The involvement of lipoxygenases in inflammatory signalling pathways of human sebocytes in vitro

Title and Contents Introduction Aim_of_the_study Methods_and_Materials Results Discussion Conclusion Fig-1 Fig-2 Fig-3 Fig-4 Fig-5 Fig-6 Fig-7 Fig-8 Fig-9-10 Fig-11-12-13 Fig-14 Fig-15 Fig-16 Fig-17 ReferencesLipoxygenases (LOXs) form a family of lipid peroxidising enzymes. Among LOXs, the functions of 5-LOX are better understood thanks to implication of leukotrienes (LTs). LTB4 is the most potent pro-inflammatory mediator. LOX derivatives, namely eicosanoids are present in skin, but little is known in the field of sebaceous gland disorders. A very common disorder of the skin, which affects the majority of human population is acne. The main characteristic of acne is the overproduction of sebum, the formation of comedones and the bacterial colonization. However the primary cause of acne seems to be the inflammation. Here, the presence of eicosanoids is reasonable. In order to investigate the presence of eicosanoids in sebaceous glands, we have used the human cultured immortalized SZ95 sebocytes. We have demonstrated the presence of 5-LOX, LTA4 hydrolase and 15-LOX-1 in human cultured sebocytes. The enzymes are expressed at protein and mRNA level. It is interesting that 5- and 15-LOX are translocated to the membranes fraction after stimulation with calcium ionophore (CaI) and arachidonic acid (AA). This occurs within the first 30 minutes of the stimulation. Besides, 5-LOX has been detected by immunocytochemistry. The enzyme is stained at least in the cytosol of SZ95 cells. Well differentiated SZ95 cells are mostly stained. The presence of 5-LOX and LTA4 hydrolase in sebocytes is evidence that sebaceous glands can utilize fatty acids and covert them into eicosanoids. SZ95 cells are not only capable of generating LTB4, but this formation is upregulated by AA. Furthermore, LOX stimulators (CaI and AA) induce cytokine production such as IL-6 and IL-8 in sebocytes. SZ95 sebocytes produce IL-1 and TNF-α, too. It might be an evidence of eicosanoids capability to amplify the potential of sebocytes to attract pro-inflammatory cells, such as leukocytes and macrophages. On the other hand, we have found that AA induces lipid production in SZ95 sebocytes. The co-existence of 5- and 15-LOX in human sebocytes is another important point. The isozymes have opposing properties. 5-LOX- derivatives are potent pro-inflammatory mediators. Unlike, products of 15-LOX act as anti-inflammatory molecules. The antagonism between the two isoforms may regulate the inflammation in acne since 5-LOX has been expressed stronger in SZ95 cells. We have tested the effect of caffeic acid and zileuton on the inhibition of 5-LOX in SZ95 sebocytes. 5-LOX inhibitors reduce the enzyme activity in sebocytes. We have tested also the ability of 5-LOX inhibitors to down-regulate the lipid formation of SZ95 sebocytes. Here the tested molecules have reduced non-polar lipid accumulation. Therefore, human sebocytes possess the enzyme machinery to produce LTB4 and a reduction of LTB4 may be effective in acne skin lesions. In conclusion, the presence of LOX activity in sebocytes opens a new amazing chapter in the treatment of acne as well as in the theory of inflammatory origin of acne.Lipoxygenasen (LOX) bilden eine Gruppe von Lipid-Peroxidierten Enzyme. Zwischen den LOX, werden die Funktionen von 5-LOX besser verstanden, dank der Beteiligung der Leukotrienen (LT). LTB4 ist der meist wirkender von den pro- inflammatorischen mediatoren. LOX Derivate, nämlich Eicosanoide sind in der Haut präsent, aber wenig ist in dem Gebiet der Talgdrüsenskrankheiten bekannt. Akne ist die meist erscheinende Krankheit der Haut und kommt in einem grossen Teil der Bevölkerung vor. Die eigentlichen Merkmale der Akne sind Seborrhö, die Comedogenese und die bakterielle Kolonisation. Dennoch scheint die Entzündung, der wichtigste Grund von Akne zu sein. Die Beteiligung der Eicosanoide in der Entzündung scheint logisch zu sein. Um die Präsens der Eicosanoiden in den Talgdrüsen nachzuweisen, haben wir den humanen immortalisierten SZ95-sebozyten benutzt. Wir demonstrierten die Präsens von 5-LOX, LTA4 Hydrolase and 15-LOX-1 in den humanen Sebozyten in vitro. Die Enzyme werden auf Protein und mRNA Ebene exprimiert. Es ist interessant, dass 5- and 15-LOX nach Kalzium Ionophor (CaI)- und Arachidonsaeurestimulation (AA) zur Membranen transloziert werden. Dies geschieht innerhalb der ersten 30 Minuten der Stimulation. Gleichzeitig, wurde 5-LOX durch Immunozytochemie nachgewiesen. Das Enzym wird meistens in Zytosol von SZ95 Zellen gefärbt. Differenzierte SZ95 Zellen sind deutlich gefärbt. Die Präsens von 5-LOX und LTA4 Hydrolase in Sebozyten beweisst, dass die Talgdrüsen Fettsäuren benuetzen können und konvertieren sie in Eicosanoiden. SZ95 Zellen produzieren LTB4, das von AA reguliert wird. Zusätzlich LOX Erreger (CaI and AA) induzieren die Produktion der Zytokinen, sowie IL-6 and IL-8 in Sebozyten. SZ95 Zellen produzieren auch IL-1 and TNFα. So könnten die Eicosanoiden, die pro- inflammatorische Signale in Talgdrüsen verstärkern. Sie locken ebenfalls inflammatorische Zellen, sowie Leukozyten und Makrophagen zur Aknewunde an. Anderseits, haben wir herausgefunden, dass AA die Lipidenproduktion in SZ95 Sebozyten induziert. Die Koexistenz von 5- and 15-LOX in den humanen Sebozyten ist ein anderer wichtiger Punkt. Die Isoenzymen haben entgegengesetzte Eigenschaften. 5-LOX-Derivaten sind starke pro-inflammatorische Mediatoren. Im Gegensatz zu 5-LOX-Derivaten, verhalten sich die Produkte von 15-LOX als anti- inflammatory molecules. Die Konkurrenz zwischen den beiden Isoformen und die stärkere Expression von 5-LOX könnte die Entzündung in Akne erklären. Wir haben die Wirkung von Kaffeesäure und Zileuton bei der Hemmung von 5-LOX in SZ95 Sebozyten getestet. 5-LOX Hemmern reduzieren die Aktivität des Enzyms in Sebozyten. Wir haben auch die Fähigkeit von 5-LOX Inhibitoren die Fettproduktion von SZ95 sebocytes herunterzuregulieren, getestet. Hier haben die getesteten Molekule die non-polare Lipide Ansammlung reduziert. Folgend, humane Sebozyten beherrschen den Enzym Mechanismus, LTB4 zu produzieren. Die Reduktion von LTB4 könnte in der Hautwunde einwirken. Die Aktivität von LOX in Sebozyten öffnet ein neues Kapitel in der Therapie von Akne, so wie auch in der Theorie der Ursprünge der Entzündungen bei Akne

