Oleanolic acid (OA) is a natural compound that possesses numerous beneficial health effects, including anticancer activity. The current study aimed to investigate the role of forkhead box O3a ...(FOXO3a) in autophagy/mitophagy by OA in HCT116 cell line. OA dose-dependently reduced viability of HCT116 cells, with IC50 = 29.8 μΜ. The expression of cleaved caspase-3 and poly (ADP-ribose) polymerase 1 increased after OA treatment, suggesting induction of apoptosis. Concurrently, OA induced autophagy, evidenced by increased expression of Beclin-1, autophagy-related protein 5 and microtubule-associated protein1A/1B-light chain 3 beta (LC3B), which played a prosurvival role. The induction of mitophagy was suggested by increased expression of p62 and PTEN-induced kinase 1 and reduced expression of translocase of outer mitochondrial membrane 20, which colocalized with LC3B. OA also induced nuclear accumulation of forkhead box O3a (FOXO3a). The cytotoxic activity of OA coincided with upregulation of p38. Inhibition of p38 led to increase in FOXO3a and NAD+-dependent deacetylase sirtuin 6 expression. In vivo, OA inhibited tumor growth in colon cancer xenograft mice. Our results suggest concomitant induction of apoptosis and prosurvival mitophagy by OA in colon cancer via p38/FOXO3a/Sirt6 signaling. Additionally, our data demonstrate that OA can chemosensitize colon cancer cells to 5-fluorouracil (5-FU).
•Oleanolic acid induced apoptosis and prosurvival autophagy/mitophagy in HCT116 cells.•Oleanolic acid upregulated p38 and induces nuclear accumulation of FOXO3a.•In vivo, oleanolic acid inhibited tumor growth in the colon cancer xenograft.•Inhibition of p38 led to increase in FOXO3a and Sirt6 expression.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Sinomenine is a pharmacologically active alkaloid with antioxidant and anti-inflammatory properties. We aimed to investigate the mechanism of renoprotective activity of sinomenine in kidney injury ...induced by cisplatin (CP). Sinomenine (5 mg/kg) was administered to mice orally in two doses, the second day after intraperitoneal application of CP (13 mg/kg). Sinomenine ameliorated kidney injury and decreased serum levels of urea and creatinine and renal expression of NGAL and KIM-1. The increase in HO-1, 4-HNE, 3-NT and TNF-α renal expression was mitigated by sinomenine. Additionally, sinomenine reduced the expression of p21, Bax, Noxa, caspase-3 and -8 and PARP1 cleavage in mice kidneys as well as the number of TUNEL-positive cells. Sinomenine attenuated CP-induced activation of ERK1/2, Akt, FOXO3a, STAT3 and NF-κB and restored Sirtuin 6 expression. In the human proximal tubular cell line HK2, sinomenine 100 μM reduced the toxic effect of CP 30 μM. Our current findings suggest that sinomenine suppresses CP-induced oxidative stress, inflammation and apoptosis in mice kidneys by targeting multiple signaling pathways.
•Sinomenine ameliorated kidney injury induced by CP and decreased serum levels of urea and creatinine.•Renal expression of HO-1, 4-HNE and 3-NT, as well as TNF-α, induced by CP, was reduced by sinomenine.•Sinomenine reduced expression of p21, Bax, Noxa, cleaved caspase-3 and -8 and PARP1 in mice kidneys.•Sinomenine attenuated CP-induced activation of MAPK, Akt, FOXO3a, STAT3 and NF-κB and increased Sirt6 expression.•In human proximal tubular cell line HK2, sinomenine reduced the toxic effect of CP.
