Browsing by Author "Krosniak, Miroslaw"

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Artesunate Inhibits Melanoma Progression in Vitro Via Suppressing Stat3 Signaling Pathway
(Springer Heidelberg, 2021) Berkoz, Mehmet; Ozkan-Yilmaz, Ferbal; Ozluer-Hunt, Arzu; Krosniak, Miroslaw; Turkmen, Omer; Korkmaz, Duygu; Keskin, Siddik
Background Melanoma is a life-threatening cancer characterized with a potentially metastatic tumor of melanocytic origin. Improved methods or novel therapies are urgently needed to eliminate the development of metastases. Artesunate is a semi-synthetic derivative of artemisinin used for trarment of malaria and cancer. The purpose of this study was to investigate the anti-cancer effect of artesunate and the role on STAT3 signaling in A375 human melanoma cell line. Methods Melanoma cells were treated with artesunate at concentrations of 0-5 mu M for 24 and 48 h. The inhibition of cell viability, colony formation, migration, invasion, adhesion, percentage of apoptotic cells, and expressions of signal transducer and activator of transcription-3 (STAT3) and related proteins were examined. Results Artesunate inhibited cellular proliferation of cancer cells by induction of apoptosis at sub-toxic doses. Cells treated with artesunate showed an inhibition in adhesion to extracellular matrix substrate matrigel and type IV collagen. Artesunate treatment showed a decreased cellular migration, invasion, and colony formation in melanoma cells. Artesunate also inhibited STAT3 and Src activations and STAT3 related protein expressions; such as metalloproteinase 2 (MMP-2), MMP-9, Mcl-1, Bxl-xL, vascular endothelial growth factor (VEGF), and Twist. Moreover, overexpression of constitutively active STAT3 in A375 cells attenuated the anti-proliferative, apoptotic and anti-invasive effects of artesunate. Conclusion The results obtained from this study demonstrated that the anticancer activity of artesunate occurred via STAT3 pathway and its target proteins. Therefore, it can be suggested that artesunate may be an important candidate molecule in the treatment of melanoma.
The Health Risk Assessment of Essential Elemental Impurities (Cu, Mn and Zn) Through the Dermal Exposure of Herbal Ointment Extracted From Marjoram Herb (Majoranae Herbae Extractum)
(Springernature, 2022) Jurowski, Kamil; Folta, Maria; Tatar, Barbara; Berkoz, Mehmet; Krosniak, Miroslaw
Essential elements like Cu, Mn and Zn are extremely important for herbs' growth and physiological functions; however, from a toxicological point of view, the exposure of these elements (as essential elemental impurities) can exhibit potential harmful effects for patients. In Europe, very popular are ointments with Marjoram herb extract (Majoranae herbae extractum) as herbal medicinal products for adjunctively in rhinitis (runny nose). Based on posology of ointments with Marjoram herb extract, the exposure to these elemental impurities may be high during long-term use. Hence, the aim of this article is the health risk assessment of essential elemental impurities (Cu, Mn and Zn) through the dermal exposure of ointments with Marjoram herb extract (Majoranae herbae extractum) as herbal medicinal products applied adjunctively in rhinitis available in Polish pharmacies. The investigated essential elements were determined by well-validated methodology (R > 0.997, recoveries, LOD and LOQ values were acceptable) based on flame atomic absorption spectrometry (FAAS). Our results indicated that all analysed herbal medicinal products with Marjoram herb extract available in Polish pharmacies contain relatively low levels of essential element impurities, i.e. Cu (0.14-0.49 mg/kg), Mn (0.31-2.57 mg/kg) and Zn (0.73-3.19 mg/kg). The estimated exposure of the investigated elemental impurities confirms the safety of all products. To the best of our knowledge, the study about Cu, Mn and Zn contents in HMPs with Majoranae herbae extractum is described for the first time. The applied methodology and results are extremely important from regulatory toxicology point of view due to ICH Q3D elemental impurity guideline for pharmaceuticals.
