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An increased number of sulfate-reducing bacteria is often isolated from faeces of patients with gastrointestinal diseases, which can be the cause of the development of bowel inflammation. Frequent use of antibiotics causes the resistance of intestinal microorganisms and ineffective treatment of these diseases. The antimicrobial activity and biological properties of the selected ring-substituted 8-hydroxyquinoline-2-carboxanilides against Desulfovibrio piger Vib-7 were studied. The addition of these compounds in the cultivation medium inhibited the bacterial growth and the process of sulfate reduction dose-dependently. A significant cytotoxic activity under the influence of ring-substituted 8-hydroxyquinoline-2-carboxanilides was determined. The strongest cytotoxic effect of the derivatives was observed for compounds 8-hydroxy-N-(3-methoxyphenyl)quinoline-2-carboxamide and 8-hydroxy-N-(3-trifluoromethylphenyl)quinoline-2-carboxamide that caused a low survival of D. piger Vib-7 in concentration 17 μM and high toxicity rates.

Helicobacter pylori (H. pylori), which is found in the stomach of approximately 50% of humans, remains there for almost the entire lifetime of the infected individual, leading to various gastrointestinal tract-associated disorders following full-blown infection. Due to the emergence of antibiotic resistance, recurrence and high cost of therapy, most antibiotic-based treatment strategies are not very effective in eradicating H. pylori infections. The quest for an alternative treatment free of these inconveniences is currently in demand. One of the important alternatives is propolis, produced by the honeybee Apis mellifera, which has been used to treat different diseases since it possesses a wide range of biochemical properties. Propolis has been reported as a useful therapeutic regimen against H. pylori, which is an important cause of gastric inflammation, peptic ulcer, gastric cancer, and lymphomas of mucosa-associated lymphoid tissues. Apart from propolis, various active compounds of other natural products have also been confirmed to be effective. This review compiles the scientific evidence of the role of propolis and other natural products against H. pylori-associated gastrointestinal tract-related health complexities by acing as an anti-angiogenic, anti-inflammatory, and antioxidant factor as well as via modulation of enzymatic activities.

There is a lack of data on the state of iodine reserves and the possible consequences of iodine deficits in diabetic patients. The main aims of this study were to: a) obtain information about iodine saturation in patients with type 1 diabetes; b) determine to what extent this saturation differs from the non-diabetic population; and c) determine whether iodine levels are related to several clinical and laboratory parameters characteristic of diabetic syndrome, including thyroid status.
Subjects and methods: A total of 54 males and 51 females treated for type 1 diabetes mellitus (DM1) were included in this cross-sectional study. In addition to iodine saturation determined as the concentration of iodine in the first urine sample of the day, we measured clinical, anthropometric, and biochemical parameters in relation to DM1.
Results: Measured iodine levels were: median 152 μg/l, first quartile 117 μg/l, and third quartile 219 μg/l. More than 50% of iodine levels varied within the optimal saturation range of 100-200 μg/l, while about 14% showed incomplete saturation (200 μg/l).
Multi-dimensional regression showed significant positive relationships; (an OPLS model explaining 9% of the variability) between ioduria and male sex, body weight and height, and serum creatinine levels, which to date have not yet been published. Relationships to the other analyzed parameters (glycated hemoglobin, insulin dose, DM duration, body mass index, microalbuminuria, glomerular filtration rate, thyroid function and volume, thyroid autoimmune markers) were not significant.
Conclusions: Iodine saturation levels in our study group were within the ICCIDD (WHO) recommendations for optimal/good saturation for the non-diabetic population, and patients with diabetic syndrome did not differ with respect to the chosen normal ioduria concentrations, i.e. 100 or 150 μg/l. The question remains, however, whether past attempts to deal with iodine deficits in the Czech Republic are responsible for this satisfactory iodine status of the type 1 diabetic population, or if there are other factors involved.

