15 research outputs found
Potential of Inducible Nitric Oxide Synthase as a Therapeutic Target for Allergen-Induced Airway Hyperresponsiveness: A Critical Connection to Nitric Oxide Levels and PARP Activity
No full textAlthough expression of inducible NO synthase (iNOS) in the lungs of asthmatics and associated nitrosative damage are established, iNOS failed as a therapeutic target for blocking airway hyperresponsiveness (AHR) and inflammation in asthmatics. This dichotomy calls for better strategies with which the enzyme is adequately targeted. Here, we confirm iNOS expression in the asthmatic lung with concomitant protein nitration and poly(ADP-ribose) polymerase (PARP) activation. We show, for the first time, that iNOS is highly expressed in peripheral blood mononuclear cells (PBMCs) of asthmatics with uncontrolled disease, which did not correspond to protein nitration. Selective iNOS inhibition with L-NIL protected against AHR upon acute, but not chronic, exposure to ovalbumin or house dust mite (HDM) in mice. Supplementation of NO by nitrite administration significantly blocked AHR in chronically HDM-exposed mice that were treated with L-NIL. Protection against chronic HDM exposure-induced AHR by olaparib-mediated PARP inhibition may be associated with the partial but not the complete blockade of iNOS expression. Indeed, L-NIL administration prevented olaparib-mediated protection against AHR in chronically HDM-exposed mice. Our study suggests that the amount of iNOS and NO are critical determinants in the modulation of AHR by selective iNOS inhibitors and renews the potential of iNOS as a therapeutic target for asthma
Creation of Standard Work Instructions to Support Warehouse Processes on the Example of Skeleton Technologies GmbH Company
No full textLõputöö raames uuris autor tööjuhendite koostamise üksikasju ning selle põhjal koostas laoprotsessidele mõeldud tööjuhendid ettevõttes Skeleton Technologies GmbH. Eesmärgiks oli luua toimivad standard tööjuhendid laoprotsessidele, mida tehakse läbi ERP süsteemi Epicor. Lõputöö väljundiks on 21 standard tööjuhendit, mis aitavad uute töötajate väljaõppe protsessile kaasa ning toetavad töötajaid ka edaspidises arengus.
Lõputöö raames püstitati kolm uurimusküsimust:
1. Kuidas luua standard tööjuhendeid?
2. Milliseid kriteeriume tuleb arvestada standard tööjuhendite koostamisel?
3. Kuidas aitavad standard tööjuhendid kaasa väljaõppeprotsessile?
Vaatlustest ning intervjuudest saadud info põhjal alustati tööjuhendite loomise protsessiga. Autor kogus infot laotöötajatelt kes igapäevaselt neid protsesse läbi viivad ning tehase vahetusega seoses Skeletonist lahkuvad. Tegevuse käigus selgus, et väga palju on infot mida protsessi tegija üksi teab ning seda kuskile talletatud pole, ehk see oli suureks probleemiks, mis selle lõputööga sai lahendatud.
Standardtööjuhendid on tööriist, mis aitab uute töötajate väljaõpet kiiremaks ning efektiivsemaks muuta, andes uutele töötajatele kõigile ühesuguse informatsiooni juhendite näol ning see loob tugeva põhja edasiseks tööprotsessiks. Selleks et juhendid saaksid edastada maksimaalset väärtuslikku infot on vaja neid luues silmas pidada, et juhendisse kirja pandu oleks üheselt mõistetav ning mitte üle liia keeruline. Selleks on vaja kõigepealt kokku koguda kõik vajalik informatsioon, see meelde jätta ja enda jaoks märksõnadega ülesse kirjutada ning seejärel organiseeritult kirja panna. Tööjuhendi koostamise protsessis ei ole üht kindlat ja universaalset meetodit. Küll aga tuleb arvestada ettevõtte eripärasid ja vajadusi, et tagada tööjuhendi kasutatavus ja praktilisus. Kõige olulisem on välja töötada juhendite struktuur, kus esitatakse kõik protsessi käigus vajalikud sammud ning tagatakse, et juhendi lugemisel ei tekiks segadust ega täiendavaid küsimusi. Standardtööjuhendid toimivad väärtuslike juhistena, mille abil saavad töötajad kindluse oma ülesannete täitmisel, mis omakorda soodustab nende kiiret kohandumist ettevõtte tööprotsessidega.In the thesis, the author explored the details of creating work instructions and, based on this, developed work instructions for warehouse processes at Skeleton Technologies GmbH. The aim was to create effective standard working instructions for warehouse processes, which are carried out through the ERP system Epicor. The outcome of the thesis is 21 standard work instructions that contribute to the training process of new employees and provide ongoing support for their development.
