A Genome-Wide Analysis of the CEP Gene Family in Cotton and a Functional Study of GhCEP46-D05 in Plant Development.

C-TERMINALLY ENCODED PEPTIDEs (CEPs) are a class of peptide hormones that have been shown in previous studies to play an important role in regulating the development and response to abiotic stress in model plants. However, their role in cotton is not well understood. In this study, we identified 54, 59, 34, and 35 CEP genes from Gossypium hirsutum (2n = 4x = 52, AD1), G. barbadense (AD2), G. arboreum (2n = 2X = 26, A2), and G. raimondii (2n = 2X = 26, D5), respectively. Sequence alignment and phylogenetic analyses indicate that cotton CEP proteins can be categorized into two subgroups based on the differentiation of their CEP domain. Chromosomal distribution and collinearity analyses show that most of the cotton CEP genes are situated in gene clusters, suggesting that segmental duplication may be a critical factor in CEP gene expansion. Expression pattern analyses showed that cotton CEP genes are widely expressed throughout the plant, with some genes exhibiting specific expression patterns. Ectopic expression of GhCEP46-D05 in Arabidopsis led to a significant reduction in both root length and seed size, resulting in a dwarf phenotype. Similarly, overexpression of GhCEP46-D05 in cotton resulted in reduced internode length and plant height. These findings provide a foundation for further investigation into the function of cotton CEP genes and their potential role in cotton breeding.

CEPs suppress auxin signaling but promote cytokinin signaling to inhibit root growth in Arabidopsis.

C-terminally encoded peptides (CEPs) are peptide hormones that function as mobile signals coordinating crucial developmental programs in plants. Previous studies have revealed that CEPs exert negative regulation on root development through interaction with CEP receptors (CEPRs), CEP DOWNSTREAMs (CEPDs), the cytokinin receptor ARABIDOPSIS HISTIDINE KINASE (AHKs) and the transcriptional repressor Auxin/Indole-3-Acetic Acid (AUX/IAA). However, the precise molecular mechanisms underlying CEPs-mediated regulation of root development via auxin and cytokinin signaling pathways still necessitate further detailed investigation. In this study, we examined prior research and elucidated the underlying molecular mechanisms. The results showed that both synthetic AtCEPs and overexpression of AtCEP5 markedly supressed primary root elongation and lateral root (LR) formation in Arabidopsis. Molecular biology and genetics elucidated how CEPs inhibit root growth by suppressing auxin signaling while promoting cytokinin signaling. In summary, this study elucidated the inhibitory effects of AtCEPs on Arabidopsis root growth and provided insights into their potential molecular mechanisms, thus enhancing our comprehension of CEP-mediated regulation of plant growth and development.

The minor allele of ANGPTL8 rs2278426 has a protective effect against CAD in T2DM patients.

BACKGROUND: Coronary artery disease (CAD) is the leading cause of death worldwide despite advanced treatment and diagnosis strategies. Angiopoietin-like protein 8 (ANGPTL8) mainly functions in the lipid mechanism, which is a dysregulated mechanism during CAD pathogenesis. In this study, we aimed to determine the associations between an ANGPTL8 polymorphism rs2278426 and the severity, presence, and risk factors of CAD. METHODS: A total of 1367 unrelated Turkish individuals who underwent coronary angiography were recruited for the study and grouped as CAD (n = 736, ≥50 stenosis) and non-CAD (n = 549, ≤30 stenosis). Also, subjects were further divided into groups regarding type 2 diabetes mellitus (T2DM) status. Subjects were genotyped for rs2278426 (C/T) by quantitative real-time PCR. Secondary structure analyses of protein interactions were revealed using I-TASSER and PyMOL. RESULTS: Among CAD patients, T allele carriage frequency was lower in the T2DM group (p = 0.046). Moreover, in male non-CAD group, T allele carriage was more prevalent among T2DM patients than non-T2DM (p = 0.033). In logistic regression analysis adjusted for obesity, T allele carrier males had an increased risk for T2DM in non-CAD group (OR = 2.244, 95 % CI: 1.057-4.761, p = 0.035). Also, in T2DM group, stenosis (p = 0.002) and SYNTAX score (p = 0.040) were lower in T allele carrier males than in non-carriers. Analyzes of secondary structure showed that ANGPTL8 could not directly form complexes with ANGPTL3 or ANGPTL4. CONCLUSION: In conclusion, T allele carriage of ANGPTL8 rs2278426 has a protective effect on CAD in T2DM patients. Further research should be conducted to explore the association between ANGPTL8 polymorphism (rs2778426) and CAD.

