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Characterization of silver(I) complexes with diiodo derivatives of pyridine by NMR spectroscopy
Get PDFReakcijom srebrova(I) nitrata i derivata dijodpiridina (2,5-I2py, 3,5-I2py, 2,6-I2py) u množinskom omjeru 1 : 2 u vodeno-alkoholnom mediju pripravljena su tri nova kompleksa opće formule [Ag(NO3)(I2py)2]. Dobiveni spojevi identificirani su elementnom analizom, a njihova struktura u otopini okarakterizirana je spektrometrijom masa i spektroskopijom NMR. Od 1D tehnika NMR korištene su 1H i 13C ATP, a od 2D homonuklearni 1H-1H COSY te heteronuklearni 1H-13C HMQC i 1H-13C/15N HMBC. U čvrstom stanju, kompleksi su okarakterizirani spektroskopijom IR zračenja. Kristalna i molekulska struktura kompleksa [Ag(NO3)(2,5–I2py)2] određena je i rentgenskom strukturnom analizom. Dobiveni rezultati ukazuju na vezanje srebrovog(I) iona s dvama ligandima preko nesparenog elektronskog para atoma dušika piridinskog prstena. Rentgenska strukturna analiza monokristala spoja [Ag(NO3)(2,5–I2py)2] otkriva da su pored kovalentnih veza (Ag– Npy, Ag–O, Ag–I), u strukturu kristala uključene i nekovalentne halogenske interakcije (O···I–C) koje pridonose stvaranju polimerne strukture spoja.Three novel 1:2 complexes of general formula [Ag(NO3)(I2py)2] were prepared in water-alcohol solution by reaction of silver (I) nitrate with diiodopyridine derivatives (2,5-I2py, 3,5-I2py, 2,6-I2py). All prepared compounds were identified by elemental analysis. Their structure in solution were characterized by mass spectrometry and NMR spectroscopy (1H, 13C ATP, 1H-1H COSY, 1H-13C HMQC, 1H-13C/15N HMBC). In solid state, the complexes were characterized by IR spectroscopy. The crystal and molecular structure of the [Ag(NO3)(2,5–I2py)2] complex was revealed by single crystal X-ray analysis. The obtained results confirmed the binding of silver(I) ion with two ligands via the lone electron pair of nitrogen atoms of the pyridine ring. X-ray structural analysis of [Ag(NO3)(2,5-I2py)2] reveals that beside covalent bonds (Ag–Npy, Ag–O, Ag–I), supramolecular halogen interactions are also present in its crystal structure (O···I–C). Halogen interactions contribute to the final dimensionality by forming polymeric structure of the compound
Side effects of Antipsoriatics (ATK: D05) reported to Agency for medicinal products and medical devices of Croatia (HALMED)
No full textIako živimo u vremenu velikih otkrića i medicinskih napredaka, psorijaza se i dalje nalazi u skupini bolesti za koje nema konkretnog lijeka. Postoje brojne topikalne i sustavne terapije za ublažavanje simptoma, no najčešće dolaze s povećim brojem neželjenih reakcija. Cilj ovog rada je analizirati prijave sumnji na nuspojave dijela antipsorijatika koji pripadaju Anatomsko Terapijsko Kemijskoj (ATK) skupini D05. Navedeno se odnosi na prijave zaprimljene u Hrvatskoj agenciji za lijekove (HALMED) u razdoblju od 2015. do 2019. godine. Prijave nuspojava analizirana su prema: prijavljenim lijekovima, izvoru prijava, dobi i spolu pacijenta, očekivanosti, ozbiljnosti, mehanizmu nastanka, ishodu te pripadnosti nuspojava organskim sustavima prema medicinskom rječniku za regulatorne poslove (MedDRA). U navedenom razdoblju zaprimljeno je 46 prijava što u ukupnom broju prijava predstavlja 0,28% prijava nuspojava. Većinskim dijelom prijave nuspojava zaprimljene su od strane liječnika te su se odnosile na pacijente ženskog spola i dobnu skupinu od 18 do 64 godine. U 46 prijava zabilježeno je ukupno 136 nuspojava. Prema mehanizmu nastavka većina ih pripada nuspojavama tipa A. Najveći udio prijava nuspojava odnosi se na organski sustav (engl. System Organ Class, SOC) Poremećaji probavnog sustava, zatim na SOC Poremećaji kože i potkožnog tkiva te za SOC Opći poremećaji i reakcije na mjestu primjene. Najčešće prijavljene nuspojave su bile mučnina, dijareja, povraćanje, crvenilo, svrbež te eritem. Dobiveni rezultati na nacionalnoj razini su u skladu sa zabilježenim nuspojavama u europskoj (EudraVigilance) i svjetskoj (VigiBase) bazi nuspojava.Although we live in a time of great discoveries and medical advancements, psoriasis is still in the group of