Early diagnosis of AMI is crucial for improving patient outcomes, yet current clinical tools often lack the requisite sensitivity and specificity for reliable early detection. As neutrophils are the first innate immune responders mobilized following infarction, we employed an integrated multi-omics and machine learning approach to identify neutrophil-driven molecular signatures with diagnostic potential. By analyzing multiple peripheral blood transcriptomic datasets, we conducted differential expression and immune infiltration analyses, followed by machine learning-based feature selection to pinpoint key genes linked to neutrophil activity. Integration of these findings with single-cell transcriptomic data further clarified the neutrophil-specific expression patterns of candidate genes during AMI progression. Using a joint diagnostic model, we identified MCEMP1, NFE2, and AQP9 as the most informative predictors, with MCEMP1 emerging as the primary contributor. Experimental validation in a murine model of myocardial infarction (MI) confirmed rapid upregulation of MCEMP1 after injury, closely mirroring the kinetics of neutrophil infiltration. Collectively, these findings delineate a neutrophil-associated molecular profile of early AMI and highlight MCEMP1 as a promising noninvasive biomarker and a potential therapeutic target for modulating neutrophil-driven myocardial injury.

Excessive hepatic glucose production is a key driver of the progression of type 2 diabetes (T2DM), a highly prevalent global metabolic disorder. We previously reported that Sam68 expression is upregulated in the livers of both diabetic patients and mouse models, and hepatocyte-specific knockdown of Sam68 greatly alleviates hyperglycemia and improves insulin sensitivity in diabetic mice. Here, we engineered a series of ligand-functionalized lipid nanoparticles (LNPs) and identified a galactose-decorated formulation (LNP-Gal) that enables efficient hepatocyte-selective delivery of Sam68 siRNA, thereby achieving robust Sam68 silencing and suppressing hepatic gluconeogenesis in both cellular and animal models. In both genetic and diet-induced diabetic mouse models, systemic administration of siSam68/LNP-Gal improved glycemic control and insulin responsiveness and attenuated hepatic gluconeogenic output, accompanied by suppression of the hepatic gluconeogenic program. Thus, we establish siSam68/LNP-Gal as a hepatocyte-selective siRNA delivery system that elicits a potent antihyperglycemic effect with a favorable safety profile in vitro and in vivo, providing a promising siRNA-based strategy for the treatment of T2DM and related metabolic disorders.

Hydrogen sulfide (H2S) is a potent redox-active signaling molecule commonly dysregulated in disease states. The production of H2S and its involvement in various pathological conditions associated with mitochondrial dysfunction have extensively documented. During stress, cystathionine gamma-lyase and cystathionine beta-synthase in cytosol are copiously translocated into the mitochondria to boost H2S production, confirming its pivotal role in mitochondrial activities. However, little study has been done on H2S levels in tissues, cells and organelles, mainly due to the absence of precise and accurate detection tools. Thus, there is an urgent need to determine and monitor the levels of H2S in these important organelles. Fluorescent probes are efficient tools for detecting and monitoring various important biomolecules including biological thiols. The development of fluorescent probes is a multi-pronged approach which involves coupling fluorophores with responsive sites. The use of fluorescent probes for monitoring mitochondrial H2S levels has recently received widespread attention, resulting in numerous publications depicting their synthesis, mechanism of action, application, and potential challenges. Fluorescent probes offer precise and timely results, high sensitivity and selectivity, low biotoxicity, and minimal background interference. In this review, we aim to report designs of such probes, reaction mechanisms and their application in detecting mitochondrial H2S levels. Fluorescent probes can help uncover physio/pathological levels of H2S in essential organelles, its interactions with various biomarkers and associated consequences in biological systems.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously referred to as non-alcoholic fatty liver disease (NAFLD), is recognized as a highly heterogeneous condition. The elusive mechanisms driving its progression contribute to the lack of reliable diagnostic markers and effective treatments. In this study, we first identified 52 differentially expressed genes (DEGs) in MASLD stage by analyzing two public datasets, GSE126848 and GSE135251, using the DESeq2 and edgeR packages. Subsequently, these DEGs were subjected to protein-protein interaction (PPI) network analysis, revealing the top 10 hub genes. By intersecting the top 10 hub genes with another public dataset GSE260222, we observed that CDKN1A was the sole gene consistently upregulated in the livers of MASLD patients across all analyses. The elevated protein expression of CDKN1A was further validated in the livers of MASLD patients compared to control subjects. Consistently, compared to their respective control groups, both CDKN1A mRNA and protein levels were dramatically increased in the livers of MASLD animal models, including high-fat diet (HFD) induced obese mice, leptin-deficient obese (ob/ob) mice and leptin receptor-deficient (db/db) mice, and in mouse primary hepatocytes treated with free fatty acids (FFA), respectively. Interestingly, we found that CDKN1A transcript levels were progressively and significantly increased with the severity of MASLD in four out of five datasets and positively correlated with both the NAFLD activity score (NAS) and fibrosis stage, two important clinicopathological features of MASLD. Collectively, our results illustrated that CDKN1A may serve as a promising biomarker and therapeutic target for MASLD; however, its role in the disease's pathology warrants further investigation.

