Modeling disrupted synapse formation in wolfram syndrome using hESCs-derived neural cells and cerebral organoids identifies Riluzole as a therapeutic molecule.

Dysregulated neurite outgrowth and synapse formation underlie many psychiatric disorders, which are also manifested by wolfram syndrome (WS). Whether and how the causative gene WFS1 deficiency affects synapse formation remain elusive. By mirroring human brain development with cerebral organoids, WFS1-deficient cerebral organoids not only recapitulate the neuronal loss in WS patients, but also exhibit significantly impaired synapse formation and function associated with reduced astrocytes. WFS1 deficiency in neurons autonomously delays neuronal differentiation with altered expressions of genes associated with psychiatric disorders, and impairs neurite outgrowth and synapse formation with elevated cytosolic calcium. Intriguingly, WFS1 deficiency in astrocytes decreases the expression of glutamate transporter EAAT2 by NF-κB activation and induces excessive glutamate. When co-cultured with wildtype neurons, WFS1-deficient astrocytes lead to impaired neurite outgrowth and increased cytosolic calcium in neurons. Importantly, disrupted synapse formation and function in WFS1-deficient cerebral organoids and impaired neurite outgrowth affected by WFS1-deficient astrocytes are efficiently reversed with Riluzole treatment, by restoring EAAT2 expression in astrocytes. Furthermore, Riluzole rescues the depressive-like behavior in the forced swimming test and the impaired recognition and spatial memory in the novel object test and water maze test in Wfs1 conditional knockout mice. Altogether, our study provides novel insights into how WFS1 deficiency affects synapse formation and function, and offers a strategy to treat this disease.

Research Progress on Active Ingredients and Product Development of Lycium ruthenicum Murray.

Lycium ruthenicum Murray possesses significant applications in both food and medicine, including antioxidative, anti-tumor, anti-fatigue, anti-inflammatory, and various other effects. Consequently, there has been a surge in research endeavors dedicated to exploring its potential benefits, necessitating the organization and synthesis of these findings. This article systematically reviews the extraction and content determination methods of active substances such as polysaccharides, anthocyanins, flavonoids, and polyphenols in LRM in the past five years, as well as some active ingredient composition determination methods, biological activities, and product development. This review is divided into three main parts: extraction and determination methods, their bioactivity, and product development. Building upon prior research, we also delve into the economic and medicinal value of Lycium ruthenicum Murray, thereby contributing significantly to its further exploration and development. It is anticipated that this comprehensive review will serve as a valuable resource for advancing research on Lycium ruthenicum Murray.

Regulating Spin-State Switching by Integrating Polyoxometalate Anion into Spin Crossover System.

Polyoxometalate (POM) anions were successfully integrated into Fe(II) spin crossover (SCO) system, which demonstrates an effective role in regulating spin-state switching properties. Specifically, three drastically different magnetic behaviors of Fe(II) ion in the identical cation [Fe(bpp)2]2+ were achieved by leveraging [Mo6O19]2-, [Mo8O26]4-, and [Na(Mo8O26)]3-, respectively.

Efficacy and safety of different ticagrelor regimens versus clopidogrel in patients with coronary artery disease: a retrospective multicenter study (SUPERIOR).

Current guidelines favor dual anti-platelet therapy with ticagrelor 90 mg BID (T90BID) over clopidogrel 75 mg QD (C75QD) in addition to aspirin for acute coronary syndrome. However, an increased risk of ticagrelor-related adverse events prompted the evaluation of low-dose regimens. This study (NCT03381742) retrospectively analyzed the data from 11 hospitals on 3,043 patients with coronary artery disease, who received C75QD, T90BID, ticagrelor 45 mg BID (T45BID), or ticagrelor 90 mg QD (T90QD). Compared with C75QD, both T45BID and T90QD showed significantly higher inhibition of platelet aggregation (P < .0001) and lower platelet-fibrin clot strength (P < .0001) induced by adenosine diphosphate. Furthermore, compared with T90BID, two low-dose regimens had a much lower minor bleeding rate and a significantly higher proportion of patients within the therapeutic window for P2Y12 receptor reactivity. There were no significant differences between T45BID and T90QD in the trough plasma concentrations of ticagrelor and its active metabolite. Similar efficacy and safety outcomes were observed in the propensity score-matched analysis. In conclusion, the low-dose ticagrelor regimen, either T45BID or T90QD, may provide a more attractive benefit-risk profile than C75QD or T90BID.

