Search

This is the first study to examine the distribution of a chemokine CXCL14-like peptide in the pituitary and hypothalamus of an avian species, the Japanese quail (Coturnix japonica). We employed immunohistochemical techniques using a specific anti-human CXCL14 antibody. CXCL14-immunoreactive cells were detected in the caudal lobe of the pars distalis. CXCL14-immunoreactive puncta were densely distributed in the external layer and sparsely distributed in the internal layer of the median eminence. CXCL14 staining was absent after pre-absorption of the antibody with recombinant human CXCL14. All CXCL14-immunoreactive cells corresponded to growth hormone (GH)-producing cells in the caudal lobe. In addition, the majority of CXCL14-immunoreactive puncta in the median eminence corresponded to somatostatin-containing fibres. CXCL14 secreted from GH-producing cells and somatostatin-containing fibres may act as an inhibitor of GH release via an autocrine mechanism and neuroendocrine signalling, respectively. [ABSTRACT FROM AUTHOR]

Significance: Neutrophils are crucial components of the innate immune system that combat invading pathogens and maintain homeostasis. Nitric oxide (NO•) exerts regulatory influence on neutrophil rolling, adhesion, oxidative burst, chemotaxis, phagocytosis, cytoneme, apoptosis, and NETosis by diverse mechanisms in an autocrine and paracrine manner. Recent Advances: Recent research has identified the critical role of NO• in the proliferation of neutrophil progenitors, differentiation, survival, and other functions. Further, NO• responses depend on the concentration, proximity, and redox environment, highlighting the intricate and context-dependent mechanisms by which NO• influences neutrophil responses. Critical Issues: Neutrophils express two constitutive isoforms of nitric oxide synthase (NOS), namely iNOS and nNOS. The production of NO• or superoxide (O2•−) radical by these isoforms depends on levels of substrates L-arginine and oxygen, and cofactors such as NADPH, FAD, FMN, and redox-sensitive BH4. Importantly, the interaction between NO• and superoxide generates potent oxidants within the phagolysosomes. The coordinated collaboration and regulation of NO• and O2•− are crucial for redox signaling and neutrophil properties. Future Directions: The activity of neutrophil NOS is regulated at multiple levels, including transcriptional regulation, cofactor availability, protein-protein interactions, and post-translational modifications. However, our understanding of regulatory mechanisms during various neutrophil functions remains limited. While we now recognize the neutrophil heterogeneity, metabolic adaptability, and anti-tumoral ability; however, reports identifying NOS/NO• role remain largely unexplored on these aspects in infections, inflammation, and immunosuppression. Future studies addressing these intriguing areas will be crucial in unraveling the role of NO•/NOS signaling in neutrophils across diverse pathologies and may present therapeutic opportunities. [ABSTRACT FROM AUTHOR]

Insulin-like peptide 3 (INSL3) is a biomarker for Leydig cells in the testes of vertebrates, and it is principally involved in spermatogenesis through specific binding with the RXFP2 receptor. This study reports the insl3 gene transcript and the Insl3 prepropeptide expression in both non-reproductive and reproductive tissues of Danio rerio. An immunohistochemistry analysis shows that the hormone is present at a low level in the Leydig cells and germ cells at all stages of Danio rerio testis differentiation. Considering that the insl3 gene is transcribed in Leydig cells, our results highlight an autocrine and paracrine function of this hormone in the Danio rerio testis, adding new information on the Insl3 mode of action in reproduction. We also show that Insl3 and Rxfp2 belonging to Danio rerio and other vertebrate species share most of the amino acid residues involved in the ligand–receptor interaction and activation, suggesting a conserved mechanism of action during vertebrate evolution. [ABSTRACT FROM AUTHOR]

Background: Docetaxel resistance represents a significant obstacle in the treatment of prostate cancer. The intricate interplay between cytokine signalling pathways and transcriptional control mechanisms in cancer cells contributes to chemotherapeutic resistance, yet the underlying molecular determinants remain only partially understood. This study elucidated a novel resistance mechanism mediated by the autocrine interaction of interleukin-11 (IL-11) and its receptor interleukin-11 receptor subunit alpha(IL-11RA), culminating in activation of the JAK1/STAT4 signalling axis and subsequent transcriptional upregulation of the oncogene c-MYC. Methods: Single-cell secretion profiling of prostate cancer organoid was analyzed to determine cytokine production profiles associated with docetaxel resistance.Analysis of the expression pattern of downstream receptor IL-11RA and enrichment of signal pathway to clarify the potential autocrine mechanism of IL-11.Next, chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) was performed to detect the nuclear localization and DNA-binding patterns of phosphorylated STAT4 (pSTAT4). Coimmunoprecipitation and reporter assays were utilized to assess interaction between pSTAT4 and the cotranscription factor CREB-binding protein (CBP) as well as their role in c-MYC transcriptional activity. Results: Autocrine secretion of IL-11 was markedly increased in docetaxel-resistant prostate cancer cells. IL-11 stimulation resulted in robust activation of JAK1/STAT4 signalling. Upon activation, pSTAT4 translocated to the nucleus and associated with CBP at the c-MYC promoter region, amplifying its transcriptional activity. Inhibition of the IL-11/IL-11RA interaction or disruption of the JAK1/STAT4 pathway significantly reduced pSTAT4 nuclear entry and its binding to CBP, leading to downregulation of c-MYC expression and restoration of docetaxel sensitivity. Conclusion: Our findings identify an autocrine loop of IL-11/IL-11RA that confers docetaxel resistance through the JAK1/STAT4 pathway. The pSTAT4-CBP interaction serves as a critical enhancer of c-MYC transcriptional activity in prostate cancer cells. Targeting this signalling axis presents a potential therapeutic strategy to overcome docetaxel resistance in advanced prostate cancer. [ABSTRACT FROM AUTHOR]

Prostaglandins are synthesized from arachidonic acid through the catalytic activities of cyclooxygenase, while the production of different prostaglandin types, prostaglandin F2 alpha (PGF) and prostaglandin E2 (PGE), are regulated by specific prostaglandin synthases (PGFS and PGES). Prostaglandin ligands (PGF and PGE) bind to specific high‐affinity receptors and initiate biologically distinct signalling pathways. In the ovaries, prostaglandins are known to be important endocrine regulators of female reproduction, in addition to maintaining local function through autocrine and/or paracrine effect. Many research groups in different animal species have already identified a variety of factors and molecular mechanisms that are responsible for the regulation of prostaglandin functions. In addition, prostaglandins stimulate their intrafollicular and intraluteal production via the pathway of prostaglandin self‐regulation in the ovary. Therefore, the objective of the review article is to discuss recent findings about local regulation patterns of prostaglandin ligands PGF and PGE during different physiological stages of ovarian function in domestic ruminants, especially in bovine. In conclusion, the discussed local regulation mechanisms of prostaglandins in the ovary may stimulate further research activities in different methodological approaches, especially during final follicle maturation and ovulation, as well as corpus luteum formation and function. [ABSTRACT FROM AUTHOR]

Methamphetamine is a widely abused psychostimulant and one of the main targets of dopamine transporter (DAT). Methamphetamine reduces DAT‐mediated dopamine uptake and stimulates dopamine efflux leading to increased synaptic dopamine levels many folds above baseline. Methamphetamine also targets DAT‐expressing peripheral immune cells, reduces wound healing and increases infection susceptibility. Peripheral immune cells such as myeloid cells, B cells and T cells express DAT. DAT activity on monocytes and macrophages exhibits immune suppressive properties via an autocrine paracrine mechanism, where deletion or inhibition of DAT activity increases inflammatory responses. In this study, utilizing a mouse model of daily single dose of methamphetamine administration, we investigated the impact of the drug on DAT expression in peripheral immune cells. We found in methamphetamine‐treated mice that DAT expression was down‐regulated in most of the innate and adaptive immune cells. Methamphetamine did not increase or decrease the total number of innate and adaptive immune cells but changed their immunophenotype to low‐DAT‐expressing phenotype. Moreover, serum cytokine distributions were altered in methamphetamine‐treated mice. Therefore, resembling its effect in the CNS, in the periphery, methamphetamine regulates DAT expression on peripheral immune cell subsets, potentially describing methamphetamine regulation of peripheral immunity. [ABSTRACT FROM AUTHOR]

