Search

Hydrazoic acid (HN3) and its deprotonated form azide ion (N3−) (AHA) are toxic because they inhibit the cytochrome c oxidase complex IV (CoX IV) embedded in the inner mitochondrial membrane that forms part of the enzyme complexes involved in cellular respiration. Critical to its toxicity is the inhibition of CoX IV in the central nervous system and cardiovascular system. Hydrazoic acid is an ionizable species and its affinity for membranes, and the associated permeabilities, depend on the pH values of aqueous media on both sides of the membranes. In this article, we address the permeability of AHA through the biological membrane. In order to understand the affinity of the membrane for the neutral and ionized form of azide, we measured the octanol/water partition coefficients at pH values of 2.0 and 8.0, which are 2.01 and 0.00034, respectively. Using a Parallel Artificial Membrane Permeability Assay (PAMPA) experiment, we measured the effective permeability through the membrane, which is logPe − 4.97 and − 5.26 for pH values of 7.4 and pH 8.0, respectively. Experimental permeability was used to validate theoretical permeability, which was estimated by numerically solving a Smoluchowski equation for AHA diffusion through the membrane. We demonstrated that the rate of permeation through the cell membrane of 8.46·104 s−1 is much higher than the rate of the chemical step of CoX IV inhibition by azide of 200 s−1. The results of this study show that transport through the membrane does not represent the rate-limiting step and therefore does not control the rate of CoX IV inhibition in the mitochondria. However, the observed dynamics of azide poisoning is controlled by circulatory transport that takes place on a time scale of minutes. Nasl. z nasl. zaslona. Opis vira z dne 19. 6. 2023. Bibliografija: str. 237-238. Abstract. ARRS

The common cold is generally considered a usually harmless infectious disease of the upper respiratory pathway, with mostly mild symptoms. However, it should not be overlooked, as a severe cold can lead to serious complications, resulting in hospitalization or death in vulnerable patients. The treatment of the common cold remains purely symptomatic. Analgesics as well as oral antihistamines or decongestants may be advised to relieve fever, and local treatments can clear the airways and relieve nasal congestion, rhinorrhea, or sneezing. Certain medicinal plant specialties can be used as therapy or as complementary self-treatment. Recent scientific advances discussed in more detail in this review have demonstrated the plant’s efficiency in the treatment of the common cold. This review presents an overview of plants used worldwide in the treatment of cold diseases. Nasl. z nasl. zaslona. Opis vira z dne 3. 5. 2023. Št. članka: 662. Bibliografija: str. 19-25. Abstract.

Firefly luciferase is susceptible to inhibition and stabilization by compounds under investigation for biological activity and toxicity. This can lead to false-positive results in in vitro cell-based assays. However, firefly luciferase remains one of the most commonly used reporter genes. Here, we evaluated isoflavonoids for inhibition of firefly luciferase. These natural compounds are often studied using luciferase reporter-gene assays. We used a quantitative structure%activity relationship (QSAR) model to compare the results of in silico predictions with a newly developed in vitro assay that enables concomitant detection of inhibition of firefly and Renilla luciferases. The QSAR model predicted a moderate to high likelihood of firefly luciferase inhibition for all of the 11 isoflavonoids investigated, and the in vitro assays confirmed this for seven of them: daidzein, genistein, glycitein, prunetin, biochanin A, calycosin, and formononetin. In contrast, none of the 11 isoflavonoids inhibited Renilla luciferase. Molecular docking calculations indicated that isoflavonoids interact favorably with the D-luciferin binding pocket of firefly luciferase. These data demonstrate the importance of reporter-enzyme inhibition when studying the effects of such compounds and suggest that this in vitro assay can be used to exclude false-positives due to firefly or Renilla luciferase inhibition, and to thus define the most appropriate reporter gene. Nasl. z nasl. zaslona. Opis vira z dne 10. 8. 2021. Št. članka: 6927. Bibliografija: str. 13-14. Abstract. ARRS ARRS EFSA-CDN project Young researchers

