Emerging roles of MRG15 in liver metabolic diseases.

MORF4 (mortality factor on chromosome 4)-related gene 15 (MRG15) is a chromodomain protein that exists in various multiprotein complexes involved in transcription, DNA repair, and development. Here we summarize the recent advances involving MRG15 in modulating liver metabolism, both through its chromatin-binding capability and independently of it, highlighting MRG15 as a potential therapeutic target for liver metabolic diseases.

MircoRNA-25-3p in skin precursor cell-induced Schwann cell-derived extracellular vesicles promotes axon regeneration by targeting Tgif1.

Nerve injury often leads to severe dysfunction because of the lack of axon regeneration in adult mammal. Intriguingly a series of extracellular vesicles (EVs) have the obvious ability to accelerate the nerve repair. However, the detailed molecular mechanisms to describe that EVs switch neuron from a transmitter to a regenerative state have not been elucidated. This study elucidated the microRNA (miRNA) expression profiles of two types of EVs that promote nerve regeneration. The functions of these miRNAs were screened in vitro. Among the 12 overlapping miRNAs, miR-25-3p was selected for further analysis as it markedly promoted axon regeneration both in vivo and in vitro. Furthermore, knockdown experiments confirmed that PTEN and Klf4, which are the major inhibitors of axon regeneration, were the direct targets of miR-25-3p in dorsal root ganglion (DRG) neurons. The utilization of luciferase reporter assays and functional tests provided evidence that miR-25-3p enhances axon regeneration by targeting Tgif1. Additionally, miR-25-3p upregulated the phosphorylation of Erk. Furthermore, Rapamycin modulated the expression of miR-25-3p in DRG neurons. Finally, the pro-axon regeneration effects of EVs were confirmed by overexpressing miR-25-3p and Tgif1 knockdown in the optic nerve crush model. Thus, the enrichment of miR-25-3p in EVs suggests that it regulates axon regeneration, proving a potential cell-free treatment strategy for nerve injury.

Inhibition of CD44 suppresses the formation of fibrotic scar after spinal cord injury via the JAK2/STAT3 signaling pathway.

Fibrotic scar is one of the main impediments to axon regeneration following spinal cord injury (SCI). In this study, we found that CD44 was upregulated during the formation of fibrotic scar, and blocking CD44 by IM7 caused downregulation of fibrosis-related extracellular matrix proteins at both 2 and 12 weeks post-spinal cord injury. More Biotinylated dextran amine (BDA)-traced corticospinal tract axons crossed the scar area and extended into the distal region after IM7 administration. A recovery of motor and sensory function was observed based on Basso Mouse Scale (BMS) scores and tail-flick test. In vitro experiments revealed that inhibiting CD44 and JAK2/STAT3 signaling pathway decreased the proliferation, differentiation, and migration of fibroblasts induced by the inflammatory supernatant. Collectively, these findings highlight the critical role of CD44 and its downstream JAK2/STAT3 signaling pathway in fibrotic scar formation, suggesting a potential therapeutic target for SCI.

Application of metal-organic frameworks-based functional composite scaffolds in tissue engineering.

With the rapid development of materials science and tissue engineering, a variety of biomaterials have been used to construct tissue engineering scaffolds. Due to the performance limitations of single materials, functional composite biomaterials have attracted great attention as tools to improve the effectiveness of biological scaffolds for tissue repair. In recent years, metal-organic frameworks (MOFs) have shown great promise for application in tissue engineering because of their high specific surface area, high porosity, high biocompatibility, appropriate environmental sensitivities and other advantages. This review introduces methods for the construction of MOFs-based functional composite scaffolds and describes the specific functions and mechanisms of MOFs in repairing damaged tissue. The latest MOFs-based functional composites and their applications in different tissues are discussed. Finally, the challenges and future prospects of using MOFs-based composites in tissue engineering are summarized. The aim of this review is to show the great potential of MOFs-based functional composite materials in the field of tissue engineering and to stimulate further innovation in this promising area.

Aldehyde Dehydrogenase 2 (ALDH2) rs671 Polymorphism is a Predictor of Pulmonary Hypertension Due to Left Heart Disease.