The mechanical stimulation induced by poking cells with a glass needle activates Piezo1 receptors and the adenosine triphosphate (ATP) autocrine pathway, thus increasing intracellular Ca2+ concentration. The differences between the increase in intracellular Ca2+ concentration induced by cell poking and by ATP‐only stimulation have not been investigated. In this study, we investigated the Ca2+ signaling mechanism induced by autocrine ATP release during Madin–Darby Canine Kidney cell membrane deformation by cell poking. The results suggest that the pathways for supplying Ca2+ into the cytoplasm were not identical between cell poking and conventional ATP stimulation. The functions of the G protein‐coupled receptor (GPCR) subunits (Gα $\alpha $q, Gβγ $\beta \gamma $), ATP‐activated receptor and the upstream Ca2+ release signal from the intracellular endoplasmic reticulum Ca2+ store, were investigated. The results show that Gα $\alpha $q plays a major role in the Ca2+ response evoked by ATP‐only stimulation, while cell poking induces a Ca2+ response requiring the involvement of both Gα $\alpha $q and Gβγ $\beta \gamma $ units simultaneously. These results suggest that GPCR are not only activated by ATP‐only stimulation or autocrine ATP release during Ca2+ signaling, but also activated by the mechanical effects of cell poking. Significance statement: This paper investigated the mechanosensitivity of P2Y receptors and the role of the heterotrimeric G protein subunits in the process of elevation of intracellular Ca2+ concentration in Madin–Darby Canine Kidney cells mechanically deformed by poking. Results showed that the Ca2+ concentration increase triggered through P2Y receptors occurs independently of autocrine signaling triggered by released adenosine triphosphate. [ABSTRACT FROM AUTHOR]

Endometriosis (EMs) is a common disease among women whose pathogenesis is still unclear, although there are various hypotheses. Recent studies have considered macrophages the key part of the immune system in developing EMs, inducing inflammation, the growth and invasion of the ectopic endometrium, and angiogenesis. Extracellular vesicles (EVs) as novel intercellular vesicle traffic, can be secreted by many kinds of cells, including macrophages. By carrying long non-coding RNA (lncRNA), microRNA (miRNA), or other molecules, EVs can regulate the biological functions of macrophages in an autocrine and paracrine manner, including ectopic lesion growth, immune dysfunction, angiogenesis, and can further accelerate the progression of EMs. In this review, the interactions between macrophages and EVs for the pathogenesis of EMs are summarized. Notably, the regulatory pathways and molecular mechanisms of EVs secreted by macrophages during EMs are reviewed. [ABSTRACT FROM AUTHOR]

In this review, we provide a brief synopsis of the connections between adipose tissue and metabolic health and highlight some recent developments in understanding and exploiting adipocyte biology. Adipose tissue plays critical roles in the regulation of systemic glucose and lipid metabolism and secretes bioactive molecules possessing endocrine, paracrine, and autocrine functions. Dysfunctional adipose tissue has a detrimental impact on metabolic health and is intimately involved in key aspects of metabolic diseases such as insulin resistance, lipid overload, inflammation, and organelle stress. Differences in the distribution of fat depots and adipose characteristics relate to divergent degrees of metabolic dysfunction found in metabolically healthy and unhealthy obese individuals. Thermogenic adipocytes increase energy expenditure via mitochondrial uncoupling or adenosine triphosphate-consuming futile substrate cycles, while functioning as a metabolic sink and participating in crosstalk with other metabolic organs. Manipulation of adipose tissue provides a wealth of opportunities to intervene and combat the progression of associated metabolic diseases. We discuss current treatment modalities for obesity including incretin hormone analogs and touch upon emerging strategies with therapeutic potential including exosome-based therapy, pharmacological activation of brown and beige adipocyte thermogenesis, and administration or inhibition of adipocyte-derived factors. [ABSTRACT FROM AUTHOR]

Background: Chemerin is a novel adipokine that has been found to function in both autocrine and paracrine pathways. It draws in both innate and adaptive immune cells as a chemoattractant. There are several roles for this pro-inflammatory chemokine. Also called retinoic acid receptor responder 2 (RAR2) and tazarotene-induced gene 2 (TIG2). The protein chemerin is involved in a variety of processes, including metabolism, inflammation, and adipogenesis, as well as vascular dysregulation. Chemerin was evaluated among different inflammatory skin diseases and showed significant correlations. Objective: Review of the biological role of chemerin in inflammatory skin disease. Methods: We looked for data on Chemerin, Biological role and Inflammatory skin disease in medical journals and databases like PubMed, Google Scholar, and Science Direct. However, only the most recent or extensive study was taken into account between February 2015 and January 2023. References from related works were also evaluated by the authors. There are not enough resources to translate documents into languages other than English, hence those documents have been ignored. It was generally agreed that documents such as unpublished manuscripts, oral presentations, conference abstracts, and dissertations did not qualify as legitimate scientific study. Conclusion: Psoriatic individuals had increased chemerin levels in their skin biopsies. Also serum chemerin levels were found to increase with acne vulgaris disease severity. Recent research has found a correlation between obesity and atopic dermatitis, an inflammatory skin condition. Adipokines can be used as a marker for the degree to which eczema is present. [ABSTRACT FROM AUTHOR]

Two types of Calcitonin (Calcitonin I (CtI), Calcitonin II (CtII)) were previously determined in goldfish. The present study examined the expression levels of CtI and CtII in the ultimobranchial glands (UBGs) using quantitative PCR with a TaqMan probe and their correlation with the reproductive physiology. The results showed that the mRNA expression of CtI and CtII in females had a significant relationship with their plasma Ca concentrations, while those in males did not correlate with their plasma Ca concentrations. Furthermore, there was a significant co-relationship between plasma CALCITONIN (CT) and Ca levels or gonad somatic index in female but not male goldfish. Additionally, the plasma CT and Ca levels in females were significantly higher than those in males. The calcium-sensing receptor mRNA expression in the UBGs of female goldfish was significantly higher than that in male goldfish, indicating that the UBGs in female goldfish respond sensitively to changing plasma Ca conditions during the reproductive period. On the other hand, it has been considered that the target of the secreted CT is osteoclasts in the fish scales, while it is bone in mammals. Next, we examined the CtI and CtII mRNA expressions in the scales of goldfish. In the scales of both sexes, we found that CtII mRNA was expressed, but CtI was not detected. CtII expression was immunohistochemically observed in the osteoblasts. Furthermore, CtII mRNA expression in scales increased significantly with E2 treatment. Thus, in the present study, we demonstrate that CTI and CTII are involved in Ca metabolism, particularly in female goldfish reproductive physiology. CTII expressed in the ectopic organs such as scales has an ectopic function regarding Ca metabolism through paracrine or autocrine mechanisms during the female reproductive period. [ABSTRACT FROM AUTHOR]

Gi-coupled protein receptor 81 (GPR81) was first identified in adipocytes as a receptor for L-lactate, which upon binding inhibits cyclicAMP (cAMP)-protein kinase (PKA)-cAMP-response element binding (CREB) signaling. Moreover, incubation of myotubes with lactate augments expression of GPR81 and genes and proteins involved in lactate- and energy metabolism. However, characterization of GPR81 expression and investigation of related signaling in human skeletal muscle under conditions of elevated circulating lactate levels are lacking. Muscle biopsies were obtained from healthy men and women at rest, after leg extension exercise, with or without venous infusion of sodium lactate, and 90 and 180 min after exercise (8 men and 8 women). Analyses included protein and mRNA levels of GPR81, as well as GPR81-dependent signaling molecules. GPR81 expression was 2.5-fold higher in type II glycolytic compared with type I oxidative muscle fibers, and the expression was inversely related to the percentage of type I muscle fibers. Muscle from women expressed about 25% more GPR81 protein than from men. Global PKA activity increased by 5%-8% after exercise, with no differences between trials. CREBS133 phosphorylation was reduced by 30% after exercise and remained repressed during the entire trials, with no influence of the lactate infusion. The mRNA expression of vascular endothelial growth factor (VEGF) and peroxisome-proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) were increased by 2.5-6-fold during recovery, and that of lactate dehydrogenase reduced by 15% with no differences between trials for any gene at any time point. The high expression of GPR81-protein in type II fibers suggests that lactate functions as an autocrine signaling molecule in muscle; however, lactate does not appear to regulate CREB signaling during exercise. [ABSTRACT FROM AUTHOR]

