Evaluating the relationship of GDF-15 with clinical characteristics, cardinal features, and survival in multiple myeloma

Growth differentiation factor 15 (GDF-15), a member of the transforming growth factor-β superfamily, participates in processes associated with myeloma development and its end-organ complications. It plays a significant role in both physiological and abnormal erythropoiesis and regulates iron homeostasis through modulation of hepcidin. It is abnormally secreted in marrow stromal cells of patients with multiple myeloma (MM), which may reflect the tumor microenvironment. We analyzed the associations of serum GDF-15 with clinical characteristics of 73 MM patients (including asymptomatic MM) and the laboratory indices of renal function, anemia, and inflammation. Baseline serum GDF-15 was studied as the predictor of two-year survival. We defined five clinically relevant subgroups of patients (symptomatic MM only, patients with and without remission, patients on chemotherapy, and without treatment). Increased GDF-15 concentrations were associated with more advanced MM stage, anemia, renal impairment (lower glomerular filtration and higher markers of tubular injury), and inflammation. Most of the results were confirmed in the subgroup analysis. Serum cystatin C and urine neutrophil gelatinase-associated lipocalin were associated with GDF-15 independently of other variables. In the studied MM patients, GDF-15 did not significantly predict survival (p=0.06). Our results suggest that serum GDF-15 reflects myeloma burden and shares a relationship with several markers of prognostic significance, as well as major manifestations

Polymorphisms Related to Iron Homeostasis Associate with Liver Disease in Chronic Hepatitis C

Dysregulation of iron metabolism in chronic hepatitis C (CHC) is a significant risk factor for hepatic cirrhosis and cancer. We studied if known genetic variants related to iron homeostasis associate with liver disease progression in CHC. Retrospective analysis included 249 CHC patients qualified for antiviral therapy between 2004 and 2014. For all patients, nine SNPs within HFE, TFR2, HDAC2, HDAC3, HDAC5, TMPRSS6, and CYBRD1 genes were genotyped. Expression of selected iron–related genes, was determined with qRT-PCR in 124 liver biopsies, and mRNA expression of co-inhibitory receptors (PD-1, Tim3, CTLA4) was measured in 79 liver samples. CYBRD1 rs884409, HDAC5 rs368328, TFR2 rs7385804, and TMPRSS6 rs855791 associated with histopathological changes in liver tissue at baseline. The combination of minor allele in HDAC3 rs976552 and CYBRD1 rs884409 linked with higher prevalence of hepatocellular carcinoma (HCC) during follow up (OR 8.1 CI 2.2–29.2; p = 0.001). Minor allele in HDAC3 rs976552 associated with lower hepatic expression of CTLA4. Tested polymorphisms related to iron homeostasis associate with histopathological changes in the liver. The presence of both HDAC3 rs976552 G and CYBRD1 rs884409 G alleles correlates with HCC occurrence, especially in the group of patients with elevated AST (>129 IU/L). rs976552 in HDAC3 could impact immunological processes associated with carcinogenesis in CHC

Mutagenic activity of quaternary ammonium salt derivatives of carbohydrates

This paper presents a study on a series of quaternary ammonium salt (QAS) derivatives of glucopyranosides with an elongated hydrophobic hydrocarbon chain. The new N-[6-(β-D-glucopyranosyloxy)hexyl]ammonium bromides and their O-acetyl derivatives were analyzed via 1H and 13C NMR spectroscopy. The mutagenic activity of the newly synthesized QAS was investigated using two different techniques: The Vibrio harveyi luminescence assay and the Ames test. The obtained results support previous findings contesting QAS safety and indicate that QAS, specifically pyridinium derivatives, might be mutagenic

Differences in sequences between HBV-relaxed circular DNA and covalently closed circular DNA

The hepatitis B virus (HBV) genome exists in two forms: circular covalently closed DNA (cccDNA) and relaxed circular DNA (RCDNA). Here, we investigated the presence of differences in the sequences of both forms in paired samples of serum and liver tissue. The serum and liver biopsy samples were collected at the same time from 67 chronically infected patients. The genotyping of the RCDNA and cccDNA was performed using mass spectrometry analysis. The HBV mutations located in the HBV pol (P) and the HBV basal core promoter/pre-core (BCP/PC) regions were included. The BCP/PC and P sequences of the RCDNA extracted from liver and blood samples were different in 39% and 16% of patients, respectively. Differences were also found between RCDNA and cccDNA extracted from the same liver specimen. Moreover, the cccDNA BCP/PC region sequence had an impact on various virological and clinical parameters. We demonstrated that there are differences between the RCDNA and cccDNA sequences that were extracted from the same liver tissue. However, further investigations are needed to analyze whether the mutations in the cccDNA are conserved and whether cccDNA serves as a ‘mutation storage’ pool for HBV. This result could have profound implications for the subsequent therapy choices for treatment-experienced patients.Emerging Microbes & Infections (2017) 6, e55; doi:10.1038/emi.2017.41; published online 21 June 201

Modulatory Effects of Caffeine and Pentoxifylline on Aromatic Antibiotics: A Role for Hetero-Complex Formation

