• Heme Oxygenase-1 (HO-1) inhibitor
• In ovo antitumoral test
• Melanoma
• Metastatic cancer treatment
• Nanostructured lipid carriers (NLC)
• Selective targeting
• Triple negative breast cancer (TNBC)

• Triple Negative Breast Neoplasms/drug therapy
• Triple Negative Breast Neoplasms/pathology
• Female
• Humans
• Animals
• Cell Line, Tumor
• Lipids/chemistry
• Drug Carriers/chemistry
• Heme Oxygenase-1/antagonists & inhibitors
• Heme Oxygenase-1/metabolism
• Nanostructures/administration & dosage
• Nanostructures/chemistry
• Antineoplastic Agents/administration & dosage
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/chemistry
• Cell Proliferation/drug effects
• Mice
• Benzamides/administration & dosage
• Benzamides/pharmacology
• Benzamides/chemistry
• Xenograft Model Antitumor Assays
• Enzyme Inhibitors/administration & dosage
• Enzyme Inhibitors/pharmacology
• Enzyme Inhibitors/chemistry

• Animals
• Laminin/metabolism
• Laminin/genetics
• Laminin/deficiency
• Mice
• Muscle, Skeletal/metabolism
• Muscle, Skeletal/pathology
• Cell Differentiation/genetics
• Myoblasts/metabolism
• Oxidative Stress/genetics
• DNA Damage
• Muscular Dystrophies/metabolism
• Muscular Dystrophies/genetics
• Muscular Dystrophies/pathology
• Cell Proliferation/genetics
• Cell Line
• Muscle Development/genetics
• Disease Models, Animal
• Mutation
• Muscle Fibers, Skeletal/metabolism

• Fundação para a Ciência e Tecnologia (FCT)
• European Cooperation in Science and Technology
• Association Française contre les Myopathies (AFM)
• MATRIHEALTH Project

• Duchenne muscular dystrophy
• Heme oxygenase-1
• Satellite cells
• Skeletal muscle regeneration

• Animals
• Heme Oxygenase-1/genetics
• Heme Oxygenase-1/metabolism
• Satellite Cells, Skeletal Muscle/metabolism
• Muscular Dystrophy, Duchenne/genetics
• Muscular Dystrophy, Duchenne/metabolism
• Muscular Dystrophy, Duchenne/pathology
• Mice, Inbred mdx
• Mice, Transgenic
• Muscle, Skeletal/metabolism
• Muscle, Skeletal/pathology
• Mice
• PAX7 Transcription Factor/genetics
• PAX7 Transcription Factor/metabolism
• Male
• Mice, Inbred C57BL
• Physical Conditioning, Animal
• Membrane Proteins

• R01 DK122986 NIDDK NIH HHS
• R01DK122986 NIH HHS
• grant MAESTRO 2018/30/A/NZ3/00412 Polish National Science Centre
• NAWA grant PPN/ULM/2019/1/00304/U/00001 National Agency of Academic Exchange
• National Institutes of Health

• CP: Stem cell research
• granulin
• macrophage
• mesenchymal progenitor
• muscle satellite cell
• overload
• regeneration

• Animals
• Satellite Cells, Skeletal Muscle/metabolism
• Satellite Cells, Skeletal Muscle/pathology
• Macrophages/metabolism
• Hypertrophy
• Mesenchymal Stem Cells/metabolism
• Mice
• Cell Differentiation
• Mice, Knockout
• Granulins
• Cell Communication
• Mice, Inbred C57BL
• Muscle, Skeletal/metabolism
• Muscle, Skeletal/pathology
• Male
• Regeneration

• HO-1
• HO-1 inducer
• Skeletal muscle atrophy
• Skeletal muscles homeostasis
• Therapeutic target

• Humans
• Heme Oxygenase-1/metabolism
• Muscle, Skeletal/metabolism
• Muscular Atrophy/drug therapy
• Muscular Atrophy/metabolism

• Myogenesis
• Senescence
• Stem cells
• Transcriptomics
• myomiRs

• MicroRNAs/genetics
• MicroRNAs/metabolism
• Satellite Cells, Skeletal Muscle/metabolism
• Muscle, Skeletal/metabolism
• Stem Cells/metabolism
• Cell Differentiation/genetics

• R00 AG063994 NIA NIH HHS
• R01 AG080047 NIA NIH HHS

• Duchenne muscular dystrophy
• HO-1
• Induced pluripotent stem cells
• Mdx
• miR-206
• microRNA
• myomiRs

• Duchenne muscular dystrophy
• NRF2
• heme oxygenase-1
• microRNAs
• muscle regeneration
• oxidative stress

• Animals
• NF-E2-Related Factor 2/genetics
• NF-E2-Related Factor 2/metabolism
• Signal Transduction/physiology
• Muscle, Skeletal/metabolism
• Muscular Dystrophy, Duchenne/genetics
• Muscular Dystrophy, Duchenne/pathology
• Regeneration/physiology

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.

