Accelerating diabetic wound healing by ROS-scavenging lipid nanoparticle-mRNA formulation.

Current treatment options for diabetic wounds face challenges due to low efficacy, as well as potential side effects and the necessity for repetitive treatments. To address these issues, we report a formulation utilizing trisulfide-derived lipid nanoparticle (TS LNP)-mRNA therapy to accelerate diabetic wound healing by repairing and reprogramming the microenvironment of the wounds. A library of reactive oxygen species (ROS)-responsive TS LNPs was designed and developed to encapsulate interleukin-4 (IL4) mRNA. TS2-IL4 LNP-mRNA effectively scavenges excess ROS at the wound site and induces the expression of IL4 in macrophages, promoting the polarization from the proinflammatory M1 to the anti-inflammatory M2 phenotype at the wound site. In a diabetic wound model of db/db mice, treatment with this formulation significantly accelerates wound healing by enhancing the formation of an intact epidermis, angiogenesis, and myofibroblasts. Overall, this TS LNP-mRNA platform not only provides a safe, effective, and convenient therapeutic strategy for diabetic wound healing but also holds great potential for clinical translation in both acute and chronic wound care.

Metabolic Syndrome and Risk of Amyotrophic Lateral Sclerosis: Insights from a Large-Scale Prospective Study.

OBJECTIVE: Although metabolic abnormalities are implicated in the etiology of neurodegenerative diseases, their role in the development of amyotrophic lateral sclerosis (ALS) remains a subject of controversy. We aimed to identify the association between metabolic syndrome (MetS) and the risk of ALS. METHODS: This study included 395,987 participants from the UK Biobank to investigate the relationship between MetS and ALS. Cox regression model was used to estimate hazard ratios (HR). Stratified analyses were performed based on gender, body mass index (BMI), smoking status, and education level. Mediation analysis was conducted to explore potential mechanisms. RESULTS: In this study, a total of 539 cases of ALS were recorded after a median follow-up of 13.7 years. Patients with MetS (defined harmonized) had a higher risk of developing ALS after adjusting for confounding factors (HR: 1.50, 95% CI: 1.19-1.89). Specifically, hypertension and high triglycerides were linked to a higher risk of ALS (HR: 1.53, 95% CI: 1.19-1.95; HR: 1.31, 95% CI: 1.06-1.61, respectively). Moreover, the quantity of metabolic abnormalities showed significant results. Stratified analysis revealed that these associations are particularly significant in individuals with a BMI <25. These findings remained stable after sensitivity analysis. Notably, mediation analysis identified potential metabolites and metabolomic mediators, including alkaline phosphatase, cystatin C, γ-glutamyl transferase, saturated fatty acids to total fatty acids percentage, and omega-6 fatty acids to omega-3 fatty acids ratio. INTERPRETATION: MetS exhibits a robust association with an increased susceptibility to ALS, particularly in individuals with a lower BMI. Furthermore, metabolites and metabolomics, as potential mediators, provide invaluable insights into the intricate biological mechanisms. ANN NEUROL 2024.

The Potential Predicting Value of D-Dimer to Fibrinogen Ratio on Functional Outcome at 1 Year after Acute Ischemic Stroke: A Longitudinal Study.

INTRODUCTION: Previous studies have suggested that the D-dimer to fibrinogen ratio (DD/Fg) could be a potential predictor for deep vein thrombosis, pulmonary embolism, and stroke severity. However, the association between plasma DD/Fg and functional outcome following acute ischemic stroke (AIS) has been unclear. METHODS: Our study followed the STROBE guideline and used a prospective cohort design to investigate this association. A total of 454 patients with AIS were enrolled consecutively in our study, and the National Institute of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) were assessed for stroke severity and functional outcome, respectively. RESULTS: We found a significant difference in DD/Fg values between the three groups based on NIHSS scores at admission. Specifically, the DD/Fg values were higher in the poor functional outcome group (mRS score of 2-6) compared to the favorable functional outcome group (mRS score of 0-1) at the 1-year follow-up (p < 0.001). Additionally, the DD/Fg values were independently associated with poor functional prognosis at 1 year following the onset of stroke, even after adjusting for potential confounders (OR 9.21, 95% CI, 3.68-23.02, p < 0.001). CONCLUSIONS: Our findings suggest that DD/Fg values at admission may serve as risk predictors for poor functional outcomes in patients with AIS 1 year after the stroke.