The thesis addressed three research questions:
1. How to create standard work instructions?
2. What criteria should be considered when creating standard work instructions?
3. How do standard work instructions contribute to the training process of new employees?
Based on information gathered through observations and interviews, the process of creating work instructions was initiated. The author collected information from warehouse workers who carry out these processes daily and are leaving the company due to change of the warehouse location. During this process, it became clear that much of the information was only known to a few individuals involved in the processes, and it had not been documented anywhere. This posed a significant problem, which was addressed in this thesis.
Standard work instructions serve as a tool to make the training of new employees faster and more efficient, providing consistent information through the instructions, which creates a solid foundation for future work processes. To ensure that the instructions convey maximum value, it is essential that they are clear and not overly complicated. The first step is to gather all the necessary information, memorize it, write down key points, and then organize it systematically in writing. There is no single, universal method for creating work instructions, but it is crucial to consider the specific needs and characteristics of the company to ensure the usability and practicality of the instructions. The most important aspect is to develop a clear structure for the instructions, outlining all the necessary steps in the process and ensuring that no confusion or additional questions arise when reading the instructions. Standard work instructions serve as valuable tool, that help employees gain confidence in performing their tasks, which in turn, promotes their quick adaptation to the company’s work processes
Poly (ADP) Ribose Polymerase (PARP)-1 as a novel therapeutic target for alleviating the manifestations of Atopic Dermatitis
No full textAmerican Society for Pharmacology and Experimental Therapeutics Annual Meeting, 2024; May 16 - May 19, 2024; Arlington, V
Sulfated non-anticoagulant heparin blocks Th2-induced asthma by modulating the IL-4/signal transducer and activator of transcription 6/Janus kinase 1 pathway
No full textAbstract Background The efficacy of heparins and low-MW-heparins (LMWH) against human asthma has been known for decades. However, the clinical utility of these compounds has been hampered by their anticoagulant properties. Much effort has been put into harnessing the anti-inflammatory properties of LMWH but none have been used as therapy for asthma. Sulfated-non-anticoagulant heparin (S-NACH) is an ultra-LMWH with no systemic anticoagulant effects. Objective The present study explored the potential of S-NACH in blocking allergic asthma and examined the potential mechanism by which it exerts its effects. Methods Acute and chronic ovalbumin-based mouse models of asthma, splenocytes, and a lung epithelial cell line were used. Mice were challenged with aerosolized ovalbumin and administered S-NACH or saline 30 min after each ovalbumin challenge. Results Sulfated-non-anticoagulant heparin administration in mice promoted a robust reduction in airway eosinophilia, mucus production, and airway hyperresponsiveness even after chronic repeated challenges with ovalbumin. Such effects were linked to suppression of Th2 cytokines IL-4/IL-5/IL-13/GM-CSF and ovalbumin-specific IgE without any effect on IFN-γ. S-NACH also reduced lung fibrosis in mice that were chronically-exposed to ovalbumin. These protective effects of S-NACH may be attributed to modulation of the IL-4/JAK1 signal transduction pathway through an inhibition of STAT6 phosphorylation and a subsequent inhibition of GATA-3 and inducible NO synthase expression. The effect of the drug on STAT6 phosphorylation coincided with a reduction in JAK1 phosphorylation upon IL-4 treatment. The protective effects of S-NACH treatment was associated with reduction of the basal expression of the two isoforms of arginase ARG1 and ARG2 in lung epithelial cells. Conclusions Our study demonstrates that S-NACH constitutes an opportunity to benefit from the well-known anti-asthma properties of heparins/LMWH while bypassing the risk of bleeding. Our results show, for the first time, that such anti-asthma effects may be associated with reduction of the IL-4/JAK1/STAT6 pathway
