Corrigendum: Endothelial ß-catenin deficiency causes blood-brain barrier breakdown via enhancing the paracellular and transcellular permeability.

[This corrects the article DOI: 10.3389/fnmol.2022.895429.].

Advancing stroke therapy: A deep dive into early phase of ischemic stroke and recanalization.

Ischemic stroke, accounting for the majority of stroke events, significantly contributes to global morbidity and mortality. Vascular recanalization therapies, namely intravenous thrombolysis and mechanical thrombectomy, have emerged as critical interventions, yet their success hinges on timely application and patient-specific factors. This review focuses on the early phase pathophysiological mechanisms of ischemic stroke and the nuances of recanalization. It highlights the dual role of neutrophils in tissue damage and repair, and the critical involvement of the blood-brain barrier (BBB) in stroke outcomes. Special emphasis is placed on ischemia-reperfusion injury, characterized by oxidative stress, inflammation, and endothelial dysfunction, which paradoxically exacerbates cerebral damage post-revascularization. The review also explores the potential of targeting molecular pathways involved in BBB integrity and inflammation to enhance the efficacy of recanalization therapies. By synthesizing current research, this paper aims to provide insights into optimizing treatment protocols and developing adjuvant neuroprotective strategies, thereby advancing stroke therapy and improving patient outcomes.

Metagenomic analysis of healthy and diseased peri-implant microbiome under different periodontal conditions: a cross-sectional study.

BACKGROUND: Peri-implantitis is a polybacterial infection that can lead to the failure of dental implant rehabilitation. This study aimed to profile the microbiome of the peri-implant plaque and estimate the effect of periodontitis on it among 40 Chinese participants with dental implant prostheses and presenting with varying peri-implant and periodontal health states. METHODS: Submucosal plaque samples were collected from four distinct clinical categories based on both their implant and periodontal health status at sampling point. Clinical examinations of dental implant and remaining teeth were carried out. Metagenomic analysis was then performed. RESULTS: The microbiome of the peri-implantitis sites differed from that of healthy implant sites, both taxonomically and functionally. Moreover, the predominant species in peri-implantitis sites were slightly affected by the presence of periodontitis. T. forsythia, P. gingivalis, T. denticola, and P. endodontalis were consistently associated with peri-implantitis and inflammatory clinical parameters regardless of the presence of periodontitis. Prevotella spp. and P. endodontalis showed significant differences in the peri-implantitis cohorts under different periodontal conditions. The most distinguishing function between diseased and healthy implants is related to flagellar assembly, which plays an important role in epithelial cell invasion. CONCLUSIONS: The composition of the peri-implant microbiome varied in the diseased and healthy states of implants and is affected by individual periodontal conditions. Based on their correlations with clinical parameters, certain species are associated with disease and healthy implants. Flagellar assembly may play a vital role in the process of peri-implantitis.

Salivary and fecal microbiota: potential new biomarkers for early screening of colorectal polyps.

