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Synthesis, characterization and biological activity of harmicines, harmiquins and harmicenes
No full textRak i malarija su smrtonosne bolesti koje predstavljaju značajan globalni javnozdravstveni problem.
Učinkovitost postojećih citostatika i antimalarika opada uslijed pojave rezistencije, zbog čega je potrebno
kontinuirano istraživati nove potencijalne lijekove. Popularan pristup u razvoju novih lijekova je molekulska
hibridizacija, odnosno kovalentno povezivanje dva bioaktivna spoja s ciljem poboljšanja njihovog djelovanja. U
okviru ovog doktorskog rada sintetizirani su hibridni spojevi harmina, -karbolinskog alkaloida s izraženim
antimalarijskim i protutumorskim djelovanjem, i: 1) derivata cimetne kiseline (harmicini), 2) klorokina
(harmikini), 3) ferocena (harmiceni). U pripravi harmicina korištena je bakrom(I) katalizirana azid-alkin
cikloadicija, odnosno klik-reakcija koja je rezultirala harmicinima triazolskog tipa. Harmikini i harmiceni
pripravljeni su korištenjem klik-reakcije te reakcije povezivanja amina i karboksilnih kiselina, dajući harmikine i
harmicene triazolskog i amidnog tipa. Za potrebe klik-reakcija sintetizirani su odgovarajući alkini i azidi -
karbolina, derivata cimetne kiseline, 7-klorkinolina te ferocena, dok su amini i karboksilna kiselina harmina te
karboksilna kiselina i amini 7-klorkinolina pripravljeni za potrebe reakcija povezivanja. Novi spojevi
karakterizirani su uobičajenim analitičkim i spektroskopskim metodama te je ispitano njihovo antiproliferativno i
antimalarijsko djelovanje in vitro. U seriji harmicina najjače antiproliferativno djelovanje ostvarili su triazoli 49ae,
dok su u seriji harmikina najcitotoksičniji bili triazoli 54 i 57. Najsnažnije antiproliferativno djelovanje među
harmicenima prema svim ispitivanim staničnim linijama pokazao je amid 82, dok su harmiceni triazolskog tipa
67, odnosno 66 i 69 pokazali značajno i selektivno djelovanje prema MCF-7 i HCT116. Najbolje antimalarijsko
djelovanje na eritrocitnu fazu životnog ciklusa svih ispitanih sojeva P. falciparum, u nanomolarnim
koncentracijama, pokazali su harmikini. Spoj 63 ispoljio je 5,5 puta snažniji učinak u odnosu na klorokin (CQ)
(IC50 = 2 ± 0,3 nM), dok je spoj 65 bio najučinkovitiji prema sojevima plazmodija rezistentnima na postojeće
antimalarike. Temeljem dobivenih rezultata može se zaključiti da harmikini predstavljaju spojeve uzore za razvoj
novih potencijalnih antimalarika, dok je harmicine i harmicene potrebno razvijati kao potencijalne protutumorske
lijekove.Cancer and malaria are life-threatening diseases that pose a permanent public health problem. Existing cytostatic
and antimalarial drugs are progressively losing their efficacy due to the development of drug resistance. Thus,
there is a constant need for the development of novel and effective drugs. One of the possible approaches is
molecular hybridization, i.e. covalent linking of two bioactive moieties into a single molecule with improved
properties. In this dissertation, hybrids comprising harmin, a -carboline alkaloid with pronounced antimalarial
and antitumor activity, and: 1) cinnamic acid derivatives (harmicines), 2) chloroquine (harmiquins), 3) ferrocene
(harmicenes) were prepared. The harmicines were synthesized by a copper(I)-catalyzed azide-alkyne cycloaddition
("click" reaction) leading to triazole-type hybrids. On the other hand, harmiquins and harmicenes were prepared
by both "click" and coupling reactions, giving triazole- and amide-type harmiquins and harmicenes. To obtain the
required starting compounds for the "click" reaction, synthetic routes to -carboline-, cinnamic acid derivative-,
7-chloroquinoline-, and ferrocene-based alkynes and azides were developed. For the purpose of coupling reactions,
7-chloroquinoline- and harmine-based amines and acids were prepared. The novel compounds were characterized
by standard methods (1H and 13C NMR, IR, MS). The antimalarial activity of the prepared compounds was
evaluated in vitro against the erythrocytic and hepatic stages of the Plasmodium life cycle, as well as the
antiproliferative activity against a panel of human tumor cell lines. Among the harmicines, triazoles 49a-e
exhibited the strongest antiproliferative activity, whereas in the harmiquins series, triazoles 54 and 57 were the
most cytotoxic compounds. Among the harmicenes, amide 82 showed the strongest cytotoxic activity against all
tested cell lines (IC50 < 10 M), whereas triazole-type harmicenes 67, 66, and 69 displayed significant and selective
activity against MCF-7 and HCT116. Harmiquins have shown the best antimalarial activity against the erythrocytic
phase of chloroquine-sensitive and -resistant P. falciparum strains (IC50 in low nanomolar concentrations).
