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Endocrinology Dec 2023Vasoinhibin, a proteolytic fragment of the hormone prolactin, inhibits blood vessel growth (angiogenesis) and permeability, stimulates the apoptosis and inflammation of...
Vasoinhibin, a proteolytic fragment of the hormone prolactin, inhibits blood vessel growth (angiogenesis) and permeability, stimulates the apoptosis and inflammation of endothelial cells, and promotes fibrinolysis. The antiangiogenic and antivasopermeability properties of vasoinhibin were recently traced to the HGR motif located in residues 46 to 48 (H46-G47-R48), allowing the development of potent, orally active, HGR-containing vasoinhibin analogues for therapeutic use against angiogenesis-dependent diseases. However, whether the HGR motif is also responsible for the apoptotic, inflammatory, and fibrinolytic properties of vasoinhibin has not been addressed. Here, we report that HGR-containing analogues are devoid of these properties. Instead, the incubation of human umbilical vein endothelial cells with oligopeptides containing the sequence HNLSSEM, corresponding to residues 30 to 36 of vasoinhibin, induced apoptosis, nuclear translocation of NF-κB, expression of genes encoding leukocyte adhesion molecules (VCAM1 and ICAM1) and proinflammatory cytokines (IL1B, IL6, and TNF), and adhesion of peripheral blood leukocytes. Also, intravenous or intra-articular injection of HNLSSEM-containing oligopeptides induced the expression of Vcam1, Icam1, Il1b, Il6, and Tnf in the lung, liver, kidney, eye, and joints of mice and, like vasoinhibin, these oligopeptides promoted the lysis of plasma fibrin clots by binding to plasminogen activator inhibitor-1 (PAI-1). Moreover, the inhibition of PAI-1, urokinase plasminogen activator receptor, or NF-κB prevented the apoptotic and inflammatory actions. In conclusion, the functional properties of vasoinhibin are segregated into 2 different structural determinants. Because apoptotic, inflammatory, and fibrinolytic actions may be undesirable for antiangiogenic therapy, HGR-containing vasoinhibin analogues stand as selective and safe agents for targeting pathological angiogenesis.
Topics: Humans; Plasminogen Activator Inhibitor 1; NF-kappa B; Interleukin-6; Human Umbilical Vein Endothelial Cells; Oligopeptides
PubMed: 38057149
DOI: 10.1210/endocr/bqad185 -
International Journal of Molecular... Nov 2023Pituitary neuroendocrine tumors (PitNETs) are divided into multiple histological subtypes, which determine their clinical and biological variable behavior. Despite their...
Pituitary neuroendocrine tumors (PitNETs) are divided into multiple histological subtypes, which determine their clinical and biological variable behavior. Despite their benign evolution, in some cases, prolactin (PRL) and growth hormone (GH)-secreting PitNETs may have aggressive behavior. In this study, we investigated the potential predictive role of ER∝, alongside the clinicopathological classification of PitNETs (tumor diameter, tumor type, and tumor grade). A retrospective study was conducted with 32 consecutive cases of PRL- and mixed GH- and PRL-secreting PitNETs (5 patients with prolactinomas and 27 with acromegaly, among them, 7 patients with GH- and PRL- co-secretion) who underwent transsphenoidal intervention. Tumor specimens were histologically and immunohistochemical examined: anterior pituitary hormones, ki-67 labeling index, CAM 5.2, and ER∝; ER∝ expression was correlated with basal PRL levels at diagnosis (rho = 0.60, < 0.01) and postoperative PRL levels (rho = 0.58, < 0.001). In our study, the ER∝ intensity score was lower in female patients. Postoperative maximal tumor diameter correlated with Knosp grade ( = 0.02); CAM 5.2 pattern (densely/sparsely granulated/mixed densely and sparsely granulated) was correlated with postoperative PRL level ( = 0.002), and with ki-67 ( < 0.001). The IGF1 level at diagnosis was correlated with the postoperative GH nadir value in the oral glucose tolerance test (OGTT) (rho = 0.52, < 0.05). Also, basal PRL level at diagnosis was correlated with postoperative tumor diameter ( = 0.63, < 0.001). At univariate logistic regression, GH nadir in OGTT test at diagnostic, IGF1, gender, and invasion were independent predictors of remission for mixed GH- and PRL-secreting Pit-NETs; ER∝ can be used as a prognostic marker and loss of ER∝ expression should be considered a sign of lower differentiation and a likely indicator of poor prognosis. A sex-related difference can be considered in the evolution and prognosis of these tumors, but further studies are needed to confirm this hypothesis.
