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Polycystic ovarian syndrome (PCOS) is one of the most common gynecological endocrine disorders. MicroRNAs (miRNAs) play extensive roles in the pathogenesis of PCOS and can serve as potential diagnostic markers. However, most studies focused on the regulatory mechanisms of individual miRNAs, and the combined regulatory effects of multiple miRNAs remain unclear. The aim of this study was to identify the common targets of miR-223-3p, miR-122-5p, and miR-93-5p; and assess the transcript levels of some of these targets in PCOS rat ovaries. Transcriptome profiles of granulosa cells from PCOS patients were obtained from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs). A total of 1,144 DEGs were screened, 204 of which were upregulated and 940 were downregulated. According to the miRWalk algorithm, 4,284 genes were targeted by all three miRNAs at the same time, and intersection with DEGs was used to obtain candidate target genes. A total of 265 candidate target genes were screened, and the detected target genes were subjected to Gene ontology (GO) and KEGG pathway enrichment, followed by PPI network analysis. Then, qRT-PCR was used to determine the levels of 12 genes in PCOS rat ovaries. The expressions of 10 of these genes were found to be consistent with our bioinformatics results. In conclusion, JMJD1C, PLCG2, SMAD3, FOSL2, TGFB1, TRIB1, GAS7, TRIM25, NFYA, and CALCRL may participate in the development of PCOS. Our findings contribute to the identification of biomarkers that may promote the effective prevention and treatment of PCOS in the future. Show less

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western world. It is characterized by a high dependency on interactions with the surrounding immune landscape, highlighting its suitability for immune-mediated therapeutic interventions. We recently revealed that the cytokine IL-27 exerts a strong anti-tumor role in CLL through a T-cell-mediated mechanism. Show less

Oxidative stress plays an important role in cognitive dysfunctions and is seen in neurodegeneration and Alzheimer's disease (AD). It has been reported that the polyphenolic compound caffeic acid possesses strong neuroprotective and antioxidant effects. The current study was conducted to investigate the therapeutic potential of caffeic acid against amyloid beta (Aβ Show less

Chronic inflammation has been recognized as a canonical cancer hallmark. It is orchestrated by cytokines, which are master regulators of the tumor microenvironment (TME) as they represent the main communication bridge between cancer cells, the tumor stroma, and the immune system. Interleukin (IL)-6 represents a keystone cytokine in the link between inflammation and cancer. Many cytokines from the IL-6 family, which includes IL-6, oncostatin M, leukemia inhibitory factor, IL-11, IL-27, IL-31, ciliary neurotrophic factor, cardiotrophin 1, and cardiotrophin-like cytokine factor 1, have been shown to elicit tumor-promoting roles by modulating the TME, making them attractive therapeutic targets for cancer treatment.The development of immune checkpoint blockade (ICB) immunotherapies has radically changed the outcome of some cancers including melanoma, lung, and renal, although not without hurdles. However, ICB shows limited efficacy in other solid tumors. Recent reports support that chronic inflammation and IL-6 cytokine signaling are involved in resistance to immunotherapy. This review summarizes the available preclinical and clinical data regarding the implication of IL-6-related cytokines in regulating the immune TME and the response to ICB. Moreover, the potential clinical benefit of combining ICB with therapies targeting IL-6 cytokine members for cancer treatment is discussed. Show less

Cyclic adenosine monophosphate (cAMP) levels are directly activated by adenylate cyclase (AC) and play an anti-inflammatory role in chronic obstructive pulmonary disease (COPD). Previously, we have shown that isoforskolin (ISOF) can effectively activate AC1 and AC2 in vitro, improve pulmonary ventilation and reduce the inflammatory response in COPD model rats, supporting that ISOF may be a potential drug for the prevention and treatment of COPD, but the mechanism has not been explored in detail. The potential pharmacological mechanisms of ISOF against COPD were analyzed by network pharmacology and multi-omics based on pharmacodynamic study. To use specific agonists, inhibitors and/or SiRNA for gene regulation function studies, combined qPCR, WB were applied to detect changes in mRNA and protein expression of important targets PIK3C3, AKT, mTOR, SPP1 and AQP4 which related to ISOF effect on COPD. And the key inflammatory factors detected by ELISA. Bioinformatics suggested that the anti-COPD pharmacological mechanism of ISOF was related to PI3K-AKT signaling pathway, and suggested target protein like PIK3C3, AQP4, SPP1, AKT, mTOR. Using the AQP4 inhibitor,or inhibiting SPP1 expression by siRNA-SPP1 could block the PIK3C3-AKT-mTOR pathway and ameliorate chronic inflammation. ISOF showed cAMP-promoting effect then suppressed AQP4 expression, together with decreased level of IL-1β, IL-6, and IL-8. These findings demonstrate ISOF controlled the cAMP-regulated PIK3C3-AKT-mTOR pathway, thereby alleviating inflammatory development in COPD. The cAMP/AQP4/PIK3C3 axis also modulate Th17/Treg differentiation, revealed potential therapeutic targets for this disease. Show less