Compound 63 showed a 5.5-fold stronger effect than chloroquine (IC50 = 2 ± 0.3 nM), while compound 65 was
the most effective against resistant Plasmodium strains. The results suggest that harmiquins represent novel
antimalarial hits, whereas further studies including harmicines and harmicenes should focus on their anticancer
properties
Analysis of the difference in hydrophobicity of native and desialylated transferrin by reaction with 8-anilinonapthalenesulfonic acid
No full textU sklopu ovoga diplomskog rada proučavan je utjecaj vezanja hidrofobne probe, 8-anilino-1-naftalensulfonske kiseline, na fluorescenciju humanog nativnog apo-transferina i desijaliniziranog transferina, kao i stehiometrija vezanja kiseline na nativni protein. Ispitivanje hidrofobnosti provedeno je u fosfatnom puferu koncentracije 50 mM, dok je analiza stehiometrije vezanja hidrofobne probe na ljudski apo-transferin provedena u fosfatnom puferu koncentracije 200 mM, a ispitivanja provedena su pri neutralnoj vrijednosti pH i temperaturi od 25°C. Tehnike koje su korištene u eksperimentalnom dijelu rada su UV-Vis spektrofotometrija i fluorescencijska spektroskopija. Rezultati su obrađeni u programu Microsoft Excel. Dodatak ANS otopini ljudskog nativnog apo-transferina uzrokovao je primjetan porast intenziteta fluorescencije, što ukazuje na to da se proba veže za izloženi džep na površini polipeptidnog lanca. Analizom otopine ANS i desijaliziranog ljudskog apo-transferina nije primjećen porast intenziteta fluorescencije, što znači da nije došlo do hidrofobnih interakcija kao u slučaju nativnog apo-transferina. Ispitivanje stehiometrije vezanja ANS i ljudskog nativnog apo-transferina korištenjem Jobove metode ukazuje na to da se proba i protein vežu u omjeru 1:1 i 2:1.As part of this thesis, the influence of binding of the hydrophobic probe, 8-anilino-1-naphthalenesulfonic acid, on the fluorescence of human native apo-transferrin and desialylated transferrin, as well as the stoichiometry of ANS binding to the native protein, were studied. The hydrophobicity test was performed in a phosphate buffer with a concentration of 50 mM, while the analysis of the stoichiometry of binding of the hydrophobic probe to human apo-transferrin was performed in a phosphate buffer with a concentration of 200 mM, and both tests were performed at a neutral value pH and temperature of 25°C. The techniques used in the experimental part of the thesis are UV-Vis spectrophotometry and fluorescence spectroscopy. The results were processed in Microsoft Excel. Addition of ANS to a solution of human native apo-transferrin caused a marked increase in fluorescence intensity, indicating that the probe binds to an exposed pocket on the surface of the polypeptide chain. Analysis of the solution containing the probe and desialylated human apo-transferrin did not show an increase in fluorescence intensity, which indicates that no hydrophobic interactions occurred as was the case with native apo-transferrin solution. Analysis of the stoichiometry of binding of ANS and human native apo-transferrin using Job's plot indicates that the hydrophobic probe and protein bind in a ratio of 1:1 and 2:1
Evaluation of the sebia miniCAP flex piercing capillary electrophoresis system
No full textU medicinsko-biokemijskom laboratoriju svaki analitički uređaj prije puštanja u rutinski rad mora proći postupak verifikacije odnosno validacije kojim se procjenjuje njegova primjenjivost za predviđeni mjerni postupak. Najčešće se verificiraju analitičke karakteristike uređaja koje je proizvođač ostvario tijekom tvorničke validacije, preciznost, točnost, mjerni raspon, ali i usporedivost s eventualno prethodno korištenim sustavom kako bi se procijenio utjecaj promjene analitičkog sustava na kliničku odluku. Elektroforezom hemoglobina moguće je detektirati kvalitativne i kvantitativne poremećaje u sintezi globinskih lanaca te se danas u kliničkim laboratorijima dijagnostika hemoglobinopatija najčešće provodi koristeći automatiziranu metodologiju kapilarne zonske elektroforeze. Cilj ovog rada bio je verificirati analitičke karakteristike