Topical administration of GLP-1 eyedrops improves retinal ganglion cell function by facilitating presynaptic GABA release in early experimental diabetes.

ABSTRACT: Diabetic retinopathy is a prominent cause of blindness in adults, with early retinal ganglion cell (RGC) loss contributing to visual dysfunction or blindness. In the brain, defects in y-aminobutyric acid (GABA) synaptic transmission are associated with pathophysiological and neurodegenerative disorders, whereas glucagon-like peptide-1 (GLP-1) has demonstrated neuroprotective effects. However, it is not yet clear whether diabetes causes alterations in inhibitory input to RGCs and whether and how GLP-1 protects against neurodegeneration in the diabetic retina through regulating inhibitory synaptic transmission to RGCs. In the present study, we used the patch-clamp technique to record GABA subtype A receptor-mediated miniature inhibitory postsynaptic currents (mIPSCs) in RGCs from streptozotocin-induced diabetes model rats. We found that early diabetes (4 weeks of hyperglycemia) decreased the frequency of GABAergic mIPSCs in RGCs without altering their amplitude, suggesting a reduction in the spontaneous release of GABA to RGCs. Topical administration of GLP-1 eyedrops over a period of 2 weeks effectively countered the hyperglycemia-induced downregulation of GABAergic mIPSC frequency, subsequently enhancing the survival of RGCs. Concurrently, the protective effects of GLP-1 on RGCs in diabetic rats were eliminated by topical administration of exendin-9-39, a specific GLP-1 receptor antagonist, or SR95531, a specific antagonist of the GABA subtype A receptor. Furthermore, extracellular perfusion of GLP-1 was found to elevate the frequencies of GABAergic mIPSCs in both ON- and OFF-type RGCs. This elevation was shown to be mediated by activation of the phosphatidylinositol-phospholipase C/inositol 1,4,5-trisphosphate receptor/Ca2+/protein kinase C signaling pathway downstream of GLP-1 receptor activation. Moreover, multielectrode array recordings revealed that GLP-1 functionally augmented the photoresponses of ON-type RGCs. Optomotor response tests demonstrated that diabetic rats exhibited reductions in visual acuity and contrast sensitivity that were significantly ameliorated by topical administration of GLP-1. These results suggest that GLP-1 facilitates the release of GABA onto RGCs through the activation of GLP-1 receptor, leading to the de-excitation of RGC circuits and the inhibition of excitotoxic processes associated with diabetic retinopathy. Collectively, our findings indicate that the GABA system has potential as a therapeutic target for mitigating early-stage diabetic retinopathy. Furthermore, the topical administration of GLP-1 eyedrops represents a non-invasive and effective treatment approach for managing early-stage diabetic retinopathy.

Transcriptome study reveals tick immune genes restrict Babesia microti infection.

A systems biology approach was employed to gain insight into tick biology and interactions between vectors and pathogens. Haemaphysalis longicornis serves as one of the primary vectors of Babesia microti, significantly impacting human and animal health. Obtaining more information about their relationship is crucial for a comprehensive understanding of tick and pathogen biology, pathogen transmission dynamics, and potential control strategies. RNA sequencing of uninfected and B. microti-infected ticks resulted in the identification of 15 056 unigenes. Among these, 1 051 were found to be differentially expressed, with 796 being upregulated and 255 downregulated (P < 0.05). Integrated transcriptomics datasets revealed the pivotal role of immune-related pathways, including the Toll, Janus kinase/signal transducer and activator of transcription (JAK-STAT), immunodeficiency, and RNA interference (RNAi) pathways, in response to infection. Consequently, 3 genes encoding critical transcriptional factor Dorsal, Relish, and STAT were selected for RNAi experiments. The knockdown of Dorsal, Relish, and STAT resulted in a substantial increase in Babesia infection levels compared to the respective controls. These findings significantly advanced our understanding of tick-Babesia molecular interactions and proposed novel tick antigens as potential vaccine targets against tick infestations and pathogen transmission.

Comparison of short-term outcomes of laparoscopic surgery, robot-assisted laparoscopic surgery, and open surgery for lateral lymph-node dissection for rectal cancer: a network meta-analysis.