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease. Metabolism-related genes significantly influence the onset and progression of the disease. Hence, it is necessary to screen metabolism-related biomarkers for the diagnosis and treatment of NAFLD patients. GSE48452, GSE63067, and GSE89632 datasets including nonalcoholic steatohepatitis (NASH) and healthy controls (HC) analyzed in this study were retrieved from the Gene Expression Omnibus (GEO) database. First, differentially expressed genes (DEGs) between NASH and HC samples were obtained. Next, metabolism-related DEGs (MR-DEGs) were identified by overlapping DEGs and metabolism-related genes (MRG). Further, a protein-protein interaction (PPI) network was developed to show the interaction among MR-DEGs. Subsequently, the "Least absolute shrinkage and selection operator regression" and "Random Forest" algorithms were used to screen metabolism-related genes (MRGs) in patients with NAFLD. Next, immune cell infiltration and gene set enrichment analyses (GSEA) were performed on these metabolism-related genes. Finally, the expression of metabolism-related gene was determined at the transcription level. First, 129 DEGs related to NAFLD development were identified among patients with nonalcoholic steatohepatitis (NASH) and healthy control. Next, 18 MR-DEGs were identified using the Venn diagram. Subsequently, four genes, including AMDHD1, FMO1, LPL, and P4HA1, were identified using machine learning algorithms. Moreover, a regulatory network consisting of four genes, 25 microRNAs (miRNAs), and 41 transcription factors (TFs) was constructed. Finally, a significant increase in FMO1 and LPL expression levels and a decrease in AMDHD1 and P4HA1 expression levels were observed in patients in the NASH group compared to the HC group. Metabolism-related genes associated with NAFLD were identified, containing AMDHD1, FMO1, LPL, and P4HA1, which provide insights into diagnosing and treating patients with NAFLD. Show less

The purpose of the network meta-analysis was to make a more comprehensive comparison of different interleukins in the detection of neonatal sepsis and to pose clues in the field of clinical practice. Electronic databases of PubMed, Web of Science and Embase were systematically searched. Eligible studies included diagnostic tests utilizing interleukins to detect neonatal sepsis. We calculated pooled sensitivity, specificity, positive Likelihood Ratio (PLR) and negative Likelihood Ratio (NLR), diagnostic odds ratio (DOR), and superiority index. Fifteen studies including 1,369 neonates diagnosed of sepsis were included in this meta-analysis. For the detection of early-onset sepsis in neonates, the pooled sensitivity was 0.91 (95% CI: 0.81, 0.97; Findings of this network meta-analysis suggest that interleukins including IL-6, IL-8, IL-10, and IL-27 may have favorable performance in the detection of neonatal sepsis. IL-8 was more accurate in the detection of early-onset sepsis in neonates. IL-27 was more accurate in the detection of late-onset neonatal sepsis. Show less

Consumer demand for tasty and quality meat has been quickly increasing. This study investigated how dietary supplemented rutin affects meat quality, muscle fatty acid profile, and antioxidant capacity in the Chinese indigenous Qingyuan partridge chicken. A cohort of 180 healthy 119-day-old chickens was subjected to a randomized assignment into three groups, identified as the control, R200, and R400 groups, with respective supplementation of 0, 200, and 400 mg/kg of rutin. The results revealed insignificance in growth performance, namely, average daily gain, average daily feed intake, and feed-to-gain ratio, across the various treatment groups ( Show less

