PRSS21/testisin inhibits ovarian tumor metastasis and antagonizes proangiogenic angiopoietins ANG2 and ANGPTL4
The affiliation of Erik W. Martin is corrected in this paper.
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Rewiring of immune-metabolic crosstalk in the liver after viral infection |
Relevance of VEGFA in rat livers subjected to partial hepatectomy under ischemia-reperfusionAbstract
We examined the effects of VEGFA on damage and regeneration in steatotic and non-steatotic livers of rats submitted to PH under I/R, and characterized the underlying mechanisms involved. Our results indicated that VEGFA levels were decreased in both steatotic and non-steatotic livers after surgery. The administration of VEGFA increased VEGFA levels in non-steatotic livers, reducing the incidence of post-operative complications following surgery through the VEGFR2-Wnt2 pathway, independently of Id1. Unexpectedly, administration of VEGFA notably reduced VEGFA levels in steatotic livers, exacerbating damage and regenerative failure. After exogenous administration of VEGFA in steatotic animals, circulating VEGFA is sequestered by the high circulating levels of sFlt1 released from adipose tissue. Under such conditions, VEGFA cannot reach the steatotic liver to exert its effects. Consequently, the concomitant administration of VEGFA and an antibody against sFlt1 was required to avoid binding of sFlt1 to VEGFA. This was associated with high VEGFA levels in steatotic livers and protection against damage and regenerative failure, plus improvement in the survival rate via up-regulation of PI3K/Akt independently of the Id1-Wnt2 pathway. The current study highlights the different effects and signaling pathways of VEGFA in liver surgery requiring PH and I/R based in the presence of steatosis.
Key messages
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The orphan nuclear receptor NUR77 promotes trophoblast invasion at early pregnancy through paracrine placental growth factorAbstract
NR4A1 (NUR77) is an orphan nuclear receptor that has been implicated in both cell survival and apoptosis. However, the role of NUR77 in trophoblast function during early placenta development has not been fully elucidated. In this study, we showed that NUR77 expression was significantly lower in the villi of the recurrent miscarriage (RM) group compared to that in the healthy controls (HCs) group. We used immunohistochemistry and found that NUR77 was highly expressed in human placental villi during early pregnancy, especially in syncytiotrophoblast (STB), and was expressed at a much lower level in STB from the RM group than in those from HC group. Western blotting data further confirmed that NUR77 was highly expressed in primary human term placental STB and the FSK-induced BeWo cell line. Moreover, antibody array screening and ELISA revealed that NUR77 promoted significant placental growth factor (PGF) expression during trophoblast fusion. Ectopic overexpression and knockdown experiments demonstrated that PGF was a novel downstream target of NUR77, and serum PGF expression correlated positively with trophoblast NUR77 mRNA levels in HCs and RM patients. Importantly, bioinformatics analysis identified two NUR77 binding sites in the PGF promoter region, and chromatin immunoprecipitation (ChIP) coupled with Western blotting analysis further verified that NUR77 bound directly to the PGF promoter region and promoted PGF expression. Furthermore, in a BeWo/HTR-8 co-culture system, FSK-induced BeWo-secreted PGF promoted HTR-8 cell migration and invasion, and an anti-PGF antibody reversed this effect. Collectively, these results indicated that NUR77 may play a key role in regulating trophoblast invasion at early pregnancy.
Key messages
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Macrophage derived TNFα promotes hepatic reprogramming to Warburg-like metabolismAbstract
During infection, hepatocytes must undergo a reprioritization of metabolism, termed metabolic reprogramming. Hepatic metabolic reprogramming in response to infection begins within hours of infection, suggesting a mechanism closely linked to pathogen recognition. Following injection with polyinosinic:polycytidylic acid, a mimic of viral infection, a robust hepatic innate immune response could be seen involving the TNFα pathway at 2 h. Repeated doses led to the adoption of Warburg-like metabolism in the liver as determined by in vivo metabolic imaging, expression analyses, and metabolomics. Hepatic macrophages, Kupffer cells, were able to induce Warburg-like metabolism in hepatocytes in vitro via TNFα. Eliminating macrophages in vivo or blocking TNFα in vitro or in vivo resulted in abrogation of the metabolic phenotype, establishing an immune-metabolic axis in hepatic metabolic reprogramming. Overall, we suggest that macrophages, as early sensors of pathogens, instruct hepatocytes via TNFα to undergo metabolic reprogramming to cope with challenges to homeostasis initiated by infection. This work not only addresses a key component of end-organ physiology, but also raises questions about the side effects of biologics in the treatment of inflammatory diseases.
