ß-Hydroxybutyrate Prevents Vascular Senescence through hnRNP A1-Mediated Upregulation of Oct4.

ß-hydroxybutyrate (ß-HB) elevation during fasting or caloric restriction is believed to induce anti-aging effects and alleviate aging-related neurodegeneration. However, whether ß-HB alters the senescence pathway in vascular cells remains unknown. Here we report that ß-HB promotes vascular cell quiescence, which significantly inhibits both stress-induced premature senescence and replicative senescence through p53-independent mechanisms. Further, we identify heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) as a direct binding target of ß-HB. ß-HB binding to hnRNP A1 markedly enhances hnRNP A1 binding with Octamer-binding transcriptional factor (Oct) 4 mRNA, which stabilizes Oct4 mRNA and Oct4 expression. Oct4 increases Lamin B1, a key factor against DNA damage-induced senescence. Finally, fasting and intraperitoneal injection of ß-HB upregulate Oct4 and Lamin B1 in both vascular smooth muscle and endothelial cells in mice in vivo. We conclude that ß-HB exerts anti-aging effects in vascular cells by upregulating an hnRNP A1-induced Oct4-mediated Lamin B1 pathway.

Asymmetric and parallel subgenome selection co-shape common carp domestication.

BACKGROUND: The common carp (Cyprinus carpio) might best represent the domesticated allopolyploid animals. Although subgenome divergence which is well-known to be a key to allopolyploid domestication has been comprehensively characterized in common carps, the link between genetic architecture underlying agronomic traits and subgenome divergence is unknown in the selective breeding of common carps globally. RESULTS: We utilized a comprehensive SNP dataset in 13 representative common carp strains worldwide to detect genome-wide genetic variations associated with scale reduction, vibrant skin color, and high growth rate in common carp domestication. We identified numerous novel candidate genes underlie the three agronomically most desirable traits in domesticated common carps, providing potential molecular targets for future genetic improvement in the selective breeding of common carps. We found that independently selective breeding of the same agronomic trait (e.g., fast growing) in common carp domestication could result from completely different genetic variations, indicating the potential advantage of allopolyploid in domestication. We observed that candidate genes associated with scale reduction, vibrant skin color, and/or high growth rate are repeatedly enriched in the immune system, suggesting that domestication of common carps was often accompanied by the disease resistance improvement. CONCLUSIONS: In common carp domestication, asymmetric subgenome selection is prevalent, while parallel subgenome selection occurs in selective breeding of common carps. This observation is not due to asymmetric gene retention/loss between subgenomes but might be better explained by reduced pleiotropy through transposable element-mediated expression divergence between ohnologs. Our results demonstrate that domestication benefits from polyploidy not only in plants but also in animals.

Whole genome sequencing of Crassostrea ariakensis (Mollusca: Ostreidae) and C. hongkongensis expands understandings of stress resistance in sessile oysters.

To understand the environmental adaptations among sessile bivalves lacking adaptive immunity, a series of analyses were conducted, with special emphasis on the widely distributed C. ariakensis. Employing Pacbio sequencing and Hi-C technologies, whole genome for each of a C. ariakensis (southern China) and C. hongkongensis individual was generated, with the contig N50 reaching 6.2 and 13.0 Mb, respectively. Each genome harbored over 30,000 protein-coding genes, with approximately half of each genome consisting of repeats. Genome alignment suggested possible introgression between C. gigas and C. ariakensis (northern China), and re-sequencing data corroborated this result and indicated significant gene flow between C. gigas and C. ariakensis. These introgressed candidates, well-represented by genes related to immunity and osmotic pressure, may be associated with environmental stresses. Gene family dynamics modeling suggested immune-related genes were well represented among the expanded genes in C. ariakensis. These outcomes could be attributed to the spread of C. ariakensis.

Mitochondria-derived Vesicle Packaging as a Novel Therapeutic Mechanism in Pulmonary Hypertension.

