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Papers by Marta Rusek

International Journal of Molecular Sciences

Alzheimer’s disease is characterized by the accumulation of amyloid plaques and neurofibrillary t... more Alzheimer’s disease is characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. However, emerging evidence suggests that neuroinflammation, mediated notably by activated neuroglial cells, neutrophils, and macrophages, also plays an important role in the pathogenesis of Alzheimer’s disease. Therefore, understanding the interplay between the nervous and immune systems might be the key to the prevention or delay of Alzheimer’s disease progression. One of the most important mechanisms determining gliogenic cell fate is the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway that is influenced by the overactivation of microglia and astrocytes. The JAK/STAT signaling pathway is one of the critical factors that promote neuroinflammation in neurodegenerative diseases such as Alzheimer’s disease by initiating innate immunity, orchestrating adaptive immune mechanisms, and finally, constraining neuroinflammatory respo...

Cerebral Ischemia, 2021

Progressive accumulation of misfolded amyloid and tau protein in intracellular and extracellular ... more Progressive accumulation of misfolded amyloid and tau protein in intracellular and extracellular spaces is the most crucial etiopathological feature of brain ischemia, synaptic damage, or neural communication impairment. Clinical data suggest that dietary intake of curcumin enhances neurogenesis and offers neuroprotection. Curcumin is a natural polyphenolic compound with diverse and attractive biological properties. It may prevent aging-associated changes in cellular proteins, such as β-amyloid peptide and tau protein, that lead to protein insolubility and aggregation after ischemic brain damage. Therefore, curcumin seems to be a promising supplementary agent against neurodegeneration development after brain ischemia. The aim of this chapter is to highlight our current understanding of the neuroprotective role of curcumin in cerebral ischemia-reperfusion injury. The limitations and adverse events of curcumin are also presented.

Circulation, 2012

Background— The human 9p21.3 chromosome locus has been shown to be an independent risk factor for... more Background— The human 9p21.3 chromosome locus has been shown to be an independent risk factor for atherosclerosis in multiple large-scale genome-wide association studies, but the underlying mechanism remains unknown. We set out to investigate the potential role of the 9p21.3 locus neighboring genes, including Mtap , the 2 isoforms of Cdkn2a, p16Ink4a and p19Arf, and Cdkn2b , in atherosclerosis using knockout mice models. Methods and Results— Gene-targeted mice for neighboring genes, including Mtap , Cdkn2a , p19Arf , and Cdkn2b , were each bred to mice carrying the human APO*E3 Leiden transgene that sensitizes the mice for atherosclerotic lesions through elevated plasma cholesterol. We found that the mice heterozygous for Mtap developed larger lesions compared with wild-type mice (49623±21650 versus 18899±9604 μm 2 per section [mean±SD]; P =0.01), with morphology similar to that of wild-type mice. The Mtap heterozygous mice demonstrated changes in metabolic and methylation profiles ...

Atherosclerosis, 2011

Objective: Recent studies indicate that pravastatin improves whereas other statins impair glucose... more Objective: Recent studies indicate that pravastatin improves whereas other statins impair glucose homeostasis in humans, but the underlying mechanisms are not clear. We examined the effect of pravastatin and atorvastatin on insulin sensitivity in a rat model. Methods: Pravastatin (40 mg/kg/day) or atorvastatin (20 mg/kg/day) were administered for 3 weeks and insulin sensitivity was assessed by measuring fasting plasma insulin, HOMA-IR, non-esterified fatty acids (NEFA) and glycerol levels, as well as by the hyperinsulinemic euglycemic clamp. Results: Pravastatin had no effect on fasting insulin and HOMA-IR but significantly reduced plasma NEFA and glycerol levels and increased glucose infusion rate (GIR) during the hyperinsulinemic clamp. Increase in GIR induced by pravastatin was not abolished by NO synthase inhibitor, l-NAME, indicating that this effect did not result from the improvement of endothelial function. Atorvastatin increased fasting insulin, HOM-IR, NEFA and glycerol levels as well as reduced GIR. Statins had no effect on leptin, HMW adiponectin, resistin, visfatin, interleukin-6 and TNF-␣. Pravastatin increased plasma concentrations of 25-hydroxy-and 1,25-dyhydroxyvitamin D 3 (25-OH-D 3 and 1,25-(OH) 2-D 3), and its effect on insulin sensitivity was mimicked by exogenous 1,25-(OH) 2-D 3. Atorvastatin reduced plasma 25-OH-D 3 but had no effect on 1,25-(OH) 2-D 3. Decrease in insulin sensitivity induced by atorvastatin was not corrected by supplementation of vitamin D 3 despite normalization of plasma 25-OH-D 3 level. Conclusions: Pravastatin and atorvastatin have opposite effects on insulin sensitivity and vitamin D 3 status. Pravastatin-induced increase in insulin sensitivity is mediated by elevation of 1,25-(OH) 2-D 3. In contrast, atorvastatin-induced decrease in insulin sensitivity is independent of lowering 25-OH-D 3 .