Endocrine disrupting chemicals (EDCs) are associated with cancer development and progression due to their promotion of increased cell invasiveness and metastasis formation. However, the effects of EDCs on cell adhesion mediated through integrins have not been well studied to date. Their actions are implicated by binding sites for hormones on the vitronectin receptor (VTNR; or integrin [alpha[sub]v[beta][sub]3), which is involved in tumor angiogenesis and metastasis. VTNR-expressing human umbilical vein endothelial cells (HUVECs) were used to determine the effects of EDCs and endogenous hormones on cell adhesion to vitronectin-coated surfaces, and on VTNR activation. Cell adhesion was significantly increased for bisphenol A, triclocarban, and triclosan (10, 100nM; p0.05). No changes in cell adhesion were seen for 5alpha]-dihydrotestosterone, 17[beta]-estradiol, triiodothyronine, imatinib and paroxetine. These data indicate that EDC-mediated increases in HUVEC adhesion to vitronectin are not mediated through androgenic, estrogenic, or thyroid activities, nor through activation of VTNR. Although these effects of EDCs on HUVEC adhesion require further investigation of the underlying mechanism(s) of action to define their biological relevance, the low-dose effects and nonmonotonic responses revealed here define the need for further investigation of these EDCs. Št. članka: 105275. Abstract. Bibliografija: str. 6-7. ARRS ARRS

The incidence of resistant fungal pathogens has been increasing, especially in immuno-compromised people. As such, considerable research has been focused on discovering anti-fungal agents with new mechanisms of action and on optimizing the use of existing agents. In this context, interest in the polyene group of anti-fungals has recently been renewed, since they are known to be effective against a broad spectrum of fungal pathogens that only rarely develop a resistance to them. In the past 10 years considerable efforts have been made to improve their efficacy and, simultaneously, to reduce their toxicity. Knowledge about the basic mechanisms of their action will be of crucial importance to further optimizing their use. The mechanisms of polyene action at the membrane level are reviewed here, focusing primarily on their pore-forming activity and on the resulting osmotic responses of artificial lipid vesicles and different eukaryotic cells.

The rapid growth in the variety and quantity of contaminants of emerging concern (CEC) in wastewater indicates the necessity for developing efficient and environmentally friendly methods for their removal. This study investigates the removal efficiency of 46 CEC, including 12 bisphenols, from wastewater using a lab and pilot-scale hydrodynamic cavitation generator alone and in combination with UV illumination (pilot-scale). During lab-scale cavitation, the highest removal efficiencies of bisphenols (15-63%) for this specific design of cavitator were obtained at a rotational frequency (vcav)=9500 rpm and time (tcav)=10-min. Temperature and the physicochemical properties (e.g. Kow) of the studied compounds also had a significant effect on removal efficiency. At the pilot-scale, 11 CECs were quantifiable in the wastewater influent, and the generator operated at cav=2290 and 2700rpm. The highest removal efficiencies (15-90%) were obtained at a lower cav=2290 rpm while neither an increase in cav, tcav or the presence of UV-C light increased the removal efficiency. A lower cav also reduced the hydrodynamic power of the cavitator from 477W to 377W, resulting in reduced energy consumption. Overall, the results show the potential of hydrodynamic cavitation for a large-scale application as a pre-treatment technology and pave the way for future improvements in the design of cavitation reactors.

Background: Endocrine-disrupting chemicals can interfere with hormonal homeostasis and have adverse effects for both humans and the environment. Their identification is increasingly difficult due to lack of adequate toxicological tests. This difficulty is particularly problematic for cosmetic ingredients, because in vivo testing is now banned completely in the European Union. Objectives: The aim was to identify candidate preservatives as endocrine disruptors by in silico methods and to confirm endocrine receptors activities through nuclear receptors in vitro. Methods: We screened preservatives listed in Annex V in the European Union Regulation on cosmetic products to predict their binding to nuclear receptors using the Endocrine Disruptome and VirtualToxLab version 5.8 in silico tools. Five candidate preservatives were further evaluated for androgen receptor (AR), estrogen receptor (ER[alpha]), glucocorticoid receptor (GR), and thyroid receptor (TR) agonist and antagonist activities in cell-based luciferase reporter assays in vitro in AR-EcoScreen, hER[alpha]-HeLa-9903, MDA-kb2, and GH3.TRE-Luc cell lines. Additionally, assays to test for false positives were used (nonspecific luciferase gene induction and luciferase inhibition). Results: Triclocarban had agonist activity on AR and ER[alpha] at 1[micro]M and antagonist activity on GR at 5[micro]M and TR at 1[micro]M. Triclosan showed antagonist effects on AR, ER[alpha], GR at 10[micro]M and TR at 5[micro]M, and bromochlorophene at 1[micro]M (AR and TR) and at 10[micro]M (ER[alpha] and GR). AR antagonist activity of chlorophene was observed [inhibitory concentration at 50% (IC50) IC50=2.4[micro]M], as for its substantial ER[alpha] agonist at >5[micro]M and TR antagonist activity at 10[micro]M. Climbazole showed AR antagonist (IC50=13.6[micro]M), ER[alpha] agonist at >10[micro]M, and TR antagonist activity at 10[micro]M. Nasl. z nasl. zasl. Opis vira z dne 19. 10. 2020. Bibliografija: str. 107005-15 - 107005-17. Young Researcher ARRS