Diabetes, a chronic disease significantly affects peoples’ health and quality of life. It is a major contributor of severe health complications, such as blindness, kidney failure, heart attacks, strokes, and lower limb amputations. Autophagy is a complex cellular process regulated by specific genes. It is responsible for degrading intracellular proteins and organelles within lysosomes, a process which is crucial for maintaining internal cellular balance and clearing damaged or obsolete cellular components. In the context of diabetes, autophagy plays a key role in maintaining blood glucose homeostasis, particularly through the regulation of insulin secretion and sensitivity. Additionally, autophagy aids in preserving the survival and function of pancreatic beta (β)-cells by eliminating harmful proteins within these cells, which is vital for the prevention and treatment of diabetes. Despite the key role autophagy plays in these aspects, its exact mechanisms and effects in diabetes are still complex and not fully understood. Therefore, further research is needed to deeply explore the specific mechanisms and potential therapeutic applications of autophagy in diabetes. This review explores autophagy's classification, mechanisms, role in diabetes pathogenesis and complications, and its potential in treatment strategies of disease.

LncRNAs are involved in modulating the individual risk and the severity of progression in metabolic dysfunction-associated fatty liver disease (MASLD), but their precise roles remain largely unknown. This study aimed to investigate the role of lncRNA Snhg3 in the development and progression of MASLD, along with the underlying mechanisms. In vitro and in vivo experiments revealed that Snhg3 is involved in lipid metabolism and steatosis. The result showed that Snhg3 was significantly downregulated in the liver of high-fat-induced obesity (DIO) mice. Notably, palmitic acid promoted the expression of Snhg3 and overexpression of Snhg3 increased lipid accumulation in primary hepatocytes. Furthermore, knock-in and knock-out models showed significant changes in body and liver weight, heat production, total oxygen consumption, and carbon dioxide production. Hepatocyte-specific Snhg3 deficiency alleviated hepatic steatosis in DIO mice, whereas overexpression induced the opposite effect. Mechanistically, Snhg3 promoted the expression, stability and nuclear localization of SND1 protein via interacting with SND1, thereby inducing K63-linked ubiquitination modification of SND1. Moreover, Snhg3 decreased the H3K27me3 level and induced SND1-mediated chromatin loose remodeling, thus reducing H3K27me3 enrichment at the Pparγ promoter and enhancing Pparγ expression. In addition, the administration of PPARγ inhibitor T0070907 improved Snhg3 -aggravated hepatic steatosis. Our study revealed a new signaling pathway, Snhg3 /SND1/H3K27me3/PPARγ, responsible for MASLD and indicates that lncRNA-mediated epigenetic modification has a crucial role in the pathology of MASLD.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder marked by progressive motor and non-motor symptoms. Traditional treatments primarily manage symptoms rather than address the disease's root causes, highlighting the need for novel therapeutic approaches. Natural phytochemicals, particularly phenolic compounds, have shown potential due to their neuroprotective effects. Antiaris africana is commonly used in traditional African medicines to treat several illnesses including neurodegenerative disorders. However, its neuroprotective mechanism remains elusive. This study aimed to employ network pharmacology-based prediction to identify key targets and pathways through which A. africana exerts its effects on PD. Targets associated with Parkinsonism were identified and analyzed for interaction with compounds from A. africana. Protein-protein interaction (PPI) networks were constructed, and key hub genes were identified using Cytoscape. Functional enrichment analysis highlighted significant pathways involved in PD. Molecular docking was performed to evaluate the binding affinities of the compounds to PD-related targets. Our results reveal that compounds such as caffeic acid, chlorogenic acid, catechin, ellagic acid, epigallocatechin, gallic acid, isoquercitrin, kaempferol, quercetin, quercitrin, and rutin interact with key proteins implicated in PD, including APP, EGFR, CASP3, ESR1, AKT1, and MAPK8. Notably, rutin exhibited strong binding affinity for EGFR, and chlorogenic acid showed potential in modulating the APP pathway. These findings suggest that phenolic compounds in A. africana may exert neuroprotective effects through multiple molecular mechanisms, offering potential therapeutic strategies for PD. This study underscores the importance of integrating molecular docking and network pharmacology to elucidate the therapeutic potential of natural compounds in complex diseases like Parkinson's disease