Scientific Reports, 2020

Localized scleroderma (LoSc) is a rare disease manifested by an inflammation and sclerosis of the... more Localized scleroderma (LoSc) is a rare disease manifested by an inflammation and sclerosis of the skin. The latest studies focused on glycoprotein Krebs von den Lungen-6, surfactant protein-D, chemokine ligand 18 and dipeptidylpeptidase 4 as potential biomarkers of skin fibrosis in systemic scleroderma. Our study aimed to identify 6 miRNAs with elevated or decreased levels in 38 LoSc patients (31 females, 7 males) compared to healthy volunteers (HVs) and to correlate the selected miRNAs’ serum levels with the severity and the clinical symptoms of LoSc and some laboratory parameters with the selected miRNAs’ serum levels. The serum levels of miRNAs, i.e. miRNA-181b-5p, miRNA-223-3p, miRNA-21-5p, let 7i-5p, miRNA-29a-3p and miRNA-210-3p were significantly increased in the LoSc patients compared to the HVs. The level of let-7i increase in the female LoSc patients correlated negatively with BSA (r = − 0.355, p = 0.049) and mLoSSI (r = − 0.432, p = 0.015). Moreover, the female patients...

Polish Archives of Internal Medicine

This study documents for the first time that: (i) ANGPT2 rs2442598 polymorphism has a potentially... more This study documents for the first time that: (i) ANGPT2 rs2442598 polymorphism has a potentially strong association of higher risk of systemic sclerosis (SSc) in a population of Caucasian ancestry, and the CC variant may be a candidate genetic marker of SSc susceptibility; (ii) ANGPT2 rs3739390 genetic variants affect Angiopoietin 2 (Ang2) serum levels and are associated with certain clinical variables, including diffuse disease subtype (dcSSc) and risk of digital ulcers; (iii) ANGPT1 rs2507800 single nucleotide polymorphisms (SNPs) may significantly decrease the likelihood to develop dcSSc subtype. Hence, ANGPT2 and ANGPT1 may be considered as either disease-susceptibility or disease-modifying gene-variants in SSc with a possible, however yet unclear, pathogenic role. This preliminary study could provide reference information to drive subsequent studies on the larger cohort to better highlight the genetic function of ANGPT1/ANGPT2 polymorphisms in SSc, in particular potential role in early screening to predict the risk and course of the disease.

Genes

Epigenetic factors are heritable and ultimately play a role in modulating gene expression and, th... more Epigenetic factors are heritable and ultimately play a role in modulating gene expression and, thus, in regulating cell functions. Non-coding RNAs have growing recognition as novel biomarkers and crucial regulators of pathological conditions in humans. Their characteristic feature is being transcribed in a tissue-specific pattern. Now, there is emerging evidence that lncRNAs have been identified to be involved in the differentiation of human skin, wound healing, fibrosis, inflammation, and immunological response. Systemic sclerosis (SSc) is a heterogeneous autoimmune disease characterized by fibrosis, vascular abnormalities, and immune system activation. The pathogenesis remains elusive, but clinical manifestations reveal autoimmunity with the presence of specific autoantibodies, activation of innate and adaptive immunity, vascular changes, and active deposition of extracellular matrix components leading to fibrosis. The use of multi-omics studies, including NGS, RNA-seq, or GWAS, h...

Expert Review of Clinical Pharmacology

ABSTRACT Introduction: Comorbidities of epilepsy may significantly interfere with its treatment a... more ABSTRACT Introduction: Comorbidities of epilepsy may significantly interfere with its treatment as diseases in the general population are also encountered in epilepsy patients and some of them even more frequently (for instance, depression, anxiety, or heart disease). Obviously, some drugs approved for other than epilepsy indications can modify the anticonvulsant activity of antiepileptics. Areas covered: This review highlights the drug-drug interactions between antiepileptics and aminophylline, some antidepressant, antiarrhythmic (class I–IV), selected antihypertensive drugs and non-barbiturate injectable anesthetics (ketamine, propofol, etomidate, and alphaxalone). The data were reviewed mainly from experimental models of seizures. Whenever possible, clinical data were provided. PUBMED data base was the main search source.Expert opinion: Aminophylline generally reduced the protective activity of antiepileptics, which, to a certain degree, was consistent with scarce clinical data on methylxanthine derivatives and worse seizure control. The only antiarrhythmic with this profile of action was mexiletine when co-administered with VPA. Among antidepressants and non-barbiturate injectable anesthetics, trazodone, mianserin and etomidate or alphaxalone, respectively, negatively affected the anticonvulsant action of some antiepileptic drugs. Clinical data indicate that only amoxapine, bupropion, clomipramine and maprotiline should be used with caution. Possibly, drugs reducing the anticonvulsant potential of antiepileptics should be avoided in epilepsy patients.

Expert Opinion on Drug Metabolism & Toxicology

Scientific Reports

Systemic sclerosis (SSc) is a complex, heterogeneous connective tissue disease, characterized by ... more Systemic sclerosis (SSc) is a complex, heterogeneous connective tissue disease, characterized by fibrosis and ECM deposition in skin and internal organs, autoimmunity, and changes in the microvasculature. Profiling of circulating miRNAs in serum has been found to be changed in pathological states, creating new possibilities for molecular diagnostics as blood-based biomarkers. This study was designed to identify miRNAs that are differentially expressed in SSc and might be potentially contributing to the disease etiopathogenesis or be used for diagnostic purposes. Thus, we compared the expression pattern of multiple miRNAs in serum of 10 SSc patients to 6 healthy controls using microarray analysis, and RT-qPCR to confirm the obtained results. In addition, bioinformatics analysis was performed to explore miRNAs target genes and the signaling pathways that may be potentially involved in SSc pathogenesis. Our study shows a different expression of 15 miRNAs in SSc patients. We identified ...