Estrogen Signaling Inhibits the Expression of anti-Müllerian hormone (amh) and gonadal-soma-derived factor (gsdf) during the Critical Time of Sexual Fate Determination in Zebrafish.

The mechanism of fish gonadal sex differentiation is complex and regulated by multiple factors. It has been widely known that proper steroidogenesis in Leydig cells and sex-related genes in Sertoli cells play important roles in gonadal sex differentiation. In teleosts, the precise interaction of these signals during the sexual fate determination remains elusive, especially their effect on the bi-potential gonad during the critical stage of sexual fate determination. Recently, all-testis phenotypes have been observed in the cyp17a1-deficient zebrafish and common carp, as well as in cyp19a1a-deficient zebrafish. By mating cyp17a1-deficient fish with transgenic zebrafish Tg(piwil1:EGFP-nanos3UTR), germ cells in the gonads were labelled with enhanced green fluorescent protein (EGFP). We classified the cyp17a1-deficient zebrafish and their control siblings into primordial germ cell (PGC)-rich and -less groups according to the fluorescence area of the EGFP labelling. Intriguingly, the EGFP-labelled bi-potential gonads in cyp17a1+/+ fish from the PGC-rich group were significantly larger than those of the cyp17a1-/- fish at 23 days post-fertilization (dpf). Based on the transcriptome analysis, we observed that the cyp17a1-deficient fish of the PGC-rich group displayed a significantly upregulated expression of amh and gsdf compared to that of control fish. Likewise, the upregulated expressions of amh and gsdf were observed in cyp19a1a-deficient fish as examined at 23 dpf. This upregulation of amh and gsdf could be repressed by treatment with an exogenous supplement of estradiol. Moreover, tamoxifen, an effective antagonist of both estrogen receptor α and ß (ERα and Erß), upregulates the expression of amh and gsdf in wild-type (WT) fish. Using the cyp17a1- and cyp19a1a-deficient zebrafish, we provide evidence to show that the upregulated expression of amh and gsdf due to the compromised estrogen signaling probably determines their sexual fate towards testis differentiation. Collectively, our data suggest that estrogen signaling inhibits the expression of amh and gsdf during the critical time of sexual fate determination, which may broaden the scope of sex steroid hormones in regulating gonadal sex differentiation in fish.

Characterization of erythroferrone oligomerization and its impact on BMP antagonism.

Hepcidin, a peptide hormone that negatively regulates iron metabolism, is expressed by bone morphogenetic protein (BMP) signaling. Erythroferrone (ERFE) is an extracellular protein that binds and inhibits BMP ligands, thus positively regulating iron import by indirectly suppressing hepcidin. This allows for rapid erythrocyte regeneration after blood loss. ERFE belongs to the C1Q/TNF-related protein family and is suggested to adopt multiple oligomeric forms: a trimer, a hexamer, and a high molecular weight species. The molecular basis for how ERFE binds BMP ligands and how the different oligomeric states impact BMP inhibition are poorly understood. In this study, we demonstrated that ERFE activity is dependent on the presence of stable dimeric or trimeric ERFE and that larger species are dispensable for BMP inhibition. Additionally, we used an in silico approach to identify a helix, termed the ligand-binding domain, that was predicted to bind BMPs and occlude the type I receptor pocket. We provide evidence that the ligand-binding domain is crucial for activity through luciferase assays and surface plasmon resonance analysis. Our findings provide new insight into how ERFE oligomerization impacts BMP inhibition, while identifying critical molecular features of ERFE essential for binding BMP ligands.

