Nanodiamonds (NDs) are a class of carbon nanomaterials with sizes ranging from a few nm to micrometres. Due to their excellent physical, chemical and optical properties, they have recently attracted ...much attention in biomedicine. In addition, their exceptional biocompatibility and the possibility of precise surface functionalisation offer promising opportunities for biological applications such as cell labelling and imaging, as well as targeted drug delivery. However, using NDs for selective targeting of desired biomolecules within a complex biological system remains challenging. Urinary bladder cancer and bacterial cystitis are major diseases of the bladder with high incidence and poor treatment options. In this review, we present: (i) the synthesis, properties and functionalisation of NDs; (ii) recent advances in the study of various NDs used for better treatment of bladder cancer and (iii) bacterial cystitis; and (iv) the use of NDs in theranostics of these diseases.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Bladder cancer (BC) is the tenth most common cancer worldwide with a high recurrence rate, morbidity and mortality. Therefore, chemoprevention and improved treatment of BC are of paramount ...importance. Epidemiological studies suggest that adequate vitamin A intake may be associated with reduced BC risk. In addition, retinoids, natural and synthetic derivatives of vitamin A, are intensively studied in cancer research due to their antioxidant properties and their ability to regulate cell growth, differentiation, and apoptosis. Findings from in vivo and in vitro models of BC show great potential for the use of retinoids in the chemoprevention and treatment of BC. However, translation to the clinical practice is limited. In this narrative review we discuss: (i) vitamin A and retinoid metabolism and retinoic acid signalling, (ii) the pathobiology of BC and the need for chemoprevention, (iii) the epidemiological evidence for the role of dietary vitamin A in BC, (iv) mechanistic insights obtained from in vivo and in vitro models, (v) clinical trials of retinoids and the limitations of retinoid use, (vi) novel systems of retinoid delivery, and (vii) components of retinoid signalling pathways as potential novel therapeutic targets.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The urothelium, an epithelium of the urinary bladder, primarily functions as blood-urine permeability barrier. The urothelium has a very slow turn-over under normal conditions but is capable of ...extremely fast response to injury. During regeneration urothelium either restores normal function or undergoes altered differentiation pathways, the latter being the cause of several bladder diseases. In this review, we describe the structure of the apical plasma membrane that enables barrier function, the role of urothelium specific proteins uroplakins and the machinery for polarized membrane transports in terminally differentiated superficial umbrella cells. We address key markers, such as keratins, cancer stem cell markers, retinoic acid signalling pathway proteins and transient receptor potential channels and purinergic receptors that drive normal and altered differentiation in bladder cancer and bladder pain syndrome. Finally, we discuss uncertainties regarding research, diagnosis and treatment of bladder pain syndrome. Throughout the review, we emphasise the contribution of immunohistochemistry in advancing our understanding of processes in normal and diseased bladder as well as the most promising possibilities for improved bladder cancer and bladder pain syndrome management.
Rak sečnega mehurja je v svetovnem merilu 10. najpogostejši rak z izjemno visoko ponovljivostjo. Slovenska incidenca, umrljivost in prevalenca so pri tem raku v primerjavi z drugimi evropskimi ...državami in svetom nadpovprečne. Epidemiološke študije pa kažejo, da je zadosten vnos vitamina A in karotenoidov s prehrano povezan z zmanjšanim tveganjem, da zbolimo za rakom sečnega mehurja. Poleg tega retinoide, ki so naravni in sintetični derivati vitamina A, ter karotenoide intenzivno raziskujejo zaradi njihovih antioksidativnih lastnosti in zaradi njihove sposobnosti, da uravnavajo celično rast, delitev, diferenciacijo in apoptozo. Raziskave kažejo možnost, da se uporabijo retinoidi ter karotenoidi za preprečevanje raka sečnega mehurja in izboljšanje zdravljenja, čeprav jih v rutinski klinični praksi še niso uporabili. Pregledni članek opisuje metabolizem retinoidov in karotenoidov ter njune spremembe pri raku sečnega mehurja. Povzema rezultate epidemioloških študij z vitaminom A in karotenoidi ter kliničnih študij o zdravljenju raka sečnega mehurja z retinoidi. Opisuje tudi uporabnost novih nanometrskih dostavnih sistemov na področju prehranskih dopolnil in terapevtskih učinkovin pri preprečevanju in zdravljenju raka sečnega mehurja z retinoidi in karotenoidi.