The accurate construction of neural circuits requires the precise control of axon growth and guidance, which is regulated by multiple growth and guidance cues during early nervous system development. It is generally thought that the growth and guidance cues that control the major steps of axon development have been defined. Here, we describe cerebellin-1 (Cbln1) as a novel cue that controls diverse aspects of axon growth and guidance throughout the central nervous system (CNS) by experiments using mouse and chick embryos. Cbln1 has previously been shown to function in late neural development to influence synapse organization. Here, we find that Cbln1 has an essential role in early neural development. Cbln1 is expressed on the axons and growth cones of developing commissural neurons and functions in an autocrine manner to promote axon growth. Cbln1 is also expressed in intermediate target tissues and functions as an attractive guidance cue. We find that these functions of Cbln1 are mediated by neurexin-2 (Nrxn2), which functions as the Cbln1 receptor for axon growth and guidance. In addition to the developing spinal cord, we further show that Cbln1 functions in diverse parts of the CNS with major roles in cerebellar parallel fiber growth and retinal ganglion cell axon guidance. Despite the prevailing role of Cbln1 as a synaptic organizer, our study discovers a new and unexpected function for Cbln1 as a general axon growth and guidance cue throughout the nervous system. The accurate construction of neural circuits requires precise control of axon growth and guidance, regulated by multiple growth and guidance cues during early nervous system development. This study shows that the well-known synaptic organizer Cbln1 also plays roles during early neural development, regulating axon growth and guidance in multiple neural regions. [ABSTRACT FROM AUTHOR]

Background: Semaphorins (Sema) belong to a large family of repellent guidance cues instrumental in guiding axons during development. In particular, Class 3 Sema (Sema 3) is among the best characterized Sema family members and the only produced as secreted proteins in mammals, thereby exerting both autocrine and paracrine functions. Intriguingly, an increasing number of studies supports the crucial role of the Sema 3A in hippocampal and cortical neurodevelopment. This means that alterations in Sema 3A signaling might compromise hippocampal and cortical circuits and predispose to disorders such as autism and schizophrenia. Consistently, increased Sema 3A levels have been detected in brain of patients with schizophrenia and many polymorphisms in Sema 3A or in the Sema 3A receptors, Neuropilins (Npn 1 and 2) and Plexin As (Plxn As), have been associated to autism. Results: Here we present data indicating that when overexpressed, Sema 3A causes human neural progenitors (NP) axonal retraction and an aberrant dendritic arborization. Similarly, Sema 3A, when overexpressed in human microglia, triggers proinflammatory processes that are highly detrimental to themselves as well as NP. Indeed, NP incubated in microglia overexpressing Sema 3A media retract axons within an hour and then start suffering and finally die. Sema 3A mediated retraction appears to be related to its binding to Npn 1 and Plxn A2 receptors, thus activating the downstream Fyn tyrosine kinase pathway that promotes the threonine-serine kinase cyclin-dependent kinase 5, CDK5, phosphorylation at the Tyr15 residue and the CDK5 processing to generate the active fragment p35. Conclusions: All together this study identifies Sema 3A as a critical regulator of human NP differentiation. This may imply that an insult due to Sema 3A overexpression during the early phases of neuronal development might compromise neuronal organization and connectivity and make neurons perhaps more vulnerable to other insults across their lifespan. [ABSTRACT FROM AUTHOR]

Background: Semaphorins (Sema) belong to a large family of repellent guidance cues instrumental in guiding axons during development. In particular, Class 3 Sema (Sema 3) is among the best characterized Sema family members and the only produced as secreted proteins in mammals, thereby exerting both autocrine and paracrine functions. Intriguingly, an increasing number of studies supports the crucial role of the Sema 3A in hippocampal and cortical neurodevelopment. This means that alterations in Sema 3A signaling might compromise hippocampal and cortical circuits and predispose to disorders such as autism and schizophrenia. Consistently, increased Sema 3A levels have been detected in brain of patients with schizophrenia and many polymorphisms in Sema 3A or in the Sema 3A receptors, Neuropilins (Npn 1 and 2) and Plexin As (Plxn As), have been associated to autism. Results: Here we present data indicating that when overexpressed, Sema 3A causes human neural progenitors (NP) axonal retraction and an aberrant dendritic arborization. Similarly, Sema 3A, when overexpressed in human microglia, triggers proinflammatory processes that are highly detrimental to themselves as well as NP. Indeed, NP incubated in microglia overexpressing Sema 3A media retract axons within an hour and then start suffering and finally die. Sema 3A mediated retraction appears to be related to its binding to Npn 1 and Plxn A2 receptors, thus activating the downstream Fyn tyrosine kinase pathway that promotes the threonine-serine kinase cyclin-dependent kinase 5, CDK5, phosphorylation at the Tyr15 residue and the CDK5 processing to generate the active fragment p35. Conclusions: All together this study identifies Sema 3A as a critical regulator of human NP differentiation. This may imply that an insult due to Sema 3A overexpression during the early phases of neuronal development might compromise neuronal organization and connectivity and make neurons perhaps more vulnerable to other insults across their lifespan. [ABSTRACT FROM AUTHOR]

Platelet‐activating factor (PAF, 1‐alkyl‐2‐acetyl‐sn‐glycero‐3‐phosphorylcholine) was discovered when the mechanisms involved in the deposition of immune complex in tissues were being scrutinized in the experimental model of rabbit serum sickness. The initial adscription of PAF to IgE‐dependent anaphylaxis was soon extended after disclosing its release from phagocytes stimulated by calcium mobilizing agents, formylated peptides, and phagocytosable particles. This explains why ongoing research in the field turned to the analysis of immune cell types and stimuli involved in PAF production with the purpose of establishing its role in pathology. This was spurred by the identification of the chemical structure of PAF and the enzymic mechanisms involved in its biosynthesis and degradation, which showed commonalities with those involved in eicosanoid production and the Lands' cycle of phospholipid fatty acid remodeling. The reassignment of PAF function in immunopathology is explained by the finding that the most robust mechanisms leading to PAF production are associated with opsonic and non‐opsonic phagocytosis, depending on the cell type. While polymorphonuclear leukocytes exhibit opsonic phagocytosis, monocyte‐derived dendritic cells show a marked preference for non‐opsonic phagocytosis associated with C‐type lectin receptors. This is particularly relevant to the defense against fungal invasion and explains why PAF exerts an autocrine feed‐forwarding mechanism required for the selective expression of some cytokines. [ABSTRACT FROM AUTHOR]

Placental insufficiency affects about 10% of pregnancies and can lead to pre-eclampsia, fetal growth restriction, and preterm birth. Despite significant advances in early prediction and prevention of preterm pre-eclampsia with aspirin, the effects of prophylaxis on fetal growth restriction are less certain, and the rates of late-onset pre-eclampsia are not influenced by aspirin treatment. Pregnancies complicated by placental insufficiency are characterized by increased oxidative stress, and recent studies suggest that melatonin has antioxidant properties and contributes to maintaining placental homeostasis. We aimed to systematically review the available literature about melatonin in pregnancies complicated by placental insufficiency, specifically preeclampsia and fetal growth restriction, exploring three different aspects: 1) maternal melatonin levels; 2) expression and activity of melatonin placental receptors; 3) effects of maternal melatonin administration. PubMed (Medline) and Scopus were searched until December 2020. Identified studies were screened and assessed independently by two authors. Data were extracted and compiled in qualitative evidence synthesis. The circadian pattern of melatonin secretion seems to be altered in pregnancies complicated by placental insufficiency reflected by lower production of melatonin, with consequent lower systemic and placental concentrations and lower expression of melatonin receptors, thus reducing the local release of the indole and its autocrine function. Small intervention studies also suggest that treatment is safe and may lead to prolongation of pregnancy and better outcomes, but double-blind, randomized placebo-controlled trials are lacking. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "The adipokine leptin modulates adventitial pericyte functions by autocrine and paracrine signalling" published in Scientific Reports. The correction addresses an error in Figure 5b of the original article, where a duplication occurred. The corrected figure and accompanying legend are provided in the document. The article explores the angiocrine activity of APC-secreted LEP and its effects on HUVECs, including the proliferative effect, network formation, and vascular resistance. The authors of the article are Federica Riu, Sadie C. Slater, Eva Jover Garcia, and others. [Extracted from the article]