International Journal of Molecular Sciences

At present, the prevalence of Alzheimer’s disease, a devastating neurodegenerative disorder, is i... more At present, the prevalence of Alzheimer’s disease, a devastating neurodegenerative disorder, is increasing. Although the mechanism of the underlying pathology is not fully uncovered, in the last years, there has been significant progress in its understanding. This includes: Progressive deposition of amyloid β-peptides in amyloid plaques and hyperphosphorylated tau protein in intracellular as neurofibrillary tangles; neuronal loss; and impaired glucose metabolism. Due to a lack of effective prevention and treatment strategy, emerging evidence suggests that dietary and metabolic interventions could potentially target these issues. The ketogenic diet is a very high-fat, low-carbohydrate diet, which has a fasting-like effect bringing the body into a state of ketosis. The presence of ketone bodies has a neuroprotective impact on aging brain cells. Moreover, their production may enhance mitochondrial function, reduce the expression of inflammatory and apoptotic mediators. Thus, it has gai...

Expert Opinion on Pharmacotherapy

Advances in Dermatology and Allergology

Introduction: Evidence has accumulated for the role of endothelial damage in systemic sclerosis (... more Introduction: Evidence has accumulated for the role of endothelial damage in systemic sclerosis (SSc) and the antiendothelial cell antibodies (AECAs) might underlie vascular injury. Aim: Since endothelial microparticles (EMPs) and circulating endothelial cells (CECs) reflect endothelial damage, we aimed to investigate their possible relationship with AECAs in SSc. We examined whether AECAs could affect endothelial repair based on the number of endothelial progenitor cells (EPCs). Material and methods: Forty-seven SSc patients were screened. The AECAs were identified in serum by indirect immunofluorescence. EPCs and CECs were isolated from the peripheral blood using anti-CD34-based immunomagnetic separation, whereas EMPs were analyzed in plasma. Flow cytometry was used to quantify EMPs, CECs and EPCs. Results: AECAs were found in 21 (44.7%) SSc patients and were significantly associated with higher levels of total as well as apoptotic (AnnV+ and CD51+) EMPs, whereas activated (CD62E+/AnnV-) EMPs did not differ between groups. Patients with AECAs had significantly elevated total CECs as well as activated CD105+ CECs. Total endothelial progenitors did not differ between patients with or without AECAs; however AECAs was negatively associated with the population of EPCs that express VEGFR2 or Tie2 receptors. Conclusions: We found an association between AECAs and the severity of endothelial damage in SSc based on higher levels of total EMPs and CECs. In our study, AECAs were associated with apoptosis of ECs rather than their activation. We also identified a possible role of AECAs in the impairment of vascular repair in SSc as evidenced by significantly fewer angiogenic EPCs.

European Journal of Pharmacology

The FASEB Journal, 2016

Cystathionine β-synthase (CBS) deficiency, a genetic disorder in homocysteine (Hcy) metabolism in... more Cystathionine β-synthase (CBS) deficiency, a genetic disorder in homocysteine (Hcy) metabolism in humans, elevates plasma Hcy-thiolactone and leads to connective tissue abnormalities affecting cardiovascular and skeletal systems. However, the underlying mechanism of these abnormalities is not understood. Hcy-thiolactone has the ability to form isopeptide bonds with protein lysine residues, which generates N-homocysteinylated protein. Because lysine residues are involved in collagen crosslinking, N-homocysteinylation of these lysines should impair crosslinking. Using a Tg-I278T Cbs-/mouse model of hyperhomocysteinamia (HHcy) that recapitulates connective tissue abnormalities observed in CBS-deficient patients, we show that N-Hcy-collagen was elevated in bone, tail, and heart of Cbs-/mice, while pyridinoline crosslinks were significantly reduced. Plasma deoxypyridinoline crosslink and crosslinked carboxyterminal telopeptide of type I collagen were also significantly reduced in Cbs-/mice. Lysine oxidase activity and mRNA level were not reduced by the Cbs-/genotype. We also show that collagen carries S-linked Hcy bound to the thiol of N-linked Hcy. In vitro experiments show that Hcy-thiolactone modifies lysine residues in collagen type I alpha-1 chain. Residue K160, located in the non-helical N-telopeptide region and involved in pyridinoline crosslink formation, was also N-homocysteinylated in vivo. Taken together, our findings show that Nhomocysteinylation of collagen in Cbs-/mice impairs its crosslinking. These findings explain at least in part connective tissue abnormalities observed in HHcy.

Chemico-Biological Interactions, 2016

Bisphosphonates are potent antiresorptive agents commonly used in the treatment of osteoporosis. ... more Bisphosphonates are potent antiresorptive agents commonly used in the treatment of osteoporosis. As osteoporosis and atherosclerosis share some common risk factors and frequently coexist in the same patients, we examined the effect of bisphosphonates on paraoxonase 1 (PON1) - the high density lipoprotein-associated enzyme with potent anti-atherosclerotic activity. Bisphosphonates were administered orally to male adult rats for 4 weeks and then PON1 activity and some related biochemical parameters were measured in plasma. Clodronate, alendronate, ibandronate and pamidronate reduced PON1 activity toward synthetic (paraoxon, phenyl acetate) and natural (homocysteine thiolactone) substrates. The most marked effect was observed in animals receiving ibandronate. In contrast, risedronate increased PON1 activity toward these 3 substrates and zoledronate increased PON1 activity toward phenyl acetate but had no effect on its activity toward paraoxon and homocysteine thiolactone. Bisphosphonates had no effect on total plasma homocysteine and protein-bound homocysteine thiolactone. In addition, total plasma cholesterol, HDL-cholesterol, plasma triglycerides and alanine aminotransferase activity did not differ between groups. Bisphosphonates have differential effects on PON1 activity. Risedronate could be particularly useful in patients with high cardiovascular risk and PON1 deficiency. Bisphosphonates have no effect on plasma homocysteine and protein N-homocysteinylation as well as on the lipid profile.