Previous studies have indicated that polyphenol-rich Chrysanthemum morifolium extract (CME) may inhibit the formation of hyperlipidemic fatty liver in mice. But there has been no report about therapeutic effect on diabetes mellitus. In the present study, we investigated the action of CME and its potential mechanisms. A mouse model with diabetes mellitus was induced by alloxan. The results showed that after treatment of diabetic mice with polyphenol-rich CME 150 and 300 mg/kg for 6 weeks, the levels of fasting blood glucose (FBG) as well as water and food consumption were decreased (P < 0.05 or P < 0.01), the content of hepatic glycogen was increased, especially in the 300 mg/kg group (P < 0.05), but no significant variations in the body-weight gain, fasting serum insulin, and muscular glycogen were observed. Importantly, toxic alloxan treatment might decrease the protein expressions of hepatic peroxisome proliferator-activated receptor (PPAR) α/γ, glycogen synthase (GS), and glucose transporter-2 (Glut-2) (P < 0.05 or P < 0.01), while CME might reverse the changes (P < 0.01). These findings demonstrate that the reduction of PPARα/γ-mediated hepatic glycogen synthesis may involve in the alloxan-induced hyperglycemia, and the hypoglycemic mechanisms of CME may be mainly associated with the increment of hepatic glycogen synthesis via upregulation of PPARα/γ-mediated GS and Glut-2 protein expressions.

The aim of the presented research was the preparation and in vitro and in vivo evaluation of mucoadhesive oral films containing nystatin. Multivariate data analysis was used to evaluate an innovative approach, in which a combination of different mucoadhesive polymers was employed. The purpose of this was to assess the effects of such a combination on non-woven insoluble carmellose textile as a drug-release modifier in the structure of the film.
It was observed that the mucoadhesive films prepared using polyethylene oxide were more plastic, showed less mechanical resistance and shorter in vitro residence time in comparison with films containing sodium carmellose. The textile used in films containing sodium carmellose significantly prolonged both in vitro and in vivo residence times in rabbits from 50 ± 4 min until 74 ± 4 min and from 48 ± 6 until 80 ± 4 min, respectively. A higher degree of substitution by the acid carboxymethyl group of the textile resulted in slower nystatin dissolution, longer in vitro and in vivo residence times, and higher tensile strength. Textural parameters tensile strength and tensile deformation in conjunction with linear discriminant analysis were able to distinguish the degree of substitution of the textile due to its impact on the studied parameters.

There is a renewed interest in metabolism alterations and its impact on cancer development and progression. The metabolism of cancer cells is reprogrammed in order to support their rapid proliferation. Elevated fatty acid synthesis is one of the most important aberrations in cancer cell metabolism, and is required both for carcinogenesis and cancer cell survival. We have previously shown that cancer cells explore metabolic pathways especially autophagy and particularly enhanced glycolysis and suppressed oxidative phosphorylation to promote treatment resistance. To support cell proliferation in cancer, lipid metabolism and biosynthetic activities is required and often up-regulated. Here we bring lipid metabolic pathways into focus and summarized details that suggest a new perspective for improving chemotherapeutic responses in cancer treatment, and indicate the need to design more inclusive molecular targeting for a better treatment response.

Antenatal glucocorticoid administration is used in cases of fetuses at risk to be born prematurely to enhance fetal pulmonary surfactant production and prevent infant respiratory distress syndrome. The CYP1A1 is the most important xenobiotic-metabolizing cytochrome P450 enzyme in the human placenta. Importantly, CYP1A1 generates reactive species and its placental activity is elevated in smoking women. CYP1A1 expression is mainly controlled by aryl hydrocarbon receptor (AHR) ligands. Glucocorticoid co-regulation of CYP1A1 has been described in various cell types but has not been systematically examined in the human placental trophoblast.
We studied the effects of the glucocorticoids dexamethasone and betamethasone on inducibility of CYP1A1 and other AHR target genes CYP1A2, CYP1B1, UGT1A1 (UDP-glucuronosyltransferase 1A1) and BCRP (Breast cancer resistance protein) by prototype AHR ligand 3-methylcholanthrene (3MC) in isolated human placental trophoblast culture.
We show that glucocorticoids alone had no effect on activity and protein/mRNA expression of CYP1A1 and little effect on mRNA expression of other AHR target genes. However, glucocorticoids significantly stimulated CYP1A1 mRNA, but not CYP1A2, CYP1B1, UGT1A1 and BCRP mRNAs, induction mediated by the AHR ligand. Consistently, glucocorticoids significantly augmented 7-ethoxyresorufin-O-deethylation (EROD) enzymatic activity in primary human placental trophoblast. Dexamethasone did not influence AHR and ARNT (Aryl hydrocarbon receptor nuclear translocator) mRNAs, suggesting that this phenomenon is not due to AHR or ARNT up-regulation by glucocorticoids in human trophoblast.
In conclusion, our data suggest that glucocorticoids have no effect on AHR target genes expression per se, but they may potentiate CYP1A1 induction in human term placental trophoblast.