• NRF2
• muscle regeneration
• myoblasts
• oxidative stress
• satellite cells

• Mice
• Animals
• NF-E2-Related Factor 2/metabolism
• Satellite Cells, Skeletal Muscle/metabolism
• Reactive Oxygen Species/metabolism
• Antioxidants/metabolism
• Cell Differentiation/genetics
• Muscle, Skeletal/metabolism
• Oxidative Stress
• Cell Proliferation
• Myogenic Regulatory Factors/metabolism
• MicroRNAs/metabolism

• Duchenne muscular dystrophy
• Heme oxygenase-1
• Myoblast differentiation
• Myoblast proliferation
• Phosphorylated transforming growth factor-β-activated kinase 1

• Ab initio prediction
• Homology-based prediction
• Multiple sequence alignment-based prediction
• Secondary structure prediction
• miRNA
• miRNA prediction accuracy

• Duchenne muscular dystrophy
• H2S donors
• Hydrogen sulfide
• Inflammation
• Skeletal muscles

• Humans
• Muscular Dystrophy, Duchenne/drug therapy
• Muscular Dystrophy, Duchenne/genetics
• Hydrogen Sulfide/therapeutic use
• Muscle, Skeletal
• Muscle Fibers, Skeletal
• Mutation

• Narodowe Centrum Nauki

• C2C12 cells
• myoblast differentiation
• oxidative stress

• OCT4
• gene modulation
• heme oxygenase-1
• pluripotency transcription factors
• pluripotent stem cells
• transcription

• HIF1A
• fusion
• hypoxia-inducible factor 1 alpha
• muscle regeneration
• satellite cells

Duchenne muscular dystrophy (DMD) is a devastating chromosome X-linked disease that manifests predominantly in progressive skeletal muscle wasting and dysfunctions in the heart and diaphragm. Approximately 1/5000 boys and 1/50,000,000 girls suffer from DMD, and to date, the disease is incurable and leads to premature death. This phenotypic severity is due to mutations in the DMD gene, which result in the absence of functional dystrophin protein. Initially, dystrophin was thought to be a force transducer; however, it is now considered an essential component of the dystrophin-associated protein complex (DAPC), viewed as a multicomponent mechanical scaffold and a signal transduction hub. Modulating signal pathway activation or gene expression through epigenetic modifications has emerged at the forefront of therapeutic approaches as either an adjunct or stand-alone strategy. In this review, we propose a broader perspective by considering DMD to be a disease that affects myofibers and muscle stem (satellite) cells, as well as a disorder in which abrogated communication between different cell types occurs. We believe that by taking this systemic view, we can achieve safe and holistic treatments that can restore correct signal transmission and gene expression in diseased DMD tissues.

• DMD
• Duchenne muscular dystrophy
• Signaling pathways
• Striated muscles

• DAMP
• exercise training
• heme
• heme oxygenase-1
• hemopexin
• mitochondrial dysfunction
• muscle atrophy
• muscle microtrauma
• satellite cells

Heme oxygenase-1 (HO-1, encoded by HMOX1) is a cytoprotective enzyme degrading heme into CO, Fe²⁺, and biliverdin. HO-1 was demonstrated to affect cardiac differentiation of murine pluripotent stem cells (PSCs), regulate the metabolism of murine adult cardiomyocytes, and influence regeneration of infarcted myocardium in mice. However, the enzyme’s effect on human cardiogenesis and human cardiomyocytes’ electromechanical properties has not been described so far. Thus, this study aimed to investigate the role of HO-1 in the differentiation of human induced pluripotent stem cells (hiPSCs) into hiPSC-derived cardiomyocytes (hiPSC-CMs). hiPSCs were generated from human fibroblasts and peripheral blood mononuclear cells using Sendai vectors and subjected to CRISPR/Cas9-mediated HMOX1 knock-out. After confirming lack of HO-1 expression on the protein level, isogenic control and HO-1-deficient hiPSCs were differentiated into hiPSC-CMs. No differences in differentiation efficiency and hiPSC-CMs metabolism were observed in both cell types. The global transcriptomic analysis revealed, on the other hand, alterations in electrophysiological pathways in hiPSC-CMs devoid of HO-1, which also demonstrated increased size. Functional consequences in changes in expression of ion channels genes were then confirmed by patch-clamp analysis. To the best of our knowledge, this is the first report demonstrating the link between HO-1 and electrophysiology in human cardiomyocytes.

