imagine (Institute of molecular genetics and genetic engineering)
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Инхибиција аутофагије сензитизује ћелије глиобластома на инхибиторе Срц тирозин-киназе, деривате пиразоло[3,4- д]пиримидина Si306 и pro-Si306
Get PDFGlioblastom je jedan od najagresivnijih tumora mozga koji karakteriše
infiltrirajuća priroda, intenzivna proliferacija i rezistencija na terapiju.
Ćelije glioblastoma imaju visoku ekspresiju Src tirozin-kinaze koja reguliše
proliferaciju, preživljavanje i invazivnost tumorskih ćelija čineći je
potencijalnom metom za terapiju. Inhibitori tirozin-kinaza mogu indukovati
autofagiju koja deluje protektivno na tumorske ćelije. Sposobnost inhibitora
Src tirozin-kinaze, derivata pirazolo[3,4-d]pirimidina Si306 i njegovog proleka
pro-Si306, da indukuju autofagiju ispitana je na ćelijskoj liniji humanog
glioblastoma U87 i njenoj varijanti sa višestrukom rezistencijom na lekove
U87-TxR. Tretman ovim jedinjenjima uzrokovao je pojavu autofagozoma u ćelijama
nakon 3 sata, a efekat na indukciju autofagije opstao je i nakon 48 sati što je
utvrđeno analizom markera autofagije LC3 i p62. Inhibicija autofagnog fluksa
bafilomicinom A1 značajno je uvećala postojeće anti-proliferativno dejstvo
Si306 i pro-Si306. Takođe, kombinovani tretmani Src inhibitora sa
bafilomicinom A1 doveli su do nekroze nakon 48 sati. Dobijeni rezultati
sugerišu da autofagija indukovana ovim jedinjenjima ima zaštitnu ulogu u
ćelijama glioblastoma i da se modulacija autofagije može koristiti za
senzitizaciju ćelija glioblastoma na inhibitore Src tirozin-kinaze. Pored toga,
pomenuti efekti Si306 i pro-Si306 nisu umanjeni prisustvom višestruko-
rezistentnog fenotipa, što ovim jedinjenjima daje potencijal za lečenje
rezistentnih tumora.Глиобластом је један од најагресивнијих тумора мозга који карактерише
инфилтрирајућа природа, интензивна пролиферација и резистенција на терапију.
Ћелије глиобластома имају високу експресију Срц тирозин-киназе која регулише
пролиферацију, преживљавање и инвазивност туморских ћелија чинећи је
потенцијалном метом за терапију. Инхибитори тирозин-киназа могу индуковати
аутофагију која делује протективно на туморске ћелије. Способност инхибитора
Срц тирозин-киназе, деривата пиразоло[3,4-д]пиримидина Si306 и његовог пролека
pro-Si306, да индукују аутофагију испитана је на ћелијској линији хуманог
глиобластома U87 и њеној варијанти са вишеструком резистенцијом на лекове
U87-TxR. Третман овим једињењима узроковао је појаву аутофагозома у ћелијама
након 3 сата, а ефекат на индукцију аутофагије опстао је и након 48 сати што је
утврђено анализом маркера аутофагије LC3 и p62. Инхибиција аутофагног флукса
бафиломицином А1 значајно је увећала постојеће анти-пролиферативно дејство
Si306 и pro-Si306. Такође, комбиновани третмани Срц инхибитора са
бафиломицином А1 довели су до некрозе након 48 сати. Добијени резултати
сугеришу да аутофагија индукована овим једињењима има заштитну улогу у
ћелијама глиобластома и да се модулација аутофагије може користити за
сензитизацију ћелија глиобластома на инхибиторе Срц тирозин-киназе. Поред тога,
поменути ефекти Si306 и pro-Si306 нису умањени присуством вишеструко-
резистентног фенотипа, што овим једињењима даје потенцијал за лечење
резистентних тумора.Knjiga sažetaka: Treći Kongres biologa Srbije, Zlatibor, Srbija 21 - 25. 9. 2022
Current Opportunities for Targeting Dysregulated Neurodevelopmental Signaling Pathways in Glioblastoma
Get PDFGlioblastoma (GBM) is the most common and highly lethal type of brain tumor, with poor survival despite advances in understanding its complexity. After current standard therapeutic treatment, including tumor resection, radiotherapy and concomitant chemotherapy with temozolomide, the median overall survival of patients with this type of tumor is less than 15 months. Thus, there is an urgent need for new insights into GBM molecular characteristics and progress in targeted therapy in order to improve clinical outcomes. The literature data revealed that a number of different signaling pathways are dysregulated in GBM. In this review, we intended to summarize and discuss current literature data and therapeutic modalities focused on targeting dysregulated signaling pathways in GBM. A better understanding of opportunities for targeting signaling pathways that influences malignant behavior of GBM cells might open the way for the development of novel GBM-targeted therapies
