The FASEB Journal最新文献

There is currently a lack of pathological research on the hair loss caused by stress, and there is no effective treatment available. It has been previously reported that stress can cause sympathetic nerve activation and release of norepinephrine, which binds to beta-2 adrenergic receptors and causes a series of chemical reactions. Propranolol, as a beta-2 adrenergic receptors blocker, competitively antagonizes the effects of norepinephrine. We initiated a single-center clinical trial with a self-controlled approach to assess the effectiveness of topical applied hydrochloride salt of propranolol solution in preventing stress-induced hair loss in humans. A total of 20 volunteers were enrolled. 14 out of 20 volunteers experienced a significant reduction in the number of hair loss (p < .05) after using hydrochloride salt of propranolol solution. No local adverse reactions were found. This study showed hydrochloride salt of propranolol solution may alleviate stress-induced alopecia to a certain extent, which provides clues for the development of pharmaceutical interventions for the treatment of stress-induced alopecia.

Secondary hyperparathyroidism (SHP) associated with chronic kidney disease (CKD) contributes to morbidity and mortality, yet the related parathyroid signaling pathways are not fully understood. Previous studies have indicated that the parathyroid mTORC1 pathway is activated in both experimental CKD and hypocalcemia-induced SHP. Furthermore, mice with parathyroid-specific mTOR deficiency (PT-mTOR^−/−) exhibit disrupted parathyroid glands, but maintain normal serum PTH levels. Conversely, PT-Tsc1^−/− mice, with mTORC1 hyperactivation, have enlarged glands and high serum PTH and calcium levels. We now uncover links between mTORC1 function, parathyroid gland morphology, and the response to CKD. Despite impaired gland structure, PT-mTOR^−/− mice increased serum PTH to levels similar to controls in response to CKD, but not to acute kidney injury (AKI), highlighting the adaptability of their parathyroid glands to chronic but not acute stimulation. PT-Tsc1^−/− mice, with enlarged glands also exhibited a CKD-induced rise in serum PTH comparable to controls, but with a reduced magnitude, suggesting compromised secretion capacity. Parathyroid glands from PT-Tsc1^−/− mice displayed sustained high PTH secretion in culture, with no further increase when exposed to calcium-depleted media, unlike control glands. Complementing these findings, human data from 106 healthcare organizations demonstrated that drug-induced mTORC1 inhibition is associated with reduced serum PTH and a lower incidence of SHP in kidney transplant recipients. Collectively, our findings underscore the complex interplay between mTORC1 signaling and gland structure in the pathogenesis of SHP.

Phosphatidylethanolamine (PE) is a ubiquitous bioactive lipid in cells, which participates in regulating many metabolic processes. Exogenous PE has been reported to play a positive regulatory role in macrophage inflammatory responses. However, the molecular mechanisms of PE in regulating macrophage inflammation are not completely understood. In the present study, transcriptomic analysis of PE-stimulated macrophages of large yellow croaker revealed that differentially expressed genes were mainly active in cellular components of the mitochondrial respiratory chain, which corresponded to the significant enrichment of the oxidative phosphorylation pathway. Consistent with this result, PE significantly increased ATP content and protein expression of NDUFB3 (mitochondrial respiratory chain complex I subunit) in macrophages. Meanwhile, transcriptomic data showed that PE treatment downregulated the transcript levels of nlrp3 and upregulated the transcript levels of suppressor of cytokine signaling 3 (socs3), suggesting that PE may alleviate macrophage inflammation by interfering with the activation of NLRP3 inflammasome. Further analysis showed that PE significantly attenuated dietary PA-mediated macrophage inflammation via NLRP3-Caspase-1 in vitro and in vivo. Given that PE abundance is strongly correlated with mitochondrial function, the present study hypothesized that PE-mediated inflammatory modulation may be attributed to the positive effects on mitochondrial function. As expected, PE significantly ameliorated PA-induced mitochondrial dysfunction and reduced intracellular reactive oxygen species production and malondialdehyde content in macrophages, indicating that the improvement of mitochondrial function is an important mechanism involved in the positive effect of PE on PA-induced inflammation. In conclusion, this study elucidates the critical role of mitochondrial function in PE-mediated regulation of inflammation in macrophages, which expands the understanding of the regulatory mechanisms of phospholipid metabolism on dietary fatty acid-induced inflammation. This study may provide new intervention targets and nutritional regulation strategies for improving chronic inflammatory diseases.