Hepatoprotective Potentials of Usnea Longissima Ach. and Xanthoparmelia Somloensis (Gyelnik) Hale Extracts in Ethanol-Induced Liver Injury
(Taylor & Francis Ltd, 2025) Berkoz, Mehmet; Aslan, Ali; Yunusoglu, Oruc; Krosniak, Miroslaw; Francik, Renata
In our study, the antioxidant and anti-inflammatory effects of different lichen applications were investigated in rats using an experimental ethanol toxicity model. 48 rats were used in the study and they were divided into 6 groups with 8 rats in each group. These groups were: control, ethanol (2 g/kg), ethanol + Usnea longissima Ach. (200 mg/kg), ethanol + Usnea longissima Ach. (400 mg/kg), ethanol + Xanthoparmelia somloensis (Gyelnik) Hale (100 mg/kg) and ethanol + Xanthoparmelia somloensis (Gyelnik) Hale (200 mg/kg). The experimental work continued for 21 days. Lichen extracts and ethanol were administered by gavage to rats divided into groups. According to the experimental protocol, the experimental animals were sacrificed and their liver tissues were isolated. Biochemical parameters in serum, histological examinations, oxidative stress and inflammation parameters both at biochemical and molecular level in liver tissues were performed. Oxidative stress and inflammatory response were increased in the liver tissue of rats treated with ethanol for 21 days, and liver functions were impaired. It was found that U. longissima and X. somloensis extracts showed good antioxidant activity and conferred protective effects against ethanol-induced oxidative stress and inflammation. This could be attributed to the presence of secondary metabolites in the extract, which act as natural antioxidants and could be responsible for increasing the defence mechanisms against free radical production induced by ethanol administration.
The Influence of Organic Vanadium Complexes on an Antioxidant Profile in Adipose Tissue in Wistar Rats
(Mdpi, 2022) Francik, Renata; Kryczyk-Koziol, Jadwiga; Krosniak, Miroslaw; Francik, Slawomir; Hebda, Tomasz; Pedryc, Norbert; Slipek, Zbigniew
One of the aspects of biological activity of vanadium is its influence on carbohydrate metabolism. For more than 30 years, various vanadium complexes have been tested as antidiabetic agents. This study researched organic vanadium complexes with bipyridinium ligands and their influences on metabolic rate, as well as on the antioxidant activity of adipose tissue. The effects of sodium (2,2 '-bipyridine) oxidobisperoxovanadate (V) octahydrate (known as the V complex), bis(2,2 '-bipyridine) oxidovanadium (IV) sulfate dehydrate (known as the B complex), and bis(4.4 '-dimethyl-2,2 '-bipyridine) oxidovanadium (IV) sulfate dihydrate (labelled as the BM complex) were assessed. Solutions of the tested complexes were introduced intraperitoneally with a probe to animals fed with either a control diet or a high-fat diet. The BM complex had a significant influence on the increase in ferric reducing antioxidant power, as well as on the concentration of glutathione in the adipose tissue of rats fed with a high-fat diet. The V complex increased the concentration of glutathione in the adipose tissue of rats fed with control fodder, as well as significantly reduced the relative change in rat weight for the high-fat diet. Furthermore, the presence of each tested vanadium complex had an impact of statistically significant increase in basal metabolic rate, regardless of applied diet. Further research on these organic vanadium complexes is necessary to understand the mechanisms responsible for their ability to affect adipose tissue.