sustava miniCAP flex-piercing prije puštanja u rutinski rad. Sustav koristi dvije kapilare, u kojima se tijekom 8 minuta na 9600V pri pH 6,8 razdvajaju varijante hemoglobina. U zdravih odraslih ispitanika hemoglobin čine HbA i HbA2, dok u novorođenčadi nalazimo i HbF. Verifikacija je provedena prema CLSI EP15-A3 dokumentu koristeći tri različita kontrolna uzorka koja su uključivala različite varijante hemoglobina (HbA, HbF, HbS, HbC i HbA2). Ostvareni rezultati za preciznost i točnost u skladu su s navodima proizvođača. Usporedba rezultata sa sustavom koji se trenutno koristi u rutinskom radu, Capillarys 2, ukazala je na izvrsnu usporedivost rezultata. Manje konstantno odstupanje u vrijednostima HbF može se objasniti širokim rasponom vrijednosti koje su obuhvaćene ovom verifikacijom. Rezultati verifikacije ukazuju da ispitivani analitički sustav za kapilarnu elektroforezu hemoglobina, miniCAP flex piercing zadovoljava postavljene kriterije prihvatljivosti te se može koristiti u rutinskom laboratorijskom radu. Kao dodatna vrijednost korištenja ovog uređaja prepoznata je mogućnost provođenja analize iz začepljene primarne epruvete čime je unaprijeđena sigurnost tehničkog osoblja u laboratorijskim uvjetima.In a medical-biochemical laboratory, each analytical device must undergo a verification or validation procedure before being put into routine operation, which assesses its applicability for the intended measurement procedure. Most often, the analytical characteristics of the device that the manufacturer achieved during factory validation, precision, accuracy, measuring range, but also comparison with a possibly previously used system are verified in order to assess the impact of changing the analytical system on the clinical decision. With hemoglobin electrophoresis, it is possible to detect qualitative and quantitative disorders in the synthesis of globin chains, and nowadays in clinical laboratories diagnostics of hemoglobinopathy is most often carried out using the automated capillary zone electrophoresis. The aim of this study was to evaluate analytical performance of the miniCAP flex piercing system before putting it into routine operation. The system uses two capillaries, in which hemoglobin variants are separated for 8 minutes at 9600V and pH 6.8. In healthy adult subjects, hemoglobin consists of HbA and HbA2, while in newborns we also find HbF. Evaluation was performed according to the CLSI EP15-A3 document using three different control samples that included different hemoglobin variants (HbA, HbF, HbS, HbC and HbA2). The achieved results for precision and accuracy are in accordance with the manufacturer's specifications. Comparison of the results with the system currently used in routine work, Capillarys 2, indicated excellent correlation between results. A smaller constant deviation in HbF values can be explained by the wide range of values covered by this evaluation. Evaluation results show that the tested analytical system for capillary electrophoresis of hemoglobin, miniCAP flex piercing meets the set acceptance criteria and can be used in routine laboratory work. As an additional value of using this device, the possibility of conducting analysis from a blocked primary test tube was recognized, which improved the safety of technician in laboratory conditions
MicroRNA as potential therapeutic targets and biomarkers in chronic obstructive pulmonary disease
No full textKronična opstrukcijska plućna bolest (KOPB) jedan je od vodećih uzroka morbiditeta i mortaliteta širom svijeta. Karakterizirana je ireverzibilnim ograničenjem protoka zraka, upalom i remodeliranjem plućnog tkiva. S obzirom na povećanu izloženost populacije čimbenicima rizika za razvoj KOPB-a, simptome koji narušavaju kvalitetu života i nedostatke trenutačnog dijagnostičko-terapijskog pristupa, ova bolest predstavlja rastući javnozdravstveni problem. Napori za pronalaskom novih biomarkera i terapijskih meta u središte pozornosti smjestili su mikroRNA (miRNA, miR), 19-22 nukleotida duge i visokokonzervirane molekule, uključene u širok spektar različitih bioloških