AIM: Pulmonary hypertension due to left heart disease (PH-LHD) is commonly seen in patients with heart failure (HF), but there are limited treatment options. Recent studies have shown an association between aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphisms and pulmonary hypertension (PH). Therefore, this study aimed to investigate the occurrence of ALDH2 rs671 polymorphisms, and the association between ALDH2 and risk of PH-LHD in patients with HF. It also investigated different ALDH2 genotypes and examined their association with cardiac structure and function in HF patients with PH-LHD. METHODS: A total of 178 HF patients were consecutively enrolled in this study: 102 without PH-LHD and 76 with PH-LHD. Clinical data, parameters of echocardiography, and relevant biochemical indexes were recorded in both groups. Differences in data obtained between groups were compared, and the risk of variant ALDH2 polymorphisms with PH-LHD in HF patients was analysed using univariate and multivariate logistic regression. RESULTS: The prevalence of ALDH2 rs671 GA/AA polymorphisms (variant ALDH2) was 24 of 102 patients (23.53%) in the HF without PH-LHD group, and 32 of 76 patients (42.10%) in the HF with PH-LHD group, with a statistically significant difference. Univariate and multivariate logistical regression showed that variant ALDH2 is an independent risk factor for HF combined with PH-LHD. A higher proportion of patients with variant ALDH2 in the HF with PH-LHD group had a tricuspid regurgitation velocity >2.8 m/s, and they had higher values of peak early diastolic velocity of the mitral orifice/peak velocity of the early diastolic wave of the mitral orifice, maximum frequency shift of pulmonary valve flow, and pulmonary artery stiffness. CONCLUSIONS: Variant ALDH2 may be an independent risk factor for HF combined with PH-LHD. Variant ALDH2 may also be involved in pulmonary artery remodelling and is a potential new target for clinical treatment of PH-LHD.

Effect of Virtual Reality Upper Limb Rehabilitation Training on Older Adults.

Virtual reality has gained more attention in the physical training field, but few studies focus on the effects of VR on older adults. Based on existing study we suggest that VR-based upper limb training might be more effective for older adults and used functional near inferred spectrum and movement analysis to evaluate the effects of VR-based training on older adults. 20 older and 20 youth adults were recruited to perform VR training by extending their upper limb to reaching the objects, and non-VR training as a contrast. Both age-related and task-related differences were found in cortical activation, showing that the VR training has aroused more cortical activation. The older groups have more intensive movement but perform worse in terms of task completion. Both groups performed better in VR, and the difference in the older group was higher.

The Transcription Factor Ets1 Influences Axonal Growth via Regulation of Lcn2.

Transcription factors are essential for the development and regeneration of the nervous system. The current study investigated key regulatory transcription factors in rat spinal cord development via RNA sequencing. The hub gene Ets1 was highly expressed in the spinal cord during the embryonic period, and then its expression decreased during spinal cord development. Knockdown of Ets1 significantly increased the axonal growth of cultured spinal cord neurons. Luciferase reporter assays and chromatin immunoprecipitation assays indicated that Ets1 could directly bind to the Lcn2 promoter and positively regulate Lcn2 transcription. In conclusion, these findings provide the first direct evidence that Ets1 regulates axon growth by controlling Lcn2 expression, and Ets1 may be a novel therapeutic target for axon regeneration in the central nervous system.

RNA sequencing of exosomes secreted by fibroblast and Schwann cells elucidates mechanisms underlying peripheral nerve regeneration.