Disease-specific oligomers Tau assay system is anticipated in Alzheimer disease (AD) to elucidate their etiological roles. We developed a highly sensitive and selective ELISA for high-molecular-weight oligomer tau (HMWoTau) with LLOQ of 0.3 pg/well for the first time, using a novel mouse monoclonal antibody APNmAb005. The target molecule was identified as HMWoTau with circa 2000 kD as a minimum size and the more oligomerized species (>5000 kD), in combination analysis with Size-Exclusion-Chromatography and Sucrose-Density-Gradient-Centrifugation for both recombinant human (rh) Tau-derived aggregates and AD brain-lysates in PBS(−). HMWoTau was labeled by Thioflavin S and visualized as a homogeneous globular particle (about 30 nm in diameter) by two different technologies of atomic force microscopy and dSTORM-Nanoimager. Specific quantitation was also confirmed by immune-absorption, rhHMWoTau-spiked, and cross-reactivity studies. APNmAb005 failed to detect the HMWoTau signal by treatment with DTT/SDS under no influence on the pan-tau antibody, indicating its conformation-specific recognition. APNmAb005-ELISA showed AD-specific and statistically significant ELISA signals from 1 ng brain lysate protein/well. Analysis of the frontal neocortex (N = 40, Braak stage I–VI) by ELISA revealed the detection-limit levels of HMWoTau species at stage I–III, and drastic and statistically significant increases at stage V/VI (AD). By contrast, total Tau and p181 Tau showed 1/4–1/5 levels of AD even at Stage I, while both tau species also showed a statistically significant increase in AD. In sum, our novel APNmAb005-ELISA clarified the disease-specific increase in HMWoTau species and will be useful for not only further etiological elucidation but also the potential diagnostics in AD and relevant tauopathy.

Fetal growth restriction (FGR) increases the risk of short-term and long-term complications. Widespread N6-methyladenosine (m6A) modifications on mRNAs have been found to be involved in various biological processes. However, the role of m6A modification in the pathogenesis of FGR remains elusive. Here, we report that elevated levels of METTL3 and m6A modification were detected in FGR placentae. Functionally, cell migration, invasion, and proliferation abilities were suppressed after METTL3 overexpression in HTR8/SVneo cells. Subsequently, methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) of METTL3-knockdown HTR8/SVneo cells were utilized together to identify FOSL1 as the downstream target genes of METTL3. Furthermore, we illustrated that METTL3-mediated m6A modification enhanced the expression of FOSL1 in a IGF2BP2 dependent manner. FOSL1 inhibited trophoblast invasion and migration. Importantly, STM2457, a novel METTL3 catalytic inhibitor, was intravenously administered to FGR mice models, which restore fetal and placental weights in vivo. In vitro STM2457 regulated trophoblast proliferation, invasion, and migration in a dose-dependent manner. In summary, this study reveals that METTL3 and IGF2BP2 increase FOSL1 expression in an m6A-dependent manner. The increase of FOSL1disrupts normal trophoblast invasion, which results in the progression of FGR. METTL3 can serve as a potential target for FGR therapy.

LAG-3 is a member of the immunoglobulin superfamily expressed on activated T cells, but also on other immune cells. It has significant homology to CD4. Both molecules have four extracellular Ig-like domains with similar structural motifs but the sequence identity between LAG-3 and CD4 is low. Furthermore, unlike CD4 LAG-3 restrains T cell responses and antibodies targeting this receptor are emerging drugs in cancer immunotherapy. A combination of LAG-3 and PD-1 antibodies has already been approved for the treatment of metastatic melanoma. Despite this success, its biology is still not well understood. Here we summarize the current knowledge on expression, ligands, and function of LAG-3. We point to the differences between LAG-3 and other inhibitory immune checkpoints and describe obstacles to study the role of this receptor in T cell activation processes. Finally, we discuss future directions for scientific efforts to come to a more complete understanding of the biology of this eminent immune checkpoint.

Zhou J, Wang S, Qi Q, Yang X, Zhu E, Yuan H, Li X, Liu Y, Li X, Wang B. Nuclear factor I-C reciprocally regulates adipocyte and osteoblast differentiation via control of canonical Wnt signaling. FASEB J. 2017;31(5):1939-1952. DOI: 10.1096/fj.201600975RR

In the originally published article, incorrect images were used for Figure 2I and Figure 3I. In the legend of Figure 2, “G (n = 4)” was incorrect and this should have read: “G (n = 3).” In Figure 3D, the fourth gene was mistakenly labeled as β-actin; it should actually be adipsin. The errors do not affect the results or conclusions of the article.

