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Type 2 diabetes (T2D) is a group of metabolic disorders characterized by chronic hyperglycemia and long-term carbohydrate, fat, and protein metabolism disruptions. This study aimed to identify biomarker of T2D and analyze immune cell infiltration in the islets of T2D patients. Using the GSE76895 dataset, 112 differentially expressed genes (DEGs) were identified between islet samples from T2D and non-diabetic (ND) individuals. Then, 112 DEGs were used for functional enrichment and Gene Set Enrichment Analyses (GSEA). Through the least absolute shrinkage and selection operator (LASSO) and support vector machine-recursive feature elimination (SVM-RFE), SLC2A2 emerged as the most likely candidate biomarker of T2D. Moreover, the distribution of tissue-infiltrating immune cells between T2D and ND islet samples was assessed using the CIBERSORT algorithm. The result revealed that resting CD4 + memory T cells might play an important role in T2D and exhibited a positive correlation with SLC2A2. Single-cell RNA sequencing (scRNA-seq) data indicated that SLC2A2 was highly expressed in beta cells of T2D islets and down-regulated in T2D group. Finally, in vivo studies confirmed decreased level of SLC2A2 expression in T2D models. To sum up, these findings highlight SLC2A2 as potential biomarkers, aiding early diagnosis and pharmaceutical advancements in T2D.

Spinal cord injury (SCI), characterized by the disruption of neural pathways and an increase in inflammatory cell infiltration, leads to profound and lasting neurological deficits, with a high risk of resulting in permanent disability. Currently, the therapeutic landscape for SCI is notably sparse, with limited effective treatment options available. Methylprednisolone (MP), a widely used clinical anti-inflammatory agent for SCI, requires administration in high doses that are associated with significant adverse effects. In this study, we introduce an innovative approach by substituting cholesterol with MP to engineer a novel Lipid Nanoparticle (MP-LNP). This strategy aims to enhance the localization and concentration of MP at the injury site, thereby amplifying its therapeutic efficacy while mitigating systemic side effects. Furthermore, we explore the integration of C3 transferase mRNA into MP-LNPs. C3 transferase, a potent inhibitor of the RhoA pathway, has shown promise in facilitating neurological recovery in animal models of SCI and is currently being evaluated in clinical trials. The novel formulation, MP-LNP-C3, is designed for direct administration to the injury site during decompression surgery, offering a targeted therapeutic modality for SCI. Our findings reveal several significant advantages of this approach: Firstly, the incorporation of C3 transferase mRNA into MP-LNPs does not compromise the structural integrity of the nanoparticles, ensuring efficient mRNA expression within the spinal cord. Secondly, the MP-LNP formulation effectively attenuates inflammation and reduces the adverse effects associated with high-dose MP treatment in the acute phase of SCI. Lastly, MP-LNP-C3 demonstrates notable neuroprotective properties and promotes enhanced recovery of motor function in SCI mouse models. Together, these results underscore the potential of this innovative LNP-based therapy as a promising avenue for advancing the treatment of clinical SCI. Graphical Abstract

Targeted delivery of mRNA with lipid nanoparticles (LNPs) holds great potential for treating pulmonary diseases. However, the lack of rational design principles for efficient lung‐homing lipids hinders the prevalence of mRNA therapeutics in this organ. Herein, the combinatorial screening with structure‐function analysis is applied to rationalize the design strategy for nonpermanently charged lung‐targeted ionizable lipids. It is discovered that lipids carrying N‐methyl and secondary amine groups in the heads, and three tails originated from epoxyalkanes, exhibiting superior pulmonary selectivity and efficiency. Representative ionizable lipids with systematically variation in chemical structures are selected to study the well‐known but still puzzling “protein corona” adsorbed on the surface of LNPs. In addition to the commonly used corona‐biomarker vitronectin, other arginine‐glycine‐aspartic acid (RGD)‐rich proteins usually involved in collagen‐containing extracellular matrix, such as fibrinogen and fibronectin have also been identified to have a strong correlation with lung tropism. This work provides insight into the rational design of lung‐targeting ionizable lipids and reveals a previously unreported potential function of RGD‐rich proteins in the protein corona of lung‐homing LNPs. A novel structure‐function relationship is identified for lung‐targeting ionizable lipids with nonpermanent charges. These lipids feature N‐methyl and secondary amine groups in their heads and three tails derived from epoxyalkanes, demonstrating superior pulmonary selectivity and efficiency. The proteomic study reveals that protein corona fingerprints may serve as a more comprehensive characteristic for facilitating the lung tropism of LNPs.