Objective: Gut microbiota plays an important role in colorectal cancer (CRC) pathogenesis through microbes and their metabolites, while oral pathogens are the major components of CRC-associated microbes. Multiple studies have identified gut and fecal microbiome-derived biomarkers for precursors lesions of CRC detection. However, few studies have used salivary samples to predict colorectal polyps. Therefore, in order to find new noninvasive colorectal polyp biomarkers, we searched into the differences in fecal and salivary microbiota between patients with colorectal polyps and healthy controls. Methods: In this case-control study, we collected salivary and fecal samples from 33 patients with colorectal polyps (CP) and 22 healthy controls (HC) between May 2021 and November 2022. All samples were sequenced using full-length 16S rRNA sequencing and compared with the Nucleotide Sequence Database. The salivary and fecal microbiota signature of colorectal polyps was established by alpha and beta diversity, Linear discriminant analysis Effect Size (LEfSe) and random forest model analysis. In addition, the possibility of microbiota in identifying colorectal polyps was assessed by Receiver Operating Characteristic Curve (ROC). Results: In comparison to the HC group, the CP group's microbial diversity increased in saliva and decreased in feces (p < 0.05), but there was no significantly difference in microbiota richness (p > 0.05). The principal coordinate analysis revealed significant differences in ß-diversity of salivary and fecal microbiota between the CP and HC groups. Moreover, LEfSe analysis at the species level identified Porphyromonas gingivalis, Fusobacterium nucleatum, Leptotrichia wadei, Prevotella intermedia, and Megasphaera micronuciformis as the major contributors to the salivary microbiota, and Ruminococcus gnavus, Bacteroides ovatus, Parabacteroides distasonis, Citrobacter freundii, and Clostridium symbiosum to the fecal microbiota of patients with polyps. Salivary and fecal bacterial biomarkers showed Area Under ROC Curve of 0.8167 and 0.8051, respectively, which determined the potential of diagnostic markers in distinguishing patients with colorectal polyps from controls, and it increased to 0.8217 when salivary and fecal biomarkers were combined. Conclusion: The composition and diversity of the salivary and fecal microbiota were significantly different in colorectal polyp patients compared to healthy controls, with an increased abundance of harmful bacteria and a decreased abundance of beneficial bacteria. A promising non-invasive tool for the detection of colorectal polyps can be provided by potential biomarkers based on the microbiota of the saliva and feces.

Resveratrol reverses Palmitic Acid-induced cow neutrophils apoptosis through shifting glucose metabolism into lipid metabolism via Cav-1/ CPT 1-mediated FAO enhancement.

Elevated plasma nonesterified fatty acids (NEFAs) affect neutrophils function and longevity during the periparturient period in dairy cows. Previous research has shown that resveratrol (RSV) may protect cell viability from NEFA-induced damage by regulating energy metabolism. However, it is unclear whether RSV has a protective effect on palmitic acid (PA)-treated neutrophils. The aim of this study was to investigate the molecular regulatory mechanism of the protective effect of RSV on neutrophils. The results showed that treatment with high concentrations of RSV (50 µM, 100 µM) maintained neutrophils activity by inhibiting neutrophils apoptosis (P < 0.05). Further analysis showed that high concentrations of RSV enhanced fatty acid oxidation (FAO) to produce ATP by promoting the expression of CAV1, ACSL-1 and CPT1 (P < 0. 05) while inhibiting glycolysis by suppressing PFK1 activity (P < 0. 05) and reducing glucose transport-related protein (GLUT1/GLUT4) expression by inhibiting glucose uptake (P < 0.05). These results suggest that RSV protects neutrophils from PA-induced apoptosis by regulating energy metabolism. Our results revealed that RSV protects neutrophils from PA-induced apoptosis by shifting glucose metabolism to lipid metabolism. This study tenders to a meaningful understanding of the effects of RSV on neutrophils function in periparturient cows suffering from negative energy balance (NEB).

Endothelial ß-Catenin Deficiency Causes Blood-Brain Barrier Breakdown via Enhancing the Paracellular and Transcellular Permeability.

Disruption of the blood-brain barrier (BBB) causes or contributes to neuronal dysfunction and several central nervous system (CNS) disorders. Wnt/ß-catenin signaling is essential for maintaining the integrity of the adult BBB in physiological and pathological conditions, including stroke. However, how the impairment of the endothelial Wnt/ß-catenin signaling results in BBB breakdown remains unclear. Furthermore, the individual contributions of different BBB permeability-inducing mechanisms, including intercellular junction damage, endothelial transcytosis, and fenestration, remains unexplored. Here, we induced ß-catenin endothelial-specific conditional knockout (ECKO) in adult mice and determined its impact on BBB permeability and the underlying mechanism. ß-catenin ECKO reduced the levels of active ß-catenin and the mRNA levels of Wnt target genes in mice, indicating downregulation of endothelial Wnt/ß-catenin signaling. ß-catenin ECKO mice displayed severe and widespread leakage of plasma IgG and albumin into the cerebral cortex, which was absent in wild-type controls. Mechanistically, both the paracellular and transcellular transport routes were disrupted in ß-catenin ECKO mice. First, ß-catenin ECKO reduced the tight junction protein levels and disrupted the intercellular junction ultrastructure in the brain endothelium. Second, ß-catenin ECKO substantially increased the number of endothelial vesicles and caveolae-mediated transcytosis through downregulating Mfsd2a and upregulating caveolin-1 expression. Interestingly, fenestration and upregulated expression of the fenestration marker Plvap were not observed in ß-catenin ECKO mice. Overall, our study reveals that endothelial Wnt/ß-catenin signaling maintains adult BBB integrity via regulating the paracellular as well as transcellular permeability. These findings may have broad applications in understanding and treatment of CNS disorders involving BBB disruption.