Mechanistic Investigation of a Self-Assembling Peptide against Escherichia coli.

Because of their distinctive mode of action in targeting bacterial cell membranes, antimicrobial peptides (AMPs) are increasingly regarded as a potential candidate for the development of novel antibiotics to combat the wide spread of bacterial resistance. To date, understanding of the exact molecular process by which AMPs act on the real bacterial envelope remains challenging. Simultaneously, the aggregated state of AMPs upon interaction with bacterial envelopes is still elusive. Previously, we have demonstrated that the potent antibacterial activity of a designed surfactant-like peptide Ac-A9K-NH2 benefited greatly from its high self-assembling ability and appropriate self-assembled morphologies and sizes. By using high-resolution atomic force microscopy, we here not only follow the variations of the Escherichia coli cell envelope in the presence of Ac-A9K-NH2 but also characterize the peptide aggregates on the bacterial surface as well as on the substrate surface. The results, together with those from fluorescence, zeta potential, circular dichroism, and scanning electron microscopy measurements, indicate that both the positively charged peptide monomers and self-assembled nanostructures can directly act on the negatively charged bacterial surface, followed by their insertion into the bacterial membrane, the formation of surface nanopores, and membrane lysis. The mechanism of Ac-A9K-NH2 against E. coli is thus consistent with the detergent-like mode of action. This work enhances our mechanistic understanding of the antibacterial behaviors of self-assembling peptides that will be valuable in exploring their biomedical applications.

Simultaneous Application of Photothermal Therapy and an Anti-inflammatory Prodrug using Pyrene-Aspirin-Loaded Gold Nanorod Graphitic Nanocapsules.

Photothermal therapy (PTT) has been extensively developed as an effective approach against cancer. However, PTT can trigger inflammatory responses, in turn simulating tumor regeneration and hindering subsequent therapy. A therapeutic strategy was developed to deliver enhanced PTT and simultaneously inhibit PTT-induced inflammatory response. 1-Pyrene methanol was utilize to synthesize the anti-inflammatory prodrug pyrene-aspirin (P-aspirin) with a cleavable ester bond and also facilitate loading the prodrug on gold nanorod (AuNR)-encapsulated graphitic nanocapsule (AuNR@G), a photothermal agent, through π-π interactions. Such AuNR@G-P-aspirin complexes were used for near-infrared laser-triggered photothermal ablation of solid tumor and simultaneous inhibition of PTT-induced inflammation through the release of aspirin in tumor milieu. This strategy showed excellent effects in vitro and in vivo.

Pollution distribution and health risk assessment of heavy metals in indoor dust in Anhui rural, China.