The Proinflammatory Role of ANGPTL8 R59W Variant in Modulating Inflammation through NF-κB Signaling Pathway under TNFα Stimulation.

BACKGROUND: Angiopoietin-like protein 8 (ANGPTL8) is known to regulate lipid metabolism and inflammation. It interacts with ANGPTL3 and ANGPTL4 to regulate lipoprotein lipase (LPL) activity and with IKK to modulate NF-κB activity. Further, a single nucleotide polymorphism (SNP) leading to the ANGPTL8 R59W variant associates with reduced low-density lipoprotein/high-density lipoprotein (LDL/HDL) and increased fasting blood glucose (FBG) in Hispanic and Arab individuals, respectively. In this study, we investigate the impact of the R59W variant on the inflammatory activity of ANGPTL8. METHODS: The ANGPTL8 R59W variant was genotyped in a discovery cohort of 867 Arab individuals from Kuwait. Plasma levels of ANGPTL8 and inflammatory markers were measured and tested for associations with the genotype; the associations were tested for replication in an independent cohort of 278 Arab individuals. Impact of the ANGPTL8 R59W variant on NF-κB activity was examined using approaches including overexpression, luciferase assay, and structural modeling of binding dynamics. RESULTS: The ANGPTL8 R59W variant was associated with increased circulatory levels of tumor necrosis factor alpha (TNFα) and interleukin 7 (IL7). Our in vitro studies using HepG2 cells revealed an increased phosphorylation of key inflammatory proteins of the NF-κB pathway in individuals with the R59W variant as compared to those with the wild type, and TNFα stimulation further elevated it. This finding was substantiated by increased luciferase activity of NF-κB p65 with the R59W variant. Modeled structural and binding variation due to R59W change in ANGPTL8 agreed with the observed increase in NF-κB activity. CONCLUSION: ANGPTL8 R59W is associated with increased circulatory TNFα, IL7, and NF-κB p65 activity. Weak transient binding of the ANGPTL8 R59W variant explains its regulatory role on the NF-κB pathway and inflammation.

Characterization of erythroferrone structural domains relevant to its iron-regulatory function.

Iron delivery to the plasma is closely coupled to erythropoiesis, the production of red blood cells, as this process consumes most of the circulating plasma iron. In response to hemorrhage and other erythropoietic stresses, increased erythropoietin stimulates the production of the hormone erythroferrone (ERFE) by erythrocyte precursors (erythroblasts) developing in erythropoietic tissues. ERFE acts on the liver to inhibit bone morphogenetic protein (BMP) signaling and thereby decrease hepcidin production. Decreased circulating hepcidin concentrations then allow the release of iron from stores and increase iron absorption from the diet. Guided by evolutionary analysis and Alphafold2 protein complex modeling, we used targeted ERFE mutations, deletions, and synthetic ERFE segments together with cell-based bioassays and surface plasmon resonance to probe the structural features required for bioactivity and BMP binding. We define the ERFE active domain and multiple structural features that act together to entrap BMP ligands. In particular, the hydrophobic helical segment 81 to 86 and specifically the highly conserved tryptophan W82 in the N-terminal region are essential for ERFE bioactivity and Alphafold2 modeling places W82 between two tryptophans in its ligands BMP2, BMP6, and the BMP2/6 heterodimer, an interaction similar to those that bind BMPs to their cognate receptors. Finally, we identify the cationic region 96-107 and the globular TNFα-like domain 186-354 as structural determinants of ERFE multimerization that increase the avidity of ERFE for BMP ligands. Collectively, our results provide further insight into the ERFE-mediated inhibition of BMP signaling in response to erythropoietic stress.

Asprosin, a novel glucogenic adipokine implicated in type 2 diabetes mellitus.