Key messages
• Hepatocytes develop Warburg-like metabolism in vivo during viral infection.
• Macrophage TNFα promotes expression of glycolytic enzymes in hepatocytes.
• Blocking this immune-metabolic axis abrogates Warburg-like metabolism in the liver.
• Implications for patients being treated for inflammatory diseases with biologics.
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Critical regulation of atherosclerosis by the KCa3.1 channel and the retargeting of this therapeutic target in in-stent neoatherosclerosisAbstract
Coronary heart disease is a serious cardiovascular illness. Percutaneous coronary artery stent implantation has become a routine way to treat coronary heart disease. Although studies have shown how a drug-eluting stent could improve the efficacy of clinical treatment, 10~20% of in-stent restenosis is still an important outcome that restricts the clinical efficacy of drug-eluting stent implantations and causes cardiovascular events such as angina pectoris, acute myocardial infarction, and sudden death. The KCa3.1 channel plays an important role in neoatherosclerosis of in-stent restenosis by regulating macrophage function. Recent studies have shown that the KCa3.1 channel, which belongs to the family of calcium-activated potassium channels, plays an important role in the occurrence and development of various inflammatory diseases by regulating cell membrane potentials and calcium signaling in the processes of macrophage migration and mitogen-stimulated vascular smooth muscle cell and fibroblast proliferation. The KCa3.1 channel is activated by elevated intracellular calcium levels. Inhibition of the KCa3.1 channel can effectively slow the progression of arterial plaque rupture and reduce the degree of vascular restenosis, and so substances that can carry out this inhibition are expected to become targeted drugs for the treatment of in-stent neoatherosclerosis. This article reviews the pathological and physiological roles of the KCa3.1 channel and its roles in the disease prognosis of in-stent neoatherosclerosis.
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Early central vs. peripheral immunological and neurobiological effects of fingolimod—a longitudinal studyAbstract
Fingolimod (FTY) is known to have multiple effects on the immune system and the central nervous system (CNS) in patients with multiple sclerosis (MS). In this study, we evaluated the immunological and neurobiological effects of FTY in MS. Blood and cerebrospinal fluid (CSF) samples were collected from 15 MS patients before first FTY administration and after 4 months of FTY therapy. Immunophenotyping and evaluation of sphingosine-1-phosphate (S1P), neurofilament light chain (NFL), S-100 and neuron-specific enolase (NSE) levels were conducted. After 4 months of FTY therapy, absolute cell count in CSF was decreased from 6.33 to 2.43 MPt/l, accompanied by decreases of CD3+ (2.22 to 0.65 MPt/l) and of CD4+ counts (1.60 to 0.39 MPt/l). In blood, CD3+ (1.05 to 0.09 GPt/l), CD4+ (0.80 to 0.02 GPt/l), CD8+ (0.23 to 0.04 GPt/l) and CD19+ (0.21 to 0.01GPt/l) cell counts were as well reduced. CD14+ cell count remained stable over the same period (0.24 to 0.26GPt/l). NFL and S1P levels in CSF and blood were reduced over time (NFL: CSF 1759 to 1359 pg/l, blood 8.42 to 7.36 pg/l; S1P: CSF 2.12 to 0.71 nmol/l, blood 392.1 to 312.9 nmol/l). Strong correlations between CSF and blood NFL levels were observed. Neuronal damage markers such as S-100 (1.86 to 1.69 μg/l) and NSE (9.53 to 8.67 μg/l) were reduced to a lesser degree than other markers. FTY exerted significant effects on immunological and neurobiological markers in the central and peripheral compartment. Decreases in levels of neuroinflammatory and neurodegenerative markers were already evident after 4 months of treatment. Four-month serum NFL level appears to be a useful marker for FTY efficacy that correlates well with changes in the CNS compartment.