Multiple sclerosis (MS) is an autoimmune central nervous system (CNS) disorder indicated by demyelination, chronic inflammation, and neuronal destruction. Regional demyelination, inflammation responses, scar development, and various axonal damage are pathological characteristics of MS. Curcumin is a hydrophobic polyphenol extracted from the rhizome of the turmeric plant. In addition to anti-inflammatory effects, beneficial therapeutic effects such as antioxidant, anti-cancer and nerve protection have also been seen from this compound. The purpose of the current investigation was to provide light on the potential benefits of Curcumin in treating experimental autoimmune encephalomyelitis (EAE), the animal model of MS. in Female C57BL/6 mice were used to induce EAE through myelin oligodendroglial glycoprotein (MOG). Curcumin doses of 100 and 200 mg/kg were administered orally in the treatment groups starting on the first day of EAE induction. Brains and splenocytes were extracted from euthanized animals on day 25 following EAE induction. Demyelination and leukocyte infiltration, proliferation, cytokine, and gene expression profiles were assessed. Our findings demonstrate that both low and high doses of Curcumin decreased the progression of EAE. Histological analyses revealed low infiltration of leukocytes into the CNS. Curcumin therapy enhanced Th2 and Treg cell secretion of IL-4, IL-10, and TGF-β although considerably decreasing IFN-γ and TNF-α. Curcumin-induced Th2 and Treg cell cytokine production and transcription factor gene expression (IL-13, GATA3, STAT6 and IL-35, CTLA4, Foxp3) and anti-inflammatory cytokines (IL-27, IL-33). Overall, these findings provide additional evidence that Curcumin can slow disease development and alleviate symptoms in EAE through stimulating Treg and Th2 cell polarization. They support Curcumin's potential therapeutic role in MS. Show less

Non-obstructive azoospermia (NOA) affects approximately 1% of the male population worldwide. The underlying mechanism and gene transcription remain unclear. This study aims to explore the potential pathogenesis for the detection and management of NOA. Based on four microarray datasets from the Gene Expression Omnibus database, integrated analysis and weighted correlation network analysis (WGCNA) were used to obtain the intersected common differentially expressed genes (DESs). Differential signaling pathways were identified via GO and GSVA-KEGG analyses. We constructed a seventeen-gene signature model using least absolute shrinkage and selection operation (LASSO) regression, and validated its efficacy in another two GEO datasets. Three patients with NOA and three patients with obstructive azoospermia were recruited. The mRNA levels of seven key genes were measured in testicular samples, and the gene expression profile was evaluated in the Human Protein Atlas (HPA) database. In total, 388 upregulated and 795 downregulated common DEGs were identified between the NOA and control groups. ATPase activity, tubulin binding, microtubule binding, and metabolism- and immune-associated signaling pathways were significantly enriched. A seventeen-gene signature predictive model was constructed, and receiver operating characteristic (ROC) analysis showed that the area under the curve (AUC) values were 1.000 (training group), 0.901 (testing group), and 0.940 (validation set). The AUCs of seven key genes (REC8, CPS1, DHX57, RRS1, GSTA4, SI, and COX7B) were all > 0.8 in both the testing group and the validation set. The qRT-PCR results showed that consistent with the sequencing data, the mRNA levels of RRS1, GSTA4, and COX7B were upregulated, while CPS1, DHX57, and SI were downregulated in NOA. Four genes (CPS1, DHX57, RRS1, and SI) showed significant differences. Expression data from the HPA database showed the localization characteristics and trajectories of seven key genes in spermatogenic cells, Sertoli cells, and Leydig cells. Our findings suggest a novel seventeen-gene signature model with a favorable predictive power, and identify seven key genes with potential as NOA-associated marker genes. Our study provides a new perspective for exploring the underlying pathological mechanism in male infertility. Show less

T(14;19) is an unusual but distinct genomic alteration reported in low-grade B-cell lymphomas. This structural rearrangement places BCL3 in juxtaposition with IGH inducing proliferation and has been found in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone lymphoma (MZL), and other low-grade B-cell lymphomas. While there are some case series describing this in the context of other cytogenetic alterations, there are limited clinical cases examined from a molecular perspective. We herein describe a case of a low-grade B-cell lymphoma with t(14;19) resulting in IGH::BCL3 fusion on which we performed whole exome sequencing to investigate genetic variants that could contribute to its pathogenesis. We found pathogenic alterations including a variant in CXCR4 which has been shown to be recurrently mutated in different low-grade B-cell lymphomas including lymphoplasmacytic lymphoma (LPL) and MZL. We describe this interesting case in the context of its genomic findings and how it contributes to the literature as a whole. Show less