Simple Summary: Chronic inflammation of the gut is a multifactorial, incurable condition that involves interactions between our immune cells and the cells that line the surface layer of gut, known as the epithelium. Interleukin-10, a protein well known to be released by our immune cells, has a protective role in countering inflammation, partly due to the fact that it can block the NFκB pathway, a signalling pathway within cells that promotes genes involved in inflammatory responses. However, we recently showed that laboratory cultures of gut epithelial cells can also synthesise interleukin-10, which acts as a positive regulator of the NFκB pathway to support gut health. In this study here, we investigated further the impact of the role of interleukin-10 on the NFκB pathway and its targets within the gut using a whole animal approach, and confirmed that NFκB activation is indeed positively regulated by interleukin-10, affecting the expression of downstream target genes and their encoded proteins. This strengthens the importance of the interleukin-10/NFκB signalling pathway axis in maintenance of gut health and response to damage, inflammation, and infection. Understanding cell-specific biological roles of interleukin-10 and its interactions with NFκB could prove useful for future therapeutic intervention for interleukin-10 regulated inflammatory conditions. Interleukin-10 (IL-10) is an anti-inflammatory cytokine that has a major protective role against intestinal inflammation. We recently revealed that intestinal epithelial cells in vitro regulate NFκB-driven transcriptional responses to TNF via an autocrine mechanism dependent on IL-10 secretion. Here in this study, we investigated the impact of IL-10 deficiency on the NFκB pathway and its downstream targets in the small intestinal mucosa in vivo. We observed dysregulation of TNF, IκBα, and A20 gene and protein expression in the small intestine of steady-state or TNF-injected Il10−/− mice, compared to wild-type C57BL6/J counterparts. Upon TNF injection, tissue from the small intestine showed upregulation of NFκB p65[RelA] activity, which was totally diminished in Il10−/− mice and correlated with reduced levels of TNF, IκBα, and A20 expression. In serum, whilst IgA levels were noted to be markedly downregulated in IL-10-deficient- mice, normal levels of mucosal IgA were seen in intestine mucosa. Importantly, dysregulated cytokine/chemokine levels were observed in both serum and intestinal tissue lysates from naïve, as well as TNF-injected Il10−/− mice. These data further support the importance of the IL-10-canonical NFκB signaling pathway axis in regulating intestinal mucosa homeostasis and response to inflammatory triggers in vivo. [ABSTRACT FROM AUTHOR]

Simple Summary: In primates, prolactin (PRL) is expressed in the pituitary gland; however, the extra-pituitary expression has been reported, including in the eye. The baboon is an excellent animal model for understanding the possible role of this hormone in the eye. The objective of this study was to detect PRL and its receptor expression in the eye tissues of fetal and adult baboons. Moreover, we performed PRL gene sequencing and a phylogenetic analysis to identify the evolutionary divergence in human and primate genes of PRL. We detected PRL and PRLR expression in all retinal cell lineages in fetal and adult baboons. No expression of these genes was detected in the cornea, lens, sclera, and iris. PRL and PRLR fit the hypothesis of evolutionary purifying gene selection. According to our findings, PRL has a role in prenatal and post-natal homeostasis of the baboon eye. We suggest that the hormone triggers autocrine and paracrine-specific functions in eye development. Prolactin (PRL) is a hormone expressed in lactotrophs cells of the pituitary gland in primates. Extra pituitary expression of PRL has been reported, including the eye; however, expression in the developing eye of primates is limited. The aim of the study was determining the expression of PRL and PRL receptor (PRLR) (mRNAs and proteins) in adult and fetal baboon (Papio hamadryas) ocular tissues. Methods: We analyzed PRL and PRLR in baboon eyes tissues by immunofluorescence. The mRNAs of PRL and PRLR were detected by RT-PCR, cDNA was cloned, and sequenced. Furthermore, we performed a phylogenetic analysis to identify the evolutionary forces that underlie the divergence of PRL and PRLR primate genes. Results: We observed the expression of PRL and PRLR (mRNAs and proteins) in all retinal cell lineages of fetal and adult baboon. PRL and PRLR fit the hypothesis of evolutionary purifying gene selection. Conclusions: mRNA and protein of PRL and PRLR are expressed in fetal and adult baboon retinal tissue. PRL may trigger autocrine and paracrine-specific actions in retinal cell lines. [ABSTRACT FROM AUTHOR]

The molecular mechanisms that regulate embryogenesis and cardiac development are calibrated by multiple signal transduction pathways within or between different cell lineages via autocrine or paracrine mechanisms of action. The heart is the first functional organ to form during development, which highlights the importance of this organ in later stages of growth. Knowledge of the regulatory mechanisms underlying cardiac development and adult cardiac homeostasis paves the way for discovering therapeutic possibilities for cardiac disease treatment. Serum response factor (SRF) is a major transcription factor that controls both embryonic and adult cardiac development. SRF expression is needed through the duration of development, from the first mesodermal cell in a developing embryo to the last cell damaged by infarction in the myocardium. Precise regulation of SRF expression is critical for mesoderm formation and cardiac crescent formation in the embryo, and altered SRF levels lead to cardiomyopathies in the adult heart, suggesting the vital role played by SRF in cardiac development and disease. This review provides a detailed overview of SRF and its partners in their various functions and discusses the future scope and possible therapeutic potential of SRF in the cardiovascular system. [ABSTRACT FROM AUTHOR]

With the insufficient satisfaction rates and high cost of operative treatment for osteoarthritis (OA), alternatives have been sought. Furthermore, the inability of current medications to arrest disease progression has led to rapidly growing clinical research relating to mesenchymal stem cells (MSCs). The availability and function of MSCs vary according to tissue source. The three primary sources include the placenta, bone marrow, and adipose tissue, all of which offer excellent safety profiles. The primary mechanisms of action are trophic and immunomodulatory effects, which prevent the further degradation of joints. However, the function and degree to which benefits are observed vary significantly based on the exosomes secreted by MSCs. Paracrine and autocrine mechanisms prevent cell apoptosis and tissue fibrosis, initiate angiogenesis, and stimulate mitosis via growth factors. MSCs have even been shown to exhibit antimicrobial effects. Clinical results incorporating clinical scores and objective radiological imaging have been promising, but a lack of standardization in isolating MSCs prevents their incorporation in current guidelines. [ABSTRACT FROM AUTHOR]

Proteases are fundamental for a plethora of biological processes, including signalling and tissue remodelling, and dysregulated proteolytic activity can result in pathogenesis. In this review, we focus on a subclass of membrane‐bound and soluble proteases that are defined as channel‐activating proteases (CAPs), since they induce Na+ ion transport through an autocrine mechanism when co‐expressed with the highly amiloride‐sensitive epithelial sodium channel (ENaC) in Xenopus oocytes. These experiments first identified CAP1 (channel‐activating protease 1, prostasin) followed by CAP2 (channel‐activating protease 2, TMPRSS4) and CAP3 (channel‐activating protease 3, matriptase) as in vitro mediators of ENaC current. Since then, more serine‐, cysteine‐ and metalloproteases were confirmed as in vitro CAPs that potentially cleave and regulate ENaC, and thus this nomenclature was not further followed, but is accepted as functional term or alias. The precise mechanism of ENaC modulation by proteases has not been fully elucidated. Studies in organ‐specific protease knockout models revealed evidence for their role in increasing ENaC activity, although the proteases responsible for ENaC activation are yet to be identified. We summarize recent findings in animal models of these CAPs with respect to their implication in ENaC activation. We discuss the consequences of dysregulated CAPs underlying epithelial phenotypes in pathophysiological conditions, and the role of selected protease inhibitors. We believe that these proteases may present interesting therapeutic targets for diseases with aberrant sodium homoeostasis. [ABSTRACT FROM AUTHOR]

Hepatoblastoma is the most common pediatric liver tumor, but little research has been done on the role of macrophages in hepatoblastoma. The purpose of this study was to gain insight into potential roles for macrophages in hepatoblastoma. Paraffin-embedded specimens from 56 patients who underwent surgical resection were examined with immunohistochemical staining for the macrophage-specific markers, Iba1 and CD163. Significant differences were seen among histological subtypes. Significantly increased numbers of macrophages were detected in embryonal components compared to fetal components in the mixed epithelial type. In vitro studies using human monocyte-derived macrophages and two hepatoblastoma cell lines (HepG2 and Huh6) were performed. Conditioned medium from these cell lines induced increased CD163 expression in macrophages. Direct co-culture with macrophages induced tumor cell proliferation via induction of protumor cytokine secretion from macrophages. Direct co-culture with macrophages also induced interleukin (IL)-34 overexpression by Huh6 cells via Brd4 signaling. IL-34 overexpression promoted tumor cell proliferation and chemoresistance. High IL-34 and Brd4 expression was detected in embryonal components, which have potentially higher proliferation activity than fetal components. In conclusion, IL-34 expression in embryonal components may induce macrophage chemotaxis in a paracrine manner, and tumor cell proliferation and chemoresistance in an autocrine manner. IL-34 is a potential therapeutic target for hepatoblastoma. [ABSTRACT FROM AUTHOR]

