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Peroxisome proliferator-activated receptors (PPARs) are essential for cellular physiological processes. However, there is less research on the PPAR-related genes in lung adenocarcinoma (LUAD). Open-access data were get from the cancer genome atlas (TCGA) and gene expression omnibus (GEO) databases. All the analysis were conducted in the R software based on different R packages. In this study, we gauged the PPAR score employing a set of 72 PPAR-associated genes and probed the biological impact of this score on lung adenocarcinoma (LUAD). Subsequently, we established a unique signature composed of eight PPAR-related genes (ANGPTL4, ACSL3, ADIPOQ, FABP1, SLC27A1, ACOX2, PPARD and OLR1) to forecast the prognosis of LUAD. The signature's effectiveness in predicting survival was validated through the receiver operating characteristic curve in the TCGA-LUAD cohort. As per the pathway enrichment analysis, several crucial oncogenic pathways and metabolic processes were enriched in high-risk individuals. Further, we observed that these high-risk patients exhibited heightened genomic instability. Additionally, compared to the low-risk cohort, high-risk patients demonstrated diminished immune components and function. Intriguingly, high-risk patients exhibited a potential heightened sensitivity to immunotherapy and certain drugs, including Gefitinib, Afatinib, Erlotinib, IAP₅₆₂₀, Sapitinib, LCL161, Lapatinib and AZD3759. The prognosis model based on eight PPAR-related genes has satisfactory prognosis prediction efficiency. Meanwhile, our results can provide direction for future studies in the relevant aspects. Show less

Coronary artery disease (CAD) is a complex disease that is influenced by environmental and genetic factors. In this study, we aimed to investigate the relationship between coding variants in lipid metabolism-related genes and CAD in a Chinese Han population. A total of 252 individuals were recruited for this study, including 120 CAD patients and 132 healthy control individuals. Rare and common coding variants in 12 lipid metabolism-related genes (ANGPTL3, ANGPTL4, APOA1, APOA5, APOC1, APOC3, CETP, LDLR, LIPC, LPL, PCSK9 and SCARB1) were detected via next-generation sequencing (NGS)-based targeted sequencing. Associations between common variants and CAD were evaluated by Fisher's exact test. A gene-based association test of rare variants was performed by the sequence kernel association test-optimal (SKAT-O test). We found 51 rare variants and 17 common variants in this study. One common missense variant, LIPC rs6083, was significantly associated with CAD after Bonferroni correction (OR = 0.47, 95% CI = 0.29-0.76, p = 1.9 × 10 Targeted sequencing is a powerful tool for identifying rare and common variants in CAD. The common missense variant LIPC rs6083 confers protection against CAD. The clinical relevance of rare variants in CAD aetiology needs to be investigated in larger sample sizes in the future. Show less

High fat diets overwhelm the physiological mechanisms for absorption, storage, and utilization of triglycerides (TG); consequently TG, TG-rich lipoproteins (TGRL), and TGRL remnants accumulate, circulate systemically, producing dyslipidemia. This associates with, or is causative for increased atherosclerotic cardiovascular risk, ischemic stroke, fatty liver disease, and pancreatitis. TGRL hydrolysis by endothelial surface-bound lipoprotein lipase (LPL) generates metabolites like free fatty acids which have proinflammatory properties. While osteoblasts utilize fatty acids as an energy source, dyslipidemia is associated with negative effects on the skeleton. In this study we investigated the effects of TGRL lipolysis products (TGRL-LP) on expression of a stress responsive transcription factor, termed activating transcription factor 3 (ATF3), reactive oxygen species (ROS), ATF3 target genes, and angiopoietin-like 4 (Angptl4) in osteoblasts. As ATF3 negatively associates with osteoblast differentiation, we also investigated the skeletal effects of global ATF3 deletion in mice. TGRL-LP increased expression of Atf3, proinflammatory proteins Ptgs2 and IL-6, and induced ROS in MC3T3-E1 osteoblastic cells. Angptl4 is an endogenous inhibitor of LPL which was transcriptionally induced by TGRL-LP, while recombinant Angptl4 prevented TG-driven Atf3 induction. Atf3 global knockout male mice demonstrated increased trabecular and cortical microarchitectural parameters. In summary, we find that TGRL-LP induce osteoblastic cell stress as evidenced by expression of ATF3, which may contribute to the negative impact of dyslipidemia in the skeleton. Further, concomitant induction of Angptl4 in osteoblasts might play a protective role by reducing local lipolysis. Show less

