👤 Lu Meng

The epithelial-mesenchymal transition (EMT) is an important process during metastasis in various tumors, including colorectal cancer (CRC). Thus, the study of its characteristics and related genes is of great significance for CRC treatment. In this study, 26 EMT-related gene sets were used to score each sample from The Cancer Genome Atlas program (TCGA) colon adenocarcinoma (COAD) database. Based on the 26 EMT enrichment scores for each sample, we performed unsupervised cluster analysis and classified the TCGA-COAD samples into three EMT clusters. Then, weighted gene co-expression network analysis (WGCNA) was used to investigate the gene modules that were significantly associated with these three EMT clusters. Two gene modules that were strongly positively correlated with the EMT cluster 2 (worst prognosis) were subjected to Cox regression and least absolute shrinkage and selection operator (LASSO) regression analysis. Then, a prognosis-related risk model composed of three hub genes Show less

Excessive and chronic inflammation post myocardial infarction (MI) causes cardiac fibrosis and progressive ventricular remodeling, which leads to heart failure. We previously found high levels of IL-27 in the heart and serum until day 14 in murine cardiac ischemia‒reperfusion injury models. However, whether IL-27 is involved in chronic inflammation-mediated ventricular remodeling remains unclear. In the present study, we found that MI triggered high IL-27 expression in murine cardiac macrophages. The increased expression of IL-27 in serum is correlated with cardiac dysfunction and aggravated fibrosis after MI. Furthermore, the addition of IL-27 significantly activated the JAK/STAT signaling pathway in cardiac fibroblasts (CFs). Meanwhile, IL-27 treatment promoted the proliferation, migration and extracellular matrix (ECM) production of CFs induced by angiotensin II (Ang II). Collectively, high levels of IL-27 mainly produced by cardiac macrophages post MI contribute to the activation of CFs and aggravate cardiac fibrosis. Show less

This study aims to clarify the association between hypertrophic patterns and genetic variants in hypertrophic cardiomyopathy (HCM) patients, contributing to the advancement of personalized management strategies for HCM. A comprehensive evaluation of genetic mutations was conducted in 392 HCM-affected families using Whole Exome Sequencing. Concurrently, relevant echocardiographic data from these individuals were collected. Our study revealed an increased susceptibility to enhanced septal and interventricular septal thickness in HCM patients harbouring gene mutations compared with those without. Mid-septal hypertrophy was found to be associated predominantly with myosin binding protein C3 (MYBPC3) variants, while a higher septum-to-posterior wall ratio correlated with myosin heavy chain 7 (MYH7) variants. Mutations in MYH7, MYBPC3, and other sarcomeric or myofilament genes (troponin I3 [TNNI3], tropomyosin 1 [TPM1], and troponin T2 [TNNT2]) showed a relationship with increased hypertrophy in the anterior wall, interventricular septum, and lateral wall of the left ventricle. In contrast, alpha kinase 3 (ALPK3)-associated hypertrophy chiefly presented in the apical region, while hypertrophy related to titin (TTN) and obscurin (OBSCN) mutations exhibited a uniform distribution across the myocardium. Hypertrophic patterns varied with the type and category of gene mutations, offering valuable diagnostic insights. Our findings underscore a strong link between hypertrophic patterns and genetic variants in HCM, providing a foundation for more accurate genetic testing and personalized management of HCM patients. The novel concept of 'gene-echocardiography' may enhance the precision and efficiency of genetic counselling and testing in HCM. Show less