Chemico-Biological Interactions, 2016

Highly active antiretroviral therapy (HAART), especially protease inhibitors (PIs), commonly used... more Highly active antiretroviral therapy (HAART), especially protease inhibitors (PIs), commonly used in HIV-infected patients, effectively suppresses a viral replication. However, it is frequently associated with significant side effects, including fat redistribution, lipodystrophy, hyperlipidemia, insulin resistance and diabetes mellitus. Currently, metabolic complications and atherosclerosis resulting from them become the major cause of mortality in HIV-infected patients receiving HAART. Paraoxonase 1 (PON1) is the HDL-bound esterase, which inhibits development of atherosclerosis by decomposing lipid peroxidation products and hydrolyzing homocysteine thiolactone. The aim of this study was to characterize the effects of HIV protease inhibitors on PON1 activity, total plasma homocysteine and protein-bound homocysteine thiolactone as well as lipid profile in rats. The study was performed on seven groups of male Wistar rats: (1) control; (2) and (3) receiving ritonavir (RTV) at doses of 10 and 50 mg/kg, respectively; (4) and (5) receiving atazanavir (ATV) at 10 and 100 mg/kg, respectively; (6) and (7) receiving saquinavir (SQV) at 10 and 50 mg/kg, respectively. All drugs were administered orally for 4 weeks. Compared to control animals, rats receiving PIs had significantly higher concentration of triglycerides and total cholesterol, but the levels of HDL-cholesterol were not different between groups. PON1 activity toward paraoxon was decreased in groups receiving PIs (control: 149 ± 5 U/ml; PIs-treated: RTV at doses 10 mg/kg 133 ± 9.5 U/ml, RTV at doses 50 mg/kg 134 ± 10.8 U/ml, SQV at doses 10 mg/kg 131 ± 9.2 U/ml, ATV at doses 10 mg/kg 132 ± 11.8 U/ml, ATV at doses 100 mg/kg 108 ± 7.8 U/ml). ATV reduced total homocysteine level around 25-28%, whereas other PIs had no effect on its concentration. In contrast, 10-15% increase in protein-bound homocysteine thiolactone was observed in PIs-receiving groups, such as RTV10, RTV50, SQV50, ATV10. In conclusion, dyslipidemia induced by PIs is associated with reduced PON1 activity as well as increased protein homocysteinylation. PON1 deficiency may contribute to increased risk of atherosclerosis in these patients.

Chemico-Biological Interactions, 2016

Highly active antiretroviral therapy (HAART), especially protease inhibitors (PIs), commonly used... more Highly active antiretroviral therapy (HAART), especially protease inhibitors (PIs), commonly used in HIV-infected patients, effectively suppresses a viral replication. However, it is frequently associated with significant side effects, including fat redistribution, lipodystrophy, hyperlipidemia, insulin resistance and diabetes mellitus. Currently, metabolic complications and atherosclerosis resulting from them become the major cause of mortality in HIV-infected patients receiving HAART. Paraoxonase 1 (PON1) is the HDL-bound esterase, which inhibits development of atherosclerosis by decomposing lipid peroxidation products and hydrolyzing homocysteine thiolactone. The aim of this study was to characterize the effects of HIV protease inhibitors on PON1 activity, total plasma homocysteine and protein-bound homocysteine thiolactone as well as lipid profile in rats. The study was performed on seven groups of male Wistar rats: (1) control; (2) and (3) receiving ritonavir (RTV) at doses of 10 and 50 mg/kg, respectively; (4) and (5) receiving atazanavir (ATV) at 10 and 100 mg/kg, respectively; (6) and (7) receiving saquinavir (SQV) at 10 and 50 mg/kg, respectively. All drugs were administered orally for 4 weeks. Compared to control animals, rats receiving PIs had significantly higher concentration of triglycerides and total cholesterol, but the levels of HDL-cholesterol were not different between groups. PON1 activity toward paraoxon was decreased in groups receiving PIs (control: 149 ± 5 U/ml; PIs-treated: RTV at doses 10 mg/kg 133 ± 9.5 U/ml, RTV at doses 50 mg/kg 134 ± 10.8 U/ml, SQV at doses 10 mg/kg 131 ± 9.2 U/ml, ATV at doses 10 mg/kg 132 ± 11.8 U/ml, ATV at doses 100 mg/kg 108 ± 7.8 U/ml). ATV reduced total homocysteine level around 25-28%, whereas other PIs had no effect on its concentration. In contrast, 10-15% increase in protein-bound homocysteine thiolactone was observed in PIs-receiving groups, such as RTV10, RTV50, SQV50, ATV10. In conclusion, dyslipidemia induced by PIs is associated with reduced PON1 activity as well as increased protein homocysteinylation. PON1 deficiency may contribute to increased risk of atherosclerosis in these patients.