Asprosin, encoded by penultimate two exons (exon 65 and exon 66) of the gene Fibrillin 1 (FBN1), has been recently discovered to be a novel hormone secreted by white adipose tissues during fasting. The glucose metabolism disorders are often accompanied by increased asprosin level. Previous research suggests that asprosin may contribute to the development of diabetes by regulating glucose homeostasis, appetite, insulin secretion, and insulin sensitivity. In this review, we summarize the recent findings from studies on asprosin and its association with Type 2 diabetes mellitus, and discusses its mechanisms from various aspects, so as to provide clinical diagnosis and treatment ideas for T2DM.

Genetic predisposition to nonalcoholic fatty liver disease: insights from ANGPTL8 gene variants in Iranian adults.

Nonalcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease with a global prevalence, and modulation of ANGPTL8 expression has emerged as a promising predictor of NAFLD susceptibility. This research was conducted to scrutinize ANGPTL8 protein expression in NAFLD patients and elucidate the interplay between ANGPTL8 gene polymorphisms and their lipid profiles, thus shedding new light on the pathophysiology of this complex disease. The study comprised 423 unrelated participants, including 222 healthy controls and 201 individuals with NAFLD, screened using FibroScan/ultrasonography and laboratory tests. The main goal focused on the genotype and allele frequency distribution in the ANGPTL8 gene, specifically analyzing two genetic variations: rs737337 (T/C) and rs2278426 (C/T). The participants diagnosed with NAFLD were slightly younger (P ≥ 0.05) and had a higher body mass index (BMI) than the individuals in the control group. Notably, there was a significant difference in the occurrence of the rs737337 polymorphism between the NAFLD and control groups, with a lower frequency observed in the NAFLD group. Our results indicated that individuals with the TC + CC genotype and C allele of rs737337 (T/C) had a decreased risk of higher levels of ALT and AST. Conversely, those with the CT, CT + TT genotype, and T allele of rs2278426 (C/T) exhibited an increased risk of higher levels of ALT and AST. The results imply that the rs2278426 (C/T) variant of the ANGPTL8 gene is more strongly linked to an increased risk of NAFLD compared to the rs737337 polymorphism. However, additional research is needed to understand the specific molecular mechanisms responsible for the upregulation of ANGPTL8 in individuals with NAFLD.

Complex peptide hormone signaling in plant stem cells.

Peptide hormones influence diverse aspects of plant development through highly coordinated cell-cell signaling pathways. Many peptide hormone families play key roles in stem cell maintenance across land plants. In this review, we focus on recent work in two conserved peptide hormone families, CLAVATA3/EMBRYO-SURROUNDING REGION (CLEs) and ROOT MERISTEM GROWTH FACTOR (RGFs), and their roles in regulating plant stem cells. We discuss recent work establishing downstream crosstalk between peptide hormones and other conserved signaling mechanisms in meristem maintenance as well as highlight advances in peptide hormone gene identification that provide important context for CLE/RGF family evolution across diverse plant lineages. CLE and RGF gene families have greatly expanded in angiosperms, contributing to the complex genetic regulation of stem cell homeostasis observed in model systems over the last 30 years. Peptide hormone duplications have resulted in genetic compensation mechanisms that ensure robust development through the function of paralogous genes. Broad conservation of genetic compensation across angiosperms highlights the importance of these mechanisms in developmental signaling and understanding their regulation could inform broader understanding of morphological diversity and evolutionary innovation.

System-wide mapping of peptide-GPCR interactions in C. elegans.