diseases for which there is no efficient cure. There are numerous topical and systemic therapies to relieve the symptoms, but most often come with an increased number of adverse drug reactions. Therefore, the aim of this thesis is to analyze suspected adverse reactions of the part of antipsoriatics belonging to the Anatomical Therapeutic Chemical (ATC) group D05. This refers to the reports received in the Agency for Medicinal Products and Medical Devices of Croatia (HALMED) in the period from 2015. to 2019. The data were analyzed with regard to: reported drugs, source of the report, age and sex of the patient, expectedness, seriousness, type, outcome and the distribution of the adverse effects according to the system organ class (SOC). There were 46 reports received during the mentioned period, representing 0.28% in the total number of the reports. Majority of the reports were received from physicians, for female patients and an age group 18 to 64 years. A total of 136 adverse reactions were reported. According to the mechanism of occurrence most of them belong to the type A adverse reactions. Most of them have been reported for the System organ class (SOC) Gastrointestinal disorders, then for SOC Skin and subcutaneous tissue disorders and SOC General disorders and administration site conditions. Most commonly reported adverse reactions were nausea, diarrhea, vomiting, redness, itching and erythema. The results obtained at the national level only confirm the data reported in European (EudraVigilance) and worldwide (VigiBase) base of adverse effects
Neuroinflammatory role of miRNA in multiple sclerosis
No full textMikroRNA (miRNA) male su nekodirajuće molekule koje sudjeluju u post-transkripcijskoj regulaciji genske ekspresije. Vezanjem za komplementarne sekvence unutar ciljne glasničke RNA (mRNA) molekule uzrokuju degradaciju mRNA ili inhibiciju translacije. Regulacijom genske ekspresije utječu na ključne stanične procese poput diferencijacije, proliferacije i apoptoze. Deregulacija ekspresije miRNA povezana je s razvojem neuroinflamacije kod mnogih neurodegenerativnih bolesti, uključujući multiplu sklerozu.
Multipla skleroza autoimuni je poremećaj karakteriziran gubitkom imunološke tolerancije prema mijelinskim antigenima i stvaranjem autoreaktivnih T limfocita. Smatra se da bolest uzrokuje kombinacija okolišnih čimbenika i rizičnih gena. Kod multiple skleroze dolazi do autoimunog odgovora autoreaktivnih T limfocita na mijelinske antigene, što uzrokuje lučenje pro-inflamatornih citokina i aktivaciju stanica imunološkog sustava te vodi do neuroinflamacije, demijelinizacije i degeneracije aksona.
Rastući broj istraživanja potvrđuje ulogu miRNA molekula u regulaciji neuroinflamacije. miRNA mogu imati pro-inflamatorni ili anti-inflamatorni učinak i sukladno s time regulacijom njihove ekspresije može doći do pozitivnog ili negativnog djelovanja na razvoj neuroinflamacije. Daljnjim istraživanjem mehanizama regulacije miRNA dobit će se dublji uvid u patogenezu multiple skleroze, kako bi se identificirale miRNA pogodne za ulogu terapeutskih meta.microRNA (miRNA) are small non-coding molecules that take part in post-transcriptional regulation of gene expression. They bind to the complementary sequences within the target messenger RNA (mRNA) molecule and cause mRNA degradation or inhibition of translation. By regulating the gene expression they affect key cellular processes, such as differentiation, proliferation and apoptosis. Dysregulation of miRNA expression is associated with the development of neuroinflammation in different neurodegenerative disorders, including multiple sclerosis.
Multiple sclerosis is an autoimmune disorder characterized by the loss of immune tolerance to myelin antigens and generation of autoreactive T lymphocytes. It is thought that the cause of the disease is a combination of environmental factors and risk genes. In multiple sclerosis, autoimmune response is induced by T lymphocytes reacting to myelin antigens, which causes pro-inflammatory cytokine secretion and activation of immune cells which eventually leads to neuroinflammation, demyelination and axonal degeneration.