We conducted research on CDK4/6 inhibitors (CDK4/6i) simultaneously in the preclinical and clinical spaces to gain a deeper understanding of how senescence influences tumor growth in humans. We coordinated a first-in-kind phase II clinical trial of the CDK4/6i abemaciclib for patients with progressive dedifferentiated liposarcoma (DDLS) with cellular studies interrogating the molecular basis of geroconversion. Thirty patients with progressing DDLS enrolled and were treated with 200 mg of abemaciclib twice daily. The median progression-free survival was 33 weeks at the time of the data lock, with 23 of 30 progression-free at 12 weeks (76.7%, two-sided 95% CI, 57.7%-90.1%). No new safety signals were identified. Concurrent preclinical work in liposarcoma cell lines identified ANGPTL4 as a necessary late regulator of geroconversion, the pathway from reversible cell-cycle exit to a stably arrested inflammation-provoking senescent cell. Using this insight, we were able to identify patients in which abemaciclib induced tumor cell senescence. Senescence correlated with increased leukocyte infiltration, primarily CD4-positive cells, within a month of therapy. However, those individuals with both senescence and increased TILs were also more likely to acquire resistance later in therapy. These suggest that combining senolytics with abemaciclib in a subset of patients may improve the duration of response. Abemaciclib was well tolerated and showed promising activity in DDLS. The discovery of ANGPTL4 as a late regulator of geroconversion helped to define how CDK4/6i-induced cellular senescence modulates the immune tumor microenvironment and contributes to both positive and negative clinical outcomes. See related commentary by Weiss et al., p. 649. Show less

Renal cell carcinoma (RCC), a common and highly invasive malignant tumour, presents clinical challenges due to its propensity for easy metastasis. Inferior vena cava tumour thrombus is a common RCC complication significantly impacting patient prognosis. This study investigates C-X-C chemokine receptor type 2 ( Tissues from 51 RCC patients were analysed for Compared with that in the Short Hairpin RNA-Negative Control (ShNC) group, inhibition of Our findings suggest that Show less

Dyslipidemia stands as an autonomous peril in the realm of atherosclerotic cardiovascular maladies. Prompt identification and timely intervention in the case of dyslipidemia hold promise for substantially curbing the onset and fatality rates associated with coronary heart disease. Traditional lipid surveillance metrics employed in clinical settings, such as low-density lipoprotein cholesterol, exhibit notable limitations. Conversely, lipid-derived parameters emerge as formidable contenders, demonstrating a capacity to amalgamate and quantify disparate risk factors and multifactorial etiologies inherent in a given disease. By encompassing a broader spectrum of information than singular indices, these parameters offer a more profound insight into disease progression by virtue of their grounding in the physiological intricacies of lipid metabolism. Drawing upon extant domestic and international guidelines and research, this discourse delineates and synthesizes four lipid-derived parameters with promising clinical applications: atherogenic index of plasma, non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio, apolipoprotein B/A1 ratio, and lipoprotein combine index, and forwards a perspective grounded in current strides in clinical research. Show less

A 64-year-old man was diagnosed with diffuse large B-cell lymphoma (DLBCL). He achieved complete remission after R-CHOP therapy, but experienced relapse as lymphoplasmacytic lymphoma (LPL) 4 years after initial treatment. He was retreated with R-bendamustine therapy, resulting in a second remission. However, he once again experienced relapse as DLBCL 2 years later. Although lymph node lesions disappeared after salvage chemotherapy, facial and hypoglossal nerve paresis due to tumor infiltration appeared. His symptoms were attributed to cranial nerve invasion of transformed LPL, and treatment with tirabrutinib was started. Neurological symptoms markedly improved and high-dose chemotherapy followed by autologous stem cell transplantation was performed, resulting in long-term remission. Mutational analyses suggested that a B cell clone with MYD88 mutation caused the entire course of the disease, and our experience with this case indicates that Bruton's tyrosine kinase (BTK) inhibitor therapy might be effective for such cases. Show less

The heart relies heavily on external fatty acid (FA) for energy production. VEGFB (vascular endothelial growth factor B) has been shown to promote endothelial FA uptake by upregulating FA transporters. However, its impact on LPL (lipoprotein lipase)-mediated lipolysis of lipoproteins, a major source of FA for cardiac use, is unknown. VEGFB transgenic (Tg) rats were generated by using the α-myosin heavy chain promoter to drive cardiomyocyte-specific overexpression. To measure coronary LPL activity, Langendorff hearts were perfused with heparin. In vivo positron emission tomography imaging with [ In Tg hearts, the vectorial transfer of LPL to the vascular lumen is obstructed, resulting in LPL buildup within cardiomyocytes, an effect likely due to coronary vascular development with its associated augmentation of insulin action. With insulin insufficiency following fasting, VEGFB acted unimpeded to facilitate LPL movement and increase its activity at the coronary lumen. In vivo PET imaging following fasting confirmed that VEGFB induced a greater FA uptake to the heart from circulating lipoproteins as compared with plasma-free FAs. As this was associated with augmented mitochondrial oxidation, lipid accumulation in the heart was prevented. We further examined whether this property of VEGFB on cardiac metabolism could be useful following diabetes and its associated cardiac dysfunction, with attendant loss of metabolic flexibility. In Tg hearts, diabetes inhibited myocyte VEGFB gene expression and protein secretion together with its downstream receptor signaling, effects that could explain its lack of cardioprotection. Our study highlights the novel role of VEGFB in LPL-derived FA supply and utilization. In diabetes, loss of VEGFB action may contribute toward metabolic inflexibility, lipotoxicity, and development of diabetic cardiomyopathy. Show less