Antimicrobial peptides (AMPs) are important mediators of intestinal immune surveillance. However, the regional heterogeneity of AMPs and its regulatory mechanisms remain obscure. Here, we clarified the regional heterogeneity of intestinal AMPs at the single-cell level, and revealed a cross-lineages AMP regulation mechanism that bile acid dependent transcription factors (BATFs), NR1H4, NR1H3 and VDR, regulate AMPs through a ligand-independent manner. Bile acids regulate AMPs by perturbing cell differentiation rather than activating BATFs signaling. Chromatin accessibility determines the potential of BATFs to regulate AMPs at the pre-transcriptional level, thus shaping the regional heterogeneity of AMPs. The BATFs-AMPs axis also participates in the establishment of intestinal antimicrobial barriers of fetuses and the defects of antibacterial ability during Crohn's disease. Overall, BATFs and chromatin accessibility play essential roles in shaping the regional heterogeneity of AMPs at pre- and postnatal stages, as well as in maintenance of antimicrobial immunity during homeostasis and disease. Show less

Human microproteins encoded by long non-coding RNAs (lncRNA) have been increasingly discovered, however, complete functional characterization of these emerging proteins is scattered. Here, we show that LINC00493-encoded SMIM26, an understudied microprotein localized in mitochondria, is tendentiously downregulated in clear cell renal cell carcinoma (ccRCC) and correlated with poor overall survival. LINC00493 is recognized by RNA-binding protein PABPC4 and transferred to ribosomes for translation of a 95-amino-acid protein SMIM26. SMIM26, but not LINC00493, suppresses ccRCC growth and metastatic lung colonization by interacting with acylglycerol kinase (AGK) and glutathione transport regulator SLC25A11 via its N-terminus. This interaction increases the mitochondrial localization of AGK and subsequently inhibits AGK-mediated AKT phosphorylation. Moreover, the formation of the SMIM26-AGK-SCL25A11 complex maintains mitochondrial glutathione import and respiratory efficiency, which is abrogated by AGK overexpression or SLC25A11 knockdown. This study functionally characterizes the LINC00493-encoded microprotein SMIM26 and establishes its anti-metastatic role in ccRCC, and therefore illuminates the importance of hidden proteins in human cancers. Show less

The pathological basis for many retinal diseases, retinal ischemia is also one of the most common causes of visual impairment. Numerous ocular diseases have been linked to Endoplasmic reticulum(ER)stress. However, there is still no clear understanding of the relationship between ER stress and Müller glial cells during retinal ischemia and hypoxia. This study examined the effects of ER stress on autophagy and apoptosis-related proteins, as well as the microtubule-related protein tau in rMC-1 cells. rMC-1 cells were cultured in vitro. RT-PCR、immunofluorescence and Western blotting revealed the expression levels of associated mRNAs and proteins, and the CCK-8 and flow cytometry assays detected cell apoptosis. The results showed that under OGD(Oxygen-glucose deprivation) conditions, the number of rMC-1 cells was decreased, the PERK/eIF2a pathway was activated, and the expressions of p-tau, LC3、Beclin1 and Caspase-12 proteins were increased. After the PERK knockout, the expression of the above proteins was decreased, and the apoptosis was also decreased. According to the findings of this study, specific downregulation of PERK expression had an anti-apoptotic effect on OGD-conditioned rMC-1 cells. There is a possibility that this is one of the mechanisms of MG cell apoptosis during retinal ischemic injury. Show less

DNAJ heat shock protein family (Hsp40) member C1(DNAJC1) is a member of the DNAJ family. Some members of the DNAJ gene family had oncogenic properties in many cancers. However, the role of DNAJC1 in hepatocellular carcinoma (HCC) was unclear. In this study, expression and prognostic value of DNAJC1 in HCC were analyzed by bioinformatics. Quantitative real-time PCR and Western blotting were used to verify DNAJC1 expression in liver cancer cell lines. Furthermore, immunohistochemical (IHC) was used to detect DNAJC1 expression in liver cancer tissues. Subsequently, the effect of DNAJC1 on the proliferation, migration, invasion and apoptosis of HCC cells was detected by knocking down DNAJC1. Finally, gene set enrichment analysis (GSEA) was used to investigate the potential mechanism of DNAJC1 and was verified by Western blotting. DNAJC1 was highly expressed in HCC and was significantly associated with the prognosis of patients with HCC. Importantly, the proliferation, migration and invasion of Huh7 and MHCC97H cells were inhibited by the knockdown of DNAJC1 and the knockdown of DNAJC1 promoted Huh7 and MHCC97H cell apoptosis. Furthermore, compared to the negative control group, DNAJC1 knockdown in Huh7 and MHCC97H cells promoted the expression of p21, p53, p-p53(Ser20), Bax and E-cadherin proteins, while inhibiting the expression of PARP, MMP9, Vimentin, Snai1, Bcl-2 and N-cadherin proteins. DNAJC1 had a predictive value for the prognosis of HCC. Knockdown of DNAJC1 may inhibit HCC cell proliferation, migration and invasion and promote the HCC cell apoptosis through p53 and EMT signaling pathways. Show less