The mechanisms whereby neutrophils respond differentially to live and dead organisms are unknown. We show here that neutrophils produce 5‐ to 30‐fold higher levels of the Cxcl2 chemokine in response to live bacteria, compared with killed bacteria or isolated bacterial components, despite producing similar levels of Cxcl1 or pro‐inflammatory cytokines. Secretion of high levels of Cxcl2, which potently activates neutrophils by an autocrine mechanism, requires three signals. The first two signals are provided by two different sets of signal peptides released by live bacteria, which selectively activate formylated peptide receptor 1 (Fpr1) and Fpr2, respectively. Signal 3 originates from Toll‐like receptor activation by microbial components present in both live and killed bacteria. Mechanistically, these signaling pathways converge at the level of the p38 MAP kinase, leading to activation of the AP‐1 transcription factor and to Cxcl2 induction. Collectively, our data demonstrate that the simultaneous presence of agonists for Fpr1, Fpr2, and Toll‐like receptors represents a unique signature associated with viable bacteria, which is sensed by neutrophils and induces Cxcl2‐dependent autocrine cell activation. SYNOPSIS: The presence of viable bacteria is signaled in neutrophils by the simultaneous stimulation of formylated peptide receptor 1 (Fpr1), Fpr2 and toll like receptors. This leads to high‐level production of Cxcl2 and ROS, and to maximal cell activation. Neutrophils produce much higher levels of the Cxcl2 chemokine in response to live bacteria, compared with killed bacteria or isolated bacterial components.High‐level Cxcl2 production is recapitulated by the simultaneous stimulation with agonists for toll‐like receptors, formylated peptide receptor 1 and formylated peptide receptor 2.These stimulation pathways converge at the level of the p38 MAP kinase, leading to activation of the AP‐1 transcription factor and to Cxcl2 induction. [ABSTRACT FROM AUTHOR]

Uterine leiomyomas, the most common tumors of the female reproductive system, are known to have a hypoxic microenvironment. However, the role of such environment in leiomyoma pathobiology remains unknown. The objective was to determine the effects of hypoxia on leiomyoma cells, and the mechanisms. We found that hypoxia induces proliferation and inhibits apoptosis in human leiomyoma cells. This pro-proliferative effect was accompanied by an increase in reactive oxygen species (ROS) generation and the expression of NADPH oxidase 4 (NOX4). The specific NOX4 inhibitor GLX351322 abrogated this hypoxia-induced ROS generation, cellular proliferation, and apoptosis inhibition. To further investigate the mechanism of NOX4-mediated proliferation, we treated leiomyoma cells grown in normoxia with media from leiomyoma cells cultured under hypoxia. This resulted in increased ROS generation and NOX4 expression, suggesting the hypoxia-induced effects are mediated by an autocrine mechanism. We worked to identify the nature of this autocrine factor. We found that the expression of TGF-β3 and its downstream signaling target pSmad3, are increased in hypoxic leiomyoma cells. To examine the hypothesis that TGF-β3 is, at least, a part of this autocrine mechanism, we treated hypoxic leiomyoma cells with the HIF-1α inhibitor KC7F2 which we discovered to ameliorate the hypoxia-induced TGF-β3 expression. Furthermore, pharmacologic inhibition with the TGF-β/Smad inhibitor SB431542 reduced hypoxia-induced NOX4 expression and ROS generation and attenuated cell proliferation. Thus, we have identified a novel mechanism by which hypoxia induces proliferation in leiomyoma cells. This finding adds to our understanding of leiomyoma pathobiology and can help in identifying new therapeutic targets. [ABSTRACT FROM AUTHOR]

The tracheal epithelium is a primary target for pulmonary diseases as it provides a conduit for air flow between the environment and the lung lobes. The cellular and molecular mechanisms underlying airway epithelial cell proliferation and differentiation remain poorly understood. Hedgehog (HH) signaling orchestrates communication between epithelial and mesenchymal cells in the lung, where it modulates stromal cell proliferation, differentiation and signaling back to the epithelium. Here, we reveal a previously unreported autocrine function of HH signaling in airway epithelial cells. Epithelial cell depletion of the ligand sonic hedgehog (SHH) or its effector smoothened (SMO) causes defects in both epithelial cell proliferation and differentiation. In cultured primary human airway epithelial cells, HH signaling inhibition also hampers cell proliferation and differentiation. Epithelial HH function is mediated, at least in part, through transcriptional activation, as HH signaling inhibition leads to downregulation of cell type-specific transcription factor genes in both the mouse trachea and human airway epithelial cells. These results provide new insights into the role of HH signaling in epithelial cell proliferation and differentiation during airway development. [ABSTRACT FROM AUTHOR]

The sympathetic nervous system (SNS) contributes to immune balance by promoting anti-inflammatory B cells. However, whether B cells possess a self-regulating mechanism by which they modulate regulatory B cell (Breg) function is not well understood. In this study, we investigated the ability of B cells to synthesize their own catecholamines upon stimulation with different B cell activators and found that expression of the enzyme tyrosine hydroxylase (TH), required to generate catecholamines, is up-regulated by Toll-like receptor (TLR)9. This TLR9-dependent expression of TH correlated with up-regulation of adrenergic receptors (ADRs), enhanced interleukin (IL)-10 production, and overexpression of the co-inhibitory ligands programmed death ligand 1 (PD-L1) and Fas ligand (FasL). Moreover, concomitant stimulation of ß1-3-ADRs together with a B cell receptor (BCR)/TLR9 stimulus clearly enhances the anti-inflammatory potential of Bregs to suppress CD4 T cells, a crucial population in the pathogenesis of autoimmune diseases, like rheumatoid arthritis (RA). Furthermore, TH up-regulation was also demonstrated in B cells during the course of collagen-induced arthritis (CIA), a mouse model for the investigation of RA. In conclusion, our data show that B cells possess an autonomous mechanism to modulate their regulatory function in an autocrine and/or paracrine manner. These findings help to better understand the function of B cells in the regulation of autoimmune diseases and the interplay of SNS. The sympathetic nervous system produces neurotransmitters such as catecholamines which contribute to immune balance by promoting anti-inflammatory B cells. This study shows that mouse B cells can themselves synthesize, sense, and transport catecholamines, which in turn modulate regulatory B cell function in an autocrine and/or paracrine manner to suppress T cell proliferation. [ABSTRACT FROM AUTHOR]

While current oral antiplatelet therapies benefit many patients, they deregulate the hemostatic balance leaving patients at risk of systemic side-effects such as hemorrhage. Dual antiplatelet treatment is the standard approach, combining aspirin with P2Y12 blockers. These therapies mainly target autocrine activation mechanisms (TxA2, ADP) and, more recently, the use of thrombin or thrombin receptor antagonists have been added to the available approaches. Recent efforts to develop new classes of anti-platelet drugs have begun to focus on primary platelet activation pathways such as through the immunoreceptor tyrosine-based activation motif (ITAM)-containing collagen receptor GPVI/FcRγ-chain complex. There are already encouraging results from targeting GPVI, with reduced aggregation and smaller arterial thrombi, without major bleeding complications, likely due to overlapping activation signaling pathways with other receptors such as the GPIb–V–IX complex. An alternative approach to reduce platelet activation could be to inhibit this signaling pathway by targeting the inhibitory pathways intrinsic to platelets. Stimulation of endogenous negative modulators could provide more specific inhibition of platelet function, but is this feasible? In this review, we explore the potential of the two major platelet immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing inhibitory receptors, G6b-B and PECAM-1, as antithrombotic targets. [ABSTRACT FROM AUTHOR]

Chronic wounds continue to be a substantial public health concern contributing to both humanistic and economic burden worldwide. The magnitude of chronic wounds as a global healthcare crisis is likely to increase due to the rising geriatric and diabetic population, demanding novel therapeutic approaches that can restore the functionality of the skin at a reduced cost. Stem cell therapy has been widely acknowledged as a promising strategy for the repair of damaged tissues due to its regenerative potential. This potential attributes to a concoction of bioactive molecules secreted by the stem cells, collectively called the secretome, that mediates paracrine and autocrine functions. Among the stem cell types, adipose tissue-derived mesenchymal stem cells (ADMSCs) have been receiving increased attention for its ease of isolation, abundance in tissue and notable impact on improving chronic wound healing. Owing to the reported advantages of cell-free preparations like the secretome over cellular products, developing secretome as a ready-to-use product for wound healing applications seems promising. In this review, we discuss the functional benefits of adipose stem cell secretome in wound healing, the techniques to enrich the secretome and the recommendations for the scale-up and commercialization of secretome products. [ABSTRACT FROM AUTHOR]

