FASEB bioAdvances最新文献

Migraine is a chronic pulsating primary headache affecting billions of individuals worldwide. The condition is associated with neuroinflammation and is listed as the second most common form of headache disorders and the leading cause of disabilities. Migraineurs are susceptible to various pathological conditions ranging from mood and emotional dysregulation to neuronal disorders. Consequently, they often experience a higher rate of depression compared to non-migraineurs. Some migraineurs do not respond effectively to conventional drugs. As a result, there is a need for more alternative, effective treatment plans. Understanding the role of inflammation in migraine headache conditions could potentially bring solutions. The aim of the review is to outline the role of inflammation, focusing on neuronal excitability, pain, and inflammatory pathways involved in the context of migraine headaches. With the use of various academic and research databases, articles linked to inflammation and neuroinflammation were considered. Data were collected and analyzed surrounding inflammatory biomarkers and their link to migraine pathophysiology and current treatment plans. Studies highlight the impact of inflammatory mediators and neurotransmitters like interleukins (IL-1β,6,8,10), tumor necrosis factor-alpha (TNF-α), transforming growth-factor-beta (TNF-β), glutamate, and chemokines in the onset and severity of migraine headaches with and without aura, eliciting pain and inflammatory responses in the central nervous system. Studies also linked migraines and mood disorders, contributing to the increase in comorbidity prevalence. Further research is needed to address the increasing burden and gaps in existing treatments surrounding the inadequate relief and side effects reported with some migraine treatments. In addition, the use of medicinal plants for inflammation-targeted therapy needs to be further explored for more viable alternative treatments.

Inhalation of organic dust increases the risk for respiratory symptoms and respiratory diseases, with chronic inflammation playing a major role in their development. Previously, we reported that organic dust induction of inflammatory mediators in bronchial epithelial cells is mediated through increase of intracellular reactive oxygen species (ROS) and activation of NFκB and Stat3. Oxidative stress caused by increased ROS has been linked to the activation of endoplasmic reticulum (ER) stress and unfolded protein response (UPR). UPR modulates immune responses and plays key roles in the development of acute and chronic diseases. Herein, we hypothesized that organic dust-induced ER stress-UPR regulates airway epithelial cell inflammatory responses. We found that poultry organic dust extract (referred to as dust extract) increased the expression of ER stress/UPR sensor ERN1 in Beas2B bronchial epithelial cells. Dust extract was also found to increase ERN1 protein levels in mouse lungs with ERN1 immunostaining detected predominantly in the bronchial epithelium. Additionally, dust extract increased Ser724 ERN1 phosphorylation in the mouse bronchial epithelium indicating activation. Chemical inhibition and mRNA knockdown studies revealed that TLR2/TLR4-Myd88-ROS-NFκB/Stat3 pathway mediates ERN1 induction. ERN1 chemical inhibitors, KIRA6 and APY29, and ERN1 mRNA knockdown reduced the induction of IL6, CXCL8, and pro IL1β. KIRA6 inhibited dust extract stimulation of NFκB-p65, Stat3, Jun and MAPK 8/9 phosphorylation. Our studies have shown that ER stress and ERN1 are new players in the control of organic dust induced lung inflammation. Cross-regulation between members of cell signaling cascade, TLR2-TLR4/MyD88/ROS/ERN1/NFκB/Stat3 may fine tune immune and inflammatory responses elicited by organic dust.

TBC1 Domain Family Member 1 (TBC1D1) plays a crucial role in various cancers. However, its specific function in pancreatic cancer (PC) remains poorly understood. In this study, we aimed to evaluate the prognostic value of TBC1D1 and its correlation with the tumor microenvironment (TME) in PC. A total of 168 patients with PC were included in this study. The expression of TBC1D1 in patients was detected by immunohistochemistry. Additionally, single-cell RNA sequencing (scRNA-seq) was used to reveal the expression distribution and proportion of TBC1D1 across different cell populations. The relationship between TBC1D1 expression levels and the TME was further explored based on high and low TBC1D1 expression groups. Multivariate analysis revealed that TBC1D1 positivity was an independent adverse prognostic factor for overall survival (OS; p = 0.026). Immunohistochemistry and single-cell RNA sequencing analyses revealed that TBC1D1 expression was positively correlated with fibroblast activation protein, programmed cell death protein 1, and programmed cell death ligand-1 positivity but negatively correlated with clusters of differentiation 8T cells positivity. Our findings revealed that TBC1D1 is an independent prognostic risk factor in patients with PC and may promote PC progression by modulating the TME.