Zn, Pb, Cu, Cr, V, Ni, Co, and As concentrations of indoor dust in Anhui rural were determined by inductively coupled plasma-optical emission spectroscopy (ICP-OES). The degrees of metal pollution in indoor dust ranked as follows: Zn > Pb > Cr > Cu > V > Ni > Co > As, on average. The arithmetic means of Zn, Pb, Cu, Cr, V, Ni, Co, and As were 427.17, 348.73, 107.05, 113.68, 52.64, 38.93, 10.29, and 4.46 mg/kg, respectively. These were higher than background values of Anhui soil for Zn, Pb, Cu, Cr, and Ni, especially for Pb with the mean value of 13.21 times the background value. Heavy metal concentrations of indoor dust were different from different rural areas. House type (bungalows or storied house), sweeping frequency, and external environment around the house (such as the road grade) affected heavy metal concentrations in indoor dust. The results of factor analysis and correlation analysis indicated that Cu, Cr, Ni, Zn, and Co concentrations were mainly due to interior paint, metal objects, and building materials. Pb and As concentrations were due to vehicle emissions. V concentration was mainly of natural source. Average daily doses for the exposure pathway of the studied heavy metals decreased in children in the following order: hand-to-mouth ingestion > dermal contact > inhalation. The non-carcinogenic risks of heavy metals ranked as Pb > V > Cr > Cu > Zn > As > Co > Ni, and the carcinogenic risks of metals decreased in the order of Cr > Co > As > Ni. The non-carcinogenic hazard indexes and carcinogenic risks of metals in indoor dust were both lower than the safe values.

One-Pot Two-Stage Biocatalytic Cascade to Produce l-Phosphinothricin by Two Enantioselective Complementary Aminotransferases at High Substrate Loading via a Deracemization Process.

The bioderacemization of racemic phosphinothricin (D, L-PPT) is a promising route for the synthesis of l-phosphinothricin (L-PPT). However, the low activity and tolerance of wild-type enzymes restrict their industrial applications. Two stereocomplementary aminotransferases with high activity and substrate tolerance were identified in a metagenomic library, and a one-pot, two-stage artificial cascade biocatalytic system was developed to produce L-PPT through kinetic resolution and asymmetric amination. We observed that 500 mM D, L-PPT (100 g/L) could be converted into L-PPT with 94% final conversion and >99.9% enantiomeric excess (e.e.) within 24 h, with only 0.02 eq amino acceptor pyruvate and 1.2 eq amino donor l-aspartate required. The process could be scaled up to 10 L under sufficient oxygen and stirring. The superior catalytic performance of this system provides an eco-friendly and sustainable approach to the industrial deracemization of D, L-PPT to L-PPT.

Hibiscus manihot L. flower extract induces anticancer activity through modulation of apoptosis and autophagy in A549 cells.

Lung cancer is a major public health issue and heavy burden in China and worldwide due to its high incidence and mortality without effective treatment. It's imperative to develop new treatments to overcome drug resistance. Natural products from food source, given their wide-ranging and long-term benefits, have been increasingly used in tumor prevention and treatment. This study revealed that Hibiscus manihot L. flower extract (HML) suppressed the proliferation and migration of A549 cells in a dose and time dependent manner and disrupting cell cycle progression. HML markedly enhanced the accumulation of ROS, stimulated the dissipation of mitochondrial membrane potential (MMP) and that facilitated mitophagy through the loss of mitochondrial function. In addition, HML induced apoptosis by activation of the PTEN-P53 pathway and inhibition of ATG5/7-dependent autophagy induced by PINK1-mediated mitophagy in A549 cells. Moreover, HML exert anticancer effects together with 5-FU through synergistic effect. Taken together, HML may serve as a potential tumor prevention and adjuvant treatment for its functional attributes.

ISR inhibition reverses pancreatic ß-cell failure in Wolfram syndrome models.

Pancreatic ß-cell failure by WFS1 deficiency is manifested in individuals with wolfram syndrome (WS). The lack of a suitable human model in WS has impeded progress in the development of new treatments. Here, human pluripotent stem cell derived pancreatic islets (SC-islets) harboring WFS1 deficiency and mouse model of ß cell specific Wfs1 knockout were applied to model ß-cell failure in WS. We charted a high-resolution roadmap with single-cell RNA-seq (scRNA-seq) to investigate pathogenesis for WS ß-cell failure, revealing two distinct cellular fates along pseudotime trajectory: maturation and stress branches. WFS1 deficiency disrupted ß-cell fate trajectory toward maturation and directed it towards stress trajectory, ultimately leading to ß-cell failure. Notably, further investigation of the stress trajectory identified activated integrated stress response (ISR) as a crucial mechanism underlying WS ß-cell failure, characterized by aberrant eIF2 signaling in WFS1-deficient SC-islets, along with elevated expression of genes in regulating stress granule formation. Significantly, we demonstrated that ISRIB, an ISR inhibitor, efficiently reversed ß-cell failure in WFS1-deficient SC-islets. We further validated therapeutic efficacy in vivo with ß-cell specific Wfs1 knockout mice. Altogether, our study provides novel insights into WS pathogenesis and offers a strategy targeting ISR to treat WS diabetes.