This study attempted to compare short-term outcomes of laparoscopic surgery (LS), robot-assisted laparoscopic surgery (RS), and open surgery (OS) for lateral lymph-node dissection (LLND) in treatment of rectal cancer through network meta-analysis. Embase, Web of Science, PubMed, and The Cochrane Library databases were searched to collect cohort studies on outcomes of LS, RS, and OS for LLND for rectal cancer. Newcastle-Ottawa Scale (NOS) was utilized to evaluate the quality of cohort studies. Primary outcomes should at least include one of the following clinical outcome measures: operative time, blood loss, total lymph-node harvest, positive resection margin rate, postoperative complications, and postoperative hospital stay. A network meta-analysis was conducted using STATA software. Fourteen cohort studies including 8612 patients were eligible for inclusion. The network meta-analysis results showed that, in terms of intraoperative outcomes, the RS group had the longest operative time, while the OS group had the shortest; the LS and RS groups had significantly less blood loss than the OS group. In terms of histological outcomes, there were no significant differences in the total number of lymph nodes harvested and the positive margin rate among the LS, RS, and OS groups (P > 0.05). Regarding postoperative outcomes, the OS group had the highest probability of postoperative complications and the longest hospital stay, followed by the LS group, with the RS group being the lowest. RS was the best method in blood loss, postoperative complication rate, and postoperative hospital stay, followed by LS. OS had the shortest operative time and the highest blood loss.

Sustained-Release Hydrogen-Powered Bilateral Microneedles Integrating CD-MOFs for In Situ Treating Allergic Rhinitis.

Glucocorticoids are widely used for treating allergic rhinitis, but conventional intranasal administration encounters unfavorable nasal cilia clearance and nasal mucosal barrier. Herein, a bilateral microneedle patch is fabricated for delivering cyclodextrin-based metal-organic frameworks (CD-MOF) encapsulating dexamethasone (DXMS) and paeonol (Pae), while NaH particles are mounted on the basal part of each microneedle. By intranasal administration, the microneedles are propelled into the nasal mucosa by NaH-generated hydrogen and then swell to form a hydrogel for sustainedly releasing drugs. The DXMS/Pae combination is demonstrated to be superior to more than the twofold dose of DXMS alone for improving allergic rhinitis in rats. It involves reducing mast cell degranulation and modulating Treg/Th17 cell homeostasis, whereas inhibiting Th1 to Th2 differentiation is associated with regulating the GATA3/T-bet pathway, as well as repairing epithelial barrier function by increasing MUC1 and downregulating periostin. In addition, this delivery system modulates the lipid metabolism of the nasal mucosa. Notably, the newly designed device significantly enhances the drug's therapeutic effect, and NaH-generated hydrogen may have the potential adjunctive therapeutic effect. Collectively, such an emerging microneedle-mediated nasal drug delivery creates a new form for alleviating immune inflammation and contributes a promising solution to reduce clinical glucocorticoid abuse.

Dyslipidemia versus obesity as predictors of ischemic stroke prognosis: a multi-center study in China.

BACKGROUND: This multicenter observational study aimed to determine whether dyslipidemia or obesity contributes more significantly to unfavorable clinical outcomes in patients experiencing a first-ever ischemic stroke (IS). METHODS: The study employed a machine learning predictive model to investigate associations among body mass index (BMI), body fat percentage (BFP), high-density lipoprotein (HDL), triglycerides (TG), and total cholesterol (TC) with adverse outcomes in IS patients. Extensive real-world clinical data was utilized, and risk factors significantly linked to adverse outcomes were identified through multivariate analysis, propensity score matching (PSM), and regression discontinuity design (RDD) techniques. Furthermore, these findings were validated via a nationwide multicenter prospective cohort study. RESULTS: In the derived cohort, a total of 45,162 patients diagnosed with IS were assessed, with 522 experiencing adverse outcomes. A multifactorial analysis incorporating PSM and RDD methods identified TG (adjusted odds ratio (OR) = 1.110; 95% confidence interval (CI): 1.041-1.183; P <  0.01) and TC (adjusted OR = 1.139; 95%CI: 1.039-1.248; P <  0.01) as risk factors. However, BMI, BFP, and HDL showed no significant effect. In the validation cohort, 1410 controls and 941 patients were enrolled, confirming that lipid levels are more strongly correlated with the prognosis of IS patients compared to obesity (TC, OR = 1.369; 95%CI: 1.069-1.754; P <  0.05; TG, OR = 1.332; 95%CI: 1.097-1.618; P <  0.01). CONCLUSION: This study suggests that dyslipidemia has a more substantial impact on the prognosis of IS patients compared to obesity. This highlights the importance of prioritizing dyslipidemia management in the treatment and prevention of adverse outcomes in IS patients.

