neurons. Meanwhile, inhibition of glucose uptake significantly attenuated the antioxidant effect of GIP. GIP increased glucose transporter 3 (GLUT3) expression via up-regulating the level of hypoxia-inducible factor 1Ξ± (HIF-1Ξ±) in an Akt-dependent manner. GIP increases GLUT3 expression and promotes glucose intake in neurons, which exerts an antioxidant effect and protects neuronal cells from oxidative stress both inΒ vitro and inΒ vivo. Show less
Hepatocellular carcinoma (HCC), which is the third leading cause of cancer-related mortality in the world, presents a significant medical challenge. Triptolide (TP) has been identified as an effective Show more
Hepatocellular carcinoma (HCC), which is the third leading cause of cancer-related mortality in the world, presents a significant medical challenge. Triptolide (TP) has been identified as an effective therapeutic drug for HCC. However, its precise therapeutic mechanism is still unknown. Understanding the mechanism of action of TP against HCC is crucial for its implementation in the field of HCC treatment. We hypothesize that the anti-HCC actions of TP might be related to its modulation of HCC lipid metabolism given the crucial role that lipid metabolism plays in promoting the progression of HCC. In this work, we first demonstrate that, both in vitro and in vivo, TP significantly reduces lipid accumulation in HCC cells. Additionally, we notice that lipoprotein lipase (LPL) expression is markedly upregulated in HCC, and that its levels are positively connected with the disease's progression. It is interesting to note that TP dramatically reduces LPL activity, which in turn prevents HCC growth and reduces lipid accumulation. Additionally, the effect of TP on LPL is a direct correlation. These results definitely demonstrate that TP protects hepatocytes against abnormal accumulation of lipids by transcriptionally suppressing LPL, which reduces the development of HCC. This newly identified pathway provides insight into the process through which TP exerts its anti-HCC actions. Show less
Unfavourable lipid and glucose levels may play a crucial role in the pathogenesis of gestational diabetes mellitus (GDM). However, there is a lack of prospective studies on the relationship between li Show more
Unfavourable lipid and glucose levels may play a crucial role in the pathogenesis of gestational diabetes mellitus (GDM). However, there is a lack of prospective studies on the relationship between lipid profiles, lipid ratios and GDM during pregnancy. To prospectively investigate the relationship between lipid profile and lipid ratios in early and mid-pregnancy and their pattern of change from early to mid-pregnancy and the risk of GDM. This nested case-control study was based on maternal and child healthcare hospitals from Fujian Province, China. We included pregnant women who delivered in the hospital from January 2021 to June 2023. Lipid profiles (TC, TG, ApoA1, ApoB, HDL-c, LDL-c) and fasting glucose were measured before 14 weeks of gestation and between 20 and 28 weeks of gestation, and lipid ratios (triglyceride glucose index, TG/HDL-c and TC/HDL-c) was constructed. Logistic regression was used to assess the relationship between lipid profile, lipid ratios and GDM. Of 1586 pregnant women, 741 were diagnosed with GDM. After adjusting for potential confounders, TG, ApoA1, ApoB, LDL-c, triglyceride glucose index, TG/HDL-c, and TC/HDL-c in early pregnancy were positively associated with the risk of GDM (odds ratios [95% CI] for extreme interquartile comparisons were 2.040 (1.468-2.843), 1.506 (1.091-2.082), 1.529 (1.110-2.107), 1.504 (1.086-2.086), 1.952 (1.398-2.731), 2.127 (1.526-2.971), and 2.370 (1.700-3.312), all trend Pβ<β0.05). HDL-c was negatively associated with the risk of GDM (0.639: 0.459-0.889, trend P all less than 0.05). Similarly, in mid-pregnancy, lower levels of HDL-c, higher levels of triglyceride glucose index, TG/HDL-c ratio, and TC/HDL-c ratio were associated with increased risk of GDM (all trends Pβ<β0.05). Stably high levels (both β₯βmedian for early and mid-pregnancy) of triglyceride glucose index, TG/HDL-c and TC/HDL-c were associated with increased risk of GDM (OR [95% CI]: 2.369 (1.438-3.940), 1.588 (1.077-2.341), 1.921 (1.309-2.829), respectively). The opposite was true for HDL-c, where stable high levels were negatively associated with GDM risk (OR [95% CI]: 0.599 (0.405-0.883)). Increases in triglyceride glucose index, TG/HDL-c ratio, and TC/HDL-c ratio in early and mid-pregnancy, as well as their stable high levels from early to mid-pregnancy, are associated with a higher risk of GDM. In contrast, increased levels of HDL-c, both in early and mid-pregnancy, and their stable high levels from early to mid-pregnancy were associated with a lower risk of GDM. That highlighted their possible clinical relevance in identifying those at high risk of GDM. Show less
The objective of this study was to investigate the potential of salidroside (SAL) (a major active compound in The expression of HIF-1 SAL enhanced the expression of HIF-1 SAL promotes osteoclast proli Show more
