Gastric cancer (GC) is a malignant disease worldwide. Angiopoietin-like protein 4 (ANGPTL4) plays a role in pathophysiological processes, including metabolic reprogramming, angiogenesis, proliferation Show more
Gastric cancer (GC) is a malignant disease worldwide. Angiopoietin-like protein 4 (ANGPTL4) plays a role in pathophysiological processes, including metabolic reprogramming, angiogenesis, proliferation, and metastasis. Current evidence shows conflicting findings regarding the role of ANGPTL4 in the progression of GC. ANGPTL4 in GC was confirmed through bioinformatic analysis and immunofluorescence staining. The impact of ANGPTL4 was subsequently validated in GC cell lines using various assays, including 5-ethynyl-2-deoxyuridine (EdU), 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Flow Cytometry (FCM), wound healing, transwell, tube formation, chorioallantoic membrane model, and nude mouse model assays. RNA-seq analysis, polymerase chain reaction (PCR), western blotting (WB), immunofluorescence (IF) and coimmunoprecipitation (co-IP) were conducted to determine the potential downstream mechanism of ANGPTL4. In SNU5 and MKN7 cells, ANGPTL4 was found to augment proliferation, migration, invasion, evasion of apoptosis, and angiogenesis. Conversely, in the AGS cell line, ANGPTL4 was observed to suppress these processes. Notably, the overexpression of ANGPTL4 in AGS cells led to the upregulation of LGALS7, which has emerged as a pivotal factor contributing to the manifestation of an anticancer phenotype induced by ANGPTL4. LGALS7, which is involved in the regulation of the hedgehog pathway and subsequent promotion of GC progression through various processes, such as proliferation, migration, apoptosis evasion, angiogenesis, and lymphangiogenesis, was found to contribute to the contradictory effects of ANGPTL4. 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 carbon‑carbon 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 amyloid β (Aβ)-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 Aβ-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
Long persistent luminescence (LPL) materials with color adjustable afterglow have a wide application prospect in display and information encryption, yet there are few reports on such materials. In thi Show more
Long persistent luminescence (LPL) materials with color adjustable afterglow have a wide application prospect in display and information encryption, yet there are few reports on such materials. In this paper, SrZn 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 β (Aβ) aggregates result from dyshomeostasis between Aβ production and cle Show more
Alzheimer's disease (AD) is a neurodegenerative disorder associated with age. A wealth of evidence indicates that the amyloid β (Aβ) aggregates result from dyshomeostasis between Aβ production and clearance, which plays a pivotal role in the pathogenesis of AD. Consequently, therapies targeting Aβ 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 Aβ, APP, BACE 1, and hyperphosphorylated tau in 3×Tg-AD mice. However, the mechanism by which TBN inhibits Aβ 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 μM) to explore the mechanism of TBN in Aβ reduction. Our results indicate that TBN significantly alleviated cognitive impairment and reduced Aβ 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-β, and NF-κB, 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 (10 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
Steroid-induced osteonecrosis of the femoral head (SONFH) is a prevalent form of osteonecrosis in young individuals. More efficacious clinical strategies must be used to prevent and treat this conditi Show more