Neuropeptides and peptide hormones are ancient, widespread signaling molecules that underpin almost all brain functions. They constitute a broad ligand-receptor network, mainly by binding to G protein-coupled receptors (GPCRs). However, the organization of the peptidergic network and roles of many peptides remain elusive, as our insight into peptide-receptor interactions is limited and many peptide GPCRs are still orphan receptors. Here we report a genome-wide peptide-GPCR interaction map in Caenorhabditis elegans. By reverse pharmacology screening of over 55,384 possible interactions, we identify 461 cognate peptide-GPCR couples that uncover a broad signaling network with specific and complex combinatorial interactions encoded across and within single peptidergic genes. These interactions provide insights into peptide functions and evolution. Combining our dataset with phylogenetic analysis supports peptide-receptor co-evolution and conservation of at least 14 bilaterian peptidergic systems in C. elegans. This resource lays a foundation for system-wide analysis of the peptidergic network.

Therapeutic potential of apelin and Elabela in cardiovascular disease.

Apelin and Elabela (Ela) are peptides encoded by APLN and APELA, respectively, which act on their receptor APJ and play crucial roles in the body. Recent research has shown that they not only have important effects on the endocrine system, but also promote vascular development and maintain the homeostasis of myocardial cells. From a molecular biology perspective, we explored the roles of Ela and apelin in the cardiovascular system and summarized the mechanisms of apelin-APJ signaling in the progression of myocardial infarction, ischemia-reperfusion injury, atherosclerosis, pulmonary arterial hypertension, preeclampsia, and congenital heart disease. Evidences indicated that apelin and Ela play important roles in cardiovascular diseases, and there are many studies focused on developing apelin, Ela, and their analogues for clinical treatments. However, the literature on the therapeutic potential of apelin, Ela and their analogues and other APJ agonists in the cardiovascular system is still limited. This review summarized the regulatory pathways of apelin/ELA-APJ axis in cardiovascular function and cardiovascular-related diseases, and the therapeutic effects of their analogues in cardiovascular diseases were also included.

ANGPTL8 deletion attenuates abdominal aortic aneurysm formation in ApoE-/- mice.

Angiopoietin-like protein 8 (ANGPTL8) plays important roles in lipid metabolism, glucose metabolism, inflammation, and cell proliferation and migration. Clinical studies have indicated that circulating ANGPTL8 levels are increased in patients with thoracic aortic dissection (TAD). TAD shares several risk factors with abdominal aortic aneurysm (AAA). However, the role of ANGPTL8 in AAA pathogenesis has never been investigated. Here, we investigated the effect of ANGPTL8 knockout on AAA in ApoE-/- mice. ApoE-/-ANGPTL8-/- mice were generated by crossing ANGPTL8-/- and ApoE-/- mice. AAA was induced in ApoE-/- using perfusion of angiotensin II (AngII). ANGPTL8 was significantly up-regulated in AAA tissues of human and experimental mice. Knockout of ANGPTL8 significantly reduced AngII-induced AAA formation, elastin breaks, aortic inflammatory cytokines, matrix metalloproteinase expression, and smooth muscle cell apoptosis in ApoE-/- mice. Similarly, ANGPTL8 sh-RNA significantly reduced AngII-induced AAA formation in ApoE-/- mice. ANGPTL8 deficiency inhibited AAA formation, and ANGPTL8 may therefore be a potential therapeutic target for AAA.

An Integrated Computational Analysis of High-Risk SNPs in Angiopoietin-like Proteins (ANGPTL3 and ANGPTL8) Reveals Perturbed Protein Dynamics Associated with Cancer.