A growing number of reports confirms the role of miRNA molecules in regulation of neuroinflammation. miRNA can have a pro-inflammatory and anti-inflammatory effect and regulation of their expression can have a positive or negative effect on development of neuroinflammation. Further research of miRNA regulation mechanisms will give a better insight into the pathogenesis of multiple sclerosis, to identify miRNA that are suitable for the role of therapeutic targets
Translocation of glucose transporter 4 (GLUT4) in skeletal muscles in experimental autoimmune encephalomyelitis (EAE)
No full textUvod: Eksperimentalni autoimuni encefalomijelitis (EAE) je životinjski model za određene neuroinflamatorne bolesti središnjeg živčanog sustava (SŽS), poput multiple skleroze (MS). EAE je popraćen prolaznom slabošću ili paralizom stražnjih udova. Metode: U radu su korišteni Dark Agouti (DA) štakori na kojima je istražen učinak oštećenja SŽS-a u EAE-u na skeletne mišiće. Tijek bolesti je praćen 20 dana (jedan relaps) i 30 dana (dva relapsa). Nakon razvoja maksimalnih kliničkih znakova životinje su tretirane polifenolima lišća masline (OLP, 1 g/kg, i.p.) i žrtvovane 20.-ti dan od starta. U skeletnim mišićima gastrocnemiusu, tibialis anterioru i soleusu, određeni su TBARS, karbonilirani proteini i aktivnost glutation peroksidaze (GPX) te provedene elektroforetske metode i patohistološki pregled tkiva mišića. Rezultati: SDS-PAGE je pokazao razlike u ekspresiji proteina u mišićima. Western blot analizom određena je ekspresija transportera glukoze 4 (GLUT4), a imunofluorescentnom mikroskopijom prikazana je uspješnost translokacije GLUT4. Patohistološki nalaz skeletnih mišića pokazao je abnormalna mišićna vlakna u EAE-u, denervaciju, upalu i upalne infiltrate u vrijeme drugog relapsa te regeneraciju terapijom OLP-om. Zaključak: Nije uočeno poboljšanje translokacije GLUT4 i ugradnja u staničnu membranu pod utjecajem OLP terapije u odnosu na kontrolnu skupinu. Unatoč tome, predlažemo ove bioaktivne fenolne spojeve za terapijsku primjenu u autoimunim i neurodegenerativnim bolestima, uključujući MS.Background: Experimental autoimmune encephalomyelitis (EAE) serves as an animal model for certain neuroinflammatory diseases of the central nervous system (CNS), such as multiple sclerosis (MS). EAE is accompanied by transient weakness or paralysis of hind limbs. Methods: Dark Agouti (DA) rats were used to investigate the effect of CNS
damage in EAE on the skeletal muscles. The course of the disease was followed for 20 days (one relapse) and 30 days (two relapses). After development of maximal clinical signs the animals were treated with olive leaf polyphenols (OLP, 1 g/kg, i.p.) and sacrificed the 20th day from the induction of EAE. TBARS, carbonyl protein levels and glutathione peroxidase
(GPX) activity were measured and electrophoretic methods and pathohistological examination of muscle tissue were performed in skeletal muscles gastrocnemius, tibialis anterior and soleus. Results: SDS-PAGE showed differences in muscle protein expression. Western blot analysis determined the expression of the glucose transporter 4 and immunofluorescence microscopy showed the success of GLUT4 translocation. Pathohistological findings of skeletal muscles showed abnormal muscle fibers in EAE, denervation, inflammation and inflammatory infiltrates at the time of the second relapse and regeneration with OLP therapy. Conclusion: Improvement of GLUT4 translocation and incorporation into the cell membrane under the influence of OLP therapy was not observed relative to the control group. However, we propose these bioactive phenolic compounds for therapeutic application in autoimmune and neurodegenerative diseases including MS
The most recent strategies in the development of therapies for the treatment of nerve tissue injuries
No full textOzljeda leđne moždine (eng. spinal cord injury, SCI) predstavlja jednu od najtežih neuroloških ozljeda, kronično i razarajuće stanje koje uzrokuje motoričke, osjetilne i socijalne poremećaje koji ugrožavaju život pacijenta i njegove okoline. Osim što se još uvijek tretira simptomatski, trenutne mogućnosti liječenja SCI-a uključuju i kirurške zahvate, rehabilitacijsku njegu, stabilizaciju i dekompresiju leđne moždine. Štoviše, nakon što je SCI prepoznata kao globalni problem kontinuiranog godišnjeg rasta, znanstvenici ulažu velike napore u razvoj novijih strategija liječenja ozljeda leđne moždine. Razvijaju se noviji terapijski pristupi, uključujući staničnu terapiju neuralnim