The purpose of this paper was to construct a prognostic model, miRNA-mRNA regulatory network and protein-protein interaction (PPI) network for lung squamous cell carcinoma (LUSC) used data from the cancer genome atlas (TCGA) database. In this study, we first downloaded and sorted out the expression matrix containing 19962 mRNA transcripts (including 502 LUSC and 51 normal control (NC) samples) and the expression matrix containing 2205 miRNA transcripts (including 478 LUSC and 45 NC samples) from the TCGA database. We obtained 389 differentially expressed miRNAs (DE-miRNAs), of which 305 were upregulated and 84 down-regulated DE-miRNAs. Next, a total of 7 prognosis-related DE-miRNAs (PDE-miRNAs) were identified by Cox regression analysis, and the prognosis model consisting of three PDE-miRNAs (hsa-miR-4746-5p, hsa-miR-556-3p and hsa-miR-489-3p) was optimized. Then, we drew the survival curves and found that the survival rates of the three PDE-miRNA high and low expression groups and the survival rates of the high-risk and low-risk patients in the prognosis model had significant statistical differences. In addition, the receiver operating characteristics (ROC) curve analysis and independent prognostic analysis confirmed that the prognostic model we built has a relatively accurate ability to predict the grouping and prognosis of LUSC patients. Finally, Cox regression analysis were used to construct the miRNA-mRNA regulatory network, which showed the regulatory relationship between PDE-miRNAs and targeted mRNAs. Moreover, we constructed the PPI network composed of 145 targeted mRNAs and the subnetwork composed of 10 hub-targeted mRNAs (FCGR3A, IL13, CCR2, PPARGC1A, FCGR3B, ACSL1, PLXNA4, LPL, KAT2B and AOC3), which showed the interaction between targeted mRNAs. The above results indicated that the prognosis model we built can predict LUSC patients relatively accurately. The miRNA-mRNA regulatory network and the PPI network of targeted mRNAs illustrated the regulatory mechanisms and interactions between RNAs, which were of certain reference significance for us to further understand the molecular pathogenesis of LUSC and for clinical early diagnosis and treatment. Show less

The practical applications for aqueous Zn ion batteries (ZIBs) are promising yet still impeded by the severe side reactions on Zn metal. Here, a lysozyme protective layer (LPL) is prepared on Zn metal surface by a simple and facile self-adsorption strategy. The LPL exhibits extremely strong adhesion on Zn metal to provide stable interface during long-term cycling. In addition, the self-adsorption strategy triggered by the hydrophobicity-induced aggregation effect endows the protective layer with a gap-free and compacted morphology which can reject free water for effective side reaction inhibition performance. More importantly, the lysozyme conformation is transformed from α-helix to β-sheet structure before layer formation, thus abundant functional groups are exposed to interact with Zn Show less

The conformational state of DNA fine-tunes the transcriptional rate and abundance of RNA. Here, we report that G-quadruplex DNA (G4-DNA) accumulates in neurons, in an experience-dependent manner, and that this is required for the transient silencing and activation of genes that are critically involved in learning and memory in male C57/BL6 mice. In addition, site-specific resolution of G4-DNA by dCas9-mediated deposition of the helicase DHX36 impairs fear extinction memory. Dynamic DNA structure states therefore represent a key molecular mechanism underlying memory consolidation. Show less

Atherosclerosis (AS) is a leading cause of cardiovascular morbidity and mortality. Atherosclerotic lesions show increased levels of proteins associated with the fibroblast growth factor receptor (FGFR) pathway. However, the functional significance and mechanisms governed by FGFR signalling in AS are not known. In the present study, we investigated fibroblast growth factor receptor 1 (FGFR1) signalling in AS development and progression. Examination of human atherosclerotic lesions and aortas of Apoe-/- mice fed a high-fat diet (HFD) showed increased levels of FGFR1 in macrophages. We deleted myeloid-expressed Fgfr1 in Apoe-/- mice and showed that Fgfr1 deficiency reduces atherosclerotic lesions and lipid accumulations in both male and female mice upon HFD feeding. These protective effects of myeloid Fgfr1 deficiency were also observed when mice with intact FGFR1 were treated with FGFR inhibitor AZD4547. To understand the mechanistic basis of this protection, we harvested macrophages from mice and show that FGFR1 is required for macrophage inflammatory responses and uptake of oxidized LDL. RNA sequencing showed that FGFR1 activity is mediated through phospholipase-C-gamma (PLCγ) and the activation of nuclear factor-κB (NF-κB) but is independent of FGFR substrate 2. Our study provides evidence of a new FGFR1-PLCγ-NF-κB axis in macrophages in inflammatory AS, supporting FGFR1 as a potentially therapeutic target for AS-related diseases. Show less