Cosmology intertwined: a review of the particle physics, astrophysics, and cosmology associated with the cosmological tensions and anomalies

The standard ¿ Cold Dark Matter (¿CDM) cosmological model provides a good description of a wide range of astrophysical and cosmological data. However, there are a few big open questions that make the standard model look like an approximation to a more realistic scenario yet to be found. In this paper, we list a few important goals that need to be addressed in the next decade, taking into account the current discordances between the different cosmological probes, such as the disagreement in the value of the Hubble constant , the – tension, and other less statistically significant anomalies. While these discordances can still be in part the result of systematic errors, their persistence after several years of accurate analysis strongly hints at cracks in the standard cosmological scenario and the necessity for new physics or generalisations beyond the standard model. In this paper, we focus on the tension between the Planck CMB estimate of the Hubble constant and the SH0ES collaboration measurements. After showing the evaluations made from different teams using different methods and geometric calibrations, we list a few interesting new physics models that could alleviate this tension and discuss how the next decade's experiments will be crucial. Moreover, we focus on the tension of the Planck CMB data with weak lensing measurements and redshift surveys, about the value of the matter energy density , and the amplitude or rate of the growth of structure (). We list a few interesting models proposed for alleviating this tension, and we discuss the importance of trying to fit a full array of data with a single model and not just one parameter at a time. Additionally, we present a wide range of other less discussed anomalies at a statistical significance level lower than the – tensions which may also constitute hints towards new physics, and we discuss possible generic theoretical approaches that can collectively explain the non-standard nature of these signals. Finally, we give an overview of upgraded experiments and next-generation space missions and facilities on Earth that will be of crucial importance to address all these open questionsPeer ReviewedArticle signat per 202 autors/esPostprint (published version