procesa poput upale, stanične proliferacije, diferencijacije i smrti. Uloga miRNA u regulaciji genske ekspresije komplementarnim sparivanjem s ciljnom mRNA molekulom te njihova iznimna stabilnost u tjelesnim tekućinama čini ih izuzetno zanimljivim područjem za buduća istraživanja. Štoviše, miRNA molekule mogu biti otpuštene u izvanstanični prostor i transportirane do ciljnih stanica u sklopu vezikula posredujući tako međustaničnu komunikaciju što produbljuje tezu o potencijalnim miRNA biomarkerima i terapeuticima u KOPB-u. Ovaj pregledni rad pruža uvid u do danas najbolje opisane miRNA molekule koje su se istaknule kao moguće nove terapijske i dijagnostičke mete u KOPB-u. Također, sažeto prikazuje ulogu izvanstaničnih vezikula u patogenezi KOPB-a i njihovu upotrebu kao mogućih biomarkera, terapeutika i nosača za dostavu miRNA terapijskih molekula.Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality worldwide. It is characterised by irreversible airflow limitation, inflammation and lung tissue remodeling. Considering the increased exposure of the population to the risk factors for development of COPD, the symptoms that impair the quality of life and the shortcomings of the current diagnostic and therapeutic approach, this disease represents a growing public health problem. Efforts to find new biomarkers and therapeutic targets have placed microRNAs (miRNAs, miRs), 19-22 nucleotide long and highly conservated molecules, involved in wide range of various biological processes such as inflammation, cell proliferation, differentiation and death, into the spotlight. The role of miRNAs in the regulation of gene expression by complementary pairing with the target mRNA molecule, as well as their exceptional stability in body fluids, makes them an extremly interesting field for future reasearch. Moreover, miRNA molecules can be released into the extracellular space and transported to target cells via vesicles thus mediating intercellular communication, which deepens the thesis of potential miRNA biomarkers and therapeutics in COPD. This review provides an insight into miRNA molecules best described to date which have emerged as possible new therapeutics and diagnostic targets in COPD. It also summarizes the role of extracellular vesicles in the pathogenesis of COPD as well as their use as potential biomarkers, therapeutics, and delivery vehicles for miRNA therapeutic molecules
The influence of dietary patterns and alpha lipoic supplementation on ORAC antioxidative capacity of serum
No full textPodlogu brojnih kroničnih bolesti čini oksidativni stres, odnosno stanje neravnoteže između stvaranja slobodnih radikala (oksidansa) i antioksidativne obrane organizma u korist oksidansa. Stoga je adekvatan unos egzogenih antioksidansa važan doprinos prevenciji i/ili liječenju bolesti povezanih s oksidativnim stresom. α-lipoična kiselina (ALA) je zbog svojih višestrukih bioloških uloga (neutralizacija slobodnih radikala, regeneracija endogenih antioksidansa, popravak oksidiranih oštećenja, kelacija metala, itd.) i dobre raspodjele u organizmu moćan antioksidans. Cilj ovog diplomskog rada bio je ispitati utjecaj suplementacije α-lipoičnom kiselinom na ukupni antioksidativni potencijal seruma pacijentica s dijagnozom cervikalne intraepitelne neuroplazije. Istraživanje je provedeno kao dvostruko-slijepa placebom kontrolirana studija u kojoj su pacijentice kroz period od 3 mjeseca dnevno suplementirane sa 600 mg ALA. Modificiranom ORAC metodom izmjeren je antioksidativni potencijal seruma te uspoređen utjecaj određenih parametara životnog stila i prehrambenih navika pacijentica. Uočeno je da unos voća i povrća (3 ili više porcija dnevno) prehranom značajno povećava antioksidativni potencijal seruma pacijentica. Suprotno tome, nije uočena razlika antioksidativnog potencijala seruma pacijentica s obzirom na pušenje i indeks tjelesne mase. Suplementacija α-lipoičnom kiselinom nije značajno utjecala na vrijednosti ORAC antioksidativnog potencijala. Trenutno je dostupan vrlo ograničen broj znanstvenih studija koje pokazuju oprečne rezultate vezano uz učinkovitost