Extravillous trophoblast (EVT) cell invasion is a tightly regulated process that requires for a normal pregnancy. The epithelial-mesenchymal transition (EMT) has been implicated in EVT cell invasion. Growth differentiation factor-8 (GDF-8), a member of the transforming growth factor-beta (TGF-β) superfamily, is expressed in the human placenta and promotes EVT cell invasion by upregulating the expression of matrix metalloproteinase 2 (MMP2). However, the underlying molecular mechanism of GDF-8-induced MMP2 expression remains undetermined. Therefore, the present study aims to examine the role of Snail and Slug, the EMT-related transcriptional regulators, in GDF-8-stimulated MMP2 expression and cell invasion in HTR-8/SVneo human EVT cell line and primary cultures of human EVT cells. HTR-8/SVneo and primary cultures of human EVT cells were used to examine the effect of GDF-8 on MMP2 expression and explore the underlying mechanism. For gene silencing and overexpression, the HTR-8/SVneo cell line was used to make the experiments more technically feasible. The cell invasiveness was measured by Matrigel-coated transwell invasion assay. GDF-8 stimulated MMP2 expression in both HTR-8/SVneo and primary EVT cells. The stimulatory effect of GDF-8 on MMP2 expression was blocked by the inhibitor of TGF-β type-I receptors, SB431542. Treatment with GDF-8 upregulated Snail and Slug expression in both HTR-8/SVneo and primary EVT cells. The stimulatory effects of GDF-8 on Snail and Slug expression were blocked by pretreatment of SB431542 and siRNA-mediated knockdown of SMAD4. Interestingly, using the siRNA knockdown approach, our results showed that Snail but not Slug was required for the GDF-8-induced MMP2 expression and cell invasion in HTR-8/SVneo cells. The reduction of MMP2 expression in the placentas with preeclampsia (PE) was also observed. These findings discover the physiological function of GDF-8 in the human placenta and provide important insights into the regulation of MMP2 expression in human EVT cells. Video Abstract. Show less

GIP plays an important regulatory role in glucose and lipid metabolism. As the specific receptor, GIPR is involved in this physiological process. To assess the roles of GIPR in teleost, the GIPR gene was cloned from grass carp. The ORF of cloned GIPR gene was 1560 bp, encoding 519 amino acids. The grass carp GIPR was the G-protein-coupled receptor which contains seven predicted transmembrane domains. In addition, two predicted glycosylation sites were contained in the grass carp GIPR. The grass carp GIPR expression is in multiple tissues and is highly expressed in the kidney, brain regions, and visceral fat tissue. In the OGTT experiment, the GIPR expression is markedly decreased in the kidney, visceral fat, and brain by treatment with glucose for 1 and 3 h. In the fast and refeeding experiment, the GIPR expression in the kidney and visceral fat tissue was significantly induced in the fast groups. In addition, the GIPR expression levels were markedly decreased in the refeeding groups. In the present study, the visceral fat accumulation of grass carp was induced by overfed. The GIPR expression was significantly decreased in the brain, kidney, and visceral fat tissue of overfed grass carp. In primary hepatocytes, the GIPR expression was promoted by treatment with oleic acid and insulin. The GIPR mRNA levels were significantly reduced by treatment with glucose and glucagon in the grass carp primary hepatocytes. To our knowledge, this is the first time the biological role of GIPR is unveiled in teleost. Show less