The objective of this study was to investigate the potential of salidroside (SAL) (a major active compound in The expression of HIF-1 SAL enhanced the expression of HIF-1 SAL promotes osteoclast proliferation, differentiation and bone resorption through HIF-1 Show less
The assessment of animal genetic structure had significant importance for the preservation and breeding of animal germplasm resources. Selection signals are genotype markers generated during the proce Show more
The assessment of animal genetic structure had significant importance for the preservation and breeding of animal germplasm resources. Selection signals are genotype markers generated during the process of biological evolution, and the detection of selection signals could reveal the direction of species evolution. The aim of this study was to generate a whole-genome resequencing data from Jinding duck, Shanma duck, Youxian Partridge duck, and Taiwan Brown tsaiya duck to reveal their population structure and selection signals. The population structure analysis revealed significant genetic differences among the 4 indigenous laying ducks, indicating their independent lineage. Specifically, Shanma duck and Youxian partridge duck were closely and likely originated from a common ancestor. In addition, selection sweep analysis was performed using the population genetic differentiation coefficient (Fst) and nucleotide diversity ratio (Ο ratio). The top 5% was used as the threshold for the Fst and Ο ratio, and the 2 thresholds were combined to identify selected genomic regions. In the selected regions of the 3 comparison groups, 136, 143, and 268 candidate genes were detected. Further screening of all candidate genes revealed that 35 candidate genes appeared simultaneously in 3 comparative groups, with 16 genes annotated. The 16 genes were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The results revealed 5 functional genes (AQP3, PIK3C3, NOL6, RPP25, and DCTN3) that may be related to important economic traits in laying ducks and involved mainly invasopressin-regulated water reabsorption, ribosome biogenesis, and the PI3K signaling pathway. The results provide insights into the protection and exploitation of genetic resources of Chinese indigenous laying ducks. Show less
Breast cancer is a heterogeneous disease categorized based on molecular characteristics, including hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) expression levels. The emer Show more
Breast cancer is a heterogeneous disease categorized based on molecular characteristics, including hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) expression levels. The emergence of profiling technology has revealed multiple driver genomic alterations within each breast cancer subtype, serving as biomarkers to predict treatment outcomes. This study aimed to explore the genomic landscape of breast cancer in the Taiwanese population through comprehensive genomic profiling (CGP) and identify diagnostic and predictive biomarkers. Targeted next-generation sequencing-based CGP was performed on 116 archived Taiwanese breast cancer specimens, assessing genomic alterations (GAs), including single nucleotide variants, copy number variants, fusion genes, tumor mutation burden (TMB), and microsatellite instability (MSI) status. Predictive variants for FDA-approved therapies were evaluated within each subtype. In the cohort, frequent mutations included PIK3CA (39.7%), TP53 (36.2%), KMT2C (9.5%), GATA3 (8.6%), and SF3B1 (6.9%). All subtypes had low TMB, with no MSI-H tumors. Among HRβ+βHER2- patients, 42% (27/65) harbored activating PIK3CA mutations, implying potential sensitivity to PI3K inhibitors and resistance to endocrine therapies. HRβ+βHER2- patients exhibited intrinsic hormonal resistance via FGFR1 gene gain/amplification (15%), exclusive of PI3K/AKT pathway alterations. Aberrations in the PI3K/AKT/mTOR and FGFR pathways were implicated in chemoresistance, with a 52.9% involvement in triple-negative breast cancer. In HER2+ tumors, 50% harbored GAs potentially conferring resistance to anti-HER2 therapies, including PIK3CA mutations (32%), MAP3K1 (2.9%), NF1 (2.9%), and copy number gain/amplification of FGFR1 (18%), FGFR3 (2.9%), EGFR (2.9%), and AKT2 (2.9%). This study presents CGP findings for treatment-naΓ―ve Taiwanese breast cancer, emphasizing its value in routine breast cancer management, disease classification, and treatment selection. Show less
Mitochondrial Ts translation elongation factor (TSFM) is an enzyme that catalyzes exchange of guanine nucleotides. By forming a complex with mitochondrial Tu translation elongation factor (TUFM), TSFM Show more