Single-cell RNA-seq (scRNA-seq) technologies greatly revolutionized our understanding of cell-to-cell variability of gene expression, but few scRNA-seq technologies were used to describe the expression dynamics at the isoform and exon levels. Although the current expression profile of early embryos was studied focusing on the expression changes at the gene level, systematic investigation of gene expression dynamics of human early embryonic development remains insufficient. Here we systematically explored the gene expression dynamics of human early embryonic development integrating gene expression level with alternative splicing, isoform switching, and expression regulatory network. We found that the genes involved in significant changes in these three aspects are all gradually decreased along embryonic development from E3 to E7 stage. Moreover, these three types of variations are complementary for profiling expression dynamics, and they vary significantly across embryonic development as well as between different sexes. Strikingly, only a small number of genes exhibited prominent expression level changes between male and female embryos in the E3 stage, whereas many more genes showed variations in alternative splicing and major isoform switching. Additionally, we identified functionally important specific gene regulatory modules for each stage and revealed dynamic usage of transcription factor binding motifs (TFBMs). In conclusion, this study provides informative insights into gene dynamic characteristics of human early embryonic development by integrating gene expression level with alternative splicing, isoform switching, and gene regulatory networks. A systematic understanding of gene dynamic alteration features during embryonic development not only expands knowledge on basic developmental biology but also provides fundamental insights for regenerative medicine and developmental diseases.

Inhalation of wood smoke (WS) has been associated with increased risk of cardiovascular events, including heart attacks and strokes, both of which are caused in part by the thrombotic occlusion of blood vessels. To characterize the effects of WS on levels of established, circulating prothrombotic biomarkers, healthy human subjects at rest were exposed to WS (500 μg/m³) or filtered air for 2 h. Plasma samples were then used to assess markers of endogenous procoagulant activity: cellular activation (tissue factor-positive extracellular vesicles, TF + EVs), thrombin-antithrombin complexes (TAT), fibrin formation/breakdown (D-dimer), and thrombin generation potential. No significant differences in TF + EVs, TATs, D-dimer, or thrombin generation parameters were detected between WS- or filtered air-exposed individuals. Although females had significantly higher TATs and D-dimers, and slightly but non-significantly shorter thrombin generation lag times than males, there were no significant differences between WS- or air-exposed males or females in any measurements. These data suggest that acute WS exposure does not increase prothrombotic biomarkers in plasma.

Nicotinamide adenine dinucleotide (NAD⁺) plays an important role in the innate immune response and is depleted during SARS-CoV-2 infection due to increased turnover. It is unknown whether treatment with NAD⁺ precursors can safely raise NAD⁺ levels in patients with COVID-19. To determine whether MIB-626 (β-nicotinamide mononucleotide), an NAD⁺ precursor, can safely increase blood NAD⁺ levels and attenuate acute kidney injury (AKI) and inflammation in hospitalized patients with COVID-19, 42 adults, ≥ 18 years, hospitalized with COVID-19 and AKI, were randomized in a 3:2 ratio to MIB-626 1.0-g or placebo tablets twice daily for 14 days. Circulating NAD⁺ and its metabolites, markers of AKI, inflammation, and disease severity, were assessed. MIB-626 treatment significantly but gradually raised blood NAD⁺ levels to a peak between 5 to 14 days (16.0 ± 6.9, 25.5 ± 12.6, and 42.6 ± 25.6 μg/mL at baseline, days 5 and 14) and raised plasma concentrations of NAD⁺ metabolites 1-methylnicotinamide, N-methyl, 2-pyridone, 4-carboxamide rapidly to a peak by day 3. Changes in serum creatinine, cystatin-C, and serum markers of AKI did not differ significantly between groups. Serum CRP, IL-6, and TNFα and indices of disease severity also did not differ between groups. MIB-626 treatment of patients with COVID-19 and AKI safely and substantially raised blood NAD⁺ and plasma concentrations of NAD⁺ metabolites. Markers of AKI, inflammation, and disease severity did not differ between groups, likely due to the slow rise in NAD⁺ levels. Future studies should assess whether a rapid increase in NAD⁺ by parenteral administration can attenuate disease severity and AKI.