Fibroblast growth factor receptor 4 (FGFR4) is thought to be a driver in several cancer types, most notably in hepatocellular carcinoma. One way to achieve high potency and isoform selectivity for FGFR4 is covalently targeting a rare cysteine (C552) in the hinge region of its kinase domain that is not present in other FGFR family members (FGFR1-3). Typically, this cysteine is addressed via classical acrylamide electrophiles. We demonstrate that noncanonical covalent "warheads" based on nucleophilic aromatic substitution (S Show less

Fibroblast growth factor receptor 2 (FGFR2) fusions and rearrangements are clinically actionable genomic alterations in cholangiocarcinoma (CCA). Pemigatinib is a selective, potent, oral inhibitor of FGFR1-3 and demonstrated efficacy in patients with previously treated, advanced/metastatic CCA with FGFR2 alterations in FIGHT-202 (NCT02924376). We report final outcomes from the extended follow-up period. The multicenter, open-label, single-arm, phase II FIGHT-202 study enrolled patients ≥18 years old with previously treated advanced/metastatic CCA with FGFR2 fusions or rearrangements (cohort A), other FGF/FGFR alterations (cohort B), or no FGF/FGFR alterations (cohort C). Patients received once-daily oral pemigatinib 13.5 mg in 21-day cycles (2 weeks on, 1 week off) until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) in cohort A assessed as per RECIST v1.1 by an independent review committee; secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. FIGHT-202 enrolled 147 patients (cohort A, 108; cohort B, 20; cohort C, 17; unconfirmed FGF/FGFR alterations, 2). By final analysis, 145 (98.6%) had discontinued treatment due to progressive disease (71.4%), withdrawal by patient (8.2%), or adverse events (AEs; 6.8%). Median follow-up was 45.4 months. The ORR in cohort A was 37.0% (95% confidence interval 27.9% to 46.9%); complete and partial responses were observed in 3 and 37 patients, respectively. Median DOR was 9.1 (6.0-14.5) months; median PFS and OS were 7.0 (6.1-10.5) months and 17.5 (14.4-22.9) months, respectively. The most common treatment-emergent AEs (TEAEs) were hyperphosphatemia (58.5%), alopecia (49.7%), and diarrhea (47.6%). Overall, 15 (10.2%) patients experienced TEAEs leading to pemigatinib discontinuation; intestinal obstruction and acute kidney injury (n = 2 each) occurred most frequently. Pemigatinib demonstrated durable response and prolonged OS with manageable AEs in patients with previously treated, advanced/metastatic CCA with FGFR2 alterations in the extended follow-up period of FIGHT-202. Show less

This review endeavours to explore the aetiopathogenesis and impact of severe hypertriglyceridemia (SHTG) and chylomicronaemia on cardiovascular, and pancreatic complications and summarizes the novel pharmacological options for management. SHTG, although rare, presents significant diagnostic and therapeutic challenges. Familial chylomicronaemia syndrome (FCS), is the rare monogenic form of SHTG, associated with increased acute pancreatitis (AP) risk, whereas relatively common multifactorial chylomicronaemia syndrome (MCS) leans more towards cardiovascular complications. Despite the introduction and validation of the FCS Score, FCS continues to be underdiagnosed and diagnosis is often delayed. Longitudinal data on disease progression remains scant. SHTG-induced AP remains a life-threatening concern, with conservative treatment as the cornerstone while blood purification techniques offer limited additional benefit. Conventional lipid-lowering medications exhibit minimal efficacy, underscoring the growing interest in novel therapeutic avenues, that is, antisense oligonucleotides (ASO) and short interfering RNA (siRNA) targeting apolipoprotein C3 (ApoC3) and angiopoietin-like protein 3 and/or 8 (ANGPTL3/8). Despite advancements in understanding the genetic basis and pathogenesis of SHTG, diagnostic and therapeutic challenges persist. The rarity of FCS and the heterogenous phenotype of MCS underscore the need for the development of predictive models for complications and tailored personalized treatment strategies. The establishment of national and international registries is advocated to augment disease comprehension and identify high-risk individuals. Show less

