Effect of aqueous, methanolic and ethyl acetate extract of Origanum vulgare ssp. hirtum on type 1 diabetes induced by multiple low doses of streptozotocin in C57BL/6 mice

Dijabetes tip 1 (DT1) je autoimunsko oboljenje koje nastaje kao rezultat uništavanja insulin-produkujućih beta ćelija pankreasa od strane inflamacijskih medijatora. Uništavanje beta ćelija pankreasa dovodi do smanjene sekrecije insulina i posledične hiperglikemije. Glavna odlika DT1 je insulitis- infiltracija ćelija imunskog sistema u pankreasna ostrvca. Prve ćelije koje infiltriraju pankreasna ostrvca su makrofagi. Smatra se da inflamacijski M1 makrofagi doprinose patogenezi DT1, dok anti-inflamacijski M2 makrofagi imaju protektivnu ulogu. Makrofagi aktiviraju autoreaktivne T limfocite- smatra se da su CD4+ i CD8+ T limfociti najvažnije efektorske ćelije u patogenezi DT1. U zavisnosti od citokina koje sekretuju ćelije imunskog sistema nastaju različite subpopulacije pomoćničkih T limfocita (Th) koje usmeravaju imunski odgovor u DT1 ka destruktivnom (Th1 i Th17) ili protektivnom (Th2 i Treg) odgovoru. Različiti efektorski mehanizmi ćelija imunskog sistema dovode do stvaranja inflamacijskog miljea u paknreasnim ostrvcima koji dovodi do apoptoze beta ćelija pankreasa i razvoja DT1. Terapija DT1 podrazumeva doživotno unošenje insulina. Kako ovo sa sobom nosi potencijal kratkoročnih i dugoročnih komplikacija, ulažu se veliki napori u pronalaženje novih, efikasnih terapija u lečenju DT1. Jedan od potencijalnih pristupa u lečenju DT1 je korišćenje biljaka i njihovih ekstrakata koji se od davnina koriste u tradicionalnoj medicini. Napredak istraživanja u ovoj oblasti doveo je do saznanja da različiti biofenoli koji ulaze u sastav biljaka mogu ostvariti povoljna dejstva na patogenezu različitih oboljenja, što stavlja biljke i njihove ekstrakte u fokus naučnih studija. Origanum vulgare ssp. hirtum (grčki origano) je biljka bogata fenolskim i estarskim jedinjenjima i koja se u tradicionalnoj medicini koristi kao antiseptik, kao i u lečenju stomačnih i respiratornih jedinjenja. Glavna do sada pokazana dejstva origana su anti-bakterijsko i antioksidantno, a pokazano je i anti-hiperglikemijsko dejstvo origana u modelu toksičnog DT1, što čini origano potencijalnim kandidatom za terapiju DT1...Type 1 diabetes (T1D) is autoimmune disorder which develops as a consequence of destruction of insulin-producing pancreatic beta cells which is induced by pro-inflammatory mediators. Beta cell destruction leads to impaired insulin production and loss of glucose homeostasis. The hallmark of T1D is formation of insulitis- immune cells infiltration in pancreatic islets. Macrophages are the first cells that infiltrate pancreatic islets. It is considered that proinflammatory M1 macrophages contribute to T1D pathogenesis, while antiinflammatory M2 macrophages play a protective roll in T1D development. Macrophages can activate autoreactive CD4+ and CD8+ T lymphocites that are considered to be key players in T1D pathogenesis. Cytokines produced by immune cells lead to differentiation of specific T helper cells (Th) subsets, that can be destructive (Th1 and Th17) or protective (Th2 i Treg) in T1D development. Immune cells, by vast effector mechanisms, lead to formation of inflammatory milleu around pancreatic islets which ultimately stimulates beta cell apopotosis. Treatment for T1D includes lifetime intake of insulin which can potentially cause a number of short- and long term complications. This is why scientists invest significant efforts in developing new therapeutic approaches for T1D treatment. Plants and their extracts are promising candidates for treatment of T1D, due to their rich content of phenolic compounds which are proven to be beneficial for human health. Origanum vulgare ssp. hirtum (Greek oregano) is native plant rich in phenolic and ester compounds. It is used in traditional medicine as antiseptic, as well as in the treatment of respiratory and stomach ailments. Main known activities of oregano are antibacterial and antioxidant. Also, recently is reported anti-hyperglycaemic activity of oregano in the model of toxic diabetes. These facts make oregano a promising candidate for the treatment of T1D..

