The folded mitochondria inner membrane-cristae is the structural foundation for oxidative phosphorylation (OXPHOS) and energy production. By mechanically simulating mitochondria morphogenesis, we spec Show more
The folded mitochondria inner membrane-cristae is the structural foundation for oxidative phosphorylation (OXPHOS) and energy production. By mechanically simulating mitochondria morphogenesis, we speculate that efficient sculpting of the cristae is organelle non-autonomous. It has long been inferred that folding requires buckling in living systems. However, the tethering force for cristae formation and regulation has not been identified. Combining electron tomography, proteomics strategies, super resolution live cell imaging and mathematical modeling, we reveal that the mitochondria localized actin motor-myosin 19 (Myo19) is critical for maintaining cristae structure, by associating with the SAM-MICOS super complex. We discover that depletion of Myo19 or disruption of its motor activity leads to altered mitochondria membrane potential and decreased OXPHOS. We propose that Myo19 may act as a mechanical tether for effective ridging of the mitochondria cristae, thus sustaining the energy homeostasis essential for various cellular functions. Show less
Osteoarthritis (OA) is a frequently observed condition in aged people. OA cartilage is characterized by chondrocyte apoptosis, chondrocyte inflammation, and hyperactive catabolism of extracellular mat Show more
Osteoarthritis (OA) is a frequently observed condition in aged people. OA cartilage is characterized by chondrocyte apoptosis, chondrocyte inflammation, and hyperactive catabolism of extracellular matrix. However, the specific molecular mechanisms remain unclear. Recent data has shown that Angptl4, a multifunctional cytokine, is involved in the regulation of inflammatory and apoptosis responses in different tissues. This study is aimed at defining the role of Angptl4 in the development of OA. We employed X-ray analysis, safranin O-fast green (S-O) staining, and hematoxylin staining to evaluate histomorphological characteristics in the knee joint of mice. Real-time quantitative polymerase chain reaction, Western blot assays, immunofluorescence staining, and enzyme-linked immunosorbent assays (ELISA) were performed to analyze the changes in gene and protein expression. Mechanically, our data demonstrated that Angptl4 knockdown improved the degradation of extracellular matrix and reduced TNF- Show less
Polycyclic aromatic hydrocarbons (PAH) and tobacco-specific nitrosamines (TSNA) metabolism-related genes play an important role in the development of cancers. We assessed the associations of genetic v Show more
Polycyclic aromatic hydrocarbons (PAH) and tobacco-specific nitrosamines (TSNA) metabolism-related genes play an important role in the development of cancers. We assessed the associations of genetic variants in genes involved in the metabolism of PAHs and TSNA with risk of squamous cell carcinoma of the head and neck (SCCHN) in European populations using two published genome-wide association study datasets. In the single-locus analysis, we identified two SNPs (rs145533669 and rs35246205) in CYP2B6 to be associated with risk of SCCHN (P = 1.57 × 10 Show less
Fibroblast growth factor (FGF) 21, a key regulator of energy metabolism, is currently evaluated in humans for treatment of type 2 diabetes and non-alcoholic steatohepatitis. However, the effects of FG Show more
Fibroblast growth factor (FGF) 21, a key regulator of energy metabolism, is currently evaluated in humans for treatment of type 2 diabetes and non-alcoholic steatohepatitis. However, the effects of FGF21 on cardiovascular benefit, particularly on lipoprotein metabolism in relation to atherogenesis, remain elusive. Here, the role of FGF21 in lipoprotein metabolism in relation to atherosclerosis development was investigated by pharmacological administration of a half-life extended recombinant FGF21 protein to hypercholesterolaemic APOE*3-Leiden.CETP mice, a well-established model mimicking atherosclerosis initiation and development in humans. FGF21 reduced plasma total cholesterol, explained by a reduction in non-HDL-cholesterol. Mechanistically, FGF21 promoted brown adipose tissue (BAT) activation and white adipose tissue (WAT) browning, thereby enhancing the selective uptake of fatty acids from triglyceride-rich lipoproteins into BAT and into browned WAT, consequently accelerating the clearance of the cholesterol-enriched remnants by the liver. In addition, FGF21 reduced body fat, ameliorated glucose tolerance and markedly reduced hepatic steatosis, related to up-regulated hepatic expression of genes involved in fatty acid oxidation and increased hepatic VLDL-triglyceride secretion. Ultimately, FGF21 largely decreased atherosclerotic lesion area, which was mainly explained by the reduction in non-HDL-cholesterol as shown by linear regression analysis, decreased lesion severity, and increased atherosclerotic plaque stability index. FGF21 improves hypercholesterolaemia by accelerating triglyceride-rich lipoprotein turnover as a result of activating BAT and browning of WAT, thereby reducing atherosclerotic lesion severity and increasing atherosclerotic lesion stability index. We have thus provided additional support for the clinical use of FGF21 in the treatment of atherosclerotic cardiovascular disease. Show less
