NRF2 regulates viability, proliferation, resistance to oxidative stress, and differentiation of murine myoblasts and muscle satellite cells

Increased oxidative stress can slow down the regeneration of skeletal muscle and affect the activity of muscle satellite cells (mSCs). Therefore, we evaluated the role of the NRF2 transcription factor (encoded by the Nfe2l2 gene), the main regulator of the antioxidant response, in muscle cell biology. We used (i) an immortalized murine myoblast cell line (C2C12) with stable overexpression of NRF2 and (ii) primary mSCs isolated from wild-type and Nfe2l2 (transcriptionally)-deficient mice (Nfe2l2$^{tKO}$). NRF2 promoted myoblast proliferation and viability under oxidative stress conditions and decreased the production of reactive oxygen species. Furthermore, NRF2 overexpression inhibited C2C12 cell differentiation by down-regulating the expression of myogenic regulatory factors (MRFs) and muscle-specific microRNAs. We also showed that NRF2 is indispensable for the viability of mSCs since the lack of its transcriptional activity caused high mortality of cells cultured in vitro under normoxic conditions. Concomitantly, Nfe2l2$^{tKO}$ mSCs grown and differentiated under hypoxic conditions were viable and much more differentiated compared to cells isolated from wild-type mice. Taken together, NRF2 significantly influences the properties of myoblasts and muscle satellite cells. This effect might be modulated by the muscle microenvironment

Effect of heme oxygenase-1 on the differentiation of human myoblasts and the regeneration of murine skeletal muscles after acute and chronic injury

Background Impaired muscle regeneration is a hallmark of Duchenne muscular dystrophy (DMD), a neuromuscular disorder caused by mutations in the DMD gene encoding dystrophin. The lack of heme oxygenase-1 (HO-1, Hmox1), a known anti-inflammatory and cytoprotective enzyme, was shown to aggravate DMD pathology. Methods We evaluated the role of HO-1 overexpression in human induced pluripotent stem cell (hiPSC)-derived skeletal muscle cells (hiPSC-SkM) in vitro and in the regeneration process in vivo in wild-type mice. Furthermore, the effect of cobalt protoporphyrin IX (CoPP), a pharmacological inducer of HO-1 expression, on regeneration markers during myogenic hiPSC differentiation and progression of the dystrophic phenotype was analysed in the mdx mouse DMD model. Results HO-1 has an impact on hiPSC-SkM generation by decreasing cell fusion capacity and the expression of myogenic regulatory factors and muscle-specific microRNAs (myomiRs). Also, strong induction of HO-1 by CoPP totally abolished hiPSC-SkM differentiation. Injection of HO-1-overexpressing hiPSC-SkM into the cardiotoxin (CTX)-injured muscle of immunodeficient wild-type mice was associated with decreased expression of miR-206 and Myh3 and lower number of regenerating fibers, suggesting some advanced regeneration. However, the very potent induction of HO-1 by CoPP did not exert any protective effect on necrosis, leukocyte infiltration, fibrosis, myofiber regeneration biomarkers, and exercise capacity of mdx mice. Conclusions In summary, HO-1 inhibits the expression of differentiation markers in human iPSC-derived myoblasts. Although moderate overexpression of HO-1 in the injected myoblast was associated with partially advanced muscle regeneration, the high systemic induction of HO-1 did not improve muscle regeneration. The appropriate threshold of HO-1 expression must be established for the therapeutic effect of HO-1 on muscle regeneration

The incidence of risk factors of type 2 diabetes mellitus in relatives of the patients