IL-6 has been suggested to function as an autocrine mitogen in the psoriatic epidermis. The biological activity of IL-6 relies on interactions with its receptors, including the membrane-bound IL-6 receptor (mIL-6R) and soluble IL-6 receptor (sIL-6R). Our study presents data showing that the levels of plasma IL-6 and sIL-6R were elevated in psoriatic patients. Genotyping of two single-nucleotide polymorphisms (SNPs) in IL-6R (rs4845617 and rs2228145) demonstrated that the SNP IL-6R (rs4845617) rather than IL-6R (rs2228145) shows a significant association with psoriasis (P = 0.006). To verify the functions of sIL-6R, cultured keratinocytes and imiquimod (IMQ)-induced psoriatic model mice were treated with sIL-6R. We found that the presence of sIL-6R in the HaCaT cell culture medium enhanced the IL-6-induced Stat3 activation, which resulted in abnormal keratinocyte proliferation and aberrant differentiation. Furthermore, the application of sIL-6R in vivo accelerated the pathological development of the disease. Our results demonstrate for the first time that genetic polymorphisms in the IL-6R gene are associated with psoriasis disease phenotypes in a Chinese psoriatic patient population; sIL-6R-mediated trans-signaling pathway plays a pivotal role in keratinocyte proliferation and differentiation, suggesting potential therapeutics for psoriasis. Key messages: Patients with psoriasis displayed higher levels of IL-6 and sIL-6R compared with healthy controls. Analysis of genotypes revealed that IL-6R rs4845617 GG genotype associated with the risk of psoriasis. Supplement of sIL-6R further enhanced IL-6-induced Stat3 activation in keratinocytes. In vivo administration of sIL-6R accelerated, whereas sgp130FC alleviated, the pathological development of psoriasis. [ABSTRACT FROM AUTHOR]

"Essential" hypertension is related to multiple mechanisms that affect cardiac output and peripheral resistance and is a consequence of the interaction between external factors and genetic factors. Neuro-hormonal factors are essential in the pathophysiology of hypertension and among them the renin-angiotensin-aldosterone system (RAAS) has a main role in the physiological and pathological response of the cardiovascular system. RAAS functions as an endocrine system, but also has paracrine and autocrine functions in many tissues and organs. RAAS regulates extracellular fluid volume and peripheral resistance via systemic and local actions in various tissues. RAAS also participates in endothelial dysfunction, inflammation and vascular fibrosis, cardiac fibrosis and cardiovascular remodelling, with worsening hypertension and target organ injury. Aldosterone is involved in "essential" hypertension via discrete variations in the regulation of aldosterone synthesis in the absence of confirmed primary hyperaldosteronism. A complete evaluation of these systems is needed for a thorough understanding of hypertension. [ABSTRACT FROM AUTHOR]

Brown and beige adipose tissues are the primary sites for adaptive non-shivering thermogenesis. Although they have been known principally for their thermogenic effects, in recent years, it has emerged that, just like white adipose tissue (WAT), brown and beige adipose tissues also play an important role in the regulation of metabolic health through secretion of various brown adipokines (batokines) in response to various physiological cues. These secreted batokines target distant organs and tissues such as the liver, heart, skeletal muscles, brain, WAT, and perform various local and systemic functions in an autocrine, paracrine, or endocrine manner. Brown and beige adipose tissues are therefore now receiving increasing levels of attention with respect to their effects on various other organs and tissues. Identification of novel secreted factors by these tissues may help in the discovery of drug candidates for the treatment of various metabolic disorders such as obesity, type-2 diabetes, skeletal deformities, cardiovascular diseases, dyslipidemia. In this review, we comprehensively describe the emerging secretory role of brown/beige adipose tissues and the metabolic effects of various brown/beige adipose tissues secreted factors on other organs and tissues in endocrine/paracrine manners, and as well as on brown/beige adipose tissue itself in an autocrine manner. This will provide insights into understanding the potential secretory role of brown/beige adipose tissues in improving metabolic health. Brown/Beige adipocytes originate from distinct precursor cells and secrete various factors known as batokines. The batokines then target distant organs and tissues and perform various functions in an autocrine, paracrine, and endocrine manner. [Display omitted] • Previously, Brown/beige adipose tissues were known only for their thermogenic effects. • Recently, it has been revealed that brown/beige adipose tissues have also secretory role. • Brown/beige adipose tissues secrete various adipokines known as batokines. • The secreted batokines target distant organs and tissues, and as well as BAT itself. • Batokines play an important role in the regulation of metabolic health. [ABSTRACT FROM AUTHOR]

Silicosis is an occupational fibrotic lung disease caused by inhaling large amounts of crystalline silica dust. Transforming growth factor-β1 (TGF-β1), which is secreted from macrophages, has an important role in the development of this disease. Macrophages can recognize and capture silicon dust, undergo M2 polarization, synthesize TGF-β1 precursors, and secrete them out of the cell where they are activated. Activated TGF-β1 induces cells from different sources, transforming them into myofibroblasts through autocrine and paracrine mechanisms, ultimately causing silicosis. These processes involve complex molecular events, which are not yet fully understood. This systematic summary may further elucidate the location and development of pulmonary fibrosis in the formation of silicosis. In this review, we discussed the proposed cellular and molecular mechanisms of production, secretion, activation of TGF-β1, as well as the mechanisms through which TGF-β1 induces cells from three different sources into myofibroblasts during the pathogenesis of silicosis. This study furthers the medical understanding of the pathogenesis and theoretical basis for diagnosing silicosis, thereby promoting silicosis prevention and treatment. [ABSTRACT FROM AUTHOR]

Lipoprotein metabolism is critical to inflammation. While the periphery and central nervous system (CNS) have separate yet connected lipoprotein systems, impaired lipoprotein metabolism is implicated in both cardiometabolic and neurological disorders. Despite the substantial investigation into the composition, structure and function of lipoproteins, the lipoprotein oxylipin profiles, their influence on lipoprotein functions, and their potential biological implications are unclear. Lipoproteins carry most of the circulating oxylipins. Importantly, lipoprotein-mediated oxylipin transport allows for endocrine signaling by these lipid mediators, long considered to have only autocrine and paracrine functions. Alterations in plasma lipoprotein oxylipin composition can directly impact inflammatory responses of lipoprotein metabolizing cells. Similar investigations of CNS lipoprotein oxylipins are non-existent to date. However, as APOE4 is associated with Alzheimer's disease-related microglia dysfunction and oxylipin dysregulation, ApoE4-dependent lipoprotein oxylipin modulation in neurological pathologies is suggested. Such investigations are crucial to bridge knowledge gaps linking oxylipin- and lipoprotein-related disorders in both periphery and CNS. Here, after providing a summary of existent literatures on lipoprotein oxylipin analysis methods, we emphasize the importance of lipoproteins in oxylipin transport and argue that understanding the compartmentalization and distribution of lipoprotein oxylipins may fundamentally alter our consideration of the roles of lipoprotein in cardiometabolic and neurological disorders. [ABSTRACT FROM AUTHOR]

In ovarian carcinoma, anti-Müllerian hormone (AMH) type II receptor (AMHRII) and the AMH/AMHRII signaling pathway are potential therapeutic targets. Here, AMH dose-dependent effect on signaling and proliferation was analyzed in four ovarian cancer cell lines, including sex cord stromal/granulosa cell tumors and high grade serous adenocarcinomas (COV434-AMHRII, SKOV3-AMHRII, OVCAR8 and KGN). As previously shown, incubation with exogenous AMH at concentrations above the physiological range (12.5–25 nM) decreased cell viability. Conversely, physiological concentrations of endogenous AMH improved cancer cell viability. Partial AMH depletion by siRNAs was sufficient to reduce cell viability in all four cell lines, by 20% (OVCAR8 cells) to 40% (COV434-AMHRII cells). In the presence of AMH concentrations within the physiological range (5 to 15 pM), the newly developed anti-AMH B10 antibody decreased by 25% (OVCAR8) to 50% (KGN) cell viability at concentrations ranging between 3 and 333 nM. At 70 nM, B10 reduced clonogenic survival by 57.5%, 57.1%, 64.7% and 37.5% in COV434-AMHRII, SKOV3-AMHRII, OVCAR8 and KGN cells, respectively. In the four cell lines, B10 reduced AKT phosphorylation, and increased PARP and caspase 3 cleavage. These results were confirmed in ovarian cancer cells isolated from patients' ascites, demonstrating the translational potential of these results. Furthermore, B10 reduced COV434-MISRII tumor growth in vivo and significantly enhanced the median survival time compared with vehicle (69 vs 60 days; p = 0.0173). Our data provide evidence for a novel pro-survival autocrine role of AMH in the context of ovarian cancer, which was targeted therapeutically using an anti-AMH antibody to successfully repress tumor growth. [ABSTRACT FROM AUTHOR]

The interface between the mammalian host and its environment is formed by barrier tissues, for example, of the skin, and the respiratory and the intestinal tracts. On the one hand, barrier tissues are colonized by site‐adapted microbial communities, and on the other hand, they contain specific myeloid cell networks comprising macrophages, dendritic cells, and granulocytes. These immune cells are tightly regulated in function and cell number, indicating important roles in maintaining tissue homeostasis and immune balance in the presence of commensal microorganisms. The regulation of myeloid cell density and activation involves cell‐autonomous 'single‐loop circuits' including autocrine mechanisms. However, an array of microenvironmental factors originating from nonimmune cells and the microbiota, as well as the microanatomical structure, impose additional layers of regulation onto resident myeloid cells. This review discusses models integrating these factors into cell‐specific programs to instruct differentiation and proliferation best suited for the maintenance and renewal of immune homeostasis in the tissue‐specific environment. [ABSTRACT FROM AUTHOR]