matičnim stanicama (eng. neural stem cells, NSC), relevantnim u regenerativne svrhe pri promicanju i ponovnom uspostavljanju sinaptičke neuralne povezanosti i potpore. Nadalje, došlo je i do značajnog napretka u razumijevanju fizioloških, biokemijskih, molekularnih i staničnih promjena i složenosti patofiziologije SCI-a što u konačnici rezultira razvijanjem brojnih pretkliničkih životinjskih modela u svrhu rekapituliranja primarnih ili sekundarnih ozljeda leđne moždine. Uzimajući u obzir inhibitorno okruženje i nepravilnosti u aksonalnim spojevima nakon povrede leđne moždine, koji uvelike utječu na regeneraciju oštećenih neuronskih funkcija i tkiva, znanstvenici ističu važnost regenerativnih biomaterijala koji mogu ispuniti šupljine na mjestu ozljeda leđne moždine, dostaviti učinkovite lijekove i omogućiti adsorptivnost transplantiranih stanica ili stanica domaćina. U ovom radu predstavljena su dosadašnja istraživanja i noviji pristupi u liječenju ozljeda leđne moždine, opisani su neurološki ishodi SCI-a u ljudi, stanične terapije i pristupi. Rad je napisan u svrhu prikupljanja opsežnih i najnovijih znanstvenih otkrića koja bi mogla pružiti obećavajući uvid u potpuno razjašnjenje molekularnih mehanizama i patofiziologije SCI-a i otkrivanju relevantnih i učinkovitih terapija za liječenje iste. Integriranje dosadašnjih metoda liječenja u SCI pacijenata opisanih u brojnim znanstvenim radovima sa terapijom neuralnim matičnim stanicama predstavlja jednu od perspektivnijih budućih strategija u izlječenju ozljeda živčanog tkiva leđne moždine.Spinal cord injury (SCI) is one of the most serious neurological injuries, chronic and destructive condition that causes motor, sensory and social disturbances to the life of the patient and his or her environment. In addition to symptomatic treatment, the current possibilities for curing spinal cord injuries include surgical interventions, rehabilitative care, stabilization and decompression of the spinal cord. Moreover, since SCI is recognized as a global problem with continuous annual growth, scientists are investing hardly in developing new strategies for treating spinal cord injuries. Newer therapeutic approaches are being developed, including cell therapy using neural stem cell (NSCs), relevant for regenerative purposes in promoting and re-establishing synaptic neural linkages and support. Furthermore, significant progress has been made in understanding the physiological, biochemical, molecular and cellular changes and complexity of SCI pathophysiology, which ultimately results in the development of numerous preclinical animal models for the recapitulation of spinal cord injuries, both primary and secondary. Taking into account the inhibitory environment and irregular linkage in axonal compounds after SCI, which greatly affects the regeneration of impaired neuronal functions and tissues, scientists emphasize the importance of regenerative biomaterials that can fill cavities at the site of the spinal cord injury, deliver effective medications and allow the adsorption of transplanted cells or host cells. This paper presents current research and new approaches to the treatment of SCI, described neurological outcomes of SCI in humans, cell therapies and approaches for the purpose of collecting extensive and recent scientific discoveries that could provide a promising insight into the complete clarification of molecular mechanisms and pathophysiology of the SCI and the detection of relevant and effective therapies for treating it. The integration of the current methods of treatment in SCI patients described in numerous scientific papers with neural stem cell therapy is one of the most prospective strategies for curing spinal cord injury
Utjecaj polisaharida na probiotičke bakterije
No full textPostoji 1000 do 1150 vrsta bakterija koje sačinjavaju ljudski mikrobiom. Osim bakterija, ljudski organizam nastanjuju i virusi, gljivice, protozoe i arhee. Njihova uloga u tankom i debelom crijevu je metabolizam tvari iz lumena kako bi omogućili apsorpciju hranjivih tvari. Proizvodi koji sadrže ove ne-patogene, komenzalne mikroorganizme nazivaju se probiotici. Sojevi bakterija koji se najčešće upotrebljavaju zbog svog probiotičkog djelovanja su rodovi Lactobacillus i Bifidobacterium te kvasac Saccharomyces boulardii. Postoji mnoštvo dokaza za različita djelovanja probiotika. Smatra se da većina njihovih blagotvornih učinaka proizlazi iz kontrole ljudskog imunosnog sustava te uklanjanja patogena i njihovih štetnih nusprodukata.