ALA u prevenciji oksidativnog stresa te je u tom kontekstu potrebno provesti dodatna istraživanja.The basis of many chronic diseases is oxidative stress; that is, a state of imbalance between the creation of free radicals (oxidants) and the body's antioxidant defense, in favor of oxidants. Therefore, optimizing the intake of antioxidans is crucial in the context of prevention and/or treatment of oxidative stress-related diseases. α-lipoic acid (ALA) is a powerful antioxidant due to its multiple biological roles (neutralization of free radicals, regeneration of endogenous antioxidants, repair of oxidized damage, metal chelation, etc.) and adequate distribution in the body. The aim of this thesis was to examine the influence of supplementation with α-lipoic acid on the total antioxidant potential in the serum of patients diagnosed with cervical intraepithelial neuroplasia. The research was conducted as a double-blind placebo-controlled study in which patients were supplemented with 600 mg of ALA daily for a period of 3 months. Using the modified ORAC method, the antioxidant potential of serum was measured and the influence of certain parameters of the lifestyle and eating habits of the patients was compared. It was observed that the intake of fruits and vegetables (3 or more portions per day) significantly increased the antioxidant potential of female patients. On the contrary, no difference was observed in the antioxidant potential of female patients related to smoking and body mass index. Supplementation with α-lipoic acid did not significantly affect the ORAC serum values. The effectiveness of ALA in the prevention of oxidative stress has not been properly investigated and the number of available studies is limited. Therefore, further research is needed in order to get better insight into antioxidant efficiency of ALA
Analiza sigurnosnog profila TNF-a inhibitora na temelju zaprimljenih prijava sumnji na nuspojave u 2018. i 2019. godini
No full textThe aim of this study was to analyze the adverse drug reactions
of TNF-a inhibitors reported to the Agency for Medicina! Products
and Medica! Devices of Croatia in the period from 1 January 2018 to 31
December 2019, and to raise awareness of the safety profile of these drugs and
risk minimization measures, especially additional measures. Reports of suspected
adverse reactions were analyzed according to: reporter qualification, age and
sex of the patient, suspected drug, concomitant drugs, seriousness of reaction,
System Organ Class using the Medical Dictionary for Drug Regulatory Affairs
(MedDRA). Total of 246 ADR (Adverse drug reaction) reports were analyzed.
Majority of patients belonged to the age group 45-64 years (39.4 %) and were
female (60.6 %). ADRs were in most cases reported by physicians (86.2 %). The
most frequent suspected active substances were infliximab and adalimumab,
while concomitant substances the most often belonged to the group of immunosuppressants
and analgesics. Of all received ADR reports, 61 % were serious.
Majority of ADRs belonged to System Organ Class "General disorders and
administration site conditions" and the most commonly reported preferred tem
was "drug ineffectiveness''. The obtained results can improve prevention, detection
and treatment of possible adverse reactions
Biological effects of capsaicin from chili pepper
No full textKapsaicin je aktivna sastavnica ljute papričice (rod Capsicum, Solanaceae) s analgetskim svojstvima. Od svog otkrića,
koristi se kao homeopatski lijek za liječenje boli. Sustavni pregledi znanstvene literature potvrđuju da je kapsaicin
koristan u liječenju različitih kroničnih bolnih stanja. Novija istraživanja ukazuju na velik potencijal kapsaicina za
sistemsko liječenje brojnih drugih bolesti i stanja, kao što su pretilost, dijabetes ili metabolički sindrom no još uvijek
nema dovoljno znanstvenih dokaza koji bi opravdali njegovu upotrebu. No, pripravci s kapsaicinom se često koriste
iako je potrebno provesti više kliničkih studija za procjenjivanje učinaka ali i mogućih nuspojava korištenja kapsaicina
za pojedine indikacije.