Melanocortin 4 receptor (MC4R) in the paraventricular nucleus of the hypothalamus (PVH) shows bidirectional characterization in modulating food intake and energy homeostasis. We demonstrate that MC4R Show more
Melanocortin 4 receptor (MC4R) in the paraventricular nucleus of the hypothalamus (PVH) shows bidirectional characterization in modulating food intake and energy homeostasis. We demonstrate that MC4R knockdown (KD) in the PVH can attenuate AMPA receptor (AMPAR)-mediated postsynaptic responses by altering the phosphorylation of AMPAR GluA1 subunit through the protein kinase A (PKA)-dependent signaling cascade and simultaneously lead to rapid body weight gain. Furthermore, PKA KD in the PVH engendered similar electrophysiological and behavioral phenotypes as in MC4R KD mice. Importantly, we observed that the reduction of AMPAR GluA1 expression not only led to attenuated synaptic responses but also caused body weight gain, suggesting that the aberration of synaptic responses may be one of the crucial pathogeny of obesity. Our study provides the synaptic and molecular explanations of how body weight is regulated by MC4R in the PVH. Show less
Fat mass and obesity-associated protein (FTO) regulates critical pathways in various diseases, including malignant tumours. However, the functional link between FTO and its target genes in epithelial Show more
Fat mass and obesity-associated protein (FTO) regulates critical pathways in various diseases, including malignant tumours. However, the functional link between FTO and its target genes in epithelial ovarian cancer (EOC) development remains to be elucidated. In this study, the biological functions of FTO were verified in vitro and in vivo. The m6A modification and the binding sites of SNAI1 mRNA were confirmed by m6A RNA immunoprecipitation (MeRIP) and RIP experiments. The actinomycin D assay was used to test the stability of RNA. We found that FTO was downregulated with increased m6A levels in EOC. Reduced expression of FTO was associated with a higher FIGO stage in patients with EOC. Mechanistically, FTO decreased the m6A level and stability of SNAI1 mRNA, causing downregulation of SNAI1 and inhibiting epithelial-mesenchymal transition (EMT). Furthermore, FTO-mediated downregulation of SNAI1 expression depended on IGF2BP2, which acted as an m6A reader binding to the 3' UTR region of SNAI1 mRNA to promote its stability. In conclusion, FTO inhibits SNAI1 expression to attenuate the growth and metastasis of EOC cells in an m6A-IGF2BP2-dependent manner. Our findings suggest that the FTO-IGF2BP2-SNAI1 axis is a potential therapeutic target in EOC. Show less
The biological function of lncRNA ELF3-AS1 remains largely unknown in cancers. The cause of SNAI2 overexpression in tumor metastasis remains largely unclear. The molecular mechanisms underlying the hi Show more
The biological function of lncRNA ELF3-AS1 remains largely unknown in cancers. The cause of SNAI2 overexpression in tumor metastasis remains largely unclear. The molecular mechanisms underlying the high co-expression of antisense lncRNAs and adjacent protein-coding genes remains unclear. RNA-seq, CHIP and dual-luciferase reporter assay were performed to identify lncRNAs regulated by SNAI2. MicroRNA-seq and RNA-seq studies were conducted to reveal the biological function of ELF3-AS1 in GC. RNA pulldown and CHIRP assays were conducted to identify the protein that interacts with ELF3-AS1. A total of 123 lncRNAs were identified to be regulated by SNAI2 in GC by RNA sequencing. The ELF3 gene and antisense lncRNA ELF3-AS1 were both transcriptionally repressed by SNAI2 or SNAI1. Down-regulation of ELF3-AS1 and ELF3 predicted poor prognosis in GC. Nuclear localized lncRNA ELF3-AS1 negatively regulated GC cell cycle progression via suppressing G1/S transition and histone synthesis. ELF3-AS1 mainly inhibited GC metastasis by repressing SNAI2 signaling. Additionally, ELF3-AS1 modulated ELF3 mRNA stability by RNA-RNA interaction. The RNA duplexes formed by ELF3 mRNA and lncRNA ELF3-AS1 directly interacted with the double-stranded RNA (dsRNA) binding protein complex ILF2/ILF3 (NF45/NF90). In turn, the ILF2/ILF3 complex dynamically regulated the expression of ELF3-AS1 and ELF3 by affecting the dsRNA stability. The SNAI2-ELF3-AS1 feedback loop regulates ELF3 expression at transcriptional and post-transcriptional levels and drives gastric cancer metastasis by maintaining SNAI2 overexpression. The ILF2/ILF3 complex plays a critical role in regulating dsRNA stability. In addition, our work provides a direct evidence that head-to-head antisense lncRNAs can share promoters with neighboring coding genes, which make their expression subject to similar transcriptional regulation, leading to high co-expression. Show less
In eukaryotic cells, both alternative splicing and alternative polyadenylation (APA) play essential roles in the gene regulation network. U1 small ribonucleoprotein particle (U1 snRNP) is a major comp Show more