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Aucubin is pharmacologically active natural compound which possesses numerous beneficial properties. This study aimed to evaluate the protective effect of aucubin against cisplatin (CP)-induced acute ...kidney injury in mice and the mechanism of its action. Aucubin was administrated to mice orally or intraperitoneally (ip) (1.5 and 5 mg/kg) for two consecutive days, two days after ip injection of cisplatin (CP), 11 mg/kg. Treatment with aucubin by both routes of administration ameliorated histopathological changes and reduced elevated serum markers of kidney injury. CP administration increased renal expression of heme oxygenase-1 (HO-1) and 4-hydroxynonenal (4-HNE), as well as tumor necrosis factor-alpha (TNF-α), which was dose-dependently ameliorated by aucubin. Moreover, aucubin reduced increased renal expression of cleaved caspase-3 and -9 and decreased poly (ADP-ribose) polymerase (PARP) cleavage. Mechanistically, aucubin suppressed the activation of several signaling pathways involved in inflammation and apoptosis, including nuclear factor-kappa B (NF-κB), signal transducer and activator of transcription 3 (STAT3), Akt, extracellular signal-regulated kinase 1/2 (ERK1/2) and forkhead box O3a (FOXO3a). Parenteral application was marginally but statistically more effective in reducing CP-induced kidney injury than oral administration. The findings of this study suggest that aucubin acts as a protective agent against CP-induced nephrotoxicity, which should be further investigated.
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•Cisplatin (CP)-intoxicated mice received aucubin orally or intraperitoneally.•Aucubin ameliorated histopathological changes and reduced kidney injury.•Aucubin decreased oxidative stress, apoptosis and inflammation in the kidney.•Aucubin suppressed the activation NF-κB, STAT3, Akt, ERK1/2 and FOXO3a.•Parenteral application was the most effective in reducing CP-induced kidney injury.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•Assessed SARS-CoV-2 immunoassays have diagnostic accuracy from 99 % to 100 %.•Sensitivity of IgG assays is greater than 95 %, specificity greater than 99 %.•Longevity of SARS-CoV-2 IgG in ...symptomatic COVID patients is at least eight months.•Severe disease is associated with higher IgG titers and neutralizing activity.•IgG assays showed strong positive correlation to neutralizing activity.
Evidence is currently insufficient to know whether SARS-CoV-2 antibodies (Abs) protect from future infection and how long immunity will last. The kinetics of the immune response to SARS-CoV-2 infection and role of serology in estimating individual protective immunity is yet to be established. We evaluated diagnostic performances of three serological assays - Abbott Architect CMIA IgG, bioMerieux VIDAS ELFA IgG/IgM, and Diesse Chorus ELISA IgG/IgM, and analyzed longevity and potential neutralizing effect of SARS-CoV-2 Abs in COVID-19 patients. Clinical sensitivities of assessed IgG tests two to three weeks post symptom onset (PSO) were very high: 96.77 % for Architect, 96.77 % for Chorus, and 100.00 % for VIDAS. Sensitivities of two assessed IgM assays were moderate: 74.07 % for Chorus, and 76.92 % for VIDAS. Specificities were excellent for all assessed IgG assays: 99.01 % for Architect and 100 % for Chorus and VIDAS. Chorus and VIDAS IgM assays also achieved excellent specificity of 99.01 % and 100 %, respectively. In most cases IgG Abs were still present eight months PSO. Neutralizing antibodies were detected in majority of serum samples from convalescent patients. Serum samples from severe COVID-19 patients had higher antibody titers and higher neutralizing activity. We observed a strong positive correlation among SARS-CoV-2 IgG antibody titer and neutralizing activity. The strongest positive correlation to neutralizing activity was found for VIDAS IgG assay.