Increasing evidence suggests that mitochondrial dysfunction in pulmonary endothelial cells (ECs) plays a causative role in the initiation and progression of pulmonary hypertension (PH); how mitochondria become dysfunctional in PH remains elusive. Mitochondria-derived vesicles (MDVs) are small subcellular vesicles that excise from mitochondria. Whether MDV deregulation causes mitochondrial dysfunction in PH is unknown. The aim of this study was to determine MDV regulation in ECs and to elucidate how MDV deregulation in ECs leads to PH. MDV formation and mitochondrial morphology/dynamics were examined in ECs of EC-specific liver kinase B1 (LKB1) knockout mice (LKB1ec-/-), in monocrotaline-induced PH rats, and in lungs of patients with PH. Pulmonary ECs of patients with PH and hypoxia-treated pulmonary ECs exhibited increased mitochondrial fragmentation and disorganized mitochondrial ultrastructure characterized by electron lucent-swelling matrix compartments and concentric layering of the cristae network, together with defective MDV shedding. MDVs actively regulated mitochondrial membrane dynamics and mitochondrial ultrastructure via removing mitofission-related cargoes. The shedding of MDVs from parental mitochondria required LKB1-mediated mitochondrial recruitment of Rab9 GTPase. LKB1ec-/- mice spontaneously developed PH with decreased mitochondrial pools of Rab9 GTPase, defective MDV shedding, and disequilibrium of the mitochondrial fusion-fission cycle in pulmonary ECs. Aerosol intratracheal delivery of adeno-associated virus LKB1 reversed PH, together with improved MDV shedding and mitochondrial function in rats in vivo. We conclude that LKB1 regulates MDV shedding and mitochondrial dynamics in pulmonary ECs by enhancing mitochondrial recruitment of Rab9 GTPase. Defects of LKB1-mediated MDV shedding from parental mitochondria instigate EC dysfunction and PH.

Analysis of four hereditary protein C deficiencies associated with vascular thromboembolism.

OBJECTIVE: To analyze the clinical features and gene mutations in four families with hereditary protein C (PC) deficiency and explore their association with vascular thromboembolism. METHODS: The clinical data of four patients with PC deficiency were retrospectively analyzed. Venous blood samples were collected from the four affected patients and their family members, and relevant coagulation indexes and thrombin production and inhibition tests were performed. PCR was used to amplify and directly sequence the PROC gene of the probands. Software analysis was conducted to assess the conservativeness and pathogenicity of the mutated loci. Protein models were constructed to analyze the spatial structure before and after the mutation. RESULTS: Thrombin generation and inhibition assays demonstrated impaired anticoagulation in all four probands. Proband 1 and 4 presented clinically with pulmonary embolism and lower extremity deep vein thrombosis (DVT), Proband 2 with cerebral infarction, and Proband 3 with DVT. Genetic analysis revealed the presence of the following mutations: c.541T > G heterozygous missense mutation, c.577-579delAAG heterozygous deletion mutation, c.247-248insCT heterozygous insertion mutation, c.659G > A heterozygous missense mutation, and a new variant locus c.1146_1146delT heterozygous deletion mutation in the four probands, respectively. In particular, c.1146_1146delT heterozygous deletion mutations not reported previously. Conservativeness and pathogenicity analyses confirmed that most of these amino acid residues were conserved, and all the mutations were found to be pathogenic. Analysis of protein modeling revealed that these mutations induced structural alterations in the protein or led to the formation of truncated proteins. According to the American College of Medical Genetics and Genomics (ACMG) classification criteria and guidelines for genetic variants, c.1146_1146delT was rated as pathogenic (PVS1 + M2 + PM4 + PP1 + PP3 + PP4). CONCLUSION: The identified mutations are likely associated with decreased PC levels in each of the four families. The clinical manifestations of hereditary PC deficiency exhibit considerable diversity.

SMYD2 regulates vascular smooth muscle cell phenotypic switching and intimal hyperplasia via interaction with myocardin.