The study evaluated the association of Case-control study. Brazilian Oral Cleft Group. The study included 881 healthy controls and 800 patients with different types of NSOC: 232 with cleft lip only (NSCLO), 568 with cleft lip and palate (NSCLP), and 274 with cleft palate only (NSCPO). The genomic DNA was genotyped with allelic discrimination assays for five Although only nominal Our results demonstrate an increased risk of NSCL  ±  P in Brazilian individuals with enrichment of African ancestry in the presence of the Show less

Intervertebral disc degeneration (IVDD) is the leading cause of lower back pain (LBP). β-arrestin 1 (ARRB1) is a multifunctional protein that regulates numerous pathological processes. The aim of this study was to investigate the role of ARRB1 in IVDD. The expression of ARRB1 in nucleus pulposus (NP) of rats with IVDD was assayed. Next, rat nucleus pulposus cells (NPCs) were infected with lentiviruses containing shArrb1 (LV-shArrb1) and overexpressing Arrb1 (LV-oeArrb1). The roles of Arrb1 in serum-deprived NPCs were investigated by measuring apoptosis, extracellular matrix degradation, and autophagic flux. For experiments in vivo, LV-oeArrb1 lentivirus was injected into the NP tissues of IVDD rats to evaluate the effects of Arrb1 overexpression on NP. In the NP tissues of IVDD rats, ARRB1 and cleaved caspase-3 expression increased, and the ratio of LC3II/LC3I protein expression was upregulated. Arrb1 knockdown aggravated extracellular matrix degradation, cellular apoptosis, and impairment of autophagic flux in rat NPCs under serum-deprived conditions, whereas Arrb1 overexpression significantly reversed these effects. ARRB1 interacted with Beclin 1, and Arrb1 knockdown suppressed the formation of the Beclin1-PIK3C3 core complex. The autophagy inhibitor 3-methyladenine (3-MA) offset the protective effects of Arrb1 overexpression in serum-deprived NPCs. Furthermore, Arrb1 overexpression inhibited apoptosis and extracellular matrix degradation, promoted autophagy in NP, and delayed the development of IVDD in rats. ARRB1 prevents extracellular matrix degradation and apoptosis of NPCs by upregulating autophagy and ameliorating IVDD progression, presenting an innovative strategy for the treatment of IVDD. Show less

COVID-19 is a highly infectious respiratory disease whose progression has been associated with multiple factors. From SARS-CoV-2 infection to death, biomarkers capable of predicting different disease processes are needed to help us further understand the molecular progression of COVID-19 disease. The aim is to find differentially expressed proteins that are associated with the progression of COVID-19 disease or can be potential biomarkers, and to provide a reference for further understanding of the molecular mechanisms of COVID-19 occurrence, progression, and treatment. Data-independent Acquisition (DIA) proteomics to obtain sample protein expression data, using R language screening differentially expressed proteins. Gene Ontology and Kyoto Encyclopedia for Genes and Genomes analysis was performed on differential proteins and protein-protein interaction (PPI) network was constructed to screen key proteins. A total of 47 differentially expressed proteins were obtained from COVID-19 incubation patients and healthy population (L/H), mainly enriched in platelet-related functions, and complement and coagulation cascade reaction pathways, such as platelet degranulation and platelet aggregation. A total of 42 differential proteins were obtained in clinical and latent phase patients (C/L), also mainly enriched in platelet-related functions and in complement and coagulation cascade reactions, platelet activation pathways. A total of 10 differential proteins were screened in recovery and clinical phase patients (R/C), mostly immune-related proteins. The differentially expressed proteins in different stages of COVID-19 are mostly closely associated with coagulation, and key differential proteins, such as FGA, FGB, FGG, ACTB, PFN1, VCL, SERPZNCL, APOC3, LTF, and DEFA1, have the potential to be used as early diagnostic markers. Show less

A novel electrochemiluminescence (ECL) and electrochemical dual-mode sensor was developed for detecting the activity of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and screening its inhibitor. Specifically, the adamantane (ADA)-functionalized peptide (P1), a designed substrate peptide for BACE1, was immobilized on the electrode surface via host-guest interaction between β-cyclodextrin (β-CD) and ADA. The aggregation of the peptide (P2) and luminol co-functionalized silver nanoparticles could be induced by cucurbit [8]uril (CB[8] due to the ability of CB[8] to accommodate two aromatic residues simultaneously. The obtained (CB[8]-P2-AgNPs-luminol) Show less

