Spexin Diminishes Atrial Fibrillation Vulnerability by Acting on Galanin Receptor 2.

BACKGROUND: G protein-coupled receptors play a critical role in atrial fibrillation (AF). Spexin is a novel ligand of galanin receptors (GALRs). In this study, we investigated the regulation of spexin and GALRs on AF and the underlying mechanisms. METHODS: Global spexin knockout (SPX-KO) and cardiomyocyte-specific GALRs knockout (GALR-cKO) mice underwent burst pacing electrical stimulation. Optical mapping was used to determine atrial conduction velocity and action potential duration. Atrial myocyte action potential duration and inward rectifying K+ current (IK1) were recorded using whole-cell patch clamps. Isolated cardiomyocytes were stained with Fluo-3/AM dye, and intracellular Ca2+ handling was examined by CCD camera. A mouse model of AF was established by Ang-II (angiotensin II) infusion. RESULTS: Spexin plasma levels in patients with AF were lower than those in subjects without AF, and knockout of spexin increased AF susceptibility in mice. In the atrium of SPX-KO mice, potassium inwardly rectifying channel subfamily J member 2 (KCNJ2) and sarcolipin (SLN) were upregulated; meanwhile, IK1 current was increased and Ca2+ handling was impaired in isolated atrial myocytes of SPX-KO mice. GALR2-cKO mice, but not GALR1-cKO and GALR3-cKO mice, had a higher incidence of AF, which was associated with higher IK1 current and intracellular Ca2+ overload. The phosphorylation level of CREB (cyclic AMP responsive element binding protein 1) was upregulated in atrial tissues of SPX-KO and GALR2-cKO mice. Chromatin immunoprecipitation confirmed the recruitment of p-CREB to the proximal promoter regions of KCNJ2 and SLN. Finally, spexin treatment suppressed CREB signaling, decreased IK1 current and intracellular Ca2+ overload, which thus reduced the inducibility of AF in Ang-II-infused mice. CONCLUSIONS: Spexin reduces atrial fibrillation susceptibility by inhibiting CREB phosphorylation and thus downregulating KCNJ2 and SLN transcription by GALR2 receptor. The spexin/GALR2/CREB signaling pathway represents a novel therapeutic avenue in the development of agents against atrial fibrillation.

m6A reader YTHDF1 promotes cardiac fibrosis by enhancing AXL translation.

Cardiac fibrosis caused by ventricular remodeling and dysfunction such as post-myocardial infarction (MI) can lead to heart failure. RNA N6-methyladenosine (m6A) methylation has been shown to play a pivotal role in the occurrence and development of many illnesses. In investigating the biological function of the m6A reader YTHDF1 in cardiac fibrosis, adeno-associated virus 9 was used to knock down or overexpress the YTHDF1 gene in mouse hearts, and MI surgery in vivo and transforming growth factor-ß (TGF-ß)-activated cardiac fibroblasts in vitro were performed to establish fibrosis models. Our results demonstrated that silencing YTHDF1 in mouse hearts can significantly restore impaired cardiac function and attenuate myocardial fibrosis, whereas YTHDF1 overexpression could further enhance cardiac dysfunction and aggravate the occurrence of ventricular pathological remodeling and fibrotic development. Mechanistically, zinc finger BED-type containing 6 mediated the transcriptional function of the YTHDF1 gene promoter. YTHDF1 augmented AXL translation and activated the TGF-ß-Smad2/3 signaling pathway, thereby aggravating the occurrence and development of cardiac dysfunction and myocardial fibrosis. Consistently, our data indicated that YTHDF1 was involved in activation, proliferation, and migration to participate in cardiac fibrosis in vitro. Our results revealed that YTHDF1 could serve as a potential therapeutic target for myocardial fibrosis.

The m7G Methyltransferase Mettl1 Drives Cardiac Hypertrophy by Regulating SRSF9-Mediated Splicing of NFATc4.