In November 2018, the European medicines Agency (EmA) issued a draft of revised guideline on the environmental risk assessment of medicinal products for human use. The revised guideline upgrades the first guidelines published in 2006 and provide a more consistent and comprehensive approach to environmental risk assessment. Thus, in terms of greater transparency, a decision tree approach was introduced that clearly illustrates substances properties that trigger the need for its testing and evaluation. At the same time, the guideline defines the risk assessment approach for each environmental compartment more clearly. The revision of a twotiered assessment approach also reduces administrative burden, since the revised guideline provides more detailed technical guidance to applicants and allows the introduction of risk reduction measures in the second phase. The draft guideline also defines the tailored risk assessment approach for potential endocrine active substances and antibiotics. The updated guideline thus provides an improved guidance for environmental risk assessment and introduces more precisely evaluation of the influence of the active substances on development and reproduction as well as on the endocrine system. Evropska agencija za zdravila (EmA) je novembra 2018 izdala osnutek prenovljenih smernic za oceno tveganja za okolje za humana zdravila. Prenovljene smernice nadgrajujejo prvotne smernice iz leta 2006 in zagotavljajo bolj dosleden in celovit pristop k oceni tveganja za okolje. Zaradi večje preglednosti uvajajo pristop odločitvenega drevesa, ki nazorno prikazuje lastnosti učinkovin, za katere se zahteva testiranje in ocenjevanje. Hkrati pa bolj jasno definirajo način ocenjevanja tveganja za vsak del okolja posebej. S posodobitvijo dvostopenjskega pristopa k ocenjevanju zmanjšujejo tudi administrativno breme, saj ponujajo podrobnejše tehnične napotke za izpopolnitev ocene izpostavljenosti ter omogočajo vpeljavo ukrepov za zmanjšanje tveganja v drugi fazi. Prav tako osnutek smernice navaja prilagojen pristop k oceni tveganja za potencialne kemične motilce endokrinega sistema in antibiotike. Prenovljene smernice tako predstavljajo izboljšana navodila za oceno tveganja za okolje in uvajajo bolj natančno proučitev vpliva zdravilnih učinkovin na razvoj in reprodukcijo ter endokrini sistem.

Chagas disease, caused by the Trypanosoma cruzi parasite represents a major burden for public health in Latin America and a potential threat to other countries around the world. The infection is transmitted to a person via an infected triatomine bug and it is in the worst, chronic form often manifested as cardiomypathy with hearth rhythm disorders and cardiac failure, some infected people develop gastrointestinal, neurological or mixed changes, which also require appropriate treatment. Despite the fact that disease was first discovered more than a century ago, only two registered drugs - benznidazole (BNZ) and nifurtimox (NF) - are available for the its treatment today, where BNZ is known as the first choice medication. As nitroimidazole antiparasitic agent, BNZ does not only give unsatisfactory results but also has numerous side effects. The treatment of Chagas disease is more than obviously a major therapeutical challenge. With the aim of discovering more effective medicines, scientists started searching for new targets as well as various modifications of already registered substances. The research is currently focused on three targets - CYP51, cruzipain, and DNA of the parasite, which, in addition to the description of Chagas disease, its prevalence and current treatment, is also presented in this article. Chagasova bolezen, ki jo povzroča protozojski parazit Trypanosoma cruzi, predstavlja veliko breme javnega zdravja v Latinski Ameriki in potencialno grožnjo državam po vsem svetu. Okužba, ki se na človeka prenese najpogosteje preko okužene stenice, se v najhujši, kronični obliki izrazi kot kardiomiopatija z motnjami srčnega ritma in pojavom srčne odpovedi, nekateri okuženi pa razvijejo prebavne, nevrološke ali mešane spremembe, ki prav tako zahtevajo ustrezno zdravljenje. Kljub dejstvu, da je bila bolezen prvič odkrita že pred več kot sto leti, sta danes za njeno zdravljenje na voljo le dve registrirani zdravili - benznidazol (BNZ) in nifurtimoks (NF), pri čemer velja BNZ za zdravilo prve izbire. Ta učinkovina je nitroimidazolni antiparazitik, ki poleg tega, da pri zdravljenju ne daje zadovoljivih rezultatov, izkazuje tudi številne neželene učinke. Zdravljenje Chagasove bolezni torej več kot očitno predstavlja velik terapevtski izziv, ki so se ga z namenom odkritja učinkovitejših zdravil lotili tako z iskanjem novih tarč, kot tudi z raznimi modifikacijami že registriranih učinkovin. Raziskave so trenutno osredotočene na tri ciljne tarče - CYP51, kruzipain in DNA parazita, kar poleg opisa Chagasove bolezni, njene razširjenosti in trenutnega načina zdravljenja tudi predstavljamo v tem članku.