Steroid-induced osteonecrosis of the femoral head (SONFH) is a prevalent form of osteonecrosis in young individuals. More efficacious clinical strategies must be used to prevent and treat this condition. One of the mechanisms through which SONFH operates is the disruption of normal differentiation in bone marrow adipocytes and osteoblasts due to prolonged and extensive use of glucocorticoids (GCs). In vitro, it was observed that atorvastatin (ATO) effectively suppressed the impact of dexamethasone (DEX) on bone marrow mesenchymal stem cells (BMSCs), specifically by augmenting their lipogenic differentiation while impeding their osteogenic differentiation. To investigate the underlying mechanisms further, we conducted transcriptome sequencing of BMSCs subjected to different treatments, leading to the identification of Wnt5a as a crucial gene regulated by ATO. The analyses showed that ATO exhibited the ability to enhance the expression of Wnt5a and modulate the MAPK pathway while regulating the Wnt canonical signaling pathway via the WNT5A/LRP5 pathway. Our experimental findings provide further evidence that the combined treatment of ATO and DEX effectively mitigates the effects of DEX, resulting in the upregulation of osteogenic genes (Runx2, Alpl, Tnfrsf11b, Ctnnb1, Col1a) and the downregulation of adipogenic genes (Pparg, Cebpb, Lpl), meanwhile leading to the upregulation of Wnt5a expression. So, this study offers valuable insights into the potential mechanism by which ATO can be utilized in the prevention of SONFH, thereby holding significant implications for the prevention and treatment of SONFH in clinical settings. Show less
Elevated circulating branched-chain amino acids (BCAAs) are tightly linked to an increased risk in the development of type 2 diabetes mellitus. The rate limiting enzyme of BCAA catabolism branched-cha Show more
Elevated circulating branched-chain amino acids (BCAAs) are tightly linked to an increased risk in the development of type 2 diabetes mellitus. The rate limiting enzyme of BCAA catabolism branched-chain α-ketoacid dehydrogenase (BCKDH) is phosphorylated at E1α subunit (BCKDHA) by its kinase (BCKDK) and inactivated. Here, the liver-specific BCKDK or BCKDHA knockout mice displayed normal glucose tolerance and insulin sensitivity. However, knockout of BCKDK in the liver inhibited hepatic glucose production as well as the expression of key gluconeogenic enzymes. No abnormal gluconeogenesis was found in mice lacking hepatic BCKDHA. Consistent with the vivo results, BT2-mediated inhibition or genetic knockdown of BCKDK decreased hepatic glucose production and gluconeogenic gene expressions in primary mouse hepatocytes while BCKDK overexpression exhibited an opposite effect. Whereas, gluconeogenic gene expressions were not altered in BCKDHA-silenced hepatocytes. Mechanistically, BT2 treatment attenuated the interaction of cAMP response element binding protein (CREB) with CREB-binding protein and promoted FOXO1 protein degradation by increasing its ubiquitination. Our findings suggest that BCKDK regulates hepatic gluconeogenesis through CREB and FOXO1 signalings, independent of BCKDHA-mediated BCAA catabolism. Show less
On-chip polarization-sensitive photodetectors are highly desired for ultra-compact optoelectronic systems. It has been demonstrated that polarization-sensitive photodetection can be realized using int Show more
On-chip polarization-sensitive photodetectors are highly desired for ultra-compact optoelectronic systems. It has been demonstrated that polarization-sensitive photodetection can be realized using intrinsic chiral and anisotropy materials. However, these photodetectors can only realize the detection of either circularly polarized light (CPL) or linear polarized light (LPL) and are not applicable to multiple-polarization-sensitive photodetection. Herein, we experimentally demonstrate a metasurface-integrated semiconductor to realize multiple-polarization-sensitive photodetection at visible wavelengths. This device is composed of a MoSe Show less
MicroRNAs can regulate various biological functions including cell proliferation, differentiation, embryo formation, and implantation. The giant panda exhibits embryonic diapause, with embryo developm Show more