MINOCYCLINE BLOCKS ALLERGEN‐INDUCED EOSINOPHILIA AND PRODUCTION OF TH2 CYTOKINES AND IGE BY INTERFERING WITH THE T CELL RECEPTOR‐NF‐kB‐GATA‐3‐INTERLEUKIN (IL)‐4 AXIS IN A MURINE ASTHMA MODEL WITHOUT AN EFFECT ON PARP
No full textMicroparticles in systemic sclerosis: Potential pro‐inflammatory mediators and pulmonary hypertension biomarkers
No full textSupplements - Unconventional activation of PRKDC by TNF-α: deciphering its crucial role in Th1-mediated inflammation beyond DNA repair as part of the DNA-PK complex
No full textSupplementary Material 1
Unconventional activation of PRKDC by TNF-α: deciphering its crucial role in Th1-mediated inflammation beyond DNA repair as part of the DNA-PK complex
No full textBackground: The DNA-dependent protein kinase (DNA-PK) complex comprises a catalytic (PRKDC) and two requisite DNA-binding (Ku70/Ku80) subunits. The role of the complex in repairing double-stranded DNA breaks (DSBs) is established, but its role in inflammation, as a complex or individual subunits, remains elusive. While only ~ 1% of PRKDC is necessary for DNA repair, we reported that partial inhibition blocks asthma in mice without causing SCID. Methods: We investigated the central role of PRKDC in inflammation and its potential association with DNA repair. We also elucidated the relationship between inflammatory cytokines (e.g., TNF-α) and PRKDC by analyzing its connections to inflammatory kinases. Human cell lines, primary human endothelial cells, and mouse fibroblasts were used to conduct the in vitro studies. For animal studies, LPS- and oxazolone-induced mouse models of acute lung injury (ALI) and delayed-type hypersensitivity (DHT) were used. Wild-type, PRKDC+/−, or Ku70+/− mice used in this study. Results: A ~ 50% reduction in PRKDC markedly blocked TNF-α-induced expression of inflammatory factors (e.g., ICAM-1/VCAM-1). PRKDC regulates Th1-mediated inflammation, such as DHT and ALI, and its role is highly sensitive to inhibition achieved by gene heterozygosity or pharmacologically. In endothelial or epithelial cells, TNF-α promoted rapid PRKDC phosphorylation in a fashion resembling that induced by, but independent of, DSBs. Ku70 heterozygosity exerted little to no effect on ALI in mice, and whatever effect it had was associated with a specific increase in MCP-1 in the lungs and systemically. While Ku70 knockout blocked VP-16-induced PRKDC phosphorylation, it did not prevent TNF-α − induced phosphorylation of the kinase, suggesting Ku70 dispensability. Immunoprecipitation studies revealed that PRKDC transiently interacts with p38MAPK. Inhibition of p38MAPK blocked TNF-α-induced PRKDC phosphorylation. Direct phosphorylation of PRKDC by p38MAPK was demonstrated using a cell-free system. Conclusions: This study presents compelling evidence that PRKDC functions independently of the DNA-PK complex, emphasizing its central role in Th1-mediated inflammation. The distinct functionality of PRKDC as an individual enzyme, its remarkable sensitivity to inhibition, and its phosphorylation by p38MAPK offer promising therapeutic opportunities to mitigate inflammation while sparing DNA repair processes. These findings expand our understanding of PRKDC biology and open new avenues for targeted anti-inflammatory interventions
Inhibition of fatty acid oxidation blocks asthma in mice
No full text102nd Annual Meeting of the American Association of Immunologist, IMMUNOLOGY 2015, May 8 - 12, 2015, New Orleans, L
Sulfated non‑anticoagulant heparin blocks Th2‑induced asthma by modulating the IL‑4/signal transducer and activator of transcription 6/Janus kinase 1 pathway
No full textPMC publication<br