JOURNAL/nrgr/04.03/01300535-202408000-00035/figure1/v/2023-12-16T180322Z/r/image-tiff Exosomes exhibit complex biological functions and mediate a variety of biological processes, such as promoting axonal regeneration and functional recovery after injury. Long non-coding RNAs (lncRNAs) have been reported to play a crucial role in axonal regeneration. However, the role of the lncRNA-microRNA-messenger RNA (mRNA)-competitive endogenous RNA (ceRNA) network in exosome-mediated axonal regeneration remains unclear. In this study, we performed RNA transcriptome sequencing analysis to assess mRNA expression patterns in exosomes produced by cultured fibroblasts (FC-EXOs) and Schwann cells (SC-EXOs). Differential gene expression analysis, Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes analysis, and protein-protein interaction network analysis were used to explore the functions and related pathways of RNAs isolated from FC-EXOs and SC-EXOs. We found that the ribosome-related central gene Rps5 was enriched in FC-EXOs and SC-EXOs, which suggests that it may promote axonal regeneration. In addition, using the miRWalk and Starbase prediction databases, we constructed a regulatory network of ceRNAs targeting Rps5, including 27 microRNAs and five lncRNAs. The ceRNA regulatory network, which included Ftx and Miat, revealed that exsosome-derived Rps5 inhibits scar formation and promotes axonal regeneration and functional recovery after nerve injury. Our findings suggest that exosomes derived from fibroblast and Schwann cells could be used to treat injuries of peripheral nervous system.

Skin derived precursors induced Schwann cells mediated tissue engineering-aided neuroregeneration across sciatic nerve defect.

A central question in neural tissue engineering is how the tissue-engineered nerve (TEN) translates detailed transcriptional signals associated with peripheral nerve regeneration into meaningful biological processes. Here, we report a skin-derived precursor-induced Schwann cell (SKP-SC)-mediated chitosan/silk fibroin-fabricated tissue-engineered nerve graft (SKP-SCs-TEN) that can promote sciatic nerve regeneration and functional restoration nearly to the levels achieved by autologous nerve grafts according to behavioral, histological, and electrophysiological evidence. For achieving better effect of neuroregeneration, this is the first time to jointly apply a dynamic perfusion bioreactor and the ascorbic acid to stimulate the SKP-SCs secretion of extracellular matrix (ECM). To overcome the limitation of traditional tissue-engineered nerve grafts, jointly utilizing SKP-SCs and their ECM components were motivated by the thought of prolongating the effect of support cells and their bioactive cues that promote peripheral nerve regeneration. To further explore the regulatory model of gene expression and the related molecular mechanisms involved in tissue engineering-aided peripheral nerve regeneration, we performed a cDNA microarray analysis of gene expression profiling, a comprehensive bioinformatics analysis and a validation study on the grafted segments and dorsal root ganglia tissues. A wealth of transcriptomic and bioinformatics data has revealed complex molecular networks and orchestrated functional regulation that may be responsible for the effects of SKP-SCs-TEN on promoting peripheral nerve regeneration. Our work provides new insights into transcriptomic features and patterns of molecular regulation in nerve functional recovery aided by SKP-SCs-TEN that sheds light on the broader possibilities for novel repair strategies of peripheral nerve injury.

Case Report: Flurbiprofen-induced Type I Kounis syndrome.

Background: Kounis syndrome is a specific type of acute coronary syndrome caused by allergic or hypersensitivity response. Clinical knowledge about this syndrome is insufficient. We report a case in which intravenous administration of flurbiprofen resulted in Type I Kounis syndrome. Case summary: A 60-year-old female patient with no history of coronary artery disease developed limb erythema, hypotension, and chest tightness after receiving intravenous flurbiprofen. Electrocardiogram showed ST segment elevation in leads II, III, and aVF. Emergency coronary angiography revealed no significant stenosis or thrombus in the coronary arteries. Subsequent echocardiography showed no apparent abnormalities. Levels of troponin T were elevated. The diagnosis was flurbiprofen-induced Type I Kounis syndrome, presenting as acute ST segment elevation myocardial infarction. Conclusions: Patients with Kounis syndrome can exhibit severe clinical symptoms, and their condition may even be life-threatening. It is important for clinicians to have a thorough understanding of this syndrome in order to develop comprehensive treatment plans.

The impact of the gut microbiome on tumor immunotherapy: from mechanism to application strategies.