Corrigendum: A modified method for constructing experimental rat periodontitis model.

[This corrects the article DOI: 10.3389/fbioe.2022.1098015.].

The Nrf2 Pathway Alleviates Overloading Force-Induced TMJ Degeneration by Downregulating Oxidative Stress Reactions.

Objective: Oxidative stress is involved in the mechanisms associated with temporomandibular joint (TMJ) diseases. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial oxidative stress marker, but the specific mechanisms of its regulation in the early stages of mandibular condylar cartilage (MCC) degeneration remain unclear. This study aimed to explore the regulatory role of Nrf2 and its related oxidative stress signaling pathway in the early stage of MCC degeneration. Materials and Methods: Overloading force-induced MCC degeneration was performed in wild-type and Nrf2 knockout mice, as well as in mice after treatment with the Nrf2 activator cardamonin. Changes in MCC degeneration and the expression of oxidative stress markers in the corresponding situations were observed. Results: Nrf2 and NADPH oxidase 2 (NOX2) expression were elevated during early MCC degeneration induced by an overloading force. MCC degeneration was aggravated when Nrf2 was knocked out, accompanied by increased NOX2 and superoxide dismutase 2 (SOD2) expression. The MCC degeneration process was alleviated after cardamonin treatment, with activation of the Nrf2 pathway and decreased NOX2 and SOD2 expression. Conclusion: Early MCC degeneration is accompanied by mild oxidative stress progression. Activated Nrf2 and related pathways could alleviate the degeneration of MCC.

Charting a high-resolution roadmap for regeneration of pancreatic ß cells by in vivo transdifferentiation from adult acinar cells.

Adult mammals have limited capacity to regenerate functional cells. Promisingly, in vivo transdifferentiation heralds the possibility of regeneration by lineage reprogramming from other fully differentiated cells. However, the process of regeneration by in vivo transdifferentiation in mammals is poorly understood. Using pancreatic ß cell regeneration as a paradigm, we performed a single-cell transcriptomic study of in vivo transdifferentiation from adult mouse acinar cells to induced ß cells. Using unsupervised clustering analysis and lineage trajectory construction, we uncovered that the cell fate remodeling trajectory was linear at the initial stage and the reprogrammed cells either evolved to induced ß cells or toward a "dead-end" state after day 4.Moreover, functional analyses identified both p53 and Dnmt3a that acted as reprogramming barriers during the process of in vivo transdifferentiation. Collectively, we decipher a high-resolution roadmap of regeneration by in vivo transdifferentiation and provide a detailed molecular blueprint to facilitate mammalian regeneration.

An Updated View on Temporomandibular Joint Degeneration: Insights from the Cell Subsets of Mandibular Condylar Cartilage.

The high prevalence of temporomandibular joint osteoarthritis (TMJOA), which causes joint dysfunction, indicates the need for more effective methods for treatment and repair. Mandibular condylar cartilage (MCC), a typical fibrocartilage that experiences degenerative changes during the development of TMJOA, has become a research focus and therapeutic target in recent years. MCC is composed of four zones of cells at various stages of differentiation. The cell subsets in MCC exhibit different physiological and pathological characteristics during development and in TMJOA. Most studies of TMJOA are mainly concerned with gene regulation of pathological changes. The corresponding treatment targets with specific cell subsets in MCC may provide more accurate and reliable results for cartilage repair and TMJOA treatment. In this review, we summarized the current research progress on the cell subsets of MCC from the perspective of MCC development and degeneration. We hope to provide a reference for further exploration of the pathological process of TMJOA and improvement of TMJOA treatment.