On-chip polarization-sensitive photodetectors are highly desired for ultra-compact optoelectronic systems. It has been demonstrated that polarization-sensitive photodetection can be realized using intrinsic chiral and anisotropy materials. However, these photodetectors can only realize the detection of either circularly polarized light (CPL) or linear polarized light (LPL) and are not applicable to multiple-polarization-sensitive photodetection. Herein, we experimentally demonstrate a metasurface-integrated semiconductor to realize multiple-polarization-sensitive photodetection at visible wavelengths. This device is composed of a MoSe Show less

Pediatric hepatoblastoma (HBL) and hepatocellular carcinoma (HCC) are primary liver malignant neoplasms with 5-year event-free survival of >80% and <30%, respectively. In these patients, α-fetoprotein levels can guide surgical intervention and monitor disease progression. Although histology and immunohistochemical stains support diagnosis, genetic testing can elucidate mechanisms that drive pathogenesis. Pediatric HBL and HCC harbor well-characterized molecular signatures such as alterations in CTNNB1, TERT, and AXIN1 that alter the Wnt/β-catenin pathway. Approximately 8% of individuals with HCC harbor RPS6KA3 variants that appear with other gene mutations. Herein, we report a novel solitary pathogenic RPS6KA3 variant finding in a 6-year-old boy whose final diagnosis was hepatocellular malignant neoplasm, not otherwise specified. Show less

Psoriasis is an inflammatory skin disease, there is no radical cure. Traditional Chinese medicine has accumulated a lot of clinical experience in the treatment of psoriasis and developed a variety of treatment methods, among which Yinxieling optimization formula (PSORI-CM01) have a definite clinical effect in the treatment of psoriasis, but their mechanism of action is still unclear. To investigate the molecular mechanism of the PSORI-CM01 in the treatment of psoriasis. Firstly, potential active compounds and key signaling pathways of PSORI-CM01 were explored by the systems pharmacology method. Then MTT assay was used to screen the potentially active compounds of PSORI-CM01, and explore the combined effects of potentially active compounds. The regulation of potentially active compounds on inflammatory factors were evaluated by a Human Th17 Magnetic Bead Panel. The regulation of PSORI-CM01 on key targets in the key signaling pathways were explored by qRT-PCR method. Finally, the molecular mechanism of PSORI-CM01 in the treatment of psoriasis was explained by the systems pharmacology method. The potentially active compounds of PSORI-CM01 included gallic acid, liquiritigenin, rosmarinic acid, syringic acid, isoliquiritin apioside, caffeic acid, naringenin, cryptochlorogenic acid, (+)-taxifolin, p-coumaric acid, chlorogenic acid, fraxin, 5-hydroxymethylfurfural, lithospermic acid, isoliquiritigenin, salviandic acid B, octahydrocurcumin, catechin, syringaldehyde, methyl rosmarinate, paeonol, protocatechuic acid, astilbin, isoastilbin, isofraxidin and zederone. Both antagonistic and synergistic effects were determined in the combinations of active compounds. Most of the active compounds up-regulated IL-2, IL-6, IL-9 and TNF-α, and down-regulated IFN-γ, IL-1β, IL-2, IL-9, IL-10, IL-13, IL-15, IL-17F, IL-21, IL-22 and IL-27. The PI3K-Akt signaling pathway would be the key signaling pathway of PSORI-CM01. The qRT-PCR results showed that its compounds can effectively regulate the expression of key targets in this pathway. The molecular mechanism of PSORI-CM01 for treating psoriasis would be mediated by regulating the network of inflammatory factors through the PI3K-Akt signaling pathway. Show less

Lipid remodeling is crucial for cold tolerance in plants. However, the precise alternations of lipidomics during cold responses remain elusive, especially in maize (Zea mays L.). In addition, the key genes responsible for cold tolerance in maize lipid metabolism have not been identified. Here, we integrate lipidomic, transcriptomic, and genetic analysis to determine the profile of lipid remodeling caused by cold stress. We find that the homeostasis of cellular lipid metabolism is essential for maintaining cold tolerance of maize. Also, we detect 210 lipid species belonging to 13 major classes, covering phospholipids, glycerides, glycolipids, and free fatty acids. Various lipid metabolites undergo specific and selective alterations in response to cold stress, especially mono-/di-unsaturated lysophosphatidic acid, lysophosphatidylcholine, phosphatidylcholine, and phosphatidylinositol, as well as polyunsaturated phosphatidic acid, monogalactosyldiacylglycerol, diacylglycerol, and triacylglycerol. In addition, we identify a subset of key enzymes, including ketoacyl-acyl-carrier protein synthase II (KAS II), acyl-carrier protein 2 (ACP2), male sterility33 (Ms33), and stearoyl-acyl-carrier protein desaturase 2 (SAD2) involved in glycerolipid biosynthetic pathways are positive regulators of maize cold tolerance. These results reveal a comprehensive lipidomic profile during the cold response of maize and provide genetic resources for enhancing cold tolerance in crops. Show less