Topics: Humans; Female; Adenoma; Retrospective Studies; Ki-67 Antigen; Pituitary Neoplasms; Prolactinoma; Prolactin; Neuroendocrine Tumors
PubMed: 38003353
DOI: 10.3390/ijms242216162 -
Toxins Nov 2023is a notorious zoonotic disease caused by , which can lead to reproductive diseases in humans and animals, such as infertility and abortion. Lipopolysaccharides (LPS)...
is a notorious zoonotic disease caused by , which can lead to reproductive diseases in humans and animals, such as infertility and abortion. Lipopolysaccharides (LPS) are the main virulence factor of . LPS derived from are different and non-classical and are less toxic and less active than LPS isolated from However, the effects and possible mechanisms of LPS-caused pregnancy loss remain to be revealed. In the present study, we investigated the effects of S2 LPS on early pregnancy loss in mice. The results indicated that embryo implantation failure was induced by LPS treatment in a dose-dependent manner. The injection of LPS mainly resulted in fibrinolysis in the decidual area of the uterus on the 6th day post coition (dpc), infiltration of large granular cells among the decidual cells near the embryo on the 8th dpc, a large number of gaps in the decidual area, and cell necrosis around the embryo. In addition, the expression of Cyclin D3 mRNA in the uterus on the 7th and 8th dpc and IGFBP-1 mRNA and the progesterone receptor in the uterus on the 6th and 7th dpc were also inhibited. Moreover, the expression of decidualization marker Cyclin D3 and decidualization prolactin-associated protein (dPRP) in endometrial stromal cells were also inhibited by LPS treatment in vitro. In summary, LPS affect the process of endometrial decidualization in mice by affecting the structure of the decidua and the expression of decidual marker factors in endometrial stromal cells.
Topics: Pregnancy; Humans; Female; Mice; Animals; Decidua; Lipopolysaccharides; Brucella suis; Cyclin D3; Escherichia coli; Uterus; RNA, Messenger
PubMed: 37999525
DOI: 10.3390/toxins15110662 -
Pharmacological Research Dec 2023The burden of metabolic disorders is alarmingly increasing globally. On the other hand, sustainability is the key project of the 21st century. Natural products offer a... (Review)
Review
The burden of metabolic disorders is alarmingly increasing globally. On the other hand, sustainability is the key project of the 21st century. Natural products offer a coherent option for the complementary management of both these challenges. Ficus carica (FC), commonly known as the fig fruit, has an experimentally proven potency for the modulation of cell cycle, immunity, inflammation, metabolism, and oxidative stress. Here, we review the potential of FC-derived products (FCDP) in slowing down the progression of cancers, acute/chronic inflammation-related conditions, infections, metabolic disorders, toxicities, neurological and neuromuscular diseases, gastrointestinal disorders, vascular diseases, and skin-stressing conditions, as well as, in boosting normal healthy functions of the endocrine, immune, metabolic, and nervous systems. It reveals a variety of cellular and molecular targets for FCDP: cytokines (TNF-α, IL-1β, IL-6, IL-10, IL-12, IL-18, IFN-γ), chemokines (CCL2), other inflammatory mediators (CRP, PGE2), immune receptors (TLR-2, TLR-4, FcεRI), oxidative stress-related markers (SOD, GSH, MDA, GPx, catalase, ROS, NO, protein carbonyls), kinases (MAPKs, hexokinase, G6Pase, FBPase, PEPCK, Akt, AMPK, GSK3, CDKs), other enzymes (COX-2, iNOS, MMPs, caspases), growth factors/receptors (VEGF, EGFR), hormones (DHEAS, prolactin, GnRH, FSH, LH, estradiol, DHT, insulin), cell death-related markers (Bcl-2, Bax, Bak, FasL, gasdermins, cytochrome C), glucose transporter protein (Glut4), and transcription factors (NF-κB, HNF-4α, Foxo, PGC-1α, PPAR-γ, C/EBP-α, CREB, NFATC1, STAT3). FCDP cause both activation and inhibition of AMPK, MAPK, and NF-κB signaling to confer condition-specific advantages. Such a broad-range activity might be attributed to different mechanisms of action of FCDP in modulating functions within the classical immunometabolic system, but also beyond.