STING Agonist-Derived LNP-mRNA Vaccine Enhances Protective Immunity Against SARS-CoV-2.

Lipid nanoparticle (LNP)-mediated delivery of messenger RNA (mRNA) COVID-19 vaccines has provided large-scale immune protection to the public. To elicit a robust immune response against SARS-CoV-2 infections, antigens produced by mRNAs encoding SARS-CoV-2 Spike glycoprotein need to be efficiently delivered and presented to antigen-presenting cells such as dendritic cells (DCs). As concurrent innate immune stimulation can facilitate the antigen presentation process, a library of non-nucleotide STING agonist-derived amino lipids (SALs) was synthesized and formulated into LNPs for mRNA delivery. SAL12 lipid nanoparticles (SAL12-LNPs) were identified as most potent in delivering mRNAs encoding the Spike glycoprotein (S) of SARS-CoV-2 while activating the STING pathway in DCs. Two doses of SAL12 S-LNPs by intramuscular immunization elicited potent neutralizing antibodies against SARS-CoV-2 in mice.

Vitamin D and diabetic peripheral neuropathy: A multi-centre nerve conduction study among Chinese patients with type 2 diabetes.

AIMS: Increasing numbers of reports link vitamin D deficiency to diabetic peripheral neuropathy (DPN), yet evidence regarding neurological deficits and electromyogram is scarce. The present multi-centre study sought to investigate these associations based on objective quantifications. MATERIALS AND METHODS: Information on DPN-related symptoms, signs, all diabetic microvascular complications, and nerve conduction abilities (quantified by nerve conduction amplitude and velocity, F-wave minimum latency (FML) of peripheral nerves) were collected from a derivation cohort of 1192 patients with type 2 diabetes (T2D). Correlation, regression analysis, and restricted cubic splines (RCS) were used to explore linear and non-linear relationships between vitamin D and DPN, which were validated in an external cohort of 223 patients. RESULTS: Patients with DPN showed lower levels of vitamin D than those without DPN; patients with vitamin D deficiency (<30 nmol/L) tended to suffer more DPN-related neurological deficits (paraesthesia, prickling, abnormal temperature, ankle hyporeflexia, and distal pall hypoesthesia correlating with MNSI-exam score (Y = -0.005306X + 2.105, P = 0.048). Worse nerve conduction abilities (decreased motor nerve amplitude, sensory nerve amplitude, motor nerve velocity, and increased FML) were also observed in these patients. Vitamin D had a significant threshold association with DPN (adjusted OR = 4.136, P = 0.003; RCS P for non-linearity = 0.003) and correlates with other microvascular complications (diabetic retinopathy and diabetic nephropathy). CONCLUSIONS: Vitamin D is associated with the conduction ability of peripheral nerves and may have a nerve- and threshold-selective relationship with the prevalence and severity of DPN among patients with T2D.

Neuron-specific enolase in hypertension patients with acute ischemic stroke and its value forecasting long-term functional outcomes.

BACKGROUND: Neuron Specific Enolase (NSE), a neuro-biochemical protein marker, may correlate with the prognosis of stroke patients. Moreover, hypertension is the most common comorbidities in patients with acute ischemic stroke (AIS), and the relationship between NSE levels and long-term functional outcomes in such an increasingly large population is unclear. The aim of the study was to investigate the relationships mentioned above and optimize the prediction models. METHODS: From 2018 to 2020, 1086 admissions for AIS were grouped as hypertension and non-hypertension, while hypertension group was randomly divided into development and validation cohorts for internal validation. The severity of the stroke was staged by National Institutes of Health Stroke Scale (NIHSS) score. Stroke prognosis after 1 year of follow up was documented by modified Rankin Scale (mRS) score. RESULTS: Analysis revealed the following findings:(i) Serum NSE levels increased greatly in hypertension subjects with poor functional outcomes(p = 0.046). However, there was no association in non-hypertension individuals(p = 0.386). (ii) In addition to the conventional factors (age and NIHSS score), NSE (OR:1.241, 95% CI: 1.025-1.502) and prothrombin time were significantly related to the incidence of unfavorable outcomes. (iii)Based on the above four indicators, a novel nomogram was established to predict the prognosis of stoke in hypertension patients with the c-index values of 0.8851. CONCLUSIONS: Overall, high baseline NSE is associated with poor 1-year AIS outcomes in hypertension patients, suggesting NSE may be a potential prognostic and therapeutic target for stroke in hypertension patients.