Cardiac hypertrophy is a key factor driving heart failure (HF), yet its pathogenesis remains incompletely elucidated. Mettl1-catalyzed RNA N7-methylguanosine (m7G) modification has been implicated in ischemic cardiac injury and fibrosis. This study aims to elucidate the role of Mettl1 and the mechanism underlying non-ischemic cardiac hypertrophy and HF. It is found that Mettl1 is upregulated in human failing hearts and hypertrophic murine hearts following transverse aortic constriction (TAC) and Angiotensin II (Ang II) infusion. YY1 acts as a transcriptional factor for Mettl1 during cardiac hypertrophy. Mettl1 knockout alleviates cardiac hypertrophy and dysfunction upon pressure overload from TAC or Ang II stimulation. Conversely, cardiac-specific overexpression of Mettl1 results in cardiac remodeling. Mechanically, Mettl1 increases SRSF9 expression by inducing m7G modification of SRSF9 mRNA, facilitating alternative splicing and stabilization of NFATc4, thereby promoting cardiac hypertrophy. Moreover, the knockdown of SRSF9 protects against TAC- or Mettl1-induced cardiac hypertrophic phenotypes in vivo and in vitro. The study identifies Mettl1 as a crucial regulator of cardiac hypertrophy, providing a novel therapeutic target for HF.

LncRNA CCRR maintains Ca2+ homeostasis against myocardial infarction through the FTO-SERCA2a pathway.

Cardiac conduction regulatory RNA (CCRR) has been documented as an antiarrhythmic lncRNA in our earlier investigation. This study aimed to evaluate the effects of CCRR on SERCA2a and the associated Ca2+ homeostasis in myocardial infarction (MI). Overexpression of CCRR via AAV9-mediated delivery not only partially reversed ischemia-induced contractile dysfunction but also alleviated abnormal Ca2+ homeostasis and reduced the heightened methylation level of SERCA2a following MI. These effects were also observed in CCRR over-expressing transgenic mice. A conserved sequence domain of CCRR mimicked the protective function observed with the full length. Furthermore, silencing CCRR in healthy mice led to intracellular Ca2+ overloading of cardiomyocytes. CCRR increased SERCA2a protein stability by upregulating FTO expression. The direct interaction between CCRR and FTO protein was characterized by RNA-binding protein immunoprecipitation (RIP) analysis and RNA pulldown experiments. Activation of NFATc3 was identified as an upstream mechanism responsible for CCRR downregulation in MI. This study demonstrates that CCRR is a protective lncRNA that acts by maintaining the function of FTO, thereby reducing the m6A RNA methylation level of SERCA2a, ultimately preserving calcium homeostasis for myocardial contractile function in MI. Therefore, CCRR may be considered a promising therapeutic strategy with a beneficial role in cardiac pathology.

Kanglexin counters vascular smooth muscle cell dedifferentiation and associated arteriosclerosis through inhibiting PDGFR.

BACKGROUND: Dysregulation of vascular smooth muscle cell (VSMC) function leads to a variety of diseases such as atherosclerosis and hyperplasia after injury. However, antiproliferative drug targeting VSMC exhibits poor specificity. Therefore, there is an urgent to develop highly specific antiproliferative drugs to prevention and treatment VSMC dedifferentiation associated arteriosclerosis. Kanglexin (KLX), a new anthraquinone compound designed by our team, has potential to regulate VSMC phenotype according to the physicochemical properties. PURPOSE: This project aims to evaluate the therapeutic role of KLX in VSMC dedifferentiation and atherosclerosis, neointimal formation and illustrates the underlying molecular mechanism. METHODS: In vivo, the ApoE-/- mice were fed with high-fat diet (HFD) for a duration of 13 weeks to establish the atherosclerotic model. And rat carotid artery injury model was performed to establish the neointimal formation model. In vitro, PDGF-BB was used to induce VSMC dedifferentiation. RESULTS: We found that KLX ameliorated the atherosclerotic progression including atherosclerotic lesion formation, lipid deposition and collagen deposition in aorta and aortic sinus in atherosclerotic mouse model. In addition, The administration of KLX effectively ameliorated neointimal formation in the carotid artery following balloon injury in SD rats. The findings derived from molecular docking and surface plasmon resonance (SPR) experiments unequivocally demonstrate that KLX had potential to bind PDGFR-ß. Mechanism research work proved that KLX prevented VSMC proliferation, migration and dedifferentiation via activating the PDGFR-ß-MEK -ERK-ELK-1/KLF4 signaling pathway. CONCLUSION: Collectively, we demonstrated that KLX effectively attenuated the progression of atherosclerosis in ApoE-/- mice and carotid arterial neointimal formation in SD rats by inhibiting VSMC phenotypic conversion via PDGFR-ß-MEK-ERK-ELK-1/KLF4 signaling. KLX exhibits promising potential as a viable therapeutic agent for the treatment of VSMC phenotype conversion associated arteriosclerosis.

