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Cardiovascular diseases (CVDs) and metabolic disorders stand as formidable challenges that significantly impact the clinical outcomes and living quality for afflicted individuals. An intricate comprehension of the underlying mechanisms is paramount for the development of efficacious therapeutic strategies. Protein arginine methyltransferases (PRMTs), a class of enzymes responsible for the precise regulation of protein methylation, have ascended to pivotal roles and emerged as crucial regulators within the intrinsic pathophysiology of these diseases. Herein, we review recent advancements in research elucidating on the multifaceted involvements of PRMTs in cardiovascular system and metabolic diseases, contributing significantly to deepen our understanding of the pathogenesis and progression of these maladies. In addition, this review provides a comprehensive analysis to unveil the distinctive roles of PRMTs across diverse cell types implicated in cardiovascular and metabolic disorders, which holds great potential to reveal novel therapeutic interventions targeting PRMTs, thus presenting promising perspectives to effectively address the substantial global burden imposed by CVDs and metabolic disorders.

Diabetes mellitus is a complex chronic disease, considered as one of the most common metabolic disorders worldwide, posing a major threat to global public health. Ferroptosis emerges as a novel mechanism of programmed cell death, distinct from apoptosis, necrosis, and autophagy, driven by iron-dependent lipid peroxidation accumulation and GPx4 downregulation. A mounting body of evidence highlights the interconnection between iron metabolism, ferroptosis, and diabetes pathogenesis, encompassing complications like diabetic nephropathy, cardiomyopathy, and neuropathy. Moreover, ferroptosis inhibitors hold promise as potential pharmacological targets for mitigating diabetes-related complications. A better understanding of the role of ferroptosis in diabetes may lead to an improvement in global diabetes management.In this review, we delve into the intricate relationship between ferroptosis and diabetes development, exploring associated complications and current pharmacological treatments.

Abstract Three-dimensional (3D) bioprinting is a highly effective technique for fabricating cell-loaded constructs in tissue engineering. However, the versatility of fabricating precise and complex cell-loaded hydrogels is limited owing to the poor crosslinking ability of cell-containing hydrogels. Herein, we propose an optic-fiber-assisted bioprinting (OAB) process to efficiently crosslink methacrylated hydrogels. By selecting appropriate processing conditions for the photo-crosslinking technique, we fabricated biofunctional cell-laden structures including methacrylated gelatin (Gelma), collagen, and decellularized extracellular matrix. To apply the method to skeletal muscle regeneration, cell-laden Gelma constructs were processed with a functional nozzle having a topographical cue and an OAB process that could induce a uniaxial alignment of C2C12 and human adipose stem cells (hASCs). Significantly higher degrees of cell alignment and myogenic activities in the cell-laden Gelma structure were observed compared with those in the cell construct that was printed using a conventional crosslinking method. Moreover, an in vivo regenerative potential was observed in volumetric muscle defects in a mouse model. The hASC-laden construct significantly induced greater muscle regeneration than the cell construct without topographical cues. Based on the results, the newly designed bioprinting process can prove to be highly effective in fabricating biofunctional cell-laden constructs for various tissue engineering applications.

Volumetric muscle loss (VML) is associated with a severe loss of muscle tissue that overwhelms the regenerative potential of skeletal muscles. Tissue engineering has shown promise for the treatment of VML injuries, as evidenced by various preclinical trials. The present study describes the fabrication of a cell-laden GelMa muscle construct using an in situ crosslinking (ISC) strategy to improve muscle functionality. To obtain optimal biophysical properties of the muscle construct, two UV exposure sources, UV exposure dose, and wall shear stress were evaluated using C2C12 myoblasts. Additionally, the ISC system showed a significantly higher degree of uniaxial alignment and myogenesis compared to the conventional crosslinking strategy (post-crosslinking). To evaluate the in vivo regenerative potential, muscle constructs laden with human adipose stem cells were used. The VML defect group implanted with the bio-printed muscle construct showed significant restoration of functionality and muscular volume. The data presented in this study suggest that stem cell-based therapies combined with the modified bioprinting process could potentially be effective against VML injuries.