Papillary thyroid cancer (PTC) is the most frequent subtype of thyroid cancer, but 20% of cases are indeterminate (i.e., cannot be accurately diagnosed) based on preoperative cytology, which might lead to surgical removal of a normal thyroid gland. To address this concern, we performed an in-depth analysis of the serum proteomes of 26 PTC patients and 23 healthy controls using antibody microarrays and data-independent acquisition mass spectrometry (DIA-MS). We identified a total of 1091 serum proteins spanning 10–12 orders of magnitude. 166 differentially expressed proteins were identified that participate in complement activation, coagulation cascades, and platelet degranulation pathways. Furthermore, the analysis of serum proteomes before and after surgery indicated that the expression of proteins such as lactate dehydrogenase A and olfactory receptor family 52 subfamily B member 4, which participate in fibrin clot formation and extracellular matrix-receptor interaction pathways, were changed. Further analysis of the proteomes of PTC and neighboring tissues revealed integrin-mediated pathways with possible crosstalk between the tissue and circulating compartments. Among these cross-talk proteins, circulating fibronectin 1 (FN1), gelsolin (GSN) and UDP-glucose 4-epimerase (GALE) were indicated as promising biomarkers for PTC identification and validated in an independent cohort. In differentiating between patients with benign nodules or PTC, FN1 produced the best ELISA result (sensitivity = 96.89%, specificity = 91.67%). Overall, our results present proteomic landscapes of PTC before and after surgery as well as the crosstalk between tissue and the circulatory system, which is valuable to understand PTC pathology and improve PTC diagnostics in the future.

BackgroundOsteosarcoma patients with high propensity for metastasis and recurrence generally encounter a poor prognosis. Despite the extensive exploration of immunotherapy, particularly the anti-programmed cell death protein 1 (anti-PD-1) antibody, in clinical trials, the efficacy remains unsatisfactory. A more profound comprehension of the resistance mechanisms and the development of innovative therapeutic strategies is imperative.MethodsA screening was performed for drugs capable of upregulating major histocompatibility class I (MHC I) expression among clinically common drugs. The effects of the drug on both T cells and tumor cells, as well as its combination efficacy with anti-PD-1 antibody, were studied in vitro and in vivo osteosarcoma models. The molecular mechanisms underlying these biological processes were explored via RNA sequencing analysis.ResultsEtoposide was shown to upregulate the MHC I expression in osteosarcoma cells, thereby enhancing the cytotoxicity of CD8+ T cells. Interleukin-33 (IL-33) played a dominant role in etoposide-activated anti-tumor immune response. Etoposide promoted the secretion of IL-33 and augmented the expression of IL-33 binding suppression of tumorigenicity 2 (ST2) receptor, which activated the nuclear factor kappa-B signaling pathway and resulted in MHC I upregulation. Furthermore, etoposide was demonstrated to improve the therapeutic efficacy of anti-PD-1 antibody.ConclusionsThis study revealed the molecular mechanism underlying etoposide-activated CD8+ T cell anti-tumor immunity. The combination of Etoposide and anti-PD-1 antibody has the potential to benefit patients with advanced osteosarcoma.

The incidence of high-risk Human Papillomavirus (HR-HPV)-driven head and neck squamous cell carcinoma (HNSCC) is on the rise globally. HR-HPV-driven HNSCC displays molecular and clinical characteristics distinct from HPV-uninvolved cases. Therapeutic strategies for HR-HPV-driven HNSCC are under investigation. HR-HPVs encode the oncogenes E6 and E7, which are essential in tumorigenesis. Meanwhile, involvement of E6 and E7 provides attractive targets for developing new therapeutic regimen. Here we will review some of the recent advancements observed in preclinical studies and clinical trials on HR-HPV-driven HNSCC, focusing on nanotechnology related methods. Materials science innovation leads to great improvement for cancer therapeutics including HNSCC. This article discusses HPV-E6 or -E7- based vaccines, based on plasmid, messenger RNA or peptide, at their current stage of development and testing as well as how nanoparticles can be designed to target and access cancer cells and activate certain immunology pathways besides serving as a delivery vehicle. Nanotechnology was also used for chemotherapy and photothermal treatment. Short interference RNA targeting E6/E7 showed some potential in animal models. Gene editing by CRISPR-CAS9 combined with other treatments has also been assessed. These advancements have the potential to improve the outcome in HR-HPV-driven HNSCC, however breakthroughs are still to be awaited with nanomedicine playing an important role.

Pulmonary arterial hypertension (PAH) is a chronic progressive cardiovascular disease characterized by vascular remodeling and leading to right‐heart failure. The purpose of this research was to further study the pathogenesis of PAH and to detect potential prognostic signatures. Differentially expressed genes (DEGs) selected from GSE38267 were mostly enriched in inflammation‐related pathways, suggesting inflammation may be involved in the occurrence and development of PAH. Through the prediction and verification of related miRNAs and long noncoding RNAs using online databases and Gene Expression Omnibus (GEO) datasets, CCR7 and its related molecules, including hsa‐let‐7e‐5p and SNHG12, were identified as possible targets. The expression levels of CCR7, hsa‐let‐7e‐5p and SNHG12 were then verified by quantitative RT‐PCR in vivo and in vitro. Further study showed that silencing of SNHG12 decreased the expression of CCR7 under hypoxia treatment in vitro. Dual‐luciferase reporter assays were used to verify the relationship between hsa‐let‐7e‐5p and SNHG12. Collectively, our research reveals that a long noncoding RNA–miRNA–mRNA interaction network may be involved in the pathogenesis of PAH and suggests SNHG12, hsa‐let‐7e‐5p and CCR7 as potential biomarkers for PAH. Pulmonary arterial hypertension (PAH) is a chronic progressive cardiovascular disease characterized by vascular remodeling, leading to right‐heart failure. In this study, we detected the pathways and potential molecules related to PAH through bioinformatics and experiments in vivo and in vitro. We identified SNHG12, hsa‐let‐7e‐5p and CCR7 as potential biomarkers for PAH.