A review of the formation conditions and assessment methods of black and odorous water.

Black and odorous water is an extreme pollution phenomenon. This article reviews the formation process, formation conditions, and evaluation methods of black and odorous water. The results indicate that N, P, and TOC are the key nutrients inducing black and odorous water while S, Fe, and Mn are key elements forming blackening and odorizing pollutants. In addition, Cyanobacteria, Proteobacteria, Firmicutes, Verrucomicrobia, Planctomycetes, and Actinobacteria participate in the biogeochemistry cycles of key elements and play important roles in the blackening and odorizing process of water. The black and odorous thresholds that need further verification are as follows: 1.0 g/L of organic matrix, 2.0-8.0 mg/L of NH3-N, 0.6-1.2 mg/L of TP, 0.05 mg/L of Fe2+, 0.3 mg/L of Mn2+, 1.2-2.0 mg/L of DO, and -50 to 50 mV of the ORP. In order to propose a universal assessment method, it is suggested that NH3-N, DO, COD, BOD, and TP serve as the assessment indicators, and the levels of pollutions are I (not black odor), II (mild black odor), III (moderate black odor), IV (severe black odor), and inferior IV (extremely black odor).

Low T3 syndrome is associated with peripheral neuropathy in patients with type 2 diabetes mellitus.

INTRODUCTION/AIMS: Diabetic peripheral neuropathy (DPN) is one of the most common chronic complications of diabetes mellitus. Diabetic patients often have thyroid dysfunction. The aim of this study was to investigate the association between low triiodothyronine (T3) syndrome and DPN in patients with type 2 diabetes mellitus (T2DM). METHODS: A retrospective review was performed of 928 patients with T2DM for whom data was available for clinical manifestations and nerve conduction studies (NCS), and of 134 non-diabetic controls. The composite Z scores of conduction velocity and amplitude were calculated. Low T3 syndrome was defined as T3 levels below the lower limit of the reference interval. RESULTS: Among the patients with T2DM, 632 (68.1%) had DPN, and a larger proportion of these patients presented with low T3 syndrome than patients without DPN. After adjusting for potential confounders, low T3 syndrome was independently associated with the occurrence of DPN (odds ratio [OR] = 2.049, 95% confidence interval [CI] 1.319-3.181, p = .001) and the severity of DPN (OR = 1.597, 95% CI 1.030-2.476, p = .036). Adding the criterion of low T3 syndrome improved the prognostic performance of the traditional model (age + gender + diabetic duration + glycated hemoglobin [HbA1c]) for predicting DPN. DISCUSSION: Low T3 syndrome is associated with a higher risk and increased severity of DPN in patients with T2DM. These findings suggest that low T3 syndrome could be a predictor for risk stratification in patients with T2DM.

Application of bulbocavernosus reflex combined with anal sphincter electromyography in the diagnosis of MSA and PD.