Structure-based discovery of receptor tyrosine kinase AXL degraders with excellent anti-tumor activity by selectively degrading AXL and inducing methuosis.

The receptor tyrosine kinase (RTK) anexelekto (AXL) is mutated and/or overexpressed in various malignancies, and plays a central role in tumor development and acquired drug resistance. Although highly selective inhibitors have been developed in recent years, direct inhibition of AXL may block its ubiquitination, eventually leading to surface accumulation of the protein. Herein, we designed and synthesized a series of AXL degraders with high selectivity and without compensatory increase of AXL. In particular, compounds 20 and 22 showed significant AXL degradation capacity, which inhibited the proliferation and migration of cancer cells in vitro. In addition, these compounds induced the formation of cytoplasmic vacuoles and triggered methuosis, a new type of non-apoptotic cell death, by stimulating excessive production of macropinosomes. Vacuole formation was mediated via H-Ras activation, and was attenuated upon inhibition of its downstream regulatory factor Rac1. Furthermore, compound 20 inhibited the growth of tumor cell xenografts in vivo, and prolonged the survival of the tumor-bearing mice.

Design, synthesis and immunological evaluation of self-assembled antigenic peptides from dual-antigen targets: a broad-spectrum candidate for an effective antibreast cancer therapy.

BACKGROUND: Considering the narrow immune response spectrum of a single epitope, and the nanoparticles (NPs) as a novel adjuvant can achieve efficient delivery of antigenic peptides safely, a nano-system (denoted as DSPE-PEG-Man@EM-NPs) based on cathepsin B-responsive antigenic peptides was designed and synthesized. METHODS: Highly affinitive antigenic peptides were delivered by self-assembled NPs, and targeted erythrocyte membranes acted as a peptide carrier to improve antigenic peptides presentation and to strengthen cytotoxic T-cells reaction. Cathepsin B coupling could release antigenic peptides rapidly in dendritic cells. RESULTS: Evaluations showed that DSPE-PEG-Man@EM-NPs had obvious inhibitory effects towards both MCF-7 and MDA-MB-231 human breast cancer cell lines. CONCLUSION: Overall, this strategy provides a novel strategy for boosting cytotoxic T lymphocytes response, thereby expanding the adaptation range of tumor antigenic peptides and improving the therapeutic effect of tumor immunotherapy with nanomedicine.

Design, synthesis, and biological activity evaluation of a series of novel sulfonamide derivatives as BRD4 inhibitors against acute myeloid leukemia.

Accumulating researches have contributed much effect to discover novel chemotherapeutic drug for leukemia with expeditious curative effect, of which bromodomain-containing protein 4 (BRD4) inhibitor is considered as a eutherapeutic drug which has presented efficient cell proliferation suppression effect. In this study, we disclosed a series of phenylisoxazole sulfonamide derivatives as potent BRD4 inhibitors. Especially, compound 58 exhibited robust inhibitory potency toward BRD4-BD1 and BRD4-BD2 with IC50 values of 70 and 140 nM, respectively. In addition, compound 58 significantly suppressed cell proliferation of leukemia cell lines HL-60 and MV4-11 with IC50 values of 1.21 and 0.15 µM. In-depth study of the biological mechanism of compound 58 exerted its tumor suppression effect via down-regulating the level of oncogene c-myc. Moreover, in vivo pharmacokinetics (PK) study was conducted and the results demonstrated better pharmacokinetics features versus (+)-JQ1. In summary, our study discovers that compound 58 represents as a novel BRD4 inhibitor for further investigation in development of leukemia inhibitor with potentiality.