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Drug-specific therapeutic approaches for colorectal cancer (CRC) have contributed to significant improvements in patient health. Nevertheless, there is still a great need to improve the ...personalization of treatments based on genetic and epigenetic tumor profiles to maximize the quality and efficacy while limiting cytotoxicity. Currently, CEA and CA 19-9 are the only validated blood biomarkers in clinical practice. For this reason, laboratories are trying to identify new specific prognostics and, more importantly, predictive biomarkers for CRC patient profiling. Thus, the unique landscape of personalized biomarker data should have a clinical impact on CRC treatment strategies and molecular genetic screening tests should become the standard method for diagnosing CRC. This review concentrates on recent molecular testing in CRC and discusses the potential modifications in CRC assay methodology with the upcoming clinical application of novel genomic approaches. While mechanisms for analyzing circulating tumor DNA have been proven too inaccurate, detecting and analyzing circulating tumor cells and protein analysis of exosomes represent more promising options. Blood liquid biopsy offers good prospects for the future if the results align with pathologists' tissue analyses. Overall, early detection, accurate diagnosis and treatment monitoring for CRC with specific markers and targeted molecular testing may benefit many patients.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Ulcerative colitis (UC) is a chronic inflammatory disease with increasing incidence and prevalence worldwide. Currently used treatments of UC are unsatisfactory, while natural bioactive compounds are ...considered to be emerging therapeutic agents. Luteolin (Lut) is a natural compound with beneficial effects in a variety of diseases, however, its effect in UC has been poorly studied. In this study we investigated the effect of Lut in posttreatment and cotreatment of dextran sulfate sodium (DSS)-induced experimental colitis in mice. In addition, the role of extracellular signal-regulated kinases 1/2 (ERK1/2) in the mechanism of action of Lut in experimental colitis was investigated using the ERK inhibitor PD0325901. Lut attenuated symptoms of DSS-induced colitis in mice, ameliorated colon tissue damage and reduced inflammation, apoptosis and autophagy. The effect was more pronounced if Lut was administered simultaneously with DSS. The administration of ERK inhibitor exacerbated DSS-induced colitis symptoms and prevented the protective effects of Lut. The results provide new mechanistic details underlying the anti-inflammatory, anti-apoptotic and anti-autophagic effects of Lut through the activation of the ERK signaling pathway. This suggested that Lut can be used as a novel therapeutic candidate in the treatment of UC or could be used as a supplement to existing therapy.
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•Luteolin ameliorated symptoms of experimental colitis in mice.•The protective activity of luteolin was achieved through its anti-inflammatory, anti-apoptotic and anti-autophagic effects.•The mechanism of action of luteolin is mediated by the induction of the ERK1/2 signaling pathway.
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Voda (H2O) je polarni anorganski spoj, koji je na sobnoj temperaturi tekućina bez okusa i mirisa, gotovo bezbojna. Količinski je daleko najzastupljeniji spoj na Zemlji i među rijetkim je tvarima koje ...na Zemljinoj površini postoje u krutoj, tekućoj i plinovitoj fazi. Kao relativno jednostavan kemijski spoj, opisana je kao „univerzalno otapalo“ ili „otapalo života“. Ujedno je i treća najzastupljenija molekula u Svemiru. Molekule vode međusobno tvore snažne vodikove veze, što joj definira specifična fizikalna i kemijska svojstva. Vodikove veze zaslužne su za mnoga jedinstvena svojstva vode, poput anomalije vode (činjenice da je kruti oblik – led – manje gustoće od tekuće vode), relativno visoke temperature vrenja (100 °C) i velikog toplinskog kapaciteta, što su ključni preduvjeti za očuvanje života na Zemlji. Voda je amfoterna molekula, što znači da može pokazivati svojstva i kiseline i lužine, ovisno o kemijskom okruženju u kojem se nalazi. U radu je provedena strukturna analiza molekule vode i njenih najvažnijih fizikalnih svojstava, s naglaskom na anomaliju vode. Jedno od važnih fizikalnih svojstava tekućine, a koja uvelike utječu na naš okoliš, je niska gustoća leda u odnosu na tekuću fazu vode te fenomen negativnog koeficijenta ekspanzije hladne vode. Također je opisano rješenje nuklearne Schrödingerove jednadžbe, koja daje informacije o unutarnjim gibanjima (vibracijama i rotaciji) molekule vode.