Mitochondrial Ts translation elongation factor (TSFM) is an enzyme that catalyzes exchange of guanine nucleotides. By forming a complex with mitochondrial Tu translation elongation factor (TUFM), TSFM participates in mitochondrial protein translation. We have previously reported that TUFM regulates translation of beta-site APP cleaving enzyme 1 (BACE1) via ROS (reactive oxygen species)-dependent mechanism, suggesting a potential role in amyloid precursor protein (APP) processing associated with Alzheimer's disease (AD), which led to the speculation that TSFM may regulate APP processing in a similar way to TUFM. Here, we report that in cultured cells, knockdown or overexpression TSFM did not change protein levels in BACE1 and APP. Besides, the levels of cytoplasmic ROS and mitochondrial superoxide, in addition to ATP level, cell viability and mitochondrial membrane potential were not significantly altered by TSFM knockdown in the short term. Further transcriptome analysis revealed that expression of majority of mitochondrial genes were not remarkably changed by TSFM silencing. The possibility of TSFM involved in cardiomyopathy and cancer development was uncovered using bioinformatics analysis. Collectively, short-term regulation of TSFM level in cultured cells does not cause a significant change in proteins involved in APP processing, levels in ROS and ATP associated with mitochondrial function. Whereas our study could contribute to comprehend certain clinical features of TSFM mutations, the roles of TSFM in cardiomyopathy and cancer development might deserve further investigation. Show less
Circular RNAs (circRNAs) have been reported to be associated with the malignant phenotypes of cancer. However, the role and underlying mechanism of hsa_Circβββββββ in colorectal cancer (CRC) remains Show more
Circular RNAs (circRNAs) have been reported to be associated with the malignant phenotypes of cancer. However, the role and underlying mechanism of hsa_Circβββββββ in colorectal cancer (CRC) remains unclear. In this study, we elucidated the pivotal role of hsa_circβββββββ in gastric cancer progression and immune evasion. Elevated hsa_circβββββββ levels in gastric cancer patient serum correlated positively with disease advancement, including tumor stages and lymph node metastasis. Functional analyses revealed a negative association between hsa_circβββββββ and CD8+ T cell number and function. Mechanistically, hsa_circβββββββ encoded the novel protein EXT1-219aa, suppressing EXT1 phosphorylation and expression. Additionally, hsa_circβββββββ regulated pyruvate metabolism by influencing the nucleus localization of PKM2. The identified EXT1/PKM2 axis further underscored the intricate regulatory mechanisms orchestrated by hsa_circβββββββ in gastric cancer, offering potential diagnostic and therapeutic implications in the ongoing pursuit of targeted therapies for gastric cancer patients. Show less
Even though the enhanced permeability and retention (EPR) effect is applicable for the passive targeting of solid tumors, many nanodrugs have failed to achieve meaningful clinical outcomes due to the Show more
Even though the enhanced permeability and retention (EPR) effect is applicable for the passive targeting of solid tumors, many nanodrugs have failed to achieve meaningful clinical outcomes due to the heterogeneity of EPR effect. Therefore, understanding the mechanism of the EPR effect is crucial to overcome the obstacles nanomedicines face in clinical translation. The aim of this study was to establish a reliable method to increase awareness of the critical influencing factors of nanoparticle (NP) transport into tumors based on the EPR effect using a combined radiogenomics and clinical magnetic resonance imaging (MRI) technique and gene set pathway enrichment analysis. Employing poly(lactic- Show less
Colorectal cancer (CRC) is one of the most common cancers. Cellular senescence plays a vital role in carcinogenesis by activating many pathways. In this study, we aimed to identify biomarkers for pred Show more
Colorectal cancer (CRC) is one of the most common cancers. Cellular senescence plays a vital role in carcinogenesis by activating many pathways. In this study, we aimed to identify biomarkers for predicting the survival and recurrence of CRC through cellular senescence-related genes. Utilizing The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, RNA-sequencing data and clinical information for CRC were collected. A risk model for predicting overall survival was established based on five differentially expressed genes using least absolute shrinkage and selection operator-Cox regression (LASSO-Cox regression), receiver operating characteristic (ROC), and Kaplan-Meier analyses. The study also delved into both the tumor microenvironment and the response to immunotherapy. Moreover, we gathered clinical sample data from our center in order to confirm the findings of public database analysis. Through ROC and Kaplan-Meier analyses, a risk model was developed using five cellular senescence-related genes [i.e., Gene signatures related to cellular senescence, specifically involving CDKN2A and ETS2, are emerging as promising biomarkers for predicting CRC prognosis and guiding immunotherapy. Show less
Poultry is a source of meat that is in great demand in the world. The quality of meat is an imperative point for shoppers. To explore the genes controlling meat quality characteristics, the growth and Show more