Cigarette smoke exposure has a harmful impact on health and increases the risk of disease. However, studies on cigarette-smoke-induced adverse effects from the perspective of the gut-liver axis are lacking. In this study, we evaluated the adverse effects of cigarette smoke exposure on mice through physiological, biochemical, and histopathological analyses and explored cigarette-smoke-induced gut microbiota imbalance and changes in liver gene expression through a multiomics analysis. We demonstrated that cigarette smoke exposure caused abnormal physiological indices (including reduced body weight, blood lipids, and food intake) in mice, which also triggered liver injury and induced disorders of the gut microbiota and liver transcriptome (especially lipid metabolism). A significant correlation between intestinal bacterial abundance and the expression of lipid-metabolism-related genes was detected, suggesting the coordinated regulation of lipid metabolism by gut microbiota and liver metabolism. Specifically, Show less

Wanbei pig (WBP) is one of the indigenous pig resources in China and has many germplasm characteristics. However, research on its genome is lacking. To assess the genomic variation, population structure, and selection signatures, we resequenced 18 WBP for the first time and performed a comprehensive analysis with resequenced data of 10 Asian wild boars. In total, 590.03 Gb of data and approximately 41 million variants were obtained. Polymorphism level (θπ) ratio and genetic differentiation (fixation index)-based cross approaches were applied, and 539 regions, which harbored 176 genes, were selected. Functional analysis of the selected genes revealed that they were associated with lipid metabolism ( Show less

Chemotherapy is still the mainstay treatment for metastatic triple-negative breast cancers (TNBC) currently in clinical practice. The unmet needs of chemotherapy for metastatic TNBC are mainly from the insufficient drug delivery and unavailable targeting strategy that thwart the whole progression of metastatic TNBC. The in vivo ligands-mediated active targeting efficiency is usually affected by protein corona. While, the protein corona-bridged natural targeting, in turn, provides a new way for specific drug delivery. Herein, we develop a novel metastatic progression-oriented in vivo self-assembled Cabazitaxel nanocrystals (CNC) delivery system (PC/CNC) through the CNC automatically absorbing functional plasma proteins (transferrin, apolipoprotein A-IV and apolipoprotein E) in vivo, aiming to achieve the simultaneously targeted delivery to primary tumors, circulating tumor cells and metastatic lesions. With the unique advantages of superhigh drug-loading and protein corona empowered active targeting properties to tumor cells, HUVECs, active-platelets and blood-brain barrier/blood-tumor barrier, the PC/CNC exhibits a significantly improved therapeutic effect in metastatic TNBC therapy compared with free drug and CNC-loaded liposomes. Show less

To study the pathogenesis of diabetes mellitus (DM) and identify new biomarkers, high-throughput RNA sequencing provides a technical means to explore the regulatory network of MD gene expression. To better elucidate the genetic basis of DM, we analysed the circRNA and mRNA expression profiles in serum samples from diabetic patients. The circRNAs and mRNAs with abnormal expression in the DM group and non-diabetic group (NDM) were classified by RNA sequencing and differential expression analysis. The circRNA-miRNA-mRNA regulatory network reveals the mechanism by which competitive endogenous RNAs (ceRNAs) regulate gene expression. The biological functions and interactions of circRNA and mRNA were analysed by gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Differential expression analysis showed that 441 circRNAs (366 up-regulated, 75 down-regulated) and 683 mRNAs (354 up-regulated, 329 down-regulated) were significantly differentially expressed in the DM group compared with the NDM group. Screening of the differential genes at the nodes of the interaction network showed that a single circRNA could interact with multiple miRNAs and then jointly regulate more mRNAs. In addition, the expressions of circRNA CNOT6 and AXIN1 as well as mRNA STAT3, MYD88, and B2M were associated with the progression of diabetes. Enrichment pathway analysis indicated that differentially expressed circRNA and mRNA may participate in Nod-like receptor signalling pathway, insulin signalling pathway, sphinolipid metabolism pathway, and ribosome pathway, and play a role in the pathogenesis of diabetes. This study provides a theoretical basis for elucidating the molecular mechanism of DM occurrence and development at circRNA and mRNA levels. Show less