When producing different medicinal products in shared facilities or equipment, the potential for cross-contamination is a concern. To prevent the effect of contaminants to the effectiveness and/or safety of medicines, the manufacturing equipment needs to be cleaned regularly and the carry-over limits for cleaning validation studies need to be adequately determined. In 2014, an EMA 'Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities' (EMA/CHMP/ CVMP/ SWP/169430/2012) was published. The guideline describes an approach to review and evaluate pharmacological and toxicological data of individual active substances and thus enable determination of threshold levels. The derivation of such a threshold should be based on the use of PDE and ADE. However, other scientifically justified approaches can be used. One of them is the approach that is based on the use of occupational safety data. This article summarises the differences in setting the exposure limits between the two approaches, as well as between the PDE approach and approach used before EMA guideline. The approach in line with EMA guideline is considered more appropriate to establish appropriate exposure limits. In some cases, however, the old method is still suitable, or even more conservative than the new approach. Pri proizvodnji različnih zdravil v istih objektih ali na isti opremi lahko pride do prenosa zdravilne učinkovine ali drugih sestavin farmacevtskega izdelka v naslednji izdelek. Da bi preprečili negativen vpliv na učinkovitost in/ali varnost zdravila, moramo izvajati redno čiščenje proizvodne opreme, vrednosti ostankov zdravilnih učinkovin in pomožnih snovi po čiščenju pa ustrezno zamejiti. Leta 2014 izdana smernica EMA za določanje mejnih vrednosti pri izdelavi različnih zdravil v skupnih objektih (EMA/CHMP/ CVMP/SWP/169430/2012) opisuje pristop določitve mejne vrednosti na podlagi pregleda in vrednotenja farmakoloških in toksikoloških podatkov posameznih zdravilnih učinkovin. Kot osnovo za izračun varnih mej smernica EMA navaja principa dovoljene in sprejemljive dnevne izpostavljenosti, možna pa je tudi uporaba drugih znanstveno utemeljenih pristopov. Eden izmed pristopov je uporaba podatkov, ki so bili pridobljeni za oceno varnosti delavcev. V članku prikazujemo razlike v določanju mejne vrednosti ostankov zdravil ali pomožnih snovi med obema pristopoma, kot tudi med pristopom dovoljene dnevne izpostavljenosti in pristopom, ki se je uporabljal pred izdajo smernice EMA. Čeprav je stara metoda za nekatere primere povsem ustrezna ali celo bolj konservativna od novega pristopa, je pristop v skladu s smernico EMA bolj primeren za določitev mejnih vrednosti zdravilnih učinkovin.

The metabolic instability and high kidney retention of minigastrin (MG) analogues hamper their suitability for use in peptide-receptor radionuclide therapy of CCK2/gastrin receptor-expressing tumors. High kidney retention has been related to N-terminal glutamic acids and can be substantially reduced by coinjection of polyglutamic acids or gelofusine. The aim of the present study was to investigate the influence of the stereochemistry of the N-terminal amino acid spacer on the enzymatic stability and pharmacokinetics of (111)In-DOTA-(d-Glu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 ((111)In-PP11-D) and (111)In-DOTA-(l-Glu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 ((111)In-PP11-L). Using circular dichroism measurements, we demonstrate the important role of secondary structure on the pharmacokinetics of the two MG analogues. The higher in vitro serum stability together with the improved tumor-to-kidney ratio of the (d-Glu)6 congener indicates that this MG analogue might be a good candidate for further clinical study.