The SET and MYND domain-containing protein 2 (SMYD2) is a histone lysine methyltransferase that has been reported to regulate carcinogenesis and inflammation. However, its role in vascular smooth muscle cell (VSMC) homeostasis and vascular diseases has not been determined. Here, we investigated the role of SMYD2 in VSMC phenotypic modulation and vascular intimal hyperplasia and elucidated the underlying mechanism. We observed that SMYD2 expression was downregulated in injured carotid arteries in mice and phenotypically modulated VSMCs in vitro. Using an SMC-specific SMYD2 knockout mouse model, we found that SMYD2 ablation in VSMCs exacerbated neointima formation after vascular injury in vivo. Conversely, SMYD2 overexpression inhibited VSMC proliferation and migration in vitro and attenuated arterial narrowing in injured vessels in mice. SMYD2 downregulation promoted VSMC phenotypic switching accompanied with enhanced proliferation and migration. Mechanistically, genome-wide transcriptome analysis and loss/gain-of-function studies revealed that SMYD2 up-regulated VSMC contractile gene expression and suppressed VSMC proliferation and migration, in part, by promoting expression and transactivation of the master transcription cofactor myocardin. In addition, myocardin directly interacted with SMYD2, thereby facilitating SMYD2 recruitment to the CArG regions of SMC contractile gene promoters and leading to an open chromatin status around SMC contractile gene promoters via SMYD2-mediated H3K4 methylation. Hence, we conclude that SMYD2 is a novel regulator of VSMC contractile phenotype and intimal hyperplasia via a myocardin-dependent epigenetic regulatory mechanism.

Indoleamine 2,3-Dioxygenase 1 Deletion-Mediated Kynurenine Insufficiency in Vascular Smooth Muscle Cells Exacerbates Arterial Calcification.

BACKGROUND: IDO1 (indoleamine 2,3-dioxygenase 1) is the rate-limiting enzyme for tryptophan metabolism. IDO1 malfunction is involved in the pathogenesis of atherosclerosis. Vascular smooth muscle cells (VSMCs) with an osteogenic phenotype promote calcification and features of plaque instability. However, it remains unclear whether aberrant IDO1-regulated tryptophan metabolism causes VSMCs osteogenic reprogramming and calcification. METHODS: We generated global Apoe (apolipoprotein E) and Ido1 double knockout mice, and Apoe knockout mice with specific deletion of IDO1 in VSMCs or macrophages. Arterial intimal calcification was evaluated by a Western diet-induced atherosclerotic calcification model. RESULTS: Global deficiency of IDO1 boosted calcific lesion formation without sex bias in vivo. Conditional IDO1 loss of function in VSMCs rather than macrophages promoted calcific lesion development and the abundance of RUNX2 (runt-related transcription factor 2). In contrast, administration of kynurenine via intraperitoneal injection markedly delayed the progression of intimal calcification in parallel with decreased RUNX2 expression in both Apoe-/- and Apoe-/-Ido1-/- mice. We found that IDO1 deletion restrained RUNX2 from proteasomal degradation, which resulted in enhanced osteogenic reprogramming of VSMCs. Kynurenine administration downregulated RUNX2 in an aryl hydrocarbon receptor-dependent manner. Kynurenine acted as the endogenous ligand of aryl hydrocarbon receptor, controlled resultant interactions between cullin 4B and aryl hydrocarbon receptor to form an E3 ubiquitin ligase that bound with RUNX2, and subsequently promoted ubiquitin-mediated instability of RUNX2 in VSMCs. Serum samples from patients with coronary artery calcification had impaired IDO1 activity and decreased kynurenine catabolites compared with those without calcification. CONCLUSIONS: Kynurenine, an IDO1-mediated tryptophan metabolism main product, promotes RUNX2 ubiquitination and subsequently leads to its proteasomal degradation via an aryl hydrocarbon receptor-dependent nongenomic pathway. Insufficient kynurenine exerts the deleterious role of IDO1 ablation in promoting RUNX2-mediated VSMCs osteogenic reprogramming and calcification in vivo.