Immunotherapy is one of the fastest developing areas in the field of oncology. Many immunological treatment strategies for refractory tumors have been approved and marketed. Nevertheless, much clinical and preclinical experimental evidence has shown that the efficacy of immunotherapy in tumor treatment varies markedly among individuals. The commensal microbiome mainly colonizes the intestinal lumen in humans, is affected by a variety of factors and exhibits individual variation. Moreover, the gut is considered the largest immune organ of the body due to its influence on the immune system. In the last few decades, with the development of next-generation sequencing (NGS) techniques and in-depth research, the view that the gut microbiota intervenes in antitumor immunotherapy through the immune system has been gradually confirmed. Here, we review important studies published in recent years focusing on the influences of microbiota on immune system and the progression of malignancy. Furthermore, we discuss the mechanism by which microbiota affect tumor immunotherapy, including immune checkpoint blockade (ICB) and adoptive T-cell therapy (ACT), and strategies for modulating the microbial composition to facilitate the antitumor immune response. Finally, opportunity and some challenges are mentioned to enable a more systematic understanding of tumor treatment in the future and promote basic research and clinical application in related fields.

Biomanufacturing of γ-linolenic acid-enriched galactosyldiacylglycerols: Challenges in microalgae and potential in oleaginous yeasts.

γ-Linolenic acid-enriched galactosyldiacylglycerols (GDGs-GLA), as the natural form of γ-linolenic acid in microalgae, have a range of functional activities, including anti-inflammatory, antioxidant, and anti-allergic properties. The low abundance of microalgae and the structural stereoselectivity complexity impede microalgae extraction or chemical synthesis, resulting in a lack of supply of GDGs-GLA with a growing demand. At present, there is a growing interest in engineering oleaginous yeasts for mass production of GDGs-GLA based on their ability to utilize a variety of hydrophobic substrates and a high metabolic flux toward fatty acid and lipid (triacylglycerol, TAG) production. Here, we first introduce the GDGs-GLA biosynthetic pathway in microalgae and challenges in the engineering of the native host. Subsequently, we describe in detail the applications of oleaginous yeasts with Yarrowia lipolytica as the representative for GDGs-GLA biosynthesis, including the development of synthetic biology parts, gene editing tools, and metabolic engineering of lipid biosynthesis. Finally, we discuss the development trend of GDGs-GLA biosynthesis in Y. lipolytica.

Bionic peptide scaffold in situ polarization and recruitment of M2 macrophages to promote peripheral nerve regeneration.

Tissue regeneration requires exogenous and endogenous signals, and there is increasing evidence that the exogenous microenvironment may play an even more dominant role in the complex process of coordinated multiple cells. The short-distance peripheral nerve showed a spontaneous regenerative phenomenon, which was initiated by the guiding role of macrophages. However, it cannot sufficiently restore long-distance nerve injury by itself. Based on this principle, we firstly constructed a proinflammatory model to prove that abnormal M2 expression reduce the guidance and repair effect of long-distance nerves. Furthermore, a bionic peptide hydrogel scaffold based on self-assembly was developed to envelop M2-derived regenerative cytokines and extracellular vesicles (EVs). The cytokines and EVs were quantified to mimic the guidance and regenerative microenvironment in a direct and mild manner. The bionic scaffold promoted M2 transformation in situ and led to proliferation and migration of Schwann cells, neuron growth and motor function recovery. Meanwhile, the peptide scaffold combined with CX3CL1 recruited more blood-derived M2 macrophages to promote long-distance nerve reconstruction. Overall, we systematically confirmed the important role of M2 in regulating and restoring the injury peripheral nerve. This bionic peptide hydrogel scaffold mimicked and remodeled the local environment for M2 transformation and recruitment, favoring long-distance peripheral nerve regeneration. It can help to explicate regulative effect of M2 may be a cause not just a consequence in nerve repair and tissue integration, which facilitating the development of pro-regenerative biomaterials.

Regulatory mechanism of CaMKII δ mediated by RIPK3 on myocardial fibrosis and reversal effects of RIPK3 inhibitor GSK'872.