Ni and Cr Impurities Profile in Valeriana Officinalis L., Radix-Based Herbal Medicinal Product Available in Polish Pharmacies Due To Ich Q3d Guideline
(Academic Press inc Elsevier Science, 2021) Jurowski, Kamil; Folta, Maria; Tatar, Barbara; Berkoz, Mehmet; Krosniak, Miroslaw
Elemental impurities (EIs) profiling in final pharmaceutical products is often not adequately treated, however it is crucial problem in pharmaceutical analysis by reason of the various regulatory authorities (like ICH Q3D guideline). EIs in pharmaceuticals may arise from numerous sources of which the herbal ingredients are not a frequent subject of pharmaceutical analyses. However, based on number of traditional use registrations per year for herbal medicinal products (HMPs) in the EU, it can be stated that monocomponent HMPs are still very popular for use. Due to the high frequency of use, exposure to EIs from HMPs may be high during long-term use. The aim of our article was Ni and Cr impurities profiling of Valeriana officinalis L., radix (Valerian root) as an example of the HMP available in Polish pharmacies for the relief of mild nervous tension and sleep disorders. The choice of metals was justified by: (1) a single dose of Ni administered via oral route can induce dermatitis in nickel-sensitised individuals; (2) Cr is a very problematic element from toxicological point of view. Our results indicate that the standards of the ICH Q3D guideline are met for all EIs.
Prophylactic Effect of Biochanin a in Lipopolysaccharide-Stimulated Bv2 Microglial Cells
(Taylor & Francis Ltd, 2020) Berkoz, Mehmet; Krosniak, Miroslaw; Ozkan-Yilmaz, Ferbal; Ozluer-Hunt, Arzu
Aim/Purpose of the study:Inhibition of microglial activation using phytochemicals may be a potential candidate for the prevention of neurodegenerative diseases caused by neuroinflammation and oxidative stress. The goal of this study was to investigate the protective role of Biochanin A on lipopolysaccharide (LPS)-stimulated BV2 microglial cells. BV2 microglial cells were treated with LPS in the presence and absence of Biochanin A.Materials and methods:For this aim, nitric oxide production, nuclear factor kappa B (NF-kappa B), tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), IL-6, Prostaglandin E2 (PGE2), and reactive oxygen species (ROS) levels, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), myeloid differentiation factor-88 (MyD88), and toll like receptor-4 (TLR-4) protein expressions, Akt and ERK1/2 phosphorylation levels were measured.Results:Biochanin A pretreatment resulted in significant and concentration-dependently reduced the LPS-induced production of nitric oxide, NF-kappa B p65, TNF-alpha, IL-1 beta, IL-6, PGE2, and ROS compared to the untreated group. Biochanin A prophylaxis exerted an anti-inflammatory effect by suppressing iNOS, COX-2, MyD88, and TLR-4 protein expressions and Akt and ERK1/2 pathway activation.Conclusion:Taken together, these results show that Biochanin A exerts antioxidant and anti-inflammatory activities, thus may be beneficial for preventing neurodegenerative diseases mediated by microglial cells.
Protective Effect of Myricetin, Apigenin, and Hesperidin Pretreatments on Cyclophosphamide-Induced Immunosuppression
(Taylor & Francis Ltd, 2021) Berkoz, Mehmet; Yalin, Serap; Ozkan-Yilmaz, Ferbal; Ozluer-Hunt, Arzu; Krosniak, Miroslaw; Francik, Renata; Yildirim, Metin
Aim: Major side effects of cyclophosphamide administration are immunosuppression and myelosuppression. The immunomodulatory effects of plant bioactive compounds on chemotherapy drug-induced immunosuppression may have significant effects in cancer treatment. For this reason, we investigated the immunomodulatory effect of myricetin, apigenin, and hesperidin in cyclophosphamide-induced immunosuppression in rats. Methods: In our study, a total of 64 rats were used, and divided into eight equal groups. These groups were: control, cyclophosphamide, cyclophosphamide+myricetin (100mg/kg), cyclophosphamide+myricetin (200mg/kg), cyclophosphamide+apigenin (100mg/kg), cyclophosphamide+apigenin (200mg/kg), cyclophosphamide+hesperidin (100mg/kg), and cyclophosphamide+hesperidin (200mg/kg). Myricetin, apigenin, and hesperidin pretreatments were performed for 14d, while cyclophosphamide application (200mg/kg) was performed only on the 4th day of the study. Levels of humoral antibody production, quantitative hemolysis, macrophage phagocytosis, splenic lymphocyte proliferation, and natural killer cell cytotoxicity were determined. In addition, we measured pro-inflammatory cytokines, and followed lipid peroxidation and antioxidant markers and examined the histology of bone marrow, liver and spleen in all groups. Results: During cyclophosphamide treatment, all three phytochemicals increased the levels of humoral antibody production, quantitative hemolysis, macrophage phagocytosis, splenic lymphocyte proliferation, antioxidant markers, and natural killer cell cytotoxicity. Moreover, the agents decreased the levels of pro-inflammatory cytokines and mediators, reduced lipid peroxidation markers, and reduced tissue damage in liver, spleen, and bone marrow. Conclusion: Our study demonstrated that myricetin, apigenin, and hesperidin can reduce the immunosuppressive effect of cyclophosphamide by enhancing both innate and adaptive immune responses, and these compounds may be useful immunomodulatory agents during cancer chemotherapy.