A modified method for constructing experimental rat periodontitis model.

Background: Periodontitis is a prevalent disease caused teeth lost. The present rat models inducing periodontitis with thread ligature and metal steel ligature have some disadvantages. Methods: We modified the existing rat ligature periodontitis model by fixing the thread ligature on the metal steel ligature passed through the gap between the first and second molars of rats with detailed modeling steps and illustrations. We research the pathological process of the periodontitis induced by the modified model, and briefly compared the modified model with the thread ligature model and the metal steel ligature model. Result: Our experimental results showed that there was an aggravation in inflammatory infiltration and alveolar bone resorption in modeling area within 14 days of initial induction. After that, the inflammatory infiltration was reduced. And no significant increase in alveolar bone destruction appeared. The modified model was more reliable compared to the thread ligature model, and had greater ability of bacterial aggregation compared to the metal steel ligature model. Conclusion: The modified method covered pathological process of the periodontitis, and showed sufficient efficiency and reliability in inducing rat periodontitis.

ZnT8 loss-of-function accelerates functional maturation of hESC-derived ß cells and resists metabolic stress in diabetes.

Human embryonic stem cell-derived ß cells (SC-ß cells) hold great promise for treatment of diabetes, yet how to achieve functional maturation and protect them against metabolic stresses such as glucotoxicity and lipotoxicity remains elusive. Our single-cell RNA-seq analysis reveals that ZnT8 loss of function (LOF) accelerates the functional maturation of SC-ß cells. As a result, ZnT8 LOF improves glucose-stimulated insulin secretion (GSIS) by releasing the negative feedback of zinc inhibition on insulin secretion. Furthermore, we demonstrate that ZnT8 LOF mutations endow SC-ß cells with resistance to lipotoxicity/glucotoxicity-triggered cell death by alleviating endoplasmic reticulum (ER) stress through modulation of zinc levels. Importantly, transplantation of SC-ß cells with ZnT8 LOF into mice with preexisting diabetes significantly improves glycemia restoration and glucose tolerance. These findings highlight the beneficial effect of ZnT8 LOF on the functional maturation and survival of SC-ß cells that are useful as a potential source for cell replacement therapies.

Mendelian randomization integrating GWAS and eQTL data revealed genes pleiotropically associated with major depressive disorder.

Previous genome-wide association studies (GWAS) have identified potential genetic variants associated with the risk of major depressive disorder (MDD), but the underlying biological interpretation remains largely unknown. We aimed to prioritize genes that were pleiotropically or potentially causally associated with MDD. We applied the summary data-based Mendelian randomization (SMR) method integrating GWAS and gene expression quantitative trait loci (eQTL) data in 13 brain regions to identify genes that were pleiotropically associated with MDD. In addition, we repeated the analysis by using the meta-analyzed version of the eQTL summary data in the brain (brain-eMeta). We identified multiple significant genes across different brain regions that may be involved in the pathogenesis of MDD. The prime-specific gene BTN3A2 (corresponding probe: ENSG00000186470.9) was the top hit showing pleiotropic association with MDD in 9 of the 13 brain regions and in brain-eMeta, after correction for multiple testing. Many of the identified genes are located in the human major histocompatibility complex (MHC) region on chromosome 6 and are mainly involved in the immune response. Our SMR analysis indicated that multiple genes showed pleiotropic association with MDD across the brain regions. These findings provided important leads to a better understanding of the mechanism of MDD and revealed potential therapeutic targets for the prevention and effective treatment of MDD.

Single-cell RNA Sequencing Reveals Sexually Dimorphic Transcriptome and Type 2 Diabetes Genes in Mouse Islet ß Cells.

