Search Results (88)

Methionine restriction (MetR) is a common adjuvant treatment for cancer. However, studies of MetR have paid little attention to its potential implications for fibrosis. Hypertrophic scarring (HTS) is an abnormal fibrotic response after burn trauma that results from the excessive activation of fibroblasts. Because of the absence of a fully effective pharmacological treatment, HTS frequently causes great annoyance in patients as a common sequela of burns. To date, the effects of MetR on hypertrophic scar fibroblasts (HTSFs) remain unclear. This study aimed to investigate the anti-fibrotic effects of MetR and explore the associated alterations in signaling pathways in HTSFs. We isolated HTSFs from post-burn HTS tissues and cultured them in a specially prepared MetR medium. Cell and immunocytochemical staining images were captured using light and fluorescence microscopes, respectively. Cell proliferation was evaluated using a CellTiter-Glo Luminescent Cell Viability Assay Kit. mRNA and protein expression levels were determined using quantitative reverse transcription polymerase chain reaction and Western blotting, respectively. In HTSFs, MetR reduced cellular inflammation; downregulated multiple signaling pathways, including the TGF-β-SMAD, STAT, and AKT/mTOR pathways; and upregulated MAPKs. Furthermore, MetR arrested the cell cycle, promoted apoptosis, suppressed cell proliferation and migration, and reduced extracellular matrix protein secretion, thereby exerting multifaceted inhibitory effects on HTS. Our results demonstrated that MetR can inhibit scars’ formation and suggest that regulating methionine metabolism in the scar environment may help treat scars. Full article

Schizophrenia (SCZ) is a severe, chronic mental disorder of unknown etiology and limited therapeutic options. Bioenergetic deficits in the oxidative phosphorylation system (OXPHOS) during early postnatal brain development may underlie disrupted neuronal metabolism and synaptic signaling, contributing to the neurodevelopmental and behavioral disturbances observed in patients. This narrative review summarizes updated evidence linking mitochondrial-OXPHOS dysfunction to SCZ pathophysiology. The novelty lies in the focus on OXPHOS dysfunction at the enzymatic/functional level, rather than on genetic, transcriptional, or oxidative parameters. While complex I impairment has long been highlighted and proposed as a peripheral marker of the disease, recent studies also report alterations in other OXPHOS complexes and their precursors. These findings suggest that OXPHOS dysfunction is not isolated to a single enzymatic component but affects broader mitochondrial function, alongside oxidative stress, contributing to disease progression through mechanisms involving apoptosis, accelerated aging, and synaptic deterioration. OXPHOS dysfunction in both central and peripheral tissues further supports its relevance to SCZ. Overall, the literature points to mitochondrial OXPHOS abnormalities as a significant biological feature of SCZ. Whether these alterations are causal factors or consequences of disease processes remains unclear. Understanding OXPHOS dysregulation may open new avenues for targeted therapies. Full article

Choroideremia is a rare X-linked recessive retinal disorder characterized by progressive vision loss caused by retinal degeneration resulting from mutations in the CHM gene, which encodes Rab escort protein 1 (REP-1). In humans and mice, the Rab escort protein (REP) family consists of two members, REP-1 and REP-2, with REP-2 hypothesized to compensate for REP-1 deficiency in tissues outside the eye in choroideremia. In this study, we conducted a systematic mutational analysis of the mouse orthologs of REP-1 and REP-2. Blood analyses revealed metabolic abnormalities in the mutant mice deficient for REP-1, resembling the systemic metabolic disturbances observed in individuals with choroideremia, such as altered lipid and hemoglobin metabolism. We also observed an elevation in systemic inflammatory biomarkers in these mutant mice. Interestingly, these systemic abnormalities emerged before retinal degeneration became detectable in REP-1-deficient mice. Transcriptomic analysis of retinas isolated from REP-1 deficient mice revealed enrichment of proinflammatory signaling pathways. These results suggest important similarities between choroideremia and some forms of retinitis pigmentosa. While engineered loss of REP-2 alone caused no detectable phenotypic changes, dual deficiency in REP-1 and REP-2 resulted in lethality under both in vivo and in vitro conditions. Our findings offer novel insights into REPs and deepen our understanding of choroideremia, which may contribute to the development of new treatments for this genetic condition. Full article