BACKGROUND: Multiple system atrophy (MSA) and Parkinson's disease (PD) are characterized by abnormal changes in the extrapyramidal system and autonomic nervous system. The two diseases are consistent in some clinical manifestations and few objective indicators for preclinical prediction. METHOD: The value of anal sphincter electromyography (EAS-EMG) in the diagnosis of MSA has been recognized by researchers, while the bulbocavernosus reflex (BCR) has been found to be of great significance in the diagnosis of PD and MSA. In this study, the diagnostic value of BCR combined with EAS-EMG in patients with MSA and PD was further discussed. RESULTS: Forty-three patients with MSA, 120 patients with PD and 40 normal controls were recruited, and the BCR and EAS-EMG were evaluated. The average duration, average amplitude, percentage of polyphasic waves, satellite potential, phase pattern and amplitude of strong contraction were observed. The results showed that the abnormal rate of BCR in the control group was 0%, and the abnormal rate of EAS-EMG was 2.5%; these differences were statistically significant compared with the MSA group (BCR 90.9%, EAS-EMG 93.9%). For patients with PD, there were some significant differences in BCR and EAS-EMG between the control group and the PD group. CONCLUSION: Our study revealed that BCR combined with EAS-EMG detection can provide an objective electrophysiological basis for the diagnosis of MSA and PD, which is beneficial for the early treatment of disease.

Cardiac parameters affect prognosis in patients with non-large atherosclerotic infarction.

BACKGROUND: Although large artery atherosclerosis (LAA) is the most common type of cerebral infarction, non-LAA is not uncommon. The purpose of this paper is to investigate the prognosis of patients with non-LAA and to establish a corresponding nomogram. PATIENTS AND METHODS: Between June 2016 and June 2017, we had 1101 admissions for acute ischemic stroke (AIS). Of these, 848 were LAA and 253 were non-LAA. Patients were followed up every 3 months with a minimum of 1 year of follow-up. After excluding patients who were lost follow-up and patients who did not meet the inclusion criteria, a total of 152 non-LAA patients were included in this cohort study. After single-factor analysis and multifactor logistic regression analysis, the risk factors associated with prognosis were derived and different nomograms were developed based on these risk factors. After comparison, the best model is derived. RESULTS: Logistics regression found that the patient's National Institutes of Health Stroke Scale (NIHSS) score, ejection fraction (EF), creatine kinase-MB (CK-MB), age, neutrophil-to-lymphocyte ratio (NLR), aspartate aminotransferase (AST), and serum albumin were independently related to the patient's prognosis. We thus developed three models: model 1: single NIHSS score, AUC = 0.8534; model 2, NIHSS + cardiac parameters (CK-MB, EF), AUC = 0.9325; model 3, NIHSS + CK-MB + EF + age + AST + NLR + albumin, AUC = 0.9598. We compare the three models: model 1 vs model 2, z = - 2.85, p = 0.004; model 2 vs model 3, z = - 1.58, p = 0.122. Therefore, model 2 is considered to be the accurate and convenient model. CONCLUSIONS: Predicting the prognosis of patients with non-LAA is important, and our nomogram, built on the NIHSS and cardiac parameters, can predict the prognosis accurately and provide a powerful reference for clinical decision making.

Ubiquitin-like protein FAT10 promotes osteosarcoma growth by modifying the ubiquitination and degradation of YAP1.

Osteosarcoma is a common malignancy of the bone tissue. The rapid growth exhibited by this cancer is a primary challenge in its treatment. In many types of cancers, FAT10, a ubiquitin-like protein, is involved in several biological activities, especially cell proliferation. Herein, we demonstrate that FAT10 plays a vital role in tumorigenesis and is overexpressed in tumor tissues compared to its expression in adjacent normal tissues. Functional assays revealed that knockdown of FAT10 expression significantly repressed the proliferation of osteosarcoma in vitro and in vivo. Furthermore, our results indicate that FAT10 exhibits oncogenic functions by regulating the level of YAP1, a key protein of the Hippo/YAP signaling pathway, and a significant positive correlation exists between the levels of FAT10 and YAP1. Further analysis showed that FAT10-induced growth of osteosarcoma cells is dependent on YAP1. Mechanistically, FAT10 stabilizes YAP1 expression by regulating its ubiquitination and degradation. Taken together, our results link the two drivers of cell growth in osteosarcoma and reveal a novel pathway for FAT10 regulation. We provide new evidence for the biological and clinical significance of FAT10 as a potential biomarker for osteosarcoma.