International Journal of Molecular Sciences

Alzheimer’s disease is characterized by the accumulation of amyloid plaques and neurofibrillary t... more Alzheimer’s disease is characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. However, emerging evidence suggests that neuroinflammation, mediated notably by activated neuroglial cells, neutrophils, and macrophages, also plays an important role in the pathogenesis of Alzheimer’s disease. Therefore, understanding the interplay between the nervous and immune systems might be the key to the prevention or delay of Alzheimer’s disease progression. One of the most important mechanisms determining gliogenic cell fate is the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway that is influenced by the overactivation of microglia and astrocytes. The JAK/STAT signaling pathway is one of the critical factors that promote neuroinflammation in neurodegenerative diseases such as Alzheimer’s disease by initiating innate immunity, orchestrating adaptive immune mechanisms, and finally, constraining neuroinflammatory respo...

Cerebral Ischemia, 2021

Progressive accumulation of misfolded amyloid and tau protein in intracellular and extracellular ... more Progressive accumulation of misfolded amyloid and tau protein in intracellular and extracellular spaces is the most crucial etiopathological feature of brain ischemia, synaptic damage, or neural communication impairment. Clinical data suggest that dietary intake of curcumin enhances neurogenesis and offers neuroprotection. Curcumin is a natural polyphenolic compound with diverse and attractive biological properties. It may prevent aging-associated changes in cellular proteins, such as β-amyloid peptide and tau protein, that lead to protein insolubility and aggregation after ischemic brain damage. Therefore, curcumin seems to be a promising supplementary agent against neurodegeneration development after brain ischemia. The aim of this chapter is to highlight our current understanding of the neuroprotective role of curcumin in cerebral ischemia-reperfusion injury. The limitations and adverse events of curcumin are also presented.

Circulation, 2012

Background— The human 9p21.3 chromosome locus has been shown to be an independent risk factor for... more Background— The human 9p21.3 chromosome locus has been shown to be an independent risk factor for atherosclerosis in multiple large-scale genome-wide association studies, but the underlying mechanism remains unknown. We set out to investigate the potential role of the 9p21.3 locus neighboring genes, including Mtap , the 2 isoforms of Cdkn2a, p16Ink4a and p19Arf, and Cdkn2b , in atherosclerosis using knockout mice models. Methods and Results— Gene-targeted mice for neighboring genes, including Mtap , Cdkn2a , p19Arf , and Cdkn2b , were each bred to mice carrying the human APO*E3 Leiden transgene that sensitizes the mice for atherosclerotic lesions through elevated plasma cholesterol. We found that the mice heterozygous for Mtap developed larger lesions compared with wild-type mice (49623±21650 versus 18899±9604 μm 2 per section [mean±SD]; P =0.01), with morphology similar to that of wild-type mice. The Mtap heterozygous mice demonstrated changes in metabolic and methylation profiles ...

Atherosclerosis, 2011

Objective: Recent studies indicate that pravastatin improves whereas other statins impair glucose... more Objective: Recent studies indicate that pravastatin improves whereas other statins impair glucose homeostasis in humans, but the underlying mechanisms are not clear. We examined the effect of pravastatin and atorvastatin on insulin sensitivity in a rat model. Methods: Pravastatin (40 mg/kg/day) or atorvastatin (20 mg/kg/day) were administered for 3 weeks and insulin sensitivity was assessed by measuring fasting plasma insulin, HOMA-IR, non-esterified fatty acids (NEFA) and glycerol levels, as well as by the hyperinsulinemic euglycemic clamp. Results: Pravastatin had no effect on fasting insulin and HOMA-IR but significantly reduced plasma NEFA and glycerol levels and increased glucose infusion rate (GIR) during the hyperinsulinemic clamp. Increase in GIR induced by pravastatin was not abolished by NO synthase inhibitor, l-NAME, indicating that this effect did not result from the improvement of endothelial function. Atorvastatin increased fasting insulin, HOM-IR, NEFA and glycerol levels as well as reduced GIR. Statins had no effect on leptin, HMW adiponectin, resistin, visfatin, interleukin-6 and TNF-␣. Pravastatin increased plasma concentrations of 25-hydroxy-and 1,25-dyhydroxyvitamin D 3 (25-OH-D 3 and 1,25-(OH) 2-D 3), and its effect on insulin sensitivity was mimicked by exogenous 1,25-(OH) 2-D 3. Atorvastatin reduced plasma 25-OH-D 3 but had no effect on 1,25-(OH) 2-D 3. Decrease in insulin sensitivity induced by atorvastatin was not corrected by supplementation of vitamin D 3 despite normalization of plasma 25-OH-D 3 level. Conclusions: Pravastatin and atorvastatin have opposite effects on insulin sensitivity and vitamin D 3 status. Pravastatin-induced increase in insulin sensitivity is mediated by elevation of 1,25-(OH) 2-D 3. In contrast, atorvastatin-induced decrease in insulin sensitivity is independent of lowering 25-OH-D 3 .