Does geosite interpretation lead to conservation? A case study of the Sićevo Gorge (Serbia)

People have appreciated the beauty of natural landscapes, the result of the interplay of different natural processes, for at least three hundred years in Europe. Many have been inspired by this beauty to promote such places for visits by others. Some have understood the importance of individual places visited within the local or regional environmental system. This has led to definitions and the establishment of protected areas with special visitor rules and regulations. This article presents a case study of Sićevo Gorge Nature Park in Serbia and an opportunity to transform it into a geoheritage site, underpinned by developing its interpretation based on the results of a study using the analytical-hierarchy process (AHP) method.V   Evropi   ljudje   že   več   kot   300 let   občudujejo   lepoto   naravnih   pokrajin,   ki   je   rezultat medsebojnega učinkovanja različnih naravnih procesov. Mnoge je ta lepota spodbudila k temu, da so take kraje promovirali kot prostore, vredne obiska, nekateri pa so razumeli tudi pomen posameznih krajev, ki so jih obiskali, v lokalnem ali regionalnem okolju. Na tej podlagi so bila opredeljena in ustanovljena zavarovana območja s posebnimi pravili in predpisi za obiskovalce. V članku je obravnavan primer naravnega parka soteske Sićevo v Srbiji in možnost njegove preobrazbe v območje geološke dediščine na podlagi oblikovanja njegove interpretacije v skladu z izsledki raziskave, v kateri je bila uporabljena metoda analitičnega hierarhičnega procesa (AHP)

Profitability of food industry companies in the Republic of Serbia

Food industry is an important segment of manufacturing industry. The EU food industry is the world's leader. An important characteristic of the food sector of the Republic of Serbia is its pronounced dual structure, with a large number of small and mediumsized and a small number of large companies. It is believed that the relatively modest funds for investment in modern technology and increasing production efficiency, despite foreign direct investment, have an unfavourable effect on the perspective of this sector. Based on the number of companies, capacities, volume of production, export potential, and number of employees, confectionery industry is assessed as a significant segment of food industry and economy of the Republic of Serbia. The research objective is to examine whether reputable companies in the food industry of the Republic of Serbia are profitable and assess their profitability growth in the past four-year period. The research results show that the values of the relevant profitability indicators vary considerably in the observed period, regardless of their reputation and the competitive position on the market.Publishe

Salvianolic acid B: In vitro and in vivo effects on the immune system

Type 1 diabetes (T1D) is an autoimmune disorder with a strong inflammatory component. Autoreactive cells specifically target insulin-producing β-cells, which leads to loss of glucose homeostasis. T1D remains incurable and versatile; potentially beneficial therapeutics are being tested worldwide. Possible candidates for the treatment of autoimmune diabetes are plants and their extracts since they are rich in biophenols, substances that act as secondary metabolites, and have verified antioxidant and antiinflammatory effects. Salvianolic acid B (SalB) is a biophenol and one of the major constituents of Origanum vulgare ssp. hirtum (Greek oregano) extracts which in our previous studies was shown to exhibit an antidiabetic effect in mice. The aim of the present study was to determine whether SalB is responsible for the observed effects of Greek oregano extracts. SalB was applied in vitro to macrophages and lymphocytes isolated from C57BL/6 mice, as well as in vivo in the model of T1D induced by multiple low doses (MLD) of streptozotocin (STZ). SalB did not affect the viability of cells, but it significantly decreased secretion of nitric oxide (NO) and TNF in lipopolysaccharide (LPS)-stimulated macrophages, as well as the secretion of IFN-γ in concanavalin A (ConA)-stimulated lymphocytes. However, when applied in vivo, SalB at a dose of 2.5 mg/kg b.w., applied for 10 consecutive days, failed to protect mice from diabetes development. In conclusion, SalB exerts immunomodulatory effects in vitro, but is not effective in prevention of T1D in vivo. It probably requires cooperation with some other substances for the maximum efficacy exhibited by oregano extracts.Archives of Biological Sciences (2017), 69(4): 658-66