Three-Dimensional Lead Bromide Hybrid Ferroelectric Realized by Lattice Expansion.

Three-dimensional (3D) organic-inorganic lead halide hybrids have become a hot academic topic because of their various functional properties. However, 3D lead halide hybrid ferroelectrics are still very rare until now. Here, we report a new 3D lead halide perovskite-related ferroelectric, (EATMP)Pb2Br6 [EATMP = (2-aminoethyl)trimethylphosphanium]. Based on nonferroelectric CH3NH3PbBr3, by replacing PbBr6 octahedra with a Pb2Br10 dimer of edge-sharing octahedra as the basic building unit, the expanded 3D lead bromide perovskite analog was formed with the large [EATMP]2+ cations occupying the voids of framework. Notably, (EATMP)Pb2Br6 displays a direct bandgap of 2.81 eV, four polarization directions, and a high Curie temperature (Tc) of 518 K (much beyond that of BaTiO3, 393 K), which is the highest among all reported 3D organic-inorganic hybrid ferroelectrics. Such a high Tc may result from the high rotational energy barrier of cations induced by a larger molecular volume and relatively low crystal symmetry. Our work provides an efficient avenue to construct new 3D organic-inorganic lead halide hybrids and would inspire the further exploration of 3D lead halide ferroelectrics.

Homochiral Nickel Nitrite ABX3 (X = NO2-) Perovskite Ferroelectrics.

Chiral organic-inorganic perovskites (COIPs) have recently attracted increasing interest due to their unique inherent chirality and potential applications in next-generation optoelectronic and spintronic devices. However, COIP ferroelectrics are very sparse. In this work, for the first time, we present the nickel-nitrite ABX3 COIP ferroelectrics, [(R and S)-N-fluoromethyl-3-quinuclidinol]Ni(NO2)3 ([(R and S)-FMQ]Ni(NO2)3), where the X-site is the rarely seen NO2- bridging ligand. [(R and S)-FMQ]Ni(NO2)3 display mirror-relationship in the crystal structure and vibrational circular dichroism signal. It is emphasized that [(R and S)-FMQ]Ni(NO2)3 show splendid ferroelectricity with both an extremely high phase-transition point of 405 K and a spontaneous polarization of 12 µC/cm2. To our knowledge, [(R and S)-FMQ]Ni(NO2)3 are the first examples of nickel-nitrite based COIP ferroelectrics. This finding expands the COIP family and throws light on exploration of high-performance COIP ferroelectrics.

Evidence for a protective role of the CX3CL1/CX3CR1 axis in a model of amyotrophic lateral sclerosis.

Aberrant microglial activation and neuroinflammation is a pathological hallmark of amyotrophic lateral sclerosis (ALS). Fractalkine (CX3CL1) is mostly expressed on neuronal cells. The fractalkine receptor (CX3CR1) is predominantly expressed on microglia. Many progressive neuroinflammatory disorders show disruption of the CX3CL1/CX3CR1 communication system. But the exact role of the CX3CL1/CX3CR1 in ALS pathology remains unknown. F1 nontransgenic/CX3CR1+/- females were bred with SOD1G93A/CX3CR1+/- males to produce F2 SOD1G93A/CX3CR1-/-, SOD1G93A/CX3CR1+/+. We analyzed end-stage (ES) SOD1G93A/CX3CR1-/- mice and progression-matched SOD1G93A/CX3CR1+/+ mice. Our study showed that the male SOD1G93A/CX3CR1-/- mice died sooner than male SOD1G93A/CX3CR1+/+ mice. In SOD1G93A/CX3CR1-/- mice demonstrated more neuronal cell loss, more microglial activation and exacerbated SOD1 aggregation at the end-stage of ALS. The NF-κB pathway was activated; the autophagy-lysosome degradation pathway and the autophagosome maturation were impaired. Our results indicated that the absence of CX3CR1/CX3CL1 signaling in the central nervous system (CNS) may worsen neurodegeneration. The CX3CL1/CX3CR1 communication system has anti-inflammatory and neuroprotective effects and plays an important role in maintaining autophagy activity. This effort may lead to new therapeutic strategies for neuroprotection and provide a therapeutic target for ALS patients.