The BET PROTAC inhibitor dBET6 protects against retinal degeneration and inhibits the cGAS-STING in response to light damage.

BACKGROUND: Chronic inflammation significantly contributes to photoreceptor death in blinding retinal diseases such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP). Bromodomain and extraterminal domain (BET) proteins are epigenetic readers that act as key proinflammatory factors. We recently found the first-generation BET inhibitor JQ1 alleviated sodium iodate-induced retinal degeneration by suppressing cGAS-STING innate immunity. Here, we investigated the effects and mechanism of dBET6, a proteolysis­targeting chimera (PROTAC) small molecule that selectively degrades BET by the ubiquitin‒proteasome system, in light-induced retinal degeneration. METHODS: Mice were exposed to bright light to induce retinal degeneration, and the activation of cGAS-STING was determined by RNA-sequencing and molecular biology. Retinal function, morphology, photoreceptor viability and retinal inflammation were examined in the presence and absence of dBET6 treatment. RESULTS: Intraperitoneal injection of dBET6 led to the rapid degradation of BET protein in the retina without detectable toxicity. dBET6 improved retinal responsiveness and visual acuity after light damage (LD). dBET6 also repressed LD-induced retinal macrophages/microglia activation, Müller cell gliosis, photoreceptor death and retinal degeneration. Analysis of single-cell RNA-sequencing results revealed cGAS-STING components were expressed in retinal microglia. LD led to dramatic activation of the cGAS-STING pathway, whereas dBET6 suppressed LD-induced STING expression in reactive macrophages/microglia and the related inflammatory response. CONCLUSIONS: This study indicates targeted degradation of BET by dBET6 exerts neuroprotective effects by inhibiting cGAS-STING in reactive retinal macrophages/microglia, and is expected to become a new strategy for treatment of retinal degeneration.

tPA Mobilizes Immune Cells That Exacerbate Hemorrhagic Transformation in Stroke.

RATIONALE: Hemorrhagic complications represent a major limitation of intravenous thrombolysis using tPA (tissue-type plasminogen activator) in patients with ischemic stroke. The expression of tPA receptors on immune cells raises the question of what effects tPA exerts on these cells and whether these effects contribute to thrombolysis-related hemorrhagic transformation. OBJECTIVE: We aim to determine the impact of tPA on immune cells and investigate the association between observed immune alteration with hemorrhagic transformation in ischemic stroke patients and in a rat model of embolic stroke. METHODS AND RESULTS: Paired blood samples were collected before and 1 hour after tPA infusion from 71 patients with ischemic stroke. Control blood samples were collected from 27 ischemic stroke patients without tPA treatment. A rat embolic middle cerebral artery occlusion model was adopted to investigate the underlying mechanisms of hemorrhagic transformation. We report that tPA induces a swift surge of circulating neutrophils and T cells with profoundly altered molecular features in ischemic stroke patients and a rat model of focal embolic stroke. tPA exacerbates endothelial injury, increases adhesion and migration of neutrophils and T cells, which are associated with brain hemorrhage in rats subjected to embolic stroke. Genetic ablation of annexin A2 in neutrophils and T cells diminishes the effect of tPA on these cells. Decoupling the interaction between mobilized neutrophils/T cells and the neurovascular unit, achieved via a S1PR (sphingosine-1-phosphate receptor) 1 modulator RP101075 and a CCL2 (C-C motif chemokine ligand 2) synthesis inhibitor bindarit, which block lymphocyte egress and myeloid cell recruitment, respectively, attenuates hemorrhagic transformation and improves neurological function after tPA thrombolysis. CONCLUSIONS: Our findings suggest that immune invasion of the neurovascular unit represents a previously unrecognized mechanism underlying tPA-mediated brain hemorrhage, which can be overcome by precise immune modulation during thrombolytic therapy.