The present study was designed to investigate the antihyperglycaemic effect of ethanolic extract of Cardiospermum halicacabum Linn. (Sapindaceae) leaves on normal and streptozotocin (STZ) diabetic rats. Diabetes was induced into male albino Wistar rats by intraperitonial administration of STZ. The Cardiospermum halicacabum leaf extract (CHE) was administered orally at three different doses to normal and STZ-diabetic rats for 45 days. The diabetic rats showed an increase in levels of blood glucose and glycosylated haemoglobin (HbA_1c) and a decrease in the levels of insulin and haemoglobin (Hb). In addition, diabetic rats showed a significant reduction in the activity of glucokinase and an elevation in the activities of gluconeogenic enzymes such as glucose-6-phosphatase and fructose-1, 6-bisphosphatase. Treatment with CHE significantly decreased plasma glucose and HbA_1c, and increased the levels of insulin and Hb. CHE administration to diabetic rats reversed these enzyme activities in a significant manner. Thus, the results show that CHE possesses an antihyperglycaemic activity and provide evidence for its traditional usage in the control of diabetes. The 200 mg dose of the extract produced a better effect than 50 or 100 mg doses.

Curcumin is the most active component of turmeric. It is believed that curcumin is a potent antioxidant and anti-inflammatory agent. Tetrahydrocurcumin (THC), one of the major metabolites of curcumin, exhibits many of the same physiological and pharmacological activities as curcumin and in some systems may exert greater antioxidant activity than curcumin. The aim of this study was to evaluate the effect of THC on the blood glucose, plasma insulin and fatty acid composition of the total lipids in the liver, kidney and brain of control and streptozotocin (STZ)-nicotinamide diabetic rats. The analysis of fatty acids showed that there was a significant increase in the concentrations of palmitic acid (16:1), stearic acid (18:0) and oleic acid (18:1) in the liver, kidney and brain, whereas the concentrations of linolenic acid (18:3) and arachidonic acid (20:4) were significantly decreased. Oral administration of the THC (80 mg/kg body weight) for 45 days to diabetic rats decreased the concentrations of fatty acids, viz., palmitic, stearic, and oleic acid, whereas linolenic and arachidonic acid were elevated. These results suggest that THC exhibits antidiabetic and antihyperlipidemic effects in STZ-nicotinamide induced diabetic rats. It also prevents the fatty acid changes produced during diabetes. The antidiabetic and antihyperlipidemic effects of THC are more potent than those of curcumin at the same dose. The results of the present study indicate that THC showed an antihyperlipidemic effect in addition to its antidiabetic effect in type 2 diabetic rats.

The lipid components of pathogen cell membranes have been considered as a poor pharmacological target, due to their universal distribution and apparent homogeneity throughout living organisms. Among the rare exceptions to this view one could mention polyene antibiotics such as amphotericin, or peptide antibiotics such as the polymyxins and the gramicidins. In the last two decades, however, the above notion has been challenged by two main lines of discovery; first, natural antimicrobial peptides (AMPs) that kill pathogens by interaction with phospholipids and membrane permeabilization, and secondly, cell-penetrating peptides (CPPs), capable of introducing into cells a variety of cargoes in the absence of specific receptors, again by interaction at some point with membrane phospholipids. For both AMPs and CPPs, the pharmacological proof-of-concept has been successfully demonstrated, and promising applications as nanobiotechnological tools have been envisaged though not hitherto materialized in clinical settings. In this review we briefly examine the pros and cons of these two classes of therapeutic agents, as well as strategies aimed at rationalizing and expanding their potentiality.