Angiopoietin-like proteins (ANGPTL) constitute a family of eight proteins (1-8) which play a pivotal role in the regulation of various pathophysiological processes. The current study sought to identify high-risk, "non-synonymous, single-nucleotide polymorphisms" (nsSNPs) in both ANGPTL3 and ANGPTL8 to evaluate the role that these nsSNPs play in various types of cancer. We retrieved a total of 301 nsSNPs from various databases; 79 of these candidates constitute high-risk nsSNPs. Moreover, we identified eleven high-risk nsSNPs that cause various types of cancer: seven candidates for ANGPTL3 (L57H, F295L, L309F, K329M, R332L, S348C, and G409R) and four candidates for ANGPTL8 (P23L, R85W, R138S, and E148D). Protein-protein interaction analysis revealed a strong association of ANGPTL proteins with several tumor-suppressor proteins such as ITGB3, ITGAV, and RASSF5. 'Gene-expression profiling interactive analysis' (GEPIA) showed that expression of ANGPTL3 is significantly downregulated in five cancers: sarcoma (SARC); cholangio carcinoma (CHOL); kidney chromophobe carcinoma (KICH); kidney renal clear cell carcinoma (KIRC); and kidney renal papillary cell carcinoma (KIRP). GEPIA also showed that expression of ANGPTL8 remains downregulated in three cancers: CHOL; glioblastoma (GBM); and breast invasive carcinoma (BRCA). Survival rate analysis indicated that both upregulation and downregulation of ANGPTL3 and ANGPTL8 leads to low survival rates in various types of cancer. Overall, the current study revealed that both ANGPTL3 and ANGPTL8 constitute potential prognostic biomarkers for cancer; moreover, nsSNPs in these proteins might lead to the progression of cancer. However, further in vivo investigation will be helpful to validate the role of these proteins in the biology of cancer.

Tubular Elabela-APJ axis attenuates ischemia-reperfusion induced acute kidney injury and the following AKI-CKD transition by protecting renal microcirculation.

Rationale: Ischemia-reperfusion injury (I/R) is a common cause of acute kidney injury (AKI). Post-ischemic recovery of renal blood supply plays an important role in attenuating injury. Exogenous application of elabela (ELA) peptides has been demonstrated by us and others to alleviate AKI, partly through its receptor APJ. However, the endogenous role of ELA in renal I/R remains unclear. Methods: Renal tubule specific ELA knockout (ApelaKsp KO) mice challenged with bilateral or unilateral I/R were used to investigate the role of endogenous ELA in renal I/R. RNA-sequencing analysis was performed to unbiasedly investigate altered genes in kidneys of ApelaKsp KO mice. Injured mice were treated with ELA32 peptide, Nω-hydroxy-nor-L-arginine (nor-NOHA), prostaglandin E2 (PGE2), Paricalcitol, ML221 or respective vehicles, individually or in combination. Results: ELA is mostly expressed in renal tubules. Aggravated pathological injury and further reduction of renal microvascular blood flow were observed in ApelaKsp KO mice during AKI and the following transition to chronic kidney disease (AKI-CKD). RNA-seq analysis suggested that two blood flow regulators, arginine metabolizing enzyme arginase 2 (ARG2) and PGE2 metabolizing enzyme carbonyl reductases 1 and 3 (CBR1/3), were altered in injured ApelaKsp KO mice. Notably, combination application of an ARG2 inhibitor nor-NOHA, and Paricalcitol, a clinically used activator for PGE2 synthesis, alleviated injury-induced AKI/AKI-CKD stages and eliminated the worst outcomes observed in ApelaKsp KO mice. Moreover, while the APJ inhibitor ML221 blocked the beneficial effects of ELA32 peptide on AKI, it showed no effect on combination treatment of nor-NOHA and Paricalcitol. Conclusions: An endogenous tubular ELA-APJ axis regulates renal microvascular blood flow that plays a pivotal role in I/R-induced AKI. Furthermore, improving renal blood flow by inhibiting ARG2 and activating PGE2 is an effective treatment for AKI and prevents the subsequent AKI-CKD transition.

Investigation of the relationship between betatrophin and certain key enzymes involved in carbohydrate and lipid metabolism in insulin-resistant mice.