Water (H2O) is a polar inorganic compound that is almost colorless at room temperature. It is by far the most common substance on Earth and among very few substances, which exists on the Earth’s surface as a solid, liquid and gaseous substance. As a relatively simple chemical compound, it has been described as a “universal solvent” or “solvent of life”. It is also the third most common molecule in the Universe. Water molecules form strong polar hydrogen bonds with each other, which, in turn, define its specific physical and chemical properties. Hydrogen bonds are responsible for many unique properties such as the anomaly of water (the fact that its solid form, the ice, is less dense than the liquid form), a relatively high boiling point (100 °C) and a high heat capacity. Water is an amphoteric molecule, which means that it can show properties of both acids and alkaline solutions, depending on the chemical environment. In this paper, a structural analysis of a water molecule and its most important physical properties was carried out in detail with regard to its anomalies. One of the important physical properties of a liquid that strongly influences our environment is the low density of ice in relation to the liquid phase of water, and the phenomenon of the negative expansion coefficient of cold water. This work also describes the solutions of the nuclear Schrödinger equations, which provide information about the internal motions (vibrations and rotations) of a water molecule.
Chlorogenic acid (ChA) exhibits a multitude of positive health effects, however, the signaling mechanisms by which ChA could influence the inflammatory response in experimental colitis are unknown. ...To answer this question, we induced colitis in mice by administration of 2.5% dextran sulfate sodium (DSS) in drinking water for seven days. Oral administration of ChA significantly ameliorated clinical symptoms, improved disease activity index and colon shortening induced by DSS. Furthermore, ChA administration resulted in a suppression of phosphorylated extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinases 1 and 2 (JNK1/2), Akt and signal transducer and activator of transcription 3 (STAT3) with concomitant upregulation of phosphatase and tensin homolog (PTEN) expression. Immunohistochemical analysis showed a dose-dependent decrease in expression and nuclear translocation of nuclear factor-kappa B (NF-κB) p65 subunit, which was accompanied by suppression of pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) expression. Induction of apoptosis and oxidative stress was attenuated in a dose-dependent manner by suppressing Bax, caspase-8, caspase-9 and heme oxygenase-1 (HO-1) protein expression in mice administrated with ChA. The results of the current study suggest that ChA could be useful for the treatment of inflammation and attenuating colitis severity by suppressing activation of pro-inflammatory and apoptotic signaling pathways.
•Chlorogenic acid ameliorated experimental colitis in mice.•Chlorogenic acid suppressed inflammatory response, apoptosis and oxidative stress in the colon.•The mechanism of action involved suppression of NF-κB, p-STAT3, p-Akt, p-JNK and p-ERK expression in the colon.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
„Umjetnost medicine sastoji se u zaokupljanju bolesnika dok priroda liječi bolest”, rekao je davno slavni pisac i filozof Voltaire. Za liječenje bolesnika ključno je obrazovati buduće doktore ...medicine koji će biti sposobni integrirati različite aspekte medicine i obrazovanja. Sukladno tome, glavna vizija Medicinskog fakulteta u Rijeci je internacionalizacija kao jedan od najsnažnijih alata stvaranja svijeta u kojem medicina ne poznaje granice. Svojim znanstvenim, stručnim i općim intelektualnim kapacitetom, utemeljenim na tradiciji i kontinuiranom razvoju, Medicinski fakultet Rijeka značajna je karika na biomedicinskoj karti svijeta. Široko otvaramo nova vrata suradnje i partnerstva s međunarodnom akademskom zajednicom promicanjem znanstvene i obrazovne mobilnosti te brzog protoka informacija, obrazovanja i ideja. Naša je misija educirati, nadahnuti i potaknuti buduće liječnike da stvore bolji i zdraviji svijet usmjeren na humanost i altruizam. Internacionalizacija je most koji povezuje ljude sa svijetom znanosti i obrazovanja. S tim ciljem, od akademske godine 2017./2018. Medicinski fakultet Sveučilišta u Rijeci uveo je sveučilišni integrirani preddiplomski i diplomski studij medicine na engleskom jeziku. Danas brojimo više od 250 studenata iz različitih dijelova svijeta, uključujući mnoge europske zemlje, Sjedinjene Američke Države, Kanadu, Ujedinjeno Kraljevstvo, Kinu, Afriku, Brazil, Bliski istok i mnoge druge, koji studiraju zajedno i rastu kao jedinstven dio obrazovnog procesa, neprestano šireći svoje horizonte i međunarodnu vidljivost.