The Therapeutic Potential of Four Main Compounds of Zanthoxylum nitidum (Roxb.) DC: A Comprehensive Study on Biological Processes, Anti-Inflammatory Effects, and Myocardial Toxicity.

Zanthoxylum nitidum (Roxb.) DC. (Z. nitidum) is a traditional Chinese medicinal plant that is indigenous to the southern regions of China. Previous research has provided evidence of the significant anti-inflammatory, antibacterial, and anticancer properties exhibited by Z. nitidum. The potential therapeutic effects and cardiac toxicity of Z. nitidum remain uncertain. The aim of this research was to investigate the potential therapeutic properties of the four main compounds of Z. nitidum in cardiovascular diseases, their impact on the electrical activity of cardiomyocytes, and the underlying mechanism of their anti-inflammatory effects. We selected the four compounds from Z. nitidum with a high concentration and specific biological activity: nitidine chloride (NC), chelerythrine chloride (CHE), magnoflorine chloride (MAG), and hesperidin (HE). A proteomic analysis was conducted on the myocardial tissues of beagle dogs following the administration of NC to investigate the role of NC in vivo and the associated biological processes. A bioinformatic analysis was used to predict the in vivo biological processes that MAG, CHE, and HE were involved in. Molecular docking was used to simulate the binding between compounds and their targets. The effect of the compounds on ion channels in cardiomyocytes was evaluated through a patch clamp experiment. Organ-on-a-chip (OOC) technology was developed to mimic the physiological conditions of the heart in vivo. Proteomic and bioinformatic analyses demonstrated that the four compounds of Z. nitidum are extensively involved in various cardiovascular-related biological pathways. The findings from the patch clamp experiments indicate that NC, CHE, MAG, and HE elicit a distinct activation or inhibition of the IK1 and ICa-L in cardiomyocytes. Finally, the anti-inflammatory effects of the compounds on cardiomyocytes were verified using OOC technology. NC, CHE, MAG, and HE demonstrate anti-inflammatory effects through their specific interactions with prostaglandin-endoperoxide synthase 2 (PTGS2) and significantly influence ion channels in cardiomyocytes. Our study provides a foundation for utilizing NC, CHE, MAG, and HE in the treatment of cardiovascular diseases.

The positive feedback loop of the NAT10/Mybbp1a/p53 axis promotes cardiomyocyte ferroptosis to exacerbate cardiac I/R injury.

Ferroptosis is a nonapoptotic form of regulated cell death that has been reported to play a central role in cardiac ischemia‒reperfusion (I/R) injury. N-acetyltransferase 10 (NAT10) contributes to cardiomyocyte apoptosis by functioning as an RNA ac4c acetyltransferase, but its role in cardiomyocyte ferroptosis during I/R injury has not been determined. This study aimed to elucidate the role of NAT10 in cardiac ferroptosis as well as the underlying mechanism. The mRNA and protein levels of NAT10 were increased in mouse hearts after I/R and in cardiomyocytes that were exposed to hypoxia/reoxygenation. P53 acted as an endogenous activator of NAT10 during I/R in a transcription-dependent manner. Cardiac overexpression of NAT10 caused cardiomyocyte ferroptosis to exacerbate I/R injury, while cardiomyocyte-specific knockout of NAT10 or pharmacological inhibition of NAT10 with Remodelin had the opposite effects. The inhibition of cardiomyocyte ferroptosis by Fer-1 exerted superior cardioprotective effects against the NAT10-induced exacerbation of post-I/R cardiac damage than the inhibition of apoptosis by emricasan. Mechanistically, NAT10 induced the ac4C modification of Mybbp1a, increasing its stability, which in turn activated p53 and subsequently repressed the transcription of the anti-ferroptotic gene SLC7A11. Moreover, knockdown of Mybbp1a partially abolished the detrimental effects of NAT10 overexpression on cardiomyocyte ferroptosis and cardiac I/R injury. Collectively, our study revealed that p53 and NAT10 interdependently cooperate to form a positive feedback loop that promotes cardiomyocyte ferroptosis to exacerbate cardiac I/R injury, suggesting that targeting the NAT10/Mybbp1a/p53 axis may be a novel approach for treating cardiac I/R.