Ovaj rad doprinosi razumijevanju mehanizma djelovanja, indikacija i potencijalnih štetnih učinaka kapsaicina što u
konačnici olakšava utvrđivanje prikladnosti pripravaka s kapsaicinom u ljekarničkoj praksi.
Zaključak rada je da je upotreba proizvoda s kapsaicinom opravdana u prevenciji bolesti uzrokovanih prekomjernom
tjelesnom masom te terapiji boli dok još uvijek nema dovoljno dokaza za upotrebu kapsaicina kao protutumorskog
agensa i u liječenju bolesti probavnog sustava. Također, prilikom savjetovanja pacijenata o preparatima s kapsaicinom,
nužno je upozoriti pacijenta na klinički značajne nuspojave te na ostala ograničenja primjene.Capsaicin is an active ingredient in hot peppers (genus Capsicum, Solanaceae) with analgesic properties. Since its
discovery, it has been used as a homeopathic remedy to treat pain. Systematic reviews of the scientific literature
confirm that capsaicin is useful in the treatment of various chronic painful conditions. Recent research indicates the
great potential of capsaicin for the systemic treatment of many other diseases and conditions, such as obesity, diabetes
or metabolic syndrome, but there is still insufficient scientific evidence to justify its use. However, capsaicin
preparations are often used, although more clinical studies are needed to evaluate the effects and possible side effects
of capsaicin use for certain indications. This paper contributes to the understanding of the mechanism of action,
indications and potential adverse effects of capsaicin, which ultimately facilitates the determination of the suitability of
capsaicin preparations in pharmaceutical practice.
The paper concludes that the use of capsaicin products is justified in the prevention of overweight and pain therapy
while there is still insufficient evidence for the use of capsaicin as an antitumor agent and in the treatment of
gastrointestinal diseases. Also, when advising patients on capsaicin preparations, it is necessary to warn the patient of
clinically significant side effects and other limitations of use
Small molecule oral targeted drugs and novel approach in treating ulcerative colitis
No full textUlcerozni kolitis (UC) je autoimuna bolest crijeva karakterizirana kroničnom upalom. Lokalizacijski se može podijeliti na ulcerativni proktitis, ulcerativni proktosigmoiditis, lijevostrani kolitis i pankolitis, dok ovisno o kliničkoj težini bolesti razlikujemo blagi, umjereni i teški oblik. Stope prevalencije su više u sjevernim i razvijenim zemljama, a niže u manje razvijenim, u kojima pak bilježimo porast stopa incidencije. Glavni patofiziološki čimbenici rizika za razvoj UC-a su: genetski, okolišni, mikrobiološki i imunološki. Međudjelovanje istih, pretpostavlja se, vodi ka narušavanju funkcije intestinalne barijere i kroničnoj upali. Klinička očitovanja variraju od lokalnih intestinalnih, ekstraintestinalnih do sistemskih, a tipična klinička slika obuhvaća: abdominalne bolove, promjene u ritmu pražnjenja crijeva, kolorektalno krvarenje, anemiju, malaksalost, gubitak teka, povišenu tjelesnu temperaturu i artralgije. Metode kojima se koristimo u postavljanju dijagnoze bolesti uključuju: laboratori jske, proceduralne i
histološke testove. Osnovni terapijski cilj kojemu težimo je duga i stabilna remisija temeljem postignutog mukozalnog i/ili histološkog cijeljenja, čime osiguravamo manju vjerojatnost od komplikacija, hospitalizacija, kolorektalnog karcinoma te postižemo dulji i kvalitetniji ži vot. U liječenju UC-a svoju primjenu nalazi konvencionalna terapija – kortikosteroidi, aminosalicilati, imunomodulatori, inhibitori kalcineurina; biološka terapija – anticitokinska i anti-integrinska protutijela te niskomolekulska oralna precizna terapija – inhibitori Janus kinaze, S1PR modulatori/agonisti, inhibitori fosfodiesteraze i drugi. Tofacitinib je predstavnik među inhibitorima Janus kinaze koji svoj protuupalni učinak postiže kompetitivnom inhibicijom Janus kinaze, daljnjom inhibicijom STAT transkripcijskih faktora te posljedično smanjenjem sinteze proupalnih citokina. Među S1PR modulatorima/agonistima posebno se ističe ozanimod – funkcionalni antagonist koji putem internalizacije i degradacije receptora onemogućava