Kao i svi mikroorganizmi, bakterije i kvasci zahtijevaju određene tvari koje će im osigurati pogodan okoliš za rast i razvoj. Takve supstance su neodrživi sastojci hrane koji ostvaruju blagotvorno djelovanje na zdravlje domaćina, poznatiji kao prebiotici. Kemijski spojevi koji čine prebiotike su ugljikohidrati ili topljiva prehrambena vlakna kao što su inulin, β-glukani i fruktooligosaharidi (FOS). Različiti prebiotici će poticati na rast različite vrste bakterija. Zbog toga je važno da do probavnog sustava dođu nepromijenjeni.
Mnoga istraživanja pokazala su znatno povećanje broja kolonija probiotičkih bakterija u prisutnosti polisaharida iz gljiva. Čak su i polisaharidi iz jestivih gljiva kao što su M. procera i S. crispa pozitivno stimulirali rast laktobacila te tako dokazali vlastiti potencijal za korištenje kao nutraceutici.There are between 1000 and 1150 bacterial species that can be found in the human microbiome along with different species of viruses, fungi, protozoa and archaea. While inhabiting the distal small bowel, caecum and colon, their task is to metabolize substances in the lumen to provide an additional source of nutrients. Products that contain these commensal, nonpathogenic, microorganisms and that benefit the host are called probiotics. The most commonly used microorganism strains are the bacterial genera Lactobacillus and Bifidobacterium, as well as the probiotic yeast Saccharomyces boulardii. There is vast body of evidence documenting their beneficial effect to the host by modulating the host’s immune system or by affecting other undesired microorganisms or their products.
However, like every other microorganism, bacteria and yeast require certain substances which would provide them with a suitable environment to grow. These substances are non-viable food components that confer health benefits to the host, and are also known as prebiotics. Prebiotic compounds are defined as carbohydrates or soluble dietary fibers such as inulin, β-glucans and fructooligosaccharides. Different prebiotics stimulate the growth of different bacterial species and it is important for them to reach the colon unchanged in order to stimulate the growth and activity of intestinal microbiota.
Many studies have shown a significant increase in number of probiotic bacteria in the presence of mushroom polysaccharides. Even edible mushrooms such as M. procera and S. crispa demonstrated high stimulation on the growth of lactobacilli and thus confirmed their potential use as nutraceuticals
Adverse drug reactions of Anti-parkinson medicinal products reported to Croatian Agency for Medicinal Products and Medical Devices
Get PDFNuspojava je svaka štetna i neželjena reakcija na lijek. To uključuje nuspojave koje nastaju uz primjenu lijeka unutar odobrenih uvjeta kao i nuspojave koje nastaju uz primjenu lijeka izvan odobrenih uvjeta (predoziranje, primjenu izvan odobrene indikacije ("off-label"), pogrešnu primjenu, zlouporabu i medikacijske pogreške) te nuspojave koje nastaju zbog profesionalne izloženosti.