• CRISPR/Cas9
• HO-1
• IGF2
• electrophysiology
• hiPSC-CMs
• hypertrophy

• apoptosis
• autophagy
• carbon monoxide
• cell death
• ferroptosis
• heme oxygenase
• inflammasome
• inflammation
• necroptosis
• pyroptosis

• adipose-derived stromal cells
• heme oxygenase-1
• human induced pluripotent stem cells
• myocardial infarction
• stromal cell-derived factor-1α

Cancer-associated cachexia is a heterogeneous, multifactorial syndrome characterized by systemic inflammation, unintentional weight loss, and profound alteration in body composition. The main feature of cancer cachexia is represented by the loss of skeletal muscle tissue, which may or may not be accompanied by significant adipose tissue wasting. Such phenotypic alteration occurs as the result of concomitant increased myofibril breakdown and reduced muscle protein synthesis, actively contributing to fatigue, worsening of quality of life, and refractoriness to chemotherapy. According to the classical view, this condition is primarily triggered by interactions between specific tumor-induced pro-inflammatory cytokines and their cognate receptors expressed on the myocyte membrane. This causes a shift in gene expression of muscle cells, eventually leading to a pronounced catabolic condition and cell death. More recent studies, however, have shown the involvement of regulatory non-coding RNAs in the outbreak of cancer cachexia. In particular, the role exerted by microRNAs is being widely addressed, and several mechanistic studies are in progress. In this review, we discuss the most recent findings concerning the role of microRNAs in triggering or exacerbating muscle wasting in cancer cachexia, while mentioning about possible roles played by long non-coding RNAs and ADAR-mediated miRNA modifications.

• ADAR
• cancer cachexia
• extracellular vesicles
• long non-coding RNAs
• microRNAs
• skeletal muscle wasting

• CRISPR/Cas9
• Cell therapy
• DMD
• Duchenne muscular dystrophy
• Gene therapy
• Induced pluripotent stem cells

• Animals
• Dystrophin/genetics
• Heart/drug effects
• Humans
• Muscle, Skeletal/drug effects
• Muscular Dystrophy, Duchenne/drug therapy
• Muscular Dystrophy, Duchenne/genetics
• Mutation/genetics

• 2016/21/B/NZ1/00293 Narodowe Centrum Nauki
• 2018/30/A/NZ3/00412 Narodowe Centrum Nauki

It has been reported that Bach1-deficient mice show reduced tissue injuries in diverse disease models due to increased expression of heme oxygenase-1 (HO-1)that possesses an antioxidant function. In contrast, we found that Bach1 deficiency in mice exacerbated skeletal muscle injury induced by cardiotoxin. Inhibition of Bach1 expression in C2C12 myoblast cells using RNA interference resulted in reduced proliferation, myotube formation, and myogenin expression compared with control cells. While the expression of HO-1 was increased by Bach1 silencing in C2C12 cells, the reduced myotube formation was not rescued by HO-1 inhibition. Up-regulations of Smad2, Smad3 and FoxO1, known inhibitors of muscle cell differentiation, were observed in Bach1-deficient mice and Bach1-silenced C2C12 cells. Therefore, Bach1 may promote regeneration of muscle by increasing proliferation and differentiation of myoblasts.

• Animals
• Basic-Leucine Zipper Transcription Factors/deficiency
• Basic-Leucine Zipper Transcription Factors/genetics
• Basic-Leucine Zipper Transcription Factors/metabolism
• Cell Differentiation
• Cell Line
• Gene Knockdown Techniques
• Gene Silencing
• Mice
• Muscle, Skeletal/cytology
• Muscle, Skeletal/physiology
• Myoblasts/cytology
• Regeneration
• Smad Proteins/metabolism
• Transcriptome/genetics

• Japan Society for the Promotion of Science

• Atherosclerosis
• Biomarkers
• Cardiac injury
• Cardiomyocytes
• Cardioprotection
• Exosome
• Fibroblasts
• Microvesicles
• Myocardial infarction
• Stem cells
• Vascular endothelial cells
• miR
• microRNA