Poultry is a source of meat that is in great demand in the world. The quality of meat is an imperative point for shoppers. To explore the genes controlling meat quality characteristics, the growth and meat quality traits and muscle transcriptome of two indigenous Yunnan chicken breeds, Wuding chickens (WDs) and Daweishan mini chickens (MCs), were compared with Cobb broilers (CBs). The growth and meat quality characteristics of these two indigenous breeds were found to differ from CB. In particular, the crude fat (CF), inosine monophosphate content, amino acid (AA), and total fatty acid (TFA) content of WDs were significantly higher than those of CBs and MCs. In addition, it was found that MC pectoralis had 420 differentially expressed genes (DEGs) relative to CBs, and WDs had 217 DEGs relative to CBs. Among them, 105 DEGs were shared. The results of 10 selected genes were also confirmed by qPCR. The differentially expressed genes were six enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) biological pathways including lysosomes, phagosomes, PPAR signaling pathways, cell adhesion molecules, cytokine-cytokine receptor interaction, and phagosome sphingolipid metabolism. Interestingly, four genes ( Show less
Alzheimer's disease (AD) is a degenerative neurological disorder. Recent studies have indicated that histone deacetylases (HDACs) are among the most prominent epigenetic therapy targets and that HDAC Show more
Alzheimer's disease (AD) is a degenerative neurological disorder. Recent studies have indicated that histone deacetylases (HDACs) are among the most prominent epigenetic therapy targets and that HDAC inhibitors have therapeutic effects on AD. Here, we identified sodium valproate (VPA), a pan-HDAC inhibitor, and WT161, a novel HDAC6 selective inhibitor, as potential therapeutic agents for AD. Underlying molecular mechanisms were investigated. A cellular model, N2a-APPswe, was established via lentiviral infection, and the APPswe/PSEN1dE9 transgenic mouse model was employed in the study. LC-MS/MS was applied to quantify the concentration of WT161 in the mouse brain. Western blotting, immunohistochemical staining, thioflavin-S staining and ELISA were applied to detect protein expression in cells, tissues, or serum. RNA interference was utilized to knockdown the expression of specific genes in cells. The cognitive function of mice was assessed via the nest-building test, novel object recognition test and Morris water maze test. Previous studies have focused mainly on the impact of HDAC inhibitors on histone deacetylase activity. Our study discovered that VPA and WT161 can downregulate the expression of multiple HDACs, such as HDAC1 and HDAC6, in both AD cell and mouse models. Moreover, they also affect the expression of APP and APP secretases (BACE1, PSEN1, ADAM10). RNA interference and subsequent vitamin C induction further confirmed that the expression of APP and APP secretases is indeed regulated by HDAC1 and HDAC6, with the JNK pathway being the intermediate link in this regulatory process. Through the above pathways, VPA and WT161 effectively reduced AΞ² deposition in both AD cell and mouse models and significantly improved cognitive function in AD mice. In general, we have discovered that the HDAC6-JNK-APP secretases cascade is an important pathway for VPA and WT161 to exert their therapeutic effects on AD. Investigations into the safety and efficacy of VPA and WT161 were also conducted, providing essential preclinical evidence for assessing these two epigenetic drugs for the treatment of AD. Show less
Patent foramen ovale (PFO) is a congenital defect between the atria, resulting in abnormal hemodynamics. We conducted a genome-wide association study (GWAS) to identify common genetic variants associa Show more
Patent foramen ovale (PFO) is a congenital defect between the atria, resulting in abnormal hemodynamics. We conducted a genome-wide association study (GWAS) to identify common genetic variants associated with PFO. We performed a whole genome sequencing in a discovery cohort of 3,227 unrelated Chinese participants screened for PFO via contrast transthoracic echocardiography (cTTE). Single-nucleotide polymorphisms (SNPs) associated with PFO were further validated by Sanger sequencing and subsequently were evaluated in a validation cohort. Expression quantitative trait loci (eQTL) analysis was conducted using the GTEx database. Single-cell sequencing analyses with pseudotime trajectory modeling were employed to evaluate their expression in human fetal hearts. The case-control GWAS of discovery cohort ultimately included 517 cases and 517 demographically matched controls. Of the 7,040,407 variants assessed, we identified rs1227675732 (OR = 2.903; 95% CI, 1.961 to 4.297; The identification of susceptible loci for PFO might provide insights into the pathogenesis of PFO and contribute to understanding heart development. https://www.chictr.org.cn/showproj.html?proj=40590, identifier ChiCTR1900024623. Show less