MicroRNAs can regulate various biological functions including cell proliferation, differentiation, embryo formation, and implantation. The giant panda exhibits embryonic diapause, with embryo development resuming in late pregnancy. However, the changes in microRNAs during late pregnancy remain poorly understand. After mating, plasma samples were collected on day 40 of early pregnancy (EP; n = 3) and 30 days before delivery of late pregnancy (LP; n = 3). Following microRNAs screening, a total of 120 microRNAs were detected in the plasma exosomes of pregnant pandas. Nine differentially expressed microRNAs (DEmicroRNAs) were identified in LP compared to EP, including three that were upregulated and six that were downregulated. Notably, miR-25b and miR-47 were significantly downregulated in LP group. All DEmicroRNAs were predicted to target a total of 2,675 genes. Pathway enrichment analysis of these target genes revealed significant enrichment in the MAPK and Rap1 signaling pathways, which are closely related to cell proliferation, differentiation, and cell-cell and cell-matrix interactions. Analysis of protein-protein interaction networks showed that most of the hub genes (five out of eight), including Fgfr1, Fgf2, Fgf18, Erbb4, and Kras within the MAPK and Rap1 pathways are associated with the cell proliferation and differentiation. Significantly, Erbb4 was regulated by significantly differentially expressed miRNA-47. We suggest that plasma exosomal microRNAs are involved in cell proliferation and differentiation during embryonic development by regulating key hub genes within MAPK and Rap1 pathways. These findings provided new insights into the development of giant panda embryos. Show less
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia worldwide. Dysregulation of various metabolism pathways may mediate the development of AD pat Show more
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia worldwide. Dysregulation of various metabolism pathways may mediate the development of AD pathology and cognitive dysfunction. Variants of triggering receptor expressed on myeloid cells-2 (TREM2) are known to increase the risk of developing AD. TREM2 plays a role in AD development by maintaining cellular energy and biosynthesis, but the precise mechanism through which it accomplishes this is unknown. Metabolomic analysis of hippocampal tissue from APP/PS1 and APP/PS1-TREM2 knockout (KO) mice found that TREM2 KO was associated with abnormalities in several metabolism pathways, and the effect was particularly pronounced in lipid metabolism and glucose metabolism pathways. Consistently, transcriptomic analysis of these mice determined that most differentially expressed genes were involved in energy metabolism pathways. We screened seven differentially expressed genes in APP/PS1-TREM2 KO mice that may influence AD development by altering energy metabolism. Integrative analysis of the metabolomic and transcriptomic profiles showed that TREM2 may regulate lipid metabolism and sphingolipid metabolism by affecting lipoprotein lipase (LPL) expression, thereby influencing AD progression. Our results prompt further studies of the interactions among TREM2, LPL, glucolipid metabolism, and sphingolipid metabolism in AD to identify new diagnostic and treatment strategies. Show less
Heart failure (HF), an end-stage clinical syndrome secondary to cardiac impairment, significantly affects patients' quality of life and long-term prognosis. Myocardial fibrosis leads to systolic and d Show more
Heart failure (HF), an end-stage clinical syndrome secondary to cardiac impairment, significantly affects patients' quality of life and long-term prognosis. Myocardial fibrosis leads to systolic and diastolic dysfunction, and promotes the progression of HF. Several studies involving the modulation of myocardial fibrosis have been conducted in an effort to improve cardiac function. Heat shock protein 27 (HSP27) is a small chaperone protein that is overexpressed in cellular stress states. HSP27 modulates epithelial-mesenchymal transition, playing a crucial role in the pathology of several fibrotic diseases. However, its association with myocardial fibrosis regulation is unknown. This study aimed to investigate the mechanisms by which HSP27 regulates myocardial fibrosis. We created cardiac-specific HSP25 (the murine ortholog of human HSP27) knockout mice and found that HSP25 knockdown inhibited endothelial-mesenchymal transition (EndMT), attenuated myocardial fibrosis, and ameliorated diastolic dysfunction in isoproterenol-induced HF mice via echocardiography, histology, and western bloting. In vitro, HSP27 knockdown attenuated transforming growth factor beta-induced EndMT, whereas HSP27 overexpression promoted EndMT. Furthermore, the SMAD3/SNAIL1 pathway was found to be crucial for HSP27-mediated EndMT regulation. As an essential molecule in EndMT regulation and myocardial fibrosis modulation, HSP27 may hold promise as a therapeutic target for patients with HF. Show less