Design, synthesis, and biological evaluation of novel 4,4-difluoro-1-methyl-N, 6-diphenyl-5, 6-dihydro-4H-pyrimido [4, 5-b] [1, 2, 4] triazolo [4, 3-d] [1, 4] diazepin-8-amine derivatives as potential BRD4 inhibitors.

Bromodomain-containing protein 4 (BRD4) plays an extremely important physiological role in cancer, and the BRD4 inhibitors can effectively inhibit the proliferation of tumor cells. By taking BI-2536 (PLK1 and BRD4 inhibitor) as the lead compound, sixteen novel BRD4 inhibitors with the 4,4-difluoro-1-methyl-N,6-diphenyl-5,6-dihydro-4H-pyrimido[4,5-b] [1,2,4] triazolo[4,3-d] [1,4] diazepine-8-amine structure were designed and synthetized. Among the target compounds, compound 15h exhibited outstanding inhibition for BRD4-BD1 (IC50 value of 0.42 µM) in the BRD4-BD1 inhibitory activity assay. Additionally, cell growth inhibition assay demonstrated that compound 15h potently suppressed the proliferation of MV4-11 cells (IC50 value of 0.51 µM). Besides, compound 15h induced apoptosis and G0/G1 cycle arrest in MV4-11 leukemia cells effectively, and downregulated the expression of c-Myc in a dose-dependent manner. In summary, the optimal compound 15h is expected to become the clinical therapeutic drug for further research.

Synthetic tumor-specific antigenic peptides with a strong affinity to HLA-A2 elicit anti-breast cancer immune response through activating CD8+ T cells.

Researches on tumor-associated antigen have become a hot target in immunotherapy, but it stagnated in the pre-clinical/clinical stages. Here, we developed a series of MAGE-A1-restricted antigenic peptides, which exhibited prominent inhibiting effect on specific breast cancer. Peptides were synthesized by Fmoc solid phase method and analyzed by online servers. The stability and affinity to HLA-A2 was assessed by inverted fluorescence and flow cytometry qualitatively and quantitatively. In vitro effect on dendritic cells (DCs) maturation was observed by morphology and surface markers. The secretion of IFN-γ in the supernatant was detected by co-incubation of DCs loaded with as-synthesized peptides and CD8+ T lymphocytes. The specific immune response was evaluated against 4 cell lines, and the response in MCF-7 xenografted BALB/c nude mice were further assessed. Most of the derived peptides, especially I-6, showed great HLA-A2 binding ability. Compared with cytokines, I-6 significantly induced DCs maturation and promoted CD8+ T lymphocytes activation. Additionally, it is more specific for the lethality of MAGE & HLA-A2 double positive cells compared with others. We successfully developed I-6 with a high affinity to HLA-A2 which could induce strong specific immune response. It could be a potential candidate for breast cancer immunotherapy, which deserves further studies.

Quantum interference mediated vertical molecular tunneling transistors.

Molecular transistors operating in the quantum tunneling regime represent potential electronic building blocks for future integrated circuits. However, due to their complex fabrication processes and poor stability, traditional molecular transistors can only operate stably at cryogenic temperatures. Here, through a combined experimental and theoretical investigation, we demonstrate a new design of vertical molecular tunneling transistors, with stable switching operations up to room temperature, formed from cross-plane graphene/self-assembled monolayer (SAM)/gold heterostructures. We show that vertical molecular junctions formed from pseudo-p-bis((4-(acetylthio)phenyl)ethynyl)-p-[2,2]cyclophane (PCP) SAMs exhibit destructive quantum interference (QI) effects, which are absent in 1,4-bis(((4-acetylthio)phenyl)ethynyl)benzene (OPE3) SAMs. Consequently, the zero-bias differential conductance of the former is only about 2% of the latter, resulting in an enhanced on-off current ratio for (PCP) SAMs. Field-effect control is achieved using an ionic liquid gate, whose strong vertical electric field penetrates through the graphene layer and tunes the energy levels of the SAMs. The resulting on-off current ratio achieved in PCP SAMs can reach up to ~330, about one order of magnitude higher than that of OPE3 SAMs. The demonstration of molecular junctions with combined QI effect and gate tunability represents a critical step toward functional devices in future molecular-scale electronics.