The role of lncRNA-mediated ceRNA regulatory networks in liver fibrosis.

In the dynamic realm of molecular biology and biomedical research, the significance of long non-coding RNAs (lncRNAs) acting as competing endogenous RNAs (ceRNAs) continues to grow, encompassing a broad spectrum of both physiological and pathological conditions. Particularly noteworthy is their pivotal role in the intricate series of events leading to the development of hepatic fibrosis, where hepatic stellate cells (HSCs) play a central role. Recent strides in scientific exploration have unveiled the intricate involvement of lncRNAs as ceRNAs in orchestrating the activation of HSCs. This not only deepens our comprehension of the functioning of proteins, DNA, and the extensive array of coding and noncoding RNAs but also sheds light on the intricate molecular interactions among these molecules. Furthermore, the well-established ceRNA networks, involving classical interactions between lncRNAs, microRNAs (miRNAs), and messenger RNAs (mRNAs), are not mere bystanders; they actively participate in instigating and advancing liver fibrosis. This underscores the pressing need for additional thorough research to fully grasp the potential of ceRNA. The unyielding pursuit of knowledge in this field remains a potent driving force with the capacity to enhance the quality of life for numerous individuals grappling with such diseases. It holds the promise of ushering in a new era of precision medicine, signifying a relentless dedication to unraveling the intricacies of molecular interactions that could pave the way for transformative advancements in the diagnosis and treatment of hepatic fibrosis.

Innovative pharmacotherapy for hepatic metabolic and chronic inflammatory diseases in China.

Liver disease constitutes a significant global health concern, particularly in China where it has distinctive characteristics. China grapples with a staggering 300 million cases, predominantly due to hepatitis B and metabolic non-alcoholic fatty liver disease. Additionally, hepatocellular carcinoma has become a prevalent which is a lethal type of cancer. Despite the scarcity of innovative treatment options, Chinese hepatologists and researchers have achieved notable breakthroughs in the prevention, diagnosis, management and treatment of liver diseases. Traditional Chinese medicines have found widespread application in the treatment of various liver ailments owing to their commendable pharmacological efficacy and minimal side effects. Furthermore, there is a growing body of research in extracellular vesicles, cell therapy and gene therapy, offering new hope in the fight against liver diseases. This paper provides a comprehensive overview of the epidemiological characteristics of liver diseases and the diverse array of treatments that Chinese scholars and scientists have pursued in critical field.

EEBR induces Caspase-1-dependent pyroptosis through the NF-κB/NLRP3 signalling cascade in non-small cell lung cancer.

Lung cancer is a leading cause of cancer-related deaths worldwide. Recent studies have identified pyroptosis, a type of programmed cell death, as a critical process in the development and progression of lung cancer. In this study, we investigated the effect of EEBR, a new compound synthesized by our team, on pyroptosis in non-small cell lung cancer cells (NSCLC) and the underlying molecular mechanisms. Our results demonstrated that EEBR significantly reduced the proliferation and metastasis of NSCLC cells in vitro. Moreover, EEBR-induced pyroptosis in NSCLC cells, as evidenced by cell membrane rupture, the release of cytokines such as interleukin-18 and interleukin-1 beta and the promotion of Gasdermin D cleavage in a Caspase-1-dependent manner. Furthermore, EEBR promoted the nuclear translocation of NF-κB and upregulated the protein level of NLRP3. Subsequent studies revealed that EEBR-induced pyroptosis was suppressed by the inhibition of NF-κB. Finally, EEBR effectively suppressed the growth of lung cancer xenograft tumours by promoting NSCLC pyroptosis in animal models. Taken together, our findings suggest that EEBR induces Caspase-1-dependent pyroptosis through the NF-κB/NLRP3 signalling cascade in NSCLC, highlighting its potential as a candidate drug for NSCLC treatment.