Biodegradability Assessment of Polyester Copolymers Based on Poly(ethylene adipate) and Poly(epsilon-caprolactone)
Get PDFBiodegradable polymers contain chains that are hydrolytically or enzymatically cleaved, resulting in soluble degradation products. Biodegradability is particularly desired in biomedical applications, in which degradation of the polymer ensures clearance from the body and eliminates the need for retrieval or explant. In this study, a homologues series of poly(epsilon-caprolactone)-b-poly(ethylene adipate)-b-poly(epsilon-caprolactone) (PCL-b-PEA-b-PCL) block copolymers, with constant PEA molar mass and different PCL sequence lengths was obtained. The starting point of these copolymers was a dihydroxy-PEA precursor with a molar mass (M-n) of 2500 g/mol. Mn values of the PCL varied between 1000 and 10,000 g/mol. Both the precursors and the copolymers were characterized using different physicochemical methods, such as: NMR, SEC, Maldi-TOFF, DSC, and ATG. The molecular characteristics of the copolymers were in a direct correlation with the sequence length of the PCL. Enzymatic degradability studies were also conducted by using cell-free extract containing Pseudomonas aeruginosa PAO1 for 10 and 21 days, and it appeared that the presence of the PEA central sequence has an important influence on the biodegradability of the copolymer samples. In fact, copolymer PCL7000-PEA(2500)-PCL7000 had a weight loss of around 50% after 10 days whereas the weight loss of the homopolymer PCL, with a similar M-n of 14,000 g/mol, was only 6%. The results obtained in this study indicate that these copolymer samples can be further used for the preparation of drug delivery systems with modulated biodegradability
The pharmacogenomics of vincristine-induced peripheral neuropathy in pediatric acute lymphoblastic leukemia patients in Serbia: A single center experience
Get PDFUvod/Cilj Vinkristin je jedan od ključnih lekova u protokolima lečenja dečje akutne limfoblastne leukemije (ALL). Vinkristin dovodi do destabilizacije mikrotubula, čime se ćelija zaustavlja u metafazi i indukuje apoptoza. Takođe dovodi do degradacije aksona i poremećaja aksonskog transporta, uzrokujući vinkristinom indukovanu perifernu neuropatiju (VIPN). Cilj ove studije bio je da istraži povezanost pet varijanti u farmakogenima uključenim u metabolizam vinkristina kod dece obolele od ALL koja su razvila VIPN, u Srbiji. Takođe, cilj nam je bio da otkrijemo kandidate za nove farmakogenomske markere VIPN-a u srpskoj populaciji. Metode Detekcija varijanti gena CYP3A5, CEP72, ACTG1, MIR3117 i MIR4481 izvedena je metodologijom zasnovanom na PCR-u i sekvenciranju. Statističkim metodama je ispitana njihova asocijacija sa VIPN-om kod 56 pedijatrijskih bolesnika obolelih od ALL. Urađena je i populaciona vinkristin farmakogenomska analiza 17 farmakogena iz postojećih podataka dobijenih sekvenciranjem nove generacije u srpskoj populaciji. Podaci o distribuciji frekvencija alela za evropsko stanovništvo preuzeti su iz javnih baza podataka. Rezultati Tokom lečenja, 17,86% bolesnika je razvilo VIPN. Asocijativne analize pokazale su da nijedna genetička varijanta nije bila povezana sa VIPN-om u našoj studiji. Naše populaciono farmakogenomsko istraživanje nije otkrilo validne farmakovarijante za VIPN. Naši rezultati ne preporučuju preventivno farmakogenetičko ispitivanje vinkristina u Srbiji. Zaključak Potreban je sveobuhvatniji pristup kako bi se identifikovao panel gena kojim bi se mogao objasniti razvoj VIPN-a posle primene vinkristina kod pedijatrijskih bolesnika obolelih od ALL. Bolje osmišljene studije asocijacija na nivou genoma (GWAS) i robusniji alati koji koriste veštačku inteligenciju doveli bi do dizajniranja panela farmakogena za preventivno testiranje predispozicije za razvoj VIPN-a, doprinoseći individualizaciji i unapređenju terapije dece obolele od ALL.Introduction/Objective Vincristine (VCR) is one of the key drugs in current treatment protocols for pediatric acute lymphoblastic leukemia (ALL). By destabilizing