FASEB bioAdvances最新文献

Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), presents a global public health challenge. Although the relationships between gut microbiota, inflammatory proteins, and IBD are recognized, their causal associations and mediating roles remain unclear. Large-scale genome-wide association study data on 473 gut microbiota, 91 circulating inflammatory proteins, and IBD (including CD and UC) were analyzed. Univariable Mendelian randomization (UVMR), Bayesian Weighted MR (BWMR), mediation MR, and sensitivity analyses were used to explore causal associations and quantify mediating effects. MR results indicate that 24, 20, and 22 gut microbiota exhibit causal effects on IBD (nine protective factors, 15 risk factors), CD (nine protective factors, 11 risk factors) and UC (seven protective factors, 15 risk factors). Three inflammatory proteins (one protective factors, two risk factors) have causal effects on IBD, with five having causal effects on CD (one protective factors, four risk factors) and UC (two protective factors, three risk factors). Mediation analysis reveals that Interleukin-17C levels mediate the causal effects of Acetobacterales and Bifidobacterium on IBD. T-cell surface glycoprotein CD6 isoform levels mediate the causal effect of Faecalibacterium prausnitzii E on CD. Interleukin-17C levels also mediate the causal effects of Acetobacterales on UC and Phocea massiliensis on UC. Gut microbiota and circulating inflammatory proteins play key roles in IBD pathogenesis, with Interleukin-17C and T-cell surface glycoprotein CD6 identified as key intermediates in the causal pathway. These findings provide novel biomarkers and potential therapeutic targets for preventing and treating IBD, CD, and UC.

Cell homeostasis and metabolic control require the efficient function of mitochondria and implementation of quality control pathways following damage. Cells have various discrete pathways of mitochondrial quality control (mitoQC) to maintain the healthy network. PINK1 and Parkin are two key players in mitoQC, most highly associated with the ubiquitin-dependent capture and degradation of whole mitochondria by autophagy. However, these proteins have alternative roles in repair routes directing locally damaged cargo to the lysosome, such as the mitochondrial-derived vesicle (MDV) pathway. We aimed to clarify the role of PINK1 and determine how its loss of function impacts mitochondrial dynamics and quality control. Results indicate PINK1 knockout (KO) has little impact on whole mitochondrial turnover in response to damage in SH-SY5Y cells, whereas both PINK1 and Parkin KO cells have healthy mitochondrial networks with efficient ATP production. However, TOM20 positive outer-membrane and damage-induced PDH-positive inner-membrane MDVs are elevated in PINK1 KO cells. Although, in contrast to Parkin KO, this is not due to a defect in trafficking to a LAMP1-positive compartment and may instead indicate increased damage-induced flux. In comparison, loss of Atg5-dependent mitophagy has no effect on whole mitochondrial turnover and only results in a limited elevation in inner-membrane MDVs in response to damage, indicating autophagy-independent mechanisms of whole mitochondrial turnover and a minor compensatory increase in damage-induced MDVs. Therefore, these data suggest PINK1 and Parkin are dispensable for whole mitochondrial turnover, but following their perturbation have disparate effects on the MDV pathway.

Microgravity exposure affects both tissues and cells, and, in this regard, one of the most affected targets is the skeletal muscle system due to the significant loss of bone and muscle mass leading to osteoporosis and sarcopenia, respectively. Several efforts are underway to counteract the effects of microgravity, and recent studies on irisin, a myokine with anabolic effects on the musculoskeletal system, have shown promising results. Due to the practical challenges of conducting experiments in actual microgravity, different devices generating a simulated microgravity condition on Earth have been developed. Here, we exposed myoblasts, osteoblasts, osteocytes to a random position machine (RPM) for five days to assess microgravity effect on the expression of key differentiation factors in cells untreated or treated with irisin. In myoblasts (C2C12), exposure to RPM led to increased expression of early myogenesis maker genes Pax7 (p = 0.0016), Myf5 (p = 0.0005) and MyoD (p = 0.0009). Irisin treatment in the last 8 h of RPM cultures prevented these increases by returning Pax7 (p = 0.0008) and MyoD (p = 0.01) to control values, and only partially Myf5. In bone cells, exposure to RPM for 5 days showed no effect in osteoblasts (MC3T3) but decreased the expression of Pdpn (p = 0.0285) and Dmp-1 (p = 0.0423) genes in osteocytes (MLO-Y4). Irisin treatment completely prevented the decline in Pdpn (p = 0.293) and Dmp-1 (p = 0.0339) levels. Overall, our data showed that the impact of RPM exposure keeps myoblasts and osteocytes in a proliferative state, and irisin treatment restores them to their baseline biological condition, suggesting that irisin can counteract the changes induced by simulated microgravity.

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.