Scientific Reports, 2020

Localized scleroderma (LoSc) is a rare disease manifested by an inflammation and sclerosis of the... more Localized scleroderma (LoSc) is a rare disease manifested by an inflammation and sclerosis of the skin. The latest studies focused on glycoprotein Krebs von den Lungen-6, surfactant protein-D, chemokine ligand 18 and dipeptidylpeptidase 4 as potential biomarkers of skin fibrosis in systemic scleroderma. Our study aimed to identify 6 miRNAs with elevated or decreased levels in 38 LoSc patients (31 females, 7 males) compared to healthy volunteers (HVs) and to correlate the selected miRNAs’ serum levels with the severity and the clinical symptoms of LoSc and some laboratory parameters with the selected miRNAs’ serum levels. The serum levels of miRNAs, i.e. miRNA-181b-5p, miRNA-223-3p, miRNA-21-5p, let 7i-5p, miRNA-29a-3p and miRNA-210-3p were significantly increased in the LoSc patients compared to the HVs. The level of let-7i increase in the female LoSc patients correlated negatively with BSA (r = − 0.355, p = 0.049) and mLoSSI (r = − 0.432, p = 0.015). Moreover, the female patients...

Polish Archives of Internal Medicine

This study documents for the first time that: (i) ANGPT2 rs2442598 polymorphism has a potentially... more This study documents for the first time that: (i) ANGPT2 rs2442598 polymorphism has a potentially strong association of higher risk of systemic sclerosis (SSc) in a population of Caucasian ancestry, and the CC variant may be a candidate genetic marker of SSc susceptibility; (ii) ANGPT2 rs3739390 genetic variants affect Angiopoietin 2 (Ang2) serum levels and are associated with certain clinical variables, including diffuse disease subtype (dcSSc) and risk of digital ulcers; (iii) ANGPT1 rs2507800 single nucleotide polymorphisms (SNPs) may significantly decrease the likelihood to develop dcSSc subtype. Hence, ANGPT2 and ANGPT1 may be considered as either disease-susceptibility or disease-modifying gene-variants in SSc with a possible, however yet unclear, pathogenic role. This preliminary study could provide reference information to drive subsequent studies on the larger cohort to better highlight the genetic function of ANGPT1/ANGPT2 polymorphisms in SSc, in particular potential role in early screening to predict the risk and course of the disease.

Genes

Epigenetic factors are heritable and ultimately play a role in modulating gene expression and, th... more Epigenetic factors are heritable and ultimately play a role in modulating gene expression and, thus, in regulating cell functions. Non-coding RNAs have growing recognition as novel biomarkers and crucial regulators of pathological conditions in humans. Their characteristic feature is being transcribed in a tissue-specific pattern. Now, there is emerging evidence that lncRNAs have been identified to be involved in the differentiation of human skin, wound healing, fibrosis, inflammation, and immunological response. Systemic sclerosis (SSc) is a heterogeneous autoimmune disease characterized by fibrosis, vascular abnormalities, and immune system activation. The pathogenesis remains elusive, but clinical manifestations reveal autoimmunity with the presence of specific autoantibodies, activation of innate and adaptive immunity, vascular changes, and active deposition of extracellular matrix components leading to fibrosis. The use of multi-omics studies, including NGS, RNA-seq, or GWAS, h...

Expert Review of Clinical Pharmacology

ABSTRACT Introduction: Comorbidities of epilepsy may significantly interfere with its treatment a... more ABSTRACT Introduction: Comorbidities of epilepsy may significantly interfere with its treatment as diseases in the general population are also encountered in epilepsy patients and some of them even more frequently (for instance, depression, anxiety, or heart disease). Obviously, some drugs approved for other than epilepsy indications can modify the anticonvulsant activity of antiepileptics. Areas covered: This review highlights the drug-drug interactions between antiepileptics and aminophylline, some antidepressant, antiarrhythmic (class I–IV), selected antihypertensive drugs and non-barbiturate injectable anesthetics (ketamine, propofol, etomidate, and alphaxalone). The data were reviewed mainly from experimental models of seizures. Whenever possible, clinical data were provided. PUBMED data base was the main search source.Expert opinion: Aminophylline generally reduced the protective activity of antiepileptics, which, to a certain degree, was consistent with scarce clinical data on methylxanthine derivatives and worse seizure control. The only antiarrhythmic with this profile of action was mexiletine when co-administered with VPA. Among antidepressants and non-barbiturate injectable anesthetics, trazodone, mianserin and etomidate or alphaxalone, respectively, negatively affected the anticonvulsant action of some antiepileptic drugs. Clinical data indicate that only amoxapine, bupropion, clomipramine and maprotiline should be used with caution. Possibly, drugs reducing the anticonvulsant potential of antiepileptics should be avoided in epilepsy patients.

Expert Opinion on Drug Metabolism & Toxicology

Scientific Reports

Systemic sclerosis (SSc) is a complex, heterogeneous connective tissue disease, characterized by ... more Systemic sclerosis (SSc) is a complex, heterogeneous connective tissue disease, characterized by fibrosis and ECM deposition in skin and internal organs, autoimmunity, and changes in the microvasculature. Profiling of circulating miRNAs in serum has been found to be changed in pathological states, creating new possibilities for molecular diagnostics as blood-based biomarkers. This study was designed to identify miRNAs that are differentially expressed in SSc and might be potentially contributing to the disease etiopathogenesis or be used for diagnostic purposes. Thus, we compared the expression pattern of multiple miRNAs in serum of 10 SSc patients to 6 healthy controls using microarray analysis, and RT-qPCR to confirm the obtained results. In addition, bioinformatics analysis was performed to explore miRNAs target genes and the signaling pathways that may be potentially involved in SSc pathogenesis. Our study shows a different expression of 15 miRNAs in SSc patients. We identified ...