Type 2 diabetes (T2D) is characterized by the malfunction of pancreatic ß cells. Susceptibility and pathogenesis of T2D can be affected by multiple factors, including sex differences. However, the mechanisms underlying sex differences in T2D susceptibility and pathogenesis remain unclear. Using single-cell RNA sequencing (scRNA-seq), we demonstrate the presence of sexually dimorphic transcriptomes in mouse ß cells. Using a high-fat diet-induced T2D mouse model, we identified sex-dependent T2D altered genes, suggesting sex-based differences in the pathological mechanisms of T2D. Furthermore, based on islet transplantation experiments, we found that compared to mice with sex-matched islet transplants, sex-mismatched islet transplants in healthy mice showed down-regulation of genes involved in the longevity regulating pathway of ß cells. Moreover, the diabetic mice with sex-mismatched islet transplants showed impaired glucose tolerance. These data suggest sexual dimorphism in T2D pathogenicity, indicating that sex should be considered when treating T2D. We hope that our findings could provide new insights for the development of precision medicine in T2D.

Serum lncRNAs in early pregnancy as potential biomarkers for the prediction of pregnancy-induced hypertension, including preeclampsia.

Long noncoding RNAs (lncRNAs) are key mediators of biological regulation with diagnostic value as disease biomarkers. We explored serum lncRNA levels in early pregnancy as potential biomarkers of pregnancy-induced hypertension (PIH), including gestational hypertension (GH) and preeclampsia (PE). We performed a two-phase nested case-control study in pregnant women before 20 weeks' gestation (before clinical diagnosis). The screening phase assessed lncRNA expression profiles with a human lncRNA microarray in 5 pairs of serum samples (5 PE patients and 5 matched controls). The second phase validated levels of 8 candidate lncRNAs selected via the random walk method by quantitative real-time polymerase chain reaction (qRT-PCR). Serum levels of the 8 lncRNAs were markedly increased in women with PIH compared with matched normotensive pregnant (NP) women (p < 0.001), consistent with the microarray results. In addition, 7 candidate lncRNAs were correlated with PIH severity. Logistic regression analysis revealed that serum levels of ENST00000527727 (odds ratio [OR], 1.113; 95% confidence interval [CI], 1.024-1.209; p = 0.0113) and ENST00000415029 (OR, 1.126; 95% CI, 1.000-1.267; p = 0.0496) were associated with adverse pregnancy outcomes, such as fetal growth restriction (FGR) and placenta accreta of PIH. Nine pathways associated with the candidate lncRNAs had confirmed associations with PIH.

Dual Mode of Anti-Biofilm Action of G3 against Streptococcus mutans.

Oral biofilms, formed by multiple microorganisms and their extracellular polymeric substances, seriously affect people's life. The emergence of the resistance of biofilms to conventional antibiotics and their side effects on the oral cavity have posed a great challenge in the treatment of dental diseases. Recently, antimicrobial peptides have been recognized as promising alternatives to conventional antibiotics due to their broad antibacterial spectrum, high antibacterial activity, and specific mechanism. However, the research of their anti-biofilm behaviors is still in its infancy, and the underlying mechanism remains unclear. In this study, we investigated the anti-biofilm activities of a designed helical peptide (G3) against Streptococcus mutans (S. mutans), one of the primary causative pathogens of caries. The results indicated that G3 inhibited S. mutans biofilm formation by interfering with different stages of biofilm development. At the initial stage, G3 inhibited the bacterial adhesion by decreasing the bacterial surface charges, hydrophobicity, membrane integrity, and adhesion-related gene transcription. At the later stage, G3 interacted with extracellular DNA to destabilize the 3D architecture of mature biofilms and thus dispersed them. The high activity of G3 against S. mutans biofilms, along with its specific modes of action, endows it great application potential in preventing and treating dental plaque diseases.