In eukaryotic cells, both alternative splicing and alternative polyadenylation (APA) play essential roles in the gene regulation network. U1 small ribonucleoprotein particle (U1 snRNP) is a major component of spliceosome, and U1 snRNP complex can suppress proximal APA sites through crosstalking with 3' end processing factors. However, here we show that both knockdown and overexpression of SNRPA, SNRPC, SNRNP70, and SNRPD2, the U1 snRNP proteins, promote the usage of proximal APA sites at the transcriptome level. SNRNP70 can drive the phase transition of PABPN1 from droplet to aggregate, which may reduce the repressive effects of PABPN1 on the proximal APA sites. Additionally, SNRNP70 can also promote the proximal APA sites by recruiting CPSF6, suggesting that the function of CPSF6 on APA is related with other RNA-binding proteins and cell context-dependent. Consequently, these results reveal that, on the contrary to U1 snRNP complex, the free proteins of U1 snRNP complex can promote proximal APA sites through the interaction with 3' end processing machinery. Show less
Sheng Li, Lin Cao · 2022 · Bioengineered · Taylor & Francis · added 2026-04-24
N6-Methyladenosine (m6A) is the most abundant modifications in human messenger RNAs (mRNAs). This study aimed at investigating the function and mechanism of demethyltransferase fat mass and obesity-as Show more
N6-Methyladenosine (m6A) is the most abundant modifications in human messenger RNAs (mRNAs). This study aimed at investigating the function and mechanism of demethyltransferase fat mass and obesity-associated protein (FTO) in prostate cancer(PCa). The expression level of FTO in PCa was detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot. Besides, the impacts of FTO on the proliferation, migration and invasion of PCa cells were also detected by cell counting kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU) and transwell assays. Furthermore, we also explored the potential mechanism of FTO in PCa. The results showed that FTO expression was decreased in PCa, and the low expression of FTO showed an obvious relevance to the clinical characteristics. Downregulation of FTO facilitated the proliferation, migration, invasion and tumor growth of PCa cells. Besides, MC4R displayed a remarkably high expression in PCa tissues, whose expression and m6A level were regulated by FTO. Meanwhile, the in vitro experiments revealed that highly expressed FTO partially reversed the facilitating effect of highly expressed MC4R on the malignant phenotype of PCa cells. Overall, FTO was downregulated in PCa and its expression level showed a relevance to the prognosis of PCa patients. Additionally, FTO could regulate the proliferation, migration and invasion of PCa via regulating the expression level of MC4R. Show less
Alcohol intoxication combined with burn injury can lead to life-threatening complications, including sepsis, multiple organ failure, and death. After an acute burn, the gastrointestinal system becomes Show more
Alcohol intoxication combined with burn injury can lead to life-threatening complications, including sepsis, multiple organ failure, and death. After an acute burn, the gastrointestinal system becomes hypoxic because of fluid loss and reduction of intestinal blood flow. This can cause perturbations in the intestinal epithelial barrier, immune function, and the composition of the gut microbiome. Increased gut permeability leads to proinflammatory signaling, contributing to further damage to the intestinal barrier. Recent studies have suggested that IL-27 plays an anti-inflammatory role, which may be beneficial in intestinal barrier repair. Therefore, in this study, we examined the effect of ethanol and burn injury on IL-27 in the small intestine, as well as the potential beneficial role of IL-27 in restoring the intestinal barrier after intoxication and burn. Male C57BL/6 mice were gavaged with 2.9 g/kg ethanol before receiving a ∼12.5% total body surface area scald burn with or without rIL-27 in resuscitation fluid. Our results demonstrate that IL-27-producing cells are reduced in the small intestine after injury. When IL-27 is supplemented in resuscitation fluid, we were able to restore intestinal barrier integrity and transit, mediated through increased intestinal epithelial cell proliferation, reduced inflammatory cytokines, and increased anti-inflammatory cytokine IL-10. We also observed increased gene expression of tight junction proteins. These findings suggest that IL-27 may be a contributor to maintaining proper intestinal barrier function after injury through multiple mechanisms, including preventing excess inflammation and promoting intestinal epithelial cell proliferation and tight junction integrity. Show less
Alzheimer's disease (AD) is the most common form of neurodegenerative dementia, characterized by cognitive deficits and memory dysfunction, which is clinically incurable so far. Novel small molecular Show more