International Journal of Molecular Sciences

At present, the prevalence of Alzheimer’s disease, a devastating neurodegenerative disorder, is i... more At present, the prevalence of Alzheimer’s disease, a devastating neurodegenerative disorder, is increasing. Although the mechanism of the underlying pathology is not fully uncovered, in the last years, there has been significant progress in its understanding. This includes: Progressive deposition of amyloid β-peptides in amyloid plaques and hyperphosphorylated tau protein in intracellular as neurofibrillary tangles; neuronal loss; and impaired glucose metabolism. Due to a lack of effective prevention and treatment strategy, emerging evidence suggests that dietary and metabolic interventions could potentially target these issues. The ketogenic diet is a very high-fat, low-carbohydrate diet, which has a fasting-like effect bringing the body into a state of ketosis. The presence of ketone bodies has a neuroprotective impact on aging brain cells. Moreover, their production may enhance mitochondrial function, reduce the expression of inflammatory and apoptotic mediators. Thus, it has gai...

Expert Opinion on Pharmacotherapy

Advances in Dermatology and Allergology

Introduction: Evidence has accumulated for the role of endothelial damage in systemic sclerosis (... more Introduction: Evidence has accumulated for the role of endothelial damage in systemic sclerosis (SSc) and the antiendothelial cell antibodies (AECAs) might underlie vascular injury. Aim: Since endothelial microparticles (EMPs) and circulating endothelial cells (CECs) reflect endothelial damage, we aimed to investigate their possible relationship with AECAs in SSc. We examined whether AECAs could affect endothelial repair based on the number of endothelial progenitor cells (EPCs). Material and methods: Forty-seven SSc patients were screened. The AECAs were identified in serum by indirect immunofluorescence. EPCs and CECs were isolated from the peripheral blood using anti-CD34-based immunomagnetic separation, whereas EMPs were analyzed in plasma. Flow cytometry was used to quantify EMPs, CECs and EPCs. Results: AECAs were found in 21 (44.7%) SSc patients and were significantly associated with higher levels of total as well as apoptotic (AnnV+ and CD51+) EMPs, whereas activated (CD62E+/AnnV-) EMPs did not differ between groups. Patients with AECAs had significantly elevated total CECs as well as activated CD105+ CECs. Total endothelial progenitors did not differ between patients with or without AECAs; however AECAs was negatively associated with the population of EPCs that express VEGFR2 or Tie2 receptors. Conclusions: We found an association between AECAs and the severity of endothelial damage in SSc based on higher levels of total EMPs and CECs. In our study, AECAs were associated with apoptosis of ECs rather than their activation. We also identified a possible role of AECAs in the impairment of vascular repair in SSc as evidenced by significantly fewer angiogenic EPCs.

European Journal of Pharmacology

The FASEB Journal, 2016

Cystathionine β-synthase (CBS) deficiency, a genetic disorder in homocysteine (Hcy) metabolism in... more Cystathionine β-synthase (CBS) deficiency, a genetic disorder in homocysteine (Hcy) metabolism in humans, elevates plasma Hcy-thiolactone and leads to connective tissue abnormalities affecting cardiovascular and skeletal systems. However, the underlying mechanism of these abnormalities is not understood. Hcy-thiolactone has the ability to form isopeptide bonds with protein lysine residues, which generates N-homocysteinylated protein. Because lysine residues are involved in collagen crosslinking, N-homocysteinylation of these lysines should impair crosslinking. Using a Tg-I278T Cbs-/mouse model of hyperhomocysteinamia (HHcy) that recapitulates connective tissue abnormalities observed in CBS-deficient patients, we show that N-Hcy-collagen was elevated in bone, tail, and heart of Cbs-/mice, while pyridinoline crosslinks were significantly reduced. Plasma deoxypyridinoline crosslink and crosslinked carboxyterminal telopeptide of type I collagen were also significantly reduced in Cbs-/mice. Lysine oxidase activity and mRNA level were not reduced by the Cbs-/genotype. We also show that collagen carries S-linked Hcy bound to the thiol of N-linked Hcy. In vitro experiments show that Hcy-thiolactone modifies lysine residues in collagen type I alpha-1 chain. Residue K160, located in the non-helical N-telopeptide region and involved in pyridinoline crosslink formation, was also N-homocysteinylated in vivo. Taken together, our findings show that Nhomocysteinylation of collagen in Cbs-/mice impairs its crosslinking. These findings explain at least in part connective tissue abnormalities observed in HHcy.

Chemico-Biological Interactions, 2016

Bisphosphonates are potent antiresorptive agents commonly used in the treatment of osteoporosis. ... more Bisphosphonates are potent antiresorptive agents commonly used in the treatment of osteoporosis. As osteoporosis and atherosclerosis share some common risk factors and frequently coexist in the same patients, we examined the effect of bisphosphonates on paraoxonase 1 (PON1) - the high density lipoprotein-associated enzyme with potent anti-atherosclerotic activity. Bisphosphonates were administered orally to male adult rats for 4 weeks and then PON1 activity and some related biochemical parameters were measured in plasma. Clodronate, alendronate, ibandronate and pamidronate reduced PON1 activity toward synthetic (paraoxon, phenyl acetate) and natural (homocysteine thiolactone) substrates. The most marked effect was observed in animals receiving ibandronate. In contrast, risedronate increased PON1 activity toward these 3 substrates and zoledronate increased PON1 activity toward phenyl acetate but had no effect on its activity toward paraoxon and homocysteine thiolactone. Bisphosphonates had no effect on total plasma homocysteine and protein-bound homocysteine thiolactone. In addition, total plasma cholesterol, HDL-cholesterol, plasma triglycerides and alanine aminotransferase activity did not differ between groups. Bisphosphonates have differential effects on PON1 activity. Risedronate could be particularly useful in patients with high cardiovascular risk and PON1 deficiency. Bisphosphonates have no effect on plasma homocysteine and protein N-homocysteinylation as well as on the lipid profile.