Profitability of food industry companies in the Republic of Serbia

Food industry is an important segment of manufacturing industry. The EU food industry is the world's leader. An important characteristic of the food sector of the Republic of Serbia is its pronounced dual structure, with a large number of small and mediumsized and a small number of large companies. It is believed that the relatively modest funds for investment in modern technology and increasing production efficiency, despite foreign direct investment, have an unfavourable effect on the perspective of this sector. Based on the number of companies, capacities, volume of production, export potential, and number of employees, confectionery industry is assessed as a significant segment of food industry and economy of the Republic of Serbia. The research objective is to examine whether reputable companies in the food industry of the Republic of Serbia are profitable and assess their profitability growth in the past four-year period. The research results show that the values of the relevant profitability indicators vary considerably in the observed period, regardless of their reputation and the competitive position on the market

Ethyl Pyruvate Stimulates Regulatory T Cells and Ameliorates Type 1 Diabetes Development in Mice.

Type 1 diabetes (T1D) is an autoimmune disease in which a strong inflammatory response causes the death of insulin-producing pancreatic β-cells, while inefficient regulatory mechanisms allow that response to become chronic. Ethyl pyruvate (EP), a stable pyruvate derivate and certified inhibitor of an alarmin-high mobility group box 1 (HMGB1), exerts anti-oxidant and anti-inflammatory properties in animal models of rheumatoid arthritis and encephalomyelitis. To test its therapeutic potential in T1D, EP was administered intraperitoneally to C57BL/6 mice with multiple low-dose streptozotocin (MLDS)-induced T1D. EP treatment decreased T1D incidence, reduced the infiltration of cells into the pancreatic islets and preserved β-cell function. Apart from reducing HMGB1 expression, EP treatment successfully interfered with the inflammatory response within the local pancreatic lymph nodes and in the pancreas. Its effect was restricted to boosting the regulatory arm of the immune response through up-regulation of tolerogenic dendritic cells (CD11c+CD11b-CD103+) within the pancreatic infiltrates and through the enhancement of regulatory T cell (Treg) levels (CD4+CD25highFoxP3+). These EP-stimulated Treg displayed enhanced suppressive capacity reflected in increased levels of CTLA-4, secreted TGF-β, and IL-10 and in the more efficient inhibition of effector T cell proliferation compared to Treg from diabetic animals. Higher levels of Treg were a result of increased differentiation and proliferation (Ki67+ cells), but also of the heightened potency for migration due to increased expression of adhesion molecules (CD11a and CD62L) and CXCR3 chemokine receptor. Treg isolated from EP-treated mice had the activated phenotype and T-bet expression more frequently, suggesting that they readily suppressed IFN-γ-producing cells. The effect of EP on Treg was also reproduced in vitro. Overall, our results show that EP treatment reduced T1D incidence in C57BL/6 mice predominantly by enhancing Treg differentiation, proliferation, their suppressive capacity, and recruitment into the pancreas

Development of novel gamma radiation dosimeter based on metallophthalocyanine

In this study, zinc phthalocyanine was evaluated as a possible chemical dosimeter for gamma rays at low-medium dose ranges in solution form and PVA film. The zinc phthalocyanine was successfully synthesized with a high yield under microwave irradiation at 200 °C. The calibration curves of absorbance versus dose of gamma irradiation show excellent linearity over a wider dose range (1 - 25kGy). After being irradiated, the samples' color changed from blue to yellow