Alzheimer's disease (AD) is the most common form of neurodegenerative dementia, characterized by cognitive deficits and memory dysfunction, which is clinically incurable so far. Novel small molecular compound 2JY-OBZ4 is one of structural analogue of Huperzine A (Hup-A), an anti-AD drug in China. In our previous work, 2JY-OBZ4 exhibited potent effects on tau hyperphosphorylation, Aβ production and acetylcholinesterase (AChE) activity. However, 2JY-OBZ4's anti-AD effects and the underlying molecular mechanisms remain unclear. We here reported that 2JY-OBZ4 resisted tau hyperphosphorylation at Thr181 and Ser396 sites in HEK293-hTau cells transfected with GSK-3β, decreased tau phosphorylation via upregulating the activity of PP2A in HEK293-hTau cells and reduced Aβ production through regulating protein levels of APP cleavage enzymes in N2a-hAPP cells. Meanwhile, we found that 2JY-OBZ4 had no adverse effects on cell viability of mice primary neuron even at high concentration, and ameliorated synaptic loss induced by human oligomeric Aβ42. 2JY-OBZ4 had moderate AChE inhibitory activity with the half maximal inhibitory concentration (IC50) to be 39.48 μg/ml Show less
Acquired chemotherapy resistance is one of the main culprits in the relapse of breast cancer. But the underlying mechanism of chemotherapy resistance remains elusive. Here, we demonstrate that a small Show more
Acquired chemotherapy resistance is one of the main culprits in the relapse of breast cancer. But the underlying mechanism of chemotherapy resistance remains elusive. Here, we demonstrate that a small adaptor protein, SH3BGRL, is not only elevated in the majority of breast cancer patients but also has relevance with the relapse and poor prognosis of breast cancer patients. Functionally, SH3BGRL upregulation enhances the chemoresistance of breast cancer cells to the first-line doxorubicin treatment through macroautophagic/autophagic protection. Mechanistically, SH3BGRL can unexpectedly bind to ribosomal subunits to enhance PIK3C3 translation efficiency and sustain ATG12 stability. Therefore, inhibition of autophagy or silence of PIK3C3 or ATG12 can effectively block the driving effect of SH3BGRL on doxorubicin resistance of breast cancer cells in vitro and in vivo. We also validate that SH3BGRL expression is positively correlated with that of PIK3C3 or ATG12, as well as the constitutive occurrence of autophagy in clinical breast cancer tissues. Taken together, our data reveal that SH3BGRL upregulation would be a key driver to the acquired chemotherapy resistance through autophagy enhancement in breast cancer while targeting SH3BGRL could be a potential therapeutic strategy against breast cancer. Show less
Hypertrophic cardiomyopathy (HCM) is the most common heterogeneous myocardial disease. MYBPC3 variants are the leading cause of HCM. In the present study, a human induced pluripotent stem cell (iPSC) Show more
Hypertrophic cardiomyopathy (HCM) is the most common heterogeneous myocardial disease. MYBPC3 variants are the leading cause of HCM. In the present study, a human induced pluripotent stem cell (iPSC) line ZZUNEUi025-A was generated from peripheral blood mononuclear cells of a male HCM patient with c. 772+1G > A in MYBPC3 gene. This cell line expressed pluripotency markers, had normal male karyotype and could differentiate into three germ layers in vitro. Show less
Cardiomyocyte dysfunction and apoptosis induced by ischemia-hypoxia are common features of many acute and chronic heart diseases. WW domain-containing E3 ubiquitin ligase (WWP2) has been identified as Show more
Cardiomyocyte dysfunction and apoptosis induced by ischemia-hypoxia are common features of many acute and chronic heart diseases. WW domain-containing E3 ubiquitin ligase (WWP2) has been identified as an important regulator in pathogenesis of some health-threatening diseases. Although a couple of recent reports prompted the potential role of WWP2 in heart dysfunction, however, its exact role and how its expression was regulated in ischemic-hypoxic cardiomyocytes are still elusive. Here, we found that WWP2 protein level was induced in anoxia/reoxygenation (A/R) treated cardiomyocytes in a time-dependent manner, accompanied by synchronous expression of LINC01588 and HNRNPL. Knockdown of LINC01588 increased cardiomyocyte apoptosis, the level of oxidative stress, and expression of pro-inflammatory cytokine genes, down-regulated the expression of WWP2 and promoted expression of SEPT4 gene that contributed to cardiomyocyte dysfunction and was a target gene of WWP2. LINC01588 overexpression improved the functions of A/R treated cardiomyocytes, up-regulated WWP2 and reduced SEPT4 expression. In the mechanism exploration, we found that LINC01588 could directly bind with HNRNPL protein that could interact with WWP2, suggesting that WWP2 was involved in the regulation of LINC01588 in A/R treated cardiomyocytes. Moreover, WWP2 inhibition declined the protective role of LINC01588 in cardiomyocyte dysfunction induced by A/R. Finally, we demonstrated that LINC01588 overexpression improved acute myocardial infarction in mice in vivo. In conclusion, LINC01588 improved A/R-induced cardiomyocyte dysfunction by interacting with HNRNPL and promoting WWP2-mediated degradation of SEPT4. Show less
Acute respiratory infection by influenza virus is a persistent and pervasive public health problem. Antiviral innate immunity initiated by type I interferon (IFN) is the first responder to pathogen in Show more