Topics: Humans; NF-kappa B; Ficus; AMP-Activated Protein Kinases; Glycogen Synthase Kinase 3; Inflammation; Metabolic Diseases
PubMed: 37995897
DOI: 10.1016/j.phrs.2023.107010 -
Journal of Ovarian Research Nov 2023The prolactin receptor gene (PRLR) may contribute to polycystic ovarian syndrome (PCOS) since it plays important roles in physiological ovarian functions. PRLR-knockout...
The prolactin receptor gene (PRLR) may contribute to polycystic ovarian syndrome (PCOS) since it plays important roles in physiological ovarian functions. PRLR-knockout mice have irregular cycles and subfertility and variants in or around the PRLR gene were associated in humans with female testosterone levels and recurrent miscarriage. We tested 40 variants in the PRLR gene in 212 Italian families phenotyped by type 2 diabetes (T2D) and PCOS and found two intronic PRLR-variants (rs13436213 and rs1604428) significantly linked to and/or associated with the risk of PCOS. This is the first study to report PRLR as a novel risk gene in PCOS. Functional studies are needed to confirm these results.
Topics: Humans; Female; Animals; Mice; Polycystic Ovary Syndrome; Receptors, Prolactin; Prolactin; Diabetes Mellitus, Type 2; Infertility; Hyperandrogenism
PubMed: 37993904
DOI: 10.1186/s13048-023-01280-5 -
Poultry Science Jan 2024Heterosis is the major benefit of crossbreeding and has been exploited in laying hens breeding for a long time. This genetic phenomenon has been linked to various modes...
Transcriptome analysis of ovarian tissues highlights genes controlling energy homeostasis and oxidative stress as potential drivers of heterosis for egg number and clutch size in crossbred laying hens.
Heterosis is the major benefit of crossbreeding and has been exploited in laying hens breeding for a long time. This genetic phenomenon has been linked to various modes of nonadditive gene action. However, the molecular mechanism of heterosis for egg production in laying hens has not been fully elucidated. To fill this research gap, we sequenced mRNAs and lncRNAs of the ovary stroma containing prehierarchical follicles in White Leghorn, Rhode Island Red chickens as well as their reciprocal crossbreds that demonstrated heterosis for egg number and clutch size. We further delineated the modes of mRNAs and lncRNAs expression to identify their potential functions in the observed heterosis. Results showed that dominance was the principal mode of nonadditive expression exhibited by mRNAs and lncRNAs in the prehierarchical follicles of crossbred hens. Specifically, low-parent dominance was the main mode of mRNA expression, while high-parent dominance was the predominant mode of lncRNA expression. Important pathways enriched by genes that showed higher expression in crossbreds compared to either one or both parental lines were cell adhesion molecules, tyrosine and purine metabolism. In contrast, ECM-receptor interaction, focal adhesion, PPAR signaling, and ferroptosis were enriched in genes with lower expression in the crossbred. Protein network interaction identified nonadditively expressed genes including apolipoprotein B (APOB), transferrin, acyl-CoA synthetase medium-chain family member (APOBEC) 3, APOBEC1 complementation factor, and cathepsin S as hub genes. Among these potential hub genes, APOB was the only gene with underdominance expression common to the 2 reciprocal crossbred lines, and has been linked to oxidative stress. LncRNAs with nonadditive expression in the crossbred hens targeted natriuretic peptide receptor 1, epidermal differentiation protein beta, spermatogenesis-associated gene 22, sperm-associated antigen 16, melanocortin 2 receptor, dolichol kinase, glycine amiinotransferase, and prolactin releasing hormone receptor. In conclusion, genes with nonadditive expression in the crossbred may play crucial roles in follicle growth and atresia by improving follicle competence and increasing oxidative stress, respectively. These 2 phenomena could underpin heterosis for egg production in crossbred laying hens.