EDITORIAL article Front. Pharmacol., 15 January 2024Sec. Gastrointestinal and Hepatic Pharmacology Volume 15 - 2024 | https://doi.org/10.3389/fphar.2024.1364290

LncRNAs are involved in modulating the individual risk and the severity of progression in metabolic dysfunction-associated fatty liver disease (MASLD), but their precise roles remain largely unknown. This study aimed to investigate the role of lncRNA Snhg3 in the development and progression of MASLD, along with the underlying mechanisms. The result showed that Snhg3 was significantly downregulated in the liver of high-fat diet-induced obesity (DIO) mice. Notably, palmitic acid promoted the expression of Snhg3 and overexpression of Snhg3 increased lipid accumulation in primary hepatocytes. Furthermore, hepatocyte-specific Snhg3 deficiency decreased body and liver weight, alleviated hepatic steatosis and promoted hepatic fatty acid metabolism in DIO mice, whereas overexpression induced the opposite effect. Mechanistically, Snhg3 promoted the expression, stability and nuclear localization of SND1 protein via interacting with SND1, thereby inducing K63-linked ubiquitination modification of SND1. Moreover, Snhg3 decreased the H3K27me3 level and induced SND1-mediated chromatin loose remodeling, thus reducing H3K27me3 enrichment at the Pparg promoter and enhancing PPARγ expression. The administration of PPARγ antagonist T0070907 improved Snhg3-aggravated hepatic steatosis. Our study revealed a new signaling pathway, Snhg3/SND1/H3K27me3/PPARγ, responsible for mice MASLD and indicates that lncRNA-mediated epigenetic modification has a crucial role in the pathology of MASLD.

Obesity has escalated into a critical global health crisis, tripling in prevalence since the mid-1970s. This increase mirrors the rise in metabolic-associated diseases such as type 2 diabetes (T2D) and its complications, certain cancers, and cardiovascular conditions. While substantial research efforts have enriched our understanding and led to the development of innovative management strategies for these diseases, the suboptimal response rates of existing therapies remain a major obstacle to effectively managing obesity and its associated conditions. Over the years, inter-organ communication (IOC) has emerged as a crucial factor in the development and progression of metabolic disorders. Exosomes, which are nano-sized vesicular couriers released by cells, play a significant role in this communication by transporting proteins, lipids, and nucleic acids across cellular landscapes. The available evidence indicates that exosomal RNAs present in biofluids such as blood, urine, milk, vitreous humor (VH), and cerebrospinal fluid (CSF) are altered in numerous diseases, suggesting their diagnostic and therapeutic potential. Long non-coding RNAs contained in exosomes (exo-lncRNAs) have attracted considerable interest, owing to their ability to interact with critical components involved in a multitude of metabolic pathways. Recent studies have found that alterations in exo-lncRNAs in biofluids correlate with several metabolic parameters in patients with metabolic-associated conditions; however, their exact roles remain largely unclear. This review highlights the diagnostic and therapeutic potential of exosomal lncRNAs in obesity and its associated conditions, emphasizing their role in IOC and disease progression, aiming to pave the way for further research in this promising domain.

Long noncoding RNAs (lncRNAs) are strongly associated with glucose homeostasis, but their roles remain largely unknown. In this study, the potential role of lncRNA-Snhg3 in glucose metabolism was evaluated both in vitro and in vivo. Here, we found a positive relationship between Snhg3 and hepatic glycogenesis. Glucose tolerance improved in hepatocyte-specific Snhg3 knock-in (Snhg3-HKI) mice, while it worsened in hepatocyte-specific Snhg3 knockout (Snhg3-HKO) mice. Furthermore, hepatic glycogenesis had shown remarkable increase in Snhg3-HKI mice and reduction in Snhg3-HKO mice, respectively. Mechanistically, Snhg3 increased mRNA and protein expression levels of PPP1R3B through inducing chromatin remodeling and promoting the phosphorylation of protein kinase B. Collectively, these results suggested that lncRNA-Snhg3 plays a critical role in hepatic glycogenesis.