Previous studies have shown that ovarian estrogens are involved in the occurrence and pathology of Alzheimer's disease (AD) through regulation on hippocampal synaptic plasticity and spatial memory; however, the underlying mechanisms have not yet been elucidated at the genomic scale. In this study, we established the postmenopausal estrogen-deficient model by ovariectomy (OVX). Then, we used high-throughput Affymetrix Clariom transcriptomics and found 143 differentially expressed genes in the hippocampus of OVX mice with the absolute fold change ≥ 1.5 and P < 0.05. GO analysis showed that the highest enrichment was seen in long-term memory. Combined with the response to steroid hormone enrichment and GeneMANIA network prediction, the serum and glucocorticoid-regulated kinase 1 gene (Sgk1) was found to be the most potent candidate for ovarian estrogenic regulation. Sgk1 overexpression viral vectors (oSgk1) were then constructed and injected into the hippocampus of OVX mice. Morris water maze test revealed that the impaired spatial learning and memory induced by OVX was rescued by Sgk1 overexpression. Additionally, the altered expression of synaptic proteins and actin remodeling proteins and changes in CA1 spine density and synapse density induced by OVX were also significantly reversed by oSgk1. Moreover, the OVX-induced increase in Aβ-producing BACE1 and Aβ and the decrease in insulin degrading enzyme were significantly reversed by oSgk1. The above results show that multiple pathways and genes are involved in ovarian estrogenic regulation of the function of the hippocampus, among which Sgk1 may be a novel potent target against estrogen-sensitive hippocampal dysfunctions, such as Aβ-initiated AD. Show less

To explore the correlation of cytochrome B-245 alpha chain ( The study was a case-control trial. A total of 372 GAgP patients and 133 periodontally healthy controls were recruited. The The mean age of GAgP group and control group was (27.5±5.2) years and (28.8±7.1) years respectively. There was significant difference in age between the two groups ( Show less

Nitrite is a ubiquitous toxic compound in aquatic ecosystems and has negative effects on aquatic organisms. The intestine and the trillions of microbes that inhabit it, play an integral role in maintaining digestive and immune functions. However, the effects of nitrite on intestinal health and microflora have been poorly investigated. Therefore, the present study evaluated the response of intestinal histology, immunity, digestive enzyme activities and microbiota to nitrite exposure in Bufo gargarizans tadpoles. The results showed that nitrite caused damage to the intestine and impaired digestive performance. Significant changes in the transcriptional profiles of genes involved in oxidative stress (sod, gpx and hsp), inflammation, and immunity (socs3, il-27, il-1β and il-17d) were observed in the NO Show less

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

While multiple transcription factors (TFs) have been recognized to drive epithelial-mesenchymal transition (EMT) in cancer, their interdependence and context-dependent functions are poorly understood. In this study, we show that FOXQ1 and SNAI1 act as independent TFs within the EMT program with a shared ability to upregulate common EMT TFs without reciprocally impacting the expression of one another. Despite this independence, human mammary epithelial cells (HMLE) with ectopic expression of either FOXQ1 or SNAI1 share a common gene set that is enriched for a DDR2 coexpression signature. Further analysis identified DDR2 as the most upregulated receptor tyrosine kinase and a shared downstream effector of FOXQ1 and SNAI1 in triple-negative breast cancer (TNBC) cell lines. Alteration of DDR2 expression in either FOXQ1 or SNAI1 driven EMT models or in TNBC cells resulted in a profound change of cell motility without significantly impacting EMT marker expression, cell morphology, or the stem cell population. Lastly, we demonstrated that knockdown of DDR2 in the FOXQ1-driven EMT model and TNBC cell line significantly altered the global metabolic profile, including glutamine-glutamate and Aspartic acid recycling. Show less