BACKGROUND: Myocardial fibrosis (MF) remains a prominent challenge in heart disease. The role of receptor-interacting protein kinase 3 (RIPK3)-mediated necroptosis is evident in the pathogenesis of numerous heart diseases. Concurrently, the activation of Ca2+/calmodulin-dependent protein kinase (CaMKII) is pivotal in cardiovascular disease (CVD). This study aimed to evaluate the impact and underlying mechanisms of RIPK3 on myocardial injury in MF and to elucidate the potential involvement of CaMKII. METHODS: Building upon our previous research methods [1], wild-type (WT) mice and RIPK3 knockout (RIPK3 -/-) mice underwent random assignment for transverse aortic constriction (TAC) in vivo. Four weeks post-procedure, the MF model was effectively established. Parameters such as the extent of MF, myocardial injury, RIPK3 expression, necroptosis, CaMKII activity, phosphorylation of mixed lineage kinase domain-like protein (MLKL), mitochondrial ultrastructural details, and oxidative stress levels were examined. Cardiomyocyte fibrosis was simulated in vitro using angiotensin II on cardiac fibroblasts. RESULTS: TAC reliably produced MF, myocardial injury, CaMKII activation, and necroptosis in mice. RIPK3 depletion ameliorated these conditions. The RIPK3 inhibitor, GSK'872, suppressed the expression of RIPK3 in myocardial fibroblasts, leading to improved fibrosis and inflammation, diminished CaMKII oxidation and phosphorylation levels, and the rectification of CaMKIIδ alternative splicing anomalies. Furthermore, GSK'872 downregulated the expressions of RIPK1, RIPK3, and MLKL phosphorylation, attenuated necroptosis, and bolstered the oxidative stress response. CONCLUSIONS: Our data suggested that in MF mice, necroptosis was augmented in a RIPK3-dependent fashion. There seemed to be a positive correlation between CaMKII activation and RIPK3 expression. The adverse effects on myocardial fibrosis mediated by CaMKII δ through RIPK3 could potentially be mitigated by the RIPK3 inhibitor, GSK'872. This offered a fresh perspective on the amelioration and treatment of MF and myocardial injury.

Promoting axon regeneration by inhibiting RNA N6-methyladenosine demethylase ALKBH5.

A key limiting factor of successful axon regeneration is the intrinsic regenerative ability in both the peripheral nervous system (PNS) and central nervous system (CNS). Previous studies have identified intrinsic regenerative ability regulators that act on gene expression in injured neurons. However, it is less known whether RNA modifications play a role in this process. Here, we systematically screened the functions of all common m6A modification-related enzymes in axon regeneration and report ALKBH5, an evolutionarily conserved RNA m6A demethylase, as a regulator of axonal regeneration in rodents. In PNS, knockdown of ALKBH5 enhanced sensory axonal regeneration, whereas overexpressing ALKBH5 impaired axonal regeneration in an m6A-dependent manner. Mechanistically, ALKBH5 increased the stability of Lpin2 mRNA and thus limited regenerative growth associated lipid metabolism in dorsal root ganglion neurons. Moreover, in CNS, knockdown of ALKBH5 enhanced the survival and axonal regeneration of retinal ganglion cells after optic nerve injury. Together, our results suggest a novel mechanism regulating axon regeneration and point ALKBH5 as a potential target for promoting axon regeneration in both PNS and CNS.

Nerve cells, or neurons, are the key communication components of the body. Each neuron takes signals from many inputs and transmits them through a single output called the axon. In the central nervous system, which consists of the brain and spinal cord, damaged neurons do not generally repair themselves. But in the peripheral nervous system, where neurons branch out to other parts of the body, they can regenerate. For this to happen, genes which promote axon regrowth must be expressed. Messenger RNA carries DNA information from the nucleus of a cell to the cytoplasm where it serves as instructions for generating proteins. Certain enzymes can modify messenger RNA, changing how long it lasts, where it goes in the cell and what proteins it makes. It has been suggested that a particular RNA modification, known as m⁶A, plays an important role in axon regrowth as increased m⁶A levels have been reported in some neurons after a peripheral nerve injury. Wang et al. studied the impact of m⁶A modifications on axon regrowth by examining the effects of several genes associated with these modifications in rats. The experiments showed that expression of a gene called Alkbh5 ­ which codes for an enzyme that removes m⁶A modifications ­ regulates the amount of axon regrowth following an injury to peripheral nerves. Reducing the amount of Alkbh5 expression rates increased axon regrowth, whereas in rats where Alkbh5 was overexpressed, regrowth was reduced. Further experiments showed that the ALKBH5 enzyme helps to make mRNA from the gene Lpin2 more stable, which affects how it processes fats and lipids during the regeneration process. Moreover, in the central nervous system, reducing Alkbh5 expression enhanced survival and axon regrowth of neurons in the eye after they were injured in mice. The findings suggest that Alkbh5 influences axon regrowth and are an important step towards understanding how biological systems repair nerve damage. Future work should investigate if stopping Alkbh5 expression allows injured neurons to recover their function and how different m⁶A-associated enzymes work together in this process.