Urinary bladder cancer is the ninth most common cancer in developed countries with poor prognosis and outcome for the patient due to the challenging diagnosis and limited treatment possibilities. ...Bladder cancer arises mainly from urothelial cells lining the lumen. Urothelial cells form a three- to five-layered urothelium, which maintains the blood-urine barrier. The carbohydrates that cover the apical surface of superficial urothelial cells, i.e. umbrella cells, are crucial for this function. The composition of the carbohydrate covering is altered during urothelial cancer transformation. These bladder cancer-associated carbohydrate changes are a promising field for diagnosis, therapy and management. Lectins, which are carbohydrate-binding proteins, can be used to detect subtle alterations in carbohydrate composition during urothelial cancer transformation. Extensive research into various lectin applications has already been conducted, but the results are often contradictory and confusing. None of these applications have reached clinical trials. We review the literature and discuss (i) current bladder cancer management, (ii) lectin-based assays for detection of various cancer subtypes, (iii) lectin-based strategies for innovative bladder cancer treatment and finally (iv) lectins in nanotheranostics for personalized bladder cancer management.
Endothelial glycocalyx is a carbohydrate-rich layer lining the luminal side of blood vessels. Its damage was demonstrated in different groups of critically ill patients. Indirect evidence showed that ...endothelial glycocalyx degradation might be an important factor in pathophysiology of preeclampsia. The aim of our study was to demonstrate endothelial glycocalyx by transmission electron microscopy and to compare its amount in the omentum vessels of pregnant patients with severe preeclampsia and two control groups.
Patients with severe preeclampsia who had a cesarean section were included in the study. Controls were healthy pregnant people at term with an elective cesarean section and non-pregnant patients of reproductive age who underwent laparoscopy for benign conditions. We performed omentum biopsies in all three groups. Samples were prepared for transmission electron microscopy using perfusion with ruthenium red. We measured the amount of endothelial glycocalyx attached to apical plasma membrane of endothelial cells as the area of glycocalyx observed with transmission electron microscope.
In the analysis we included nine patients from each group and demonstrated statistically significant difference in the amount of endothelial glycocalyx among the three groups (p = 0.018). Glycocalyx was significantly reduced in severe preeclampsia (median 1.90 μm2, interquartile range 0.80–4.1 μm2) compared to non-pregnant controls (median 14.34 μm2, interquartile range 3.80–73.32 μm2); p = 0.021. A trend towards reduced glycocalyx amount in preeclampsia vs. pregnant controls and pregnant controls vs. non-pregnant controls was observed but without statistical significance.
Compared to non-pregnant controls the endothelial glycocalyx was significantly reduced in pregnant patients with severe preeclampsia.
•There is indirect evidence on endothelial glycocalyx damage in preelampsia•Direct measurements of endothelial gylcocalyx in preeclampsia have not been reported.•Rutenium red perfusion allows visualizing gylcocalyx on electron microscopy.•Glycocalyx is reduced in severe preeclampsia.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Lectin histochemistry (LHC) and immunohistochemistry (IHC), which demonstrate the composition and localisation of sugar residues and proteins in cell membranes, respectively, are generally used ...separately. Using these two methods, we previously demonstrated that malignant transformation of urothelial cells results in the alterations of protein glycosylation and reduced expression of urothelium-specific integral membrane proteins uroplakins (UPs). However, the correlation between these changes was not studied yet. To evaluate this correlation, we developed innovative method, which we named combined lectin- and immuno- histochemistry (CLIH). We used human biopsies of 6 normal urothelia and 9 papillary urothelial carcinomas, i.e. 3 papillary urothelial neoplasms of low malignant potential (PUNLMP), 3 non-invasive papillary urothelial carcinomas of low grade (pTa, l.g.), and 3 invasive papillary urothelial carcinomas of high grade (pT1, h.g.). We tested five different protocols (numbered 1-5) of CLIH on paraffin and cryo-semithin sections and compared them with LHC and IHC performed separately. Additionally, we carried out western and lectin blotting with antibodies against UPs and lectins Amaranthus caudatus agglutinin (ACA), Datura stramonium agglutinin (DSA), and jacalin, respectively. We showed that incubation with primary antibodies first, followed by the mixture of secondary antibodies and lectins is the most efficient CLIH method (protocol number 5). Additionally, 300 nm thick cryo-semithin sections enabled better resolution of co-localisation between sugar residues and proteins than 5 µm thick paraffin sections. In the normal urothelium, CLIH showed co-localisation of lectins ACA and jacalin with UPs in the apical plasma membrane (PM) of superficial umbrella cells. In papillary urothelial carcinomas, all three lectins (ACA, DSA and jacalin) labelled regions of apical PM, where they occasionally co-localised with UPs. Western and lectin blotting confirmed the differences between normal urothelium and papillary urothelial carcinomas. Our results show that CLIH, when used with various sets of lectins and antigens, is a useful, quick, and reliable method that could be applied for basic cell biology research as well as detailed subtyping of human urothelial carcinomas.