microtubules, VCR arrests cells in metaphase, inducing apoptosis of malignant cells. VCR also causes axonal degradation and impairment of axonal transport, which leads to VCR-induced peripheral neuropathy (VIPN). This study aimed to investigate the association of five variants in pharmacogenes involved in VCR metabolism with VIPN in Serbian ALL children. We also wanted to discover candidate pharmacogenomic markers of VIPN in Serbian population. Methods PCR and sequencing-based methodology was used to detect variants in CYP3A5, CEP72, ACTG1, MIR3117, and MIR4481 genes. Statistical analyses were performed for investigating their association with VIPN in 56 pediatric ALL patients. Population VCR pharmacogenomics analysis of 17 pharmacogenes from in-house next-generation sequencing data was also done. Data on allele frequency distribution for the European population were extracted from public databases. Results During the treatment, 17.86% of patients developed VIPN. Association analyses have shown that none of the genetic variants contributed to the occurrence of VIPN in our study. Population pharmacogenomics study did not reveal valid candidate pharmacovariants for VIPN. Our results suggested that pre-emptive pharmacogenetic testing for VCR is not applicable presently. Conclusion More comprehensive approaches are needed to identify the panel of genes that could explain the VIPN development after VCR administration in ALL patients. Utilizing better designed genome-wide association studies and more robust artificial intelligence-based tools would provide a panel of pharmacogenes for pre-emptive tests of VIPN to individualize therapy for ALL in children
Alpha-Synuclein Aggregation Pathway in Parkinson's Disease: Current Status and Novel Therapeutic Approaches
Get PDFFollowing Alzheimer's, Parkinson's disease (PD) is the second-most common neurodegenerative disorder, sharing an unclear pathophysiology, a multifactorial profile, and massive social costs worldwide. Despite this, no disease-modifying therapy is available. PD is tightly associated with alpha-synuclein (alpha-Syn) deposits, which become organised into insoluble, amyloid fibrils. As a typical intrinsically disordered protein, alpha-Syn adopts a monomeric, random coil conformation in an aqueous solution, while its interaction with lipid membranes drives the transition of the molecule part into an alpha-helical structure. The central unstructured region of alpha-Syn is involved in fibril formation by converting to well-defined, beta-sheet rich secondary structures. Presently, most therapeutic strategies against PD are focused on designing small molecules, peptides, and peptidomimetics that can directly target alpha-Syn and its aggregation pathway. Other approaches include gene silencing, cell transplantation, stimulation of intracellular clearance with autophagy promoters, and degradation pathways based on immunotherapy of amyloid fibrils. In the present review, we summarise the current advances related to alpha-Syn aggregation/neurotoxicity. These findings present a valuable arsenal for the further development of efficient, nontoxic, and non-invasive therapeutic protocols for disease-modifying therapy that tackles disease onset and progression in the future
Challenges facing early career women in thrombosis and hemostasis—meeting the needs of the next generation
No full textEarly career professionals in the field of thrombosis and hemostasis may experience significant gender-dependent challenges across research, clinical practice, industry, and beyond. Individuals who identify as women, hereafter referred to as women, may face systemic biases and discrimination that hinder career advancement and leadership opportunities. These barriers are more pronounced in marginalized groups, including racial and ethnic minorities and the LGBTQIA+ community. Here, we highlight some of the challenges disproportionally impacting early career women in our community and discuss potential strategies that might begin to close gender-related gaps
Matrix metalloproteinase-2 (MMP-2) and-9 (MMP-9) gene variants and microvascular complications in type 2 diabetes patients