FGF9 modulates Schwann cell myelination in developing nerves and induces a pro-inflammatory environment during injury.

Myelin sheath is critical for the proper functioning of the peripheral nervous system (PNS), which allows the effective conduction of nerve impulses. Fibroblast growth factor 9 (FGF9) is an autocrine and paracrine protein in the fibroblast growth factor family that regulates cell differentiation and proliferation. Fgf9 Schwann cell (SC) conditional knockout mice were developed to detect the role of FGF9 in the PNS. In our study, the absence of Fgf9 led to delayed myelination in early development. The expression of mature SC-related genes decreased, and the expression of genes associated with immature SCs increased in the Fgf9 knockout mice. These data were consistent with the morphology and praxeology we observed during the development of the peripheral nerves. Extracellular-regulated kinases 1/2 (ERK1/2) are key signals for myelination, and our results showed that Fgf9 ablation led to the inactivation of ERK1/2. Further research was performed to detect the role of FGF9 in peripheral nerve injury. In superoxide dismutase 1-G93A mice with Fgf9 SC knockout, we found that Fgf9 ablation inhibited the expressions of Cd68, Il-1ß, and Cd86, which contributed to the degeneration of the axon and myelin sheath.

Progressive Degeneration and Inhibition of Peripheral Nerve Regeneration in the SOD1-G93A Mouse Model of Amyotrophic Lateral Sclerosis.

BACKGROUND: Myelination, degeneration and regeneration are implicated in crucial responses to injury in the peripheral nervous system. Considering the progression of amyotrophic lateral sclerosis (ALS), we used the superoxide dismutase 1 (SOD1)-G93A transgenic mouse model of ALS to investigate the effects of mutant SOD1 on the peripheral nerves. METHODS: Changes in peripheral nerve morphology were analyzed in SOD1 mutant mice at various stages of the disease by toluidine blue staining and electron microscopy (EM). Schwann cell proliferation and recruitment of inflammatory factors were detected by immunofluorescence staining and quantitative reverse transcription PCR and were compared between SOD1 mutant mice and control mice. Furthermore, western blotting (WB) and TUNEL staining were used to investigate axonal damage and Schwann cell survival in the sciatic nerves of mice in both groups. RESULTS: An analysis of the peripheral nervous system in SOD1-G93A mice revealed the following novel features: (i) Schwann cells and axons in mutant mice underwent changes that were similar to those seen in the control mice during the early development of peripheral nerves. (ii) The peripheral nerves of SOD1-G93A mice developed progressive neuropathy, which presented as defects in axons and myelin, leading to difficulty in walking and reduced locomotor capacity at a late stage of the disease. (iii) Macrophages were recruited and accumulated, and nerve injury and a deficit in the blood-nerve barrier were observed. (iv) Proliferation and the inflammatory micro-environment were inhibited, which impaired the regeneration and remyelination of axons after crush injury in the SOD1-G93A mice. CONCLUSIONS: The mutant human SOD1 protein induced axonal and myelin degeneration during the progression of ALS and participated in axon remyelination and regeneration in response to injury.

Crystal structure of the alpha(6)beta(6) holoenzyme of propionyl-coenzyme A carboxylase.