Previous studies have shown that interleukin-27 (IL-27) can reduce bleomycin (BLM)-induced pulmonary fibrosis (PF). However, the underlying mechanism by which IL-27 attenuates PF is not fully clear. In this research, we used BLM to construct a PF mouse model, and MRC-5 cells stimulated by transforming growth factor-β1 (TGF-β1) were used to construct a PF model in vitro. The lung tissue status was observed by Masson and hematoxylin and eosin (HE) staining. To detect gene expression, RT‒qPCR was used. The protein levels were detected by western blotting and immunofluorescence staining. EdU and ELISA were used to detect cell proliferation viability and hydroxyproline (HYP) content, respectively. Aberrant IL-27 expression was observed in BLM-induced mouse lung tissues, and the use of IL-27 attenuated mouse lung tissue fibrosis. TGF-β1 induced autophagy inhibition in MRC-5 cells, and IL-27 alleviated MRC-5 cell fibrosis by activating autophagy. The mechanism is inhibition of DNA methyltransferase 1 (DNMT1)-mediated lncRNA MEG3 methylation and ERK/p38 signaling pathway activation. Overexpression of DNMT1, knockdown of lncRNA MEG3, autophagy inhibitor or ERK/p38 signaling pathway inhibitors reversed the positive effect of IL-27 in a lung fibrosis model in vitro. In conclusion, our study shows that IL-27 upregulates MEG3 expression through inhibition of DNMT1-mediated lncRNA MEG3 promoter methylation, which in turn inhibits ERK/p38 signaling pathway-induced autophagy and attenuates BLM-induced PF, providing a contribution to the elucidation of the potential mechanisms by which IL-27 attenuates PF. Show less

"Precision nutrition" is an emerging area of nutrition research that focuses on understanding metabolic variability within and between individuals and helps develop customized dietary plans and interventions to maintain optimal individual health. It encompasses nutritional genomic (gene-nutrient interactions), epigenetic, microbiome, and environmental factors. Obesity is a complex disease that is affected by genetic and environmental factors and thus a relevant target of precision nutrition-based approaches. Recent studies have shown significant associations between obesity phenotypes (body weight, body mass index, waist circumference, and central and regional adiposity) and genetic variants, epigenetic factors (DNA methylation and noncoding RNA), microbial species, and environment (sociodemographics and physical activity). Additionally, studies have also shown that the interactions between genetic variants, microbial metabolites, and epigenetic factors affect energy balance and adiposity. These include variants in Show less

The global coronavirus disease 2019 (COVID-19) pandemic has a detrimental impact on public health. COVID-19 usually manifests as pneumonia, which can progress into acute respiratory distress syndrome (ARDS) related to uncontrolled TH17 immune reaction. Currently, there is no effective therapeutic agent to manage COVID-19 with complications. The currently available anti-viral drug remdesivir has an effectiveness of 30% in SARS-CoV-2-induced severe complications. Thus, there is a need to identify effective agents to treat COVID-19 and the associated acute lung injury and other complications. The host immunological pathway against this virus typically involves the THαβ immune response. THαβ immunity is triggered by type 1 interferon and interleukin-27 (IL-27), and the main effector cells of the THαβ immune response are IL10-CD4 T cells, CD8 T cells, NK cells, and IgG1-producing B cells. In particular, IL-10 exerts a potent immunomodulatory or anti-inflammatory effect and is an anti-fibrotic agent for pulmonary fibrosis. Concurrently, IL-10 can ameliorate acute lung injury or ARDS, especially those caused by viruses. Owing to its anti-viral activity and anti-pro-inflammatory effects, in this review, IL-10 is suggested as a possible treatment agent for COVID-19. Show less