WSTĘP. Celem niniejszej pracy była ocena występowania zaburzeń gospodarki węglowodanowej u krewnych I stopnia chorych na cukrzycę typu 2 zależnie od obecności innych czynników ryzyka tej choroby. MATERIAŁ I METODY. Ocenianą grupę tworzyło 42 krewnych I stopnia chorych leczonych w Przyklinicznej Poradni Diabetologicznej Szpitala Uniwersyteckiego w Bydgoszczy. Przeprowadzano badanie podmiotowe, przedmiotowe oraz test doustnego obciążenia 75 g glukozy. WYNIKI. U 13 osób (31%) rozpoznano zaburzenia gospodarki węglowodanowej (grupa ZGW), zaś u 29 ich nie stwierdzono (grupa BZGW). Badani z grupy ZGW byli istotnie statystycznie starsi od osób z grupy BZGW (59,8 &#177; 14,6 vs. 37,8 &#177; 15,5 roku; p < 0,001), cechowały ich znamiennie większe rodzinne obciążenie cukrzycą typu 2 (2,0 &#177; 1,1 vs. 1,1 &#177; 0,4; p < 0,001 - liczba krewnych w rodzinie) i istotnie wyższa liczba czynników ryzyka choroby (2,9 &#177; 1,2 vs. 2,0 &#177; 1,2; p < 0,01). Najczęstsze, istotne statystycznie okazało się występowanie w wywiadzie nieprawidłowego stężenia glukozy we krwi - 61,5% (BZGW - 6,9%). Obie grupy nie różniły się pod względem liczby chorych rodziców, natomiast rodzeństwo chore na cukrzycę miało 92,3% osób z grupy ZGW i tylko 13,8% z grupy BZGW. Przynajmniej jedno dziecko chore na cukrzycę miało 23% osób z grupy ZGW, natomiast nikt z BZGW. Nie wykazano istotnych różnic między grupami odnośnie wskaźnika masy ciała (28,3 &#177; &#177; 4,5 kg/m2 vs. 25,9 &#177; 4,9 kg/m2) oraz wskaźnika talia- biodro (0,86 &#177; 0,08 vs. 0,83 &#177; 0,07, odpowiednio). Cukrzyca ciążowa wystąpiła u 7,7% vs. 6,9% badanych, urodzenie dziecka z masą ciała powyżej 4000 g dotyczyło 7,7% versus 11,9%, a zespół policystycznych jajników stwierdzono u 7,7% versus 3,4%. WNIOSKI. U krewnych I stopnia chorych na cukrzycę typu 2 wystąpienie zaburzeń gospodarki węglowodanowej zależało od: wieku, sumy czynników ryzyka cukrzycy, a zwłaszcza stwierdzenia nieprawidłowych wartości glikemii w wywiadzie, liczby krewnych chorych na cukrzycę typu 2, w szczególności chorego rodzeństwa i dzieci.INTRODUCTION. The aim of the study was the evaluation of glucose metabolism disturbances in I° relatives of the patients with type 2 diabetes, depending on the other present risk factors. MATERIAL AND METHODS. The evaluated group consisted of 42 I° relatives of the patients treated in Outpatient Diabetology Clinic of the University Hospital in Bydgoszcz. A subjective, objective examination and the oral glucose tolerance test were carried out. RESULTS. In 13 patients (31%) glucose metabolism disturbances (ZGW group) were identified, in 29 they were not stated (BZGW group). The examined ZGW group patients were considerably statistically older than the BZGW (59.8 &#177; 14.6 vs. 37.8 &#177; 15.5 years; p < 0.001), had a remarkably greater inherited susceptibility to type 2 diabetes (2.0 &#177; 1.1 vs. 1.1 &#177; &#177; 0.4; p < 0.001 of the number of relatives in the family) and were characterized by a significantly higher number of the diabetes risk factors (2.9 &#177; 1.2 vs. 2.0 &#177; 1.2; p < 0.01). The occurrence of the abnormal glycaemia - 61.5% (BZGW - 6.9%) in the anamnesis turned out to be the most common and statistically important. Both groups did not differ in the number of parents with diabetes, whereas 92.3% patients of the ZGW and only 13.8% of the BZGW had siblings with diabetes. 23% people with ZGW had at least one child with diabetes while no-one thase with BZGW. No significant differences between the groups, regarding BMI were stated: 28.3 &#177; 4.5 kg/m2 versus 25.9 &#177; 4.9 kg/m2 and WHR: 0.86 &#177; 0.08 versus 0.83 &#177; &#177; 0.07 respectively. Gestational diabetes mellitus occurred in 7.7% versus 6.9%, giving birth to a newborn with birth weight above 4000 g: 7.7% versus 11.9%, polycystic ovary syndrome: 7.7% versus 3.4%. CONCLUSIONS. In the I° relatives of the patients with type 2 diabetes the occurrence of glucose metabolism disturbances depended on: age, the amount of diabetes risk factors, especially stating abnormal glycaemia values in the anamnesis, the number of relatives with type 2 diabetes, siblings and children in particular