Trial Registration: ClinicalTrials.gov Identifier: NCT05038488

Iron (Fe)-deficiency (ID) and Fe-deficiency anemia (IDA) are highly prevalent conditions and are of particular concern to maternal–child health. ID and IDA are typically linked to nutritional deficiencies, but maternal exposure to heavy metals including cadmium (Cd) also leads to offspring with low levels of circulating Fe. Another comorbidity of ID and IDA is metabolic dysfunction-associated steatotic liver disease (MASLD), a liver condition characterized by lipid accumulation and fibrosis. We have previously shown that maternal Cd exposure also leads to the development of MASLD in offspring. We hypothesized that providing Fe fortification would prevent Cd-induced ID, which would in turn rescue offspring from growth restriction and MASLD. To test this, virgin dams were exposed to 30 ppm of cadmium chloride (CdCl₂) in their drinking water during the preconception, gestation, and lactation periods. Fe fortification was supplied in the form of dietary ferric citrate, which amounted to two (2×) or five times (5×) the normal dietary Fe in standard chow. Our study provides evidence that perinatal Cd exposure does not prevent absorption of supplemental Fe, and that the chosen Fe supplementation dosages are sufficient to prevent Cd-induced growth restriction, ID, IDA, and MASLD in offspring at postnatal day 21 (PND21). Our findings suggest that Fe supplementation may be a viable therapy to prevent these developmental effects of maternal Cd exposure.

The central dogma indicates the basic direction of gene expression pathways. For activated gene expression, the quantitative relationship between various links from the binding of transcription factors (TFs) to DNA to protein synthesis remains unclear and debated. There is consensus that at a steady state, protein levels are largely determined by the mRNA level. How can we find this steady state? Taking p53 as an example, based on the previously discovered Hill-type equation that characterizes mRNA expression under p53 pulsing, I proved that the same equation can be used to describe the average steady state of target protein expression. Therefore, at steady state, the average fold changes in mRNA and protein expression under TFs pulsing were the same. This consensus has been successfully demonstrated. For the p53 target gene BAX, the observed fold changes in mRNA and protein expression were 1.40 and 1.28, respectively; the fold changes in mRNA and protein expression calculated using the Hill-type equation were both 1.35. Therefore, using this equation, we can not only fine-tune gene expression, but also predict the proteome from the transcriptome. Furthermore, by introducing two quantitative indicators, we can determine the degree of accumulation and stability of protein expression.

Plasmalogens are natural glycerophospholipids that account for approximately 15%–20% (mol%) of human tissues' cellular membrane phospholipid composition. They play an important role in lipid membrane organization and function, including acting as endogenous antioxidants. Plasmalogens contain a vinyl-ether linked alkyl chain at position sn-1, characteristic of vinyl-ether lipids, and often a polyunsaturated fatty acid (PUFA) acyl chain at position sn-2 of the glycerol backbone. The role of plasmalogens in various patho-physiological processes has been revealed in recent years, including various neurological disorders associated with plasmalogen deficiency. Plasmalogen Replacement Therapy (PRT) is a therapeutic approach that aims to increase plasmalogen levels in the body and address plasmalogen deficiencies in diseases such as age-related neurodegenerative diseases, cardiovascular diseases, certain genetic peroxisomal disorders, and metabolic disorders. We provide a detailed overview of current information on the role of plasmalogens in health and disease. We summarize various strategies for regulating plasmalogen levels and highlight recent advancements in therapeutic applications. We also focus on the potential application of nanomedicine for treating disorders associated with PUFA-lipid and plasmalogen deficiencies.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is associated with neurological symptoms, but the molecular mechanisms have not yet been identified. Since the S1 subunit (S1) of the envelope of the SARS-CoV2 Spike glycoprotein can reach the CNS, we studied whether S1 could cause neuronal death in a direct manner. Transfection of the S1 plasmid in SH-SY5Y cells reduces cell survival in a time-dependent manner, whereas the overexpression of the S2 subunit does not. Notably, isoform 4 of histone deacetylases (HDAC4) is involved in S1-induced cell toxicity, whereas, among the different cell death drug inhibitors, only the necroptosis blocker Necrostatin-1 counteracted the neurodetrimental effect of S1. Coherently, an increase of the necroptosis marker receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and a reduction of its transcriptional repressor cAMP response element-binding protein (CREB) occur in S1-overexpressing cells. Noteworthy, HDAC4 interacts with CREB determining its protein reduction and the consequent increase of RIPK1. Importantly, we found that S1 recombinant protein (S1rp), through the internalization of the surface receptor Neuropilin 1 (NRP1), but not via Angiotensin-Converting Enzyme 2 (ACE 2) receptor, enters the cytoplasm causing cell death in differentiated SH-SY5Y cells. Finally, in accordance with other papers demonstrating that COVID-19 patients had more severe ischemic strokes with worse outcomes, we found that S1rp increased oxygen glucose deprivation/reoxygenation-induced toxicity in an additive manner, via the NRP1/HDAC4/CREB/RIPK1 pathway. In conclusion, this is the first report identifying the molecular determinants involved in Spike S1-induced neurotoxicity.