Hepatoblastoma (HB) accounts for the majority of hepatic malignancies in children. Although the prognosis of patients with HB has improved in past decades, metastasis is an indicator of poor overall survival. Herein, we applied single-cell RNA sequencing to explore the transcriptomic profiling of 25,264 metastatic cells isolated from the lungs of two patients with HB. The transcriptomes uncovered the heterogeneity of malignant cells after metastatic lung colonization, and these cells had varied expression signatures associated with the cell cycle, epithelial-mesenchymal plasticity, and hepatic differentiation. Single-cell regulatory network inference and clustering (SCENIC) was utilized to identify the co-expressed transcriptional factors which regulated and represented the different cell states. We further screened the key factor by bioinformatics analysis and found that MYBL2 upregulation was significantly associated with metastasis and poor prognosis. The relationship between ectopic MYBL2 and metastasis was subsequently proved by immunohistochemistry (IHC) of HB tissues, and the functions of MYBL2 in promoting proliferation, migration, and epithelial-to-mesenchymal transition (EMT) were verified by in vitro and in vivo assays. Importantly, the levels of Smad2/3 phosphorylation and SNAI1 expression were increased in Show less

Epigenetic alteration is a pivotal factor in tumor metastasis. PHD finger protein 13 (PHF13) is a recently identified epigenetic reader of H3K4me2/3 that functions as a transcriptional co-regulator. In this study, we demonstrate that PHF13 is required for pancreatic-cancer-cell growth and metastasis. Integrative analysis of transcriptome and epigenetic profiles provide further mechanistic insights into the epigenetic regulation of genes associated with cell metastasis during the epithelial-to-mesenchymal transition (EMT) induced by transforming growth factor β (TGFβ). Our data suggest PHF13 depletion impairs activation of TGFβ stimulated genes and correlates with a loss of active epigenetic marks (H3K4me3 and H3K27ac) at these genomic regions. These observations argue for a dependency of TGFβ target activation on PHF13. Furthermore, PHF13-dependent chromatin regions are enriched in broad H3K4me3 domains and super-enhancers, which control genes critical to cancer-cell migration and invasion, such as SNAI1 and SOX9. Overall, our data indicate a functional and mechanistic correlation between PHF13 and EMT. Show less

Endometrial cancer is one of the most common gynecological tumors in developed countries. Our understanding of the pathogenesis of endometrial cancer and the changes in the immune microenvironment are still unclear. It is necessary to explore new biomarkers to guide the diagnosis and treatment of endometrial cancer. The GEO database was used to download the endometrial cancer single cell sequencing dataset GSE173682. The UCSC database was used to download transcriptome sequencing data. The validation set was the transcriptome dataset GSE119041, which was retrieved from the GEO database. On the DrLLPS website, liquid-liquid phase separation-related genes can be downloaded. Relevant hub genes were found using weighted co-expression network analysis and dimension reduction clustering analysis. Prognostic models were built using Lasso regression and univariate COX regression. Analyses of immune infiltration were employed to investigate the endometrial cancer immunological microenvironment. The expression of model genes in endometrial cancer was confirmed using a PCR test. We created an LLPS-related predictive model for endometrial cancer by extensive study, and it consists of four genes: EIF2S2, SNRPC, PRELID1, and NDUFB9. Patients with endometrial cancer may be classified into high-risk and low-risk groups based on their risk scores, and those in the high-risk group had significantly worse prognoses (P<0.05). Additionally, there were notable variations in the immunological milieu between the groups at high and low risk. EIF2S2, SNRPC, PRELID1, and NDUFB9 were all up-regulated in endometrial cancer tissues, according to PCR results. Our study can provide a certain reference for the diagnosis and treatment of endometrial cancer. Show less