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Circular RNAs&mdash;New Kids on the Block in Cancer Pathophysiology and Management

The ever-increasing number of cancer cases and persistently high mortality underlines the urgent need to acquire new perspectives for developing innovative therapeutic approaches. As the research on protein-coding genes brought significant yet only incremental progress in the development of anticancer therapy, much attention is now devoted to understanding the role of non-coding RNAs (ncRNAs) in various types of cancer. Recent years have brought about the awareness that ncRNAs recognized previously as &ldquo;dark matter&rdquo; are, in fact, key players in shaping cancer development. Moreover, breakthrough discoveries concerning the role of a new group of ncRNAs, circular RNAs, have evidenced their high importance in many diseases, including malignancies. Therefore, in the following review, we focus on the role of circular RNAs in cancer, particularly in cancer stem-like cells, summarize their mechanisms of action, and provide an overview of the state-of-the-art toolkits to study them

Circular RNAs—New Kids on the Block in Cancer Pathophysiology and Management

The ever-increasing number of cancer cases and persistently high mortality underlines the urgent need to acquire new perspectives for developing innovative therapeutic approaches. As the research on protein-coding genes brought significant yet only incremental progress in the development of anticancer therapy, much attention is now devoted to understanding the role of non-coding RNAs (ncRNAs) in various types of cancer. Recent years have brought about the awareness that ncRNAs recognized previously as “dark matter” are, in fact, key players in shaping cancer development. Moreover, breakthrough discoveries concerning the role of a new group of ncRNAs, circular RNAs, have evidenced their high importance in many diseases, including malignancies. Therefore, in the following review, we focus on the role of circular RNAs in cancer, particularly in cancer stem-like cells, summarize their mechanisms of action, and provide an overview of the state-of-the-art toolkits to study them

Regional Climate Change Competitiveness—Modelling Approach

The article deals with the competitiveness of regions in the face of climate change. The aim was to present the concept of measuring the Regional Climate Change Competitiveness Index. We used a comparative and logical analysis of the concept of regional competitiveness and heuristic conceptual methods to construct the index and measurement scale. The structure of the index includes six broad sub-indexes: Basic, Natural, Efficiency, Innovation, Sectoral, Social, and 89 indicators. A practical application of the model was presented for the Mazowieckie province in Poland. This allowed the region’s performance in the context of climate change to be presented, and regional weaknesses in the process of adaptation to climate change to be identified. The conclusions of the research confirm the possibility of applying the Regional Climate Change Competitiveness Index in the economic analysis and strategic planning. The presented model constitutes one of the earliest tools for the evaluation of climate change competitiveness at a regional level

Seemingly Unrelated Mixed-Effects Biomass Models for Black Locust in West Poland

Information about tree biomass is important not only in the assessment of wood resources but also in the process of preparing forest management plans, as well as for estimating carbon stocks and their flow in forest ecosystems. The study aimed to develop empirical models for determining the dry mass of the aboveground parts of black locust trees and their components (stem, branches, and leaves). The research was carried out based on data collected in 13 stands (a total of 38 sample trees) of black locust located in western Poland. The model system was developed based on multivariate mixed-effect models using two approaches. In the first approach, biomass components and tree height were defined as dependent variables, while diameter at breast height was used as an independent variable. In the second approach, biomass components and diameter at breast height were dependent variables and tree height was defined as the independent variable. Both approaches enable the fixed-effect and cross-model random-effect prediction of aboveground dry biomass components of black locust. Cross-model random-effect prediction was obtained using additional measurements of two extreme trees, defined as trees characterized by the smallest and largest diameter at breast height in sample plot. This type of prediction is more precise (root mean square error for stem dry biomass for both approaches equals 77.603 and 188.139, respectively) than that of fixed-effects prediction (root mean square error for stem dry biomass for both approaches equals 238.716 and 206.933, respectively). The use of height as an independent variable increases the possibility of the practical application of the proposed solutions using remote data sources