Sitagliptin, an anti-diabetic drug, is a dipeptidyl peptidase (DPP)-4/CD26 inhibitor with additional anti-inflammatory and immunomodulatory properties. In this study, we investigated for the first time the effect of sitagliptin on the differentiation and functions of human dendritic cells generated from monocytes (MoDCs) for 4 days using the standard GM-CSF/IL-4 procedure. LPS/IFN-γ treatment for an additional 24 h was used for maturation induction of MoDCs. Sitagliptin was added at the highest non-cytotoxic concentration (500 µg/mL) either at the beginning (sita 0d protocol) or after MoDC differentiation (sita 4d protocol). Sitagliptin impaired differentiation and maturation of MoDCs as judged with the lower expression of CD40, CD83, CD86, NLRP3, and HLA-DR, retention of CD14 expression, and inhibited production of IL-β, IL-12p70, IL-23, and IL-27. In contrast, the expression of CD26, tolerogenic DC markers (ILT4 and IDO1), and production of immunoregulatory cytokines (IL-10 and TGF-β) were increased. Generally, the sita 0d protocol was more efficient. Sitagliptin-treated MoDCs were poorer allostimulators of T-cells in MoDC/T-cell co-culture and inhibited Th1 and Th17 but augmented Th2 and Treg responses. Tolerogenic properties of sitagliptin-treated MoDCs were additionally confirmed by an increased frequency of CD4+CD25+CD127- FoxP3+ Tregs and Tr1 cells (CD4+IL-10+FoxP3-) in MoDC/T-cell co-culture. The differentiation of IL-10+ and TGF-β+ Tregs depended on the sitagliptin protocol used. A Western blot analysis showed that sitagliptin inhibited p65 expression of NF-kB and p38MAPK during the maturation of MoDCs. In conclusion, sitagliptin induces differentiation of tolerogenic DCs, and the effect is important when considering sitagliptin for treating autoimmune diseases and allotransplant rejection. Show less

Carbamoyl phosphate synthetase 1 (CPS1) deficiency is a severe urea cycle disorder. Patients can present with hyperammonemic coma in the first days of life. Treatment includes nitrogen scavengers, reduced protein intake and supplementation with L-arginine and/or L-citrulline. N-carbamoyl glutamate (NCG) has been hypothesized to stimulate the residual CPS1 function, although only few patients are reported. We report a patient with neonatal-onset CPS1 deficiency who received NCG in association with nitrogen scavenger and L-citrulline. The patient carried the novel variants Our data show that the response to NCG can be indicated based on the protein structure. We hypothesize that variants in the C-terminal domain may be responsive to NCG therapy. Show less

Improvement of nutrient utilization to promote growth performance is always pursued in poultry. In this study, a total of 360 1-d-old male ducklings was randomly assigned to 3 treatments in terms of diet treatment groups. Three treatments were as follows: basal diet (Con group) or basal diet supplemented with 300 mg/kg multi-enzymes (ENZ group) or 500 mg/kg lysophospholipids (LPL group). On day 42, ducks were slaughtered for samplings. The results revealed that supplementary LPL improved the body weight (BW) at day 14 and average daily gain (ADG) during days 1 to 14 and improved the feed conversion rate (FCR) for the overall period (P < 0.05) by improving nutrient utilization of dry matter and ether extract (P < 0.05) compared with the Con group. Dietary ENZ improved the FCR from days 15-42 and 1-42, and nitrogen utilization (P < 0.05) compared with the Con group. Jejunal villus height and villus height/crypt depth ratio were higher (P < 0.05) in the LPL group and tended to be higher (P < 0.1) in the ENZ group compared to the Con group. Supplementation with either LPL or ENZ reduced interleukin-1β concentration in jejunal mucus (P < 0.05). Both LPL and ENZ enhanced serum total superoxide dismutase activity (P < 0.05), whereas only supplementation with LPL elevated total antioxidant capacity (P < 0.05). In terms of cecal microbiota, microbial richness tended to be reduced by LPL, with low observed-OTUs and Chao1 (0.05 < P < 0.1). Supplementation with ENZ led to higher abundances of cellulolytic bacteria such as Fibrobacterota, [Eubacterium]_xylanophilum_group, and Bifidobacterium. Overall, both LPL and ENZ improved FCR, which may be relevant to ameliorative intestinal health, overall antioxidant ability, and cecal microbiome. Show less