OBJECTIVES: The present study sought to examine the relationship of betatrophin with certain key enzymes, namely lactate dehydrogenase-5 (LDH5), citrate synthase (CS), and acetyl-CoA carboxylase-1 (ACC1), in insulin-resistant mice. METHODS: Eight-week-old male C57BL6/J mice were used in this study (experimental group n=10 and control group n=10). S961 was administered using an osmotic pump to induce insulin resistance in the mice. The betatrophin, LDH5, CS, and ACC1 expression levels were determined from the livers of the mice using the real-time polymerase chain reaction (RT-PCR) method. Moreover, biochemical parameters such as the serum betatrophin, fasting glucose, insulin, triglyceride, total cholesterol, and high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol levels were analyzed. RESULTS: The betatrophin expression and serum betatrophin (p=0.000), fasting glucose, insulin, triglyceride (p≤0.001), and total cholesterol (p=0.013) levels were increased in the experimental group. In addition, the CS gene expression level was statistically significantly decreased in the experimental group (p=0.01). Although strong correlation was found between the expression and serum betatrophin and triglyceride levels, no correlation was found between the betatrophin gene expression and the LDH5, ACC1, and CS gene expression levels. CONCLUSIONS: The betatrophin level appears to play an important role in the regulation of triglyceride metabolism, while insulin resistance increases both the betatrophin gene expression and serum levels and decreases the CS expression level. The findings suggest that betatrophin may not regulate carbohydrate metabolism through CS and LDH5 or lipid metabolism directly through the ACC1 enzyme.

Reduced Apela/APJ system expression in patients with pulmonary artery hypertension secondary to chronic obstructive pulmonary disease.

BACKGROUND: Pulmonary artery hypertension (PAH) is a common disease that seriously threatens human physical and mental health. Chronic obstructive pulmonary disease (COPD) is the main cause of secondary PAH. OBJECTIVES: This study observed the differential expression of the endogenous Apela/APJ system in COPD patients with or without PAH. METHODS: A total of 69 COPD patients were enrolled, including 31 patients with PAH (COPD+PAH). Lung tissue from healthy controls, COPD patients, and COPD patients with PAH was used for RT-PCR and histological examination. RESULTS: The serum level of endogenous Apela in COPD+PAH patients was significantly lower than those in the control and COPD groups. Correlation analysis showed that systolic pulmonary artery pressure in COPD+PAH patients was negatively correlated with the serum level of endogenous Apela (r = -0.3842, p < 0.05). The percentage of intima thickening and muscularization of pulmonary arterioles was increased in COPD+PAH patients, while the expression of Apela/APJ was decreased. Compared with the healthy controls and COPD patients, the expression of endothelial markers vWF and CD34 mRNA in the pulmonary arterioles in COPD+PAH patients decreased, while the expression of interstitial markers α-SMA and vimentin mRNA was up-regulated. CONCLUSION: The present study suggests that expression of the Apela/APJ system is decreased in PAH secondary to COPD. The pathological changes involved in PAH secondary to COPD include thickening of the intima and muscularization of the pulmonary arterioles, as well as endothelial-to-mesenchymal transition. Corrective action targeting the diminished Apela/APJ system may be a promising therapeutic strategy for PAH in the future.

Associations of ANGPTL6, DOCK6, FABP1, and PCSK9 single-nucleotide variants with hypercholesterolemia in the Polish population: a cross-sectional study.

INTRODUCTION: Hypercholesterolemia is a chronic noncommunicable disease predisposing to cardiovascular diseases. Genome­wide association studies have shown that more than 500 common nucleotide variants are associated with dyslipidemia. OBJECTIVES: We evaluated associations between selected nucleotide variants in ANGPTL6, DOCK6, FABP1, and PCSK9 genes and hypercholesterolemia in the Polish adult population sample. PATIENTS AND METHODS: The study included 109 patients with hypercholesterolemia and 251 individuals with no diagnosed lipid disorder. Genotyping of ANGPTL6 rs8112063, DOCK6 rs737337 and rs17699089, FABP1 rs2241883 and rs2919872, and PCSK9 rs562556 and rs11206510 was carried out using highresolution melting curve analysis. Serum concentrations of FABP1, PCSK9, ANGPTL6, and ANGPTL8 were determined in 51 individuals by enzyme­linked immunosorbent assay. RESULTS: Carriers of the FABP1 rs2919872 CC genotype were over 2.5­fold less likely to be diagnosed with hypercholesterolemia than carriers of the T allele (odds ratio [OR], 0.386; 95% CI, 0.203-0.735; P = 0.003; Pcorr = 0.006). There were no associations between rs2919872 and serum lipid concentrations. Carriers of the ANGPTL6 rs8112063 C allele had an almost 2­fold higher risk of developing hypercholesterolemia than carriers of the T allele (OR, 1.820; 95% CI, 1.053-3.144; P = 0.03; Pcorr = 0.046). Moreover, the carriers of the ANGPTL6 rs8112063 C allele had higher serum concentrations of high-density lipoprotein cholesterol than those with TT genotype (P = 0.009). There were no significant associations between the other tested variants and hypercholesterolemia. CONCLUSIONS: FABP1 rs2919872 and ANGPTL6 rs8112063 are associated with a risk of hypercholesterolemia in the Polish population.