The role of NUPR1 in lymphocyte proliferation and apoptosis

Nuclear protein 1 (NUPR1) is a transcription cofactor that senses stressful conditions and modulates cellular response by promoting or inhibiting apoptosis. NUPR1 is usually highly expressed in tumor cells where it enables them to adapt and resist environmental stress or chemotherapeutic compounds. NUPR1 can be involved in cell proliferation. Data about the involvement of NUPR1 in the proliferation and apoptosis of lymphocytes are scarce. Therefore, in this study we focused on the role of NUPR1 in lymphocyte physiology and found that NUPR1 might be involved in the initiation of their proliferation. Lymphocytes were isolated from the cervical lymph nodes of C57BL/6 mice. NUPR1 expression subsided 24 h after the induction of proliferation by a mitogen. Also, stressful conditions after cell isolation led to increased NUPR1 mRNA and protein expression in vitro that coincided with cell apoptosis. Similarly, apoptosis induction by staurosporine, a broad-range protein kinase inhibitor, led to increased NUPR1 expression. In addition, NUPR1 inhibition by smallinterfering RNA prevented the staurosporine-induced apoptosis (judging from decreased caspase activity) in the whole cell population of cervical lymph nodes. However, NUPR1 absence was irrelevant to the induction of apoptosis in CD3+ T lymphocytes, suggesting that NUPR1 is probably a mediator of apoptosis in other immune cell populations within the lymph node, such as B lymphocytes. In conclusion, our results suggest that NUPR1 is important for the initiation of lymphocyte cell division and for the apoptotic process of non-T cells during stressful conditions.Archives of Biological Sciences (2016

Chokeberry (Aronia melanocarpa) fruit extract modulates immune response in vivo and in vitro

Chokeberry (Aronia melanocarpa) is known for its anti-oxidant, anti-inflammatory and anti-diabetic properties. Since the effects of chokeberry extract on the immune response have been only sporadically assessed, our aim was to investigate chokeberry fruit water extract on the immune response in vivo and in vitro. When administered orally to healthy mice, the extract exerted immunomodulatory effects in the gut evidenced by the altered proportion of macrophages, dendritic cells and T cells. Importantly, oral consumption of the chokeberry extract resulted in blood glucose level increase in C57BL/6 mice with chemically-induced diabetes. These in vivo results were corroborated by observed up-regulation of nitric oxide and interelukin-1β production in macrophages and dendritic cells, up-regulated phagocytic activity of macrophages, increased T and B lymphocytes proportions and differentiation of interferon-γ-producing T cells in vitro. The obtained results imply that our chokeberry extract stimulates pro-inflammatory properties in immune cells of innate and adaptive immunity

Protective effects of carbonyl iron against multiple low-dose streptozotocin-induced diabetes in rodents.

Particulate adjuvants have shown increasing promise as effective, safe, and durable agents for the stimulation of immunity, or alternatively, the suppression of autoimmunity. Here we examined the potential of the adjuvant carbonyl iron (CI) for the modulation of organ-specific autoimmune disease-type 1 diabetes (T1D). T1D was induced by multiple low doses of streptozotocin (MLDS) that initiates beta cell death and triggers immune cell infiltration into the pancreatic islets. The results of this study indicate that the single in vivo application of CI to MLDS-treated DA rats, CBA/H mice, or C57BL/6 mice successfully counteracted the development of insulitis and hyperglycemia. The protective action was obtained either when CI was applied 7 days before, simultaneously with the first dose of streptozotocin, or 1 day after MLDS treatment. Ex vivo cell analysis of C57BL/6 mice showed that CI treatment reduced the proportion of proinflammatory F4/80+ CD40+ M1 macrophages and activated T lymphocytes in the spleen. Moreover, the treatment down-regulated the number of inflammatory CD4+ IFN-γ+ cells in pancreatic lymph nodes, Peyer's patches, and pancreas-infiltrating mononuclear cells, while simultaneously potentiating proportion of CD4+ IL17+ cells. The regulatory arm of the immune system represented by CD3+ NK1.1+ (NKT) and CD4+ CD25+ FoxP3+ regulatory T cells was potentiated after CI treatment. In vitro analysis showed that CI down-regulated CD40 and CD80 expression on dendritic cells thus probably interfering with their antigen-presenting ability. In conclusion, particulate adjuvant CI seems to suppress the activation of the innate immune response, which further affects the adaptive immune response directed toward pancreatic beta cells