Ionising radiation (IR) is one of the main treatment modalities in oncology. However, we still search for substances which can radio-sensitize tumour cells. In this study we used caffeine, a non-specific ataxia-telangiectasia mutated kinase (ATM) inhibitor, and studied its effect on the activation of the proteins involved in cell cycle control and the induction of apoptosis in human T-lymphocyte leukaemic MOLT-4 cells (p53 wt). We evaluated the expression of the tumour-suppressor p53 (itself and phosphorylated on Ser¹⁵ and Ser³⁹²), the cell cycle regulator p21, and the anti-apoptotic protein myeloid cell leukemia 1 (Mcl-1). After treatment with 2 mM caffeine, the cells were irradiated by 1 or 3 Gy, lysed and the proteins detected by Western-blotting. Apoptosis was determined by flow-cytometric annexin V/propidium iodine detection. Irradiation by 1 or 3 Gy induced p53 phosphorylation at Ser¹⁵ and Ser³⁹² after 2 h with maximum after 4 h. Adding caffeine significantly inhibited Ser¹⁵ phosphorylation, which is ATM-dependent but surprisingly also Ser³⁹² phosphorylation, which is ATM-independent, suggesting that caffeine might have another cellular target (protein kinase). Similarly, caffeine caused a substantial decrease in p21 in combination with both doses of IR and also Mcl-1 was down-regulated. Three days after irradiation, caffeine significantly increased induction of apoptosis. The ATM/p53 pathway was suppressed by caffeine, which led to increased apoptosis accompanied by a p53-independent decrease in Mcl-1. It also caused down-regulation of p21, which possibly contributed to the shortened cell cycle arrest necessary for effective DNA repair and thus impeded radio-resistance. Caffeine promotes the cytotoxic effect of ionising radiation and provides a possible platform for the development of new anti-cancer therapeutics known as radio-sensitizers.

DNA replication of plasmids in Gram-negative bacteria has been an object of study at CIB-CSIC for nearly 30 years. We have been focused on the enterobacterial antibiotic resistance factor R1 (1981-1992) and the pPS10 replicon from the phytopathogen Pseudomonas savastanoi (since 1984). Our group has used multidisciplinary (genetic, biochemical and biophysical-structural) approaches to unravel the molecular mechanism for the activation of RepA. Rep-type plasmidic proteins are either transcriptional repressors or replication initiators/inhibitors, depending on their association state (dimers vs. monomers) and targeting of alternative (operator or iteron) DNA sites. We discovered that allosteric DNA-binding remodels the structure of RepA N-terminal domain (WH1), transforming α-helical portions into β-strands. This precisely tunes the distances between the DNA reading heads in WH1 and the C-terminal domain (WH2), to match the target operator or iteron sequences. We have recently moved into engineering such structural transformation in RepA-WH1 to build-up synthetic protein devices that allow for customized ligand (DNA)-promoted amyloidogenesis. Our basic studies on plasmid DNA replication are relevant for settling the bases of a minimalist bacterial model to tackle transmissible amyloid proteinopathies and are a valuable tool for bottom-up synthetic biology.

The most common cause of dementia in the elderly is Alzheimer disease (AD). In Europe, AD is a leading cause of death. The prevalence of this disease in developed countries is increasing because of very significant shifts in life expectancy and demographic parameters. AD is characterized by progressive cognitive impairment, resulting from dysfunction and degeneration of neurons in the limbic and cortical regions of the brain. Two prominent abnormalities in the affected brain regions are extracellular deposits of β-amyloid, and intracellular aggregates of tau protein in neurofibrillary tangles. The role of these features in AD pathogenesis and progression is not yet completely elucidated. Research over the last decade has revealed that the activation of cell cycle machinery in postmitotic neurons is one of the earliest events in neuronal degeneration in AD. Here we summarize evidence to support the hypothesis that cell cycle alterations occur in cells other than neurons in AD sufferers. Immortalized lymphocytes from AD patients have show an enhanced rate of proliferation associated with G1/S regulatory failure induced by alterations in the cyclin/CDK/pRb/E2F pathway. In addition, these cells have a higher resistance to serum deprivation-induced apoptosis. These neoplastic-like features, cell cycle dysfunction and impaired apoptosis can be considered systemic manifestations of AD disease.