Feed efficiency is a major constraint in the beef industry and has a significant negative correlation with residual feed intake (RFI). RFI is widely used as a measure of feed efficiency in beef cattle and is independent of economic traits such as body weight and average daily gain. However, key traits with commonality or specificity among beef cattle breeds at the same level of RFI have not been reported. Accordingly, the present study hypothesized that signatures associated with feed efficiency would have commonality or specificity in the liver of cattle breeds at the same RFI level. By comparing and integrating liver transcriptome data, we investigated the critical signatures closely associated with RFI in beef cattle using weighted co-expression network analysis, consensus module analysis, functional enrichment analysis and protein network interaction analysis. The results showed that the consensus modules in Angus and Charolais cattle were negatively correlated, and four (turquoise, red, tan, yellow) were significantly positively correlated in Angus liver, while (turquoise, red) were significantly negatively correlated in Charolais liver. These consensus modules were found to be primarily involved in biological processes such as substance metabolism, energy metabolism and gene transcription, which may be one of the possible explanations for the difference in feed efficiency between the two beef breeds. This research also identified five key candidate genes, PLA2G12B, LCAT, MTTP, LCAT, ABCA1 and FADS1, which are closely associated with hepatic lipid metabolism. The present study has identified some modules, genes and pathways that may be the major contributors to the variation in feed efficiency among different cattle breeds, providing a new perspective on the molecular mechanisms of feed efficiency in beef cattle and a research basis for investigating molecular markers associated with feed efficiency in beef cattle. Show less

Genome and epigenome wide association studies identified variants in carnitine palmitoyltransferase 1a (CPT1a) that associate with lipid traits. The goal of this study was to determine the impact by which liver-specific CPT1a deletion impacts hepatic lipid metabolism. Six-to-eight-week old male and female liver-specific knockout (LKO) and littermate controls were placed on a low-fat or high-fat diet (HFD; 60% kcal fat) for 15 weeks. Mice were necropsied after a 16 hour fast, and tissues were collected for lipidomics, matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI), kinome analysis, RNA-sequencing, and protein expression by immunoblotting. Female LKO mice had increased serum alanine aminotransferase (ALT) levels which were associated with greater deposition of hepatic lipids, while male mice were not affected by CPT1a deletion relative to male control mice. Mice with CPT1a deletion had reductions in DHA-containing phospholipids at the expense of monounsaturated fatty acids (MUFA)-containing phospholipids in both whole liver and at the level of the lipid droplet (LD). Male and female LKO mice increased RNA levels of genes involved in LD lipolysis ( Liver-specific deletion of CPT1a promotes sexually dimorphic steatotic liver disease (SLD) in mice, and here we have identified new mechanisms by which females are protected from HFD-induced liver injury. Show less

Shuganzhi Tablet (SGZT) originates from a famous traditional Chinese herbal formula Chaihu Decoction which can be applied to treat liver diseases, however, the pharmacodynamic mechanism of SGZT needs to be evaluated. To study the mechanism of SGZT in the treatment of non-alcoholic fatty liver disease (NAFLD), and screen out its effective ingredients. In this study, firstly, the main components of SGZT were analyzed qualitatively. And a rat model of NAFLD was established by feeding high-fat diet. Serum biochemical indexes and liver pathological analysis were used to evaluate the pharmacodynamic effect of SGZT in the treatment of NAFLD. In order to explore the pharmacodynamic mechanism, proteomics and metabolomics analysis were used. Western blotting was used to verify the expression of important differential proteins. And L02 cells were treated with free fatty acids (FFA) and the main substances of SGZT to establish the cell model of NAFLD in vitro and to reveal the pharmacodynamic substance of SGZT. Twelve components were detected in SGZT, and according to the results of serum biochemical indexes and liver pathological analysis, SGZT could effectively treat NAFLD. Combined with the results of bioinformatics analysis, we found that 133 differentially expressed proteins were reversed in liver samples of rats treated with SGZT. The important proteins in PPAR signaling pathway, steroid biosynthesis, cholesterol metabolism and fatty acid metabolism were mainly regulated to maintain cholesterol homeostasis and improve lipid metabolism. SGZT also affected various metabolites in rat liver, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and taurine. In addition, the main components contained in SGZT (hesperidin, polydatin, naringin, emodin, specnuezhenide, saikosaponin A) and a metabolite (resveratrol) could significantly reduce FFA-induced intracellular lipid accumulation. SGZT effectively treated NAFLD, and PPAR-γ, Acsl4, Plin2 and Fads1 may be the main targets of SGZT. And Fads1-EPA/DHA-PPAR-γ may be the potential pharmacodynamic pathway. Cell experiments in vitro revealed that the main components of SGZT and their metabolites, such as hesperidin, polydatin, naringin, emodin, specnuezhenide, saikosaponin A and resveratrol may be the main components of its efficacy. Further research is needed to reveal and validate the pharmacodynamic mechanism. Show less