Association between inflammatory biomarkers and venous thromboembolism: a systematic review and meta-analysis.

BACKGROUND: Venous thromboembolism (VTE) is a common thrombotic vascular disease that has a significant impact on people's well-being and quality of life. A plethora of clinical studies explore the relationship between inflammatory biomarkers and VTE but yield conflicting results. This article proposed to pool these studies to draw a more convincing conclusion. METHODS: We searched several databases for studies before April 2023. Available data was processed using Stata software (version 15.0 SE) and R (version 4.1.2). This meta-analysis has been registered in PROSPERO (CRD42022321815). The VTE in this review encompassed pulmonary embolism, deep vein thrombosis, and cerebral venous thrombosis. RESULTS: A total of 25 articles were finally involved in this study. Our results revealed that higher levels of high-sensitivity C-reactive protein (hs-CRP, MD, 0.63, 95%CI, 0.21-1.05) and C-reactive protein (CRP)> 3ug/ml (OR, 1.52, 95%CI, 1.18-1.96) might be regarded as risk factors for future VTE occurrence. The elevated levels of monocyte (MD, 0.03, 95%CI, 0.00-0.05), hs-CRP (0.85, 0.61-1.08), CRP (0.66, 0.20-1.13) and IL-6 (0.47, 0.25-0.70) might represent the previous VTE; a series of markers such as white blood cell (1.43, 0.88-1.98), neutrophil (1.79, 1.02-2.56), monocyte (0.17, 0.14-0.21), hs-CRP (3.72, 1.45-5.99), IL-6 (5.99, 4.52-7.46), platelet-lymphocyte ratio (33.1, 24.45-41.78) and neutrophil-lymphocyte ratio (1.34, 0.95-1.73) increased during the acute phase of VTE. CONCLUSIONS: In general, activated inflammatory biomarkers might not only be correlated with an increased risk of VTE, but may also give a hint of the occurrence of VTE in clinical settings.

Clinicopathological characteristics and prognostic factors in axial chondroblastomas: a retrospective analysis of 61 cases and comparison with extra-axial chondroblastomas.

BACKGROUND: A comprehensive understanding of the clinical characteristics and prognostic factors associated with axial chondroblastoma (ACB) is still lacking. This study aimed to understand the clinical characteristics and prognostic factors of axial chondroblastoma (ACB) and compare them with extra-axial chondroblastoma (EACB). METHODS: A retrospective review of our institution's local database was conducted, encompassing a total of 132 CB patients, of which 61 were diagnosed with ACB and 71 with EACB. Immunohistochemistry was employed to evaluate the expression levels of vimentin, S100, and cytokeratin. RESULTS: ACB and EACB shared similar characteristics, with the exception of advanced age, tumor size, elevated Vim expression, incidence of surrounding tissue invasion, and postoperative sensory or motor dysfunction. While wide resection and absence of surrounding tissue invasion consistently showed a favorable association with survival in both ACB and EACB cohorts during univariate analysis, most parameters exhibited differential prognostic significance between the two groups. Notably, the significant prognostic factors for local recurrence-free survival in the ACB cohort included the type of resection and the presence of chicken-wire calcification. In the multivariate analysis of overall survival, the type of resection emerged as a significant predictor in the ACB cohort, whereas in the EACB group, the type of resection and the occurrence of postoperative sensory or motor dysfunction were predictive of overall survival. CONCLUSION: There may exist distinct biological behaviors between ACB and EACB, thereby providing valuable insights into the prognostic characteristics of ACB patients and contributing to enhanced outcome prediction in this particular patient population.

Prognostic Prediction Value and Biological Functions of Non-Apoptotic Regulated Cell Death Genes in Lung Adenocarcinoma.