Late-transition versus smooth H(z)-deformation models for the resolution of the Hubble crisis

Gravitational transitions at low redshifts (zt < 0.1) have been recently proposed as a solution to the Hubble and growth tensions. Such transitions would naturally lead to a transition in the absolute magnitude M of type Ia supernovae (SnIa) at zt (Late M Transitions - LMT) and possibly in the dark energy equation of state parameter w (Late w − M Transitions - LwMT). Here, we compare the quality of fit of this class of models to cosmological data, with the corresponding quality of fit of the cosmological constant model (ΛCDM) and some of the best smooth H(z) deformation models (wCDM, CPL, PEDE). We also perform model selection via the Akaike Information Criterion and the Bayes factor. We use the full CMB temperature anisotropy spectrum data, the baryon acoustic oscillations (BAO) data, the Pantheon SnIa data, the SnIa absolute magnitude M as determined by Cepheid calibrators and the value of the Hubble constant H0 as determined by local SnIa calibrated using Cepheids. We find that smooth H(z) deformation models perform worse than transition models for the following reasons: 1) They have a worse fit to low-z geometric probes (BAO and SnIa data); 2) They favor values of the SnIa absolute magnitude M that are lower as compared to the value Mc obtained with local Cepheid calibrators at z < 0.01; 3) They tend to worsen the Ωm,0−σ8,0 growth tension. We also find that the w−M transition model (LwMT) does not provide a better quality of fit to cosmological data than a pure M transition model (LMT) where w is fixed to the ΛCDM value w = −1 at all redshifts. We conclude that the LMT model has significant statistical advantages over smooth late-time H(z) deformation models in addressing the Hubble crisis

Cosmology intertwined: A review of the particle physics, astrophysics, and cosmology associated with the cosmological tensions and anomalies

The standard Cold Dark Matter (CDM) cosmological model provides a good description of a wide range of astrophysical and cosmological data. However, there are a few big open questions that make the standard model look like an approximation to a more realistic scenario yet to be found. In this paper, we list a few important goals that need to be addressed in the next decade, taking into account the current discordances between the different cosmological probes, such as the disagreement in the value of the Hubble constant H0, the σ8–S8 tension, and other less statistically significant anomalies. While these discordances can still be in part the result of systematic errors, their persistence after several years of accurate analysis strongly hints at cracks in the standard cosmological scenario and the necessity for new physics or generalisations beyond the standard model. In this paper, we focus on the 5.0 σ tension between the Planck CMB estimate of the Hubble constant H0 and the SH0ES collaboration measurements. After showing the H0 evaluations made from different teams using different methods and geometric calibrations, we list a few interesting new physics models that could alleviate this tension and discuss how the next decade’s experiments will be crucial. Moreover, we focus on the tension of the Planck CMB data with weak lensing measurements and redshift surveys, about the value of the matter energy density m, and the amplitude or rate of the growth of structure (σ8, f σ8). We list a few interesting models proposed for alleviating this tension, and we discuss the importance of trying to fit a full array of data with a single model and not just one parameter at a time. Additionally, we present a wide range of other less discussed anomalies at a statistical significance level lower than the H0–S8 tensions which may also constitute hints towards new physics, and we discuss possible generic theoretical approaches that can collectively explain the non-standard nature of these signals. Finally, we give an overview of upgraded experiments and next-generation space missions and facilities on Earth that will be of crucial importance to address all these open questions