Key messages
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A non-beta-lactam antibiotic inhibitor for enterohemorrhagic Escherichia coli O104:H4Abstract
The overuse of antibiotics has caused an increased prevalence of drug-resistant bacteria. Bacterial resistance in E. coli is regulated via production of β-lactam-hydrolyzing β-lactamases enzymes. Escherichia coli O104: H4 is a multi-drug resistant strain known to resist β-lactam as well as several other antibiotics. Here, we report a molecular dynamic simulation–combined docking approach to identify, screen, and verify active pharmacophores against enterohemorrhagic Escherichia coli (EHEC). Experimental studies revealed a boronic acid cyclic monomer (BACM), a non-β-lactam compound, to inhibit the growth of E. coli O104: H4. In vitro Kirby Bauer disk diffusion susceptibility testing coupled interaction analysis suggests BACM inhibits E. coli O104:H4 growth by not only inhibiting the β-lactamase pathway but also via direct inhibition of the penicillin-binding protein. These results suggest that BACM could be used as a lead compound to develop potent drugs targeting beta-lactam resistant Gram-negative bacterial strains.
Key messages
• An in silico approach was reported to identify pharmacophores against E. coli O104: H4.
• In vitro studies revealed a non-β-lactam compound to inhibit the growth of E. coli O104: H4.
• This non-β-lactam compound could be used as a lead compound for targeting beta-lactam strains.
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Exosomes from patients with Parkinson’s disease are pathological in miceAbstract
Cell-to-cell transport of risk molecules is a highly anticipated pathogenic mechanism in the initiation and progression of various neurodegenerative diseases. Extracellular exosome-mediated neuron to neuron transport of α-synuclein (α-syn) is increasingly recognized as a potential etiologic mechanism in Parkinson’s disease (PD). Exosomal inflammation has also been increasingly implicated in PD pathogenesis and could trigger, facilitate, or aggravate disease development. However, these mechanisms have not been verified systematically, especially in vivo. Since serum contains abundant exosomes, the correlation between serum exosomes and PD pathogenesis remains unknown. Here, we show that exosomes from PD patient serum contain more α-syn and inflammatory factors such as IL-1β and TNF-α than neurological normal controls, eventually cause α-syn, ubiquitin, and P62 aggregation in recipient cells. More importantly, the intravenous or intrastriatal treatment of mice with exosomes from PD patient serum could evoke protein aggregation, trigger dopamine neuron degeneration, induce microglial activation, and cause apomorphine-coaxed rotation and movement defects. All these findings imply the exosome pathway as a new pathogenesis mechanism for PD, and therefore may present new targets for therapeutics.
Key messages
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UPARANT is an effective antiangiogenic agent in a mouse model of rubeosis iridisAbstract
Puncture-induced iris neovascularization (rubeosis iridis; RI) in mice is associated with upregulation of extracellular matrix (ECM) degradation and inflammatory factors. The anti-angiogenic and anti-inflammatory efficacy of UPARANT in reducing RI was determined by noninvasive, in vivo iris vascular densitometry, and confirmed in vitro by quantitative vascular-specific immunostaining. Intravitreal administration of UPARANT successfully and rapidly reduced RI to non-induced control levels. Molecular analysis revealed that UPARANT inhibits formyl peptide receptors through a predominantly anti-inflammatory response, accompanied with a significant reduction in ECM degradation and inflammation markers. Similar results were observed with UPARANT administered systemically by subcutaneous injection. These data suggest that the tetrapeptide UPARANT is an effective anti-angiogenic agent for the treatment of RI, both by local and systemic administrations. The effectiveness of UPARANT in reducing RI in a model independent of the canonical vascular endothelial growth factor (VEGF) proposes an alternative for patients that do not respond to anti-VEGF treatments, which could improve treatment in proliferative ocular diseases.
Key messages
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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,
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Δευτέρα 2 Σεπτεμβρίου 2019
Αναρτήθηκε από
Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,
στις
10:58 μ.μ.
Ετικέτες
00302841026182,
00306932607174,
alsfakia@gmail.com,
Anapafseos 5 Agios Nikolaos 72100 Crete Greece,
Medicine by Alexandros G. Sfakianakis
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