Salvianolic acid A provides neuroprotective effects on cerebral ischemia-reperfusion injury in rats via PKA/CREB/c-Fos signaling pathway.

BACKGROUND: Cerebral ischemia-reperfusion injury (CIRI) is a phenomenon that pathological injury of ischemic brain tissue is further aggravated after the restoration of blood supply. The complex pathological mechanism of CIRI has led to the failure of multiple neuroprotective agents in clinical studies. Salvianolic acid A (SAA) is a neuroprotective extract from Salvia miltiorrhiza Bge., with significant pharmacological activities in the treatment of brain injury. However, the neuroprotective mechanisms of SAA remain unclear. PURPOSE: To explore the potential protective effect of SAA on CIRI and its mechanism, and to provide experimental basis for the research of new drugs for CIRI. STUDY DESIGN: A model of transient middle cerebral artery occlusion (tMCAO) in rats was used to simulate clinical CIRI, and the neuroprotective effect of SAA on tMCAO rats was investigated within 14 days after reperfusion. The improvement effects of SAA on cognitive impairment of tMCAO rats were investigated by behavioral tests from days 7-14. Finally, the neuroprotective mechanism of SAA was investigated on day 14. METHODS: The neuroprotective effects and mechanism of SAA were investigated by behavioral tests, HE and TUNEL staining, RNA sequence (RNA-seq) analysis and Western blot in tMCAO rats. RESULTS: The brain protective effects of SAA were achieved by alleviating cerebral infarction, cerebral edema, cerebral atrophy and nerve injury in tMCAO rats. Meanwhile, SAA could effectively improve the cognitive impairment and pathological damage of hippocampal tissue, and inhibit cell apoptosis in tMCAO rats. Besides, SAA could provide neuroprotective effects by up-regulating the expression of Bcl-2, inhibiting the activation of Caspase 3, and regulating PKA/CREB/c-Fos signaling pathway. CONCLUSION: SAA can significantly improve brain injury and cognitive impairment in CIRI rats, and this neuroprotective effect may be achieved through the anti-apoptotic effect and the regulation of PKA/CREB/c-Fos signaling pathway.

Cannabidiol represses miR-143 to promote cardiomyocyte proliferation and heart regeneration after myocardial infarction.

Mammalian heart is capable to regenerate almost completely early after birth through endogenous cardiomyocyte proliferation. However, this regenerative capacity diminishes gradually with growth and is nearly lost in adulthood. Cannabidiol (CBD) is a major component of cannabis and has various biological activities to regulate oxidative stress, fibrosis, inflammation, and cell death. The present study was conducted to investigate the pharmacological effects of CBD on heart regeneration in post-MI mice. MI models in adult mice were constructed via coronary artery ligation, which were administrated with or without CBD. Our results demonstrate that systemic administration (10 mg/kg) of CBD markedly increased cardiac regenerative ability, reduced infarct size, and restored cardiac function in MI mice. Consistently, in vitro study also showed that CBD was able to promote the proliferation of neonatal cardiomyocytes. Mechanistically, the expression of miR-143-3p related to cardiomyocyte proliferation was significantly down-regulated in CBD-treated cardiomyocytes, while the overexpression of miR-143-3p inhibited cardiomyocyte mitosis and eliminated CBD-induced cardiomyocyte proliferation. Moreover, CBD enhanced the expression of Yap and Ctnnd1, which were demonstrated as the target genes of miR-143-3p. Silencing of Yap and Ctnnd1 hindered the proliferative effects of CBD. We further revealed that inhibition of the cannabinoid receptor 2 impeded the regulatory effect of CBD on miR-143-3p and its downstream target Yap/Ctnnd1, which ultimately eliminated the pro-proliferative effect of CBD on neonatal and adult cardiomyocytes. Taken together, CBD promotes cardiomyocyte proliferation and heart regeneration after MI via miR-143-3p/Yap/Ctnnd1 signaling pathway, which provides a new strategy for cardiac repair in adult myocardium.