Arsenic trioxide (As₂O₃, ATO) is a very efficacious, clinically established agent for the treatment of acute promyelocytic leukaemia, and also potentially useful against other haematological and non-haematological malignancies. Nonetheless, the relative resistance of many tumour cell types requires the generation of sensitizing strategies. One of the properties of ATO which might be exploited for therapeutic purposes is its sensitivity to the intracellular oxidant state, as revealed by increased apoptosis production under conditions of reduced glutathione (GSH) depletion and/or elevated reactive oxygen species (ROS) content. This review summarizes some studies from our laboratory demonstrating that experimental modulation of protein kinase activities (PI3K/Akt, JNK, MEK/ERK) potentiates ATO-provoked apoptosis in relatively resistant human acute myeloid leukaemia (U937, HL60) cell lines by mechanisms involving GSH depletion and/or increased ROS content. In a similar manner, co-treatment with dietary flavonoides such as genistein, normally considered as anti-oxidants, may potentiate apoptosis via generation of moderate oxidative stress and activation of ROS-inducible protein kinases. Finally, co-treatment with ATO may sensitize otherwise refractory leukaemia cells to TNFα-family cytokine-produced apoptosis, by mechanisms involving the interplay between the "intrinsic" (mitochondrial) and "extrinsic" (death receptor-mediated) pathways.

The present study was carried out to investigate the hypoglycaemic effect of S-allyl cysteine (SAC), a garlic component, on some biochemical parameters of STZ induced diabetic rats. STZ induced diabetic rats were treated with SAC at two different doses (100 mg/kg b.w. and 150 mg/kg b.w.) for 45 days. Treatment with SAC significantly decreased the levels of blood glucose, glycosylated hemoglobin, blood urea, serum uric acid, serum creatinine, and diminished activities of pathophysiological enzymes such as aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP). The antihyperglycaemic nature of SAC is also evidenced from the improvement in the levels of plasma insulin and haemoglobin. Further, the results are comparable with glyclazide, an oral standard drug. A 150 mg/kg b.w. dose produced a better effect than a 100 mg dose. Thus, the present findings suggest that SAC may be considered as an effective therapeutic agent for the treatment of diabetes mellitus.

This study was designed to evaluate the effect of Terminalia chebula fruit extract on the levels of plasma and tissue glycoprotein components in streptozotocin-induced-diabetic rats. Oral administration of T. chebula fruit extract at a concentration of 200 mg/kg body weight for 30 days significantly reduced the levels of blood glucose, glycosylated hemoglobin, urea, and creatinine as well as fucose, hexose, hexosamine and sialic acid in the diabetic rats treated with the fruit extract. The observed decrease in the levels of plasma insulin and C-peptide in the diabetic rats was elevated to near normal by T. chebula fruit extract treatment. Histological observations made on the pancreatic tissue of control and experimental groups also revealed the beneficial effect of T. chebula fruit extract. The efficacy of the fruit extract was comparable with glibenclamide, a known hypoglycaemic drug.

Down syndrome (DS) is often accompanied by autoimmune diseases. Among those, autoimmune thyroid disease, type 1 diabetes and celiac disease are the most common. The major cause of enhanced vulnerability of DS patients to a variety of autoimmune diseases is impaired immune response, with multiple abnormalities in all components of the immune system, especially in cell-mediated immunity. This could explain a significantly higher frequency of autoimmune disorders in DS compared to the general population. The diagnosis of autoimmune diseases accompanying DS could be complicated by masking effects of the underlying features of the syndrome such as failure to thrive, short stature and delayed puberty. However, screening for immunological signs of coexistent autoimmunity such as tissue-specific antibodies and monitoring insulin secretion, glucose levels, thyroid function and other metabolic parameters should help in early diagnosis of coexistent autoimmunity in DS patiens.