Elimination of autoreactive developing B cells is an important mechanism to prevent autoantibody production. However, how B cell receptor (BCR) signaling triggers apoptosis of immature B cells remains poorly understood. We show that BCR stimulation up-regulates the expression of the lysosomal-associated transmembrane protein 5 (LAPTM5), which in turn triggers apoptosis of immature B cells through two pathways. LAPTM5 causes BCR internalization, resulting in decreased phosphorylation of SYK and ERK. In addition, LAPTM5 targets the E3 ubiquitin ligase WWP2 for lysosomal degradation, resulting in the accumulation of its substrate PTEN. Elevated PTEN levels suppress AKT phosphorylation, leading to increased FOXO1 expression and up-regulation of the cell cycle inhibitor p27Kip1 and the proapoptotic molecule BIM. In vivo, LAPTM5 is involved in the elimination of autoreactive B cells and its deficiency exacerbates autoantibody production. Our results reveal a previously unidentified mechanism that contributes to immature B cell apoptosis and B cell tolerance. Show less

Contrasting to the established role of the hypothalamic agouti-related protein (AgRP) neurons in feeding regulation, the neural circuit and signaling mechanisms by which they control energy expenditure remains unclear. Here, we report that energy expenditure is regulated by a subgroup of AgRP neurons that send non-collateral projections to neurons within the dorsal lateral part of dorsal raphe nucleus (dlDRN) expressing the melanocortin 4 receptor (MC4R), which in turn innervate nearby serotonergic (5-HT) neurons. Genetic manipulations reveal a bi-directional control of energy expenditure by this circuit without affecting food intake. Fiber photometry and electrophysiological results indicate that the thermo-sensing MC4R Show less

Glucagon-like peptide-2 (GLP-2) is secreted from enteroendocrine L-type cells of the gut and also released from preproglucagonergic (PPG) neurons in the nucleus tractus solitarius (NTS) and adjacent medial reticular nucleus of the brain stem. The neurons in the NTS express GLP-2, and the neurons send extensive projections to the hypothalamus. Recent studies show that the intracerebroventricular administration of GLP-2 significantly suppresses food intake in animals and some evidence suggest that the melanocortin receptor-4 (MC4-R) signaling in the hypothalamus is required for intracerebroventricular GLP-2-mediated inhibition of feeding. There is proopiomelanocortin (POMC) positive neurons expressing MC4-R in the NTS. Suppression of MC4-R expressing neurons in the brain stem inhibits gastric emptying. In this study, we tested the effects of NTS GLP-2R activation and blockade on feeding behavior and evaluated the endogenous melanocortin system's role in the NTS in mediating effects of GLP-2 on feeding behavior in fed and fasted rats. Our results demonstrated that microinjection of GLP-2 into the NTS suppressed food intake in fasted-refeeding rats but did not affect food intake in free-feeding rats, and this inhibition was blocked by pretreatment of either Exendin Show less

The high comorbidity between obesity and mental disorders, such as depression and anxiety, often exacerbates metabolic and neurological symptoms significantly. However, neural mechanisms that underlie reciprocal control of feeding and mental states are largely elusive. Here we report that melanocortin 4 receptor (MC4R) neurons located in the dorsal bed nucleus of the stria terminus (dBNST) engage in the regulation of mentally associated weight gain by receiving GABAergic projections from hypothalamic AgRP neurons onto α5-containing GABA Show less

Angiopoietin like 4 (ANGPTL4) has been proved to play an important role in lipid and glucose metabolism disorders and related cardiovascular diseases, but its role in the formation of cirrhosis still needs to be further explored. Therefore, the aim of this study was to investigate the role of ANGPTL4 in the development of liver cirrhosis and its mechanism, as well as its effect on Kupffer cell polarization and hepatic stellate cell activation. The ELISA and RT-qPCR assay were used to detect the content of ANGPTL4 in serum and mRNA expression in cells and tissues respectively. The expression of ANGPTL4, Arg1 and Mrc2 in Kupffer cells was measured by Western blot. The percentage of CD163 Show less