Acute respiratory infection by influenza virus is a persistent and pervasive public health problem. Antiviral innate immunity initiated by type I interferon (IFN) is the first responder to pathogen invasion and provides the first line of defense. We discovered that Axin1, a scaffold protein, was reduced during influenza virus infection. We also found that overexpression of Axin1 and the chemical stabilizer of Axin1, XAV939, reduced influenza virus replication in lung epithelial cells. This effect was also observed with respiratory syncytial virus and vesicular stomatitis virus. Axin1 boosted type I IFN response to influenza virus infection and activated JNK/c-Jun and Smad3 signaling. XAV939 protected mice from influenza virus infection. Thus, our studies provide new mechanistic insights into the regulation of the type I IFN response and present a new potential therapeutic of targeting Axin1 against influenza virus infection. Show less
Angiopoietin-like 4 (ANGPTL4) was recently shown to be associated with cancer progression but little is known about its contribution to cancer metabolism. The purpose of this study was to elucidate th Show more
Angiopoietin-like 4 (ANGPTL4) was recently shown to be associated with cancer progression but little is known about its contribution to cancer metabolism. The purpose of this study was to elucidate the role of ANGPTL4 in glucose metabolism in colorectal cancer (CRC). Immunohistochemical staining of CRC specimens classified 84 patients into two groups according to ANGPTL4 expression. Clinicopathological characteristics, gene mutation status obtained by next-generation sequencing, and fluorodeoxyglucose (FDG) uptake measured by positron emission tomography/computed tomography (PET/CT) were compared between the two groups. Furthermore, the impact of ANGPTL4 expression on cancer metabolism was investigated by a subcutaneous xenograft mouse model using the ANGPTL4 knockout CRC cell line, and glucose transporter (GLUT) expression was evaluated. There were significantly more cases of T3/4 tumours (94.3% vs. 57.1%, P < 0.001) and perineural invasion (42.9% vs. 22.4%, P = 0.046) in the ANGPTL4-high group than in the low group. Genetic exploration revealed a higher frequency of KRAS mutation (54.3% vs. 22.4%, P = 0.003) in the ANGPTL4-high tumours. All the FDG uptake parameters were significantly higher in ANGPTL4-high tumours. In vivo analysis showed a significant reduction in tumour size due to ANGPTL4 knockout with lower expression of GLUT1 and GLUT3, and suppression of AKT phosphorylation. ANGPTL4 regulates the expression of GLUTs by activating the PI3K-AKT pathway and thereby promoting glucose metabolism in CRC. These findings establish a new functional role of ANGPTL4 in cancer progression and lay the foundation for developing a novel therapeutic target. Show less
Gut microbiome may influence tumor growth and cancer treatment efficacy, so it is a potential target for tumor prevention/treatment. This pilot study investigated the preventive and therapeutic effect Show more
Gut microbiome may influence tumor growth and cancer treatment efficacy, so it is a potential target for tumor prevention/treatment. This pilot study investigated the preventive and therapeutic effects of a probiotic strain, Lacticaseibacillus rhamnosus Probio-M9 (Probio-M9), against murine mammary cancer. Thirty-six female mice were randomly divided into three groups (n = 12 per group): control (without tumor transplantation), model (tumor transplantation; no probiotic administration), and probiotic (30-day oral gavage of probiotic, started seven days before tumor transplantation). Changes in tumor size were recorded, and blood, tumor tissue, and stool samples were collected at the end of the trial for analyses. Comparing with the model group, the probiotic group had a significantly smaller tumor volume (p < 0.05), a higher fecal microbiota Shannon diversity index, with significant modifications in the gut microbiota structure (p < 0.05), characterized by more Alistipes sp.₂, Porphyromonadaceae bacterium₇, and Bacteroidales bacterium 55₉ (p < 0.05). Additionally, Probio-M9 administration elevated the serum IFN-γ, IL-9, IL-13, and IL-27 levels and several metabolites (e.g., pyridoxal, nicotinic acid, 3-hydroxybutyric acid, glutamine; p < 0.05), while reducing IL-5 (p < 0.05). These changes might be associated with the protective effect of Probio-M9 against mammary tumor growth. Thus, probiotic administration could harness host gut microbiome in anti-cancer responses. Show less
Papillary thyroid cancer (PTC), accounting for more than 80 percent of all cases of thyroid cancer, is a form of a cancerous tumor that has a very favorable prognosis. However, patients diagnosed with Show more
Papillary thyroid cancer (PTC), accounting for more than 80 percent of all cases of thyroid cancer, is a form of a cancerous tumor that has a very favorable prognosis. However, patients diagnosed with PTC who are already in an advanced state have a dismal outlook. This study aimed to establish the diagnostic relevance of PRR15 expression in PTC patients as well as its levels in PTC samples and its connection with immune infiltrates. The TCGA and GEO datasets were combed through to obtain information on PTC patients. The "Limma" program was used to screen for differentially expressed mRNAs (DEMs), and the results were displayed using volcano plots and heat maps. The Wilcoxon test was used to examine the level of PRR15 expression in PTC patients in comparison with that of normal tissues. To study the connection between the immune infiltration level and PRR15 expression in PTC, the single-sample