MiRNAs and Their Role in Venous Thromboembolic Complications.

Venous thromboembolic complications (VTCs), which include deep vein thrombosis (DVT) and pulmonary embolism (PE), have remained a pressing problem in modern clinical medicine for a long time. Despite the already wide arsenal of modern methods for diagnosing and treating this disease, VTCs rank third in the structure of causes of death among all cardiovascular diseases, behind myocardial infarction (MI) and ischemic stroke (IS). Numerous studies have confirmed the importance of understanding the molecular processes of VTCs for effective therapy and diagnosis. Significant progress has been made in VTC research in recent years, where the relative contribution of microRNAs (miRNAs) in the mechanism of thrombus formation and their consideration as therapeutic targets have been well studied. In this case, accurate, timely, and as early as possible diagnosis of VTCs is of particular importance, which will help improve both short-term and long-term prognoses of patients. This case accounts for the already well-studied circulating miRNAs as non-invasive biomarkers. This study presents currently available literature data on the role of miRNAs in VTCs, revealing their potential as therapeutic targets and diagnostic and prognostic tools for this terrible disease.

Long non-coding RNA LHX1-DT regulates cardiomyocyte differentiation through H2A.Z-mediated LHX1 transcriptional activation.

Long non-coding RNAs (lncRNAs) play widespread roles in various processes. However, there is still limited understanding of the precise mechanisms through which they regulate early stage cardiomyocyte differentiation. In this study, we identified a specific lncRNA called LHX1-DT, which is transcribed from a bidirectional promoter of LIM Homeobox 1 (LHX1) gene. Our findings demonstrated that LHX1-DT is nuclear-localized and transiently elevated expression along with LHX1 during early differentiation of cardiomyocytes. The phenotype was rescued by overexpression of LHX1 into the LHX1-DT-/- hESCs, indicating LHX1 is the downstream of LHX1-DT. Mechanistically, we discovered that LHX1-DT physically interacted with RNA/histone-binding protein PHF6 during mesoderm commitment and efficiently replaced conventional histone H2A with a histone variant H2A.Z at the promoter region of LHX1. In summary, our work uncovers a novel lncRNA, LHX1-DT, which plays a vital role in mediating the exchange of histone variants H2A.Z and H2A at the promoter region of LHX1.

SHP2 potentiates anti-PD-1 effectiveness through intervening cell pyroptosis resistance in triple-negative breast cancer.

Triple negative breast cancer (TNBC) presents a formidable challenge due to the lack of effective treatment modalities. Immunotherapy stands as a promising therapeutic approach; however, the emergence of drug resistance mechanisms within tumor cells, particularly those targeting apoptosis and pyroptosis, has hampered its clinical efficacy. SHP2 is intricately involved in diverse physiological processes, including immune cell proliferation, infiltration, and tumor progression. Nevertheless, the precise contribution of SHP2 to tumor cell pyroptosis resistance remains inadequately understood. Herein, we demonstrate that SHP2 inhibition hampers the proliferative, migratory, and invasive capabilities of TNBC, accompanied by noticeable alterations in cellular membrane architecture. Mechanistically, we provide evidence that SHP2 depletion triggers the activation of Caspase-1 and GSDMD, resulting in GSDMD-dependent release of LDH, IL-1ß, and IL-18. Furthermore, computational analyses and co-localization investigations substantiate the hypothesis that SHP2 may hinder pyroptosis through direct binding to JNK, thereby impeding JNK phosphorylation. Our cellular experiments further corroborate these findings by demonstrating that JNK inhibition rescues pyroptosis induced by SHP2 knockdown. Strikingly, in vivo experiments validate the suppressive impact of SHP2 knockdown on tumor progression via enhanced JNK phosphorylation. Additionally, SHP2 knockdown augments tumor sensitivity to anti-PD-1 therapy, thus reinforcing the pro-pyroptotic effects and inhibiting tumor growth. In summary, our findings elucidate the mechanism by which SHP2 governs TNBC pyroptosis, underscoring the potential of SHP2 inhibition to suppress cell pyroptosis resistance and its utility as an adjunctive agent for tumor immunotherapy.