Dual-Use Strain Sensors for Acoustic Emission and Quasi-Static Bending Measurements.

In this paper, a MEMS piezoresistive ultrathin silicon membrane-based strain sensor is presented. The sensor's ability to capture an acoustic emission signal is demonstrated using a Hsu-Nielsen source, and shows comparable frequency content to a commercial piezoceramic ultrasonic transducer. To the authors' knowledge, this makes the developed sensor the first known piezoresistive strain sensor which is capable of recording low-energy acoustic emissions. The improvements to the nondestructive evaluation and structural health monitoring arise from the sensor's low minimum detectable strain and wide-frequency bandwidth, which are generated from the improved fabrication process that permits crystalline semiconductor membranes and advanced polymers to be co-processed, thus enabling a dual-use application of both acoustic emission and static strain sensing. The sensor's ability to document quasi-static bending is also demonstrated and compared with an ultrasonic transducer, which provides no significant response. This dual-use application is proposed to effectively combine the uses of both strain and ultrasonic transducer sensor types within one sensor, making it a novel and useful method for nondestructive evaluations. The potential benefits include an enhanced sensitivity, a reduced sensor size, a lower cost, and a reduced instrumentation complexity.

Unraveling the role of HIF-1α in sepsis: from pathophysiology to potential therapeutics-a narrative review.

Sepsis is characterized by organ dysfunction resulting from a dysregulated inflammatory response triggered by infection, involving multifactorial and intricate molecular mechanisms. Hypoxia-inducible factor-1α (HIF-1α), a notable transcription factor, assumes a pivotal role in the onset and progression of sepsis. This review aims to furnish a comprehensive overview of HIF-1α's mechanism of action in sepsis, scrutinizing its involvement in inflammatory regulation, hypoxia adaptation, immune response, and organ dysfunction. The review encompasses an analysis of the structural features, regulatory activation, and downstream signaling pathways of HIF-1α, alongside its mechanism of action in the pathophysiological processes of sepsis. Furthermore, it will delve into the roles of HIF-1α in modulating the inflammatory response, including its association with inflammatory mediators, immune cell activation, and vasodilation. Additionally, attention will be directed toward the regulatory function of HIF-1α in hypoxic environments and its linkage with intracellular signaling, oxidative stress, and mitochondrial damage. Finally, the potential therapeutic value of HIF-1α as a targeted therapy and its significance in the clinical management of sepsis will be discussed, aiming to serve as a significant reference for an in-depth understanding of sepsis pathogenesis and potential therapeutic targets, as well as to establish a theoretical foundation for clinical applications.

Dual electrical stimulation at spinal-muscular interface reconstructs spinal sensorimotor circuits after spinal cord injury.

The neural signals produced by varying electrical stimulation parameters lead to characteristic neural circuit responses. However, the characteristics of neural circuits reconstructed by electrical signals remain poorly understood, which greatly limits the application of such electrical neuromodulation techniques for the treatment of spinal cord injury. Here, we develop a dual electrical stimulation system that combines epidural electrical and muscle stimulation to mimic feedforward and feedback electrical signals in spinal sensorimotor circuits. We demonstrate that a stimulus frequency of 10-20 Hz under dual stimulation conditions is required for structural and functional reconstruction of spinal sensorimotor circuits, which not only activates genes associated with axonal regeneration of motoneurons, but also improves the excitability of spinal neurons. Overall, the results provide insights into neural signal decoding during spinal sensorimotor circuit reconstruction, suggesting that the combination of epidural electrical and muscle stimulation is a promising method for the treatment of spinal cord injury.

Microneedle-mediated nose-to-brain drug delivery for improved Alzheimer's disease treatment.