Antimicrobial resistance is a major healthcare threat globally. Xanthines, including caffeine and pentoxifylline, are attractive candidates for drug repurposing, given their well-established safety and pharmacological profiles. This study aimed to analyze potential interactions between xanthines and aromatic antibiotics (i.e., tetracycline and ciprofloxacin), and their impact on antibiotic antibacterial activity. UV-vis spectroscopy, statistical-thermodynamical modeling, and isothermal titration calorimetry were used to quantitatively evaluate xanthine-antibiotic interactions. The antibacterial profiles of xanthines, and xanthine-antibiotic mixtures, towards important human pathogens Staphylococcus aureus, Enterococcus faecium, Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, and Enterobacter cloacae were examined. Caffeine and pentoxifylline directly interact with ciprofloxacin and tetracycline, with neighborhood association constant values of 15.8–45.6 M−1 and enthalpy change values up to −4 kJ·M−1. Caffeine, used in mixtures with tested antibiotics, enhanced their antibacterial activity in most pathogens tested. However, antagonistic effects of caffeine were also observed, but only with ciprofloxacin toward Gram-positive pathogens. Xanthines interact with aromatic antibiotics at the molecular and in vitro antibacterial activity level. Given considerable exposure to caffeine and pentoxifylline, these interactions might be relevant for the effectiveness of antibacterial pharmacotherapy, and may help to identify optimal treatment regimens in the era of multidrug resistance

Antimicrobial, Cytotoxic and Mutagenic Activity of Gemini QAS Derivatives of 1,4:3,6-Dianhydro-l-iditol

A series of quaternary diammonium salts derivatives of 1,4:3,6-dianhydro-l-iditol were synthesized, using isommanide (1,4:3,6-dianhydro-d-mannitol) as a starting material. Both aromatic (pyridine, 4-(N,N-dimethylamino)pyridine (DMAP), (3-carboxamide)pyridine; N-methylimidazole) and aliphatic (trimethylamine, N,N-dimethylhexylamine, N,N-dimethyloctylamine, N,N-dimethyldecylamine) amines were used, giving eight gemini quaternary ammonium salts (QAS). All salts were tested for their antimicrobial activity against yeasts, Candida albicans and Candida glabrata, as well as bacterial Staphylococcus aureus and Escherichia coli reference strains. Moreover, antibacterial activity against 20 isolates of S. aureus collected from patients with skin and soft tissue infections (n = 8) and strains derived from subclinical bovine mastitis milk samples (n = 12) were evaluated. Two QAS with octyl and decyl residues exhibited antimicrobial activity, whereas those with two decyl residues proved to be the most active against the tested pathogens, with MIC of 16–32, 32, and 8 µg/mL for yeast, E. coli, and S. aureus reference and clinical strains, respectively. Only QAS with decyl residues proved to be cytotoxic in MTT assay against human keratinocytes (HaCaT), IC50 12.8 ± 1.2 μg/mL. Ames test was used to assess the mutagenic potential of QAS, and none of them showed mutagenic activity in the concentration range 4–2000 µg/plate

TNF‐α polymorphisms affect persistence and progression of HBV infection

Abstract Background Hepatitis B virus (HBV) infections are a major threat worldwide. Disease progression and outcome is diverse and depends on host genetic background. Recently, a high rate of HBV reactivation in individuals receiving tumor necrosis factor‐α (TNF‐α) antagonists showed the importance of this cytokine in HBV infection control. Here, we investigated the influence of TNF‐α promoter polymorphisms on susceptibility to chronic HBV infection (CHB), liver injury progression and outcomes. Methods A total of 231 patients with CHB constituted the study group and 100 healthy volunteers—the local control group. TNF‐α −1031T/C, −863C/A, −857C/T, −308G/A, and −238G/A were genotyped using MALDI‐TOF mass spectrometry. Results TNF‐α −1031C and −863A alleles were observed more frequently in CHB group than in healthy controls. Carriers of TNF‐α −1031C and −863A variant alleles had lower baseline levels of serum HBV DNA and lower liver necroinflammatory activity than dominant homozygotes. A −857CT genotype predisposed to higher necroinflammatory activity. No associations between TNF‐α variants and liver fibrosis were found. Conclusion This study indicates that TNF‐α −863A and −1031C alleles are associated with increased susceptibility to CHB in individuals from northern Poland. The same variants determine the course of CHB, lowering viremia and reducing necroinflammatory activity of the liver

Caffeine and Other Methylxanthines as Interceptors of Food-Borne Aromatic Mutagens: Inhibition of Trp-P‑1 and Trp-P‑2 Mutagenic Activity

Caffeine is one of the most important biologically active food components. In this article, we demonstrate that caffeine and other methylxanthines significantly reduce the mutagenic activity of two food-derived heterocyclic aromatic amines, Trp-P-1 and Trp-P-2 in the <i>Salmonella typhimurium</i> TA98 strain. Moreover, protection against Trp-P-1-induced mutagenicity was independent of liver S9 enzymatic fraction, suggesting that mechanisms other than modulation of mutagen bioactivation can contribute to the observed protective effects. UV–vis spectroscopy and computational studies revealed that methylxanthines intercept Trp-P-1 and Trp-P-2 in noncovalent molecular complexes, with association constants (<i>K</i>_AC) in the 10² M^–1 range. Enthalpy values (Δ<i>H</i> about −30 kJ·mol^–1) of mutagen–methylxanthine heterocomplexation obtained microcalorimetrically correspond to stacking (π–π) interactions. Finally, we demonstrated that the biological activity of Trp-P-1 and Trp-P-2 is strictly dependent on the presence of the mutagen in a free (unbound with methylxanthine) form, suggesting that mutagen sequestration in stacking heterocomplexes with methylxanthines can decrease its bioavailability and diminish its biological effects