Methods of miRNA delivery and possibilities of their application in neuro-oncology.

In the current phase of medical progress, practical neuro-oncology faces critical challenges. These include the quest for and development of innovative methodological approaches, as well as the enhancement of conventional therapies to boost their efficacy in treating brain tumors, especially the malignant varieties. Recent strides in molecular and cellular biology, molecular genetics, and immunology have charted the primary research pathways in the development of new anti-cancer medications, with a particular focus on microRNA (miRNA)-based therapy. MiRNAs possess the ability to function as suppressors of tumor growth while also having the potential to act as oncogenes. MiRNAs wield control over numerous processes within the human body, encompassing tumor growth, proliferation, invasion, metastasis, apoptosis, angiogenesis, and immune responses. A significant impediment to enhancing the efficacy of brain tumor treatment lies in the unresolved challenge of traversing the blood-brain barrier (BBB) and blood-tumor barrier (BTB) to deliver therapeutic agents directly to the tumor tissue. Presently, there is a worldwide effort to conduct intricate research and design endeavors aimed at creating miRNA-based dosage forms and delivery systems that can effectively target various structures within the central nervous system (CNS). MiRNA-based therapy stands out as one of the most promising domains in neuro-oncology. Hence, the development of efficient and safe methods for delivering miRNA agents to the specific target cells within brain tumors is of paramount importance. In this study, we will delve into recent findings regarding various methods for delivering miRNA agents to brain tumor cells. We will explore the advantages and disadvantages of different delivery systems and consider some clinical aspects of miRNA-based therapy for brain tumors.

Role of exosomal ncRNAs in traumatic brain injury.

Traumatic brain injury (TBI) is a complex neurological disorder that often results in long-term disabilities, cognitive impairments, and emotional disturbances. Despite significant advancements in understanding the pathophysiology of TBI, effective treatments remain limited. In recent years, exosomal non-coding RNAs (ncRNAs) have emerged as potential players in TBI pathogenesis and as novel diagnostic and therapeutic targets. Exosomal ncRNAs are small RNA molecules that are secreted by cells and transported to distant sites, where they can modulate gene expression and cell signaling pathways. They have been shown to play important roles in various aspects of TBI, such as neuroinflammation, blood-brain barrier dysfunction, and neuronal apoptosis. The ability of exosomal ncRNAs to cross the blood-brain barrier and reach the brain parenchyma makes them attractive candidates for non-invasive biomarkers and drug delivery systems. However, significant challenges still need to be addressed before exosomal ncRNAs can be translated into clinical practice, including standardization of isolation and quantification methods, validation of their diagnostic and prognostic value, and optimization of their therapeutic efficacy and safety. This review aims to summarize the current knowledge regarding the role of exosomal ncRNAs in TBI, including their biogenesis, function, and potential applications in diagnosis, prognosis, and treatment. We also discuss the challenges and future perspectives of using exosomal ncRNAs as clinical tools for TBI management.