Chemico-Biological Interactions, 2016

Highly active antiretroviral therapy (HAART), especially protease inhibitors (PIs), commonly used... more Highly active antiretroviral therapy (HAART), especially protease inhibitors (PIs), commonly used in HIV-infected patients, effectively suppresses a viral replication. However, it is frequently associated with significant side effects, including fat redistribution, lipodystrophy, hyperlipidemia, insulin resistance and diabetes mellitus. Currently, metabolic complications and atherosclerosis resulting from them become the major cause of mortality in HIV-infected patients receiving HAART. Paraoxonase 1 (PON1) is the HDL-bound esterase, which inhibits development of atherosclerosis by decomposing lipid peroxidation products and hydrolyzing homocysteine thiolactone. The aim of this study was to characterize the effects of HIV protease inhibitors on PON1 activity, total plasma homocysteine and protein-bound homocysteine thiolactone as well as lipid profile in rats. The study was performed on seven groups of male Wistar rats: (1) control; (2) and (3) receiving ritonavir (RTV) at doses of 10 and 50 mg/kg, respectively; (4) and (5) receiving atazanavir (ATV) at 10 and 100 mg/kg, respectively; (6) and (7) receiving saquinavir (SQV) at 10 and 50 mg/kg, respectively. All drugs were administered orally for 4 weeks. Compared to control animals, rats receiving PIs had significantly higher concentration of triglycerides and total cholesterol, but the levels of HDL-cholesterol were not different between groups. PON1 activity toward paraoxon was decreased in groups receiving PIs (control: 149 ± 5 U/ml; PIs-treated: RTV at doses 10 mg/kg 133 ± 9.5 U/ml, RTV at doses 50 mg/kg 134 ± 10.8 U/ml, SQV at doses 10 mg/kg 131 ± 9.2 U/ml, ATV at doses 10 mg/kg 132 ± 11.8 U/ml, ATV at doses 100 mg/kg 108 ± 7.8 U/ml). ATV reduced total homocysteine level around 25-28%, whereas other PIs had no effect on its concentration. In contrast, 10-15% increase in protein-bound homocysteine thiolactone was observed in PIs-receiving groups, such as RTV10, RTV50, SQV50, ATV10. In conclusion, dyslipidemia induced by PIs is associated with reduced PON1 activity as well as increased protein homocysteinylation. PON1 deficiency may contribute to increased risk of atherosclerosis in these patients.

Chemico-Biological Interactions, 2016

Highly active antiretroviral therapy (HAART), especially protease inhibitors (PIs), commonly used... more Highly active antiretroviral therapy (HAART), especially protease inhibitors (PIs), commonly used in HIV-infected patients, effectively suppresses a viral replication. However, it is frequently associated with significant side effects, including fat redistribution, lipodystrophy, hyperlipidemia, insulin resistance and diabetes mellitus. Currently, metabolic complications and atherosclerosis resulting from them become the major cause of mortality in HIV-infected patients receiving HAART. Paraoxonase 1 (PON1) is the HDL-bound esterase, which inhibits development of atherosclerosis by decomposing lipid peroxidation products and hydrolyzing homocysteine thiolactone. The aim of this study was to characterize the effects of HIV protease inhibitors on PON1 activity, total plasma homocysteine and protein-bound homocysteine thiolactone as well as lipid profile in rats. The study was performed on seven groups of male Wistar rats: (1) control; (2) and (3) receiving ritonavir (RTV) at doses of 10 and 50 mg/kg, respectively; (4) and (5) receiving atazanavir (ATV) at 10 and 100 mg/kg, respectively; (6) and (7) receiving saquinavir (SQV) at 10 and 50 mg/kg, respectively. All drugs were administered orally for 4 weeks. Compared to control animals, rats receiving PIs had significantly higher concentration of triglycerides and total cholesterol, but the levels of HDL-cholesterol were not different between groups. PON1 activity toward paraoxon was decreased in groups receiving PIs (control: 149 ± 5 U/ml; PIs-treated: RTV at doses 10 mg/kg 133 ± 9.5 U/ml, RTV at doses 50 mg/kg 134 ± 10.8 U/ml, SQV at doses 10 mg/kg 131 ± 9.2 U/ml, ATV at doses 10 mg/kg 132 ± 11.8 U/ml, ATV at doses 100 mg/kg 108 ± 7.8 U/ml). ATV reduced total homocysteine level around 25-28%, whereas other PIs had no effect on its concentration. In contrast, 10-15% increase in protein-bound homocysteine thiolactone was observed in PIs-receiving groups, such as RTV10, RTV50, SQV50, ATV10. In conclusion, dyslipidemia induced by PIs is associated with reduced PON1 activity as well as increased protein homocysteinylation. PON1 deficiency may contribute to increased risk of atherosclerosis in these patients.