izlazak limfocita iz limfoidnih organa, cirkulaciju limfocita i time uzrokuje limfopeniju. Ostali niskomolekulski oralni precizni lijekovi su: inhibitori fosfodiesteraze 4 (pr. apremilast), analozi fosfatidilkolina (pr. LT-02), anti-integrini (pr. AJM300), antiviralni imunomodulatori (pr. ABX464), antisense oligonukleotidi (pr. alicaforsen) i drugi.Ulcerative colitis (UC) is an autoimmune bowel disease, characterized by chronic inflammation. UC is classified by localization into ulcerative proctitis, ulcerative proctosigmoiditis, left-sided colitis and pancolitis and by clinical severity into mild, moderate and severe form. The prevalence rates are higher in the northern and developed countries and lower in the developing countries, but latter also experience incidence growth. Major pathophysiological risk factors for developing UC are: genetic, environmental, microbiological and immunological. Interraction among those leads to impaired intestinal barrier function and chronic inflammation. Clinical manifestations vary from local intestinal, extraintestinal to systemic manifestations. Typical symptoms are abdominal pain, irregular bowel movements, colorectal bleeding, anemia, malaise, loss of appetite, increased body temperature and arthralgias. Most commonly used diagnostic tools are laboratory, procedural and histopathological studies. The main therapeutic goal represents a long and stable remission based on the achieved mucosal and/or histological healing, which reduces the risk of complications, hospitalizations, colorectal cancer and ensures a better quality of life. Therapeutic strategies used in UC treatment are: conventional therapy – corticosteroids, aminosalicylates, immunomodulators, calcineurin inhibitors; biological therapy – anti-cytokine and anti-intregrin antibodies
and small molecule oral targeted therapies – Janus kinase inhibitors, S1PR modulators/agonists, phosphodiesterase inhibitors and others. Tofacitinib is a lead Janus kinase inhibitor which exerts its anti-inflammatory effect by competitive inhibition of Janus kinase, further inhibition of STAT transcription factors and a subsequent decrease in the synthesis of inflammatory cytokines. One of the key S1PR modulators/agonists is ozanimod – a functional antagonist that prevents lymphocyte egress from lymphoid organs, lymphocyte circulation and thus causes lymphopenia by the mechanism of internalization and degradation of receptors. Other small molecule oral targeted therapies are: phosphodiesterase-4 inhibitors (e.g. apremilast), phosphatidylcholine analogues (e.g. LT-02), anti-integrins (e.g. AJM300), antiviral immunomodulators (e.g. ABX464), antisense oligonucleotides (e.g. alicaforsen) and others
Ultrasound-assisted extraction optimisation and biological effects of black medic extract (Medicago lupulina L.)
No full textBiljni polifenoli su predmetom mnogobrojnih istraživanja zbog svojih pozitivnih učinaka na ljudski organizam. U ovom diplomskom radu određeni su uvjeti optimalne ekstrakcije ukupnih polifenola iz hmeljaste vije pomoću Bex-Behnken dizajna. Uvjeti su određivani s obzirom na maseni udio glicerola u otapalu, temperaturu i vrijeme ekstrakcije, a sadržaj polifenola određivan je spektrofotometrijski. Zaključeno je da su optimalni uvjeti 60%-tni udio glicerola, temperatura od 80 °C te vrijeme ekstrakcije od 20 mina. Dobiveni optimalni ekstrakt dalje je korišten u biološkim testovima ispitivanja aktivnosti inhibicije enzima tirozinaze, lipoksigenaze i elastaze te u β-karoten linoleatnoj analizi za određivanje antioksidativne aktivnosti ekstrakta. Ekstrakt pokazuje određenu sposobnost inhibicije tirozinaze, lipoksigenaze i elastaze, a njegova antioksidativna aktivnost nadmašuje onu butil-hidroksianisola koji je korišten kao pozitivna kontrola.Plant polyphenols have been the subject of numerous studies due to their positive effects on the human body. In this diploma thesis, the conditions of optimal extraction for total polyphenols from black medic were determined using Bex-Behnken design. Conditions were determined with respect to glycerol concentration in the solvent, temperature and extraction time, and polyphenol content was determined spectrophotometrically. It was concluded that the optimal conditions were a 60% glycerol concentration, a temperature of 80 C and an extraction time of 20 min. The obtained optimal extract was further used in biological assays to test the inhibition activity of the enzymes tyrosinase, lipoxygenase and elastase and in β-carotene linoleate analysis to determine the antioxidant activity of the extract. The extract shows a certain ability to inhibit tyrosinase, lipoxygenase and elastase, and its antioxidant activity surpasses that of butylhydroxyanisole which was used as a positive control
Bioaktivne biljne sastavnice i mikronutrijenti za ublažavanje simptoma endometrioze
No full textCilj istraživanja
Cilj ovog specijalističkog rada je dati sveobuhvatan pregled znanstvenih spoznaja o učincima i mehanizmima djelovanja bioaktivnih biljnih sastavnica i mikronutrijenata na ublažavanje simptoma endometrioze kako bi se prema znanstveno utemeljenim dokazima mogli donijeti relevantni zaključci o njihovom potencijalu terapijske primjene.