“The art of medicine consists in amusing the patient while nature cures the disease”, the famous writer and philosopher Voltaire once said. In order to heal patients, the key is to educate future medical doctors who will be capable of integrating different aspects of medicine and education. Accordingly, the main vision of the Faculty of Medicine Rijeka is internationalization as one of the most powerful ways to create a world without borders, a world where medicine knows no frontiers. With its scientific, professional, and general intellectual capacity, based on tradition and continuous development, the Faculty of Medicine Rijeka is an important factor on the biomedical map worldwide. We widely open new doors of cooperation and partnership with the international academic community by promoting the input and output of scientific and educational mobility and rapid flow of information, education, and ideas. Our mission is to educate, inspire, and encourage future physicians to create a better and healthier world focused on humanity and altruism. Internationalization is a bridge that connects people to the world of science and education. Since the academic year 2017/2018, the Faculty of Medicine at the University of Rijeka introduced the University integrated undergraduate and graduate study program of Medicine in English. Today we count more than 250 students from different parts of the world, including many European countries, the United States, Canada, the United Kingdom, China, Africa, Brazil, the Middle East, and many others, who study together and grow as a unique part of the educational process, constantly expanding our horizons and international visibility.
It is not entirely clear how the interaction between joint inflammation and the central nervous system (CNS) response in rheumatoid arthritis (RA) works, and what pathophysiology underlies the sex ...differences in coexisting neuropsychiatric comorbidities. It is known that estrogen hormones reduce inflammation in RA and that this occurs mainly via the stimulation of G protein-coupled receptor-30 (GPR30), also known as G protein-coupled estrogen receptor (GPER) 1. However, changes in GPR30 expression and sex differences induced by local and systemic inflammation in RA are not yet known. Our aim was to reveal sex differences in the expression and association of joint GPR30 with local and systemic inflammation, clinical course and furthermore with hippocampal GPR30 expression during pristane-induced arthritis (PIA) in Dark Agouti (DA) rats, an animal model of RA. Furthermore, we demonstrated sex-specific differences in the association between joint and systemic inflammation and hippocampal microglia during PIA. Our results suggest sex-specific differences not only in the clinical course and serum levels of pro-inflammatory cytokines but also in the expression of GPR30. Female rats show greater synovial inflammation and greater damage to the articular cartilage compared to males during PIA attack. Male rats express higher levels of synovial and cartilaginous GPR30 than females during PIA, which correlates with a less severe clinical course. The correlation between synovial and cartilaginous GPR30 and joint inflammation scores (Krenn and Mankin) in male rats suggests that the more severe the joint inflammation, the higher the GPR30 expression. At the same time, there is no particular upregulation of hippocampal GPR30 in males. On the other hand, female rats express higher levels of neuroprotective GPR30 in the hippocampus than male rats at the basic level and during PIA attack. In addition, females have a higher number of Iba-1+ cells in the hippocampus during PIA attack that strongly correlates with the clinical score, serum levels of IL-17A, and Krenn and Mankin scores. These results suggest that male rats are better protected from inflammation in the joints and female rats are better protected from the inflammation in the hippocampus during a PIA attack, independently of microglia proliferation. However, in the remission phase, synovial GPR30 expression suddenly increases in female rats, as does hippocampal GPR30 expression in males. Further experiments with a longer remission period are needed to investigate the molecular background of these sex differences, as well as microglia phenotype profiling.
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