Alzheimer's disease (AD) is the most common neurodegenerative disease. Intestinal flora and its metabolism play a significant role in ameliorating central nervous system disorders, including AD, throu Show more
Alzheimer's disease (AD) is the most common neurodegenerative disease. Intestinal flora and its metabolism play a significant role in ameliorating central nervous system disorders, including AD, through bidirectional interactions between the gut-brain axis. A naturally occurring alkaloid compound called berberine (BBR) has neuroprotective properties and prevents Aβ-induced microglial activation. Additionally, BBR can suppress the synthesis of Aβ and decrease BACE1 expression. However, it is still unclear if BBR therapy can alleviate AD by changing the gut flora. In this study, we examined whether a partial alleviation of AD could be achieved with BBR treatment and the molecular mechanisms involved. We did this by analyzing alterations in Aβ plaques, neurons, and related neuroinflammation-related markers in the brain and the transcriptome of the mouse brain. The relationship between the intestinal flora of 5xFAD model mice and BBR treatment was investigated using high-throughput sequencing analysis of 16S rRNA from mouse feces. The findings demonstrated that treatment with BBR cleared Aβ plaques, alleviated neuroinflammation, and ameliorated spatial memory dysfunction in AD. BBR significantly alleviated intestinal inflammation, decreased intestinal permeability, and could improve intestinal microbiota composition in 5xFAD mice. Show less
Ovarian cancer (OC) is a malignant neoplasm that displays increased vascularization. Angiopoietin-like 4 (ANGPTL4) is a secreted glycoprotein that functions as a regulator of cell metabolism and angio Show more
Ovarian cancer (OC) is a malignant neoplasm that displays increased vascularization. Angiopoietin-like 4 (ANGPTL4) is a secreted glycoprotein that functions as a regulator of cell metabolism and angiogenesis and plays a critical role in tumorigenesis. However, the precise role of ANGPTL4 in the OC microenvironment, particularly its involvement in angiogenesis, has not been fully elucidated. The expression of ANGPTL4 was confirmed by bioinformatics and IHC in OC. The potential molecular mechanism of ANGPTL4 was measured by RNA-sequence. We used a series of molecular biological experiments to measure the ANGPTL4-JAK2-STAT3 and ANGPTL4-ESM1 axis in OC progression, including MTT, EdU, wound healing, transwell, xenograft model, oil red O staining, chick chorioallantoic membrane assay and zebrafish model. Moreover, the molecular mechanisms were confirmed by Western blot, Co-IP and molecular docking. Our study demonstrates a significant upregulation of ANGPTL4 in OC specimens and its strong association with unfavorable prognosis. RNA-seq analysis affirms that ANGPTL4 facilitates OC development by driving JAK2-STAT3 signaling pathway activation. The interaction between ANGPTL4 and ESM1 promotes ANGPTL4 binding to lipoprotein lipase (LPL), thereby resulting in reprogrammed lipid metabolism and the promotion of OC cell proliferation, migration, and invasion. In the OC microenvironment, ESM1 may interfere with the binding of ANGPTL4 to integrin and vascular-endothelial cadherin (VE-Cad), which leads to stabilization of vascular integrity and ultimately promotes angiogenesis. Our findings underscore that ANGPTL4 promotes OC development via JAK signaling and induces angiogenesis in the tumor microenvironment through its interaction with ESM1. Show less
Protein tyrosine kinases (RTKs) modulate a wide range of pathophysiological events in several non-malignant disorders, including diabetic complications. To find new targets driving the development of Show more