Neuromuscular dysfunction is tightly associated with muscle wasting that occurs with age or due to degenerative diseases. However, the molecular mechanisms underlying neuromuscular dysfunction are currently unclear. Recent studies have proposed important roles of Protein arginine methyltransferase 1 (Prmt1) in muscle stem cell function and muscle maintenance. In the current study, we set out to determine the role of Prmt1 in neuromuscular function by generating mice with motor neuron-specific ablation of Prmt1 (mnKO) using Hb9-Cre. mnKO exhibited age-related motor neuron degeneration and neuromuscular dysfunction leading to premature muscle loss and lethality. Prmt1 deficiency also impaired motor function recovery and muscle reinnervation after sciatic nerve injury. The transcriptome analysis of aged mnKO lumbar spinal cords revealed alterations in genes related to inflammation, cell death, oxidative stress, and mitochondria. Consistently, mnKO lumbar spinal cords of sciatic nerve injury model or aged mice exhibited elevated cellular stress response in motor neurons. Furthermore, Prmt1 inhibition in motor neurons elicited mitochondrial dysfunction. Our findings demonstrate that Prmt1 ablation in motor neurons causes age-related motor neuron degeneration attributing to muscle loss. Thus, Prmt1 is a potential target for the prevention or intervention of sarcopenia and neuromuscular dysfunction related to aging.

Abstract Neurite growth is controlled by a complex molecular signaling network that regulates filamentous actin (F-actin) dynamics at the growth cone. The evolutionarily conserved ezrin, radixin, and moesin family of proteins tether F-actin to the cell membrane when phosphorylated at a conserved threonine residue and modulate neurite outgrowth. Here we show that Akt binds to and phosphorylates a threonine 573 residue on radixin. Akt-mediated phosphorylation protects radixin from ubiquitin-dependent proteasomal degradation, thereby enhancing radixin protein stability, which permits proper neurite outgrowth and growth cone formation. Conversely, the inhibition of Akt kinase or disruption of Akt-dependent phosphorylation reduces the binding affinity of radixin to F-actin as well as lowers radixin protein levels, resulting in decreased neurite outgrowth and growth cone formation. Our findings suggest that Akt signaling regulates neurite outgrowth by stabilizing radixin interactions with F-actin, thus facilitating local F-actin dynamics.

Mechanistic studies of axon growth during development are beneficial to the search for neuron-intrinsic regulators of axon regeneration. Here, we discovered that, in the developing neuron from rat, Akt signaling regulates axon growth and growth cone formation through phosphorylation of serine 14 (S14) on Inhibitor of DNA binding 2 (Id2). This enhances Id2 protein stability by means of escape from proteasomal degradation, and steers its localization to the growth cone, where Id2 interacts with radixin that is critical for growth cone formation. Knockdown of Id2, or abrogation of Id2 phosphorylation at S14, greatly impairs axon growth and the architecture of growth cone. Intriguingly, reinstatement of Akt/Id2 signaling after injury in mouse hippocampal slices redeemed growth promoting ability, leading to obvious axon regeneration. Our results suggest that Akt/Id2 signaling is a key module for growth cone formation and axon growth, and its augmentation plays a potential role in CNS axonal regeneration.

ErbB3-binding protein 1 (EBP1) is implicated in diverse cellular functions, including apoptosis, cell proliferation, and differentiation. Here, by generating genetic inactivation of Ebp1 mice, we identified the physiological roles of EBP1 in vivo. Loss of Ebp1 in mice caused aberrant organogenesis, including brain malformation, and death between E13.5 and 15.5 owing to severe hemorrhages, withmassive apoptosis and cessation of cell proliferation. Specific ablation of Ebp1 in neurons caused structural abnormalities of brain with neuron loss in [Nestin-Cre; Ebp1flox/flox] mice. Notably, global methylation increased with high levels of the gene-silencing unit Suv39H1/DNMT1 in Ebp1-deficient mice. EBP1 repressed the transcription of Dnmt1 by binding to its promoter region and interrupted DNMT1-mediated methylation at its target gene, Survivin promoter region. Reinstatement of EBP1 into embryo brain relived gene repression and rescued neuron death. Our findings uncover an essential role for EBP1 in embryonic development and implicate its function in transcriptional regulation. [ABSTRACT FROM AUTHOR]

Akt signaling is an important regulator of neural development, but the distinctive function of Akt isoforms in brain development presents a challenge. Here we show Siah1 as an ubiquitin ligase that preferentially interacts with Akt3 and facilitates ubiquitination and degradation of Akt3. Akt3 is enriched in the axonal shaft and branches but not growth cone tips, where Siah1 is prominently present. Depletion of Siah1 enhanced Akt3 levels in the soma and axonal tips, eliciting multiple branching. Brainspecific somatic mutation in Akt3-E17K escapes from Siah1- mediated degradation and causes improper neural development with dysmorphic neurons. Remarkably, coexpression of Siah1 with Akt3-WT restricted disorganization of neural development is caused by Akt3 overexpression, whereas forced expression of Siah1 with the Akt3-E17K mutant fails to cope with malformation of neural development. These findings demonstrate that Siah1 limits Akt3 turnover during brain development and that this event is essential for normal organization of the neural network. [ABSTRACT FROM AUTHOR]