Conventional transnasal brain-targeted drug delivery strategies are limited by nasal cilia clearance and the nasal mucosal barrier. To address this challenge, we designed dissolving microneedles combined with nanocarriers for enhanced nose-to-brain drug delivery. To facilitate transnasal administration, a toothbrush-like microneedle patch was fabricated with hyaluronic acid-formed microneedles and tannic acid-crosslinked gelatin as the base, which completely dissolved in the nasal mucosa within seconds leaving only the base, thereby releasing the loaded cyclodextrin-based metal-organic frameworks (CD-MOFs) without affecting the nasal cilia and nasal microbial communities. As nanocarriers for high loading of huperzine A, these potassium-structured CD-MOFs, reinforced with stigmasterol and functionalized with lactoferrin, possessed improved physical stability and excellent biocompatibility, enabling efficient brain-targeted drug delivery. This delivery system substantially attenuated H2O2- and scopolamine-induced neurocyte damage. The efficacy of huperzine A on scopolamine- and D-galactose & AlCl3-induced memory deficits in rats was significantly improved, as evidenced by inhibiting acetylcholinesterase activity, alleviating oxidative stress damage in the brain, and improving learning function, meanwhile activating extracellular regulated protein kinases-cyclic AMP responsive element binding protein-brain derived neurotrophic factor pathway. Moreover, postsynaptic density protein PSD-95, which interacts with two important therapeutic targets Tau and ß-amyloid in Alzheimer's disease, was upregulated. This fruitful treatment was further shown to significantly ameliorate Tau hyperphosphorylation and decrease ß-amyloid by ways including modulating beta-site amyloid precursor protein cleaving enzyme 1 and a disintegrin and metalloproteinase 10. Collectively, such a newly developed strategy breaks the impasse for efficient drug delivery to the brain, and the potential therapeutic role of huperzine A for Alzheimer's disease is further illustrated.

Advances and Prospects for Hydrogel-Forming Microneedles in Transdermal Drug Delivery.

Transdermal drug delivery (TDD) is one of the key approaches for treating diseases, avoiding first-pass effects, reducing systemic adverse drug reactions and improving patient compliance. Microneedling, iontophoresis, electroporation, laser ablation and ultrasound facilitation are often used to improve the efficiency of TDD. Among them, microneedling is a relatively simple and efficient means of drug delivery. Microneedles usually consist of micron-sized needles (50-900 µm in length) in arrays that can successfully penetrate the stratum corneum and deliver drugs in a minimally invasive manner below the stratum corneum without touching the blood vessels and nerves in the dermis, improving patient compliance. Hydrogel-forming microneedles (HFMs) are safe and non-toxic, with no residual matrix material, high drug loading capacity, and controlled drug release, and they are suitable for long-term, multiple drug delivery. This work reviewed the characteristics of the skin structure and TDD, introduced TDD strategies based on HFMs, and summarized the characteristics of HFM TDD systems and the evaluation methods of HFMs as well as the application of HFM drug delivery systems in disease treatment. The HFM drug delivery system has a wide scope for development, but the translation to clinical application still has more challenges.

Elevated MMP-8 levels, inversely associated with BMI, predict mortality in mechanically ventilated patients: an observational multicenter study.

BACKGROUND: The present study aimed to investigate the correlation between weight status and mortality in mechanically ventilated patients and explore the potential mediators. METHODS: Three medical centers encompassing 3301 critically ill patients receiving mechanical ventilation were assembled for retrospective analysis to compare mortality across various weight categories of patients using machine learning algorithms. Bioinformatics analysis identified genes exhibiting differential expression among distinct weight categories. A prospective study was then conducted on a distinct cohort of 50 healthy individuals and 193 other mechanically ventilated patients. The expression levels of the genes identified through bioinformatics analysis were quantified through enzyme-linked immunosorbent assay (ELISA). RESULTS: The retrospective analysis revealed that overweight individuals had a lower mortality rate than underweight individuals, and body mass index (BMI) was an independent protective factor. Bioinformatics analysis identified matrix metalloproteinase 8 (MMP-8) as a differentially expressed gene between overweight and underweight populations. The results of further prospective studies showed that overweight patients had significantly lower MMP-8 levels than underweight patients ((3.717 (2.628, 4.191) vs. 2.763 (1.923, 3.753), ng/ml, P = 0.002). High MMP-8 levels were associated with increased mortality risk (OR = 4.249, P = 0.005), indicating that elevated level of MMP-8 predicts the mortality risk of underweight patients receiving mechanical ventilation. CONCLUSIONS: This study provides evidence for a protective effect of obesity in mechanically ventilated patients and highlights the potential role of MMP-8 level as a biomarker for predicting mortality risk in this population.