Značaj opterećenja nuspojava za javno zdravstvo najbolje ilustriraju podaci Europske Komisije, koja ocjenjuje da su u EU nuspojave razlogom oko 5% svih hospitalizacija. Nadalje, oko 5% hospitaliziranih bolesnika doživi nuspojavu za vrijeme hospitalizacije, a nuspojave su peti po redu uzrok mortaliteta meĎu hospitaliziranim bolesnicima. Ukupno se procjenjuje da je oko 197.000 smrti godišnje u EU uzrokovano nuspojavama. TakoĎer se ocjenjuje da u EU ukupni direktni troškovi zbog nuspojava iznose godišnje oko 79 milijardi eura. S obzirom da se i prema najkonzervativnijim procjenama smatra da se barem 30% nuspojava može prevenirati, to znači da godišnji troškovi nuspojava koje se mogu spriječiti u EU iznose više od 23,5 milijarde eura. Stoga Europska Komisija ocjenjuje da čak i mala unaprjeĎenja na području sigurnosti primjene lijekova mogu imati velik i značajan utjecaj na javno zdravlje i društvo u cjelini. U Parkinsonovoj bolesti, koncentracija dopamina u bazalnim ganglijima je značajno snižena te farmakološko obnavljanje dopaminergičke aktivnosti levodopom ili dopaminskim agonistima ublažava motoričke simptome. Alternativan i komplementaran pristup je obnova ravnoteže kolinergičkih i dopaminergičkih utjecaja na bazalne ganglije. Najčešće nuspojave uzrokovane levodopom jesu: mučnina, povraćanje, abdominalni grčevi, noćne more, ortostatska hipotenzija, pospanost, diskinezija i, osobito u starijih i dementnih bolesnika, povremene halucinacije. Nuspojave izravnih agonista dopaminskih receptora jesu: sedacija, mučnina, ortostatska hipotenzija, psihoza. Antikolinergički
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lijekovi imaju mnogo zabilježenih nuspojava kao što su suhoća usta, retencija urina, opstipacija i smetnje vida itd. Zbog hepatotoksničnosti inhibitori katekol-O-metiltransferaze se rijetko primjenjuju.Adverse reaction is every response to a medicinal product which is noxious and unintended. This includes adverse reactions arising from use of the product within or outside (including overdose, off-label use, misuse, abuse and medication errors) the terms of the marketing authorisation or from occupational exposure.
The significance of public health barriers is best illustrated by the data of the European Commission, which estimates that 5% of all hospitalizations in the EU are adverse reactions . Furthermore, approximately 5% of hospitalized patients experience adverse reactions during hospitalization, and adverse reactions are the fifth leading cause of mortality among hospitalized patients. It is estimated that approximately 197.000 deaths per year in the EU are caused by side effects. It is also estimated that in the EU total direct costs due to adverse reactions amount to about 79 billion euros annually. Given that, according to the most conservative estimates, at least 30% of adverse reactions can be prevented, this means that the annual costs of preventable side effects in the EU are over 23,5 billion euros. Therefore, the European Commission estimates that even small advances in the field of drug safety can have a major and significant impact on public health and society.
In Parkinson's disease, dopamine concentration in basal ganglia has been significantly reduced and pharmacological regeneration of dopaminergic activity with levodopa or dopamine agonists mitigates motor symptoms. An alternative and complementary approach is the restoration of the balance of cholinergic and dopaminergic influences on banal ganglia.
The most common adverse reactions caused by levodopa are: nausea, vomiting, abdominal cramps, nightmares, orthostatic hypotension, drowsiness, dyskinesia and, especially in older and demented patients, occasional hallucinations. Side effects of direct dopamine receptor agonists are: sedation, nausea, orthostatic hypotension, psychosis. Anti-
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cholinergic drugs have many reported adverse reactions such as dry mouth, urinary retention, constipation and visual disturbances. Because of hepatotoxicity, catechol-O-methyltransferases are rarely used
Roles of optineurin in herpes simplex virus 1 infection
No full textOptineurin je multifunkcionalni protein čija se uloga pokazala bitnom u
IRF3/7 signalnom putu, važnim za obranu od patogena. Nedostatak
optineurina ili njegove ubikvitin vežuće regije ima za posljedicu slabiju
aktivaciju TBK1 i smanjenu sekreciju interferona tipa 1. Herpes simpleks
virus 1 (HSV-1) je virus iz obitelji alphaherpesviridae, koji inficira ljude
uspješno izbjegavajući imunosni odgovor domaćina različitim
mehanizmima. Kako bismo ispitali ima li optineurin ulogu u infekciji HSV-