Protein tyrosine kinases (RTKs) modulate a wide range of pathophysiological events in several non-malignant disorders, including diabetic complications. To find new targets driving the development of diabetic cardiomyopathy (DCM), we profiled an RTKs phosphorylation array in diabetic mouse hearts and identified increased phosphorylated fibroblast growth factor receptor 1 (p-FGFR1) levels in cardiomyocytes, indicating that FGFR1 may contribute to the pathogenesis of DCM. Using primary cardiomyocytes and H9C2 cell lines, we discovered that high-concentration glucose (HG) transactivates FGFR1 kinase domain through toll-like receptor 4 (TLR4) and c-Src, independent of FGF ligands. Knocking down the levels of either TLR4 or c-Src prevents HG-activated FGFR1 in cardiomyocytes. RNA-sequencing analysis indicates that the elevated FGFR1 activity induces pro-inflammatory responses Show less
Angiopoietin-like protein 4 (ANGPTL4) is recognized as a crucial regulator in lipid metabolism. Acetyl-CoA carboxylases (ACACAs) play a role in the β-oxidation of fatty acids. Yet, the functions of AN Show more
Angiopoietin-like protein 4 (ANGPTL4) is recognized as a crucial regulator in lipid metabolism. Acetyl-CoA carboxylases (ACACAs) play a role in the β-oxidation of fatty acids. Yet, the functions of ANGPTL4 and ACACA in dyslipidemia of obstructive sleep apnea (OSA) remain unclear. This study included 125 male OSA subjects from the Shanghai Sleep Health Study (SSHS) who were matched for age, body mass index (BMI), and lipid profile. Serum ANGPTL4 levels were measured Serum ANGPTL4 levels significantly decreased with increasing OSA severity (non-OSA: 59.6 ± 17.4 ng/mL, mild OSA: 50.0 ± 17.5 ng/mL, moderate OSA: 46.3 ± 15.5 ng/mL, severe OSA: 19.9 ± 14.3 ng/mL, respectively, Serum ANGTPL4 levels were significantly decreased in OSA patients, particularly among individuals with severe OSA. Although functional ANGTPL4 T266M variants were not associated with lipid levels in OSA, ANGTPL4 T266M could enhance binding affinity for the ACACA protein, potentially regulating lipid metabolism. Show less
Immune checkpoint inhibitors, particularly PD-1/PD-L1 blockades, have been approved for unresectable hepatocellular carcinoma (HCC). However, high resistance rates still limit their efficacy, highligh Show more
Immune checkpoint inhibitors, particularly PD-1/PD-L1 blockades, have been approved for unresectable hepatocellular carcinoma (HCC). However, high resistance rates still limit their efficacy, highlighting the urgent need to understand the underlying mechanisms and develop strategies for overcoming the resistance. In this study, tankyrasel binding protein 1 (TNKS1BP1) was found to interact with tripartite motif containing 21 (TRIM21) and mediated the ubiquitination of CCR4-NOT transcription complex subunit 4 (CNOT4) at the K239 residue via K48 and K6 linkage, which was essential for its tumorigenesis function. Autophagy and lipid reprogramming were identified as two possible mechanisms underlying the pro-tumor effect of TNKS1BP1. Upregulated TNKS1BP1 inhibited autophagy while induced lipid accumulation by inhibiting the JAK2/STAT3 pathway upon the degradation of CNOT4 in HCC. Importantly, knocking down TNKS1BP1 synergized with anti-PD-L1 treatment by upregulating PD-L1 expression on tumor cells via the JAK2/STAT3 pathway, and remodeling the tumor microenvironment by increasing infiltration of tumor-infiltrating lymphocytes as well as augmenting the effect of cytotoxic T lymphocytes. In conclusion, this study identified TNKS1BP1 as a predictive biomarker for patient prognosis and a promising therapeutic target to overcome anti-PD-L1 resistance in HCC. Show less
The lion-head goose is the only large goose species in China, and it is one of the largest goose species in the world. Lion-head geese have a strong tolerance for massive energy intake and show a prio Show more