Gate-tunable frequency combs in graphene-nitride microresonators.

Optical frequency combs, which emit pulses of light at discrete, equally spaced frequencies, are cornerstones of modern-day frequency metrology, precision spectroscopy, astronomical observations, ultrafast optics and quantum information1-7. Chip-scale frequency combs, based on the Kerr and Raman nonlinearities in monolithic microresonators with ultrahigh quality factors8-10, have recently led to progress in optical clockwork and observations of temporal cavity solitons11-14. But the chromatic dispersion within a laser cavity, which determines the comb formation15,16, is usually difficult to tune with an electric field, whether in microcavities or fibre cavities. Such electrically dynamic control could bridge optical frequency combs and optoelectronics, enabling diverse comb outputs in one resonator with fast and convenient tunability. Arising from its exceptional Fermi-Dirac tunability and ultrafast carrier mobility17-19, graphene has a complex optical dispersion determined by its optical conductivity, which can be tuned through a gate voltage20,21. This has brought about optoelectronic advances such as modulators22,23, photodetectors 24 and controllable plasmonics25,26. Here we demonstrate the gated intracavity tunability of graphene-based optical frequency combs, by coupling the gate-tunable optical conductivity to a silicon nitride photonic microresonator, thus modulating its second- and higher-order chromatic dispersions by altering the Fermi level. Preserving cavity quality factors up to 106 in the graphene-based comb, we implement a dual-layer ion-gel-gated transistor to tune the Fermi level of graphene across the range 0.45-0.65 electronvolts, under single-volt-level control. We use this to produce charge-tunable primary comb lines from 2.3 terahertz to 7.2 terahertz, coherent Kerr frequency combs, controllable Cherenkov radiation and controllable soliton states, all in a single microcavity. We further demonstrate voltage-tunable transitions from periodic soliton crystals to crystals with defects, mapped by our ultrafast second-harmonic optical autocorrelation. This heterogeneous graphene microcavity, which combines single-atomic-layer nanoscience and ultrafast optoelectronics, will help to improve our understanding of dynamical frequency combs and ultrafast optics.

Monolayer atomic crystal molecular superlattices.

Artificial superlattices, based on van der Waals heterostructures of two-dimensional atomic crystals such as graphene or molybdenum disulfide, offer technological opportunities beyond the reach of existing materials. Typical strategies for creating such artificial superlattices rely on arduous layer-by-layer exfoliation and restacking, with limited yield and reproducibility. The bottom-up approach of using chemical-vapour deposition produces high-quality heterostructures but becomes increasingly difficult for high-order superlattices. The intercalation of selected two-dimensional atomic crystals with alkali metal ions offers an alternative way to superlattice structures, but these usually have poor stability and seriously altered electronic properties. Here we report an electrochemical molecular intercalation approach to a new class of stable superlattices in which monolayer atomic crystals alternate with molecular layers. Using black phosphorus as a model system, we show that intercalation with cetyl-trimethylammonium bromide produces monolayer phosphorene molecular superlattices in which the interlayer distance is more than double that in black phosphorus, effectively isolating the phosphorene monolayers. Electrical transport studies of transistors fabricated from the monolayer phosphorene molecular superlattice show an on/off current ratio exceeding 107, along with excellent mobility and superior stability. We further show that several different two-dimensional atomic crystals, such as molybdenum disulfide and tungsten diselenide, can be intercalated with quaternary ammonium molecules of varying sizes and symmetries to produce a broad class of superlattices with tailored molecular structures, interlayer distances, phase compositions, electronic and optical properties. These studies define a versatile material platform for fundamental studies and potential technological applications.