Heme Oxygen-1 (HO-1)-modified bone marrow mesenchymal stem cells (BMMSCs) are effective to protect and repair transplanted small bowel and intestinal epithelial cells (IECs); however, the mechanism and the role of HO-1/BMMSCs-derived exosomes is unclear. In the present study, we aimed to verify that exosomes from a HO-1/BMMSCs and IEC-6 cells (IEC-6s) co-culture system could reduce the apoptosis of IEC-6s and decrease the expression of the tight junction protein, zona occludens 1, in the inflammatory environment. Using mass spectrometry, we revealed that high mobility group box 3 (HMGB3) and phosphorylated c-Jun NH2-terminal kinase (JNK), under the influence of differentially abundant proteins identified through proteomic analysis, play critical roles in the mechanism. Further studies indicated that microRNA miR-200b, which was upregulated in exosomes derived from the co-culture of HO-1/BMMSCs and IEC-6s, exerted its role by targeting the 3′ untranslated region of Hmgb3 in this biological process. Functional experiments confirmed that miR-200b overexpression could reduce the inflammatory injury of IEC-6s, while intracellular miR-200b knockdown could significantly block the protective effect of HO-1/BMMSCs exosomes on the inflammatory injury of IEC-6s. In addition, the level of miR-200b in cells and exosomes derived from HO-1/BMMSCs stimulated by tumor necrosis factor alpha was significantly upregulated. In a rat small bowel transplantation model of allograft rejection treated with HO-1/BMMSCs, we confirmed that the level of miR-200b in the transplanted small bowel tissue was increased significantly, while the level of HMGB3/JNK was downregulated significantly. In conclusion, we identified that exosomes derived from HO-1/BMMSCs play an important role in alleviating the inflammatory injury of IECs. The mechanism is related to miR-200b targeting the abnormally increased expression of the Hmgb3 gene in IECs induced by inflammatory injury. The reduced level of HMGB3 then decreases the inflammatory injury.

• Genetic diseases
• Muscle
• Muscle Biology
• Noncoding RNAs

• MicroRNA
• oxidative stress
• signal transduction
• therapeutic target

Duchenne muscular dystrophy (DMD) is a genetic disease evoked by a mutation in the dystrophin gene. It is associated with progressive muscle degeneration and increased inflammation. Up to this date, mainly anti-inflammatory treatment is available for patients suffering from DMD. miR-146a is known to diminish inflammation and fibrosis in different tissues by downregulating the expression of proinflammatory cytokines. However, its role in DMD has not been studied so far.

In our work, we have generated mice globally lacking both dystrophin and miR-146a (miR-146a^−/−mdx) and examined them together with wild-type, single miR-146a knockout and dystrophic (mdx—lacking dystrophin) mice in a variety of aspects associated with DMD pathophysiology (muscle degeneration, inflammatory reaction, muscle satellite cells, muscle regeneration, and fibrosis).

We have shown that miR-146a level is increased in dystrophic muscles in comparison to wild-type mice. Its deficiency augments the expression of proinflammatory cytokines (IL-1β, CCL2, TNFα). However, muscle degeneration was not significantly worsened in mdx mice lacking miR-146a up to 24 weeks of age, although some aggravation of muscle damage and inflammation was evident in 12-week-old animals, though no effect of miR-146a deficiency was visible on quantity, proliferation, and in vitro differentiation of muscle satellite cells isolated from miR-146a^−/−mdx mice vs. mdx. Similarly, muscle regeneration and collagen deposition were not changed by miR-146a deficiency. Nevertheless, the lack of miR-146a is associated with decreased Vegfa and increased Tgfb1.

Overall, the lack of miR-146a did not aggravate significantly the dystrophic conditions in mdx mice, but its effect on DMD in more severe conditions warrants further investigation.

• Duchenne muscular dystrophy
• Inflammation
• Regeneration
• Skeletal muscle
• mdx
• miR-146a

• Angiogenesis
• Dystrophy
• Heme oxygenase-1
• Statins
• mdx

• Age Factors
• Animals
• Disease Models, Animal
• Disease Progression
• Dystrophin/deficiency
• Heme Oxygenase-1/therapeutic use
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
• Male
• Muscle, Skeletal/blood supply
• Muscle, Skeletal/pathology
• Muscular Dystrophy, Duchenne/pathology
• Muscular Dystrophy, Duchenne/therapy
• Neovascularization, Pathologic/pathology
• Neovascularization, Pathologic/therapy
• Nitric Oxide/metabolism
• Sex Factors
• Vascular Endothelial Growth Factor A/therapeutic use

• 2016/21/B/NZ1/00293 Narodowe Centrum Nauki
• 2012/06/A/NZ1/00004 Narodowe Centrum Nauki

A biotinylated carbon monoxide-releasing molecule (BiotinCORM) releases CO by photoirradiation at 400 nm; an avidin–biotinCORM adduct is an effective CO-releasing molecule.