Maternal n-3 PUFA (omega-3) deficiency can affect brain development in utero and postnatally. Despite the evidence, the impacts of n-3 PUFA deficiency on the expression of neurogenesis genes in the postnatal hippocampus remained elusive. Since postnatal brain development requires PUFAs via breast milk, we examined the fatty acid composition of breast milk and hippocampal expression of neurogenesis genes in n-3 PUFA deficient 21d mice. In addition, the expression of fatty acid desaturases, elongases, free fatty acids signaling receptors, insulin and leptin, and glucose transporters were measured. Among the genes involved in neurogenesis, the expression of brain-specific tenascin-R (TNR) was downregulated to a greater extent (∼31 fold), followed by adenosine A2A receptor (A2AAR), dopamine receptor D2 (DRD2), glial cell line-derived neurotrophic factor (GDNF) expression in the n-3 PUFA deficient hippocampus. Increasing dietary LA to ALA (50:1) elevated the ARA to DHA ratio by ∼8 fold in the n-3 PUFA deficient breast milk, with an overall increase of total n-6/n-3 PUFAs by ∼15:1 (p<0.05) compared to n-3 PUFA sufficient (LA to ALA: 2:1) diet. The n-3 PUFA deficient mice exhibited upregulation of FADS1, FADS2, ELOVL2, ELOVL5, ELOVL6, GPR40, GPR120, LEPR, IGF1 and downregulation of GLUT1, GLUT3, and GLUT4 mRNA expression in hippocampus (p<0.05). Maternal n-3 PUFA deficiency affects the hippocampal expression of key neurogenesis genes in the offspring with concomitant expression of desaturase and elongase genes, suggesting the importance of dietary n-3 PUFA for neurodevelopment. Show less

Interleukin 27 (IL-27) is a pleiotropic cytokine that is involved in the regulation of the body's innate and adaptive immunity. Previous studies have shown that IL-27 mediates a variety of inflammatory responses in vivo. With the development of animal models and technical tools, several studies have shown that it is also closely associated with autoimmune diseases and other immune related diseases, and is considered as an important candidate for the treatment of viral disease, autoimmune diseases, tumors and obesity. Therefore, this paper reviews recent progress on the role of IL-27 in acquired immunodeficiency syndrome (AIDS), rheumatoid arthritis, tumors and obesity, with the aim of providing new ideas for the treatment of immune related diseases. Show less

The fibroblast growth factor receptor (FGFR) family is highly expressed in a variety of tumor types and represents a new target for cancer therapy. Different FGFR subtype aberrations have been found to exhibit highly variable sensitivity and efficacy to FGFR inhibitors. The present study is the first to suggest an imaging method for assessing FGFR1 expression. The FGFR1-targeting peptide NOTA-PEG2-KAEWKSLGEEAWHSK was synthesized by manual solid-phase peptide synthesis and high-pressure liquid chromatography (HPLC) purification and then labeled with fluorine-18 using NOTA as a chelator. The radiochemical purity of [18F]F-FGFR1 was 98.66% ± 0.30% (n = 3) with excellent stability. The cellular uptake rate of [18F]F-FGFR1 in the RT-112 cell line (FGFR1 overexpression) was higher than that in the other cell lines and could be blocked by the presence of excess unlabeled FGFR1 peptide. Micro-PET/CT imaging revealed a significant concentration of [18F]F-FGFR1 in RT-112 xenografts with no or very low uptake in nontargeted organs and tissues, which demonstrated that [18F]F-FGFR1 was selectively taken up by FGFR1-positive tumors. [18F]F-FGFR1 showed high stability, affinity, specificity and good imaging capacity for FGFR1-overexpressing tumors Show less