The authors apologize for the errors.

The corrected Figure 2 and Figure 3 are presented below.

Heart regeneration was mainly achieved by intrinsic capacity. Exosomes are crucial in cardiovascular disease, yet their involvement in myocardial regeneration remains underexplored. To understand the role of cardiomyocyte-derived exosomes (CM-Exos) in heart regeneration. We established mouse models of myocardial infarction and apical resection in neonates to investigate the potential benefits of exosomes in response to injury. Rab27a knockout (KO) mice were constructed as an exosome decrease model. Distinct fibrosis appears in the infarcted and resection area in the KO mice 21 days after heart injury. The proliferation marker pH 3, Ki67, and Aurora B were detected 3 days after surgery, which decreased in KO mice compared to WT mice. Intravenous injection of CM-Exos increased cardiomyocyte proliferation and partially restored heart function in KO mice. Rab27a knockdown in vitro reduced the expression of pH 3, Ki67, and Aurora B positive cardiomyocytes. However, the supplementation of CM-Exos increased the proliferation of cardiomyocytes. Exosomal miRNA sequencing was subsequently applied, and miR-21-5p was a promising candidate that promoted cardiomyocyte proliferation through its target genes Spry-1 and PDCD4. Intravenous injection of miR-21-5p exhibited similar proliferative effects as CM-Exos. Our results indicate that CM-Exos promotes cardiomyocyte cycle reentry by delivering miR-21-5p, highlighting the endogenous factors of myocardial regeneration.

Intramuscular injection of botulinum neurotoxin type A (BoNT-A) is commonly used to improve or maintain the joint range of motion in young children with spasticity. However, the effectiveness of BoNT-A treatment is variable and movement limitations are recurrent. Here we show long-term effects of a single, bilateral abobotulinumtoxinA (aboBoNT-A) injection in the gastrocnemius medialis and soleus muscles of wild-type and spastic (B6.Cg-Glrbspa/J with a mutation in the glycine receptor) mice at a young age (6–7 days). Specifically, we evaluated the impact of aboBoNT-A-A on gait, physical performance, and spontaneous physical behavior, as well as on contractile force characteristics, morphology, and histological phenotype of soleus and gastrocnemius muscles by comparing their results to those of saline-injected controls up to 9 weeks after the injection. The detailed time course of the study specifies the timing of the aboBoNT-A injection at 1 week, the period of behavioral studies from 4–9 weeks, and the age of the mice (10 weeks) at the time of contractile force characteristics and histology assessments. In spastic mice, aboBoNT-A injection had a minor and very specific effect on physical performance, by only modestly increasing stride length as a function of age. aboBoNT-A injection caused a reduction in the force-generating capacity and a slightly smaller physiological cross-sectional area in gastrocnemius medialis, but not in soleus. Reduced physiological cross-sectional area in aboBoNT-A-injected muscles was due to a lower number of muscle fibers, rather than reduced muscle fiber cross-sectional area. The percentage of slow-type muscle fibers and mitochondrial succinate dehydrogenase activity were increased, which was associated with an improved muscle endurance capacity. In conclusion, aboBoNT-A injection reduced the number of muscle fibers, causing muscle hypertrophy in remaining fibers and a shift towards more oxidative fibers, resulting in an improved endurance capacity and gait. This study proposed potential cellular mechanisms for the therapeutic efficacy of aboBoNT-A in spasticity.

African swine fever virus (ASFV) is a large, icosahedral, double-stranded DNA virus in the Asfarviridae family and the causative agent of African swine fever (ASF). ASFV causes a hemorrhagic fever with high mortality rates in domestic and wild pigs. ASFV contains an open reading frame named EP152R, previous research has shown that EP152R is an essential gene for virus rescue in swine macrophages. However, the detailed functions of ASFV EP152R remain elusive. Herein, we demonstrate that EP152R, a membrane protein located in the endoplasmic reticulum (ER), induces ER stress and swelling, triggering the PERK/eIF2α pathway, and broadly inhibiting host protein synthesis in vitro. Additionally, EP152R strongly promotes immune evasion, reduces cell proliferation, and alters cellular metabolism. These results suggest that ASFV EP152R plays a critical role in the intracellular environment, facilitating viral replication. Furthermore, virus-level experiments have shown that the knockdown of EP152R or PERK inhibitors efficiently affects viral replication by decreasing viral gene expression. In summary, these findings reveal a series of novel functions of ASFV EP152R and have important implications for understanding host-pathogen interactions.