SnRNA-seq reveals the heterogeneity of spinal ventral horn and mechanism of motor neuron axon regeneration.

Spinal motor neurons, the distinctive neurons of the central nervous system, extend into the peripheral nervous system and have outstanding ability of axon regeneration after injury. Here, we explored the heterogeneity of spinal ventral horn cells after rat sciatic nerve crush via single-nuclei RNA sequencing. Interestingly, regeneration mainly occurred in a Sncg+ and Anxa2+ motor neuron subtype (MN2) surrounded by a newly emerged microglia subtype (Mg6) after injury. Subsequently, microglia depletion slowed down the regeneration of sciatic nerve. OPCs were also involved into the regeneration process. Knockdown of Cacna2d2 in vitro and systemic blocking of Cacna2d2 in vivo improved the axon growth ability, hinting us the importance of Ca2+. Ultimately, we proposed three possible phases of motor neuron axon regeneration: preparation stage, early regeneration stage, and regeneration stage. Taken together, our study provided a resource for deciphering the underlying mechanism of motor neuron axon regeneration in a single cell dimension.

Porous microneedle patch with sustained delivery of extracellular vesicles mitigates severe spinal cord injury.

The transplantation of mesenchymal stem cells-derived secretome, particularly extracellular vesicles is a promising therapy to suppress spinal cord injury-triggered neuroinflammation. However, efficient delivery of extracellular vesicles to the injured spinal cord, with minimal damage, remains a challenge. Here we present a device for the delivery of extracellular vesicles to treat spinal cord injury. We show that the device incorporating mesenchymal stem cells and porous microneedles enables the delivery of extracellular vesicles. We demonstrate that topical application to the spinal cord lesion beneath the spinal dura, does not damage the lesion. We evaluate the efficacy of our device in a contusive spinal cord injury model and find that it reduces the cavity and scar tissue formation, promotes angiogenesis, and improves survival of nearby tissues and axons. Importantly, the sustained delivery of extracellular vesicles for at least 7 days results in significant functional recovery. Thus, our device provides an efficient and sustained extracellular vesicles delivery platform for spinal cord injury treatment.

Oxidative stress: Roles in skeletal muscle atrophy.

Oxidative stress, inflammation, mitochondrial dysfunction, reduced protein synthesis, and increased proteolysis are all critical factors in the process of muscle atrophy. In particular, oxidative stress is the key factor that triggers skeletal muscle atrophy. It is activated in the early stages of muscle atrophy and can be regulated by various factors. The mechanisms of oxidative stress in the development of muscle atrophy have not been completely elucidated. This review provides an overview of the sources of oxidative stress in skeletal muscle and the correlation of oxidative stress with inflammation, mitochondrial dysfunction, autophagy, protein synthesis, proteolysis, and muscle regeneration in muscle atrophy. Additionally, the role of oxidative stress in skeletal muscle atrophy caused by several pathological conditions, including denervation, unloading, chronic inflammatory diseases (diabetes mellitus, chronic kidney disease, chronic heart failure, and chronic obstructive pulmonary disease), sarcopenia, hereditary neuromuscular diseases (spinal muscular atrophy, amyotrophic lateral sclerosis, and Duchenne muscular dystrophy), and cancer cachexia, have been discussed. Finally, this review proposes the alleviation oxidative stress using antioxidants, Chinese herbal extracts, stem cell and extracellular vesicles as a promising therapeutic strategy for muscle atrophy. This review will aid in the development of novel therapeutic strategies and drugs for muscle atrophy.