CD8+ T cells, which play a vital role in response to adaptive immunity, are closely related to the immunization responses to kill tumor cells. Understanding the effects exerted by tumor-infiltrated CD8+ T cells in HPV+ and HPV- head and neck squamous cell carcinoma (HNSCC) patients is critical for predicting their prognosis as well as their responses towards immunization-related therapy. HNSCC single cell transcriptome was used to screen for differentially expressed genes (DEGs) based on CD8+ T cells. A gene signature associated with CD8+ T cells was built and verified with the cancer genome atlas dataset with a view to predicting the prognosis of HNSCC patients. Risk scores were calculated for HNSCC cases and categorized into either high- or low-risk cohorts. The prognosis-correlated data of the risk scores were analyzed by using Kaplan-Meier survival curves and multi-variate Cox regression plots. In addition, the possibility of using the genetic profiles to predict responses toward immunization-related therapy was explored. From the DEGs screened from the sequencing of single-cell RNA, a gene signature of 4 genes (ACAP1, ANKRD28, C12orf75, and M6PR) were identified. It was seen that these genes could predict overall survival in HPV+ HNSCC patients. In addition, high- and low-risk HPV+ HNSCC patients showed marked differences in their CD8+ T-cell infiltration due to immunization when clinical characteristics were taken into consideration. This correlated with their immunization therapy responses. Our work provides insights into explaining the restricted responses of current immunization checkpoint inhibiting substances in HPV+ HNSCC patients. A novel genetic signature to predict the prognosis and immunization-correlated therapeutic responses is presented. This will provide potential new therapeutic opportunities for HPV+ HNSCC patients. Show less

White matter hyperintensity (WMH) is an important factor leading to cognitive impairment, and the mechanism has not been clarified. In recent years, studies have found that circular RNA (circRNA) has differential expression in cerebrovascular diseases. This study aims to analyze the expression profile of circRNA in peripheral blood mononuclear cell (PBMC) of patients with WMH with cognitive impairment, to screen the differentially expressed circRNA, and to explore the possible role of circRNA in WMH with cognitive impairment. CircRNA microarray was used to detect the circRNA expression profile of PBMC in patients with WMH with cognitive impairment, and in patients with WMH without cognitive impairment as well as in normal controls (3 cases each, male to female ratio of 2꞉1). The differentially expressed circRNA in patients with WMH with cognitive impairment was screened. The screening criteria for differentially expressed circRNA was fold change (FC) ≥2.0 (|log Compared with the control group, there were 5 significantly up-regulated circRNA and 3 down-regulated circRNA in the WMH with cognitive impairment group; 8 circRNA were significantly up-regulated and 2 were down-regulated in the WMH without cognitive impairment group. When compared with the WMH with cognitive impairment group, no co-differentially expressed circRNA was found in WMH without cognitive impairment group and control group. Compared with the control group, the expression of hsa_circ₀₀₉₂₂₂₂ was up-regulated and the expressions of hsa_circ₀₀₀₀₆₆₂ and hsa_circ₀₀₈₃₇₇₃ were down-regulated in the WMH with cognitive impairment group and the WMH without cognitive impairment group, and there was no significant difference between the 2 groups (all The circRNA expression profile of patients with WMH is changed significantly. The differentially expressed circRNA may be the cause of WMH; Hsa_circ₀₀₉₂₂₂₂, hsa_circ₀₀₀₀₆₆₂, and hsa_circ₀₀₈₃₇₇₃ may regulate the expression of target genes by targeting adsorption of the target miRNA, leading to brain white matter damage through Janus kinase 2 (JAK2)/signal transducers and activators of transcription (STAT3) signal pathway and Wnt signal pathway.There is no significant difference in circRNA expression profile between WMH with or without cognitive impairment. Cognitive impairment in patients with WMH may have other reasons. Show less