Succinic acid monoethyl ester (EMS) was recently proposed as an insulinotropic agent for the treatment of non-insulin dependent diabetes mellitus. The present study investigated the effect of EMS and Metformin on dearrangement in glycoprotein levels in the streptozotocin-nicotinamide induced type 2 diabeteic model. Succinic acid monoethyl ester was administered intraperitoneally for 30 days to normal and diabetic rats. The effect of EMS on glucose, insulin, and plasma and tissue glycoproteins were studied. The effect of EMS was compared with Metformin, a reference drug. The levels of glucose, glycosylated haemoglobin and plasma glycoproteins containing hexose, hexosamine and fucose were increased significantly whereas the level of plasma insulin and haemoglobin were decreased significantly in diabetic rats. There was a significant decrease in the level of sialic acid and elevated levels of hexose, hexosamine and fucose in the liver and kidney of streptozotocin-nicotinamide diabetic rats. Administration of EMS to diabetic rats was followed by a decreased level of glucose, glycosylated haemoglobin and plasma glycoproteins. The levels of plasma insulin, haemoglobin and tissue sialic acid were increased whereas the levels of tissue hexose, hexosamine and fucose were near normal. The present study indicates that the EMS possesses a significantly beneficial effect on the glycoprotein moiety in addition to its antidiabetic effect.

Lymphoedema, a pathological accumulation of extracellular water (ECW), is a severe post-operative complication. Multifrequency bioimpedance analysis (MFBIA) is a method for the detection of changes in ECW. Our aim is to establish the methodology of MFBIA and to apply it on to group of patients undergoing breast cancer surgery.
We measured a control group of 60 women, another group of 5 women with pronounced lymphoedema and a group of 36 patients undergoing breast cancer surgery during a 9-month period after surgery using MFBIA and circumferential measurements for recording volume changes in the upper limb. Different linear extrapolations from 1, 5, 50, 100, 200 kHz were determined to find resistance at 0 Hz for each patient; ratios of R₀ were evaluated for non-dominant/dominant and non-operated/operated limbs. Pearson's correlation coefficient was used to compare the correlation between the results and patient characteristics.
Extrapolation using 5, 50, 100 kHz had the lowest standard deviation. Within the patients with pronounced lymphoedema, bigger differences were found by MFBIA as compared with circumference measurements. A stronger correlation between limb volumes calculated from circumference measurements with weight and BMI as compared with MFBIA was found. Lymphoedema was found in 14 women in the tested group. The best association between patients' subjective symptoms was with the MFBIA measurement.

Calli cultures of higher plants cultivated for a long-time in vitro conditions are characterized by higher resistance to γ-irradiation. The causes of this resistance are both genetic and epigenetic induced factors including cultivation conditions and exogenous growth regulators.
The γ-irradiation of ¹³⁷Cs with the doses D=1, 5, 10, 100 and 500 Gy applied on the partially synchronized peanut calli cultures showed that small doses D∈ Gy had a slight stimulation effect on the growth processes. Inhibition of the growth began for the dose D≥100 Gy. Dose LD₅₀ reached 250±50 Gy. Necrose was not detected but cells of calli cultures changed their color. Stimulating doses D∈ Gy of γ-irradiation decreased morphological polymorphism of cells and nuclei. Gene expression was changed in the first minutes after irradiation. The spectrum of proteins and polypeptides synthesized de novo changed depending on the doses used. Protein Hsp60 was registered only for doses D=100 and 500 Gy. Proteins connected with the apoptosis pathway (p21, p27, and p53) were synthesized in two waves, the first appeared between 24-48 hours after irradiation and the second appeared in the stationary growth phase. Changes in the content of GTP-binding proteins as well as auxin and cytokinin binding proteins are indicated by their participation in post-radiation repair mechanisms. The role of rad genes is discussed.