Background A certain degree of self-repair is initiated following spinal cord injury (SCI). Although intraneuronal regeneration and a supportive growth environment are limited, they serve as the foundation for functional recovery after SCI. Methods In this study, we conducted single-cell RNA sequencing combined with spatial transcriptomics and spatial metabolomics to reveal the spatial molecular characteristics of self-repair processes after SCI at single-cell resolution. Results We identified three cell subsets-Mic2 (a microglia subset), Mac4 (a macrophage subset), and Fib4 (a fibroblast subset)-that express markers associated with spinal cord repair. Mic2 and Mac4 exhibit clustered spatial distribution patterns, whereas Fib4 is predominantly located around the injured spinal cord. Additionally, Mic2 is predominantly distributed in the white matter, particularly in the dorsal region of the injured spinal cord, and exhibits high expression of taurine. Mac4 and Fib4 exhibit high expression of copalic acid and uridine, respectively. Conclusions In this study, we have identified three distinct cell subsets that express markers associated with wound healing and may promote regenerative processes, and we have determined their spatial transcriptional and metabolic features enriched within these regions. Our dataset represents a valuable resource that offers novel mechanistic insights into the pathobiology of spinal cord injury.

The vasculature plays an important role in spinal cord function. Traumatic spinal cord injury (SCI) often results in a vascular disruption after primary insult, following secondary injury in neighbouring tissue. However, standard angiography methods such as digital subtraction angiography (DSA) still have difficulties in microvasculature imaging, especially for spinal cord with small size and non-rigid motion. The ultrasound localization microscopy (ULM) disrupts the compromise between penetration and resolution and provides super-resolution images of microvasculature. In this study, the applicability of the ULM for in vivo SCI evaluation was investigated on rat models with varying severities (different compression time durations correspond to mild and severe injury). Ultrasonic parameters including vessel saturation and blood velocity were measured via ULM. Basso, Beattie, Bresnahan (BBB) locomotion test was applied for injury severity validation and comparison with ultrasonic measurements.

Optic neuritis is one of main symptoms in multiple sclerosis (MS) that causes visual disability. Astrocytes are pivotal regulators of neuroinflammation in MS, and astrocytic yes-associated protein (YAP) plays a critical role in neuroinflammation. Meanwhile, YAP signaling is involved in visual impairment, including glaucoma, retinal choroidal atrophy and retinal detachment. However, the roles and underlying mechanisms of astrocytic YAP in neuroinflammation and demyelination of MS-related optic neuritis (MS-ON) remains unclear. To assess the functions of YAP in MS-ON, experimental autoimmune encephalomyelitis (EAE, a common model of MS) was established, and mice that conditional knockout (CKO) of YAP in astrocytes, YAP -CKO mice, were successfully generated. Behavior tests, immunostaining, Nissl staining, Hematoxylin-Eosin (HE) staining, TUNEL staining, Luxol Fast Blue (LFB) staining, electron microscopy (EM), quantitative real-time PCR (qPCR), gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) by RNA sequencing were used to examine the function and mechanism of YAP signaling based on these YAP -CKO mice and EAE model mice. To further explore the potential treatment of YAP signaling in EAE, EAE mice were treated with various drugs, including SRI-011381 that is an agonist of transforming growth factor-β (TGF-β) pathway, and XMU-MP-1 which inhibits Hippo kinase MST1/2 to activate YAP. We found that YAP was significantly upregulated and activated in the astrocytes of optic nerve in EAE mice. Conditional knockout of YAP in astrocytes caused more severe inflammatory infiltration and demyelination in optic nerve, and damage of retinal ganglion cells (RGCs) in EAE mice. Moreover, YAP deletion in astrocytes promoted the activation of astrocytes and microglia, but inhibited the proliferation of astrocytes of optic nerve in EAE mice. Mechanically, TGF-β signaling pathway was significantly down-regulated after YAP deletion in astrocytes. Additionally, both qPCR and immunofluorescence assays confirmed the reduction of TGF-β signaling pathway in YAP -CKO EAE mice. Interestingly, SRI-011381 partially rescued the deficits in optic nerve and retina of YAP -CKO EAE mice. Finally, activation of YAP signaling by XMU-MP-1 relieved the neuroinflammation and demyelination in optic nerve of EAE mice. These results suggest astrocytic YAP may prevent the neuroinflammatory infiltration and demyelination through upregulation of TGF-β signaling and provide targets for the development of therapeutic strategies tailored for MS-ON.