Protective Role of Myricetin and Fisetin Against Nephrotoxicity Caused by Lead Acetate Exposure Through Up-Regulation of Nrf2/Ho-1 Signalling Pathway
(Springernature, 2024) Berkoz, Mehmet; Yigit, Ayhan; Krosniak, Miroslaw
The effect of various flavonoids against oxidative stress and inflammation caused by lead exposure has been investigated. However, the protective effects of myricetin (MYC) and fisetin (FST), which are known to have potent antioxidant properties, against nephrotoxicity caused by exposure to lead acetate (LA), the water-soluble form of lead, have not been investigated. Our study investigated the protective role of these flavonoids against LA intoxication-induced nephrotoxicity. In our study, 42 male rats were used. The rats were randomly selected and divided into 6 groups. These groups were: control, LA (100 g/kg), LA + MYC (100 mg/kg), LA + MYC (200 mg/kg), LA + FST (100 mg/kg) and LA + FST (200 mg/kg). All chemicals were administered daily by gavage for 28 days. According to the experimental protocol, the animals were sacrificed and their kidney tissues were isolated. Serum biochemical parameters, histological examinations, levels of several trace elements, oxidative stress and inflammatory parameters at both biochemical and molecular levels in kidney tissues were examined. After LA administration, tissue lead levels increased and zinc levels decreased. This situation was reversed by MYC and FST treatment. Oxidative stress and inflammatory response were increased in the kidney tissue of LA-treated rats and renal function was impaired. It was observed that both doses of MYC and high dose of FST could prevent nephrotoxicity. Oral administration of both doses of MYC and high dose FST ameliorated the changes in biochemical, oxidative and inflammatory parameters. Restoration of normal renal tissue architecture was also demonstrated by histological studies. MYC and FST were found to have promising biological activity against LA-induced nephrotoxicity, acting by attenuating inflammation and oxidative stress and improving antioxidant status.
Punicalagin Induces Apoptosis in A549 Cell Line Through Mitochondria-Mediated Pathway
(General Physiol and Biophysics, 2020) Berkoz, Mehmet; Krosniak, Miroslaw
Lung cancer is the most common cause of cancer-related deaths worldwide. Punicalagin is an ellagitannin mostly found in pomegranate husk and shows very strong antitumoral activity. The purpose of this study was to investigate the mechanism in which punicalagin acts as an antiproliferative agent on A549 cell line (adenocarcinomic human alveolar basal epithelial cells) and MRC-5 cell line (normal lung fibroblast cells). The cultured cells were treated with punicalagin at concentrations of 1-100 mu M for 24 h. For this aim, cell growth inhibition, percentage of apoptotic cells, cell cycle distribution, morphological changes, cellular and mitochondrial reactive oxygen species (ROS) production, and expression of apoptotic proteins were evaluated. Cell viability test and morphological examinations showed that punicalagin at 50 and 75 mu M concentrations exhibited toxic effect against lung cancer cells but not toxic against normal lung cells. Cytoplasmic ROS production decreased with the application of punicalagin, while the level of ROS released from mitochondria increased due to mitochondrial dysfunction. Studies of apoptosis indicated that both punicalagin concentrations induced apoptotic process in A549 cells. However, cell cycle was arrested in the G(1)/S phase after punicalagin treatment. These findings suggest that punicalagin has antiproliferative and apoptotic properties in these concentrations.