Cullin-associated and neddylation-dissociated protein 1 (CAND1) alleviates NAFLD by reducing ubiquitinated degradation of ACAA2.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder with high morbidity and mortality. The current study aims to explore the role of Cullin-associated and neddylation-dissociated protein 1 (CAND1) in the development of NAFLD and the underlying mechanisms. CAND1 is reduced in the liver of NAFLD male patients and high fat diet (HFD)-fed male mice. CAND1 alleviates palmitate (PA) induced lipid accumulation in vitro. Hepatocyte-specific knockout of CAND1 exacerbates HFD-induced liver injury in HFD-fed male mice, while hepatocyte-specific knockin of CAND1 ameliorates these pathological changes. Mechanistically, deficiency of CAND1 enhances the assembly of Cullin1, F-box only protein 42 (FBXO42) and acetyl-CoA acyltransferase 2 (ACAA2) complexes, and thus promotes the ubiquitinated degradation of ACAA2. ACAA2 overexpression abolishes the exacerbated effects of CAND1 deficiency on NAFLD. Additionally, androgen receptor binds to the -187 to -2000 promoter region of CAND1. Collectively, CAND1 mitigates NAFLD by inhibiting Cullin1/FBXO42 mediated ACAA2 degradation.

YTHDF2 Promotes Cardiac Ferroptosis via Degradation of SLC7A11 in Cardiac Ischemia-Reperfusion Injury.

Aims: Myocardial ischemia-reperfusion (I/R) injury facilitates cardiomyocyte death and endangers human health. N6-methyladenosine (m6A) methylation plays a critical role in cardiovascular diseases. The m6A reader YTHDF2 identifies m6A-modified RNA and promotes target RNA degradation. Hence, we hypothesized that YTHDF2 affects I/R injury by regulating RNA stability. Results: Both messenger RNA (mRNA) and protein levels of YTHDF2 were upregulated in I/R mice and hypoxia-reoxygenation (H/R)-induced cardiomyocytes. Silencing endogenous YTHDF2 abrogated cardiac dysfunction and lowered the infarct size in I/R mice, and the forced expression of YTHDF2 aggravated these adverse pathological processes. Consistently, the protective effect of silencing YTHDF2 occurred in cardiomyocytes exposed to H/R and erastin. Further, RNA-Seq and RNA-binding protein immunoprecipitation (RIP) revealed that YTHDF2 recognized the m6A modification sites of the ferroptosis-related gene solute carrier family 7 member 11 (SLC7A11) mRNA to promote its degradation both in vivo and in vitro. Inhibition of SLC7A11 impaired cardiac function, increased infarct size, and the release of lactate dehydrogenase (LDH) in I/R mice after silencing YTHDF2. The beneficial effects of si-YTHDF2 on H/R injury were reversed by co-transfection with SLC7A11-specific siRNA (si-SLC7A11), which substantially exacerbated ferroptosis and the production of reactive oxygen species. Innovation and Conclusion: The cardioprotective effects of silencing YTHDF2 are accomplished by increasing SLC7A11 stability and expression, reducing ferroptosis, and providing novel potential therapeutic targets for treating ischemic cardiac diseases.

The roles of long noncoding RNAs in atrial fibrillation.

Atrial fibrillation (AF) is a common cardiac arrhythmia that often occurs in patients with structural heart disease and is a significant cause of morbidity and mortality in clinical settings. AF is typically associated with significant changes of both the structure of the atria and the cardiac conduction system. AF can result in reduced heart function, heart failure, and various other complications. Current drug therapy for AF patients is often ineffective and may have adverse effects. Radiofrequency ablation is more effective than traditional drug therapy, but this invasive procedure carries potential risks and may lead to postoperative recurrence, limiting the clinical benefits to some extent. Therefore, in-depth research into the molecular mechanisms of AF and exploration of new treatment strategies based on research findings are prerequisites for improving the treatment of AF and the associated cardiac conditions. Long noncoding RNAs (lncRNAs) are a new class of noncoding RNA (ncRNAs) with a length exceeding 200 nt, which regulate gene expression at multiple levels. Increasing evidence suggests that lncRNAs participate in many pathological processes of AF initiation, development, and maintenance, such as structural remodeling, electrical remodeling, renin-angiotensin system anomalies, and intracellular calcium deregulation s. LncRNAs that play key roles in structural and electrical remodeling may become molecular markers and targets for AF diagnosis and treatment, respectively, while lncRNAs critical to autonomic nervous system remodeling may bring new insights into the prognosis and recurrence of AF. This review article provides a synopsis on the up-to-date research findings relevant to the roles of lncRNAs in AF.