Topics: Male; Animals; Female; Chickens; Clutch Size; Hybrid Vigor; RNA, Long Noncoding; Plant Breeding; Gene Expression Profiling; Homeostasis; Oxidative Stress; Apolipoproteins B
PubMed: 37980751
DOI: 10.1016/j.psj.2023.103163 -
Scientific Reports Nov 2023In euryhaline fish, prolactin (Prl) plays an essential role in freshwater (FW) acclimation. In the euryhaline and eurythermal Mozambique tilapia, Oreochromis...
In euryhaline fish, prolactin (Prl) plays an essential role in freshwater (FW) acclimation. In the euryhaline and eurythermal Mozambique tilapia, Oreochromis mossambicus, Prl cells are model osmoreceptors, recently described to be thermosensitive. To investigate the effects of temperature on osmoreception, we incubated Prl cells of tilapia acclimated to either FW or seawater (SW) in different combinations of temperatures (20, 26 and 32 °C) and osmolalities (280, 330 and 420 mOsm/kg) for 6 h. Release of both Prl isoforms, Prl and Prl, increased in hyposmotic media and were further augmented with a rise in temperature. Hyposmotically-induced release of Prl, but not Prl, was suppressed at 20 °C. In SW fish, mRNA expression of prl increased with rising temperatures at lower osmolalities, while and prl decreased at 32 °C and higher osmolalities. In Prl cells of SW-acclimated tilapia incubated in hyperosmotic media, the expressions of Prl receptors, prlr1 and prlr2, and the stretch-activated Ca channel, trpv4,decreased at 32 °C, suggesting the presence of a cellular mechanism to compensate for elevated Prl release. Transcription factors, pou1f1, pou2f1b, creb3l1, cebpb, stat3, stat1a and nfat1c, known to regulate prl and prl, were also downregulated at 32 °C. Our findings provide evidence that osmoreception is modulated by temperature, and that both thermal and osmotic responses vary with acclimation salinity.
Topics: Animals; Prolactin; Tilapia; Temperature; Receptors, Prolactin; Osmolar Concentration
PubMed: 37980366
DOI: 10.1038/s41598-023-47044-5 -
Acta Pharmaceutica Sinica. B Nov 2023Dopamine D receptor (DR) is implicated in multiple psychotic symptoms. Increasing the DR selectivity over dopamine D receptor (DR) would facilitate the antipsychotic...
Dopamine D receptor (DR) is implicated in multiple psychotic symptoms. Increasing the DR selectivity over dopamine D receptor (DR) would facilitate the antipsychotic treatments. Herein, novel carbazole and tetrahydro-carboline derivatives were reported as DR selective ligands. Through a structure-based virtual screen, ZLG-25 (DR = 685 nmol/L; DR > 10,000 nmol/L) was identified as a novel DR selective bitopic ligand with a carbazole scaffold. Scaffolds hopping led to the discovery of novel DR-selective analogs with tetrahydro--carboline or tetrahydro--carboline core. Further functional studies showed that most derivatives acted as hDR-selective antagonists. Several lead compounds could dose-dependently inhibit the MK-801-induced hyperactivity. Additional investigation revealed that and could decrease the apomorphine-induced climbing without cataleptic reaction. Furthermore, demonstrated unusual antidepressant-like activity in the forced swimming tests and the tail suspension tests, and alleviated the MK-801-induced disruption of novel object recognition in mice. Additionally, preliminary studies confirmed the favorable PK/PD profiles, no weight gain and limited serum prolactin levels in mice. These results revealed that provided potential opportunities to new antipsychotic drugs with the multiple antipsychotic-like properties.
PubMed: 37969740
DOI: 10.1016/j.apsb.2023.07.024 -
Microbiology Spectrum Dec 2023In this study, whole-blood RNAs (prolactin and toll-like receptor 3) involved in the prognosis of patients with COVID-19 were identified. The RNA endotypes classified by...
In this study, whole-blood RNAs (prolactin and toll-like receptor 3) involved in the prognosis of patients with COVID-19 were identified. The RNA endotypes classified by these important RNAs highlight the possibility of stratifying the COVID-19 patient population and the need for targeted therapy based on these phenotypes.
Topics: Humans; COVID-19; RNA; Prospective Studies; Phenotype; Prognosis
PubMed: 37966347
DOI: 10.1128/spectrum.02645-23