(1) Background: Bovine mastitis is a lactational disease caused by infection and milk stagnation in the mammary glands. Danggui buxue decoction (DBD), a traditional remedy for blood tonification, anti-inflammation, and antioxidation, has not been used previously to treat mastitis. (2) Methods: In this study, an Escherichia coli mastitis model was established by infecting lactating Kunming mice with clinically isolated bovine mastitis-derived E. coli. Based on this, the effects of DBD on inflammation and oxidative stress in mastitis model mice were evaluated by conducting routine blood tests, H&E staining, qRT-PCR analysis, ELISA, and microcolorimetry. (3) Results: We found that DBD treatment reduced body weight loss, abnormal organ indices, abnormal blood cell counts, pathological damage to breast tissue, and the upregulation of the expression of inflammatory factor in mice caused by E. coli infection. We also found that DBD increased the expression of antioxidants and antioxidant genes and decreased the expression of oxidation products and oxidation-related genes in breast tissue. The therapeutic effect of DBD on inflammation and oxidative stress (OS) in mice occurred through the regulation of the TLR4/NF-κB and Nrf2/HO-1 signaling pathways. (4) Conclusions: DBD imparted its anti-inflammatory and antioxidant effects by inhibiting the TLR4/NF-κB signaling pathway and activating the antioxidant Nrf2/HO-1 signaling pathway Full article

Background: Prenatal alcohol exposure (PAE) models can cause neurodevelopmental abnormalities like those observed in fetal alcohol spectrum disorder (FASD). Previous studies link experimental PAE effects in the brain to impaired signaling through insulin/IGF and Notch pathways that mediate neuronal survival, growth, migration, energy metabolism, and plasticity. Importantly, concurrent administration of peroxisome proliferator-activated receptor agonists or dietary soy prevented many aspects of FASD due to their insulin-sensitizing, anti-inflammatory, and antioxidant properties. Objective: To determine if dietary soy interventions during pregnancy would be sufficient to normalize central nervous system structure and function, we examined the effects of maternal gestation-limited dietary soy on cerebellar postnatal development, motor function, and critical signaling pathways. Methods: Pregnant Long Evans rats were fed isocaloric liquid diets containing 0% or 26% caloric ethanol with casein or soy isolate as the protein source. The ethanol and soy feedings were discontinued upon delivery. The offspring were subjected to rotarod motor function tests, and on postnatal day 35, they were sacrificed to harvest cerebella for histological and molecular studies. Results: Despite the postnatal cessation of alcohol exposure, chronic gestational exposure reduced brain weight, caused cerebellar hypoplasia, and impaired motor performance. Gestational dietary soy prevented the ethanol-associated reduction in brain weight and largely restored the histological integrity of the cerebellum but failed to normalize motor performance. Ethanol withdrawal abolished the impairments in insulin/IGF signaling that were previously associated with ongoing ethanol exposures, but ethanol’s inhibitory effects on Notch and Wnt signaling persisted. Soy significantly increased cerebellar expression of the insulin and IGF-1 receptors and abrogated several ethanol-associated impairments in Notch and Wnt signaling. Conclusions: Although gestation-restricted dietary soy has significant positive effects on neurodevelopment, optimum prevention of FASD’s long-term effects will likely require dietary soy intervention during the critical periods of postnatal development, even after alcohol exposures have ceased. Full article

Accurate forecasting of wind power is crucial for addressing energy demands, promoting sustainable energy practices, and mitigating environmental challenges. In order to improve the prediction accuracy of wind power, a VMD-CNN-BiLSTM hybrid model with physical constraints is proposed in this paper. Initially, the isolation forest algorithm identifies samples that deviate from actual power outputs, and the LightGBM algorithm is used to reconstruct the abnormal samples. Then, leveraging the variational mode decomposition (VMD) approach, the reconstructed data are decomposed into 13 sub-signals. Each sub-signal is trained using a CNN-BiLSTM model, yielding individual prediction results. Finally, the XGBoost algorithm is introduced to add the physical penalty term to the loss function. The predicted value of each sub-signal is taken as the input to get the predicted result of wind power. The hybrid model is applied to the 12 h forecast of a wind farm in Zhangjiakou City, Hebei province. Compared with other hybrid forecasting models, this model has the highest score on five performance indicators and can provide reference for wind farm generation planning, safe grid connection, real-time power dispatching, and practical application of sustainable energy. Full article