Vitamin D is a fat-soluble vitamin involved in the regulation of calcium homeostasis, glucose metabolic pathway and renin expression. It is also capable of immunomodulation and anticancerogenic activity. Vitamin D status of inhabitants at some geographical latitudes is insufficient because of limited UVB radiation. The question that arises from this is what the appropriate vitamin D concentration for maintaining health is and how much dosage is needed to prevent its deficiency. When measuring 25-hydroxyvitamin D, insufficiency starts at levels lower than 75 nmol/l. The purpose of this review is to inform how simple it is to provide the appropriate body amount of vitamin D as well as to elucidate vitamin D involvement in mechanisms of some other diseases besides its well-known roles in bone remodelling disorders(e.g. rickets, osteoporosis). Vitamin D je v maščobi topen vitamin, vpleten v regulacijo homeostaze kalcija, metabolične poti glukoze in ekspresije renina, sposoben pa je tudi imunomodulacije ter ima protirakavo delovanje. Na določenih geografskih širinah je preskrbljenost prebivalstva z vitaminom D zaradi omejene količine ultravijoličnih žarkov B neustrezna, zato se poraja vprašanje, katere koncentracije vitamina D lahko zadostijo osnovnim potrebam človeškega telesa, ter predvsem, kolikšni so primerni odmerki, da preprečimo njegovo pomanjkanje.Le-to naj bi nastopilo, ko koncentracija merjenega serumskega 25-hidroksivitamina Dpade pod 75 nmol/l. Namen članka je opozoriti, kako preprosta je pot, da si zagotovimo ustrezno koncentracijo vitamina D v telesu,ter poleg znanih motenj v izgradnji kostnine (rahitis, osteoporoza), ki nastanejo zaradi njegovega pomanjkanja, osvetliti vlogo vitamina D v mehanizmih nastanka nekaterih drugih bolezni.

Biomarkers are biological indicators of health, disease or poisoning, and are now widely applicable in determining the etiology of the disease, pathophysiological, pharmacological, toxicological processes and diagnostics. In the process of research and development of new drugs we can use validated biomarkers to measure the effectiveness of therapy and predict the adverse effects of drugs. So biomarkers can increase the success rates in drug development. They can reduce the costs and shorten the drug development process, they can help in selecting the best drug candidates and they can predict efficacy and safety of the drugs and open the way for personalized medicine. Biološki označevalci so biološki kazalniki ali napovedniki zdravja, bolezni ali zastrupitve in so široko uporabni pri ugotavljanju etiologije bolezni, patofizioloških, farmakoloških in toksikoloških procesih ter v diagnostiki. V procesu raziskav in razvoja novih zdravil lahko s pomočjo ocenjenih bioloških označevalcev merimo učinkovitost zdravljenja ter predvidimo neželene učinke zdravil. Biološki označevalci tako pripomorejo k razvoju zdravil, znižajo stroške in skrajšajo čas razvoja zdravila, pomagajo pri izbiri najboljših kandidatov za učinkovine, bolje napovejo učinkovitost in varnost zdravila in odpirajo pot osebni medicini.

Chemical warfare agents are defined as any chemical substance whose toxic properties are utilized to kill, injure or incapacitate an enemy in warfare and associated military operations. There has been a legislative effort worldwide to ban the use of them under the chemical weapons convention which came into force in 1997. However the manufacture of these agents cannot be completely prohibited as some of them have potential industrial uses. The easeof manufacturing these agents and effectiveness during combat or small-scale terrorist operations still make them a powerful weapon to reckon with. In this review we will discuss briefly about properties, mechanism of toxicity, clinical features of exposure and pharmacological management of poisoning caused by chemical agents. Kot kemijski bojni strupi so definirane vse tiste kemične snovi, ki zaradi svojih toksičnih lastnosti delujejo na sovražnika in povzročijo bodisi njegovo smrt, poškodbe ali ga onesposobijo za nadaljnje bojevanje. Kljub sprejemu konvencije leta 1997, ki prepoveduje njihovo uporabo kot orožje, proizvodnja nekaterih izmed njih ni popolnoma prepovedana zaradi njihove uporabnosti kot industrijske surovine. Zaradi enostavnosti priprave teh snovi in njihove učinkovitosti moramo še vedno računati na njihovo možno uporabo v vojaške ali teroristične namene. V prispevku navajamo lastnosti teh snovi, mehanizme, preko katerih povzročajo škodljive učinke, v kratkem pa so predstavljene tudi klinične značilnosti izpostavitve tem snovem in priporočila za zdravljenje zastrupitev z njimi.