sequence set enrichment analysis (ssGSEA) from the R package was utilized. The expression of PRR15 was analyzed with RT-PCR in PTC cells and normal cells. In order to evaluate the diagnostic significance of PRR15 expression, ROC assays were carried out. Experiments using CCK-8 were carried out to investigate the impact that PRR15 knockdown could have on the proliferation of PTC cells. In this study, 17 overlapped DEMs between PTC specimens and normal specimens were identified, including MPPED2, IPCEF1, SLC4A4, PKHD1L1, DIO1, CRABP1, TPO, TFF3, SPX, TCEAL2, ZCCHC12, SYTL5, PRR15, CHI3L1, SERPINA1, GABRB2, and CITED1. Our attention focused on PRR15 which was highly expressed in PTC specimens as compared with nontumor specimens. PRR15 had an AUC value of 0.926 (95% CI 0.902-0.950) for PTC based on TCGA datasets. Pan-cancer assays suggested PRR15 as an oncogenic gene in many types of tumors. Moreover, we found that PRR15 expression was positively correlated with eosinophils, NK cells, NK CD56bright cells, IDC, macrophages, DC, mast cells, and Th1 cells. Further investigations with CCK-8 demonstrated that inhibiting PRR15 resulted in a decrease in the proliferation of PTC cells. Overall, PRR15 was confirmed to be a biomarker for PTC patients and a predictor of response to immunotherapy. Show less
Glucocorticoid (GC), secreted by adrenal cortex, plays important roles in regulating many physiological functions, while chronic stress level of GC exposure has many adverse effects on the structure a Show more
Glucocorticoid (GC), secreted by adrenal cortex, plays important roles in regulating many physiological functions, while chronic stress level of GC exposure has many adverse effects on the structure and function of hippocampal neurons, and is closely implicated to the deterioration of Alzheimer's disease (AD). Oxidative stress and neuroinflammation play an important role in the occurrence and development of AD. However, it is still unclear whether chronic GC exposure promotes beta-amyloid (Aβ) accumulation and neuronal injury by increasing oxidative stress and neuroinflammation. In this study, we investigated the effects of chronic GC exposure on NOX2-NLRP1 inflammasome activation and the protective effects of NLRP1-siRNA against GC-induced neuronal injury in primary hippocampal neurons of APP/PS1 mice. The results showed that chronic dexamethasone (DEX, 1 µM) exposure 72 h had no significant effect on the primary hippocampal neurons of WT mice, but significantly increased Aβ Show less
Hereditary multiple exostosis (HME) is an autosomal dominant skeletal disorder characterized by the development of multiple cartilage-covered tumors on the external surfaces of bones (osteochondromas) Show more
Hereditary multiple exostosis (HME) is an autosomal dominant skeletal disorder characterized by the development of multiple cartilage-covered tumors on the external surfaces of bones (osteochondromas). Most of HME cases result from heterozygous loss-of-function mutations in EXT1 or EXT2 gene. Clinical examination was performed to diagnose the patients: Whole exome sequencing (WES) was used to identify pathogenic mutations in the proband, which is confirmed by Sanger sequencing and co-segregation analysis: qRT-PCR was performed to identify the mRNA expression level of EXT1 in patient peripheral blood samples: minigene splicing assay was performed to mimic the splicing process of EXT1 variants in vitro. We evaluated the pathogenicity of EXT1 c.1056 + 1G > T in a Chinese family with HME. The clinical, phenotypic, and genetic characterization of patients in this family were described. The variant was detected by whole-exome sequencing (WES) and confirmed by Sanger sequencing. Sequencing of the RT-PCR products from the patient's blood sample identified a large deletion (94 nucleotides), which is the whole exome 2 of the EXT1 cDNA. Splicing assay indicated that the mutated minigene produced alternatively spliced transcripts, which cause a frameshift resulting in an early termination of protein expression. Our study establishes the pathogenesis of the splicing mutation EXT1 c.1056 + 1G > T to HME and provides scientific foundation for accurate diagnosis and precise medical intervention for HME. Show less
Obesity plays an important role in type 2 diabetes mellitus (T2DM) and myocardial infarction (MI). Ferroptosis and ferritinophagy are related to metabolic pathways, such as fatty acid metabolism and m Show more
Obesity plays an important role in type 2 diabetes mellitus (T2DM) and myocardial infarction (MI). Ferroptosis and ferritinophagy are related to metabolic pathways, such as fatty acid metabolism and mitochondrial respiration. We aimed to investigate the ferroptosis- and autophagy-related differentially expressed genes (DEGs) that might be potential targets for MI progression. GSE116250 was analyzed to obtain DEGs. A Venn diagram was used to obtain the overlapping ferroptosis- and autophagy-related DEGs. The enrichment pathway analysis was performed and the hub genes were obtained. Pivotal miRNAs, transcription factors, and drugs with the hub genes interactions were also predicted. The MI mice model was constructed, and qPCR analysis and single-cell sequencing were used to validate the hub genes. Utilizing the limma package and the Venn diagram, 