GNAS (Guanine Nucleotide-Binding Protein, Alpha Stimulating) is a complex gene that encodes the alpha subunit of the stimulatory G protein (G_sα), critical for signaling through various G protein-coupled receptors. Inactivating genetic and epigenetic changes in GNAS, resulting in G_sα deficiency, cause different variants of pseudohypoparathyroidism, which may manifest features of Albright hereditary osteodystrophy (AHO, a syndrome characterized by early-onset obesity and other developmental defects). Recent findings have linked G_sα deficiency with isolated, severe, early-onset obesity, suggesting it as a potential, underrecognized cause of monogenic, non-syndromic obesity. This study was prompted by identifying several GNAS variants of uncertain significance (VUSs) in pediatric patients presenting with unexplained, severe, early-onset obesity at Sidra Medicine in Qatar. To functionally characterize these variants, we developed the first zebrafish model of G_sα deficiency, offering numerous advantages over other model systems. This was achieved by knockdown of the ortholog through microinjection of translation-blocking Morpholino antisense oligonucleotides into the yolks of 1-8-cell-stage zebrafish embryos. The morphant larvae displayed an obese phenotype, marked by significantly enlarged yolk sacs, increased neutral lipid accumulation, and reduced metabolic rates, among other developmental abnormalities resembling those in AHO. This zebrafish model lays the foundation for efficient functional characterization of GNAS VUSs and paves the way for enhancing our understanding of G_sα deficiency-associated early-onset obesity. Full article

Localized scleroderma (LS) is an autoimmune disease characterized by inflammation and fibrosis, leading to severe cutaneous manifestations such as skin hardening, tightness, discoloration, and other textural changes that may result in disability. While LS shares similar histopathologic features and immune-fibroblast interactions with systemic sclerosis (SSc), its molecular mechanisms remain understudied. Endothelial cells (EC) are known to play a crucial role in SSc but have not been investigated in LS. Single-cell RNA sequencing (scRNA-seq) now allows for detailed examination of this cell type in the primary organ of interest for scleroderma, the skin. In this study, we analyzed skin-isolated cells from 27 LS patients (pediatric and adult) and 17 healthy controls using scRNA-seq. Given the known role of EC damage as an initial event in SSc and the histologic and clinical skin similarities to LS, we focused primarily on endothelial cells. Our analysis identified eight endothelial subclusters within the dataset, encompassing both disease and healthy samples. Interaction analysis revealed that signaling from diseased endothelial cells was predicted to promote fibrosis through SELE interaction with FGFBP1 and other target genes. We also observed high levels of JAG in arterial endothelial cells and NOTCH in capillary endothelial cells, indicating the activation of a signaling pathway potentially responsible for epidermal abnormalities and contributing to LS pathogenesis. In summary, our scRNA-seq analysis identified potential disease-propagating endothelial cell clusters with upregulated pathways in LS skin, highlighting their importance in disease progression. Full article

In the present study, a series of coumarins, including eight undescribed bis-isoprenylated ones Spinifoliumin A-H, were isolated and identified from the aerial parts of Zanthoxylum dimorphophyllum var. spinifolium (ZDS), a plant revered in traditional Chinese medicine, particularly for treating rheumatoid arthritis (RA). The structures of the compounds were elucidated using 1D and 2D NMR spectroscopy, complemented by ECD, [Rh₂(OCOCF₃)₄]-induced ECD, Mo₂(OAc)₄ induced ECD, IR, and HR-ESI-MS mass spectrometry. A network pharmacology approach allowed for predicting their anti-RA mechanisms and identifying the MAPK and PI3K-Akt signaling pathways, with EGFR as a critical gene target. A CCK-8 method was used to evaluate the inhibition activities on HFLS-RA cells of these compounds. The results demonstrated that Spinifoliumin A, B, and D-H are effective at preventing the abnormal proliferation of LPS-induced HFLS-RA cells. The results showed that compounds Spinifoliumin A, D, and G can significantly suppress the levels of IL-1β, IL-6, and TNF-α. Moreover, molecular docking methods were utilized to confirm the high affinity between Spinifoliumin A, D, and G and EGFR, SRC, and JUN, which were consistent with the results of network pharmacology. This study provides basic scientific evidence to support ZDS’s traditional use and potential clinical application. Full article