This study aimed to address the challenges of treating advanced stages of colon cancer (CRC) by exploring potential therapeutic options. The research focused on the genetic aspects of CRC, specifically the mutation rate of the KRAS gene, along with other genes like TTN, APC, MUC16, and TP53, using the TCGA dataset. Additionally, the study investigated the efficacy of Oleuropein, a polyphenolic compound found in olives, in combating CRC by using iron oxide nanoparticles coated with glucose and conjugated with Oleuropein. The study characterized the physicochemical properties of the nanoparticles, and the cytotoxic effects of the nanoparticles were evaluated on CRC and normal fibroblast cell lines, demonstrating significantly higher cytotoxicity against CRC cells compared to normal cells. Furthermore, the study analyzed gene expression changes using the GSE124627 dataset to understand the influence of KRAS alterations. It identified numerous upregulated and downregulated genes in KRAS-overexpressing samples, suggesting their involvement in critical cancer-related pathways. These findings suggest that KRAS-influenced genes could serve as potential therapeutic targets for CRC treatment. The study also examined the expression levels of identified genes in CRC samples compared to normal samples. Among the upregulated genes, 22 showed significant increases in cancer samples, while 14 downregulated genes exhibited decreased expression in both KRAS-influenced and cancer samples. Cox regression analysis identified specific upregulated genes, including ANKZF1, SNAI1, PPFIA4, SIX4, and NOTUM, associated with poor prognosis. Kaplan-Meier analysis further confirmed the correlation between increased expression of these genes and higher patient mortality rates. In conclusion, this study provided valuable insights into the genetic aspects of CRC and potential therapeutic strategies. The use of Oleuropein-conjugated iron oxide nanoparticles showed promising cytotoxic effects on colon cancer cells. These findings contribute to advancing our understanding of CRC and offer potential targets for further investigation and the development of novel therapeutic approaches. Show less

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of invasive non-Hodgkin lymphoma. 60-70% of patients are curable with current chemoimmunotherapy, whereas the rest are refractory or relapsed. Understanding of the interaction between DLBCL cells and tumor microenvironment raises the hope of improving overall survival of DLBCL patients. P2X7, a member of purinergic receptors P2X family, is activated by extracellular ATP and subsequently promotes the progression of various malignancies. However, its role in DLBCL has not been elucidated. In this study, the expression level of P2RX7 in DLBCL patients and cell lines was analyzed. MTS assay and EdU incorporation assay were carried out to study the effect of activated/inhibited P2X7 signaling on the proliferation of DLBCL cells. Bulk RNAseq was performed to explore potential mechanism. The results demonstrated high level expression of P2RX7 in DLBCL patients, typically in patients with relapse DLBCL. 2'(3')-O-(4-benzoylbenzoyl) adenosine 5-triphosphate (Bz-ATP), an agonist of P2X7, significantly accelerated the proliferation of DLBCL cells, whereas delayed proliferation was detected when administrated with antagonist A740003. Furthermore, a urea cycle enzyme named CPS1 (carbamoyl phosphate synthase 1), which up-regulated in P2X7-activated DLBCL cells while down-regulated in P2X7-inhibited group, was demonstrated to involve in such process. Our study reveals the role of P2X7 in the proliferation of DLBCL cells and implies that P2X7 may serve as a potential molecular target for the treatment of DLBCL. Show less

Reducing the levels of dietary protein is an effective nutritional approach in lowering feed cost and nitrogen emissions in ruminants. The purpose of this study was to evaluate the effects of dietary Lys/Met ratio in a low protein diet (10%, dry matter basis) on the growth performance and hepatic function (antioxidant capacity, immune status, and glycolytic activity) in Tibetan lambs. Ninety two-month-old rams with an average weight of 15.37 ± 0.92 kg were randomly assigned to LP-L (dietary Lys/Met = 1:1), LP-M (dietary Lys/Met = 2:1) and LP-H (dietary Lys/Met = 3:1) treatments. The trial was conducted over 100 d, including 10 d of adaption to the diets. Hepatic phenotypes, antioxidant capacity, immune status, glycolytic activity and gene expression profiling was detected after the conclusion of the feeding trials. The results showed that the body weight was higher in the LP-L group when compared to those on the LP-M group (P < 0.05). In addition, the activities of the catalase (CAT) and glutathione peroxidase (GSH-Px) in the LP-L group were significantly increased compared with the LP-M group (P < 0.05), while the malondialdehyde (MDA) levels in LP-H group were significantly decreased (P < 0.05). Compared with LP-H group, both hepatic glycogen (P < 0.01) and lactate dehydrogenase (LDH) (P < 0.05) were significantly elevated in LP-L group. For the LP-L group, the hepatocytes were arranged radially with the central vein in the center, and hepatic plates exhibited tight arrangement. Transcriptome analysis identified 29, 179, and 129 differentially expressed genes (DEGs) between the LP-M vs. LP-L, LP-H vs. LP-M, and LP-H vs. LP-L groups, respectively (Q-values < 0.05 and |log2Fold Change| > 1). Gene Ontology (GO) and correlation analyses showed that in the LP-L group, core genes (C1QA and JUNB) enriched in oxidoreductase activity were positively correlated with antioxidant indicators, while the MYO9A core gene enriched in the immune response was positively associated with immune indicators, and core genes enriched in molecular function (PDK3 and PDP2) were positively correlated with glycolysis indicators. In summary, low-protein diet with a low Lys/Met ratio (1:1) could reduce the hepatic oxidative stress and improve the glycolytic activity by regulating the expression of related genes of Tibetan sheep. Show less