26 ferroptosis-related and 29 autophagy-related DEGs were obtained. The list of ferroptosis-related DEGs was analyzed, which were involved in the cellular response to a toxic substance, cellular oxidant detoxification, and the IL-17 signaling pathway. The list of autophagy-related DEGs was involved in the regulation of autophagy, the regulation of JAK-STAT signaling pathway, and the regulation of MAPK cascade. In the protein-protein interaction network, the hub DEGs, such as IL-6, PTGS2, JUN, NQO1, NOS3, LEPR, NAMPT, CDKN2A, CDKN1A, and Snai1, were obtained. After validation using qPCR analysis in the MI mice model and single-cell sequencing, the 10 hub genes can be the potential targets for MI deterioration. The screened hub genes, IL-6, PTGS2, JUN, NQO1, NOS3, LEPR, NAMPT, CDKN2A, CDKN1A, and Snai1, may be therapeutic targets for patients with MI and may prevent adverse cardiovascular events. Show less
Blood-brain barrier (BBB) injury is involved in the pathogenesis of sepsis-associated encephalopathy. In this study, we used dihydroartemisinin (DHA), a derivative of artemisinin, to treat a cecal lig Show more
Blood-brain barrier (BBB) injury is involved in the pathogenesis of sepsis-associated encephalopathy. In this study, we used dihydroartemisinin (DHA), a derivative of artemisinin, to treat a cecal ligation and puncture (CLP)-induced mouse sepsis model and a tumour necrosis factor α (TNF-α)-stimulated human cerebral microvessel endothelial cells (hCMEC)/D3 cell line. We found that DHA decreased BBB permeability and increased the expression of the tight junction protein occludin (OCLN) in the CLP model. In hCMEC/D3 cells, DHA decreased TNF-α-induced hyperpermeability and increased the expression of OCLN. DHA also repressed SNAI1 expression in the CLP mouse model and in TNF-α-stimulated hCMEC/D3 cells. These data suggest that DHA protects BBB permeability during sepsis by stimulating the expression of OCLN, by downregulating the expression of the SNAI1 transcription factor. Show less
To investigate associations of genetic and environmental factors with coronary artery disease (CAD), we collected medical reports, lifestyle details, and blood samples of 2113 individuals, and then us Show more
To investigate associations of genetic and environmental factors with coronary artery disease (CAD), we collected medical reports, lifestyle details, and blood samples of 2113 individuals, and then used the polymerase chain reaction (PCR)-ligase detection reaction (LDR) to genotype the targeted 102 SNPs. We adopted elastic net algorithm to build an association model that considered simultaneously genetic and lifestyle/clinical factors associated with CAD in Chinese Han population. In this study, we developed an all covariates-based model to explain the risk of CAD, which incorporated 8 lifestyle/clinical factors and a gene-score variable calculated from 3 significant SNPs (rs671, rs6751537 and rs11641677), attaining an area under the curve (AUC) value of 0.71. It was found that, in terms of genetic variants, the AA genotype of rs671 in the additive (adjusted odds ratio (OR) = 2.51, p = 0.008) and recessive (adjusted OR = 2.12, p = 0.021) models, the GG genotype of rs6751537 in the additive (adjusted OR = 3.36, p = 0.001) and recessive (adjusted OR = 3.47, p = 0.001) models were associated with increased risk of CAD, while GG genotype of rs11641677 in additive model (adjusted OR = 0.39, p = 0.044) was associated with decreased risk of CAD. In terms of lifestyle/clinical factors, the history of hypertension (unadjusted OR = 2.37, p < 0.001) and dyslipidemia (unadjusted OR = 1.82, p = 0.007), age (unadjusted OR = 1.07, p < 0.001) and waist circumference (unadjusted OR = 1.02, p = 0.05) would significantly increase the risk of CAD, while height (unadjusted OR = 0.97, p = 0.006) and regular intake of chicken (unadjusted OR = 0.78, p = 0.008) reduced the risk of CAD. A significantinteraction was foundbetween rs671 and dyslipidemia (the relative excess risk due to interaction (RERI) = 3.36, p = 0.05). In this study, we constructed an association model and identified a set of SNPs and lifestyle/clinical risk factors of CAD in Chinese Han population. By considering both genetic and non-genetic risk factors, the built model may provide implications for CAD pathogenesis and clues for screening tool development in Chinese Han population. Show less
Crohn's disease (CD) is a type of heterogeneous, dysfunctional immune-mediated intestinal chronic and recurrent inflammation caused by a variety of etiologies. Cuproptosis is a newly discovered form o Show more