Get PDFAbstractVascular complications are the leading cause of increased morbidity and mortality of diabetic patients. It has been postulated that matrix metalloproteinases MMP-2 and MMP-9, zinc-dependent endopeptidases through remodeling of the extracellular matrix, can contribute to the onset and progression of diabetic vascular complications. The aim of our study was to assess whether there is a major difference in single nucleotide polymorphisms in the MMP-2 (at position -1306C˃T) and MMP-9 (at position -1562C˃T) gene in type 2 diabetic patients and healthy controls and to determine whether there is an association of these gene variants with the presence of microvascular complications in diabetic patients. Our study included 102 type 2 diabetes patients and a control group which was comprised of 56 healthy controls. All diabetic patients were screened for microvascular diabetes complications. Genotypes were detected by polymerase chain reactions followed by restriction analyses with specific endonucleases and their frequencies were determined. The MMP-2 variant -1306C>T showed a negative correlation with type 2 diabetes (p=0.028). It was also shown that the presence of the -1306C allele increases the probability of developing type 2 diabetes. This was a 2.2 fold increase and that the -1306 T allele has a protective role in regards t
Uticaj tumorske mikrosredine na razvoj i progresiju maligniteta
Get PDFTumorska mikrosredina predstavlja specifično okruženje sastavljeno od okoloćelijskog matriksa
i nemalignih elemenata kao što su krvni sudovi, fibroblasti i makrofagi. Ona se aktivno stvara
od strane malignih ćelija i ima uticaj na njihovo ponašanje. Tumorski okoloćelijski matriks ima znatno
izmenjene biofizičke i biohemijske osobine u odnosu na netumorsko tkivo, što posledično
uzrokuje promene u ćelijskoj signalizaciji. Recipročna interakcija između tumorske ćelije i njenog
okruženja je ključna za nastanak i progresiju maligniteta, orkestrirajući sve faze malignog procesa:
epitelo-mezenhimsku tranziciju, održavanje besmrtnosti maligne ćelije, neoangiogenezu, izbegavanje
imunskog odgovora, formiranje metastaza i rezistenciju na hemoterapeutike. U ovom poglavlju
daćemo pregled najvažnijih karakteristika tumorskog okruženja, i osvrnućemo se na najnovija
saznanja o njihovom uticaju na malignu progresiju.The tumor microenvironment is a specific surrounding composed of extracellular matrix and
non-malignant elements such as blood vessles, fibroblasts and macrophages. It is actively generated
by malignant cells and has an influence on their behavior. The tumor extracellular matrix acquires altered
biochemical and biophysical properties compared to healthy tissue, with many repercussions
on cellular signaling. The mutual interaction between the tumor cell and its surroundings is crucial for
the onset and progression of malignant tumors, orcestrating all phases of the malignant process: epithelial-
mesenchimal transition, maintenance of cellular immortality, angiogenesis, avoidance of immune
survailance, formation of metastases, and resistance to therapeutics. In this chapter, we will review
the most important features of the tumor microenvironment and revise the most recent understandings
on its influence on malignant progression
TRPV1: A Promising drug target for the treatment of various conditions
Get PDFNobelova nagrada za fiziologiju i medicinu za 2021. dodeljena je naučnicima koji su identifikovali receptore
za temperaturu i dodir. Da bi sproveli ovo ispitivanje, istraživači su koristili kapsaicin, jedinjenje koje
čili paprici daje toplotu, kako bi otkrili receptore koji omogućavaju ljudima da osete “gorući” ukus čilija.
Pokazano je da se transient receptor potential vanilloid 1 (TRPV1), koji predstavlja jonski kanal prisutan na
senzornim neuronima, otvara u prisustvu kapsaicina ili toplote, propuštajući naelektrisane jone kalcijuma
u ćeliju. Takav priliv kalcijuma pokreće električne signale koji se šalju u mozak da upozore na toplotu. TRPV1
se nalazi u somatosenzornom sistemu i služi kao multimodalni senzor različitih štetnih stimulusa.
Brojne farmakološke i genetičke studije su potvrdile TRPV1 kao terapeutsku metu u nekoliko pretkliničkih
modela hroničnog bola, uključujući maligni, neuropatski, postoperativni i mišićno-skeletni bol.