Objective To explore the potential biological functions and prognostic prediction values of non-apoptotic regulated cell death genes (NARCDs) in lung adenocarcinoma.Methods Transcriptome data of lung adenocarcinoma were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus databases. We identified differentially expressed NARCDs between lung adenocarcinoma tissues and normal tissues with R software. NARCDs signature was constructed with univariate Cox regression analysis and the least absolute shrinkage and selection operator Cox regression. The prognostic predictive capacity of NARCDs signature was assessed by Kaplan-Meier survival curve, receiver operating characteristic curve, and univariate and multivariate Cox regression analyses. Functional enrichment of NARCDs signature was analyzed with gene set variation analysis, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes. In addition, differences in tumor mutational burden, tumor microenvironment, tumor immune dysfunction and exclusion score, and chemotherapeutic drug sensitivity were analyzed between the high and low NARCDs score groups. Finally, a protein-protein interaction network of NARCDs and immune-related genes was constructed by STRING and Cytoscape software. Results We identified 34 differentially expressed NARCDs associated with the prognosis, of which 16 genes (ATIC, AURKA, CA9, ITGB4, DDIT4, CDK5R1, CAV1, RRM2, GAPDH, SRXN1, NLRC4, GLS2, ADRB2, CX3CL1, GDF15, and ADRA1A) were selected to construct a NARCDs signature. NARCDs signature was identified as an independent prognostic factor (P < 0.001). Functional analysis showed that there were significant differences in mismatch repair, p53 signaling pathway, and cell cycle between the high NARCDs score group and low NARCDs score group (all P < 0.05). The NARCDs low score group had lower tumor mutational burden, higher immune score, higher tumor immune dysfunction and exclusion score, and lower drug sensitivity (all P < 0.05). In addition, the 10 hub genes (CXCL5, TLR4, JUN, IL6, CCL2, CXCL2, ILA, IFNG, IL33, and GAPDH) in protein-protein interaction network of NARCDs and immune-related genes were all immune-related genes. Conclusion The NARCDs prognostic signature based on the above 16 genes is an independent prognostic factor, which can effectively predict the clinical prognosis of patients of lung adenocarcinoma and provide help for clinical treatment.

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OBJECTIVES: To explore the association between maternal gestational diabetes mellitus (GDM) exposure and the development of autism spectrum disorder (ASD) in offspring. METHODS: A case-control study was conducted, recruiting 221 children with ASD and 400 healthy children as controls. Questionnaires and interviews were used to collect information on general characteristics of the children, socio-economic characteristics of the family, maternal pregnancy history, and maternal disease exposure during pregnancy. Multivariate logistic regression analysis was used to investigate the association between maternal GDM exposure and the development of ASD in offspring. The potential interaction between offspring gender and maternal GDM exposure on the development of ASD in offspring was explored. RESULTS: The proportion of maternal GDM was significantly higher in the ASD group compared to the control group (16.3% vs 9.4%, P=0.014). After adjusting for variables such as gender, gestational age, mode of delivery, parity, and maternal education level, maternal GDM exposure was a risk factor for ASD in offspring (OR=2.18, 95%CI: 1.04-4.54, P=0.038). On the basis of adjusting the above variables, after further adjusting the variables including prenatal intake of multivitamins, folic acid intake in the first three months of pregnancy, and assisted reproduction the result trend did not change, but no statistical significance was observed (OR=1.94, 95%CI: 0.74-5.11, P=0.183). There was an interaction between maternal GDM exposure and offspring gender on the development of ASD in offspring (P<0.001). Gender stratified analysis showed that only in male offspring of mothers with GDM, the risk of ASD was significantly increased (OR=3.67, 95%CI: 1.16-11.65, P=0.027). CONCLUSIONS: Maternal GDM exposure might increase the risk of ASD in offspring. There is an interaction between GDM exposure and offspring gender in the development of ASD in offspring.

Novel prospects for scarless wound healing: The roles of myofibroblasts and adipocytes.