Neurological diseases are one of the most pressing issues in modern times worldwide. It thus possesses explicit attention from researchers and medical health providers to guard public health against such an expanding threat. Various treatment modalities have been developed in a remarkably short time but, unfortunately, have yet to lead to the wished-for efficacy or the sought-after clinical improvement. The main hurdle in delivering therapeutics to the brain has always been the blood-brain barrier which still represents an elusive area with lots of mysteries yet to be solved. Meanwhile, nanotechnology has emerged as an optimistic platform that is potentially holding the answer to many of our questions on how to deliver drugs and treat CNS disorders using novel technologies rather than the unsatisfying conventional old methods. Nanocarriers can be engineered in a way that is capable of delivering a certain therapeutic cargo to a specific target tissue. Adding to this mind-blowing nanotechnology, the revolutionizing gene-altering biologics can have the best of both worlds, and pave the way for the long-awaited cure to many diseases, among those diseases thus far are Alzheimer's disease (AD), brain tumors (glioma and glioblastoma), Down syndrome, stroke, and even cases with HIV. The review herein collects the studies that tested the mixture of both sciences, nanotechnology, and epigenetics, in the context of brain therapeutics using three main categories of gene-altering molecules (siRNA, miRNA, and CRISPR) with a special focus on the advancements regarding the new favorite, intranasal route of administration.

Exosomes are a subtype of extracellular vesicles (EVs) with a diameter of 30~150 nm (averaging ~100 nm) that are primarily produced through the endosomal pathway, and carry various components such as lipids, proteins, RNA, and other small molecular substances. Exosomes can mediate intercellular communication through the bioactive substances they carry, thus participating in different physiological activities. Metabolic syndrome (MS) is a disease caused by disturbances in the body's metabolism, mainly including insulin resistance (IR), diabetes, obesity, non-alcoholic fatty liver disease (NAFLD), hyperlipidemia, and atherosclerosis (AS). Recent studies have shown that exosomes are closely related to the occurrence and development of MS. Exosomes can act as messengers to mediate signaling transductions between metabolic cells in the organism and play a bidirectional regulatory role in the MS process. This paper mainly reviews the components, biogenesis, biological functions and potential applications of exosomes, and exosomes involved in the pathogenesis of MS as well as their clinical significance in MS diagnosis.

Hydrogen sulfide (H2S), a gaseous biomolecule, is considered a key player in the regulation of various essential cellular events. Normal physiology is determined by the level of endogenous H2S. Any alterations (upregulation and downregulation) to the level of endogenous H2S may lead to illness, including the onset of tumorigenesis. Over the past two decades, extensive research on the role of H2S in cancer development has affirmed the potential pharmacological means to suppress cancer progression by either inhibiting H2S synthesis in cells or exposing exogenously supplied H2S donors to treat different cancers. Some H2S donors and inhibitors release H2S or affect its synthesis. As a result, they have progressed through the development process into widespread clinical use and become increasingly important. The present study draws a detailed discussion on the types of H2S donors and inhibitors and their role in cancer research. We believe that this state-of-the-art review will empower the synthesis of H2S -based chemopreventive drugs and promote the need for further in-depth exploration of the associations between H2S and cancer treatments in clinical settings.

Background: Skin cancer has been the leading type of cancer worldwide. Melanoma and non-melanoma skin cancers are now the most common types of skin cancer that have been reached to epidemic proportion. Based on the rapid prevalence of skin cancers, and lack of efficient drug delivery systems, it is essential to surge the possible ways to prevent or cure the disease. Aim of review: Although surgical modalities and therapies have been made great progress in recent years, however, there is still an urgent need to alleviate its increased burden. Hence, understanding the precise pathophysiological signaling mechanisms and all other factors of such skin insults will be beneficial for the development of more efficient therapies. Key scientific concepts of review: In this review, we explained new understandings about onset and development of skin cancer and described its management via polymeric micro/nano carriers-based therapies, highlighting the current key bottlenecks and future prospective in this field. In therapeutic drug/gene delivery approaches, polymeric carriers-based system is the most promising strategy. This review discusses that how polymers have successfully been exploited for development of micro/nanosized systems for efficient delivery of anticancer genes and drugs overcoming all the barriers and limitations associated with available conventional therapies. In addition to drug/gene delivery, intelligent polymeric nanocarriers platforms have also been established for combination anticancer therapies including photodynamic and photothermal, and for theranostic applications. This portfolio of latest approaches could promote the blooming growth of research and their clinical availability.