Phytosterol-mediated glycerosomes combined with peppermint oil enhance transdermal delivery of lappaconitine by modulating the lipid composition of the stratum corneum.

Although the introduction of glycerosomes has enriched strategies for efficient transdermal drug delivery, the inclusion of cholesterol as a membrane stabilizer has limited their clinical application. The current study describes the development and optimization of a new type of glycerosome (S-glycerosome) that is formed in glycerol solution with ß-sitosterol as the stabilizer. Moreover, the transdermal permeation properties of lappaconitine (LA)-loaded S-glycerosomes and peppermint oil (PO)-mediated S-glycerosomes (PO-S-glycerosomes) are evaluated, and the lipid alterations in the stratum corneum are analyzed via lipidomics. The LA-loaded S-glycerosomes prepared by the preferred formulation from the uniform design have a mean size of 145.3 ± 7.81 nm and an encapsulation efficiency of 73.14 ± 0.35%. Moreover, the addition of PO positively impacts transdermal flux, peaking at 0.4% (w/v) PO. Tracing of the fluorescent probe P4 further revealed that PO-S-glycerosomes penetrate deeper into the skin than S-glycerosomes and conventional liposomes. Additionally, treatment with PO-S-glycerosomes alters the isoform type, number, and composition of sphingolipids, glycerophospholipids, glycerolipids, and fatty acids in the stratum corneum, with the most notable effect observed for ceramides, the main component of sphingolipids. Furthermore, the transdermal administration of LA-loaded PO-S-glycerosomes improved the treatment efficacy of xylene-induced inflammation in mice without skin irritation. Collectively, these findings demonstrate the feasibility of ß-sitosterol as a stabilizer in glycerosomes. Additionally, the inclusion of PO improves the transdermal permeation of S-glycerosomes, potentially by altering the stratum corneum lipids.

mTOR inhibition suppresses Myc-driven polyposis by inducing immunogenic cell death.

Myc is a key driver of colorectal cancer initiation and progression, but remains a difficult drug target. In this study, we show that mTOR inhibition potently suppresses intestinal polyp formation, regresses established polyps, and prolongs lifespan of APCMin/+ mice. Everolimus in diet strongly reduces p-4EBP1, p-S6, and Myc levels, and induces apoptosis of cells with activated ß-catenin (p-S552) in the polyps on day 3. The cell death is accompanied by ER stress, activation of the extrinsic apoptotic pathway, innate immune cell recruitment, and followed by T-cell infiltration on day 14 persisting for months thereafter. These effects are absent in normal intestinal crypts with physiologic levels of Myc and a high rate of proliferation. Using normal human colonic epithelial cells, EIF4E S209A knockin and BID knockout mice, we found that local inflammation and antitumor efficacy of Everolimus requires Myc-dependent induction of ER stress and apoptosis. These findings demonstrate mTOR and deregulated Myc as a selective vulnerability of mutant APC-driven intestinal tumorigenesis, whose inhibition disrupts metabolic and immune adaptation and reactivates immune surveillance necessary for long-term tumor control.

IDENTIFICATION AND CLINICAL VALIDATION OF HYPOXIA-INDUCIBLE FACTOR 1α PROTEIN AS THE POTENTIAL BIOMARKER IN PATIENTS WITH SEPSIS.