1, pratili smo tijek infekcije u divljem tipu mišjih embrionalnih fibroblasta
u usporedbi s mišjim embrionalnim fibroblastima u kojima je u genu za
optineurin deletirana ubikvitin vežuća regija. Kod infekcije divljeg tipa
stanica primijetili smo da razina optineurina pada s progresijom infekcije i
to u ovisnosti o količini virusa koji se koristi. Ovaj rezultat ukazuje na
virusom posredovano aktivno uklanjanje optineurina. U skladu s
prethodno opisanom ulogom optineurina u pozitivnoj regulaciji TBK1,
uočili smo da je TBK1 slabije fosforiliran tijekom infekcije kod stanica s
nedostatkom optineurina u odnosu na divlji tip stanica. Međutim, u
stanicama sa mutiranim optineurinom, virusna replikacija je, usprkos
oslabljenoj TBK1 aktivaciji interferona, bila otežana u usporedbi sa
stanicama divljeg tipa. Nadalje, nismo uočili značajne razlike kod
replikacije HSV-1 kod divljeg tipa ili mutiranog nakon indukcije autofagije
izgladnjivanjem. Preliminarni rezultati ovog istraživanja sugeriraju da
optineurin olakšava replikaciju HSV-1, ali su potrebna daljnja istraživanja
da bi se razjasnio točan mehanizam kojim se to postiže.Optineurin is a multifunctional protein, which plays an important role in
the IRF3/7 signaling pathway, an important mechanism through which
the host defends itself against pathogens. The lack of optineurin or his
ubiquitin binding domain results in attenuated activation of TBK1 and
decreased secretion of type 1 interferons. Herpes simplex virus (HSV-1) is
a virus from the alphaherpesviridae family which infects people while
successfully evading the hosts immune response through various
mechanisms. To study the role of optineurin in HSV-1 infection, we
compared the progression of the infection in wild tipe mouse embryonic
fibroblasts, and compared them to mouse embryonic fibroblasts whose
ubiquitin binding domain has been deleted. We noticed that the level of
optineurin in wild type infected cells decreased as the infection progressed
depending on the amount of virus used. This result points to the active
removal of optineurin mediated by the virus. In accordance with the
previously described role of optineurin in the positive regulation TBK1, we
noticed that TBK1 phosphorylation is weaker in cells with lacking
optineurin than in wild type cells. However, viral replication in cells with
mutated optineurin was impeded, despite the impaired TBK1 mediated
interferon activation, compared to wild type cells. Moreover, we did not
notice a significant difference in viral replication in wild type and mutated
cells after the induction of autophagy. The preliminary results in this
study suggest that optineurin facilitates HSV-1 replication, but more
research is needed to clarify the mechanism behind it
The role of IFN-β in the pathogenesis and therapy of multiple sclerosis
No full textMultipla skleroza (MS) je kronična autoimuna bolest koja napada mijelinizirane aksone u središnjem živčanom sustavu (SŽS-u). Posljedica autoimunog napada je demijelinizacija koja dovodi do gubitka neuronske signalizacije, a ponekad i do smrti neurona. MS se može očitovati različitim simptomima poput senzoričkih, vizualnih i motoričkih poremećaja, umora, boli i kognitivnih deficita, a njihova manifestacija varira od pacijenta do pacijenta. Točan uzrok nastanka MS-a nije poznat, no niz genetskih i okolišnih faktora može doprinijeti njenoj patogenezi pa se bolest smatra multifaktorijalnom. Javlja se u dobi od 20-40 godina, a pogađa 2,5 milijuna ljudi širom svijeta. Postoje 4 tipa MS-a: relapsno remitirajući, sekundarno progresivni, primarno progresivni i progresivno relapsni. Terapije za MS smanjuju trajanje akutnih napada bolesti, njihovu frekvenciju i ublažavaju simptome, ali nažalost, ne liječe MS. Budući da imunološki sustav igra centralnu ulogu u patogenezi bolesti, sve trenutno dostupne terapije su imunomodulacijske. Uloga imunološkog sustava u patogenezi bolesti je detaljno objašnjena u ovom radu. Napravljen je i iscrpan pregled mehanizama djelovanja i učinkovitosti terapije imunomodulacijskim citokinom IFN-β, prvom terapijom za MS. IFN-β smanjuje godišnju stopu pojave napada te smanjuje aktivnost i napredovanje bolesti, ali s vremenom gubi kliničku učinkovitost. U ovom radu je obrađen učinak IFN-β na transport imunoloških stanica do SŽS-a, aktivnost B stanica, antigen prezentirajućih stanica i T stanica te njegovo direktno neuroprotektivno djelovanje. Unatoč njegovom pleiotropnom učinku na imunološki sustav, IFN-β ne liječi MS, a kao glavni razlog neuspjeha smatra se pojava neutralizirajućih protutijela koja se razvijaju u velikom broju pacijenata tijekom liječenja s IFN-β. Terapija IFN-β je napredovala s novom formulacijom pegiliranog IFN-β koja ima veću kliničku