The future of rural tourism in The Republic of Serbia

The Republic of Serbia has numerous predispositions for the development of rural tourism, considering that it represents a factor in the revitalization of the surrounding rural areas. Development and orientation towards "rural Serbia" could bring numerous advantages that relate to stopping migration flows from rural areas to urban areas and provide revitalizing the agricultural sector and other complementary activities. The aim of paper is to point out the importance of rural tourism, as one of the priority products of the Republic of Serbia, through the analysis of the current level of its development, and predicting future trends that promote the future of rural tourism. The methodology includes an overview of the theoretical framework of rural tourism collection of existing statistical data, obtained on the basis of previous research.Publishe

Lipid peroxidation, detoxification capacity, and genome damage in mice after transplacental exposure to pharmaceutical drugs

Data on genome damage, lipid peroxidation, and levels of glutathione peroxidase (GPX) in newborns after transplacental exposure to xenobiotics are rare and insufficient for risk assessment. The aim of the current study was to analyze, in an animal model, transplacental genotoxicity, lipid peroxidation, and detoxification disturbances caused by the following drugs commonly prescribed to pregnant women: paracetamol, fluconazole, 5- nitrofurantoin, and sodium valproate. Genome damage in dams and their newborn pups transplacentally exposed to these drugs was investigated using the in vivo micronucleus (MN) assay. The drugs were administered to dams intraperitoneally in three consecutive daily doses between days 12 and 14 of pregnancy. The results were correlated, with detoxification capacity of the newborn pups measured by the levels of GPX in blood and lipid peroxidation in liver measured by malondialdehyde (HPLC-MDA) levels. Sodium valproate and 5-nitrofurantoin significantly increased MN frequency in pregnant dams. A significant increase in the MN frequency of newborn pups was detected for all drugs tested. This paper also provides reference levels of MDA in newborn pups, according to which all drugs tested significantly lowered MDA levels of newborn pups, while blood GPX activity dropped significantly only after exposure to paracetamol. The GPX reduction reflected systemic oxidative stress, which is known to occur with paracetamol treatment. The reduction of MDA in the liver is suggested to be an unspecific metabolic reaction to the drugs that express cytotoxic, in particular hepatotoxic, effects associated with oxidative stress and lipid peroxidation

The NRF2, Thioredoxin, and Glutathione System in Tumorigenesis and Anticancer Therapies

Cancer remains an elusive, highly complex disease and a global burden. Constant change by acquired mutations and metabolic reprogramming contribute to the high inter- and intratumor heterogeneity of malignant cells, their selective growth advantage, and their resistance to anticancer therapies. In the modern era of integrative biomedicine, realizing that a personalized approach could benefit therapy treatments and patients’ prognosis, we should focus on cancer-driving advantageous modifications. Namely, reactive oxygen species (ROS), known to act as regulators of cellular metabolism and growth, exhibit both negative and positive activities, as do antioxidants with potential anticancer effects. Such complexity of oxidative homeostasis is sometimes overseen in the case of studies evaluating the effects of potential anticancer antioxidants. While cancer cells often produce more ROS due to their increased growth-favoring demands, numerous conventional anticancer therapies exploit this feature to ensure selective cancer cell death triggered by excessive ROS levels, also causing serious side effects. The activation of the cellular NRF2 (nuclear factor erythroid 2 like 2) pathway and induction of cytoprotective genes accompanies an increase in ROS levels. A plethora of specific targets, including those involved in thioredoxin (TRX) and glutathione (GSH) systems, are activated by NRF2. In this paper, we briefly review preclinical research findings on the interrelated roles of the NRF2 pathway and TRX and GSH systems, with focus given to clinical findings and their relevance in carcinogenesis and anticancer treatments

The Appearance of 4-Hydroxy-2-Nonenal (HNE) in Squamous Cell Carcinoma of the Oropharynx