The "NALCN channelosome" is an ion channel complex that consists of multiple proteins, including NALCN, UNC79, UNC80, and FAM155A. Only a small number of individuals with a neurodevelopmental syndrome have been reported with disease causing variants in NALCN and UNC80. However, no pathogenic UNC79 variants have been reported, and in vivo function of UNC79 in humans is largely unknown. We used international gene-matching efforts to identify patients harboring ultrarare heterozygous loss-of-function UNC79 variants and no other putative responsible genes. We used genetic manipulations in Drosophila and mice to test potential causal relationships between UNC79 variants and the pathology. We found 6 unrelated and affected patients with UNC79 variants. Five patients presented with overlapping neurodevelopmental features, including mild to moderate intellectual disability and a mild developmental delay, whereas a single patient reportedly had normal cognitive and motor development but was diagnosed with epilepsy and autistic features. All displayed behavioral issues and 4 patients had epilepsy. Drosophila with UNC79 knocked down displayed induced seizure-like phenotype. Mice with a heterozygous loss-of-function variant have a developmental delay in body weight compared with wild type. In addition, they have impaired ability in learning and memory. Our results demonstrate that heterozygous loss-of-function UNC79 variants are associated with neurologic pathologies. Show less

RA is an autoimmune disease characterized by destructive polyarthritis. CD4+ T cells are pivotal to its pathogenesis, and our previous study revealed the expression of fibroblast growth factor receptor 1 (FGFR1) is modulated by MTX treatment in CD4+ T cells of RA patients; however, the roles of FGFR1 in CD4+ T cells in the pathogenesis of RA is unclear. Therefore, in this study, we aimed to characterize FGFR1-positive CD4+ T cells in RA patients. The abundance of FGFR1-positive CD4+ T cells in peripheral blood and synovium was determined. Single-cell RNA sequencing (scRNA-seq) was performed on synovial CD4+ T cells to characterize FGFR1-positive cells. In addition, T cell activation status and cytokine production were determined using flow cytometry. The percentage of FGFR1-positive CD4+ T cells in the peripheral blood was higher in RA patients than in healthy controls (P =0.0035). They were also present in the synovium of active RA patients. The results of scRNA-seq revealed that peripheral Th (Tph) cells preferentially expressed FGFR1. Additionally, these FGFR1-positive Tph cells displayed a terminal effector cell phenotype. Consistent with this finding, FGFR1-positive CD4+ T cells in peripheral blood expressed IL-21 and IFN-γ. Our study provides evidence that FGFR1 marks terminal effector Tph cells in patients with RA. Show less

Dyslipidemias are known risk factors for chronic diseases. Precision nutrition interventions are designed according to characteristics, such as diet, phenotype, and genotype. This systematic review aims to define a panel of genetic variants associated with lipid abnormalities that could be later used in nutrigenetic intervention studies. A systematic review is conducted following the PRISMA-P. Studies published from January 2010 to December 2020 in English language and humans are included from PubMed and ScienceDirect databases. Articles that demonstrate a strong association between polymorphisms (single nucleotide variation) of genes involved in lipid metabolism and increased risk for dyslipidemia are included. A total of 3031 articles are screened, but only 51 articles fulfill the inclusion criteria. The genes included are FABP2, MTTP related to CM synthesis and secretion; LPL, LIPC involved in triglyceride hydrolysis; CETP, APOA1, LCAT, ABCA1, and APOA5 related to lipoprotein metabolism, and APOE, LDLR, SCARB1, APOC3 involved in lipid clearance. In this systematic review, genetic variants related to chylomicron synthesis, triglyceride hydrolysis, lipoprotein metabolism, and lipid clearance demonstrate a strong association with lipid abnormalities, which can be used to design precision nutrition interventions that may help to prevent and treat dyslipidemia effectively. Show less

Scutellarein hybrids were designed, synthesized and evaluated as multifunctional therapeutic agents for the treatment of Alzheimer's disease (AD). Compounds 11a-i, containing a 2-hydroxymethyl-3,5,6-trimethylpyrazine fragment at the 7-position of scutellarein, were found to have balanced and effective multi-target potencies against AD. Among them, compound 11e exhibited the most potent inhibition of electric eel and human acetylcholinesterase enzymes with IC Show less