Vitamin D (calciferol), measured by maternal serum 1,25-dihydroxyvitamin D, is important for the fetal-placental unit development. Decidua and trophoblast cells express vitamin D receptor and 1α-OHase, suggesting an autocrine or paracrine role for 1,25(OH)2D3 for fetal and placental development. During pregnancy, maternal circulating levels of 1,25(OH)2D3 double with the advancing gestation age, resulting in a concomitant increase in calcium uptake by the maternal intestine, with a concomitant decrease in calcium serum levels. In this narrative review, we want to highlight the current knowledge regarding vitamin D and pregnancy. A literature research was performed. The significant data were extracted and summarized in tables. It remains to validate whether the measurement of vitamin D levels and vitamin D supplementation (and calcium) during pregnancy should be recommended. Further studies are recommended to demonstrate any connection between the 25-OH-D level and prematurity, gestational diabetes and low birth weight, and, if present, to specify when and how vitamin D level should be dosed. [ABSTRACT FROM AUTHOR]

The neuropeptide Y (NPY) system is considered one of the primary neural signaling pathways. NPY, produced by osteoblasts and other peripheral tissues, is known to inhibit biological functions of osteoblasts. However, until recently, little was known of the autocrine mechanism by which NPY is regulated. To investigate this mechanism, overexpression plasmids and small interfering RNA (siRNA) targeting NPY were transfected into the MC3T3-E1 cell line to observe its effects on osteogenesis. NPY overexpression was found to markedly enhance the osteogenic ability of MC3T3-E1 cells by an autocrine mechanism, coincident with the upregulation of osterix and runt-related transcription factor 2 (Runx2). Furthermore, NPY increased the activities of alkaline phosphatase (ALP) and osteocalcin (OCN) by upregulating their osteoblastic expression in vitro (as well as that of osterix and Runx2). Following transfection with NPY-siRNA, the osteoblastic ability of MC3T3-E1 cells was markedly decreased, and NPY deficiency inhibited the protein expression of osterix, Runx2, OCN and ALP in primary osteoblasts. Collectively, these results indicated that NPY played an important role in osteoblast differentiation by regulating the osterix and Runx2 pathways. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) affects nearly 10% of the population of the United States and other industrialized countries and, at present, short of surgical joint replacement, there is no therapy available that can reverse the progression of the disease. Adenosine, acting at its A2A receptor (A2AR), is a critical autocrine factor for maintenance of cartilage homeostasis and here we report that injection of liposomal suspensions of either adenosine or a selective A2AR agonist, CGS21680, significantly reduced OA cartilage damage in a murine model of obesity-induced OA. The same treatment also improved swelling and preserved cartilage in the affected knees in a rat model of established post-traumatic OA (PTOA). Differential expression analysis of mRNA from chondrocytes harvested from knees of rats with PTOA treated with liposomal A2AR agonist revealed downregulation of genes associated with matrix degradation and upregulation of genes associated with cell proliferation as compared to liposomes alone. Studies in vitro and in affected joints demonstrated that A2AR ligation increased the nuclear P-SMAD2/3/P-SMAD1/5/8 ratio, a change associated with repression of terminal chondrocyte differentiation. These results strongly suggest that targeting the A2AR is an effective approach to treat OA. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor-A (VEGF) is the angiogenic factor promoting the pathological neovascularization in age-related macular degeneration (AMD) or diabetic macular edema (DME). Evidences have suggested a neurotrophic and neuroprotective role of VEGF, albeit in retina, cellular mechanisms underlying the VEGF neuroprotection remain elusive. Using purified adult retinal ganglion cells (RGCs) in culture, we demonstrated here that VEGF is released by RGCs themselves to promote their own survival, while VEGF neutralization by specific antibodies or traps drastically reduced the RGC survival. These results indicate an autocrine VEGF neuroprotection on RGCs. In parallel, VEGF produced by mixed retinal cells or by mesenchymal stem cells exerted a paracrine neuroprotection on RGCs. Such neuroprotective effect was obtained using the recombinant VEGF-B, suggesting the involvement of VEGF-R1 pathway in VEGF-elicited RGC survival. Finally, glaucomatous patients injected with VEGF traps (ranibizumab or aflibercept) due to either AMD or DME comorbidity, showed a significant reduction of RGC axon fiber layer thickness, consistent with the plausible reduction of the VEGF autocrine stimulation of RGCs. Our results provide evidence of the autocrine neuroprotective function of VEGF on RGCs is crucially involved to preserve injured RGCs such as in glaucomatous patients. [ABSTRACT FROM AUTHOR]

Summary: Root hair (RH) size has vital physiological implications, since it influences the surface area of the root and thus the ability of the plant to absorb water and nutrients from the soil. Arabidopsis ROOT HAIR DEFECTIVE 6‐LIKE 4 (RSL4), a bHLH transcription factor, controls the expression of hundreds of RH genes, and RSL4 expression itself can trigger ectopic RH growth. Recent studies reveal an autocrine mechanism governing plant RH cell growth in which the extracellular peptide RAPID ALKALINIZATION FACTOR 1 (RALF1) and receptor FERONIA (FER) act as a central hub between the cell surface and downstream signaling events. RALF1‐FER promotes the phosphorylation of eIF4E1. Then, phosphorylated eIF4E1 further regulates the synthesis of RH proteins, including RSL4, to promote RH growth. High levels of RSL4 exert a negative feedback on RALF1 expression via directly binding to the RALF1 gene promoter, slowing RH growth and determining final RH cell size. [ABSTRACT FROM AUTHOR]

Using the isopod Armadillidium vulgare as a case study, we review the significance of the "bacterial dosage model", which connects the expression of the extended phenotype to the rise of the Wolbachia load. In isopods, the Insulin-like Androgenic Gland hormone (IAG) induces male differentiation: Wolbachia feminizes males through insulin resistance, presumably through defunct insulin receptors. This should prevent an autocrine development of the androgenic glands so that females differentiate instead: feminization should translate as IAG silencing and increased Wolbachia load in the same developmental window. In line with the autocrine model, uninfected males expressed IAG from the first larval stage on, long before the androgenic gland primordia begin to differentiate, and exponentially throughout development. In contrast in infected males, expression fully stopped at stage 4 (juvenile), when male differentiation begins. This co-occurred with the only significant rise in the Wolbachia load throughout the life-stages. Concurrently, the raw expression of the bacterial Secretion Systems co-increased, but they were not over-expressed relative to the number of bacteria. The isopod model leads to formulate the "bacterial dosage model" throughout extended phenotypes as the conjunction between bacterial load as the mode of action, timing of multiplication (pre/post-zygotic), and site of action (soma vs. germen). [ABSTRACT FROM AUTHOR]

Introduction: The liver is well known for its enormous regenerative capacity. If the hepatocytes are compromised the reserve stem cells can regrow the lost tissue by means of oval cells differentiating into hepatocytes. We were curious whether this standby system was able to compensate for ontogenic liver growth arrested by 2-acetylaminofluorene (AAF) treatment or if it can be influenced by cholic acid, known to promote liver growth in several reactions. Methods: (i) Four weeks-old (60-70g) male F344 rats were kept on standard chow and treated with solvent only, (ii) others were kept on 0,2% cholic acid (CA) enriched diet, (iii) treated with AAF, or (iiii) given a combination of CA diet and AAF treatment (AAF/CA). The proliferative response of epithelial cells was characterized by pulse bromodeoxyuridine labelling. The relative gene expression levels of senescence-related factors and bile acid receptors were determined by quantitative real-time polymerase chain reaction analysis. Results: AAF administration efficiently inhibited the physiological proliferation of hepatocytes in young, male F344 rats after weaning. The activation of stem cells was indicated by the increased proliferation of periportal biliary/oval cells (B/OC). If the rats were fed additionally by cholic acid enriched diet, typical oval cell reaction emerged, subsequently the oval cells differentiated into hepatocytes restituting liver growth. This reaction was mediated by increased production of HGF, IL-6 and SCF by the damaged liver. Moreover, upregulation of FXR expression on B/OC made them competent for bile acids. Our results indicate that endogenous, autocrine mechanisms involved in liver ontogeny are also able to activate the backup regenerative machinery of stem cells. [ABSTRACT FROM AUTHOR]