ABSTRACT: Objective: Sepsis is a complex disease characterized by an inflammatory response and tissue hypoxia. Hypoxia-inducible factor 1α (HIF-1α) expression level is regulated by hypoxia and inflammation. This study aimed to explore the correlation between HIF-1α expression level and sepsis by bioinformatics analysis and clinical investigation. Methods: Bioinformatics tools were used to identify differentially expressed genes between sepsis and nonsepsis groups using the Gene Expression Omnibus data set. A clinical investigation was carried out to validate HIF-1α protein level in 54 nonseptic patients and 173 septic patients who were followed up for 28 days. Results: Bioinformatics analysis revealed that HIF-1α messenger RNA level was significantly different between septic and nonseptic patients ( P < 0.05). Consistent with the study hypothesis, higher HIF-1α levels in plasma were found in septic patients compared with those in nonseptic patients. The diagnostic accuracy for sepsis, as quantified by the area under the curve, was 0.926 (0.885-0.968) for HIF-1α expression level combined with oxygen saturation to fraction of inspired oxygen (SpO 2 /FiO 2 ), white blood cell, and blood urea nitrogen. The HIF-1α expression level was also significantly correlated with the severity of the disease. The results of the restricted cubic splines model indicated a U-shaped relationship between HIF-1α expression level and intensive care unit (ICU) mortality. Univariate and multivariate linear regression analyses indicated that septic patients with the elevated HIF-1α expression levels had shorter length of ICU stay versus those with the lower HIF-1α expression levels. Conclusion: Hypoxia-inducible factor 1α expression level can be used for diagnosing disease, assessing severity, and predicting length of ICU stay in septic patients.

Lipogenesis promotes mitochondrial fusion and maintains cancer stemness in human NSCLC.

Cancer stem-like cells (CSCs) are critically involved in cancer metastasis and chemoresistance, acting as one major obstacle in clinical practice. While accumulating studies have implicated the metabolic reprogramming of CSCs, mitochondrial dynamics in such cells remain poorly understood. Here we pinpointed OPA1hi with mitochondrial fusion as a metabolic feature of human lung CSCs, licensing their stem-like properties. Specifically, human lung CSCs exerted enhanced lipogenesis, inducing OPA1 expression via transcription factor SAM Pointed Domain containing ETS transcription Factor (SPDEF). In consequence, OPA1hi promoted mitochondrial fusion and stemness of CSCs. Such lipogenesishi, SPDEFhi, and OPA1hi metabolic adaptions were verified with primary CSCs from lung cancer patients. Accordingly, blocking lipogenesis and mitochondrial fusion efficiently impeded CSC expansion and growth of organoids derived from patients with lung cancer. Together, lipogenesis regulates mitochondrial dynamics via OPA1 for controlling CSCs in human lung cancer.

Multi-omics characterization of synthetic lethality-related molecular features: implications for SL-based therapeutic target screening.

Synthetic lethality (SL) represents the co-occurrence of two or more non-lethal disordered genes that could lead to cell death. SL-based anticancer therapeutics could specifically kill the cancer cells carrying the targeted mutated gene while leaving normal cells alive. Recent large-scale computational and experimental screenings provide rich resources of SL information while lacking systematic research on molecular features of SL genes. Combined with comprehensive multi-omics data analysis and experimental validation of one SL gene pair, Guo et al. portrayed a systematic layout of cancer-specific SL interactions that could improve understanding of carcinogenesis and potentially assist the subsequent screening of anticancer therapeutic targets.

Characterization of circular RNAs with advanced sequencing technologies in human complex diseases.

Circular RNAs (circRNAs) are one category of non-coding RNAs that do not possess 5' caps and 3' free ends. Instead, they are derived in closed circle forms from pre-mRNAs by a non-canonical splicing mechanism named "back-splicing." CircRNAs were discovered four decades ago, initially called "scrambled exons." Compared to linear RNAs, the expression levels of circRNAs are considerably lower, and it is challenging to identify circRNAs specifically. Thus, the biological relevance of circRNAs has been underappreciated until the advancement of next generation sequencing (NGS) technology. The biological insights of circRNAs, such as their tissue-specific expression patterns, biogenesis factors, and functional effects in complex diseases, namely human cancers, have been extensively explored in the last decade. With the invention of the third generation sequencing (TGS) with longer sequencing reads and newly designed strategies to characterize full-length circRNAs, the panorama of circRNAs in human complex diseases could be further unveiled. In this review, we first introduce the history of circular RNA detection. Next, we describe widely adopted NGS-based methods and the recently established TGS-based approaches capable of characterizing circRNAs in full-length. We then summarize data resources and representative circRNA functional studies related to human complex diseases. In the last section, we reviewed computational tools and discuss the potential advantages of utilizing advanced sequencing approaches to a functional interpretation of full-length circRNAs in complex diseases. This article is categorized under: RNA Evolution and Genomics > Computational Analyses of RNA RNA in Disease and Development > RNA in Disease.