Materijali i metode
Istraživanje u okviru specijalističkog rada je teorijskog karaktera i uključuje pregled dostupne stručne i znanstvene literature o predloženoj temi. Pretražene su dostupne elektronske baze podataka na engleskom jeziku: PubMed, Scopus, ScienceDirect, Cochrane. Prikupljeni podaci obuhvatili su pretklinička i klinička ispitivanja koja su zatim sistematično prikazana.
Rezultati
U sklopu ovog specijalističkog rada prikazani su rezultati nekliničkih i manje brojnih kliničkih istraživanja kurkumina, resveratrola, epigalokatehin-3-galata, krocina i genisteina te ekstrakata konopljikina ploda, vrkutine zeleni i kore primorskog bora. Bioaktivne biljne sastavnice i biljni ekstrakti razmatrani u ovom radu pokazali su antiproliferativne, proapoptotske, antiangiogenetske, protuupalne i antioksidacijske učinke u uvjetima in vitro i in vivo. Istaknut je potencijal alfa-lipoične kiseline, vitamina C, E i D, melatonina te akupunkture i višekomponentnih smjesa tradicionalne kineske medicine. No, postojeći klinički dokazi nedovoljno podupiru njihovu praktičnu primjenu za ublažavanje simptoma endometrioze.
Zaključci
Iako razina kliničkih dokaza o djelovanju bioaktivnih biljnih sastavnica i mikronutrijenata u endometriozi nije zadovoljavajuća, tradicionalna primjena i dosadašnje znanstvene spoznaje ukazuju na njihov veliki potencijal i ohrabruju daljnja klinička istraživanja.Objectives
The objective of this research is to provide a comprehensive overview of scientific knowledge on the effects and mechanisms of action of bioactive plant components and micronutrients on the alleviation of endometriosis symptoms in order to draw relevant conclusions about their potential for therapeutic application.
Materials and methods
Research in this paper is a theoretical one and includes a detailed overview of the available professional and scientific data on the topic. Relevant bibliographic database in English language, such as PubMed, Scopus, ScienceDirect and Cochrane were searched. The collected data included preclinical and clinical trials, which were then presented systematically.
Results
This work presents the results of nonclinical and a small number of clinical studies of curcumin, resveratrol, epigallocatechin-3-gallate, crocin, genistein and extracts of Agnus castus fruit, Alchemilla and French maritime pine bark. The bioactive plant components and plant extracts considered in this work demonstrated in vitro and in vivo antiproliferative, proapoptotic, antiangiogenic, anti-inflammatory and antioxidant effects. The potential of alpha-lipoic acid, vitamins C, E and D, melatonin, acupuncture and multi-component mixtures of TCM was also highlighted. However, the clinical evidence does not sufficiently support their practical application to alleviate the symptoms of endometriosis.
Conclusion
Although the level of clinical evidence on the effect of bioactive plant components and micronutrients in endometriosis is insufficient, traditional use and current scientific knowledge indicate their great potential and encourage further clinical research