Pored toga, ekspresija TRPV1 se takođe primećuje na ne-neuronskim lokalizacijama, kao što su epitel bešike
i pluća, ćelije kohlee u uhu. Stoga, lekovi koji mogu da modulišu aktivnost kanala TRPV1 mogu biti korisni
za lečenje različitih stanja u rasponu od hroničnog bola do gubitka sluha. Iako je utvrđeno da
antagonisti TRPV1 mogu predstavljati važan dodatak terapiji bola, njihova klinička upotreba je i dalje ograničena
značajnim neželjenim efektima, kao što je hipertermija.
U ovom radu ćemo opisati najvažnije uloge TRPV1 u fiziološkim i patofiziološkim procesima i predstaviti
najperspektivnije lekove koji deluju preko TRPV1.The 2021. Nobel Prize in Physiology or Medicine was awarded to scientists who have identified receptors
for temperature and touch. In order to conduct this examination, researchers used capsaicin, the
compound that gives chili peppers their heat, to discover receptor proteins that allow people to feel chili’s
burn. It is shown that transient receptor potential vanilloid 1 (TRPV1), which represents an ion channel
present on sensory neurons, opens when it encounters capsaicin or heat, allowing charged calcium ions
into the cell. That flood of calcium triggers electrical signals that are sent to the brain to warn of heat.
TRPV1 is found in the somatosensory system and serves as a multimodal sensor of different noxious stimuli.
Numerous pharmacological and genetic studies have validated TRPV1 as a therapeutic target in several
preclinical models of chronic pain, including cancer, neuropathic, postoperative and musculoskeletal
pain. Additionally, expression of TRPV1 is also observed in non-neuronal sites such as the epithelium
of bladder and lungs, cells of the cochlea. Therefore, drugs which could modulate TRPV1 channel activity
could be useful for the treatment of conditions ranging from chronic pain to hearing loss. While antagonists
of TRPV1 were found to be a valuable addition to therapy of pain, their clinical use has still been limited
by significant side effects, such as hyperthermia.
In this review, we will describe the most important roles of TRPV1 in physiological and pathophysiological
processes and present the most promising TRPV1-targeted drugs
Antitumor potential of new steroidal hydrazone derivatives
Get PDFKako maligne ćelije vremenom mutiraju i postaju rezistentne na postojeće lekove postoji stalna potreba
za novim antitumorskim lekovima. Steroidni molekuli igraju vrlo važne uloge u biološkim sistemima.
Usled hidrofobnosti nesmetano prolaze kroz ćelijske membrane pa su pogodan polazni materijal za dizajn
novih lekova. Trasformacijama krutog tetracikličnog steroidnog skeleta nastaju biološki aktivni molekuli
sa novim fiziološkim funkcijama. Sa druge strane, hidrazoni sadrže heteroatome i smatraju se
značajnim intermedijerima pri sintezi heterocikličnih jedinjenja. Stoga je sintetisano i okarakterisano pedeset
novih derivata steroidnih hidrazona, a zatim je određena njihova citotoksičnost i ispitani su mehanizmi
citotoksičnog delovanja.
Prema testiranim malignim ćelijskim linijama (HeLa, K562, MDA-MB-361, MDA-MB-453, LS174, A549),
naročito prema HeLa ćelijama adenokarcinoma cerviksa i prema K562 ćelijama hronične mijeloidne leukemije,
nova jedinjenja su ispoljila selektivnu citotoksičnost zavisnu od koncentracije na mikrogramskoj
skali, u mnogim slučajevima bolju od hemioterapeutika cisplatina. Nasuprot tome, pokazala su vrlo slabu
citotoksičnost na humane PBMC, što se ogleda u koeficijentima selektivnosti daleko višim od vrednosti
2,5. Morfološkom analizom HeLa ćelija tretiranih novim derivatima utvrđeno je njihovo pro-apoptotsko dejstvo
što je potvrđeno rezultatima protočne citometrije. Određivanjem ciljnih kaspaza ustanovljeno je da
do apoptoze dolazi posredstvom kaspaze-3, -8 i -9. Svi ispitivani derivati su pokazali sposobnost da inhibiraju
angiogenezu ćelija EA.hy926 in vitro. Testirani tiazolidin-4-oni nisu prouzrokovali značajne promene
u nivoima ekspresije gena MMP2, MMP9 i VEGFA u tretiranim HeLa ćelijama.
Rezultati sprovedenih in vitro istraživanja mogu da ukažu na značajan antitumorski potencijal što ova
jedinjenja ubraja u potencijalne kandidate za in vivo ispitivanja