Tumor growth is associated with oxidative stress, which causes lipid peroxidation. The most intensively studied product of lipid peroxidation is 4- hydroxy-2-nonenal (HNE), which is considered as a “second messenger of free radicals” that binds to proteins and acts as a growth-regulating signaling factor. The incidence of squamous cell carcinoma of the oropharynx is associated with smoking, alcohol and infection of human papilloma virus (HPV), with increasing incidence world-wide. The aim of this retrospective study involving 102 patients was to determine the immunohistochemical appearance of HNE-protein adducts as a potential biomarker of lipid peroxidation in squamous cell carcinoma of the oropharynx. The HNE-protein adducts were detected in almost all tumor samples and in the surrounding non-tumorous tissue, while we found that HNE is differentially distributed in squamous cell carcinomas in dependence of clinical stage and histological grading of these tumors. Namely, the level of HNE-immunopositivity was increased in comparison to the normal oropharyngeal epithelium in well- and in moderately- differentiated squamous cell carcinoma, while it was decreasing in poorly differentiated carcinomas and in advanced stages of cancer. However, more malignant and advanced cancer was associated with the increase of HNE in surrounding, normal tissue. This study confirmed the onset of lipid peroxidation, generating HNE-protein adducts that can be used as a valuable bioactive marker of carcinogenesis in squamous cell carcinoma of the oropharynx, as well as indicating involvement of HNE in pathophysiological changes of the non-malignant tissue in the vicinity of cancer

Nova metoda za dokazivanje HNE-histidinskih konjugata u {takorskim upalnim stanicama

Oxidative stress, excessive production of reactive oxygen species, is considered an important part of different disorders, as well as of physiological processes (inflammation). The difference between physiological and pathological oxidative stress is often the occurrence of lipid peroxidation and its final toxic products, among which is 4-hydroxy-2-nonenal (HNE), a reactive aldehyde that forms protein conjugates. The aim of this study was to determine the distribution of HNE-histidine conjugates in leukocytes during systemic inflammation. We used genuine monoclonal antibodies against HNE-histidine conjugates for immuno-cytochemical, immuno- histochemical and immuno-electronmicroscopical analyses of HNE in inflammatory cells. Spleen tissue, leukocytes from blood and macrophages from the peritoneum of rats intraperitoneally (i.p.) injected with micronized zeolite (MZ) were analyzed. HNE-histidine conjugates were predominantly detected near cell membranes, phagosomes and macrophage granules. Immunodetection of HNE-histidine conjugates may be used as an analytical immunochemical method to study HNE formation in pathological and physiological processes and for pathomorphological diagnostic procedures.Oksidacijski stres, stanje prekomjernoga stvaranja reaktivnih kisikovih tvari, bitna je sastavnica različitih bolesti, ali i fizioloških procesa (upala). Često je razlika između fiziološkoga i patološkoga oksidacijskoga stresa pojava lipidne peroksidacije i njenih završnih toksičnih produkata, među kojima posebnu ulogu ima 4-hidroksi- 2-nonenal (HNE), reaktivni aldehid koji tvori konjugate s bjelančevinama. Cilj ovoga istraživanja bio je utvrditi distribuciju HNE-histidinskih konjugata u leukocitima tijekom nespecifične upalne reakcije. Rabili smo izvorna monoklonalna protutijela na HNE-histidinski konjugat, za imuno-citokemijsko, histokemijsko i elektronskomikroskopsko dokazivanje HNE-a u upalnim stanicama. Analizirano je tkivo slezene, leukociti iz krvi te makrofazi štakora kojima je intraperitonealno injiciran mikronizirani zeolit (MZ). HNE-histidinski konjugati pretežito su uočeni uz stanične membrane te pored fagosoma i makrofagnih granula. Imunodetekcija HNE-histidinskih konjugata mogla bi se stoga rabiti kao analitička imunokemijska metoda za istraživanja fizioloških i patoloških procesa te u patomorfološkim dijagnostičkim postupcima

Oxidative stress and cancer heterogeneity orchestrate NRF2 roles relevant for therapy response

Oxidative stress and its end-products, such as 4-hydroxynonenal (HNE), initiate activation of the Nuclear Factor Erythroid 2-Related Factor 2 (NRF2)/Kelch Like ECH Associated Protein 1 (KEAP1) signaling pathway that plays a crucial role in the maintenance of cellular redox homeostasis. However, an involvement of 4-HNE and NRF2 in processes associated with the initiation of cancer, its progression, and response to therapy includes numerous, highly complex events. They occur through interactions between cancer and stromal cells. These events are dependent on many cell-type specific features. They start with the extent of NRF2 binding to its cytoplasmic repressor, KEAP1, and extend to the permissiveness of chromatin for transcription of Antioxidant Response Element (ARE)-containing genes that are NRF2 targets. This review will explore epigenetic molecular mechanisms of NRF2 transcription through the specific molecular anatomy of its promoter. It will explain the role of NRF2 in cancer stem cells, with respect to cancer therapy resistance. Additionally, it also discusses NRF2 involvement at the cross-roads of communication between tumor associated inflammatory and stromal cells, which is also an important factor involved in the response to therapy