• heme oxygenase-1
• inflammation
• microRNA
• muscle satellite cells
• muscular dystrophy
• skeletal muscle

• antioxidant gene response
• heme
• mesenchymal stem cell
• stem cells

Heme oxygenase-1 (HO-1), encoded by HMOX1 gene and regulated by Nrf2 transcription factor, is a cytoprotective enzyme. Its deficiency may exacerbate abdominal aortic aneurysm (AAA) development, which is also often associated with hyperlipidemia. Beneficial effects of statins, the broadly used antilipidemic drugs, were attributed to modulation of Nrf2/HO-1 axis. However, the effect of statins on Nrf2/HO-1 pathway in patients with AAA has not been studied yet. We analyzed AAA tissue from patients treated with simvastatin (N = 28) or without statins (N = 14). Simvastatin treatment increased HO-1 protein level in AAA, both in endothelial cells (ECs) and in smooth muscle cells (SMCs), but increased Nrf2 localization was restricted only to vasa vasorum. Nrf2 target genes HMOX1, NQO1, and GCLM expression remained unchanged in AAA. In vitro studies showed that simvastatin raises HO-1 protein level slightly in ECs and to much higher extent in SMCs, which is not related to Nrf2/ARE activation, although HMOX1 expression is upregulated by simvastatin in both cell types. In conclusion, simvastatin-induced modulation of HO-1 level in ECs and SMCs in vitro is not related to Nrf2/ARE activity. Likewise, divergent HO-1 and Nrf2 localization together with stable expression of Nrf2 target genes, including HMOX1, in AAA tissue denotes Nrf2 independency.

Heme oxygenase-1 (HO-1, encoded by HMOX1) through degradation of pro-oxidant heme into carbon monoxide (CO), ferrous ions (Fe²⁺) and biliverdin, exhibits cytoprotective, anti-apoptotic and anti-inflammatory properties. All of these potentially beneficial functions of HO-1 may play an important role in tumors’ development and progression. Moreover, HO-1 is very often upregulated in tumors in comparison to healthy tissues, and its expression is further induced upon chemo-, radio- and photodynamic therapy, what results in decreased effectiveness of the treatment. Consequently, HO-1 can be proposed as a therapeutic target for anticancer treatment in many types of tumors. Nonetheless, possibilities of specific inhibition of HO-1 are strongly limited. Metalloporphyrins are widely used in in vitro studies, however, they are unselective and may exert serious side effects including an increase in HMOX1 mRNA level. On the other hand, detailed information about pharmacokinetics and biodistribution of imidazole-dioxolane derivatives, other potential inhibitors, is lacking. The genetic inhibition of HO-1 by RNA interference (RNAi) or CRISPR/Cas9 approaches provides the possibility to specifically target HO-1; however, the potential therapeutic application of those methods are distant at best. In summary, HO-1 inhibition might be the valuable anticancer approach, however, the ideal strategy for HO-1 targeting requires further studies.

• CRISPR/Cas9
• HO-1 inhibitors
• anticancer strategy
• siRNA
• tumorigenesis

• ALS
• Alzheimer’s disease
• Drosha
• Huntington’s disease
• Inflammation
• Neurodegeneration
• Parkinson’s disease

• Animals
• DNA Damage
• Gene Expression Regulation
• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Models, Genetic
• Protein Binding
• RNA Processing, Post-Transcriptional
• Signal Transduction/genetics
• Transcription Factors/genetics
• Transcription Factors/metabolism

• N N302 633240 NSC
• 2015/18/E/NZ2/00678 NSC
• KNOW NSC

• muscle stem cells
• oxidative stress
• skeletal muscle regeneration

• Animals
• Humans
• Muscle, Skeletal/metabolism
• Muscle, Skeletal/physiology
• Oxidation-Reduction
• Oxidative Stress/genetics
• Oxidative Stress/physiology
• Reactive Oxygen Species/metabolism
• Regeneration/genetics
• Regeneration/physiology
• Signal Transduction/genetics
• Signal Transduction/physiology
• Wound Healing/genetics
• Wound Healing/physiology

• C/EBPβ
• Carbon monoxide
• Granulocyte colony-stimulating factor
• Granulopoiesis
• Heme oxygenase 1