Crohn's disease (CD) is a type of heterogeneous, dysfunctional immune-mediated intestinal chronic and recurrent inflammation caused by a variety of etiologies. Cuproptosis is a newly discovered form of programmed cell death that seems to contribute to the advancement of a variety of illnesses. Consequently, the major purpose of our research was to examine the role of cuproptosis-related genes in CD. We obtained two CD datasets from the gene expression omnibus (GEO) database, and immune cell infiltration was created to investigate immune cell dysregulation in CD. Based on differentially expressed genes (DEGs) and the cuproptosis gene set, differentially expressed genes of cuproptosis (CuDEGs) were found. Then, candidate hub cuproptosis-associated genes were found using machine learning methods. Subsequently, using 437 CD samples, we explored two distinct subclusters based on hub cuproptosis-related genes. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, Gene set variation analysis (GSVA) and immune infiltration analysis studies were also used to assess the distinct roles of the subclusters. Overall, 25 CuDEGs were identified, including ABCB6, BACE1, FDX1, GLS, LIAS, MT1M, PDHA1, etc. And most CuDEGs were expressed at lower levels in CD samples and were negatively related to immune cell infiltration. Through the machine learning algorithms, a seven gene cuproptosis-signature was identified and two cuproptosis-related subclusters were defined. Cluster-specific differentially expressed genes were found only in one cluster, and functional analysis revealed that they were involved in several immune response processes. And the results of GSVA showed positive significant enrichment in immune-related pathways in cluster A, while positive significant enrichment in metabolic pathways in cluster B. In addition, an immune infiltration study indicated substantial variation in immunity across different groups. Immunological scores were higher and immune infiltration was more prevalent in Cluster A. According to the current research, the cuproptosis phenomenon occurs in CD and is correlated with immune cell infiltration and metabolic activity. This information indicates that cuproptosis may promote CD progression by inducing immunological response and metabolic dysfunction. This research has opened new avenues for investigating the causes of CD and developing potential therapeutic targets for the disease. Show less
Memory deficits and loss are the earliest and most prominent features of Alzheimer's disease (AD). This study was aimed to clarify the mechanistic basis of an active fraction of
HMO (Hereditary Multiple Osteochondroma), an uncommon autosomal dominant disorder, is characterized by the development of multiple osteochondromas, which are nonmalignant cartilage-capped bone tumors Show more
HMO (Hereditary Multiple Osteochondroma), an uncommon autosomal dominant disorder, is characterized by the development of multiple osteochondromas, which are nonmalignant cartilage-capped bone tumors growing outwards from long bone metaphyses. The present work retrospectively analyzed seven children with HMO who were enrolled for routine clinical diagnosis and treatment, including X-ray examination. Subsequent genetic detection was carried out using whole exome sequencing (WES). In addition, this work applied Sanger sequencing to be the validation approach. Moreover, this work also examined amino acid (AA) evolutionary conservatism under the influence of certain missense variants. The clinical indications of all seven patients and their family members were thoroughly indexed. WES identified diagnostic variants in the Our results expanded HMO variation spectrum, and laid certain foundations for the precise counseling of those affected families. Show less
Small interfering RNA (siRNA) therapeutic is considered to be a promising modality for the treatment of hyperlipidemia. Establishment of a thermostable clinically applicable delivery system remains a Show more
Small interfering RNA (siRNA) therapeutic is considered to be a promising modality for the treatment of hyperlipidemia. Establishment of a thermostable clinically applicable delivery system remains a most challenging issue for siRNA drug development. Here, a series of ionizable lipid-like materials were rationally designed; 4 panels of lipid formulations were fabricated and evaluated on the basis of four representative structures. The lead lipid (A1-D1-5) was stable at 40°C, and the optimized formulation (iLAND) showed dose and time dual-dependent gene silencing pattern with median effective dose of 0.18 mg/kg. In addition, potent and durable reduction of serum cholesterol and triglyceride were achieved by administering siRNAs targeting Show less
In People with HIV (PWH), chronic immune activation and systemic inflammation are associated with increased risk to develop comorbidities including bone loss. Numerous cells of the immune system, name Show more
In People with HIV (PWH), chronic immune activation and systemic inflammation are associated with increased risk to develop comorbidities including bone loss. Numerous cells of the immune system, namely, T cells are involved in the regulation of the bone homeostasis and osteoclasts (OCs) activity. IL-27, a cytokine that belongs to the IL-12 family can regulate the secretion of pro- and anti-inflammatory cytokines by T cells, however its role in the setting of HIV is largely unknown. In the present study, we determined the impact of OCs in T cell secretion of cytokines and whether IL-27 can regulate this function. We found that the presence of OCs in the T cell cultures significantly enhanced secretion of IFNγ, TNFα, IL-17, RANKL, and IL-10 in both PWH and healthy controls. In PWH, IL-27 inhibited IL-17 secretion and downregulated surface expression of RANKL in CD4 T cells. All together these results suggest that in the context of HIV infection IL-27 may favor IFNγ and TNFα secretion at the sites of bone remodeling. Show less