učinkovitost. Još uvijek ima prostora za poboljšanje terapije IFN-β, a potencijalni načini su predloženi u ovom radu.Multiple sclerosis is a chronic autoimmune disorder that targets myelinated axons in the central nervous system (CNS). This results in demyelinization which leads to loss of neuronal signalization and sometimes even to neuronal death. MS is characterized by various symptoms such as sensory, visual and motor disorders, fatigue, pain and cognitive deficits. Their manifestation varies from patient to patient. MS is a multifactorial disease that can be influenced by various genetic and environmental factors, but the exact cause is still unknown. It occurs at the age of 20-40 and affects 2,5 million people worldwide. There are 4 types of MS: relapsing remitting, secondary progressive, primary progressive and progressive relapsing. MS therapies reduce the duration of acute exacerbations, their frequency and relieve symptoms, but unfortunately, they are unable to cure the disease. Since the immune system plays a central role in disease pathogenesis, all currently available therapies are immunomodulatory. The role of the immune system in pathogenesis of the disease is described in detail in this work. This work also contain an extensive overview of the mechanisms of action and efficacy of immunomodulatory cytokine IFN-β, the first MS therapy. IFN-β treatment reduces the annual relapse rate, reduces activity and progression of the disease, but generally does not have long-term effect because its clinical efficacy is decreasing over time. This work explains effects of IFN-β on transport of immune cells to the CNS, B cell activity, antigen presenting cells, T cell activity and its direct neuroprotective functions. Despite its pleiotropic effect on the immune system, IFN-β does not cure MS and neutralizing antibodies that develop in a large number of patients treated with IFN-β have been proposed as the main cause of treatment failure. IFN-β therapy has progressed with the new formulation of pegylated IFN-β that has greater clinical efficacy. There
is still room for improvement of IFN-β therapy and potential ways are discussed in this work
Metabolic reprogramming of tumour cells: Main features and therapeutic potential
Get PDFTumori su oduvijek bili zanimljiva tema raznih istraživanja, te je njihov promijenjeni metabolizam iznimno interesantan znanstvenicima u istraživanjima za antitumorsku terapiju. Stanice raka ne zahtijevaju potrošnju kisika kako bi proizvodile energiju kao što je to slučaj kod normalnih stanica. Umjesto toga, te stanice se oslanjaju na glukozu za otprilike 5 do 10 puta više od normalnih stanica za primarnu proizvodnju energije. Istraživači često aludiraju na stanice raka kao "metaboličke parazite" zbog njihove sposobnosti da "ukradu" energiju od domaćina kako bi potaknule svoj vlastiti rast. Organel odgovoran za preusmjeravanje metabolizma koji karakterizira stanice raka je mitohondrij. Mitohondriji u tumorskim stanicama sadrže mutiranu DNA i promjenjene strukture proteina i enzima. Te promjene povećavaju proizvodnju slobodnih radikala i narušavaju normalnu proizvodnju energije.
Ovim radom dan je pregled literature o mogućim metama tumorskog metabolizma koje bi se mogle ciljati kako bi se, u budućnosti, razvila moguća adekvatna protutumorska terapija. Fokus je na metabolički put glikolize, glutaminolize te oksidativne fosforilacije. U nastavku dan je detaljan opis na koji način tumori „promijene“ svoj metabolizam u odnosu na normalne stanice.Tumors have always been an interesting topic of various research, and their changed metabolism is extremely interesting to scientists in antitumor therapy research. Cancer cells do not require oxygen consumption to produce energy as well as normal cells. Instead, these cells rely on glucose (sugar) for about 5 to 10 times the normal cells for their primary energy production. Researchers often allude to cancer cells as "metabolic parasites" because of their ability to "steal" energy from the hosts to boost their own growth. The organel responsible for redirecting the metabolism that characterizes cancer cells is a mitochondria. Mitochondria in tumor cells contain mutated DNA and modified structure of proteins and enzymes. These changes increase the production of free radicals and disrupt normal energy production.
This paper gives an overview of possible tumor metabolic targets that could be targeted in order to develop an adequate anti-tumor therapy in the future. Focus is given on the glycolysis, glutaminolysis and oxidative phosphorylation. The following is a detailed description of how the tumors "change" their metabolism relative to normal cells