Disturbances or defects in the process of wound repair can disrupt the delicate balance of cells and molecules necessary for complete wound healing, thus leading to chronic wounds or fibrotic scars. Myofibroblasts are one of the most important cells involved in fibrotic scars, and reprogramming provides a potential avenue to increase myofibroblast clearance. Although myofibroblasts have long been recognized as terminally differentiated cells, recent studies have shown that myofibroblasts have the capacity to be reprogrammed into adipocytes. This review intends to summarize the potential of reprogramming myofibroblasts into adipocytes. We will discuss myofibroblast lineage tracing, as well as the known mechanisms underlying adipocyte regeneration from myofibroblasts. In addition, we investigated different changes in myofibroblast gene expression, transcriptional regulators, signalling pathways and epigenetic regulators during skin wound healing. In the future, myofibroblast reprogramming in wound healing will be better understood and appreciated, which may provide new ideas for the treatment of scarless wound healing.

Role of the hydrogen sulfide-releasing donor ADT-OH in the regulation of mammal neural precursor cells.

Neural precursor cells (NPCs) generate new neurons to supplement neuronal loss as well as to repair damaged neural circuits. Therefore, NPCs have potential applications in a variety of neurological diseases, such as spinal cord injury, traumatic brain injury, and glaucoma. Specifically, improving NPCs proliferation and manipulating their differentiated cell types can be a beneficial therapy for a variety of these diseases. ADT-OH is a slow-releasing organic H2 S donor that produces a slow and continuous release of H2 S to maintain normal brain functions. In this study, we aimed to explore the effect of ADT-OH on NPCs. Our results demonstrated that ADT-OH promotes self-renewal and antiapoptosis ability of cultured NPCs. Additionally, it facilitates more NPCs to differentiate into neurons and oligodendrocytes, while inhibiting their differentiation into astrocytes. Furthermore, it enhances axonal growth. Moreover, we discovered that the mRNA and protein expression of ß-catenin, TCF7L2, c-Myc, Ngn1, and Ngn2, which are key genes that regulate NPCs self-renewal and differentiation, were increased in the presence of ADT-OH. Altogether, these results indicate that ADT-OH may be a promising drug to regulate the neurogenesis of NPCs, and needs to be studied in the future for clinical application potential.

Insight into the role of dermal white adipose tissue loss in dermal fibrosis.

The loss of dermal white adipose tissue (dWAT) is vital to the formation of dermal fibrosis (DF), but the specific mechanism is not well understood. A few studies are reviewed to explore the role of dWAT in the formation of DF. Recent findings indicated that the adipocytes-to-myofibroblasts transition in dWAT reflects the direct contribution to the DF formation. While adipose-derived stem cells (ADSCs) contained in dWAT express antifibrotic cytokines, the loss of ADSCs leads to skin protection decreased, which indirectly exacerbates DF and tissue damage. Therefore, blocking or reversing the adipocytes-to-myofibroblasts transition or improving the survival of ADSCs in dWAT and the expression of antifibrotic cytokines may be an effective strategy for the treatment of DF.

Crotonianoids A-C, Three Unusual Tigliane Diterpenoids from the Seeds of Croton tiglium and Their Anti-Prostate Cancer Activity.

Crotonianoids A-C (1-3), three unusual tigliane diterpenoids, were isolated from the seeds of Croton tiglium. Compound 1 is a 13,14:13,15-diseco-tigliane featuring a unique spiro[bicyclo[5.3.0]decane-2,5'-2'(3'H,4'H)-furanone] core; 2 is a 13,15-seco-tigliane incorporating a rare peroxide bridge between C-13 and C-15; and 3 is the first example of a phorbol ester with a 10R-configuration. Their structures were determined by spectroscopic, computational, and X-ray diffraction methods. Compounds 1 and 2 markedly inhibited the growth and survival of prostate cancer cell C4-2B at micromolar concentrations and induced cell apoptosis. Mechanistic study revealed that 1 and 2 could suppress androgen receptor (AR) signaling pathway by promoting the degradation of AR protein.

Frequent occurrence of respiratory symptoms in children is associated with exposure to air pollution, land use types, and parental mental health in the Greater Taipei area.