Acute lung injury is a major complication of hemorrhagic shock and the required resuscitation with large volumes of crystalloid fluids and blood products. We previously identified a role of macrophagederived chemokine (CCL22/MDC) pulmonary inflammation following hemorrhage and resuscitation. However, further details regarding the induction of CCL22/MDC and its precise role in pulmonary inflammation after trauma remain unknown. In the current study we used in vitro experiments with a murine alveolar macrophage cell line, as well as an in vivo mouse model of hemorrhage and resuscitation, to identify key regulators in CCL22/MDC production. We show that trauma induces expression of IFNγ, which leads to production of CCL22/MDC through a signaling mechanism involving p38 MAPK, NF-κB, JAK, and STAT-1. IFNγ also activates TNFα production by alveolar macrophages, potentiating CCL22/MDC production via an autocrine mechanism. Neutralization of IFNγ or TNFα with specific antibodies reduced histological signs of pulmonary injury after hemorrhage and reduced inflammatory cell infiltration into the lungs. [ABSTRACT FROM AUTHOR]

Background. Interleukin 6 (IL6) is a multifunctional cytokine produced by various cells, including vascular endothelial cells. IL6 has both pro- and non-/anti-inflammatory functions, and the response to IL6 is dependent on whether it acts via the membrane-bound IL6 receptor α (IL6Rα) (classic signaling) or the soluble form of the receptor (transsignaling). As human endothelial cells produce IL6 and at the same time express IL6Rα, we hypothesized that IL6 may have autocrine functions. Methods. Knockdown of IL6 in cultured human endothelial cells was performed using siRNA. Knockdown efficiency was evaluated using ELISA. RNA sequencing was employed to characterize the transcriptional consequence of IL6 knockdown, and Ingenuity Pathway Analysis was used to further explore the functional roles of IL6. Results. Knockdown of IL6 in cultured endothelial cells resulted in a 84-92% reduction in the release of IL6. Knockdown of IL6 resulted in dramatic changes in transcriptional pattern; knockdown of IL6 in the absence of soluble IL6Rα (sIL6Rα) led to differential regulation of 1915 genes, and knockdown of IL6 in the presence of sIL6Rα led to differential regulation of 1967 genes (fold change 1.5, false discovery rate < 0.05). Pathway analysis revealed that the autocrine functions of IL6 in human endothelial cells are mainly related to basal cellular functions such as regulation of cell cycle, signaling, and cellular movement. Furthermore, we found that knockdown of IL6 activates functions related to adhesion, binding, and interaction of endothelial cells, which seem to be mediated mainly via STAT3. Conclusion. In this study, a large number of novel genes that are under autocrine regulation by IL6 in human endothelial cells were identified. Overall, our data indicate that IL6 acts in an autocrine manner to regulate basal cellular functions, such as cell cycle regulation, signaling, and cellular movement, and suggests that the autocrine functions of IL6 in human endothelial cells are mediated via IL6 classic signaling. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a degenerative joint disease that seriously affects the quality of life of patients. Irisin has been reported to regulate bone metabolism via the cellular autocrine mechanism and play a protective role in rat OA. In the present study, a SW1353 chondrosarcoma cell line was treated with interleukin (IL)-1β and irisin. The present study evaluated cell viability, expression levels of collagen II (Col II) and matrix metalloproteinase-13 (MMP-13), and activity of the Wnt/β-catenin and NF-κB signaling pathways in treated SW1353 cells. The present results suggested that IL-1β could decrease Col II expression and increase MMP-13 expression at both the mRNA and protein levels, and also activate the Wnt/β-catenin and NF-κB signaling pathways in SW1353 cells. By contrast, irisin was identified to reverse the effects of IL-1β in IL-1β-induced SW1353 cells. The present results suggested that irisin treatment may have a cartilage-protective role in an IL-1β-induced SW1353 cell model. [ABSTRACT FROM AUTHOR]

Inhibins are glycoproteins which belong to the transforming growth factor beta family (TGF-ß), which contains more than 60 proteins as well as activins, which are structurally similar but differ in terms of function. Inhibins in women are formed in the ovarian granulosa cells, inhibin A is also produced during pregnancy by the yellow body and the placenta. Inhibins play an important role in the regulation of folliculogenesis and oocyte maturation. In males, inhibins are predominantly produced in the testicular Sertoli cells and in a smaller quantity also in the Leydig cells. Their synthesis is stimulated by the effects of androgens but is primarily regulated by spermatogenesis. Currently, it is also clear that the function of inhibins include a much broader spectrum of effects, which are not only related to the reproductive system. In pregnancy, the source of inhibin A is the yellow body and later the placenta. Inhibin (and also activin) have a paracrine and autocrine function in the human placenta and locally affect the production of hormones in the placenta, cellular immunity, cell growth and differentiation of the placenta and embryo. Placental cytotrophoblast and syncytiotrophoblast secrete inhibin A, which inhibits the placental secretion hCG and progesterone. In some cases, biochemical markers that are produced by the placenta during pregnancy are used as markers for Down syndrome screening. It has been discovered that an increase in the level of inhibin A is to some degree associated with the presence of Down syndrome and may be used in combination with other biochemical markers produced by the fetoplacental unit as a biochemical screening marker. [ABSTRACT FROM AUTHOR]

Background: CXCL12(chemokine ligand 12, CXCL12) and its receptors CXCR4 are widely expressed in maternal-fetal interface and plays an adjust role in materno-fetal dialogue and immune tolerance during early pregnancy. This study aimed to evaluate the role and mechanism of self-derived CXCL12 in modulating the functions of human first-trimester endometrial epithelial cells (EECs) and to identify the potential protein kinase signaling pathways involved in the CXCL12/CXCR4's effect on EECs.Methods: The expression of CXCL12 and CXCR4 in EECs was measured by using immunohistochemistry, immunofluorescence, real-time polymerase chain reaction and enzyme-linked immunosorbent assay. The effects of EEC-conditioned medium (EEC-CM) and recombinant human CXCL12 (rhCXCL12) on EEC migration and invasion in vitro were evaluated with migration and invasion assays. In-cell western blot analysis was used to examine the phosphorylation of protein kinase B (AKT), extracellular regulated protein kinases (ERKs) and phosphatidylinositol 3-kinase (PI3K) after CXCL12 treatment.Results: CXCL12 and CXCR4 were both expressed in human first-trimester EECs at the mRNA and protein level. Both EEC-CM and rhCXCL12 significantly increased the migration and invasion of EECs (P < 0.05), which could be blocked by neutralizing antibodies against CXCR4 (P < 0.05) or CXCL12 (P < 0.05), respectively. CXCL12 activated both PI3K/AKT and ERK1/2 signaling and CXCR4 neutralizing antibody effectively reduced CXCL12-induced phosphorylation of AKT and ERK1/2. LY294002, a PI3K-AKT inhibitor, was able to reverse the promotive effect of EEC-CM or rhCXCL12 on EEC migration and invasion.Conclusions: Human first-trimester EECs promoted their own migration and invasion through the autocrine mechanism with CXCL12/CXCR4 axis involvement by activating PI3K/AKT signaling. This study contributes to a better understanding of the epithelium function mediated by chemokine and chemokine receptor during normal pregnancy. [ABSTRACT FROM AUTHOR]

A link between periodontitis and atherothrombosis has been highlighted. The aim of this study was to determine the influence of Porphyromonas gingivalis on endothelial microvesicles (EMVPg) shedding and their contribution to endothelial inflammation. Endothelial cells (EC) were infected with P. gingivalis (MOI = 100) for 24 h. EMVPg were isolated and their concentration was evaluated by prothrombinase assay. EMVPg were significantly increased in comparison with EMVCtrl shedded by unstimulated cells. While EMVCtrl from untreated EC had no effect, whereas, the proportion of apoptotic EC was increased by 30 nM EMVPg and viability was decreased down to 25%, a value elicited by P. gingivalis alone. Moreover, high concentration of EMVPg (30 nM) induced a pro-inflammatory and pro-oxidative cell response including up-regulation of TNF-α, IL-6 and IL-8 as well as an altered expression of iNOS and eNOS at both mRNA and protein level. An increase of VCAM-1 and ICAM-1 mRNA expression (4.5 folds and 3 folds respectively (p < 0.05 vs untreated) was also observed after EMVPg (30 nM) stimulation whereas P. gingivalis infection was less effective, suggesting a specific triggering by EMVPg. Kinasome analysis demonstrated the specific effect induced by EMVPg on main pro-inflammatory pathways including JNK/AKT and STAT. EMVPg are effective pro-inflammatory effectors that may have detrimental effect on vascular homeostasis and should be considered as potential autocrine and paracrine effectors involved in the link between periodontitis and atherothrombosis. [ABSTRACT FROM AUTHOR]