Background: Vision-based pulmonary diagnostics present a unique approach for tracking and measuring natural breathing behaviors through remote imaging. While many existing methods correlate chest and diaphragm movements to respiratory behavior, we look at how the direct visualization of thermal CO₂ exhale flow patterns can be tracked to directly measure expiratory flow. Methods: In this work, we present a novel method for isolating and extracting turbulent exhale flow signals from thermal image sequences through flow-field prediction and optical flow measurement. The objective of this work is to introduce a respiratory diagnostic tool that can be used to capture and quantify natural breathing, to identify and measure respiratory metrics such as breathing rate, flow, and volume. One of the primary contributions of this work is a method for capturing and measuring natural exhale behaviors that describe individualized pulmonary traits. By monitoring subtle individualized respiratory traits, we can perform secondary analysis to identify unique personalized signatures and abnormalities to gain insight into pulmonary function. In our study, we perform data acquisition within a clinical setting to train an inference model (FieldNet) that predicts flow-fields to quantify observed exhale behaviors over time. Results: Expiratory flow measurements capturing individualized flow signatures from our initial cohort demonstrate how the proposed flow field model can be used to isolate and analyze turbulent exhale behaviors and measure anomalous behavior. Conclusions: Our results illustrate that detailed spatial flow analysis can contribute to unique signatures for identifying patient specific natural breathing behaviors and abnormality detection. This provides the first-step towards a non-contact respiratory technology that directly captures effort-independent behaviors based on the direct measurement of imaged CO₂ exhaled airflow patterns. Full article

Post-burn hypertrophic scars often exhibit abnormal pigmentation. Exosomes play important roles in maintaining normal physiological homeostasis and in the pathological development of diseases. This study investigated the effects of the exosomes derived from hypertrophic scar fibroblasts (HTSFs) on melanocytes, which are pigment-producing cells. Normal fibroblasts (NFs) and HTSFs were isolated and cultured from normal skin and hypertrophic scar (HTS) tissue. Both the NF- and HTSF-exosomes were isolated from a cell culture medium and purified using a column-based technique. The normal human epidermal melanocytes were treated with both exosomes at a concentration of 100 μg/mL at different times. The cell proliferation, melanin content in the medium, apoptotic factors, transcription factors, melanin synthesis enzymes, signaling, signal transduction pathways, and activators of transcription factors (STAT) 1, 3, 5, and 6 were investigated. Compared with the Dulbecco’s phosphate-buffered saline (DPBS)-treated controls and NF-exosomes, the HTSF-exosomes decreased the melanocyte proliferation and melanin secretion. The molecular patterns of apoptosis, proliferation, melanin synthesis, Smad and non-Smad signaling, and STATs were altered by the treatment with the HTSF-exosomes. No significant differences were observed between the DPBS-treated control and NF-exosome-treated cells. HTSF-derived exosomes may play a role in the pathological epidermal hypopigmentation observed in patients with HTS. Full article

Selective IgA deficiency (SIgAD) is the most common form and common variable immunodeficiency (CVID) is the most symptomatic form of predominant antibody deficiency. Despite differences in the clinical picture, a similar genetic background is suggested. A common feature of both disorders is the occurrence of autoimmune conditions. Regulatory T cells (T_regs) are the major immune cell type that maintains autoimmune tolerance. As the different types of abnormalities of T_reg cells have been associated with autoimmune disorders in primary immunodeficiency (PID) patients, in our study we aimed to analyze the gene expression profiles of T_reg cells in CVID and SIgAD patients compared to age-matched healthy controls. The transcriptome-wide gene profiling was performed by microarray technology. As a result, we analyzed and visualized gene expression patterns of isolated population of T_reg cells. We showed the differences at the gene level between patients with and without autoimmunizations. Our findings suggest that the gene signatures of T_reg cells isolated from SIgAD and CVID patients differ from age-matched healthy controls and from each other, presenting transcriptional profiles enriched in innate immune or Th response, respectively. The occurrence of autoimmunity in both types of PID is associated with down-regulation of class I IFNs signaling pathways. In summary, our findings improve our understanding of T_reg dysfunctions in patients with common PIDs and associated autoimmunity. Full article