Although studies have investigated the individual effects of air pollution, land use types, and parental mental health on children's respiratory health, few studies have examined the effects of these risk factors simultaneously in children aged <2 years. We investigated the effects of exposure to air pollution, land use types surrounding residences, and parental mental health on the frequent occurrence of respiratory symptoms in children aged <2 years in the Greater Taipei area. Participants were recruited from an ongoing Taiwanese birth cohort study. We analyzed the data of the participants who had been recruited from January 2011 to April 2014 and had responded to the follow-up questionnaires at 6, 12, and 24 months. Self-administered questionnaires were used to collect participants' sociodemographic background and health, such as respiratory symptoms, and parental mental health. Pre- and postnatal pollution levels were estimated using the spatial interpolation technique (ordinary kriging) at children's residential addresses. Land use types surrounding participants' homes were evaluated by performing buffer analysis. Multiple logistic regression analyses were conducted to examine the effects of risk factors on the frequent occurrence of child respiratory symptoms in children aged 6, 12, and 24 months. We included 228, 360, and 441 children aged 6, 12, and 24 months, respectively. Our results indicated that postnatal exposure to PM2.5 and O3 was positively associated with children's respiratory symptoms. Traffic-related land-use types, sports facilities, and commercial land surrounding homes exerted adverse effects on children's respiratory symptoms, whereas the presence of schools in the neighborhood was beneficial. Parental mental health was also associated with children's respiratory symptoms. Postnatal exposure to air pollution and land use types surrounding residences were associated with respiratory health in children aged <2 years. The residential environment is a critical factor affecting children's respiratory health of children aged <2 years.

Vitelline Membrane Protein 26 Mutagenesis, Using CRISPR/Cas9, Results in Egg Collapse in Plutella xylostella.

Vitelline membrane proteins (VMPs) are the main proteins that form the inner shell (vitelline membrane layer) of insect eggs and are an integral part of egg formation and embryo development. Here, we characterized the molecular structure and expression patterns of the VMP26 gene and analyzed its reproductive functions in diamondback moth, Plutella xylostella (L.), a worldwide migratory pest of cruciferous plants. The PxVMP26 gene was shown to be a single exon gene that contained an open reading frame of 852 base pairs (bp) encoding 283 amino acids. Both qPCR and western blot analyses showed that PxVMP26 was specifically expressed in female adults and was significantly highly expressed in the ovary. Further anatomical analysis indicated that the expression level of PxVMP26 in the ovarian tube with an incomplete yolk was significantly higher than that in the ovarian tube with a complete yolk. CRISPR/Cas9-induced PxVMP26 knockout successfully created two homozygous strains with 8- and 46-bp frameshift mutations. The expression deficiency of the PxVMP26 protein was detected in the mutant strains using immunofluorescence and western blot. No significant difference was found in the number of eggs laid within three days between wild and mutant individuals, but there was a lower egg hatchability. The loss of the PxVMP26 gene changed the mean egg size, damaged the structure of the vitelline membrane, and increased the proportion of abnormal eggs due to water loss, resulting in egg collapse. This first analysis of the roles of the VMP gene in the oocyte formation and embryonic development of P. xylostella, using CRISPR/Cas9 technology, provides a basis for screening new genetic control targets of P. xylostella.

Emerging Effects of Resveratrol on Wound Healing: A Comprehensive Review.

Resveratrol (RSV) is a natural extract that has been extensively studied for its significant anti-inflammatory and antioxidant effects, which are closely associated with a variety of injurious diseases and even cosmetic medicine. In this review, we have researched and summarized the role of resveratrol and its different forms of action in wound healing, exploring its role and mechanisms in promoting wound healing through different modes of action such as hydrogels, fibrous scaffolds and parallel ratio medical devices with their anti-inflammatory, antioxidant, antibacterial and anti-ageing properties and functions in various cells that may play a role in wound healing. This will provide a direction for further understanding of the mechanism of action of resveratrol in wound healing for future research.