Cystitis is a urinary bladder disease with many causes and symptoms. The severity of cystitis ranges from mild lower abdominal discomfort to life-threatening haemorrhagic cystitis. The course of ...disease is often chronic or recurrent. Although cystitis represents huge economical and medical burden throughout the world and in many cases treatments are ineffective, the mechanisms of its origin and development as well as measures for effective treatment are still poorly understood. However, many studies have demonstrated that urothelial dysfunction plays a crucial role. In the present review we first discuss fundamental issues of urothelial cell biology, which is the core for comprehension of cystitis. Then we focus on many forms of cystitis, its current treatments, and advances in its research. Additionally we review haemorrhagic cystitis with one of the leading causative agents being chemotherapeutic drug cyclophosphamide and summarise its management strategies. At the end we describe an excellent and widely used animal model of cyclophosphamide induced cystitis, which gives researches the opportunity to get a better insight into the mechanisms involved and possibility to develop new therapy approaches.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Urinary bladder cancer can be treated by intravesical application of therapeutic agents, but the specific targeting of cancer urothelial cells and the endocytotic pathways of the agents are not ...known. During carcinogenesis, the superficial urothelial cells exhibit changes in sugar residues on the apical plasma membranes. This can be exploited for selective targeting from the luminal side of the bladder. Here we show that the plant lectins Jacalin (from
Artocarpus integrifolia
), ACA (from
Amaranthus caudatus
) and DSA (from
Datura stramonium
) selectively bind to the apical plasma membrane of low- (RT4) and high-grade (T24) cancer urothelial cells in vitro and urothelial tumours ex vivo. The amount of lectin binding was significantly different between RT4 and T24 cells. Endocytosis of lectins was observed only in cancer urothelial cells and not in normal urothelial cells. Transmission electron microscopy analysis showed macropinosomes, endosome-like vesicles and multivesicular bodies filled with lectins in RT4 and T24 cells and also in cells of urothelial tumours ex vivo. Endocytosis of Jacalin and ACA in cancer cells was decreased in vitro after addition of inhibitor of macropinocytosis 5-(N-ethyl-N-isopropyl) amiloride (EIPA) and increased after stimulation of macropinocytosis with epidermal growth factor (EGF). Clathrin, caveolin and flotillin did not colocalise with lectins. These results confirm that the predominant mechanism of lectin endocytosis in cancer urothelial cells is macropinocytosis. Therefore, we propose that lectins in combination with conjugated therapeutic agents are promising tools for improved intravesical therapy by targeting cancer cells.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Rak sečnega mehurja je ena najpogostejših rakavih bolezni pri moških in ima visoko stopnjo ponovljivosti, zaradi česar predstavlja velik ekonomski in socialni problem. Za izboljšanje diagnosticiranja ...in zdravljenja raka sečnega mehurja se uporablja veliko različnih raziskovalnih modelov. V preglednem članku so predstavljeni najpogosteje uporabljeni modeli, saj predstavljajo približek dejanskemu molekularnobiološkemu dogajanju v človeku med boleznijo. Procesi na celični ravni se raziskujejo na in vitro modelih celičnih kultur, obnašanje celic v živem organizmu pa v različnih živalskih modelih. Izsledke raziskav na teh modelih je potrebno ovrednotiti tudi na človeških vzorcih, ki so nepogrešljivi, preden pride nov diagnostični postopek ali določena nova učinkovina v proces kliničnih študij. V članku so kritično ovrednotene prednosti in slabosti posameznega modela raka sečnega mehurja ter predstavljene nekatere raziskovalne študije.
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