The culture confirmation of Mycobacterium tuberculosis (MTB) remains the gold standard for the diagnosis of Tuberculosis (TB) with culture conversion representing proof of cure. However, over 40% of TB samples fail to isolate MTB even though many patients remain infectious due to the presence of viable non-culturable forms. Previously, we have shown that two short cationic peptides, T14D and TB08L, induce a hormetic response at low concentrations, leading to a stimulation of growth in MTB and the related animal pathogen Mycobacterium bovis (bTB). Here, we examine these peptides showing they can influence the mycobacterial membrane integrity and function through membrane potential reduction. We also show this disruption is associated with an abnormal reduction in transcriptomic signalling from specific mycobacterial membrane sensors that normally monitor the immediate cellular environment and maintain the non-growing phenotype. We observe that exposing MTB or bTB to these peptides at optimal concentrations rapidly represses signalling mechanisms maintaining dormancy phenotypes, which leads to the promotion of aerobic metabolism and conversion into a replicative phenotype. We further show a practical application of these peptides as reagents able to enhance conventional routine culture methods by stimulating mycobacterial growth. We evaluated the ability of a peptide-supplemented sample preparation and culture protocol to isolate the MTB against a gold standard routine method tested in parallel on 255 samples from 155 patients with suspected TB. The peptide enhancement increased the sample positivity rate by 46% and decreased the average time to sample positivity of respiratory/faecal sampling by seven days. The most significant improvements in isolation rates were from sputum smear-negative low-load samples and faeces. The peptide enhancement increased sampling test sensitivity by 19%, recovery in samples from patients with a previously culture-confirmed TB by 20%, and those empirically treated for TB by 21%. We conclude that sample decontamination and culture enhancement with D-enantiomer peptides offer good potential for the much-needed improvement of the culture confirmation of TB. Full article

Axial piston pumps are critical components of hydraulic systems due to their compact design and high volumetric efficiency, making them widely used. However, they are prone to failure in harsh environments characterized by high pressure and heavy loads over extended periods. Therefore, detecting abnormal behavior in axial piston pumps is of significant importance. Traditional detection methods often rely on vibration signals from the pump casings; however, these signals are susceptible to external environmental interference. In contrast, pressure signals exhibit greater stability. In this study, we propose a novel anomaly detection method for axial piston pumps, referred to as DTW-RCK-IF, which combines dynamic time warping (DTW) for data segmentation, a random convolutional kernel (RCK) for feature extraction, and isolation forest (IF) for anomaly detection using pressure signals. The model is trained using normal operating data to enable the effective detection of abnormal states. First, the DTW algorithm is employed to segment the raw data, ensuring a high degree of similarity between the segmented data. Next, the random convolutional kernel approach is used in a convolutional neural network for feature extraction, resulting in features that are representative of normal operating conditions. Finally, the isolation forest algorithm calculates the anomaly scores for anomaly detection. Experimental simulations on axial piston pumps demonstrate that, compared with vibration signals, the DTW-RCK-IF approach using pressure signals yields superior results in detecting abnormal data, with an average F1 score of 98.79% and a good fault warning effect. Validation using the publicly available CWRU-bearing and XJTU-SY-bearing full-life datasets further confirms the effectiveness of this method, with average F1 scores of 99.35% and 99.73%, respectively, highlighting its broad applicability and potential for widespread use. Full article

Although the efficiency of cloning remains very low, this technique has become the most reliable way to produce transgenic pigs. However, the high rate of abnormal offspring such as an enlarged tongue lowers the cloning efficiency by reducing the early survivability of piglets. Thus, the present study was conducted to identify the characteristics of the enlarged tongue from cloned piglets by histologic and transcriptomic analysis. As a result, it was observed that the tissues from enlarged tongues (n = 3) showed isolated and broken muscle bundles with wide spaces while the tissues from normal tongues (n = 3) showed the tight connection of muscle bundles without space by histological analysis. Additionally, transmission electron microscopy results also showed the formation of isolated and broken muscle bundles in enlarged tongues. The transcriptome analysis showed a total of 197 upregulated and 139 downregulated genes with more than 2-fold changes in enlarged tongues. Moreover, there was clear evidence for the difference between groups in the muscle system process with high relation in the biological process by gene ontology analysis. The analysis of the Kyoto Encyclopedia of Gene and Genomes pathway of differentially expressed genes indicated that the pentose phosphate pathway, glycolysis/gluconeogenesis, and glucagon signaling pathway were also involved. Conclusively, our results could suggest that the abnormal glycolytic regulation may result in the formation of an enlarged tongue. These findings might have the potential to understand the underlying mechanisms, abnormal development, and disease diagnosis in cloned pigs. Full article