Roe Protein Hydrolysate of Alburnus Tarichi Induces Apoptosis in Breast Cancer Mcf-7 and Mda-Mb Cells Through a Caspase-Dependent Pathway
(General Physiol and Biophysics, 2020) Berkoz, Mehmet; Ozkan-Yilmaz, Ferbal; Ozluer-Hunt, Arzu; Krosniak, Miroslaw; Turkmen, Omer; Yunusoglu, Oruc
The protein hydrolysates of fishes have been reported to be a potential source of many health benefits components for pharmaceutical or nutritional applications. The aim of this study is to examine the possible antiproliferative function of roe protein hydrolysates of Alburnus tarichi using enzymatic hydrolysis against breast cancer cells and explore its detailed mechanisms. In addition, we evaluated the effects of protein hydrolysate on the proliferation and apoptosis of two human breast cancer cell lines (MCF-7 and MDA-MB-231). The cultured cells were treated with protein hydrolysate at concentrations of 0-5 mu g/ml for 24 h and 48 h. Inhibition of cell proliferation, percentage of apoptotic cells, cell cycle distribution, morphological changes, DNA fragmentation, intracellular reactive oxygen species (ROS) production, and apoptotic protein levels were also examined. Decreases in proliferation of MCF-7 and MDA-MB-231 cells were observed after treatment with the protein hydrolysate in a dose-dependent manner. Distinct morphological changes, a typical pattern of fragmented DNA, and increased intracellular ROS production and apoptotic protein levels were observed in both cell lines after hydrolysate treatment (p < 0.05). The results suggested that the protein hydrolysate inhibits the proliferation of human breast cancer cell lines by introducing apoptosis through a caspase-dependent pathway in a dose-dependent manner.
The Toxicological Risk Assessment of Cu, Mn, and Zn as Essential Elemental Impurities in Herbal Medicinal Products With Valerian Root (Valeriana Officinalis L., Radix) Available in Polish Pharmacies
(Springernature, 2022) Jurowski, Kamil; Folta, Maria; Tatar, Barbara; Berkoz, Mehmet; Krosniak, Miroslaw
The toxicological risk assessment (TRA) of elemental impurities (EI) in especially herbal medicinal products (HMP) is a significant challenge for pharmaceutical industry. In Europe, very popular are traditional HMP with valerian root (Valeriana officinalis L., radix) for relief of mild symptoms of mental stress and to aid sleep. The aim of our unique article is the comprehensive TRA of Cu, Mn, and Zn as EI in HMP with V. officinalis L., radix available in Polish pharmacies. This article is a continuation of our previously conducted studies about TRA of heavy metals (Pb and Cd) in these same samples. Investigated elements were determined by flame atomic absorption spectrometry (F AAS). The values of the correlation coefficients (R > 0.998) confirm the linearity of the applied instrument for precision and accuracy of results. The recoveries, LOD and LOQ values were acceptable. Our results show that all investigated HMP with valerian root available in Polish pharmacies contain Cu (0.16-0.23 mg/L), Mn (0.11-0.76 mg/L), and Zn (0.22-0.48 mg/L) at a very low level. Based on our estimation of EI including single dose (mu g/20 mL) and estimated daily intake (mu g/day), our results confirm the safety of all pharmaceuticals. To the best of our knowledge, the Cu, Mn, and Zn impurity profile in HMP with V. officinalis L., radix is described for the first time. The applied methodology and results are extremely important from regulatory toxicology point of view (ICH Q3D elemental impurities guideline for pharmaceuticals).