Despite enormous research efforts, a sufficiently sensitive and reliable biomarker for the assessment of zinc (Zn) status has not been identified to date. Zn affects fatty acid metabolism and alters the activity of certain desaturases; thus, desaturase activity has been proposed as a potential new biomarker of Zn status. This systematic review complied and assessed studies that examined changes in fatty acid desaturase 1 (FADS1) and fatty acid desaturase 2 (FADS2) activities in relation to modifications in dietary Zn intake. A systematic search was performed in PubMed, Web of Science, Scopus, Web of Knowledge, and Central with strictly defined search, inclusion, and exclusion criteria. Twenty-one studies were included, 8 animal and 13 human trials (5 randomized controlled trials, two non-randomized controlled trials, and 6 cross-sectional studies). This systematic review was performed using PRISMA guidelines and where feasible a random-effects meta-analysis was conducted. No significant correlation was seen between the delta 6 desaturase and Zn status (-0.0958, 95% CIs (-0.2912; 0.1074), p = 0.2928). Delta 6 desaturase seems to respond in a greater magnitude than Zn status to Zn-containing interventions (the standardized mean difference for delta 6 desaturase was -0.6052, 95% CIs (-2.7162; 1.5058), p = 0.4289, while for plasma/serum Zn it was 0.0319, 95% CIs (-0.9133; 0.9770), p = 0.9213). Finally, two separate meta-analyses on same studies that assessed the correlations between LA:DGLA and Zn intake and Zn status and Zn intake revealed that the magnitude of correlations was only slightly different (the pooled correlation coefficient between the LA:DGLA ratio and Zn intake had a value of -0.1050, 95% CIs (-0.5356; 0.3690), p = 0.454, while between plasma Zn and Zn intake had a value of -0.0647, 95% CIs (-0.4224; 0.3106), p = 0.5453). According to the descriptive analysis, the magnitude of variation in desaturase activities in response to Zn intake was not consistent among studies, FADS1 and FADS2 activity corresponded to dietary Zn manipulations, both in animals and humans. A plausible explanation for this observation might be the difference between the studies in study populations, types of dietary interventions, study durations, etc. In addition, several potential confounders and covariates are identified from the qualitative synthesis, such as gender, age, the type of fat provided within the dietary intervention, the size of Zn particles, among others. Further high-quality studies are needed to additionally clarify the suggested associations and applicability of utilizing fatty acid desaturase activities as Zn status biomarkers. Show less

Recent studies have shown that in Arabian horse muscle, long-term exercise-induced expression of genes related to fatty acid degradation and the downregulation of genes belonging to the glycolysis/gluconeogenesis and insulin signalling pathways. Long-lasting physical exertion may trigger the metabolism to switch the main energy source from carbohydrates to lipids due to higher caloric content. To describe the metabolism adaptation at the whole transcriptome of blood to endurance effort in Arabian horses. In vivo experiment. Venous blood samples from 10 Arabian horses were taken before and after a 120 km long endurance ride to isolate the RNA and perform the high-throughput NGS transcriptome sequencing. The results, including KEGG (Kyoto Encyclopaedia of Genes and Genomes) and GO (Gene Ontology) analyses, allowed us to describe the most significantly upregulated-ARV1, DGAT2, LIPE, APOA2, MOGAT1, MOGAT2, GYS1, GYS2 and downregulated-ACACA, ACACB, FADS1, FADS2 genes involved in carbohydrate and lipid metabolism. Also, the increased expression of RAF1, KRAS and NRAS genes involved in the Insulin pathway and PI3K-Akt was shown. Limited sample size, Arabians used for endurance racing were not compared to Arabians from other equestrian disciplines. This general insight into the processes described supports the thesis of the lipid-carbohydrates metabolism switch in endurance Arabian horses and provides the basis for further research. Show less