The lion-head goose is the only large goose species in China, and it is one of the largest goose species in the world. Lion-head geese have a strong tolerance for massive energy intake and show a priority of fat accumulation in liver tissue through special feeding. Therefore, the aim of this study was to investigate the impact of high feed intake compared to normal feeding conditions on the transcriptome changes associated with fatty liver development in lion-head geese. In this study, 20 healthy adult lion-head geese were randomly assigned to a control group (CONTROL, n = 10) and high-intake-fed group (CASE, n = 10). After 38 d of treatment, all geese were sacrificed, and liver samples were collected. Three geese were randomly selected from the CONTROL and CASE groups, respectively, to perform whole-transcriptome analysis to analyze the key regulatory genes. We identified 716 differentially expressed mRNAs, 145 differentially expressed circRNAs, and 39 differentially expressed lncRNAs, including upregulated and downregulated genes. GO enrichment analysis showed that these genes were significantly enriched in molecular function. The node degree analysis and centrality metrics of the mRNA-lncRNA-circRNA triple regulatory network indicate the presence of crucial functional nodes in the network. We identified differentially expressed genes, including Show less
Rare study of the non-coding and regulatory regions of the genome limits our ability to decode the mechanisms of fatty liver hemorrhage syndrome (FLHS) in chickens. Herein, we constructed the high-fat Show more
Rare study of the non-coding and regulatory regions of the genome limits our ability to decode the mechanisms of fatty liver hemorrhage syndrome (FLHS) in chickens. Herein, we constructed the high-fat diet-induced FLHS chicken model to investigate the genome-wide active enhancers and transcriptome by H3K27ac target chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-Seq) profiles of normal and FLHS liver tissues. Concurrently, an integrative analysis combining ChIP-seq with RNA-Seq and a comparative analysis with chicken FLHS, rat non-alcoholic fatty liver disease (NAFLD) and human NAFLD at the transcriptome level revealed the enhancer and super enhancer target genes and conservative genes involved in metabolic processes. In total, 56 and 199 peak-genes were identified in upregulated peak-genes positively regulated by H3K27ac (Cor (peak-gene correlation) ≥0.5 and log2(FoldChange) ≥1) (PP) and downregulated peak-genes positively regulated by H3K27ac (Cor (peak-gene correlation) ≥0.5 and log2(FoldChange)≤-1) (PN), respectively; then we screened key regulatory targets mainly distributing in lipid metabolism (PCK1, APOA4, APOA1, INHBE) and apoptosis (KIT, NTRK2) together with MAPK and PPAR signaling pathway in FLHS. Intriguingly, PCK1 was also significantly covered in up-regulated super-enhancers (SEs), which further implied the vital role of PCK1 during the development of FLHS. Together, our studies have identified potential therapeutic biomarkers of PCK1 and elucidated novel insights into the pathogenesis of FLHS, especially for the epigenetic perspective. Show less
Cyclic dipeptides (CDPs), known for their diverse biological activities, have potential therapeutic applications in mental and behavioral disorders (MBDs), particularly schizophrenia. This study explo Show more
Cyclic dipeptides (CDPs), known for their diverse biological activities, have potential therapeutic applications in mental and behavioral disorders (MBDs), particularly schizophrenia. This study explores the CDPs' therapeutic potential using bibliometric analysis, network pharmacology, molecular docking, and experimental verification, focusing on the interactions with the SIGMA1 receptor. A literature review over three decades utilizing the Web of Science Core Collection (WOSCC) was conducted to identify the emerging trends in CDPs research. A compound library was constructed from the PubChem database, and target prediction using SwissTargetPrediction revealed 800 potential protein targets. A compound-target network highlighted the key interactions with kinases, G protein-coupled receptors, and chromatin-modifying enzymes. Enrichment analysis revealed significant associations with schizophrenia and other MBDs. Schizophrenia-related targets among the potential protein targets were identified using the GEO database. Molecular docking results showed interactions of MC4R, OPRK1, SIGMA1, and CDK5R1 with various CDPs compounds, with SIGMA1 being especially noteworthy. Most CDPs exhibited lower binding energies than the control compounds NE-100 and duloxetine. Experimental validation demonstrated that CDPs such as Cyclo(Ala-Gln), Cyclo(Ala-His), and Cyclo(Val-Gly) exhibited IC Show less