Propionyl-coenzyme A carboxylase (PCC), a mitochondrial biotin-dependent enzyme, is essential for the catabolism of the amino acids Thr, Val, Ile and Met, cholesterol and fatty acids with an odd number of carbon atoms. Deficiencies in PCC activity in humans are linked to the disease propionic acidaemia, an autosomal recessive disorder that can be fatal in infants. The holoenzyme of PCC is an alpha(6)beta(6) dodecamer, with a molecular mass of 750 kDa. The alpha-subunit contains the biotin carboxylase (BC) and biotin carboxyl carrier protein (BCCP) domains, whereas the beta-subunit supplies the carboxyltransferase (CT) activity. Here we report the crystal structure at 3.2-A resolution of a bacterial PCC alpha(6)beta(6) holoenzyme as well as cryo-electron microscopy (cryo-EM) reconstruction at 15-A resolution demonstrating a similar structure for human PCC. The structure defines the overall architecture of PCC and reveals unexpectedly that the alpha-subunits are arranged as monomers in the holoenzyme, decorating a central beta(6) hexamer. A hitherto unrecognized domain in the alpha-subunit, formed by residues between the BC and BCCP domains, is crucial for interactions with the beta-subunit. We have named it the BT domain. The structure reveals for the first time the relative positions of the BC and CT active sites in the holoenzyme. They are separated by approximately 55 A, indicating that the entire BCCP domain must translocate during catalysis. The BCCP domain is located in the active site of the beta-subunit in the current structure, providing insight for its involvement in the CT reaction. The structural information establishes a molecular basis for understanding the large collection of disease-causing mutations in PCC and is relevant for the holoenzymes of other biotin-dependent carboxylases, including 3-methylcrotonyl-CoA carboxylase (MCC) and eukaryotic acetyl-CoA carboxylase (ACC).

An Orthogonal Array Optimization of Lipid-like Nanoparticles for mRNA Delivery in Vivo.

Systemic delivery of mRNA-based therapeutics remains a challenging issue for preclinical and clinical studies. Here, we describe new lipid-like nanoparticles (TT-LLNs) developed through an orthogonal array design, which demonstrates improved delivery efficiency of mRNA encoding luciferase in vitro by over 350-fold with significantly reduced experimental workload. One optimized TT3 LLN, termed O-TT3 LLNs, was able to restore the human factor IX (hFIX) level to normal physiological values in FIX-knockout mice. Consequently, these mRNA based nanomaterials merit further development for therapeutic applications.

How inflammation dictates diabetic peripheral neuropathy: An enlightening review.

BACKGROUND: Diabetic peripheral neuropathy (DPN) constitutes a debilitating complication associated with diabetes. Although, the past decade has seen rapid developments in understanding the complex etiology of DPN, there are no approved therapies that can halt the development of DPN, or target the damaged nerve. Therefore, clarifying the pathogenesis of DPN and finding effective treatment are the crucial issues for the clinical management of DPN. AIMS: This review is aiming to summary the current knowledge on the pathogenesis of DPN, especially the mechanism and application of inflammatory response. METHODS: We systematically summarized the latest studies on the pathogenesis and therapeutic strategies of diabetic neuropathy in PubMed. RESULTS: In this seminal review, the underappreciated role of immune activation in the progression of DPN is scrutinized. Novel insights into the inflammatory regulatory mechanisms of DPN have been unearthed, illuminating potential therapeutic strategies of notable clinical significance. Additionally, a nuanced examination of DPN's complex etiology, including aberrations in glycemic control and insulin signaling pathways, is presented. Crucially, an emphasis has been placed on translating these novel understandings into tangible clinical interventions to ameliorate patient outcomes. CONCLUSIONS: This review is distinguished by synthesizing cutting-edge mechanisms linking inflammation to DPN and identifying innovative, inflammation-targeted therapeutic approaches.

Engineering LNPs with polysarcosine lipids for mRNA delivery.

Since the approval of the lipid nanoparticles (LNP)-mRNA vaccines against the SARS-CoV-2 virus, there has been an increased interest in the delivery of mRNA through LNPs. However, current LNP formulations contain PEG lipids, which can stimulate the generation of anti-PEG antibodies. The presence of these antibodies can potentially cause adverse reactions and reduce therapeutic efficacy after administration. Given the widespread deployment of the COVID-19 vaccines, the increased exposure to PEG may necessitate the evaluation of alternative LNP formulations without PEG components. In this study, we investigated a series of polysarcosine (pSar) lipids as alternatives to the PEG lipids to determine whether pSar lipids could still provide the functionality of the PEG lipids in the ALC-0315 and SM-102 LNP systems. We found that complete replacement of the PEG lipid with a pSar lipid can increase or maintain mRNA delivery efficiency and exhibit similar safety profiles in vivo.