In Silico Pan-Cancer Analysis Reveals Prognostic Role of the Erythroferrone (ERFE) Gene in Human Malignancies.

The erythroferrone gene (ERFE), also termed CTRP15, belongs to the C1q tumor necrosis factor-related protein (CTRP) family. Despite multiple reports about the involvement of CTRPs in cancer, the role of ERFE in cancer progression is largely unknown. We previously found that ERFE was upregulated in erythroid progenitors in myelodysplastic syndromes and strongly predicted overall survival. To understand the potential molecular interactions and identify cues for further functional investigation and the prognostic impact of ERFE in other malignancies, we performed a pan-cancer in silico analysis utilizing the Cancer Genome Atlas datasets. Our analysis shows that the ERFE mRNA is significantly overexpressed in 22 tumors and affects the prognosis in 11 cancer types. In certain tumors such as breast cancer and adrenocortical carcinoma, ERFE overexpression has been associated with the presence of oncogenic mutations and a higher tumor mutational burden. The expression of ERFE is co-regulated with the factors and pathways involved in cancer progression and metastasis, including activated pathways of the cell cycle, extracellular matrix/tumor microenvironment, G protein-coupled receptor, NOTCH, WNT, and PI3 kinase-AKT. Moreover, ERFE expression influences intratumoral immune cell infiltration. Conclusively, ERFE is aberrantly expressed in pan-cancer and can potentially function as a prognostic biomarker based on its putative functions during tumorigenesis and tumor development.

The rubber tree RALF peptide hormone and its receptor protein kinase FER implicates in rubber production.

RAPID ALKALINIZATION FACTORs (RALFs), which are secreted peptides serving as extracellular signals transduced to the inside of the cell, interact with the receptor-like kinase FERONIA (FER) and participates in various biological pathways. Here, we identified 23 RALF and 2 FER genes in Hevea brasiliensis (para rubber tree), and characterized their expression patterns in different tissues, across the process of leaf development, and in response to the rubber yield-stimulating treatments of tapping and ethylene. Four Hevea latex (the cytoplasm of rubber-producing laticifers)-abundant RALF isoforms, HbRALF19, HbRALF3, HbRALF22, and HbRALF16 were listed with descending expression levels. Of the four HbRALFs, expressions of HbRALF3 were markedly regulated in an opposite way by the treatments of tapping (depression) and ethylene (stimulation). All of the four latex-abundant RALFs specifically interacted with the extracellular domain of HbFER1. Transgenic Arabidopsis plants overexpressing these HbRALFs displayed phenotypes similar to those reported for AtRALFs, such as shorter roots, smaller plant architecture, and delayed flowering. The application of HbRALF3 and HbRALF19 recombinant proteins significantly reduced the pH of Hevea latex, an important factor regulating latex metabolism. An in vitro rubber biosynthesis assay in a mixture of latex cytosol (C-serum) revealed a positive role of HbFER1 in rubber biosynthesis. Taken together, these data provide evidence for the participation of the HbRALF-FER module in rubber production.