The Toxicological Risk Assessment of Dermal Exposure of Patients Exposed To Nickel and Chromium Due To Application of Ointments With Marjoram Herb Extract (Majoranae Herbae Extractum) Available in Polish Pharmacies
(Springernature, 2022) Jurowski, Kamil; Folta, Maria; Tatar, Barbara; Berkoz, Mehmet; Krosniak, Miroslaw
For elemental impurities that have been studied for transcutaneous absorption, the available data are rarely suitable for proper toxicological risk assessment - there are multiple factors that can influence this dermal absorption. Hence, in our studies, we applied generic and conservative approach - cutaneous permitted daily exposure (CPDE) described in International Conference on Harmonisation's Q3D Guideline on Elemental Impurities (ICH Q3D). The aim of this article is toxicological risk assessment (TRA) of dermal exposure of patients exposed to nickel and chromium due to application of ointments with Marjoram herb extract (Majoranae herbae extractum) available in Polish pharmacies (n = 5, because only five manufacturers produce this kind of pharmaceutical products in Poland). To make the appropriate TRA approach, we considered (1) raw results (metal per kg of ointment), (2) one-time administration of applied ointments, and (3) daily exposure versus CPDE. Due to the fact the concentrations of Ni generally present in cutaneous products as impurities are not considered sufficient to induce sensitization, the cutaneous and transcutaneous concentration limits (CTCLs) approach was applied for this element assessment. The toxicological analysis was carried out using microwave-assisted wet digestion with concentrated nitric acid and electrothermal atomization atomic absorption spectrometry. Our results show that the ointments with Marjoram herb extract from pharmacies in Poland represent a potential health hazard to patients; however, there may be a requirement for the monitoring of impurities of nickel in future. To the best of our knowledge, this paper is the first study about nickel and chromium content in ointments with Marjoram herb extract (Majoranae herbae extractum).
The Toxicological Risk Assessment of Lead and Cadmium in Valeriana Officinalis L., Radix (Valerian Root) as Herbal Medicinal Product for the Relief of Mild Nervous Tension and Sleep Disorders Available in Polish Pharmacies
(Springernature, 2022) Jurowski, Kamil; Folta, Maria; Tatar, Barbara; Berkoz, Mehmet; Krosniak, Miroslaw
Studies related to the toxicological risk assessment (TRA) of heavy metal impurities (HMIs) in pharmaceuticals are an important issue but there is a lack of refereed literature around the safety of Valeriana officinalis L., radix (Valerian root) as herbal medicinal product (HMP) for the relief of mild nervous tension and sleep disorders according to lead and cadmium impurities. The aim of the study was to estimate the TRA of lead and cadmium in Valeriana officinalis L., radix (Valerian root) as HMP (n = 5) available in Polish pharmacies. In the case of herbal pharmaceuticals, it is particularly important to control the level of HMIs accumulated during the plant's growth. Perhaps, the exposure for a single dose is not relevant; however, justification of our studies is a fact that herbal therapies are usually long term. Therefore, even small HMI doses as present in particular plant may accumulate in patient body over a long period of time. Levels of lead and cadmium were measured by electrothermal atomization atomic absorption spectrometry. The levels of lead and cadmium as HMIs (independently of the producer and declared composition) are quite similar. Our results are satisfactory, confirming the safety of Valeriana officinalis L., radix (Valerian root) as herbal medicinal product for the relief of mild nervous tension and sleep disorders available in Polish pharmacies according to ICH guideline Q3D. To the best of our knowledge, this paper is the first study about lead and cadmium content as HMIs in HMP containing Valeriana officinalis L., radix (Valerian root).