Oral diseases are among the most common human diseases yet less studied. These diseases affect both the physical, mental, and social health of the patients resulting in poor quality of life. They affect all ages, although severe stages are mostly observed in older individuals. Poor oral hygiene, genetics, and environmental factors contribute enormously to the development and progression of these diseases. Although there are available treatment options for these diseases, the recurrence of the diseases hinders their efficiency. Oral volatile sulfur compounds (VSCs) are highly produced in oral cavity as a result of bacteria activities. Together with bacteria components such as lipopolysaccharides, VSCs participate in the progression of oral diseases by regulating cellular activities and interfering with the immune response. Hydrogen sulfide (H2S) is a gaseous neurotransmitter primarily produced endogenously and is involved in the regulation of cellular activities. The gas is also among the VSCs produced by oral bacteria. In numerous diseases, H2S have been reported to have dual effects depending on the cell, concentration, and donor used. In oral diseases, high production and subsequent utilization of this gas have been reported. Also, this high production is associated with the progression of oral diseases. In this review, we will discuss the production of H2S in oral cavity, its interaction with cellular activities, and most importantly its role in oral diseases.

The discovery of circular RNAs and exploration of their biological functions are increasingly attracting attention in cell bio-sciences. Owing to their unique characteristics of being highly conserved, having a relatively longer half-life, and involvement in RNA maturation, transportation, epigenetic regulation, and transcription of genes, it has been accepted that circRNAs play critical roles in the variety of cellular processes. One of the critical importance of these circRNAs is the presence of small open reading frames that enable them to encode peptides/proteins. In particular, these encoded peptides/proteins mediate essential cellular activities such as proliferation, invasion, epithelial–mesenchymal transition, and apoptosis and develop an association with the development and progression of cancers by modulating diverse signaling pathways. In addition, these peptides have potential roles as biomarkers for the prognosis of cancer and are being used as drug targets against tumorigenesis. In the present review, we thoroughly discussed the biogenesis of circRNAs and their functional mechanisms along with a special emphasis on the reported chimeric peptides/proteins encoded by circRNAs. Additionally, this review provides a perspective regarding the opportunities and challenges to the potential use of circRNAs in cancer diagnosis and therapeutic targets in clinics.

In recent years, processing bodies (P-bodies) formed by liquid–liquid phase separation, have attracted growing scientific attention due to their involvement in numerous cellular activities, including the regulation of mRNAs decay or storage. These cytoplasmic dynamic membraneless granules contain mRNA storage and decay components such as deadenylase and decapping factors. In addition, different mRNA metabolic regulators, including m6A readers and gene-mediated miRNA-silencing, are also associated with such P-bodies. Cancerous cells may profit from these mRNA decay shredders by up-regulating the expression level of oncogenes and down-regulating tumor suppressor genes. The main challenges of cancer treatment are drug resistance, metastasis, and cancer relapse likely associated with cancer stem cells, heterogeneity, and plasticity features of different tumors. The mRNA metabolic regulators based on P-bodies play a great role in cancer development and progression. The dysregulation of P-bodies mediators affects mRNA metabolism. However, less is known about the relationship between P-bodies mediators and cancerous behavior. The current review summarizes the recent studies on P-bodies mediators, their contribution to tumor development, and their potential in the clinical setting, particularly highlighting the P-bodies as potential drug-carriers such as exosomes to anticancer in the future.

Nasopharyngeal carcinoma (NPC) is an epithelia-derived malignancy with a distinctive geographic distribution. Cystathionine γ-lyase (CSE) is involved in cancer development and progression. Nevertheless, the role of CSE in the growth of NPC is unknown. In this study, we found that CSE levels in human NPC cells were higher than those in normal nasopharyngeal cells. CSE overexpression enhanced the proliferative, migrative, and invasive abilities of NPC cells and CSE downregulation exerted reverse effects. Overexpression of CSE decreased the expressions of cytochrome C, cleaved caspase (cas)-3, cleaved cas-9, and cleaved poly-ADP-ribose polymerase, whereas CSE knockdown exhibited reverse effects. CSE overexpression decreased reactive oxygen species (ROS) levels and the expressions of phospho (p)-extracellular signal-regulated protein kinase 1/2, p-c-Jun N-terminal kinase, and p-p38, but promoted the expressions of p-phosphatidylinositol 3-kinase (PI3K), p-AKT, and p-mammalian target of rapamycin (mTOR), whereas CSE knockdown showed oppose effects. In addition, CSE overexpression promoted NPC xenograft tumor growth and CSE knockdown decreased tumor growth by modulating proliferation, angiogenesis, cell cycle, and apoptosis. Furthermore, DL-propargylglycine (an inhibitor of CSE) dose-dependently inhibited NPC cell growth via ROS-mediated mitogen-activated protein kinase (MAPK) and PI3K/AKT/mTOR pathways without significant toxicity. In conclusion, CSE could regulate the growth of NPC cells through ROS-mediated MAPK and PI3K/AKT/mTOR cascades. CSE might be a novel tumor marker for the diagnosis and prognosis of NPC. Novel donors/drugs that inhibit the expression/activity of CSE can be developed in the treatment of NPC.